Tuberculosis PDF

Contributors i
TUBERCULOSIS
TUBERCULOSIS
Second Edition
Editor
SURENDRA K. SHARMA
Chief, Division of Pulmonary, Critical Care and Sleep Medicine
Professor and Head, Department of Medicine
All India Institute of Medical Sciences
New Delhi 110 029, India
Assistant Editor
ALLADI MOHAN
Chief, Division of Pulmonary and Critical Care Medicine
Professor and Head, Department of Medicine
Sri Venkateswara Institute of Medical Sciences
Tirupati 517 507, India
Foreword by
MARIO C. RAVIGLIONE
Director
Stop TB Department
World Health Organization
Geneva, Switzerland
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Tuberculosis
© 2009, Editors
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any
means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editors and the publisher.
This book has been published in good faith that the material provided by contributors is original. Every effort is made to ensure
accuracy of material, but the publisher, printer and editors will not be held responsible for any inadvertent error(s). In case of any
dispute, all legal matters are to be settled under Delhi jurisdiction only.
First Edition: 2001
Second Edition: 2009
ISBN 978-81-8448-514-1
Typeset at JPBMP typesetting unit

Printed at Ajanta Press
This book is dedicated to
Our Parents for their encouragement
Our Teachers and Students for their inspiration
Anju and Himabala for their moral support
Abhishek, Animesh and Vikram Chandra for their cheerful enthusiasm
Contributors
S.K. Acharya M. Bajpai
Professor and Head Professor
Department of Gastroenterology and Human Nutrition Department of Paediatric Surgery
All India Institute of Medical Sciences All India Institute of Medical Sciences
New Delhi 110 029, India New Delhi 110 029, India
S.K. Agarwal V.H. Balasangameshwara

Additional Professor Former Chief Medical Officer
Department of Nephrology National Tuberculosis Institute
All India Institute of Medical Sciences ‘AVALON’, No. 8, Bellary Road
New Delhi 110 029, India Bengaluru 560 003, India
A.N. Aggarwal Rani Balasubramanian

Associate Professor Former Deputy Director [Senior Grade]
Department of Pulmonary Medicine Tuberculosis Research Center
Postgraduate Institute of Medical Education [Indian Council of Medical Research]
and Research Mayor Ramanathan Road, Chetpet
Chandigarh 160 012, India Chennai 600 031, India
Praveen Aggarwal Sharmistha Banerjee

Professor Lecturer
Department of Emergency Medicine Department of Biochemistry
All India Institute of Medical Sciences School of Life Sciences
New Delhi 110 029, India University of Hyderabad
Hyderabad 500 046, India
G. Ahluwalia
Professor S. Basu
Department of Medicine Yale University School of Medicine
Dayanand Medical College and Hospital 367 Cedar St., New Haven
Ludhiana 141 001, India Connecticut, USA
D. Behera
Vineet Ahuja
Director
Associate Professor LRS Institute of Tuberculosis and
Department of Gastroenterology and Human Nutrition
Respiratory Diseases
Sri Aurobindo Marg, Mehrauli
Jason Andrews Surya Bhan

Resident Physician Former Professor and Head
Department of Medicine Department of Orthopaedics
University of California All India Institute of Medical Sciences
San Francisco, USA New Delhi 110 029, India
viii Tuberculosis
Rajesh Bhatia S. Datta Gupta

Regional Adviser Professor
WHO Regional Office for South-East Asia Department of Pathology
WHO House IP Estate, Ring Road All India Institute of Medical Sciences
V.K. Chaddha Sajal De

Senior Epidemiologist Vallabhbhai Patel Chest Institute
National Tuberculosis Institute University of Delhi, P.O. Box No. 2101
‘AVALON’, No. 8, Bellary Road Delhi 110 007, India
Bengaluru 560 003, India
Bappaditya Dey
Major A.K. Chakraborty Department of Biochemistry
Epidemiology Analyst University of Delhi South Campus
“BIKALPA” # 557, 4th Block, 8th Main Benito Juarez Road
Koramangala, Bengaluru 560 034, India New Delhi 110 021, India
S.S. Dhillon
V.K. Challu
Department of Pulmonary, Critical Care and Sleep
National Tuberculosis Institute
Medicine
‘AVALON’, No. 8, Bellary Road
85 Spring Street, 3rd Floor
Bengaluru 560 003, India
Lakes Region General Hospital
Laconia, New Hampshire 03246, USA
Abha Chandra
Professor
Tania Di Pietrantonio
Department of Cardiovascular and Thoracic Surgery
Department of Human Genetics
Sri Venkateswara Institute of Medical Sciences
The Centre for the Study of Host Resistance
Tirupati 517 507, India
McGill University
Montreal, QC, Canada
L.S. Chauhan
Deputy Director General TB
D. Dilip
Central TB Division
Professor
Directorate General of Health Services
Department of Cardiovascular and Thoracic Surgery
Ministry of Health and Family Welfare Sri Venkateswara Institute of Medical Sciences
Government of India Tirupati 517 507, India
Thomas R. Frieden
Rohan Chawla Commissioner, New York City
Dr Rajendra Prasad Centre for Department of Health and Mental Hygiene
Ophthalmic Sciences 125 Worth Street, Room 331
All India Institute of Medical Sciences New York, NY 10013, USA
Caroline J. Gallant
E. Cooreman Department of Human Genetics
Regional Advisor The Centre for the Study of Host Resistance
WHO Regional Office for South-East Asia McGill University
Dhaka, Bangladesh Montreal, QC, Canada
Contributors ix
P.K. Garg Arun K. Gupta

Associate Professor Professor and Head
Department of Gastroenterology Department of Radiodiagnosis
S.P. Garg
Puneet Gupta
Professor Lecturer
Dr Rajendra Prasad Centre for Ophthalmic Sciences
Department of Surgical Oncology
Institute of Medical Sciences
New Delhi 110 029, India Banaras Hindu University
Col. S.S. Gill Varanasi 221 005, India
Associate Professor
Department of Pathology Nicola A. Hanania
Armed Forces Medical College Associate Professor
Pune 411 040, India Department of Pulmonary and Critical Care Medicine
Director, Asthma Clinical Research
P.C.F.M. Gondrie Baylor College of Medicine
KNCV Tuberculosis Foundation 1504 Taub Loop, Houston, Texas 77030, USA
Post Box 146, 2501CC
The Hague, Holland Seyed E. Hasnain
Vice Chancellor
R. Goswami University of Hyderabad
Associate Professor Hyderabad 500 046, India
Department of Endocrinology and Metabolism
All India Institute of Medical Sciences A.K. Hemal
New Delhi 110 029, India Professor
Department of Urology
Reuben Granich All India Institute of Medical Sciences
Medical Officer [HIV/TB] New Delhi 110 029, India
Antiretroviral Treatment and HIV Care
Department of HIV/AIDS N.C. Jain
Building D, 1st Floor, Room No. 1005 Scientist F
World Health Organization Division of Publication and Information
Geneva 27, Switzerland Indian Council of Medical Research
V. Ramalingaswami Bhawan, Ansari Nagar
J.S. Guleria New Delhi 110 029, India
Former Dean, Professor and Head
Department of Medicine Ruchi Jain
All India Institute of Medical Sciences Department of Biochemistry
New Delhi 110 029, India University of Delhi, South Campus
Benito Juarez Road
K.K. Guntupalli New Delhi 110 021, India
Professor of Medicine
Chief, Pulmonary, Critical Care and V. Jain
Sleep Medicine Section Department of Paediatric Surgery
Baylor College of Medicine All India Institute of Medical Sciences
Houston TX 77030, USA New Delhi 110 029, India
x Tuberculosis
S.K. Jindal Arvind Kumar

Professor and Head Professor
Department of Pulmonary Medicine Department of Surgical Disciplines
Postgraduate Institute of Medical Education and All India Institute of Medical Sciences
Research, Chandigarh 160 012, India New Delhi 110 029, India
Rajnish Joshi Ashok Kumar

Department of Medicine Professor
Mahatma Gandhi Institute of Medical Sciences Department of Medicine
Sevagram, Wardha 442 102, India All India Institute of Medical Sciences
S.K. Kabra
Additional Professor Shaji Kumar
Department of Paediatrics Associate Professor
All India Institute of Medical Sciences Division of Hematology, Mayo Clinic
New Delhi 110 029, India 200 First Street SW
Rochester, MN 55906, USA
S.P. Kalantri
Professor Subirendra Kumar
Department of Medicine Former Associate Professor
Mahatma Gandhi Institute of Medical Sciences Department of Otorhinolaryngology and
Sevagram, Wardha 442 102, India Head and Neck Surgery
D.R. Karnad New Delhi 110 029, India
Professor and Chief
Medical - Neuro Intensive Care Unit Sunesh Kumar
Department of Medicine Professor
Seth G.S. Medical College and K.E.M. Hospital Department of Obstetrics and Gynecology
Parel, Mumbai 400 012, India All India Institute of Medical Sciences
V.M. Katoch
Secretary, Department of Health Research J. Kumaresan
Ministry of Health and Family Welfare Executive Secretary
Government of India, and Stop TB Secretariat, World Health Organization
Director General Geneva 27, Switzerland
Indian Council of Medical Research
New Delhi 110 029, India Rakesh Lodha
Assistant Professor
N. Kochupillai
Department of Paediatrics
Former Professor and Head
Department of Endocrinology and Metabolism
Knut Lonnroth
S.S. Kothari Medical Officer,
Professor TB Strategy and Health Systems
Department of Cardiology Stop TB Department
All India Institute of Medical Sciences World Health Organization
New Delhi 110 029, India Geneva 27, Switzerland
Contributors xi
A.N. Malaviya T. Mohan Kumar

Consultant Rheumatologist A&R Clinic and Senior Consultant Pulmonologist
Visiting Senior Consultant Rheumatologist Sri Ramakrishnan Hospital, Sarojini Naidu Street
Indian Spinal Injuries Centre [ISIC] Superspeciality Avarampalayam, Coimbatore 641 044, India
Hospital
Sima Mukhopadhyay
Ben J. Marais Department of Radiodiagnosis
Professor All India Institute of Medical Sciences
Department of Pediatrics and Child Health New Delhi 110 029, India
Faculty of Health Sciences
Stellenbosch University, South Africa H.L. Nag
Additional Professor
D.S. Maru Department of Orthopaedics
Yale University School of Medicine All India Institute of Medical Sciences
367 Cedar St. New Haven New Delhi 110 029, India
Connecticut, USA
Nani Nair
P.S. Mathuranath
Regional Adviser – Tuberculosis
Department of Neurology
WHO Regional Office for South-East Asia
Sree Chitra Tirunal Institute for Medical Sciences
World Health House, IP Estate
and Technology
Mahatma Gandhi Marg
Trivandrum 695 011, India
N.K. Mehra
J.P. Narain
Professor and Head
Director, Department of Communicable Diseases
Department of Transplant Immunology
WHO Regional Office for South-East Asia
and Immunogenetics
World Health House, IP Estate
Mahatma Gandhi Marg
S. Mishra
Sujatha Narayanan
Department of Endocrinology
Deputy Director, Department of Immunology
Tuberculosis Research Centre
Mayor V.R. Ramanathan Road, Chetpet
D.K. Mitra Chennai 600 031, India
Associate Professor
Department of Transplant Immunology L.M. Nath
and Immunogenetics Former Professor and Head
All India Institute of Medical Sciences Centre for Community Medicine
New Delhi 110 029, India All India Institute of Medical Sciences
Alladi Mohan
Chief, Division of Pulmonary and Critical Care Medicine C.B. Ogbunugafor
Professor and Head, Department of Medicine Yale University School of Medicine
Sri Venkateswara Institute of Medical Sciences 367 Cedar St., New Haven
Tirupati 517 507, India Connecticut, USA
xii Tuberculosis
Madhukar Pai Rajeswari Ramachandran

Assistant Professor Former Deputy Director
Department of Epidemiology, Biostatistics and Tuberculosis Research Centre
Occupational Health [Indian Council of Medical Research]
McGill University Mayor V.R. Ramanathan Road, Chetpet
1020 Pine Avenue West Montreal Chennai 600 031, India
Canada H3A1A2
M. Ramam
Myo Paing Additional Professor
National Programme Officer Department of Dermatology and Venereology
WHO Country Office All India Institute of Medical Sciences
Myanmar New Delhi 110 029, India
C.N. Paramasivan Ruma Ray

Project Manager Professor
Tuberculosis – Laboratory Aspects Department of Pathology
Foundation For Innovative New Diagnostics [FIND] All India Institute of Medical Sciences
71, av. Lovis Casaï, P.O. Box 93 New Delhi 110 029, India
CH-1216 Cointrin/Geneva
Switzerland A. Roy
Department of Cardiology
John Porter All India Institute of Medical Sciences
Professor of International Health and New Delhi 110 029, India
Public Health and Policy
Department of Infectious and Tropical Diseases B.C. Roy
London School of Hygiene and Tropical Medicine Department of Otorhinolaryngology and
Keppel Street London WC1E7HT, UK Head and Neck Surgery
G.A. Prasad New Delhi 110 029, India
Assistant Professor
Division of Gastroenterolgy and Hepatology S.P. Sahoo
Mayo Clinic, College of Medicine Department of Surgical Oncology
Rochester, MN 55906, USA Institute of Medical Sciences
Banaras Hindu University
K. Radhakrishnan Varanasi 221 005, India
Senior Professor and Head
Department of Neurology Erwin Schurr
Sree Chitra Tirunal Institute for McGill Centre for the Study of Host Resistance
Medical Sciences and Technology Department of Human Genetics
Trivandrum 695 011, India McGill University, Montreal, QC, Canada
A.K. Rai Ashu Seith

Department of Transplant Immunology and Associate Professor
Immunogenetics Department of Radiodiagnosis
Contributors xiii
Anju Sharma Ramnath Subbaraman

Scientist E Resident Physician
Division of Publication and Information Department of Medicine, University of California
Indian Council of Medical Research San Francisco, USA
V. Ramalingaswami Bhawan, Ansari Nagar
New Delhi 110 029, India R.K. Tandon
Senior Consultant Gastroenterologist
S.C. Sharma Pushpawati Singhania Research Institute
Professor New Delhi 110 017, India
Department of Otorhinolaryngology and
M. Tewari
Head and Neck Surgery
Lecturer
Institute of Medical Sciences
Banaras Hindu University
Surendra K. Sharma
Varanasi 221 005, India
Chief, Division of Pulmonary, Critical Care
and Sleep Medicine Srikanth Tripathy
Professor and Head, Department of Medicine Scientist F
All India Institute of Medical Sciences National AIDS Research Institute
[Indian Council of Medical Research]
Plot No. 73, Block G, MIDC Complex
H.S. Shukla
Bhosari, Pune 411 026, India
Institute of Medical Sciences Anil K. Tyagi
Banaras Hindu University Professor
Varanasi 221 005, India Department of Biochemistry
University of Delhi, South Campus
Noman Siddiqi Benito Juarez Road
Director, ABSL3 New Delhi 110 021, India
Department of Immunology and Infectious Diseases
SPH1, Room No. 906 Mukund Uplekar
Harvard School of Public Health Medical Officer
665 Huntington Avenue TB Strategy and Health Systems
Boston MA 02445, USA Stop TB Department, World Health Organization
Geneva 27, Switzerland
Meenakshi Singh
Department of Transplant Immunology and M. van Cleeff
Immunogenetics KNCV Tuberculosis Foundation
All India Institute of Medical Sciences Post Box 146, 2501CC
New Delhi 110 029, India The Hague, Holland
Ian Smith J. Veen

Adviser to the Director-General WHO KNCV Tuberculosis Foundation
World Health Organization Post box 146, 2501CC, The Hague
Geneva 27, Switzerland Holland
xiv Tuberculosis
Pradeep Venkatesh D. Fraser Wares

Associate Professor Medical Officer – Tuberculosis
Dr Rajendra Prasad Centre for Ophthalmic Sciences WHO Country Office for India
All India Institute of Medical Sciences Shri Ram Bharatiya Kala Kendra
New Delhi 110 029, India 1, Copernicus Marg, 5th Floor
Near Mandi House
V.K. Vijayan New Delhi 110 001, India
Director
Vallabhbhai Patel Chest Institute W.W. Yew
University of Delhi Chief, Tuberculosis and Chest Unit
P.O. Box No. 2101 Grantham Hospital
Delhi 110 007, India Hong Kong, China
Foreword
Rarely has any epidemic tormented the humankind with the tenacity and destructive impact of tuberculosis [TB].
While TB never disappeared from the developing world, it re-emerged globally from the oblivion and has resurged
with a vengeance with the advent of the global pandemic of human immunodeficiency virus [HIV] infection in the
1980s. Additionally, in the new millennium, TB, especially in the multidrug-resistant [MDR] and extensively drug
resistant [XDR] forms, continues to haunt us as a dark reminder from the past. Indeed, TB still constitutes a social,
economic and political threat set to impede development of entire populations.
The war between human race and Mycobacterium tuberculosis is far from over and the relentless fight against this
ancient scourge is still going on globally. During the last decade, the realization that mere availability of drugs,
which became available starting in the 1940s, was not enough to cure, control and eliminate TB has led to the
establishment of the DOTS strategy. The DOTS is a five-element approach including: governmental commitment;
bacteriological diagnosis; standardized treatment with supervision; an effective drug supply system; and monitoring
and evaluation of programme performance. DOTS, which has been promoted by the World Health Organization
[WHO] starting in 1995 as the most cost-effective strategy currently available to conquer this scourge, has taken firm
roots in the national TB control programmes world over with virtually all countries implementing it.
The Millennium Development Goals set by the United Nations for 2015 include, under Goal 6, target 8 which
calls for halting and beginning to reverse the incidence of TB. The Stop TB Partnership, additionally, set the ambitious
targets to halve TB prevalence and deaths by 2015, compared to 1990. To achieve these targets, WHO has defined a
new Stop TB strategy endorsed by the World Health Assembly in 2007, that addresses current challenges preventing
progress towards TB elimination and emphasizes the importance of individual care besides confirming a sound
public health approach to TB control. Such strategy begins with reiteration that quality DOTS and proper
implementation of its essential elements are the sine-qua-non for TB control. The strategy also explicitly recognizes
that HIV-associated TB, multidrug- resistant TB, and other special challenges must be addressed with additional
interventions. It defines that contributing to health system strengthening is a concern of TB control implementers. It
clearly acknowledges that the non-state, private sector has to be engaged fully if TB control is to be achieved in any
community, and it promotes The International Standards for TB Care [ISTC], developed to facilitate the effective
engagement of all care providers, public as well as private in delivering high-quality care to patients with TB. It also
provides the basis for empowerment of communities as a key step to effective delivery of care and broad, grass-
roots mobilization. It finally emphasizes the urgent need for research, both basic, to develop new more effective
tools, and operational, to optimize use of current ones.
In this scenario, the publication of the second edition of “Tuberculosis” by Professor S.K. Sharma is indeed a
welcome and extremely useful addition to the literature on TB. Keeping with the spirit of providing a comprehensive
first-hand account regarding all aspects of TB from that part of the world where it is a crisis, with which the first
edition was conceived eight years ago, the thoroughly and extensively revised, rewritten and updated second edition
has contributions from leading experts on TB from India and all over the world. This comprehensive, well-referenced
textbook which contains a wealth of information and is richly illustrated with clinical and gross pathology specimen
photographs and photomicrographs, provides a perfect blend between the remarkable advances in the molecular
pathogenesis, laboratory diagnosis, the latest innovations in terms of medical and surgical management and global
efforts for TB control. The book also contains useful internet links for obtaining the latest updated information
regarding various guidelines that are published periodically by international bodies such as the WHO, American
Thoracic Society [ATS], U.S. Centers for Disease Control and Prevention [CDC], Infectious Diseases Society of America
xvi Tuberculosis
[IDSA], National Institute for Health and Clinical Excellence [NICE], European Respiratory Society [ERS], and the
Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, among others.
Undergraduate and postgraduate medical students, clinicians, practitioners, nurses, paramedical personnel and
health authorities caring for patients with TB should find this book to be a valuable asset and source of information.
The book deserves a place in the shelves of every medical college library. It is my fond hope that Professor Sharma’s
“Tuberculosis” will be a useful companion for all those involved in the fight against TB.
Mario C. Raviglione M.D.

Director
Stop TB Department
World Health Organization
Geneva, Switzerland
Preface to the Second Edition
Welcome to the second edition of “Tuberculosis”! In 2001, we had brought out the first edition of “Tuberculosis”, with
an aim to provide a well referenced standard textbook on tuberculosis [TB], that will chronicle the rich and vast
experience of clinicians and researchers from India. The first edition was widely received by the faculty, graduate
and postgraduate students, researchers and practitioners not only in India and South-East Asia, but also in several
other parts of the world and the book established itself as a standard textbook on tuberculosis. The recent years have
witnessed an enormous change in various aspects related to our understanding of TB. Furthermore, there were
overwhelming requests for an updated version of the textbook. This prompted us to bring out the second edition.
In the preface to the first edition we mentioned that we “attempted to present tuberculosis as it is seen in India”.
With the second edition, we have gone one step further and have strived to bring out a textbook that provides a
“global perspective” of TB. The second edition has several new contributors, all of them leading authorities, from
various parts of the world. All the chapters have been thoroughly re-written and updated, many of them are by new
contributors. With this edition, we have introduced a full-colour format that is easy to the readers’ eye and facilitates
inclusion of several high quality clinical and gross pathology specimen photographs, radiographic images and
photomicrographs for the readers’ convenience.
The recent years have witnessed several spectacular advances in TB research. Our understanding of the host-
pathogen interaction at the molecular level, especially, immunology and immunopathogenesis of TB has improved
enormously and this has led to the development of several new drug and vaccine candidates. We have also witnessed
exciting developments, such as the interferon-gamma release assays [IGRAs] for latent TB infection, use of liquid
culture and molecular method of diagnosis ushering in a new era in TB diagnostics. Furthermore, issues concerning
quality assurance in antituberculosis drug susceptibility testing are getting established. We have accumulated over
a decade of experience with DOTS strategy. The global efforts to contain and eventually eliminate TB are still ongoing.
The recent guidelines issued by the World Health Organization [WHO] for the treatment of TB under national
programmes, drug-resistant tuberculosis, management of human immunodeficiency virus- [HIV-] TB coinfection;
new Stop-TB strategy; and International Standards for Tuberculosis Care have all been brought out. Data are rapidly
accumulating from all over the world regarding the efficacy of standardized treatment regimens for drug-sensitive,
drug-resistant TB and latent TB infection. Several innovative strategies such as ‘public-private mix’, involvement of
medical colleges in TB control, have entrenched themselves as useful measures to contain TB. While we were coming
to terms to tackle the menace of multidrug-resistant TB [MDR-TB], extensively drug-resistant tuberculosis [XDR-
TB] has emerged threatening to undermine global efforts at TB control. Further refinements in the imaging modalities
such as ultrasonography, computed tomography and magnetic resonance imaging have not only enhanced the
localization, and diagnosis of TB of various organ systems, but also have facilitated objective follow-up. The second
edition of “Tuberculosis” covers all these developments in great detail; several new chapters that were not present in
the first edition have been introduced covering immunology, immunogenetics, vaccine development, public-private
mix, building partnerships, the Revised National Tuberculosis Control Programme [RNTCP] of the Government of
India, and global efforts at TB control. The second edition has also been enriched by many new tables, figures and
high quality images. The first decade in the new millennium has also witnessed the widespread availability of
broadband internet connectivity globally. In order to facilitate the interested readers to update themselves, we have
introduced a chapter that provides details on various web resources available on the internet that may be useful to
persons interested in TB.
We sincerely believe that the second edition will help undergraduate and postgraduate students to update their
knowledge. We hope that it will be a valuable source of reference to researchers and better the understanding of
xviii Tuberculosis
practising physicians and contribute to patient management. We also hope that the second edition will serve as a
practical guide for health care workers, nurses, and other paramedical staff.
This effort would not have been possible but for the kind cooperation and magnanimity of our contributors who
patiently went through endless series of revisions and constant updating. We thank them for their valuable time.
We would like to thank Shri Jitendar P. Vij (Chairman and Managing Director) and Mr Tarun Duneja (Director-
Publishing) M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi for their encouragement and support and
excellent technical assistance.
Our march towards the second edition saw the sad demise of mother of Surendra K. Sharma, and both parents
of Alladi Mohan. Our families have stood by us through these turbulent times and without their unstinting support,
constant encouragement, this second edition would not have seen the light of the day.
Surendra K. Sharma
Alladi Mohan
Preface to the First Edition
Tuberculosis is an ancient disease which continues to haunt us even as we step into the next millennium. Tuberculosis
is the most common cause of death world over due to a single infectious agent in adults and accounts for over a
quarter of all avoidable deaths globally. One third of India’s population is infected with Mycobacterium tuberculosis,
there are 12 million active tuberculosis cases in India. One person dies of tuberculosis every minute in India. The
deadly synergy between Mycobacterium tuberculosis and the human immunodeficiency virus [HIV] has resulted in a
resurgence of tuberculosis world over. The impact of this “cursed duet” on human suffering has been enormous.
With HIV making rapid inroads in India, the spectre of dual infection with HIV and tuberculosis is going to be a
daunting prospect. Inspite of this gloomy scenario, the treatment of tuberculosis is one of the most cost-effective
methods of cure. Research work carried out in India has had a tremendous impact on tuberculosis control. The
observations from the well-known, randomized controlled trial “The Madras Study” carried out at the Tuberculosis
Research Centre [TRC], Chennai, established efficacy of the domiciliary treatment and has paved way for the National
Tuberculosis Programme in India and several other countries. Pioneering contributions from eminent clinicians,
bacteriologists and epidemiologists from the TRC, Chennai; National Tuberculosis Institute, Bangalore; Sanatoria at
Madanapalle, Kasauli, Dharampur, Bhowali, have greatly enhanced our understanding of tuberculosis.
The changing clinical presentation of tuberculosis, advances in laboratory and imaging diagnostic modalities
and therapeutic measures such as directly observed treatment, short-course [DOTS] all suggest a pressing need to
have a recent textbook of tuberculosis. Furthermore, while every doctor working in India encounters the disease in
one or other form, very little has been documented regarding the Indian perspective of tuberculosis. Often, the
medical students, postgraduates and researchers returning empty handed from libraries expressed their desire for
a book which documents the Indian experience. Paucity of a well referenced, standard textbook of tuberculosis
which chronicles the rich and vast clinical experience of clinicians from India prompted us to undertake this venture.
We have attempted to present a picture of tuberculosis as it is seen in India with contributions from experts who
have vast experience in managing tuberculosis in the Indian setting. Our book contains chapters on History, Pathology,
Epidemiology, Clinical Presentation, Diagnosis, Treatment, Prevention and Control of tuberculosis highlighting the
Indian perspective of tuberculosis. We have also provided guidelines published by authorities concerned with
tuberculosis control, and other statements as useful appendices. Though we have made an effort to maintain a
uniform style and format, we have been careful to preserve the views expressed by the contributors in their original
form. As we step into the new millennium, it is obvious that the crusade against this ancient foe of mankind is still
going on. Contrary to the wishful thinking in the 1980s, tuberculosis still remains to be a research priority of paramount
importance and is an important component of curricula of medical schools. Keeping in mind the need of the hour,
we have attempted to highlight the rationale behind DOTS and its importance in tuberculosis control. We believe
that our book will help undergraduate and postgraduate medical students to update their knowledge. It will also be
a source of reference to researchers and better the understanding of practising physicians and help in patient
management. We also hope that the book can serve as a practical guide on the management of tuberculosis to health
care workers, nurses and other paramedical staff.
A book of this magnitude would not have been possible but for the magnanimity and kindness of our contributors
who took time off their busy schedule to prepare their manuscripts. We would like to thank Mr. Jitendar P Vij,
Chairman and Managing Director and Mr RK Yadav, Publishing Director, M/s Jaypee Brothers Medical Publishers
Pvt Ltd., for their support, co-operation and technical excellence. Without the unstinting support, constant
encouragement and help from our families this endeavour would not have been possible.
S.K. Sharma
A. Mohan
Acknowledgements
We would like to specially thank the Editors and Authors to permit us to reproduce their work. We have acknowledged
their help in the respective chapters. The kind help of the World Health Organization [WHO], Geneva for liberally
granting permission to reproduce figures and tables from several of their publications is thankfully acknowledged.
We are indebted to Dr L.S. Chauhan, Deputy Director General [Tuberculosis], Directorate General of Health
Services, Ministry of Health and Family Welfare, Government of India, for his constant support and encouragement.
We express our gratitude to the following from the WHO, Geneva, Drs Mario Raviglione, Ian Smith, Mukund
Uplekar, Reuben Granich, Knut Lonnroth and J. Kumaresan for their excellent contributions. We specially thank
Dr Jai P. Narain, Director, Department of Communicable Diseases, WHO Regional Office for South-East Asia, New
Delhi, for his contribution, critical comments, and stimulating discussions. We will also like to thank Drs Nani Nair,
New Delhi, E. Cooreman, Dhaka, WHO Regional Office for South-East Asia, and Dr Myo Paing, WHO Country
Office, Myanmar, for their useful suggestions and contributions. We are greatly indebted to WHO India Staff
Drs D. Fraser Wares, Rajesh Bhatia, for their valuable contributions. We express our heartfelt thanks to Drs Thomas
Frieden, New York, USA, Madhukar Pai, Montreal, Canada, Dr S.E. Hasnain, Hyderabad, India for their creative
inputs and contributions. We wish to thank Drs M van Cleeff, PCFM Gondrie, J Veen, KNCV Tuberculosis Foundation
and Dr John Porter, UK for their contributions. We will also like to thank Dr D.S. Maru, USA for his valuable
suggestions. Special thanks are also due to Dr P.C. Hopewell, University of California, San Francisco, USA for his
suggestions on the International Standards for Tuberculosis Care [ISTC]. We would like to thank Dr N.K. Ganguly,
former Director General, Indian Council of Medical Research [ICMR], Dr V.M. Katoch, Secretary, Department of
Health Research, Ministry of Health and Family Welfare, Government of India, and Director General, ICMR, New
Delhi, India, and Dr C.N. Paramasivan, FIND, Geneva, for their constant encouragement.
We are deeply grateful to Departments of Pathology, All India Institute of Medical Sciences [AIIMS], New Delhi;
Sri Venkateswara Institute of Medical Sciences [SVIMS], Tirupati; and Postgraduate Institute of Medical Education
and Research [PGIMER], Chandigarh for providing gross pathology specimen figures and histopathology
photomicrographs. We wish to thank the Departments of Radiodiagnosis, AIIMS, New Delhi and SVIMS, Tirupati
for providing classic radiological imaging figures. We also wish to thank Directors of Tuberculosis Research Centre
[ICMR], Chennai and National Tuberculosis Institute, Bengaluru, The Administration of Arogyavaram Medical
Centre, Madanapalle and TB Sanatorium at Bhowali [now, Kamla Nehru Chest Institute] for permitting us to
reproduce the images of these well known institutions.
We also wish to thank faculty members of AIIMS, New Delhi; SVIMS, Tirupati; and other medical colleges
across India and several other parts of the world, several generations of undergraduate and postgraduate students,
for their constructive criticism and useful suggestions during our discussions. These inputs proved to be crucial in
shaping the second edition of the book.
Our special thanks are also due to the technical staff of the K.L. Wig Centre for Medical Education and Technology
[CMET], AIIMS, New Delhi, and Mr Vaka Sudarsan, Photo Artist, SVIMS, Tirupati for their help in organizing
clinical and radiographic photographs.
Invaluable help rendered by Krishna Srihasam, Boston, USA, and Srinivas Bollineni, Houston, USA, in obtaining
full text references is also thankfully acknowledged. We also wish to thank Alladi V. Srikumar’s timely help with
broadband connectivity. We wish to specially thank Mr Shree Prakash Kandpal for his constant encouragement and
for facilitating visit to Bhowali sanatorium.
xxii Tuberculosis
We wish to thank Mr Mukesh Juyal, Mrs Rekha Sharma, Ms Deepa Dhawan and Mrs Veena Dawar Department
of Medicine, AIIMS, New Delhi, and Mrs Radha, Department of Medicine, SVIMS, Tirupati, for their excellent help
in typing the early drafts of the book and ushering the later drafts with their cheerful enthusiasm and competence.
Special thanks are also due to Mrs Samina Khan and Mrs Yashu Kapoor of Jaypee Brothers Medical Publishers (P)
Ltd for their untiring help and assistance.
Contents
1. Introduction 1
S.K. Sharma
2. History 7
Alladi Mohan, S.K. Sharma
3. Epidemiology 16
A.K. Chakraborty
4. Epidemiology: Global Perspective 55
D.S. Maru, Jason Andrews
5. Pathology 66
S. Datta Gupta, Ruma Ray, S.S. Gill
6. The Mycobacteria 102
Rajesh Bhatia
7. Immunology of Tuberculosis 108
D.K. Mitra, A.K. Rai
8. Genetic Susceptibility Parameters in Tuberculosis 124
N.K. Mehra, Meenakshi Singh
9. Genetics of Susceptibility to Tuberculosis 143
Caroline J. Gallant, Tania Di Pietrantonio, Erwin Schurr
10. Laboratory Diagnosis 160
Rajesh Bhatia
11. The Tuberculin Skin Test 173
V.K. Chadha, V.K. Challu
12. Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 186
Madhukar Pai, Rajnish Joshi, Shriprakash Kalantri
13. Roentgenographic Manifestations of Pulmonary Tuberculosis 200
Sima Mukhopadhyay, Ashu Seith
14. Pulmonary Tuberculosis 217
V.K. Vijayan, Sajal De
15. Lower Lung Field Tuberculosis 227
G. Ahluwalia, S.K. Sharma
16. Endobronchial Tuberculosis 232
S.S. Dhillon, N.A. Hanania
17. Tuberculosis Pleural Effusion 245
A.N. Aggarwal
18. Silicotuberculosis 268
Praveen Aggarwal
19. Abdominal Tuberculosis 275
M. Tewari, S.P. Sahoo, H.S. Shukla
xxiv Tuberculosis
20. Granulomatous Hepatitis 294

Vineet Ahuja, S.K. Acharya
21. Neurological Tuberculosis 304
P.S. Mathuranath, K. Radhakrishnan
22. Tuberculosis and the Heart 330
S.S. Kothari, A. Roy
23. Skeletal Tuberculosis 342
S. Bhan, H.L. Nag
24. Musculoskeletal Manifestations of Tuberculosis 373
Ashok Kumar, A.N. Malaviya
25. Cutaneous Tuberculosis 384
M. Ramam
26. Lymph Node Tuberculosis 397
Arvind Kumar
27. Tuberculosis in Otorhinolaryngology 410
Subirendra Kumar, B.C. Roy, S.C. Sharma
28. Ocular Tuberculosis 420
S.P. Garg, Rohan Chawla, Pradeep Venkatesh
29. Breast Tuberculosis 434
Puneet Gupta, M. Tewari, H.S. Shukla
30. Tuberculosis in Pregnancy 441
Sunesh Kumar
31. Female Genital Tuberculosis 449
Sunesh Kumar
32. Genitourinary Tuberculosis 463
A.K. Hemal
33. Tuberculosis in Chronic Renal Failure 479
S.K. Agarwal
34. Disseminated and Miliary Tuberculosis 493
S.K. Sharma, Alladi Mohan
35. Complications of Pulmonary Tuberculosis 519
D. Behera
36. Tuberculosis and Acute Lung Injury 532
D.R. Karnad, K.K. Guntupalli
37. Haematological Manifestations of Tuberculosis 542
Shaji Kumar
38. Adrenocortical Reserve in Tuberculosis 553
G.A. Prasad, S.K. Sharma, N. Kochupillai
39. Endocrine Implications of Tuberculosis 561
R. Goswami, S. Mishra, N. Kochupillai
40. Tuberculosis and Human Immunodeficiency Virus Infection 574
Srikanth Tripathy, Myo Paing, Jai P. Narain
Contributors xxv
41. Tuberculosis in Children 591

S.K. Kabra, Rakesh Lodha
42. Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools 602
Ben J. Marais, Madhukar Pai
43. Surgical Aspects of Childhood Tuberculosis 615
M. Bajpai, V. Jain, Arun K. Gupta
44. Tuberculosis in Elderly 625
M. van Cleeff, P.C.F.M. Gondrie, J. Veen
45. Tuberculosis in Health Care Workers 634
S.K. Jindal
46. Nutrition and Tuberculosis 646
Jason Andrews, Ramnath Subbaraman
47. Reactivation and Reinfection Tuberculosis 656
Sujatha Narayanan, J.S. Guleria
48. Nontuberculous Mycobacterial Infections 665
V.M. Katoch, T. Mohan Kumar
49. Drug-Resistant Tuberculosis 682
Sharmistha Banerjee, N. Siddiqi, Seyed E. Hasnain
50. Antituberculosis Drug Resistance Surveillance 714
C.N. Paramasivan, V.H. Balasangameshwara
51. Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and
their Scientific Rationale 734
Rani Balasubramanian, Rajeswari Ramachandran
52. Treatment of Tuberculosis 751
W.W. Yew
53. Treatment of Latent Tuberculosis Infection 776
D.S. Maru, C.B. Ogbunugafor, S. Basu
54. Antituberculosis Treatment Induced Hepatotoxicity 783
P.K. Garg, R.K. Tandon
55. Surgery for Pleuropulmonary Tuberculosis 796
Arvind Kumar, D. Dilip, Abha Chandra
56. DOTS: The Strategy that Ensures Cure of Tuberculosis 814
Thomas R. Frieden
57. Directly Observed Therapy 827
Ian Smith
58. The Role of Medical Colleges in Tuberculosis Control 839
Jai P. Narain, E. Cooreman, L.M. Nath
59. Public-Private Mix for Tuberculosis Control 846
Mukund Uplekar, Knut Lonnroth
60. Building Partnerships for Tuberculosis Control 854
Nani Nair, J. Kumaresan
61. Non-Governmental Organizations and Tuberculosis Control 866
Ian Smith
xxvi Tuberculosis
62. Global Tuberculosis Control: The Future Prospects 874

D. Fraser Wares
63. The Revised National Tuberculosis Control Programmme [RNTCP] 894
Reuben Granich, L.S. Chauhan
64. Tuberculosis Vaccine Development: Current Status and Future Expectations 918
Anil K. Tyagi, Bappaditya Dey, Ruchi Jain
65. Ethical and Legal Issues in Tuberculosis Control 947
John Porter
66. Tuberculosis: Some Web-based Resources on the Internet 963
Anju Sharma, N.C. Jain
67. International Standards for Tuberculosis Care [ISTC] 980
Index 1041
Introduction 1
Introduction
1
SK Sharma
INTRODUCTION logical data on TB that were lacking in the pre-1990 period

(7-13). Table 1.1 and Figure 1.1 (13) provide a glimpse of
Tuberculosis [TB] continues to intimidate the human race
the current global TB scenario. The year 2005 data cited in
since time immemorial not only due to its effects as a
the WHO Report 2007 (7) suggest, for the first time since
medical malady, but also by its impact as a social and
1993 that, the TB incidence rates have stabilized or are in
economic tragedy. At the dawn of the new millennium,
decline in all six WHO regions. A similar trend has also
we are still mute witnesses to the silent yet efficient march
been observed in the year 2006 data cited in the WHO
of this sagacious disease, its myriad manifestations and
Report 2008 [Figure 1.2] (8).
above all its unequalled, vicious killing power. Through
the millennia, TB never ever disappeared from the
Table 1.1: Current global tuberculosis scenario (2006)
developing world. In the developed world, it only went
into hibernation for a while in the mid and late 1970s, to New TB cases 9.2 millions [139/100 000]
explode once again with the advent of human immuno- HIV co-infected cases 0.7 millions [7.7%]
New sputum smear-positive cases 4.1 millions [62/100 000]
deficiency virus [HIV] infection and acquired immuno-
Prevalence of TB 14.4 millions [219/100 000]
deficiency syndrome [AIDS] pandemic in the 1980s. Total TB deaths 1.7 millions [25/100 000]
In 1991, the World Health Assembly [WHA] resolution Deaths due to HIV-TB 0.23 millions
recognized TB as a major global public health problem (1)
TB = tuberculosis; HIV = human immunodeficiency virus
and suggested two targets for National Tuberculosis Source: reference 8
Programmes, of detecting 70 per cent of new smear-positive
patients and curing 85 per cent of such cases by the year
Towards the end of 1990s it was apparent that the
2000 in an attempt to rejuvenate global TB control.
WHA 1991 targets for TB were not likely to be achieved by
Thereafter, in 1993, the World Health Organization [WHO]
the year 2000 as planned. The WHA had postponed the
recognized the lethal impact of this disease and declared
target date to 2005 (9) or as soon as possible thereafter.
it a “Global Emergency” (2). The DOTS strategy was
Global TB case detection rate significantly increased
launched in 1994, and became the globally recommended
from 11 per cent in 1995 to 60 per cent by 2005 (10).
strategy for TB control since then (3). The DOTS strategy
Similarly, the global TB treatment success rate had reached
was rapidly adopted all over the world and has become
84 per cent by 2003 (10). Thus, even though the deferred
the standard of TB care (4-6).
deadline had already passed, these goals are yet to be
achieved (10-12). While results have been exceedingly
TUBERCULOSIS EPIDEMIC
good in the WHO Western Pacific region, the cure rates
During the last decade, DOTS not only facilitated control have been disappointing in the African region, the
of TB, but was also instrumental in establishing a system established market economies, and eastern Europe (4,11).
of documentation and generation of reliable epidemio- This patchy performance can be attributed to several
2 Tuberculosis
Figure 1.1: Trajectories of tuberculosis epidemic for nine epidemiologically different regions of the world. Points mark trends in estimated
incidence rates, derived from case notifications for 1990–2003. Groupings of countries based on WHO regions. High HIV = incidence > 4% in
adults aged 15–49 years in 2003; low HIV = incidence < 4%. Established market economies = all 30 Organization for Economic Co-operation and
Development [OECD] countries, except Mexico, Slovakia, and Turkey, plus Singapore
Reproduced with permission from “Dye C. Global epidemiology of tuberculosis. Lancet 2006;367:938-49 (reference 13)” Copyright
[2006] Elsevier
Figure 1.2: Estimated global prevalence, mortality and incidence rates 1990-2006. Note the different scales on the y-axes
Adapted and reproduced with permission from “World health Organization. WHO report 2008. Global tuberculosis control: surveillance,
planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 8)”
reasons including expanding HIV/AIDS epidemic and [XDR-TB] (19,20), widespread use of immunosuppressive
poor health systems. drugs following organ transplantation (21,22), and
Looking back at the last decade, several factors have increasing use of anti-tumour necrosis factor-α [TNF-α]
threatened to thwart the TB control (11,13,14). These agents [e.g., infliximab and etanercept] (23,24). Further,
include HIV-TB co-infection (15), the global presence of recently, several systematic reviews and meta-analyses
multidrug-resistant tuberculosis [MDR-TB] (16-18), the have provided evidence that tobacco smoking is associated
emergence of extensively drug-resistant tuberculosis with an increased risk of TB (25-27). The HIV/AIDS
Introduction 3
pandemic fuels the TB epidemic and has a catastrophic This technology is considered to be inexpensive and
effect on TB control. Reduced numbers in revised global suitable for use in resource limited settings. The initial
as well as Indian estimates of HIV epidemic is a good results have been promising (33,34).
news (28) and should be welcomed as it provides a good Accurate and speedy diagnosis is required especially
opportunity for HIV care but there is no room for in paucibacillary smear-negative pulmonary TB, extra-
complacency and all efforts must continue towards its pulmonary TB and HIV associated TB. A number of
prevention as well as control. exciting technologies are being developed to facilitate an
early diagnosis, especially in HIV associated TB. Revised
TUBERCULOSIS DIAGNOSTICS diagnostic algorithms, improved microscopy and rapid
mycobacterial culture may become available in near future
Widespread use of newer imaging facilities such as (35). Several TB diagnostic tests using newer technologies
ultrasonography [US], computed tomography [CT] and are in various phases of development. These aim at case
magnetic resonance imaging [MRI] has revolutionized the detection [growth-based detection, direct visualization,
diagnosis of extra-pulmonary TB. These imaging volatile organic compound {VOC} detection, antigen,
modalities can also be used to follow the disease course in antibody detection, and molecular diagnosis], species
an individual patient. Nevertheless, these tests cannot identification [luminescent probe of culture isolate,
provide mycobacteriological diagnosis of TB (29). fluorescent probe of smear-positive sputum, reverse
As the conventional mycobaterial culture and hybridization line probe from culture isolates, dipstick
sensitivity testing is time consuming, impetus has been detection of TB antigens in positive cultures, species-
on evolving rapid methods of reliable diagnosis. Thus, specific amplification or sequencing] and detection of
laboratories are a key component of TB control, providing latent TB infection [LTBI] using MPB-64 skin patch,
inputs on the diagnosis, surveillance and treatment whole-blood interferon-γ [IFN-γ] release assay, enzyme
monitoring (30). There is a need to strengthen laboratory linked immunospot [ELISPOT] IFN-γ release assay, skin
capacity as the implementation of new and rapid diag- testing with TB-specific antigens, among others.
nostic methods for TB not only requires provision of The advent of the interferon-γ [IFN-γ] release assays
supplies and equipment, but also ensuring quality [IGRAs] heralds a new era in the diagnosis of LTBI as
standards, appropriate human resource, and attention to these assays have shown potential to overcome the
safety. A network of laboratories with quality management problems that hamper the interpretation of tuberculin skin
systems needs to be established for ensuring internal and test [TST] in situations, such as prior bacille Calmette-
external quality assurance and periodic accreditation of Guerin [BCG] vaccination, infection with HIV and
laboratories to ensure high standards and quality of infection with nontuberculous mycobacteria [NTM]
mycobacterial culture and sensitivity testing. At the same (36,37). The IGRAs are considered to be more specific for
time, the cost involved in these new and rapid diagnostic TB infection than the TST. However, high cost has been a
methods needs to be kept under wraps, through inno- problem for their wide spread use in resource limited
vations in technology and/or funding. settings (38). Reliable method of detecting LTBI opens up
Deciphering the biology of Mycobacterium tuberculosis, new avenues for halting the progression of LTBI to active
from the complete genome sequence, in 1998 (31) evoked TB disease by administering effective treatment and has
immense interest as it marked a paradigm shift in the been an area of intense research.
understanding of the molecular genetics of TB and Several agencies have evinced interest in TB diagnos-
signalled a hope for evolving tools to address the needs of tics in recent times. One such non-profit product
TB control. Efforts are underway to sequence several development partnership based in Geneva, Switzerland,
Mycobacterium tuberculosis clinical isolates to identify Foundation for Innovative New Diagnostics [FIND] (39)
specific genes that have potential for development of new has been involved in innovative research. In partnership
diagnostic tools or targets for drug discovery. Recent with Eiken Chemical Co. of Japan, FIND has been develop-
introduction of microscopic-observation drug-suscepti- ing LAMP [loop-mediated isothermal amplification]
bility [MODS] assay (32) for the bacteriologic diagnosis of technology for use in TB diagnosis. Field studies are
TB and detection of drug resistance in such an example. underway in several countries including India, Vietnam,
4 Tuberculosis
South Africa and Brazil. Several such inputs are required predict relapse risk may act as tools for individual patient
to strengthen the laboratory set-up in resource limited treatment and thus assist National TB control prog-
countries. rammes. The last few years have increased our under-
standing of immunity to TB. We now recognize that in
NEWER ANTITUBERCULOSIS DRUG DISCOVERY addition to Th1 and Th2 cell mediated immune response,
innate and regulatory immune responses play an
The fact that no exciting antituberculosis drug as good important role in the disease process. Animal and human
and effective as rifampicin has become available has been studies also indicate that although IFN-γ is essential for
a stumbling block in the further refinement of the treatment protective immunity but other cytokines may also be
of TB, be it shortening the duration of treatment or treating involved in immunoprotection. Several clinical studies
LTBI, MDR-TB, or XDR-TB (13). The quest for the ideal have shown that the cytokine IFN-γ is secreted in response
antituberculosis drug is still on and the advances in to TB antigens in patients with TB; however, in some
mycobacterial genetics and related bioinformatics are patients the secretion of IFN-γ is reduced. This apparent
expected to turn the tide to realize this goal in the years to reduction in secretion of IFN-γ may be due to suppressive
come (40). Currently, several TB drug candidates including effects of regulatory T-cells [Treg, CD4 + CD25 + FoxP3 +],
fluoroquinolones [gatifloxacin, moxifloxacin], diarylqui- a class of T-cells, that may mediate this effect through
noline [TMC207], nitroimidazoles [OPC-67683 and secretion of cytokines, such as interleukin-10 [IL-10] and
PA-824], pyrrole [LL-3858] and diamine [SQ-109] are in transforming growth factor-β [TGF-β]. Further, persistent
various phases of clinical development (41). These com- signalling through toll-like receptor-2 [TLR-2] as a result
pounds may further shorten the duration of antituber- of chronic exposure to Mycobacterium tuberculosis antigens
culosis treatment and some of them may be useful for the can downregulate major histocompatibility complex
treatment of MDR-TB. [MHC] class II mediated immune responses (46,47).
Further advances in technologies such as DNA microarray
VACCINE analysis and flow cytometry may unravel surrogate novel
markers of immunoprotection (48).
The BCG, one of the world’s most widely used vaccines,
has shown consistently high efficacy against miliary TB Response to the Challenge of Multidrug-resistant
and childhood TB meningitis, however, its efficacy against and Extensively Drug-resistant Tuberculosis
adult pulmonary TB and other forms of TB is variable.
Availability of quality assured, periodically accredited
A recent meta-analysis of the effect of worldwide BCG
mycobacteriology laboratory services and good quality
vaccination on miliary TB and childhood TB meningitis
second-line antituberculosis drugs with proven
found it to be a highly cost-effective intervention against
bioavailability are essential elements in the battle against
severe childhood TB and recommended that it should be
drug-resistant TB. Since it has become evident that DOTS
retained in high-incidence countries as a strategy to
alone may be inadequate to contain TB in areas where
supplement the chemotherapy of active TB (42). It has been
MDR-TB is highly prevalent, as a first step in moving
possible to construct the recombinant BCG [rBCG] strains
beyond DOTS, the DOTS-Plus strategy, has been evolved
with the assistance of DNA technology. These improved
as the WHO’s supplemental strategy. The Working Group
candidates have superior immunogenicity (43). Several on DOTS-Plus for MDR-TB was established in 1999 (18).
vaccine candidates are being tried in various phases of In 2000, the “Green Light Committee” [GLC] was launched
clinical trials, and they must show superior efficacy as as a sub-group of the working group in order to increase
well as safety as compared with the currently available access to low-price, quality-assured second-line drugs and
BCG vaccine (44,45). ensure their proper use (49). In 2001, this has been integra-
ted into the Stop TB Partnership and has now been termed
CORRELATES OF IMMUNOPROTECTION FROM
as the Stop TB Working Group on MDR-TB. The earliest
TUBERCULOSIS
beneficiaries of this scheme were Estonia, Lativia, Peru,
There is an urgent need to identify new correlates of the Phillippines, and the Russian Federation [Tomsk
immune protection to facilitate the design and testing of Oblast]. As of December 2006, there were 53 GLC
new drugs and vaccines for TB. Surrogate markers to approved projects underway in 42 countries globally (18).
Introduction 5
In India, provision of standardized DOTS-Plus regimen 3. World Health Organization. WHO Tuberculosis Programme:
is underway in Gujarat and Maharashtra and is likely to framework for effective tuberculosis control. WHO/TB/
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cover the entire country in a phased manner (50).
4. Sharma SK, Liu JJ. Progress of DOTS in global tuberculosis
The DOTS strategy, by ensuring standard treatment of control. Lancet 2006;367:951-2.
TB, prevents the emergence of MDR-TB. The DOTS-Plus 5. Frieden TR, Munsiff SS. The DOTS strategy for controlling the
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Other Innovations
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ensure treatment compliance has been found to yield Assembly, Resolutions and Decisions. Resolution WHA 53.1.
promising results (51). Similarly, the efforts to involve non- Geneva: World Health Organization; 2000.
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[public-private mix DOTS], use of paramedical persons tuberculosis control? Bull World Health Organ 2007;85:364-9.
11. Dye C, Watt CJ, Bleed DM, Hosseini SM, Raviglione MC.
such as Anganwadi workers to promote treatment
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Care [ISTC] (52) also provides insights into what is 12. Dye C, Maher D, Weil D, Espinal M, Raviglione M. Targets for
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Medical Schools in TB control that has been tried in India. ahead of print].
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has an association between the academicians and the epidemiology, diagnosis and management. Indian J Med Res
2005;121:550-67.
public health experts been so fruitful (53-55). This venture
16. Sharma SK, Mohan A. Multidrug-resistant tuberculosis: a
has been tremendously successful in bridging the gap menace that threatens to destabilize tuberculosis control. Chest
between what is practiced and what is preached. 2006;130:261-72.
Though the achievements in the field of TB control are 17. Zignol M, Hosseini MS, Wright A, Weezenbeek CL, Nunn P,
gratifying, the march ahead is long and the end [TB Watt CJ, et al. Global incidence of multidrug-resistant tuber-
elimination] is nowhere in sight. It is time to sustain the all culosis. J Infect Dis 2006;194:479-85. Epub 2006 Jul 12.
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pronged onslaught against this ancient foe. Any let down
control: multidrug-resistant tuberculosis. Bull World Health
in the guard and slackening of the commitment in this battle Organ 2007;85:387-90; discussion 391-4.
is likely to have disastrous consequences and the dreadful 19. Iseman MD. Extensively drug-resistant Mycobacterium
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24. Theis VS, Rhodes JM. Minimizing tuberculosis during anti- 43. Kaufmann SH, Baumann S, Nasser Eddine A. Exploiting
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Oct 16. 44. Doherty TM, Rook G. Progress and hindrances in tuberculosis
25. Pai M, Mohan A, Dheda K, Leung CC, Yew WW, Christopher vaccine development. Lancet 2006;367:947-9.
DJ, et al. Lethal interaction: the colliding epidemics of tobacco 45. Rook GA, Dheda K, Zumla A. Immune responses to tuber-
and tuberculosis. Expert Rev Anti Infect Ther 2007;5:385-91. culosis in developing countries: implications for new vaccines.
26. Lin HH, Ezzati M, Murray M. Tobacco smoke, indoor air Nat Rev Immunol 2005;5:661-7.
pollution and tuberculosis: a systematic review and meta- 46. Pai RK, Pennini ME, Tobian AA, Canaday DH, Boom WH,
analysis. PLoS Med 2007;4:e20. Harding CV. Prolonged toll-like receptor signaling by Myco-
27. Bates MN, Khalakdina A, Pai M, Chang L, Lessa F, Smith KR. bacterium tuberculosis and its 19-kilodalton lipoprotein
Risk of tuberculosis from exposure to tobacco smoke: a inhibits gamma interferon-induced regulation of selected genes
systematic review and meta-analysis. Arch Intern Med in macrophages. Infect Immun 2004;72:6603-14.
2007;167:335-42. 47. Tobian AA, Potter NS, Ramachandra L, Pai RK, Convery M,
28. Steinbrook R. HIV in India – a downsized epidemic. N Engl J Boom WH, et al. Alternate class I MHC antigen processing is
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29. Sharma SK, Kadhiravan T. Sarcoidosis. N Engl J Med 2008; molecular patterns: Mycobacterium tuberculosis 19-kDa
358:1402. lipoprotein, CpG DNA, and lipopolysaccharide. J Immunol
30. Ridderhof JC, van Deun A, Kam KM, Narayanan PR, Aziz 2003;171:1413-22.
MA. Roles of laboratories and laboratory systems in effective 48. Cox RA. A scheme for the analysis of microarray measure-
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the complete genome sequence. Nature 1998;393:537-44. drug-resistant tuberculosis and access to expensive drugs: a
32. Moore DA, Evans CA, Gilman RH, Caviedes L, Coronel J, Vivar rational framework. Bull World Health Organ 2002;80:489-95.
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33. Caws M, Ha DT, Torok E, Campbell J, Thu do DA, Chau TT, [DOTS-Plus treatment] for multi-drug resistant tuberculosis
et al. Evaluation of the MODS culture technique for the patients in Gujarat on the 29th of August 2007. Available at
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the diagnosis of latent tuberculosis infection: areas of 53. Tahir M, Sharma SK, Rohrberg DS, Gupta D, Singh UB, Sinha
uncertainty and recommendations for research. Ann Intern PK. DOTS at a tertiary care center in northern India: successes,
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Allied Sci 2006;48:5-6. centre at a tertiary care teaching hospital: lessons learned and
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History 7
History
2
Alladi Mohan, SK Sharma
INTRODUCTION Holmes referred to the disease as “white plague” (6).

While scores of other diseases like smallpox and plague
As a destroyer of mankind, tuberculosis has no equal...
killed millions of people, their reign has been relatively
VA Moore (1)
short-lived. Tuberculosis has been ever present and is
Tuberculosis [TB] has been a major cause of suffering resurging with a vengeance.
and death since times immemorial. Thought to be one of
the oldest human diseases, the history of TB is at least as TUBERCULOSIS IN ANCIENT TIMES
old as the mankind. Over the years, not only the medical
It is thought that TB probably existed in cattle before its
implications but also the social and economic impact of
advent in man. There have been references to TB in the
TB has been enormous.
Vedas and it was called “rajayakshma”.
There have been references to this ancient scourge in
the Vedas [vide infra] and it was called “rajayakshma” muncami tva havisa jivanayakam
[meaning “wasting disease”]. Hippocrates [460-377 B.C.] agnatayaksmad uta rajayakshma...
called the disease “pthisis”, a Greek word which meant [I deliver you by means of oblation so that you may live from
“to consume”, “to spit” and “to waste away“ (2,3). The the unknown disease and from the “rajayakshma”]
word “consumption” [derived from the Latin word [RV, X,161,1]
“consumere”] has also been used to describe TB in In the Krishna Yajurveda Samhita, there is reference to
English literature. The Hebrew word “schachepheth”
how, Soma [Moon] had been affected by “yakshma”.
[meaning “waste away”] has been used in the Bible. J.L.
Since “Soma”, who was the “King and Ruler” was affec-
Schonlein, Professor of Medicine at Zurich, is credited ted by “yakshma”, it came to be known as “rajayakshma”
to have named the disease “tuberculosis” (1). The word
[Figure 2.1].
“tuberculosis” is a derivative of the Latin word “tuber-
In Sanskrit, the disease has been called “rajaya-
cula” which means “a small lump” (2,4,5). Several names kshma”, “ksayah”, and “sosa”.
have been used to refer to TB in the years gone by. Acute
progressive TB has been referred to as “galloping Rajayakshma ksayah soso rogarad iti cha smritah
naksatranam, dvijanam cha rajno bhud yad aym pura
consumption”. Pulmonary TB has been referred to as
yach cha raja cha yakshma cha rajayakshma tato matah
“tabes pulmonali”. Tuberculosis cervical lymphadenitis
has been called as “scrofula”, “King’s Evil”, “stroma”. [Vagabhata, Ast-s and Ast-hrd, Nidana V, 1-2]
Abdominal TB has been called as “tabes mesenterica”. Krodho yakshma jvaro roga eko ‘rtho dukhasamjnitah
Cutaneous TB has been called “lupus vulgaris”. Vertebral yasmat sa rajnah prag asid rajayakshma tatomatah
TB has been called as “Pott’s disease”. Oliver Wendell [Charaka Samhita, Chikitsasthanam VIII, 11]
8 Tuberculosis
Figure 2.1: Krishna Yajurveda Samhita, II Kanda, III prasna, V anuvaka, 25th stanza, where
the legend of “Soma” being afflicted with “rajayakshma” is described
Changes resembling those caused by TB have been DIAGNOSIS

described in the skeletal remains of neolithic man (7).
Why, when one comes near consumptives... does one
Terms such as “lung cough” and “lung fever” have been
contract their disease, while one does not contract
used in ancient Chinese literature to describe a disease
dropsy, apoplexy, fever, or many other ills?....
which may have been TB (8). There have been references
Aristotle
to what could have been TB in the Code of Hammurabi
of the Babylonian era (6). Evidence of TB lesions of bone In the early days, diagnosis of TB was based on symp-
have also been found in Egyptian mummies dating back toms and signs. In Charaka Samhita [Nidanasthana, VI, 14],
to 3400 B.C. (7). Mycobacterium tuberculosis has been heaviness in the head, coughing, dyspnoea, hoarseness
demonstrated microscopically in the mummy of a child of voice, vomiting of phlegm, spitting of blood, pain in
about five years of age (8). the sides of the chest, grinding pain in the shoulder, fever,
There are several references to conditions resembl- diarrhoea and anorexia have been described as the eleven
ing TB in Greek literature by Homer [800 B.C.], symptoms of TB. Furthermore, a physician who is well
Hippocrates, Aristotle [384-322 B.C.] and Plato [430-347 versed in the aetiology, clinical presentation and premoni-
B.C.], Galen [129-199], Vegetius [420] were also familiar tory symptoms of “consumption” was considered to be a
with consumption. Arabic physicians Al Razi [850-953], “Royal Physician” [Charaka Samhita, Nidanasthana, VI, 17].
Ibn Sina [980-1037] correlated lung cavities with skin The earliest classical descriptions of TB in Greek
ulceration. literature date back to the writings by Hippocrates.
During the middle ages, there are records of healing Aretaeus the Cappodocian [50 B.C.], in his book The causes
touch of monarchs was being used to treat “scrofula” and symptoms of chronic diseases gave a very accurate
[King’s Evil]. King Charles II bestowed the royal touch description of TB and mentioned that fever, sweating,
on an astounding 92 102 patients with “scrofula” (9). By fatigue and lassitude were symptoms of TB. He suggested
around 1629, death certificates in London specified the testing the sputum with fire or water was of diagnostic
disease as “consumption” which was a leading cause of value (7). Galen described that patients with “consump-
death. By this time the contagious nature of TB was tion” manifest cough, sputum, wasting, chest pain and
strongly believed though there were people who fever and considered haemoptysis to be pathognomonic
contested this opinion. The Republic of Lucca is credited of the disease (6).
to have passed the first legislative action aimed at Following the pioneering efforts by Andreas Vesalius
controlling TB in the world (4,9). This was followed by [1514-1564] post-mortem examination was performed
similar measures in several Italian cities and Spain. frequently. This method of study facilitated under-
History 9
standing of pathological findings such as lung cavities, For unknown reason the work of Marten went into
empyema among others. Franciscus de Boe [1614-1672] oblivion for a long time. The likely reason could be that
[also known as Sylvius] for the first time associated small he was thinking very much ahead of his time.
hard nodules discovered in various tissues at autopsy Jean Antoine Villemin [1827-1892] in a series of
with symptoms of “consumption” which the patients experiments provided conclusive evidence that TB was
suffered during their life-time though his explanation indeed a contagious disease though some workers of that
for the same was not correct (7). John Jacob Manget in era did not accept these results. He presented his results
1700 gave the description of classical miliary TB (10). The to the Academie de Medcine on December 5, 1865 and
clinical presentation of consumption was described in stated that TB was a specific infection caused by an
detail by Thomas Willis [1621-1675]. Richard Morton inoculable agent (3,6).
[1637-1698] had described several pathological ”During my wandering through medicine, I encountered
appearances of “pthisis” in his treatise Pthisiologica (4,6,7). sites where gold was lying around.
Meaningful clinical examination became possible It needs a lot of serendipity to distinguish gold from
with the description of the technique of percussion ignobility; this, however, is not a particular achievement.”
by Leopold Auenbrugger [1722-1809]. However, Robert Koch (13)
Auenbrugger’s work was virtually ignored until the time
of Jean Nicolas Covisart [1775-1821] who rediscovered Robert Koch [Figure 2.2], the son of a mining engineer,
and propagated the technique. Gaspard Bayle [1774- was born on December 11, 1843 in Clausthal village in
1816] accurately described many of the pathological the Harz mountains (3,6,14). Koch pursued medical
changes of TB, but unfortunately succumbed to the studies at the Gottingen University in 1862 and qualified
disease which he probably contracted while performing maxima cum laude in 1866 with his M.D. thesis on
autopsy studies (11). The technique of physical exami-
nation of the lung was further refined by the invention
of stethoscope by Rene Theophile Hyacinthe Laennec
[1781-1826] who was a student of Corvisart and a friend
of Bayle. Sadly, Laennec, his younger brother, mother
and two uncles all succumbed to TB (6).
Fracastorius [1443-1553] is credited to have originated
the “germ theory” and believed that TB was contagious.
He also mentioned about antiseptics in his chapter on
the treatment of TB.
In 1720, the English physician Benjamin Marten
conjectured, in his publication A new theory of consump-
tion, that TB could be caused by “certain species of
animalcula or wonderfully minute living creatures”,
which, once they had gained a foothold in the body, could
generate the lesions and symptoms of the disease. He
also stated that
“it may be therefore very likely that by an habitual lying in
the same bed with a consumptive patient, constantly eating
and drinking with him, or by very frequently conversing so
Figure 2.2: Robert Koch: the discoverer of Mycobacterium tuber-
nearly as to draw in part of the breath he emits from the
culosis
lungs, consumption may be caught by a sound person...I Reproduced with permission from: “Rubin SA. Tuberculosis. The
imagine that slightly conversing with consumptive patients captain of all these men of death. Radiol Clin North Am 1995;33:619-
is seldom or never sufficient to catch the disease” (12) 39 (reference 6)”
10 Tuberculosis
succinic acid. On 24th March 1882 Koch announced the He travelled to the Himalayan mountains where he could
discovery of the tubercle bacillus during the monthly pursue his botanical studies while trying to rid himself of
evening meeting of the Berlin Physiological Society. In the disease. He returned home cured and began to study
1884, he published a more comprehensive paper Die medicine. In 1854, he presented his doctoral dissertation
aetiologic der tuberculose in the second volume of the bearing the title, “Tuberculosis is a curable disease”. In
Reports of the Imperial Health Office. In 1905, he was the same year, he built an institution in Gorbersdorf
awarded the Nobel Prize for his contributions in the field where, in the midst of fir trees, and with good nutrition,
of TB research (3,5,6). patients were exposed on their balconies to continuous
It was Robert Koch who finally demystified the secret fresh air. This set up became the blueprint for the
of the cause of TB and after thousands of years, the orga- subsequent development of sanatoria (12). During this
nism finally revealed itself to humans. Though, Robert period, surgery was extensively used for the treatment
Koch was wrong in his belief that tuberculin would cure of TB. The reader is referred to the chapter “Surgery for
TB, tuberculin became an invaluable tool for the pleuropulmonary tuberculosis” [Chapter 55] for the details.
diagnosis of latent TB infection (15). Efforts by Albert Calmette and his assistant Camille
With the advent of Wilhelm Conrad Roentgen [1845- Guérin resulted in the introduction of bacille Calmette-
1923], the technique of radiological imaging became Guérin [BCG] vaccine (16). Pioneering work of Selman
available. Francis Williams in Boston, L. Bouchard and Waksman led to the introduction of streptomycin as an
A. Beclere in France, John MacIntyre and David Lawson effective antituberculosis agent. Jorgen Lehman was
in Britain were pioneers in the use of radiography in the instrumental in the discovery of para-amino salicylic acid
study of TB (3,6). By this time, the deep mystery that [PAS]. With the availability of these drugs and isoniazid,
was TB, became demystified to some extent in that basic the era of modern predictably effective treatment ushered
concepts of the agent, the pathology as a result of it and in. With the availability of rifampicin, the treatment
its detection became established ushering in the era of duration could be further shortened to the present day
definitive diagnosis of TB. six-month short-course chemotherapy.
TUBERCULOSIS IN ARTS AND LITERATURE

TREATMENT
Youth grows pale, and spectre thin, and dies
In the Yajurveda there are references to Soma perform-
John Keats
ing a “yagna” [sacred offering] seeking cure form TB.
Ode to a Nightingale
Since ancient times amulets, invocations, charms, Royal
touch and prayers have been used to treat TB. Chemicals There have been references to TB in several works
such as arsenic, sulphur, calcium, several vegetable, plant of fiction. There are references to TB in William
and animal products including excreta of humans and Shakespeare’s plays such as the “consumptive lover” of
animals, blood letting have been used over the centuries Much Ado About Nothing and “scrofula” in Macbeth.
in the fond hope of curing TB. Robert Koch, soon after Charles Dickens describes the sufferings of Little Blossom
his discovery of the tubercle bacillus, ambitiously in David Copperfield. Thomas Mann’s The Magic Mountain
introduced treatment with “Koch’s lymph” with contains one of the most well-known descriptions of TB
disastrous results. It would later be known that the sanatorium. Little Eva of Harriet Beecher Stowe’s Uncle
substance was a glycerin extract of the tubercle bacillus Tom’s Cabin, Milly Theale in Henry James’ The Wings of
and would be named as “tuberculin” (3,6). the Dove, Marguerite Gautier in Alexander Dumas’ La
During the 19th century, bed rest and change in Dame aux Cameilas also suffered from TB.
environment emerged as important forms of treatment Tuberculosis does not respect anybody. Several
of TB. Hermann Brehmer, Peter Dettweiler, George important personalities, statesmen, writers, poets,
Bodington, Edward Livingstone Trudeau were all performing artists have been consumed by TB [Table 2.1].
pioneers of the sanatorium movement. Hermann John Keats and Percy Bysshe Shelley symbolized the era
Brehmer, a Botany student suffering from TB, was of the “romantic consumptive youths of the 19th century”
instructed by his physician to seek out a healthier climate. (3). The image of John Keats conveyed by the writings of
History 11
Table 2.1: Well known victims of tuberculosis From the contagion of the world’s slow stain
He is secure, and now can never mourn
Mathematician
Srinivasa Ramanujan
A heart grown cold, a head grown gray in vain;
Doctors Nor, when spirit’s self has ceased to burn,
Rene Theophile Hyacinthe Laennec With sparkless ashes load an unlamented urn...
Edward Livingston Trudeau
Writers and Poets The Bronte family included six children all of whom
Alexander Pope succumbed to TB. Maria and Elizabeth died at a very
Samuel Johnson young age. The son died of consumption, alcohol and
Jean-Jacques Rosseau opium. Emily [Wuthering Heights] and Charlotte [Jane
Johann Wolfgang von Goethe
Eyre] died aged 29 and 39 respectively. It was thought
Sir Walter Scott
Percy Bysshe Shelley
that, their father Rev. Patrick Bronte was the source of
John Keats infection. The families of Ralph Waldo Emerson and
Leigh Hunt Henry David Thoreau were also wiped out by consump-
Elizabeth Barret Browning tion (3,6).
Charlotte Bronte Several famous Indians had also succumbed to TB.
Emily Bronte
The list includes the famous mathematician Srinivasa
Anne Bronte
Fyodor Dostoyevsky Ramanujan, writer Munshi Prem Chand, Kamala Nehru,
Robert Louis Stevenson among others.
Anton Chekov
Franz Kafka
HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Katherine Mansfield
George Orwell No account of the history of TB would be complete
Munshi Prem Chand
without a reference to this modern foe. The impact of
Statesmen/Stateswomen
Kamala Nehru
the twin disaster of human immunodeficiency virus
Eleanor Roosevelt [HIV] infection and TB on human suffering has been
Mohammed Ali Jinnah covered in the chapter “Tuberculosis and human immuno-
Nelson Mandela deficiency virus infection” [Chapter 40].
Musicians
Frederic Francois Chopin
Niccolo Paganini INDIA AND TUBERCULOSIS CONTROL
Carl Maria Von Weber
Research carried out in India has had a tremendous impact
Performing Artists
Vivian Leigh on TB and this experience has been of immense value in
Elisa Rachel Felix the control of TB worldwide. The first sanatorium in India
was started in 1906 in Tilaunia, Rajasthan. Subsequently,
contemporaries of his era is that of a fragile poet who other sanatoria were setup in Almora in 1908 and Pendra
fell victim to TB because his sensitive nature had been Road, Central Provinces in Madhya Pradesh, at about the
unable to withstand contact with a crude world (3). In a same time. The first sanatorium outside the patronage of
well known anecdote, when his friend John Brown Christian missionary organizations, called Hardinge
discovers a drop of blood on the sheet while examining Sanatorium was established at Dharampur, near Shimla
him, Keats says: in 1909 with the help of donations from some Mumbai-
based philanthropists, mainly Parsis, under the banner of
“I know the colour of that blood. It’s ‘arterial blood’...
the Consumptives’ Homes Society. The first Government
That blood is my death warrant, I must die ... (3)
run sanatorium [King Edward Sanatorium] was started
Shelley, a fellow poet also suffered from TB pleurisy at Bhowali in Uttaranchal [Figure 2.3]. The Union Mission
but did not succumb to the disease. On hearing the Tuberculosis Sanatorium [UMTS] was established
passing of Keats, Shelley wrote: in Arogyavaram, Madanapalle, Chittoor district,
12 Tuberculosis
Figure 2.3: Sanatorium at Bhowali, Nainital, Uttaranchal state [A,B]. Late Dr Tarachand, originally a physician, who became a famous
thoracic surgeon and his wife Dr Shanti Tarachand [expert in anaesthesiology] are well-known names at this King Edward Sanatorium.
The museum in the sanatorium houses many of the surgically resected gross pathology specimens [C,D,E and F]
Andhra Pradesh in 1915. With the advent of the National

Tuberculosis Programme [NTP] in 1962, the UMTS
sanatorium was converted to a general hospital called the
Aroyavaram Medical Centre [Figure 2.4] which is
continuing to function even today. Till the mid-1950s,
important TB research activity in India was pioneered by
the UMTS (17,18).
India became a member of the International Union
Against Tuberculosis in 1929. From the funds generated
in response to the appeal made on behalf of the
government by the then Vicereine Lady Linithgow, . and
the King George V Thanksgiving [Anti-TB] Fund, The
Tuberculosis Association of India [TAI] was formed in Figure 2.4: The Union Mission Tuberculosis Sanatorium [UMTS],
February, 1939. In 1940 the Tuberculosis Association of at Arogyavaram, Madanapalle, Chittoor district, Andhra Pradesh,
India and Government of India decided to set up jointly that later became the Arogyavaram Medical Centre
the New Delhi Tuberculosis Centre as a model clinic. In
1951, the clinic was upgraded as first TB Training and done in these institutions has contributed significantly
Demonstration Centre in the country. In 1941, the Lady to the understanding of the epidemiology and treatment
Linlithgow sanatorium, was setup at Kasauli (17-20). The of TB in India.
subsequent years saw the establishment of the
Tuberculosis Research Centre, Chennai
Tuberculosis Chemotherapy Centre at Chennai [then
called Madras] and the National Tuberculosis Institute In the early days, TB being a chronic disease required
[NTI] at Bengaluru [then called Bangalore]. The work hospitalization of patients for a prolonged period. As the
History 13
TB burden was enormous it was not possible to

accommodate all needy patients for the treatment. In
October 1955, at the request of the Government of India,
the World Health Organization [WHO] sponsored the
visit to India of three representatives of the British
Medical Research Council [BMRC] to advise on studies
designed to provide information on the mass domiciliary
application of chemotherapy in the treatment of
pulmonary TB. This was particularly relevant as the
number of patients with TB far outnumbered the number
of beds available for their admission at that time. It was
feared that out-patient treatment might prove inadequate
for the treatment of the disease, and that a high
proportion of patients so treated might become chronic Figure 2.5: Tuberculosis Research Centre, Chennai
excretors of drug-resistant organisms and might pose a
serious public health risk if use of domiciliary chemo-
therapy was widespread. With the knowledge then finding that TB patients can be effectively treated as out-
available, it was agreed that it would be premature to patients and continue to live in their homes without
begin mass domiciliary application of chemotherapy, added risk to their family contacts has revolutionized
even in a limited area. It was finally decided, to undertake the whole concept of the management of TB (21). These
a controlled comparative study of the treatment of pioneering studies also form the conceptual basis for the
patients at home and in a sanatorium initially, and to modern day “DOTS”.
follow up the family contacts. Patients were to be
admitted to study from among those routinely diagnosed National Tuberculosis Institute
by the chest clinic service of a large city. In order to
In order to formulate an effective strategy to control TB
implement these decisions, the Tuberculosis
in India, the NTI was established under Directorate
Chemotherapy Centre was established at Madras General of Health Services, Ministry of Health and
[Chennai] in 1956 as a five-year project, under the joint
Family Welfare, Government of India, at Bengaluru
auspices of the Indian Council of Medical Research
[then, called Bangalore] in 1959, and was formally
[ICMR], the Government of Tamil Nadu, the WHO and inaugurated on 16th September 1960 by Pandit
the BMRC. The Centre is housed in two main blocks, in
Jawaharlal Nehru, the first Prime Minister of India (22).
a one-and-a-quarter hectare campus on Spur Tank Road,
The NTI is located in the northern part of the Bengaluru
Chetput, in the heart of Chennai city. The Centre, which near Rajamahal Guttahally on a sprawling field of 23
had an initial lease of life of only five years and had faced
acres of land [Figure 2.6A]. The main central old building
the threat of closure in 1961, has moved from strength to
of oriental architecture called “Avalon”, was a palace
strength and has now firmly established itself as one of belonging the erstwhile Maharaja of Mysore [Figure
the foremost internationally recognized institutions in
2.6B]. The NTI has grown rapidly and has been
TB research. In keeping with the wide sphere of activities
designated as the WHO Collaborating Centre for TB
of the Centre, the ICMR in 1978 renamed the Tuberculosis research and training since June 1985. The NTI plays an
Chemotherapy Centre as the “Tuberculosis Research
important role in organising training activities in TB
Centre”. The Tuberculosis Research Centre [TRC] is now
control for medical and paramedical personnel, in
housed in a new building [Figure 2.5] (21). policies and procedures consistent with the WHO-
recommended DOTS strategy. Other functions of the NTI
The Madras Experiment
include monitoring and supervising TB control
The findings of the “Home-Sanatorium study” programme in the country, to plan, co-ordinate and
conducted by the TRC, Madras [Chennai], have found execute research in TB epidemiology in India. The NTI
their way into several journals and textbooks on TB. The has to its credit several outstanding contributions in the
14 Tuberculosis
Figures 2.6: National Tuberculosis Institute, Bengaluru: A. Entrance. B. Avalon building
Figure 2.7: A brief history of TB

HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; TB = tuberculosis; MDR-TB = multidrug-resistant
tuberculosis; XDR-TB = extensively drug-resistant tuberculosis
History 15
field of TB research, the most recent one being the annual 3. Webb GB. Tuberculosis. New York: Hoeber; 1936.
risk of infection [ARI] study (23). 4. Dubos R, Dubos J. The white plague. Tuberculosis, man and
society. Boston: Little, Brown and Company; 1952.
5. Waksman SA. The conquest of tuberculosis. Berkeley and
Revised National Tuberculosis Control Programme Los Angeles: University of California Press; 1964.
Considered to be one of the most spectacular cost-effective 6. Rubin SA. Tuberculosis. The captain of all these men of death.
Radiol Clin North Am 1995;33:619-39.
health interventions ever conceived, the Revised National
7. Keers RY. Pulmonary tuberculosis. A journey down the
Tuberculosis Control Programme [RNTCP] of the centuries. London: Bailliere-Tindall; 1978.
Government of India, which began in 1997, now covers 8. Zimmerman MR. Pulmonary and osseus tuberculosis in an
the whole country. The RNTCP, has been the fastest Egyptian mummy. Bull NY Acad Med 1979;55:604-8.
expanding programme, and the largest in the world in 9. Evans CC. Historical background. In: Davies PDO, editor.
Clinical tuberculosis. London: Chapman and Hall Medical;
terms of patients initiated on treatment. The reader is
1994.
referred to the chapter “Revised National Tuberculosis 10. Mangett JJ. Sepulchretum sive anatomica practice, vol 1.
Control Programme” [Chapter 63] for details on this topic. Observatio XLVII [3 vols]. London: Cramer and Perachon;
1700.
EPILOGUE 11. Duffin JM. Sick doctors: Bayle and Laennec on their own
pthisis. J Hist Med Allied Sci 1988;43:165-82.
A look at the history of TB [Figure 2.7] reveals that it took
12. Brief history of tuberculosis. Available from URL: http://
several thousands of years for humans to identify the www.umdnj.edu/~ntbcweb/history.htm. Accessed on
causative organism, another 60 years to arrive at effective September 24, 2008.
treatment. Towards the end of the twentieth century, the 13. Kaufmann SHE. Robert Koch, the Nobel Prize, and the
twin disaster of HIV and TB and multidrug-resistant ongoing threat of tuberculosis. N Engl J Med 2005;353:2423-
tuberculosis [MDR-TB] seem to be on the verge of 6.
14. Sakula A. Robert Koch: centenary of the discovery of the
threatening to ruin the mankind. While it is heatedly
tubercle bacillus, 1882. Thorax 1982;37:246-51.
debated that TB is “resurging”, this may hold true for the 15. Daniel TM. Robert Koch and the pathogenesis of tuberculosis.
industrialized countries. But in the third world countries Int J Tuberc Lung Dis 2005;9:1181-2.
like India, TB never seems to have “disappeared” to 16. Calmette A. Tubercle bacillus infection and tuberculosis in
“resurge” later. Tuberculosis has always been with us, only man and animals [translated by Soper WB, Smith GB].
Baltimore: Williams and Wilkins; 1923.
revealing itself every now and then and making us wiser.
17. Leaves from history-12. Anti-tuberculosis movement in India.
Indian J Tuberc 2002;49:132.
ACKNOWLEDGEMENTS 18. Leaves from history-15. The Union Mission Tuberculosis
Sanatorium, Arogyavaram, Madanapalle. Indian J Tuberc
The authors wish to acknowledge the help rendered by Vedic
2003;50:70.
scholars K. Gopala Ghanapatigal, Vedaparayandar, Tirumala
19. Mahadev B, Kumar P. History of tuberculosis control in India.
Tirupati Devasthanams, Tirupati and V. Swaminatha Iyer, J Indian Med Assoc 2003;101:142-3.
Retired Principal, Kendriya Vidyapeetha, Guruvayoor, Kerala 20. The early days. Available from URL: http://
for their invaluable help in tracing the references to TB in the www.tbcindia.org/history.asp. Accessed on October 5, 2008.
Vedas. 21. Tuberculosis Research Centre. Available from URL: http://
www.icmr.nic.in/pinstitute/trc.htm. Accessed on October 5,
REFERENCES 2008.
22. National Tuberculosis Institute. Available from URL: http:/
1. Rosenblatt MB. Pulmonary tuberculosis: evolution of modern /ntiindia.kar.nic.in. Accessed on October 5, 2008.
therapy. Bull NY Acad Med 1973;49:163-96. 23. Chadha VK, Kumar P, Jagannatha PS, Vaidyanathan PS,
2. Flick LF. Development of our knowledge of tuberculosis. Unnikrishnan KP. Average annual risk of tuberculous
Philadelphia: Wickersham; 1925. infection in India. Int J Tuberc Lung Dis 2005;9:116-8.
16 Tuberculosis
Epidemiology
3
AK Chakraborty
INTRODUCTION where in India was carried out by Frimodt-Moller (4) to

study the time dynamics of TB with or without an
For the planning and subsequent review of the strategy
intervention, these were restricted to a small population
for control of any communicable disease, information on
group in south India. It was open to doubt at the time, to
its epidemiological situation and the trend is a virtual
what extent the findings could be extrapolated to the
prerequisite. In a chronic infectious disease like
country as a whole. In the mid 1950s, large-scale TB
tuberculosis [TB], the precise estimate on mortality as
control measures were being contemplated as part of the
well as the prevalence or incidence over long-term needs
five years plans. In the wake of it, it was thought essential
to be obtained in order to study its time trend. Health
to secure additional data, in order to provide the baseline
information systems in developing countries are as yet
information for assessing the effectiveness of the
inadequate to provide meaningful information on the
above. Surveys therefore, need to be conducted, if possi- contemplated antituberculosis measures in course of
ble repeatedly, in order to study the situation, especially time. A nationwide TB prevalence survey was accor-
in time dimension (1). At the same time, it should be dingly conducted in India in 1955-58 (5).
realized that a TB survey is an expensive proposition. It The nationwide sample survey conducted by the
is difficult to set up an organization with the required Indian Council of Medical Research [ICMR] 1955-58 (5)
expertise and discipline and to ensure the availability of had succeeded in providing the basis for planned action
funds to carry out the surveys. The problems could be in India, as was intended. Data generated from the study
compounded many times over in the case of repeat were profitably used by the programme-planners to
surveys, necessary for studying the long-term time trend, decide upon the form and scale of the National Tuber-
as in TB, to be organized in a country of India’s propor- culosis Programme [NTP], which was formulated a few
tion, and socioeconomic diversity. years later both for diagnosis and treatment of TB (6).
Until the early 1950s, the TB problem in India was For example, the relative stress on the planned efforts
estimated on the basis of some isolated surveys towards making the TB services available in the rural
conducted at different times in several areas (2,3). The areas was based on the observed distribution of both the
main conclusion that could be drawn from these studies population and the disease. Further, the overwhelmingly
was that TB was one of the major health problems in the large distribution of the sputum smear-positive cases
country. The limited size of the population studied, and among the adults had a considerable bearing on the
that too among special groups examined in these surveys, development of a simplified symptom-based programme
coupled with the differences in methodology, had made of detecting cases on a national scale. Guided by the
it difficult to compare the results obtained from these epidemiological dimensions and as a part of operational
and make precise observations. Though, a series of research activities, many other studies were carried
surveys in the same community for the first time any- out in the following years to pave the way for the
Epidemiology 17
development of a feasible programme. In the decades During the last four decades or so, when the develop-
following the launching of the NTP in India, it has rather ing countries like India were trying to solve the nitty-
been an intriguing experience to observe the gradually gritties of running the TB programme, global research
ebbing levels of efficiency of the activities under it. It did make considerable headway towards reducing the
became clear that opportunities for meaningful interven- morbidity and mortality from TB, to be achieved through
tion were being insidiously lost in India, principally due effective management of cases. The key to success was
to a low level of programme management coupled with identified to be the ability to obtain a massive cure-rate
a grossly inadequate success rate of standard regimens, of the positive cases. Epidemiologists contend today, that
given under the programme conditions. The shortfall in through the achievement of an effective cure-rate [more
expectations was attributed to the fact that the health than 85 per cent for sputum smear-positive cases], the
care system could not afford the resources, both for the problem could be drastically reduced in a foreseeable
technology [diagnostic and treatment services] as well future (10). For an example, it is stated that an annual
as for the running of a sensitive and effective manage- decline in the newly occurring TB infection to the extent
ment system required to ensure an adequate logistics of 14 per cent could halve the problem in five years. In
support for the countrywide NTP. There was an all round contrast, an annual decrease of one to two per cent could
realization on this as articulated by Pio (7), perhaps the achieve the same in about a century.
most serious source of uncertainty is the possibility that
Indian government with assistance from the World
there has been an overestimate of what can be achieved
Bank and the WHO (11), in early nineties evaluated
by the basic TB programme. In fact, there was no detailed
performance of the NTP and decided to start a Revised
information on how great a reduction in the problem can
National Tuberculosis Control Programme [RNTCP]. The
be obtained through the basic control programme in
programme was introduced in a phased manner and now
developing countries (7). As a result of this continued
covers the entire country (12,13).
shortfall in cure-rate over the years, the TB situation in
In this chapter, the data on TB in India are reviewed
India was interpreted to be showing signs of an ‘epidemic
keeping in view the special areas requiring to be addres-
of left-overs’, i.e., partially treated cases with extended
sed while planning, as also to suit needs of evaluation
life-span increasing the problem in terms of prevalence
processes. It needs to be recalled that the load of infection
of disease, even though a reduction in incidence of cases
or in transmission of infection was the expectation (1,8). and disease in the community, in its various forms and
This situation had developed over the last few decades presentations, happens to be the result of some complex
prior to the nineties in India, notwithstanding the World epidemiological processes at play. A short review of this
Health Organization [WHO] observing in a 1974 background is followed by analysis of the Indian situa-
document, ‘An effective national TB programme can be tion. Related information from the western epidemiolo-
delivered under any situation, provided planning and gical scenario are also presented in appropriate context,
application are guided by a clear understanding of the wherever necessary, in order to help appreciate the
epidemiological, technical, operational, economic and social underlying principles and the concept.
aspects’ (9). The dynamics as outlined by Grzybowski (1) The following aspects of the Indian situation are
need to be viewed in the light of relative uncertainty and discussed: [i] the course of progress from infection to
lack of unanimity among the intervention planners (8,9), disease in individuals as well as the community – the
regarding the possible role of intervention dynamics in background behind the epidemiological concept of
altering the course of epidemiology of TB in these disease accumulation in the community; [ii] prevalence
countries. The dominant issue with the epidemiologists and incidence of TB infection as well as sputum smear-
has for long been the challenge of observing a change positive and -negative pulmonary TB, by age and sex in
following intervention in such situations. The foregoing India; [iii] prevalence of TB infection and disease by
has in fact been the essence of epidemiological situation socioeconomic status of population; [iv] time-trend and
and the human efforts to come to terms with it in the epidemiology of intervention in India, including predic-
developing countries, especially in those with large tion through modelling; and [v] risk factors impinging
population sizes, as in India and China. on the trend.
18 Tuberculosis
INFECTION AND ITS PROGRESS IN INDIVIDUALS stasis has already set in at the site of entry [primary site],
AND COMMUNITY: THE BACKGROUND BEHIND leading to stoppage of bacillary growth at that site. Even
EPIDEMIOLOGICAL LOAD as their growth stops at the site of the primary infection,
the bacilli, however, still continue to multiply in the
The epidemiology of TB in a community is the resultant
primary free lobe of the lungs, and at other sites [Figure
of the interplay between the environmental conditions,
3.2] probably because of local macrophage activation.
socioeconomic state of the population, the host factors
Approximately, a period of 70 days or so is needed for
and the agent characteristics. The course of the events
the bacilli to get reduced to significant numbers at the
following infection as observed in a susceptible animal
primary site, followed by a similar phenomenon at the
host is recalled here, before studying the course in human
other sites. Through the CMI-activation, the site of entry
beings, followed by that in the community at large.
is sterilized. However, the bacilli are still capable of
surviving in low numbers at the apical and sub-apical
Experience from Animal Models of
regions.
Pulmonary Tuberculosis
Thus, it could be observed during the course of these
In a susceptible host, following infection, the tubercle events that the host factor has a decisive role in limiting
bacilli grow unhindered and exponentially at the site of the effect of infection, on its own. It is postulated that
entry [the lung], till three weeks or so [Figure 3.1] (14). subsequent development of the pulmonary TB [post-
The growth then ceases and this event is near synchro- primary TB] could be the result of suppression of the
nous with the development of tuberculin positivity in CMI and consequent reactivation of the dormant bacilli
the animal. Simultaneously with this, the phase of harboured in the apical and sub-apical regions [endo-
bacillaemia ensues and the bacilli can be recovered from genous reactivation pathway]. Alternatively, it could also
the other lobes of the lung and extra-pulmonary sites be conceived to be due to infection by the bacilli afresh,
such as spleen also. In the immediate post-primary phase, and in an overwhelming dose, enough to override the
bacillaemia results in bacillary implantation in the apical CMI-barrier [exogenous reinfection pathway]. The latter
and sub-apical regions of the lungs. It is presumed that is considered to be a strong possibility, especially in areas
the dissemination takes place approximately at the time with a high risk of infection transmission. However, what
cell mediated immunity [CMI] supervenes and bacterio- strikes one as remarkable in the entire process of primary
Figure 3.2: Change with time in the number [log10] of Mycobacterium

Figure 3.1: Number of Mycobacterium tuberculosis recovered from tuberculosis recovered from excised primary lung lesions and from
the lungs in guinea pigs killed between 3 and 35 days after infection lung lobes without primary lesions in guinea pigs killed 16, 22, 30,
via the respiratory route 41 or 56 days after challenge via the respiratory route
Reproduced with permission from “Smith DW, Weigeshaus EH. Reproduced with permission from “Smith DW, Weigeshaus EH.
What animal models can teach us about the pathogenesis of What animal models can teach us about the pathogenesis of
tuberculosis in humans. Rev Infect Dis 1989;11[Suppl2]:S385-93 tuberculosis in humans. Rev Infect Dis 1989;11[Suppl2]:S385-93
(reference 14)” (reference 14)”
Epidemiology 19
and post-primary phases of host-agent interaction clinical horizon, never manifesting disease. Even when
appears to be the dominant host reaction in the large clinical forms develop and the line showing the course
majority of cases, so as to prevent TB infection manifest- of clinical events is traced to be crossing the ‘Clinical
ing as a clinical form of TB disease in the susceptible host. Horizon’, the dominant host factor supervenes and there
is at all times, an overriding possibility of self-cure. This
Progress of Infection into Clinical Tuberculosis has been observed even in pulmonary TB, as its natural
dynamics, both during the pre-chemothera-peutic days,
The course of development of clinical TB in an infected
as also during the longitudinal surveys carried out by
human being, during the entire period following the National Tuberculosis Institute [NTI], Bengaluru,
infection is shown in Figure 3.3 (15). Primary infection is [earlier called Bangalore] (15).
mostly a silent event and so could be many of the events The self-limiting predilection for the curve of disease
taking place in the immediate post-primary phase. These development in the course of its natural dynamics, as
go unrecognized. Only when symptoms develop, that a observed both in animal models as also in human hosts,
person is subjected to diagnostic testing. Most of the finds an almost synonymous replay in the epidemic
clinical forms tend to be cured in a natural course of curve of TB in the community as well.
events, and the affected individuals may become asymp-
tomatic without treatment. The hypothetical dividing The Course of Tuberculosis Epidemic
line, drawn in Figure 3.3, separates the recognizable A hypothetical epidemic curve of TB (15), adapted from
clinical forms of TB from the silent ones, and could be Grigg (16) is depicted in Figure 3.4. The epidemic curve
called as the ‘Clinical Horizon’ (15). It could be observed is essentially, the same as for any other infectious disease,
that most of the infected persons remain below the with an ascending limb, the peak or transitional phase, a
Figure 3.3: Natural history of tuberculosis

Reproduced with permission from “Gothi GD. Natural history of tuberculosis. Indian J Tuberc 1977;25[suppl]:1-12 (reference 15)”
20 Tuberculosis
Figure 3.4: Secular curve of epidemics

Adapted from references 15,16
descending limb and a steady endemic phase. The whole

epidemic would last several centuries, instead of a few Figure 3.5: Development of the wave of tuberculosis epidemic
weeks or days, as in the case of other epidemics. The through time as described by Grigg (reference 16). The tuberculosis
epidemic curve develops through centuries. The essential proximity
ascending limb is characterized by proximity between
of infection, disease and mortality curves characterises the phase
the rates of infection, disease and deaths, the gap between of spread [shown with arrow ‘a”]. Wide gaps between one and the
them widening as the epidemic would progress. The other rate develop at the peak and descending limb [shown with
ascending limb is steeper than the descending one. The arrow ‘b’]. In India, gaps similar to the latter, exist now
former is characterized by higher rate of disease and Reproduced with permission from “Chakraborty AK. Tuberculosis
situation in India: measuring it through time. Indian J Tuberc
death in the underprivileged and in those who are
1993;40:215-25 (reference 17)”
relatively more susceptible, e.g., the females and young
ones. The epidemic curve in the urban areas could be
uniform, even within a given nation or a community.
faster to develop, with higher rates than in the rural,
This factor of course finds an expression in Grigg’s model
because of higher transmission of infection taking place
(16) for urban and rural curves following different
due to factors related to relatively more intercourse of courses. Because of this disparity and variable attributes
population and destabilization of population groups. As of socio-economic nature within nations, it may not be
the epidemic would develop in time, the urban rate possible to develop an epidemic curve for the whole
would start declining, even when the rural rate is going nation, especially with those with large population sizes,
up, causing a crossover. As the epidemic curve would as the disease behaviour in groups within it may not after
be ageing, the relative peaks in respect of the mortality all be uniform. It is argued that whilst it may be
rates, disease and infection rates would be attained one appropriate to conceive of TB epidemic curves for the
by one, followed by decline; starting with the mortality industrialized nations, it may not be so for the others. In
rate—the earliest to reach the peak and start declining the latter, the transition from one to the other limb of the
[Figure 3.5]. Based on the above relative behaviour curve may not, after all, be uni-directional, as envisaged.
pattern of indices within the hypothesis of the epidemic Progress could also be followed by “counter-transition”
curve, epidemiologists would conveniently draw in the epidemic, in case there is a lack of sustained
conclusions on the age of the epidemic in a given direction of socio-economic transition over a long period
community (2,16,17). of time, say over centuries. In the case of a long sustained
It is, however, argued that the benefit of progress in phase of economic reversal, as happening in some of the
the socio-economic sector, which has often been ascribed sub-Saharan countries, there could even be several
to be the factor principally guiding the course of the epidemic curves superimposed on one another.
epidemic, even without active intervention, has been Moreover, superimposition by other variables such as
very unequally distributed both between and within HIV infection which is operational in these parts of the
nations (18). As a result, the epidemic curve may not be world is sure to influence the course of the curve.
Epidemiology 21
Grigg’s model (16) of course provides for small priate to consider only the excess mortality among the
reversals of trends following the situations of depriva- cases of TB for the purpose as per analysis carried out by
tions triggered by war and pestilences, as seen in Europe Chakraborty et al (20). The latter excludes the possible
during the world war years. Past these temporary occurrence of deaths due to natural causes in TB patients
aberrations, the course of the natural trend is resumed. and gives figures of only the deaths attributable to TB
Grigg (16) terms the former as “cyclic” and the long-term disease in the community.
one, as secure from temporary fluctuations, as the In the RNTCP of the Government of India, deaths
“secular curve”. Of course it is possible to envisage rapid reported among registered TB cases are considered to be
socio-economic changes as in Japan, hastening the due to TB unless specified otherwise.
epidemic transitions in time rather drastically. In such
an instance, the progress of the epidemic curve could Prevalence and Incidence of Infection
also be squeezed in time, one phase dovetailing into the Prevalence of infection refers to the number of persons
other in rather rapid succession [accelerated model] (18).
infected with tubercle bacilli at a given point in time,
However, in such a contingency, the decline could no
based on information obtained on tuberculin testing of
longer be as steep, after a time, as seen in the classical the population. Incidence of infection refers to the
European model.
number of persons infected between two successive
It is pertinent to emphasize here the fact that even
points in time among those not infected or, bacille
within the group of industrialized countries, the Calmette-Guérin [BCG] vaccinated initially. The figures
epidemic curves could be of different ages, for example
on incidence are obtained exclusively through commu-
the decline in England and Wales appeared to have
nity surveys, covering the same population repeatedly.
accelerated 10 years later [1950 onwards] than in the
Netherlands (19). Even within an industrialized country, Prevalence of Disease
the trend among the outside born group was different
than in those indigenously born. Prevalence of disease refers to number of persons
For the purpose of the following the epidemiological diseased at a given point in time in the community and
trend in a community over a long time dimension, the is usually arrived at through a survey.
hypothesis put forward by Grigg (16) is generally found
convenient. However, it is conceded that for countries Incidence of Disease
like India, China, etc., because of the large masses of Incidence of disease refers to the occurrence of disease
people with socio-economic disparity within them, a between two successive points in time in the community
single epidemic curve of TB for the country as a whole among those not initially affected. The information is
may be too much of simplification for a hypothesis. derived through repeat surveys examining the same
persons in the community.
INDICES USED AND DEFINITIONS Prevalence and incidence of disease are considered
Tuberculosis situation in an area is conveniently in terms of culture-positive cases with or without smear
measured in terms of death, prevalence and incidence positivity [C+], smear-positive cases [SS+] or, X-ray
of infection and disease. positive, culture/smear-negative cases [X+]. Sputum
smear-positive TB patients diagnosed under the RNTCP
Definitions Used in India are registered as ‘newly diagnosed’ SS+ cases.
These are reported every year along with the new sputum
Death
smear-negative cases with pulmonary TB. It is
Death among the known cases of TB, has been described inappropriate to consider the new SS+ cases diagnosed
as case fatality; or that attributable to TB, among total in the programme, to be equivalent to incident cases as
population in the community, mortality. The term synonymous with the incidence observed in epidemio-
‘mortality’ could be considered in terms of deaths among logical surveys. Under the programme set up, these cases
total cases of TB in a given community as indicated by could be a mix of newly arising SS+ cases during the
Frimodt-Moller (4) in India. It is, however, more appro- course of the preceding year, along with the part of the
22 Tuberculosis
prevalence of the past year[s]. Clarity in understanding of infection to be a sensitive indicator (2). In fact,
the above is required to construct the picture of incidence of infection as studied among the unvaccinated
epidemiology of intervention. subjects in younger age groups representing the “force of
infection”, is the appropriate index to measure the TB
Concepts Regarding the Use of the Indices situation in a community. However, estimating incidence
would call for repeat testing of the same children.
Death
To avoid repeat tuberculin testing of the same
Death from TB is the most severe ‘fate’. Occurrence of children, as necessary to observe the incidence of
death is the first of the indices to decline in the secular infection, a mathematical estimation is carried out, using
curve of a TB epidemic, followed by morbidity and the figures on the prevalence of infection, in younger ages
infection in that order (16). Subsequently, however, it is [say, in the 0 to 14 years old children] to obtain the
not much informative to trace the course of the epidemic incidence of infection. The latter is termed the annual
and to classify countries on the basis of their progress in risk of infection [ARI] (25). The ARI, which in the present
the epidemiological situation. For example, TB death toll times is increasingly being referred to as annual risk of
in several European metropolitan areas was nearly one TB infection, designed through the work of Styblo (26)
per cent annually, at the height of the epidemic. It had and others in the Netherlands, is an innovative index. It
reduced in course of the centuries long epidemic process, is defined by them as “the proportion of the population
to be one to two per 100 000 population by the end of which will be primarily infected or reinfected [in those
1980s, that is a 500 to 1000 fold reduction (21). Presently, who have been previously infected] with tubercle bacilli
most TB deaths among the indigenous Europeans would in the course of one year, and usually expressed as a
occur in persons above the age of 65 years. To record “percentage” or as a “rate” (26). The ARI is calculated
significant change at that level among the indigenous through the simple formula derived on the basis of the
general population group may not be practical. Thus, above work (27):
even though death ceases to be significant epidemio- R = 1 – (1 – P)1/A
logical information for the advanced countries, it could Where R = ARI;
still possibly be a measure of the extent of success of the A = average age studied;
antituberculosis programme delivery and its manage- P = prevalence of infection.
ment, in case of the developing countries. For example,
The estimated ARI is actually demonstrated to be the
it is reported that nearly 70 per cent of possible deaths same as the incidence of infection, worked out by repeat
between 1991 and 2000 in Peru (22), and nearly 46 per
testing of the same population under Indian conditions
cent in China between 1991 and 1997 (23), were averted
(28), being the only experimental evidence in this regard
among sputum smear-positive cases of TB, through a anywhere in the world.
heightened programme delivery. As an immediate and
It is understood that ARI is studied among the
the most visible effect of antituberculosis intervention,
unvaccinated subjects only (25). However, in situations
prevention of death appears without doubt, to be an where mass BCG vaccination at birth or soon after is the
attractive index to the programme planners. For the
national policy, it is not a convenient study subject to
purpose of this chapter, however, death is not included
have, as most of the children will already be vaccinated.
as an index to classify the countries in their progress The alternative could be to study the incidence of
towards “elimination” goal, in pursuance of the
infection in the vaccinated, on the lines as carried out
hypothesis of Styblo (24).
originally by Raj Narain, for identifying the newly
infected subjects by the differences of reactions method
Prevalence and Incidence
(29). Chadha et al (30) in a recent study have shown the
Infection Prevalence of infection in the Indian context infection estimates in the vaccinated and unvaccinated
cannot be estimated accurately in those aged 14 years as not materially different. The same does not stand
and above. Failure to demarcate the infected from the corroborated from other sources in India [Regional
non-infected due to high prevalence of intermediate Medical Research Centre, Port Blair 2002, personal
reactors in India in higher ages, does not allow prevalence communication].
Epidemiology 23
While on the topic, it should be noted that for Nicobar and Tamil Nadu (2). The Tuberculosis Research
developing the information base on infection, both for Centre in Chennai [TRC] has recently brought out a
prevalence and incidence, periodic community surveys comprehensive report on the disease situation in the area
have necessarily to be carried out and these serve as the 1968 to 1986, along with that from a subset for the area
only data source. This is so even for the industrially till 1996 (35), as a follow up to their original report (36).
developed countries. The isolated tribal community in Car Nicobar is also
further followed up in 2002 (37), following the first two
Disease Whereas in most of the western European surveys in 1986 and 1988.
countries and others in the industrially advanced world, Of the repeat surveys, mentioned above, Delhi and
the data on disease and death are obtained mainly from Madanapalle had efficient treatment services for TB,
national statistical reports, provided by the Ministry of provided in the study areas. The last two, namely Car
Health and National TB Organization (16,21,22,31-34), Nicobar and Chingleput areas in Tamil Nadu, also had
no such data are available for vast population groups provision for treatment for every identified case, through
elsewhere, e.g., in India and China. Tuberculosis, for the NTP operating with its given efficiency. The
example, is not considered to be a notifiable disease in Bengaluru area survey, on the other hand, was planned
India and hence routine health data have not served as to study the natural dynamics, without a programme in
the source of information for estimating the disease state the area for the initial period of five years. It was intended
in the community. Periodic community surveys, sporadic to study the baseline problem making it possible to assess
and in different areas, dependent solely on an intervention effects with the programme introduced at a
investigator’s convenience, are therefore relied upon, and later date.
extrapolated to observe and assess the TB disease At the time these surveys were originally planned, it
situation in India (2,17). had appeared logical to expect TB case prevalence rate
In the present chapter, estimates of the burden of to be reduced over a period of time, following inter-
infectious TB in India, were computed depending largely vention. However, it is now understood, both as a
on the information obtained from community surveys consequence of the above quoted Indian studies, as also
carried out from time to time, beginning with the first from the earlier and path breaking study from Kolin,
ICMR survey (5). Additionally, the WHO global reports Czechoslovakia, that prevalence and incidence of cases
on programme monitoring, and some recent Indian are not affected over relatively short periods of time,
monitoring reports (12,13) have also been used. unless of course very intensive and effective treatment
It should be understood in this context that a of sputum smear-positive cases is carried out (26). This
nationally representative statement on the magnitude of is especially true for the countries with a high infection
the TB situation in India and its direct measurement of transmission. Moreover, small rates of change neither in
change in time, with or without intervention, are beyond the case prevalence rates, nor in incidence, which are
the scope of observational studies. Several essential already small, could be appreciated in sample sizes, not
variables, identifiable or otherwise, seem to be affecting specifically decided upon to be sensitive to register very
the trend, differently, from area to area. Only very small changes in them (17).
complicated stratification procedures could probably Prevalence of real sputum smear-positive cases is
satisfy the sampling needs of a representative national likely to be a good epidemiological index, when the inter-
sample survey, which could be highly impossible (17). vention measure is either very effective [close to 100%]
However, average rates could be worked out for the or when there is no treatment at all (26). It is understood
that inefficient treatment services would only multiply
country; with best and the worst possible case scenario
the prevalence of smear-positive cases, due to pooling
as attempted in this chapter.
of inadequately converted cases [vide infra, under Car
Nicobar experience] (37).
Data Source and Indices Used for Observing Trend
The incident cases, on the other hand, occur as a result
Information on disease trend is available from repeat TB of breakdown from among those previously infected
surveys carried out 1961 onwards, in various areas decades back, as could be seen in Figure 3.3. The
namely, Delhi [urban], Madanapalle, Bengaluru, Car incidence rates are therefore constant year to year,
24 Tuberculosis
representing the ageing and progress of the infected vention-efficiency in a given area, could give a trend,
cohort of previous decades, with time. In any case, the following intervention. In the Netherlands, Styblo (24)
incident cases would represent the transmission taking estimated that of the 14 per cent annual decline that was
place in the community decades ago and would represent observed, nine per cent was due to the intervention
the risk over a long period of time among cohorts of those measures that were instituted while the remaining five
infected in the past years, at varying yearly infection per cent represented the process of natural decline. On
rates. The subsequent breakdown into cases may not, the same lines, in developing countries, the zero to two
thus, necessarily represent the instant TB risk to the per cent natural decline should be augmented by another
community. Also, incidence rates of cases are not expec- five to ten per cent decline achieved by the TB control
ted to undergo any change following the best of interven- measures for these measures to be cost-effective.
tions, in a comparatively short period of three to four As distinct from the prevalence and incidence of
years, given the long span of the TB epidemic. As against cases, ARI represents the direct and a near immediate
incidence of disease, prevalence represents a pool of “left- consequence of the presence of bacteriological case load
overs”, carried over time, reflecting a failure of the TB in the community [force of infection]. It has presently been
control measures. It should be noted that both the indices recognized to reflect the current epidemiological situation
are observed in older age groups in the population. in an area, in preference to the disease rates (25). It is
As it is to be presently discussed, the incidence also possible to calculate the TB trend in an area from
prevalence ratio in India is about 1:3. In case an efficient the current ARI, with hypothetical rates of exponential
TB control programme, targeting a sufficient number of decline. Table 3.1, gives an estimate of the ARI for an
sputum smear-positive prevalent cases in the community area five years ago, based on currently observed ARI
is run for a sufficiently long period of time, it could bring [between prevalence of infection ranging from seven and
down the case prevalence, till probably the point when ten, i.e., rates likely for Indian areas], calculated for three
incidence and prevalence come to be in the same possible levels of exponential decline as calculated by
proportions in the community [1:1]. Styblo et al (25).
From studies by Styblo and his group (25) in the It is possible to work out appropriate sample size of
Netherlands, it is now understood that incidence of population with the hypothesis of decline given above,
infection in the younger age group can really be the index to measure likely change in India or elsewhere in the
representing the current transmission situation. A series developing world, making allowance for the Design
of TB infection surveys, carried out at intervals of seven Factor [say between 2 and 3], confidence intervals [CI]
to ten years, depending on and related to the inter- of the proportions in the population studied [95%], years
Table 3.1: Annual percentage decline in ARI among children aged 5.5 years by
some selected initial prevalence rates of infection in them
Initial prevalence rates
of infection [%] * Approximate percentage decrease in ARI each year†
Risk this Risk 5 years Risk this Risk 5 years Risk this Risk 5
year ago Year ago year years ago
7.0 1.206 1.400 1.140 1.461 1.076 1.523
7.5 1.295 1.503 1.224 1.569 1.155 1.636
8.0 1.385 1.607 1.308 1.677 1.235 1.748
9.0 1.565 1.816 1.479 1.895 1.396 1.975
10.0 1.747 2.026 1.651 2.114 1.558 2.204
ARI = annual risk of infection

* Only some selected prevalence rates as are likely to be encountered for Indian areas at the given age are shown
† Percentage decline hypothetically selected to be at 3%, 5% or 7% only, to be close to Indian reality
The reader is referred to reference 25 for other alternative selections of prevalence and change in ARI
Source: reference 25
Epidemiology 25
intervening the surveys [say 7 to 10 years], relative synonymously (40). True “eradication” is ideally taken to
proportions of annual change designed to be appreciated represent a situation for the mankind, where the micro-
[say, upwards of 50% in 7 years] and relative precision organisms are totally eliminated from the nature, e.g.,
of the estimates (2,17). Given the proportion of the BCG smallpox. To call a disease state to be “eliminated”, on the
vaccinated children in India, this is also a variable to be other hand, there has to be a defined situation of the
considered in deciding the sample size. disease, falling short of total eradication of the microbes
A word of caution on following epidemiological trend in nature. However, these need to be universally and
through repeat surveys including infection surveys may globally available situations to qualify for the status of
not be out of the place here. In order to follow the inter- “elimination”. In other words, “elimination”, in the
vention-effects over a long time, large-scale ARI surveys manner the term “eradication” is used, represents a global
need to be organized in a valid sample of unvaccinated state of the disease. Intermediate states could on the other
children, from time to time. In view of the widespread hand, be visualized [“close to elimination” or “virtual
use of BCG vaccination in India, and the usual complexi- elimination”] under which, the existing situations could
ties in carrying out community surveys, gathering of such be expressed. Tuberculosis could in this context be defined
exclusive data and their appropriate interpretation at as “eliminated” either in parts of the world, or, in terms of
repeated intervals, for a country of India’s proportion [i] cut in transmission, e.g., in yaws; or, [ii] manifestation
could be a difficult proposition. Moreover, estimating the of disease to prevent it from becoming one of public health
disease incidence and prevalence from ARI is an exercise importance, when judged against arbitrary levels of
in modelling (38). The recommended rule of the thumb disease control and prevention, e.g., leprosy, TB, etc. In
is not an universally corroborated observation (2,36,39). the case of TB, depending on the current epidemiological
Whereas the figures on incidence of cases obtained on situation and trends in countries of the world, they could
conversion from ARI data could be of use in planning be seen to be on their respective paths and levels towards
for resources, its reliability in measurement of changes TB control and elimination. Whereas the required
could be open to question. specifications for qualification for intermediate levels of
Notification data on disease were considered reliable elimination have been respectively defined for a few of
when provided by programmes with an established the developed countries, as in the USA (41), these remain
surveillance system (21,34). In most developing nations undefined in the case of most countries.
it is unreliable to interpret it as community prevalence. In line with the hypothesis made by Frost (42) way
Huge costs involved in obtaining incidence rates by back in 1940, the countries of the world seem to
conducting population surveys could be avoided if the conveniently align themselves in two broad groups,
routine data could be interpreted after necessary namely, those in whom the “tubercle bacillus is losing
adjustments. However, for information derived from ground”, so that a given number of sputum smear-
monitoring data to transcend itself from mere indicators positive transmitters “do not succeed in establishing an
of programme efficiency at their best, as at the present equivalent number to carry on the succession”, and the
times, into indices of trend measurement, would require others, in whom “no such prospect is in sight” in the
considerable efforts in this direction. conceivable future. It is not a mere coincidence that the
above alignment happens to be across the socio-economic
SETTING THE GOAL OF INTERVENTION IN INDIA: divide, between the highly industrialized nations of the
THE EPIDEMIOLOGICAL CONTEXT world and the so-called developing nations. It is also
The concept involved in setting the final “goal” of relevant to take into account an additional dimension of
antituberculosis activity requires to be understood in the the problem; i.e., the huge population size in the latter,
context of the tasks to be set and performed under it. in absolute numbers, as well as in its escalation with time.
Whereas, it is theoretically possible to “eliminate” a Apart form the above two groups, there are of course
disease in humans, while the microorganisms remain at others, in whom the TB situation may not be at either
large, as could be envisaged in the case of some of the extremes of the divide.
infectious diseases, e.g., neonatal tetanus, the terms Following this broad posturing, countries of the world
“eradication” and “elimination” need not be used could be grouped in four major categories, as shown in
26 Tuberculosis
Table 3.2 (2,24,43). In arriving at the pragmatic definition Table 3.3: Suggested definition of goal
of “goal” to be pursued by countries of the world (2),
Eradication
data on incidence of sputum smear-positive cases on
“goal” to be pursued by the countries of the world, and
prevalence of TB infection, likely to be attained by 2050, Elimination
among the countries with the most favourable TB
situation are used [Table 3.3].
While the term “control” is used by policy makers Virtually identical with elimination
Incidence of smear-positive cases:
and programme managers in designating the long- term below 1 per 10 million population
objective of the programme [RNTCP] in India, it should [Prevalence of infection in
be understood that the parameters of “control” remain general population 0.1%]
yet to be defined. This is for understandable reasons, in
the context of the developing countries, where the specific
Close to elimination
‘goals’ of TB control programme, as shown in Table 3.3
Incidence of smear-positive cases:
are rather distant and remote, say in the case of India, as 1 per million population
compared to a Group I country, say the Netherlands [Prevalence of infection below 1%]
[highlighted in Table 3.4]. Even then, it should be
Source: references 2,24
understood that the ‘goals’ of human endeavour, in its Adapted and reproduced with permission from “Chakraborty AK.
fight against TB , are for the first time defined in concrete Epidemiology of tuberculosis: Current Status in India. Indian J
terms [Table 3.3]. These are based on epidemiological Med Res 2004;120:248-75 (reference 3)”
situations, attained through the best possible of human
efforts, anywhere in the world. Table 3.3 defines the eradication means “extinction of all bacillary sources of
stages that the countries could possibly pass through in TB transmission, in all the countries of the world, in an
their journey towards attainment of the final ‘goal’, i.e., irreversible manner”. In comparison, elimination is
“virtual elimination”. Table 3.5 provides the likely time- defined as a situation under which “virtual elimination”
table for the journey. is attained in all countries of the world. Though Frost
It is necessary to understand the terms “eradication” (42) had talked of an eventual “eradication”, the “goal”
and “elimination” in their proper perspective. The term of antituberculosis efforts could obviously be less opti-
mistic as seen from the preceding. Instead of “eradica-
Table 3.2: Global tuberculosis situation
[grouping of countries] tion” and “elimination”, as used interchangeably, even
by Styblo, inspite of reservations expressed by himself
ARI Annual decline Group
on this score (24), the present chapter considers “eradica-
[%] [%]
tion” and “elimination” to be outside the purview of
0.1 to 0.01 > 10 Group I human endeavour.
Industrialized Countries
Long-term epidemiological trend in TB, unaffected
[e.g., Netherlands, Norway]
0.5 to 1.5 5 to 10 Group II by and secured against short-term spikes or dips through
Middle income countries transitory influences, is termed as “secular trend”. In
[e.g., Latin America, West respect of the ARI (9), there is an exponential decline in
and North Africa] the case of countries with the best possible case scenario,
1 to 2.5 3 to 5 Group III say the Netherlands [decline up to about 14 per cent
Middle income countries
[e.g., East and South-East
annually: some five per cent of it natural and the rest
Asia] attributed to antituberculosis measures in specific]. For
1 to 2.5 0 to 3 Group IV the worst case scenario, on the other hand, there could
[e.g., sub-Saharan Africa be situations varying between a rise [Afghanistan] to a
and Indian sub-continent] position of minimal decline of between 1 and 1.4 per cent
ARI = Annual risk of infection annually [Lesotho] (9,27,32). The problem is likely to be
Source: references 2,24 halved in five years in countries with the best possible
Epidemiology 27
Table 3.4: Task in front of Group IV countries set against Group I, for pursuing close to elimination status
Country Epidemiological situation
Present Qualification for ‘close to elimination’ status
Incidence of smear- Prevalence of Incidence of smear Prevalence of

positive cases infection all ages positive cases infection all ages
per million/year [%] per million/year [%]
Most Advanced* 12-15 15 1.0 1.0

India 500† [850‡] 40
China 515‡
* Annual risk of infection 0.1% to 0.01%, annual decline 10%, ‘close to elimination’ status projected to be achieved
by the year 2025 [e.g., Norway, The Netherlands] (Source: references 17,43)
† Source: reference 39
‡ Source: reference 32
Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in
India. Indian J Med Res 2004;120:248-75 (reference 3)”
Table 3.5: Global situation-time frame of achievement (24). For the Group IV countries on the other hand, this
[best possible] could mean requiring the present incidence of sputum
smear-positive cases of about 510 per million, as say in
Group I
[e.g., The Netherlands] China (23), or 840 per million for India (32), to be brought
Prevalence of infection Time down to one to two per million by that date (24) [Table
3.4].
15% Present
Against this epidemiological scenario with respect to
[Incidence of smear-positive cases: 12-15 per million]
the Group IV countries, Canetti’s statement on priority
as quoted by Styblo (10), merits recalling, “on the global
9% [2000] level, and among the efforts required to make headway
towards TB ‘eradication’, an absolute priority stands out
imperatively: to develop chemotherapeutic methods,
1% [2025]
adapted to the conditions prevailing in “underdeveloped
[Incidence of smear-positive cases: < 1 per million]
countries” (10). Following up, Styblo (10) had highlighted
the challenge before the policy makers, “unless a massive
0.1% [2050] increase in the cure rate for sputum smear-positive
pulmonary TB was achieved, there would be no marked
Source: references 2,17,24
improvement in the TB problem in many developing
Adapted and reproduced with permission from “Chakraborty AK.
Epidemiology of tuberculosis: current status in India. Indian J countries for the fore seeable future”.
Med Res 2004;120:248-75 (reference 3)” One might consider here that the intervention effects
need to be continuously evaluated in a regular ongoing
case scenario, without any such prospect in the others manner [“monitoring”]. Without an effective monitoring,
(9). Disease rates, expressed as incidence of smear the improvements or otherwise in disease trend would
positive cases in Group IV vs Group I countries in point, not be documented. For such ongoing evaluation to take
as at present, set against those required to be achieved place, the development indicators need to be suitably
in case the goal of elimination is addressed, are given in designed, requiring these to be sensitive and easily
Table 3.4. It could be observed that for the Group I obtainable. On sustained monitoring and agglomeration
countries [The Netherlands] the annual incidence of 12 of such indicators, one could derive the course of the
to 15 per million per year observed at present, needs to disease with time. Surveillance systems are, therefore,
be reduced to less than one per million population per critical to build and sustain if one has to follow disease
year, to achieve the ‘close to elimination’ status by 2025 trend. Periodic surveys in some selected areas, do give
28 Tuberculosis
some information, but may not replace a disease Tuberculosis Sample Survey in India
surveillance system in the long run.
A Sample Survey, eponymously the ‘National Sample
TUBERCULOSIS PROBLEM: STUDIES ON INDIAN Survey’ [NSS] was carried out between 1955-58, under
SITUATION the auspices of the ICMR (5). Six zones were selected,
rather on practical considerations than otherwise;
Epidemiological Methods: Some Prominent Indian namely, Madanapalle, Hyderabad [both from Andhra
Studies Pradesh], Patna [Bihar], Trivandrum [Kerala], Delhi and
Some of the more prominent Indian studies on this Calcutta [West Bengal]. Though the survey was not
subject are described below. expected, by design, to provide average estimates of
morbidity on a national basis, it still did provide
A Community-wide Tuberculosis Study in Madanapalle, information from some selected areas covering wide
South India [Madanapalle Study] geographical expanse of the country. The six zones
It happens to be the mother of all the community surveys included in the survey had covered 40 per cent of the
conducted in India, especially of the longitudinal Indian population. The three cross-sections included in
epidemiological surveys (3,4). The field work was carried each zone [i.e., the largest city, medium sized towns and
out in the period between 1950 to 1955, in a rural area of accessible villages] had indeed covered 80 to 90 per cent
336 km2 radius, covering a population of nearly 60 000 of the population within the zones selected, with the
residing around Madanapalle town, with support from exception of Trivandrum where 62 per cent and of the
the WHO. The programme had centred around the Calcutta zone, where only Calcutta city could be covered.
Union Mission Tuberculosis Sanatorium, Arogyavaram The blocks within the cities, towns and the villages to be
and the Tuberculosis Field Research Centre at surveyed were decided upon, following random
Madanapalle. The objective was to study the incidence sampling devices. Total eligible population added up to
and prevalence of infection and disease. Another of its 131 319 for cities; 59 548 for towns and 137 271 for
aims was to see if it would be possible, within a villages. A co-efficient for variation of 15 per cent for the
foreseeable future, to reduce significantly the problem
estimates of morbidity was arbitrarily considered
of TB in the community.
adequate. As there was paucity of data on sampling
The fieldwork consisted of mass mobile miniature
variations, the sampling size for achieving the desired
X-ray [MMR] examination of the population aged five-
level of accuracy of the estimates was only approximate.
years and more and tuberculin testing of the entire
The sampling ratio was about 0.2 per cent of the eligible
population on a house-to-house basis. This was followed
population.
by bacteriological investigation [sputum culture] of the
The actual operations in the field were limited to:
persons found to have an abnormal X-ray. The BCG
vaccination was also used for prevention and its efficacy [i] population census and collection of information on
studied. All patients detected in the study were offered economic status by recording the nature of dwelling unit
treatment with provision for hospitalization of the i.e., ‘kutcha’ house [thatched hut], ‘pucca’ house [built-
infectious cases[C+]. in unit]; [ii] one miniature 70 mm X-ray of persons aged
It was an eye opener to conclude from results of the five years and more [eligibles]; [iii] collection of sputum
surveys that the intervention methods were inadequate [2 samples] and two laryngeal swab specimens for
to bring changes in disease prevalence [C+ cases] for the bacteriological examinations from persons with
period of observation between 1950-55, as reported (3,4). suspicious X-rays, by paying a single visit. The sputum
However, the finding that has been severally corrobo- samples were examined by direct smear for acid-fast
rated in India and elsewhere in the world in recent times, bacilli [AFB] and the laryngeal swabs were subjected to
appears remarkable in that, a well delivered intervention culture for Mycobacterium tuberculosis. No tuberculin
measure could succeed in visibly and dramatically testing was carried out; hence no estimate of infection
bringing down the TB-related deaths in the community was available from this cross-sectional survey.
from 200 per 100 000 to 21 per 100 000 in a span of less Information was available for X-ray active and
than four years for the study under reference. bacteriological disease status for the areas studied.
Epidemiology 29
Tuberculosis Studies in Bengaluru Area: National to-house basis. Tuberculosis testing of persons aged 0 to
Tuberculosis Institute Longitudinal Epidemiological Studies 44 years was carried out. Persons with test induration
size of 10 mm or more were eligible for sputum
The objective of these longitudinal studies was to
examination, besides all those aged 45 years or more
observe the natural history of pulmonary TB under the
without discrimination. The tuberculin test results from
existing socio-economic conditions in an area, i.e., the
this survey were converted into ARI and were compared
epidemiological dynamics which could occur, without
with ARI worked out for the area derived from earlier
the influence of any control measures, such as BCG
surveys (28). This was the first time that TB trend in the
vaccination or chemotherapy. It is probably the first time
form of ARI was available for any area in India over a
ever anywhere in the world, that the natural dynamics
fairly long period of 23 years.
of TB was studied.
The results from the above series of surveys could be
A rural population residing in 119 randomly selected
taken to represent the natural dynamics of TB in a rural
villages of three of the administrative sub-divisions
community for the first five years, followed by a TB
[Taluks] of Bengaluru district were surveyed four times
situation for the remaining 16 years or so, after implemen-
between 1961 to 1968 (39). Three surveys were carried
tation of the District Tuberculosis Programme [DTP].
out at intervals of one-and-a-half, one-and-a-half, and
Even though it was not the stated objective of the study
two years. At each of the surveys, each person was
to observe the trend of bacteriologically positive disease
identified by carrying out house-to-house visits and
in the area, there was nevertheless an opportunity to
given a tuberculin test following identification of the BCG
obtain the prevalence rate of smear-positive cases in the
scar, if any. All persons aged five years and more were
community in 1984 to 1986 and its trend over a period of
X-rayed with a 70 mm X-ray in the villages and those
23 years (45).
with radiological abnormality were bacteriologically
investigated [two samples collected in the villages, both
Tuberculosis Prevention Trial, Madras [Variously known
examined by smear test for AFB and culture for
as Feasibility Study, Chingleput Trial or BCG-Trial]
Mycobacterium tuberculosis]. No intervention of any kind,
either by offering BCG vaccination or treatment of cases This long-term study in a large population in rural south
detected during the survey, was carried out. The NTP India was started in 1968 and the population was
was not operating in the area at the time the four surveys comprehensively followed up for a period of seven-and-
were carried out. a-half years to start with (36). The elaborate follow-up
Following the fourth survey, the NTP was implemen- procedures adopted in the BCG-Trial were designed with
ted in the three taluks constituting the longitudinal the objective to study the efficacy of BCG vaccination in
survery area. Eleven years after the fourth survey, i.e., in preventing incidence of TB in the non-infected, by
1977, a fifth survey was carried out in a sub-sample of 22 different strains of BCG and their dosages. For this a
of the earlier 119 villages (44). The same methodology, factorial design was employed, the factors being the
as in the earlier surveys was followed with the objectives vaccine strain and placebo and the dosages. It was also
to study changes in TB situation for the area over a period designed to have a common control group for all the
of 16 years [1961-1977]. Even though the study popula- vaccinated groups, who were administered a placebo.
tion was only a meagre 14 382, useful observations were Thus, epidemiological data on TB in the community in
made on the trend. the form of prevalence of infection, radiological and
A follow-up to these studies was undertaken 23 years bacteriological disease as well as incidence of infection
after the first survey between 1984 and 1986 (28). Two of and disease were available from the study, both for the
the three taluks, which had formed the area under the control as well as the treated group. Adequate size of
original longitudinal survey, were selected on grounds the population was selected so as to give accepted CIs
of logistics. In these two taluks 40 villages were for incident cases etc., so necessary for the efficacy trial.
earmarked for the study on the basis of simple random This was possible as the study had prior knowledge on
sampling. These villages were different from the 119, likely incidence in the community from the Madanapalle
where longitudinal studies were earlier conducted. A study and NTI longitudinal epidemiological studies to
total of nearly 30 000 persons were surveyed on a house- arrive at a proper sample size. A very credible set of data
30 Tuberculosis
are, thus, available from the study on the epidemiological ever that a given community in India has been repeatedly
situation in India (36). surveyed for the purpose of studying disease trend [vide
A total population of 360 000 persons residing in 209 infra].
contiguous panchyats [sampling units] and one town
[sampling unit-blocks] in Chingleput district of Tamil Tuberculosis Trends in New Delhi [New Delhi Study]
Nadu was selected. Whole of one Taluk [Tiruvallur] and
Apart from the information that is available from the
part of another [Tiruttani] formed the study area. All
NSS, the New Delhi Study (48) is the only other source,
individuals aged one year and above were X-rayed, using
from which the TB situation for an urban metropolitan
70 mm miniature mass radiography [MMR] unit, visiting
area in India could be observed. The area is thickly
the villages. From such persons, whose X-rays were
populated, inhabited by low-income families. The New
interpreted as abnormals, two specimens of sputum were
Delhi Tuberculosis Centre [NDTBC] runs a TB clinic of
collected and examined by direct smear for AFB and
great repute for the area. A population of nearly 30 000
cultured for Mycobacterium tuberculosis. Total number of
persons was repeatedly surveyed for 30 years [1962 to
persons actually undergoing the tests had numbered
1991] by the NDTBC. Following the baseline survey in
263 842 for tuberculin test, and 213 000 for X-ray. 1962, seven more surveys were carried out. An interval
Immediately following the tuberculin test in an of two-and-half years was maintained up to the fifth
individual BCG vaccine and placebo were allocated survey. The interval between last four surveys [between
randomly. Intensive efforts were made, to re-survey the the survey numbers V and VI, VI and VII, VII and VIII]
population every two-and-half years and more were four, six and nine years respectively.
frequently. The same techniques of tuberculin testing and The survey procedures, which had remained
X-ray were followed at re-surveys, as during the initial unchanged throughout, consisted of [i] accurate census
survey. Selective active case finding was conducted in on house-to-house visits; [ii] about 90 per cent of all
persons found to be suspects during the initial survey. eligible persons were X-rayed and [iii] ‘X-ray abnormals’
Simultaneous efforts were made through passive case were further investigated and followed up at the Centre.
finding at the identified general health service clinics to Investigations amounted to at least two to three radio-
diagnose all new patients of TB occurring in the commu- graphic examinations, two cultures of sputum or
nity. Cases diagnosed were treated on domiciliary basis laryngeal swab for Mycobacterium tuberculosis and clinical
in an appropriate manner. Mutually exclusive random observation extending sometimes up to six months.
samples of the population were re-tested with tuberculin Between 86 to 97 per cent of X-ray abnormal were further
at intervals. investigated. All diagnosed patients were treated
After the initial survey in 1968 to 1969 [Survey I] appropriately at the NDTBC.
tuberculin testing was repeated twice in two of the A report on all eight surveys gives data on prevalence
Panchayat Unions, following the same methods, twice-at and incidence on TB for the urban area with a running
an interval of 10 years [Survey II], and then at 15 years TB control facility over a fairly long time frame. However,
[Survey III] (46). Owing to high prevalence of non-specific it could now be said that through deficient appreciation
infection in the area, the testing was carried out only in a of the relevant indices, sensitive to changes in the TB
population aged one to nine years at each survey. Data on situation for an area, only culture-positive TB disease was
incidence of infection from 8703 and 9709 children at sought to be measured in the study, leaving out SS+ case
Surveys I and II respectively were used for computing the and the ARI. To that extent the findings are less
10-year trend; and from 4808, 4965 and 4889 children at appropriate in reflecting the trend following intervention,
Surveys I, II, and III respectively, for observing the trend for a relatively short period.
for the 15-year period. Results over a period of 15 years,
both for the protective effect of BCG as well as prevalence India: Distribution of the Problem
of disease are also available from this study (47).
Annual Risk of Infection
The epidemiological situation obtained in the area
pertaining to the period 1991 to 1996 has been made Annual risk of infection from different parts of India till
available in a recent report (35). This makes it the longest the middle of the last decade [1991 to 1996] was reported
Epidemiology 31
to be between one and two per cent [Table 3.6] (2,3,35,37, epidemiological trend, along with the data from
49-55). There have been fresh estimates available from Chingleput area.
a few areas in the country since then, the best possible The recent data on ARI, as shown in Table 3.6 confirm
situation being reports from Kerala [ARI, 0.75%] (49). the author’s earlier suggestions of differences in TB
The high rates of ARI observed in Thane in the outskirts situation between areas in India (17). It could be recalled
of Mumbai [3.3%] (55) and in the Care Nicobar district that in the Bengaluru area the urban-rural difference in
[3.8%] (37) merit mention, being among the worst case ARI was also evident with rural ARI declining from 1.1
scenario on record. The rate in Thane urban area is per cent to 0.61 per cent in 23 years up to 1985 (28), urban
interpreted to be due to HIV seroprevalence and to the ARI being 1.67 per cent (50).
increasing component of slum dwellers in the fast
expanding population group inhabiting the area (55,56). Prevalence of Pulmonary Tuberculosis
The ARI from Car Nicobar, on the other hand, is the only The data presented in Table 3.7 are the outcome of several
documented instance of ARI in India, escalating with surveys, conducted from time to time in different areas
time. It is discussed in detail later, in the section on of the country. An average rate of infection and disease
Table 3.6: Annual risk of infection in various areas in India

Study (reference) State/District/Region Period of study ARI [%]
Kerala TB Association (49) Kerala, Trivandrum 1991-92 0.75

NTI, Bengaluru (2) Karnataka, Tumkur Dist 1960-72 1.66-1.08
NTI, Bengaluru (2) Karnataka, Bengaluru rural 1962 1.1
NTI, Bengaluru (2) Karnataka, Bengaluru rural 1985 0.61
NTI, Bengaluru (50) Bengaluru, urban 1996-99 1.67
NTI, Bengaluru (51) North India 2000-01 1.9
Rural 2000-01 1.62
Urban 2000-01 2.6
NTI, Bengaluru (51) Uttar Pradesh, Rae Bareilly 2000-01 2.3
Uttar Pradesh, Hardoi 2000-01 1.9
Uttar Pradesh, Jaunpur 2000-01 1.5
NTI, Bengaluru (52) Gujarat, Junagadh 2000-02 0.73
NTI, Bengaluru (53) Western India 2000-02 1.8
Rural 2000-02 1.5 [5.9-9.7]*
Urban 2000-02 2.4 [8.3-17]*
Urmul Trust (2) Rajasthan 1995 1.44
TRC, Chennai (35) Chingleput, rural 1969-84 1.8-1.9
Chingleput, rural 1991-1996 2.9-3.2
DANIDA (54) Orissa 2000-02 1.72 [7.5-11.3]*
Rural 2000-02 1.62 [7.2-10.3]*
Urban 2000-02 2.48 [7.7-19.8]*
Andaman and Nicobar Government (2) Car Nicobar 1986 1.53
RMRC, Port Blair (37) Car Nicobar 2002 3.8
MGIMS, Sevagram, NTI, Bengaluru (55) Maharashtra 2000-02
Nagpur, rural 2000-02 1.2 [6.34-6.38]*
Nagpur, urban 2000-02 1.6 [8.44-8.50]*
Thane, rural 2000-02 1.6 [8.07-8.10]*
Thane, urban 2000-02 3.3 [15.75-15.80]*
*numbers in square brackets indicate 95 per cent confidence intervals

ARI = annual risk of infection; DANIDA = Danish International Development Agency; RMRC = Regional Medical Research Centre;
MGIMS = Mahatma Gandhi Institute of Medical Sciences; NTI = National Tuberculosis Institute
Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med
Res 2004;120:248-75 (reference 3)”
32 Tuberculosis
categories for the country as a whole are presented in A more detailed and extensive exercise was
this table, along with the range, to represent the best and conducted by Dye et al (32) directed towards providing
the worst possible case scenario. Necessary corrections an average estimate for the country. This was a part of
and refinement to the existing rates of disease are also the global task, in order to make a consensus statement
suggested (2). For the latter, specific survey results of the problem, [burden] by regions of the world. The
devised to study and correct the observed inaccuracies average rates of disease and infection [both prevalence
and inconsistencies in the previous estimates are relied and incidence], as well as death were computed. Data
upon (2). Appendix Table 3.1 presents the necessary from: [i] survey results, as in previous para for India;
database for corrections given in Table 3.7. This method [ii] incidence of cases, calculated out of the ARI based on
for computation of average rate with the range is an empirical model suggested by Styblo (38); and
adopted, since a representative sample for the country [iii] the likely disease rates computed from “notification”
as a whole, has so far eluded the researchers, as also the of cases made to the WHO (13), were mutually compared
sample, sensitive enough to discriminate prevalence or and assessed for reliability and internal consistency in
incidence rates between one area and the other (17). As this work. These data are shown in Table 3.7.
already explained, notification of sputum positive or The problem is expressed in terms of rates and
other diagnosed cases of TB is not yet the source of data absolute numbers, based on a population of 1000 million,
on incidence and prevalence in India. both for prevalence as well as for incidence [Table 3.7].
Table 3.7: Problem of tuberculosis in India [average for the country] [estimated for 1000 million population]
1. Population: 1000 million [850 million in 5+ years age, 85%]

2. Prevalence of infection*
Rate: [a] 38% all ages [a1] 44% all ages Number [b] 380 Million [b1] 440 million
3. Prevalence of radiologically active abacillary pulmonary TB [X+ cases]
Rate: [a] 16 per thousand [3.0, 2.6-4.7] Number: [b] 13.6 million [2.6 million]
4. Prevalence of all forms of TB disease
Rate: [a1] 5.05 per thousand Number: [b1] 5.05 million
5. Prevalence of culture-positive cases [C+ cases]
Rate: [a] 4.0 per thousand [9.6, 3.0-11.0] Number: [b] 3.4 million [8.2 million]
6. Prevalence of smear-positive cases [SS+ cases]
7. Prevalence of total pulmonary TB cases
Rate: [a] 20.0 per thousand [9.0, 5.6-15.7] Number: [b] 17.0 million [7.7 million]
8. New culture positive [C+ cases] arising annually
Rate: [a] 1.3 per thousand Number: [b] 1.1 million
9. New smear positive [SS+ cases] arising annually
10. Mortality rate [annual]
Rate: [a] 50-80/100 000 [a1] 46, 28-71/100 000 Number: [b] 0.43-0.68 million Number: [b1]
0.39, 0.24-0.60 million
11. Case fatality rate [annual]
Rate: [a] 14% of untreated C+ cases [a1] 24% of all TB Number: [a1] 0.48 million [b1] 1.21 million
Data given under a and b = worked out by Chakraborty (2) from Indian survey data; data given under a1 and b1 = worked out by Dye
et al (32) by aligning several hypotheses and sets of data from India
*Infected: more than 50% in age group 40 years and more; disease rates applicable to population in 5+ years age for rows 3,5 and
6-9; for rows 4 and 10 = calculated for persons in all ages; rates, their ranges and numbers in millions shown in bracket = as per revision
suggested by the author on the basis of correctional surveys, vide Appendix Table 3.2. For average absolute numbers on revised rates
in bracket = range not presented; only minimum number in the range shown. Current estimates allowing for time dynamics after Corbett
et al (57)
TB = tuberculosis
Res 2004;120:248-75 (reference 3)”
Epidemiology 33
Appendix Table 3.1: Suggested revision of average standardization in calculating the burden from time to
tuberculosis rates [per 1000] [India] time, by applying age-wise prevalence rates of earlier
surveys to later populations, has been appreciated in
Variable Currently used* Suggested Correction factor‡
rate† recent times and needs to be addressed for computing
the absolute numbers (56). Being an elaborate task in
X+ 16.0 3.0 0.2
modelling in itself, the same has not been attempted here.
[10.0-19.0] [2.6-4.7]
C+ 4.0 6.0 1.4 The global data on TB burden as presented in Dye’s
[2.0-8.0] [3.0-11.0] (32) estimate are updated for 2000 and 2001 by Corbett
Total 20.0 9.0 - et al (57), based on the current results of intervention
[13.5-25.0] measures and population escalation. The rates pertaining
C+:X+ 1:4 2:1 -
to the Indian scenario for 2001 are presented in Appendix
Suggested rate = currently used rate × correction factor Table 3.2. The hypothesis used for the parameter
Numbers in square brackets indicate 95% confidence intervals estimates in arriving at the current rates and burden are
X+ = radiologically active, bacteriologically negative; C+ = culture also shown there. For the reason that the population for
positive
India has since changed, the estimated absolute numbers
Source: Chakraborty AK. Prevalence and incidence of tuberculosis
infection and disease in India: a comprehensive review. Geneva: are not quoted in Appendix Table 3.2. However, the rates
World Health Organization; 1997.p.1-26. WHO/TB/97.231. could be applied to the current population size in India
Available at URL: http://whqlibdoc.who.int/hq/1997/WHO_TB_ to get the likely Indian TB burden for the year.
97.231.pdf. Accessed on October 5, 2008 (reference 2)
Area-wise Distribution
The hypothesis in computing the numbers diseased for From the results of the country-wide sample survey
the present population, is that the disease rates in India conducted by the ICMR (5), it was observed that the
remain static, but absolute numbers increase owing to prevalence rates for this country as a whole were by and
demographic reasons. It also needs to be pointed out in large similar in six zones studied and across the urban-
this connection, that the prevalence and incidence rates rural divide (5). On a careful review of the above data, it
are applied to 1000 million population, across the board, could, however, be observed that the prevalence rates
in the manner it was applied to 8.5 million in the previous throughout the country were really not similar (17). In
estimate (2), without making allowances for changes in the first place, the sampling framework did not allow
age sex-wise composition of the population between the testing of the hypothesis of difference between the areas
two, taking place during the decade. The issue of lack of and zones, if any. Further, the prevalence rates, on further
Appendix Table 3.2: Tuberculosis prevalence and incidence: some average current estimates [per 100 000]
Prevalence of Tuberculosis cases

infection [%] Incidence* Prevalence* Mortality
All forms SS+ All forms SS+ All forms* Due to HIV [%]
46 178 79 444 199 44 4.8
*Allowing for the time dynamics following intervention, as in 2001

Hypothesis on parameters used:
[i] ARI falling at 2.5% annually
[ii] Ratio of ARI to incidence of SS+ cases [cases per 100 000 population for 1% of ARI] = 60 [range 40-80]
[iii] Trend in incidence of all forms of TB [% per year] = Best [-] 1.3
[iv] Proportion of tuberculosis cases [SS– / SS+] on treatment [%] = on DOTS 0.1, on non-DOTS 0.7
[v] HIV prevalence in new adult TB cases = 4%
[vi] Population of India in 2003 = 1 025 096 104
ARI = annual risk of infection; SS+ = sputum smear-positive; SS– = sputum smear-negative; HIV = human immuno-
deficiency virus
Data source: reference 57
34 Tuberculosis
assessment with the help of 95 per cent Cls do not support the regional diversities in terms of ethnic, economic,
the hypothesis of lack of difference between the cultural complexities and variables, pervading the vast
geographical areas [Table 3.8]. For example, for the city land masses and the population size of near continental
areas under the Madanapalle zone, the C+ case dimensions.
prevalence rates [2.40/1000; 95% CI 1.64 to 3.16 were With this background information, one could now
significantly lower than those in towns [8.13/1000, 95% argue that the average prevalence rate [and incidence
CI, 6.58 to 9.68], or in the villages [6.11/1000; 95% CI, rate also] as worked out by Dye et al (32) [Table 3.7], may
5.02 to 7.20]. It will not be out of place to mention here, not be used indiscriminately for all areas of the country,
that from the data shown in Table 3.8, as also from as a sort of target, with the ostensible purpose of evaluat-
information available from surveys elsewhere in India ing supposedly epidemiological gains, through a set of
over the years, Bengaluru area falling within the programme activities, as currently being practiced under
Madanapalle zone in the country-wide ICMR survey, the RNTCP. This could of course be used for resource
appears to have the best possible TB case scenario mobilization and advocacy purposes. Measurement of
anywhere in India [vide infra]. Further, the bacteriological change on a time series or of geographical differences
case prevalence rates [C+] for Trivandrum city [2.96/ would require statistically sensitive indices of disease
1000; 95% CI 2.14 to 3.78] were different from Patna city [and infection] in order to test a given hypothesis of
[6.38/1000; 95% CI 5.10 to 7.66]. Citing the case of change or difference [or, otherwise] by examining an
metropolitan cities also, it could be seen that the appropriate population sample, calculated for the
prevalence rate for Calcutta city [6.39/1000; 95% CI 5.16 purpose (17). The grossly average and well-rounded rates
to 7.62] differed from Delhi city [4.06/1000; 95% CI 3.23 may not lend themselves to a measurement of change in
to 4.89]. them with the required degree of precision.
Tuberculosis disease prevalence rates are not similar
between areas in India. This is understandably so, given Prevalence and Incidence by Age
Both prevalence and incidence were observed to rise with
Table 3.8: Culture-positive case [C+] prevalence of age, in both sexes, in surveys conducted so far in the
tuberculosis by geographical areas country. The rise is seen in all categories of cases, namely
Zone Area Average C+ case 95% Confidence X+, C+, and SS+ in the community [Figure 3.6] (36). The
prevalence intervals* information on the proportional distribution of smear-
[per 1000] Lower Upper positive prevalence cases in the community by age [1984
Calcutta City 6.39 5.16 7.62 to 1986] in the Chennai area, is given in Table 3.9 (35). It
Delhi City 4.06 3.23 4.89 could be observed that, of the prevalent cases in the
Towns 2.45 1.54 3.36 community, the age-wise proportion of cases were
Villages 2.49 1.87 3.11 substantially higher 35 to 44 years onwards, to be at the
Hyderabad City 4.18 3.44 4.92
Towns 3.44 2.32 4.56
peak for the age group 55 to 64 years [28.4%]. Moreover,
Villages 2.29 1.70 2.88 it remained as high as 22.67 per cent in age-group 65
Madanapalle City 2.40 1.64 3.16 years and above, being similar to that in 45 to 54 years.
Towns 8.13 6.58 9.68 This could be contrasted to the distribution proportions
Villages 6.11 5.02 7.20 of 0.7 per cent, 1.54 per cent and 7.25 per cent in age
Patna City 6.38 5.10 7.66
groups, 10 to 14, 15 to 24 and 25 to 34 years, respectively.
Towns 5.25 3.83 6.67
Villages 5.85 4.58 7.12 In contrast to the epidemiological distribution given
Trivandrum City 2.96 2.14 3.78 above, the age-wise proportional distribution of smear-
Towns 3.20 1.93 4.47 positive cases for India, diagnosed both under the NTP
Villages 2.59 2.08 3.10 and RNTCP, combined for the year 2000 (13) is presented
* Calculated from reference 4 in Table 3.10. The peak concentration is seen to be at
Adapted and reproduced with permission from “Chakraborty AK. 25 to 34 year age group, declining thereafter. In 55 to 64
Epidemiology of tuberculosis: current status in India. Indian J and 65 years and above age groups, only 10.47 per cent
Med Res 2004;120:248-75 (reference 3)” and 5.91 per cent of all the cases are respectively
Epidemiology 35
34 years, is a phenomenon also seen in some of the

African countries, who are similarly placed with India
with respect to TB situation as Group IV countries, e.g.,
Tanzania [1985-87], Mozambique [1989], Malawai [1989]
and Nicaragua [1989] (58).
The situation of less than expected detection of cases
in older age groups, as observed under the NTP and
RNTCP in India, could be attributed to deficient
attendance of the symptomatics in older age groups at
the general health service facilities, i.e., not commen-
surate with the likely prevalence of TB among them (59).
The situation in India appears not to have altered, since,
be it under NTP, or RNTCP. It appears to be a problem
of access owing possibly to a degree of discrimination
by the society. The latter seems, in a way, to decide on
the attendance pattern of the sick persons to the health
delivery outlets, younger people being possibly
encouraged and preferred to take action and seek relief.
The programme, thus, seems to benefit the younger and
socio-economically the more important group within the
population, i.e., the younger age group, as against the
older population group.
The above discriminatory situation seems to have an
epidemiologic significance of no mean consequence. The
large majority of the persons transmitting infection and
most of the uninfected and susceptible population at risk
of being infected, seem to distribute themselves at the
two extremes of the age groups, the former being in the
older age groups and the latter in the younger age groups
and children. The former remain comparatively unatten-
ded to, under the programme, and keep on increasing in
number and proportion in comparison to the middle age
groups. Thus, a relative concentration of cases seems to
be occurring by age. Due to their position in the society
Figure 3.6: Prevalence of disease by age, sex and method of and restricted movement, the persons in the older age
diagnosis
Categories of cases:
groups seem to be in close proximity to the susceptible
A = culture-positive on sputum specimens young children within the family, increasing chances of
B = culture-positive on one sputum specimen only transmission.
C = culture-negative, smear-positive [3+ or more acid-fast bacilli] The situation in the western countries, on the other
D = abacillary, rated as active on miniature mass radiography by hand, [i.e., Group I countries] appears to be quite diffe-
two readers
rent in this regard. In 1970, for example, 70 per cent of the
Adapted and reproduced with permission from “Chakraborty AK, cases in Sweden, diagnosed among the Swedish born,
Epidemiology of tuberculosis: current status in India. Indian J Med were in the age group 65 years and above. In England
Res 2004;120:248-75 (reference 3)” and Wales also similar was the case (21). The difference
in this regard may not only be among the countries,
distributed. The relative concentration of diagnosed SS+ depending on their grouping, I through IV. Even within
cases to be in the younger age group, peak in 25 to the most developed countries of the world, the age
36 Tuberculosis
Table 3.9: Age distribution of smear-positive prevalent cases [for 100 000 population]
in a survey area 1984 to 1986*
Age [years] 1968-70 1973-75 1979-81 1984-86
10-14 35 [0.88] 14 [0.3] 8 [0.20] 3 [0.07]

15-24 108 [2.73] 111 [2.40] 105 [2.61] 62 [1.54]
25-34 425 [10.74] 461 [9.96] 404 [10.06] 292 [7.25]
35-44 729 [18.42] 691 [14.93] 570 [14.19] 693 [17.20]
45-54 899 [22.71] 1127 [24.36] 1050 [26.14] 921 [22.86]
55-64 994 [25.11] 1218 [26.32] 966 [24.05] 1144 [28.40]
65+ 768 [19.40] 1005 [21.72] 914 [22.75] 913 [22.67]
All* 3958 [457] 4627 [511] 4017 [444] 4028 [428]
* Figures in square brackets indicate % of total cases

† Standardized prevalence rates
through a system of a preferential intervention dynamics,

Table 3.10: Age distribution of smear-positive cases in
India [year 2000] related both to social as well as service delivery factors.
Age [years] Total Non- DOTS DOTS

Distribution of Prevalence and Incidence by Gender
0-14 3838 [2.02] 2041 [2.08] 1797 [1.95]
15-24 35458 [18.65] 14055 [14.32] 21403 [23.26]
In Figure 3.6, the prevalence by sex and age in the BCG
25-34 45377 [23.86] 23911 [24.36] 21466 [23.33] trial area in Chingleput [TRC] is depicted (2,36). Preva-
35-44 42597 [22.40] 22750 [23.18] 19847 [21.57] lence and incidence [not shown] in all categories of
45-54 31746 [16.69] 17450 [17.78] 14296 [15.54] diagnosis had increased with age in males. For females,
55-64 19902 [10.47] 11205 [11.42] 8697 [9.457] up to 45 to 49 years of, the rates had increased, to be at a
65+ 11231 [5.91] 6735 [6.86] 4496 [4.89]
plateau thereafter. At all ages the prevalence was
All 190149 98147 92002
considerably higher in males than in females. Of all
Figures in square brackets indicate % of total cases culture positive cases, 79 per cent were found to be in
males. In the later TRC follow-up study 1968 to 1986, the
average male:female ratio was 3.7 for C+ cases and 4.5
distribution of TB cases has a direct relationship with the for SS+ cases (35).
socio-economic and ethnic variables. For example, the Of all pulmonary TB cases in males, 70 per cent were
relatively unfavourable epidemiological scenario, occurr- in the age group 20 to 54 years [39% of male population].
ing among the American minorities is distinctly different Among females on the other hand, 56 per cent of these
from that among the non-Hispanic whites, as also the cases were in age group 20 to 44 years, i.e., in the repro-
proportional age distribution of cases occurring in them ductive age [constituting 40% of female population].
(11,60). In the longitudinal epidemiological study in
It is possible that apart from the social and prog- Bengaluru rural area carried out between 1961 to 1968,
ramme driven discrimination, the concentration of cases the annual incidence rate of C+ cases in males increased
in older age could take place as a secular trend of disease during the five-year observation period from 200 to 300
(16), as also due to demographic situation, related to per 100 000 (2,39). It, however, remained stable among
higher population size in the elderly, with time. The females at 100 per 100 000. Whereas, the incidence among
situation prevalent in India is a symptom of its socio- males aged 55 years and above in successive surveys for
economic milieu, interacting with the disease situation. the five years period, ranged from 400 to 700 per
It also remains a moot point fit for investigation, whether 100 000, in females it had increased only from 150 to 200
the intervention programme, as it is in India, could result per 100 000. However, an unexplained observation in
in further concentration of cases among the elderly, these surveys was the annual incidence of about 100 per
Epidemiology 37
100 000 in both genders in the 15 to 34 year age group. be a theme of immunobiological and sociological
Aside from the above exceptional parity in incidence investigations in the Indian context.
between the genders in this age group, the observations
are similar in most Indian epidemiological studies. In Tuberculosis by Socio-Economic Criteria
general, the disease occurrence rates are similar in both The survey carried out in Wardha District [Maharashtra]
genders, till the onset of puberty in females. Thereafter, is the only source of data linking TB in the community to
a female preponderance has been observed with the socio-economic criteria [unpublished observations, cited
gender difference acutely accentuating beyond the 35 in reference 2]. In this survey, variations in the prevalence
year age mark. rate of TB was observed in terms of literacy [lowest in
In the European countries during the earlier part of the graduates and highest among the illiterates], employ-
the last century, the case rates among females between ment held [highest among the professionals, followed
the ages 15 to 35 years were generally 10 to 35 per cent by cultivators and agricultural labourers], income, living
higher than in males. Prompted by this, the postulate of standard [those living in “kutcha” houses had a higher
a higher case rate in females in India as well, has been prevalence than “pucca” house dwellers] [Table 3.11].
the recurrent theme of many investigations carried out Of the total cases among females, 48 per cent were among
in India in recent times, especially with foreign funding. those unemployed [including housewives]. For all demo-
It appears that, in so far as general distribution of graphic variables, rates in females were less than those
prevalence and incidence of TB cases in India is conce- in males.
rned, the epidemiological observations from industriali- As per Dholakia (61), evidence is lacking suggesting
zed countries of the West is a poor guide (Klaus J. Sex a difference in the prevalence of TB among workers than
and age distribution of TB cases, registered in Medak among non-workers. Of the ‘workers’ group, estimated
and Hyderabad Districts under the RNTCP, 1999. to be suffering from TB in India, about 52 per cent were
Nuffield Institute for Health, Consultancy Report under in the age group 15 to 44 years. In this age group, about
DFIDI Project, unpublished data). Instead of investigat- 40 per cent of the workers with TB, were women in the
ing the anticipated but unsubstantiated gender bias urban areas. The proportion was only 17.9 per cent in
against women reflected in the occurrence of disease in rural areas. There was much lower proportion of women
the community, the reasons for apparent protection among workers with TB in higher ages, especially in the
enjoyed by the women across the age groups, could rather urban areas. In the Wardha survey, the urban profes-
Table 3.11: Prevalence of culture-positive pulmonary tuberculosis by occupation

in Wardha [per 100 000 population]
Urban and rural Sex ratio [M:F]

Occupation Population Sex ratio Proportion of Urban Rural
[%] [M:F] total cases
[%]
Non-worker 26.8 0.34 24.9 2.30 1.41
Student 29.0 1.25 6.6 1.17 1.56
Service 5.3 - - 1.40 0.53
Professional 2.0 12.19 4.4 0.40 -
Cultivator 15.0 2.45 24.8 0.48 1.73
Agricultural labourers 16.4 0.85 21.4 2.25 1.94
Non-agricultural labourers 3.9 - - 4.22 2.05
Others 1.5 - - 1.53 2.87
Total 100.0 1.08 100.0 1.77 1.84
M = male; F = female
Source: reference 2
Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current
status in India. Indian J Med Res 2004;120:248-75 (reference 3)”
38 Tuberculosis
sionals and rural service workers, who had a higher cally negative and lastly bacteriologically positive
prevalence, had a low proportion of the female popula- disease. Table 3.12 shows the size of each of these classes/
tion in them, and had consequently accounted for a small groups, by the results of tuberculin test, chest X-ray
proportion of the total cases among females. interpretation and bacteriological examination results in
The extent of TB morbidity in the males in the each individual followed up in a given community,
economically active age and in females in the reproduc- repeatedly for a period of five years (2,62). Information
tive age, marks it out as a priority among the public health is available from the study on the attendant risk of
problems in India. breakdown into active bacillary cases [C+] and of death,
by person years of observation. It is important to
Epidemiological Classes of Tuberculosis States in appreciate that the size of each of these classes and the
the Community and Relative Risks risk of developing bacillary cases associated with each
of them would jointly influence the incidence of C+ [and/
Development of various epidemiological classes in the or, say, SS+] cases in the community and thus the size of
community as linked to their respective TB states, ranging the problem of TB. For example, the two groups with
from infection to bacteriologically positive pulmonary the highest risk of developing bacillary TB as shown in
disease, would depend largely on the inherent processes the Table 3.12 [namely, tuberculin positive persons with
of pathogenesis, and would by and large follow an chest radiograph classified as having active TB lesions,
average time line [Figure 3.3]. The consequences to these or other than active TB shadows] had together
processes keep creating groups or classes in the constituted only 5.6 per cent of the total population. Yet
population, either “infected” or “uninfected” with these classes between themselves had contributed close
tubercle bacilli, to start with. In their life time, individuals to 46 per cent to the total new C+ cases arising in the
belonging to each of these two classes go through the community in a year. Surveillance of these two could be
risk of progression into active disease, with or without rewarding under the TB programme delivery system.
reversal to a non-disease state with time [Figure 3.3]. The attendant element of risk for each of the classes
Thus, members of these two initial classes could further would surely have escalated in the era of HIV-TB,
be grouped in accordance with their TB disease status, including that among the group of “infected only” [i.e.,
as revealed from their chest radiograph and bacteriolo- without TB disease]. These need to be investigated in
gical examination results as follows: normal, and those the present scenario, and more comprehensively at that,
with inactive TB state, with non-TB disease, with pro- for the purpose of priority setting under programme
bably/possibly active TB disease state but bacteriologi- formulation exercises.
Table 3.12: Annual incidence of sputum culture-positive tuberculosis cases

in the community by epidemiological class
Epidemiological class Annual Incidence of C+ Proportional contribution to

cases [per 1000/year] annual incidence of C+ cases
Infection status Radiological activity Size [%] By each By tuberculin
status class [%] status [%]
Tuberculin-negative N 63.1 0.41 17.8

AB 5.2 1.03 3.7 23.7
CD 0.5 6.76 2.2
Tuberculin-positive N 25.6 1.73 30.4
AB 4.6 6.83 21.5 76.3
CD 1.0 35.15 24.4
N = radiologically normal; AB = Persons with chest X-ray abnormality considered non-TB or TB without active disease;
CD = persons with chest X-ray lesion considered to have active TB; TB = tuberculosis; C+ = culture-positive
Epidemiology 39
EPIDEMIOLOGICAL TREND OF TUBERCULOSIS (44). The mean age of cases was higher at later surveys,
IN INDIA up to 12 year period studied (44). The ARI had declined
[Figure 3.8] from 1.1 to 0.65 per cent in 23 years [1961 to
Tuberculosis Trend in the Bengaluru Rural Area 1984], at around 2.35 per year (28). Incidence of smear-
From the natural dynamics of TB as studied in the rural positive cases had declined for the area from about 65 to
area around Bengaluru, the TB situation is supposed to 23 per 100 000 in the same period (45). It was observed
be presenting a steady state [Figure 3.7] (2). Without to the declining in consonance with the fall in the ARI.
active intervention, a third of the existing pool of bacillary The observations from the above time series study
cases in a year would get eliminated through death and were extrapolated to the population, taking care of demo-
natural cure. But during the interval, the same proportion graphic changes in it with time, over a 50-year period
gets added to it. (63). The observed dynamics of deaths and those due to
The results of the observations from the Bengaluru transfers between the non-infected, infected, and several
study (39) presenting a trend that could be summarized epidemiological classes formed on the basis of the actual
as below. It is apt to describe the same as natural trend study findings over a period of five years, were fed into
up to the first five years (39). Thereafter an element of the mathematical construct for a period of over 50 years.
NTP-triggered intervention effect could cloud the The natural dynamics were compared with likely disease
interpretations, as it was introduced in the area after the situations, under various programme effectivity modes,
fourth survey [5 years]. hypothesized for the purpose and fed into the model.
Prevalence and incidence rates of C+ cases and X+ The above model showed that even in 50 years, TB case
cases revealed no change in the period of 12 years [1961- rates would come down only minimally. Very large
1968 to 1977-1978], for which information was available population sizes would be required to be surveyed
repeatedly to appreciate a change, if any (2). Various case
finding and treatment levels were included into the
model, as per the data available from a study on
programme dynamics (64). The model demonstrated that
high levels of intervention, could, however, result in
Figure 3.7: Pool of tuberculosis cases in the community Figure 3.8: Annual risk of infection [1962 to 1985] and observed
[natural dynamics] annual incidence of infection [1962 to 1967]
Source: reference 2 Source: reference 2
Adapted and reproduced with permission from “Chakraborty AK. Adapted and reproduced with permission from “Chakraborty AK,
Epidemiology of tuberculosis: current status in India. Indian J Med Epidemiology of tuberculosis: current status in India. Indian J Med
Res 2004;120:248-75 (reference 3)” Res 2004;120:248-75 (reference 3)”
40 Tuberculosis
substantial change in the prevalence rates [Figure 3.9] was not seen in Bengaluru rural area [surveyed for 12
(63). The projections could serve as a decision-making years] (2,35). There was a declining trend in C+ cases in
one, guiding policy planners to look at various efficiency all ages, especially in 10 to 14 years. This was in line with
modes necessary to be in place for the likely road maps the age-wise trend seen in the 12 years follow up in the
to be pursued. Bengaluru rural area (2,35). There was no change in SS+
case prevalence, for all ages [Table 3.9]. However, a
Tuberculosis Trend in a Rural Area of Tamil Nadu declining trend was visible in the younger population,
i.e., among those aged up to 35 years. It was statistically
Annual Risk of Infection
significant for 10 to 14 years old children (35).
In the study carried out in a rural population of There was a strong evidence of decline in both C+, as
Chingleput in Tamil Nadu by TRC Chennai (35) [1968 to well as SS+ case prevalence in females: [3.8% and 2.8%
1984, and in a subset of population, again in 1991 to 1992 annually, respectively]. The C+ cases had shown decline
and 1994 to 1996], the ARI had remained unchanged for at a later period of the follow up in males [i.e., between
the entire period. It was between 1.8 and 1.9 per cent in 1975 to 1978 and 1979 to 1981], without any significant
the earlier period [1969 to 1984] and 2.9 to 3.2 per cent change in the trend of SS+ cases. Because of the above
[1991 to 1992, 1994 to 1996] [Table 3.6] (35). gender related difference, the male: female ratio in C+
cases had increased from 3.5 in 1968 to 1970 to 5.2 in 1984
Prevalence of Cases to 1986 survey [average 4.7]. The average for SS+ cases
The study has shown no change in C+ case prevalence for the entire period stood at 1.7 only.
during the period 1968 to 1975. However, as the re-
surveys were extended further up to 1984 to 1986, a Incidence of Cases
decline of 2.3 per cent per year was recorded for the later There was a steady decline in the incidence of C+ cases
period [overall being 1.4% per annum]. Such a decline [at 4.3% per annum] from 352/100 000 between the first
two surveys [1968, 1971] to 189 between the last two
[1981, 1984]. The decline was seen in both genders and
in all age groups. There was only a tendency for decline
in incidence of SS+ cases. Ratio of prevalence and
incidence of SS+ cases remained 3.6, at the surveys,
probably indicating that new SS+ patients would
probably continue as SS+ cases, after occurrence,
cumulating themselves for 3.6 years in the community,
to constitute prevalence. Findings are more or less similar
for both rural Bengaluru and urban Delhi [between 3.33
and 3.7].
X+ Cases
There was significant and substantial decline in X+ case
prevalence rate from 1289/100 000 to 827/100 000
between 1968 and 1986 [average decline 3.2% per year].
The pattern was not gender specific.
Figure 3.9: Model depicting hypothetical time-trend of tuberculosis
in Bengaluru rural area
DTP = district tuberculosis programme; CF = case-finding; SR = Comments on Findings
standard regimen
It was heartening to observe that incidence of SS+ cases,
Adapted and reproduced with permission from “Chakraborty AK. arising at a later survey, from the radiographic class of
Epidemiology of tuberculosis: current status in India. Indian J Med TB shadows on X-ray in an earlier survey, was coming
Res 2004;120:248-75 (reference 3)” down significantly with time for the area. This was likely
Epidemiology 41
to be due to the treatment programme in place for the out of those with a normal chest X-ray or in those with
area, as pursued under NTP, no doubt accentuated due chest X-ray abnormalities not due to TB. However, in
to the presence and interaction with the research field those with a TB abnormality initially, the incidence of
staff of TRC Chennai. They could act either by motivating C+ cases had declined substantially [4.7% annually] and
patients and probably ensuring drug supply at treatment also in SS+ cases. Of the total C+ S+ cases, arising in 1971
centres also. Being the long-term study area for the TRC, to 1973, about a third had originated from those with an
evidently had influenced intervention situations and X-ray abnormality interpreted as TB. This proportion
brought long-term benefit to the area. declined consistently from year-to-year and was only
The decline in C+ cases, not initially seen, could also eight per cent at the 1984 to 1986 survey. .
be observed on a long-term follow up, as different from It could be interpreted that the treatment given to the
the NTI rural area. There was substantial reduction in specific epidemiological class of X-ray shadows
C+ case prevalence in later surveys [1991/1996 surveys]. consistent with TB disease [X+ cases] had caused a
Whether it had anything to do with reduction of substantially reduced incidence of SS+/C+ cases from
incidence from X+ case class, is a point to consider. A out of this class. The selective decline in incidence by
hypothesis could be considered that when the ARI and radiological classes moreover indicates a good standard
SS+ case prevalence and incidence are relatively high in of interpretation and classification of various radio-
an area, as it appears to be so in Tamil Nadu rural area, graphic abnormalities, through the survey period. An
active and intense intervention for a long enough and alternative hypothesis of likely socio-economic change
sustained span of time, are necessary to record change in the area reducing breakdown may not be tenable, as
in them. The situation in the subset for example in the same was not reflected in ARI and incidence of SS+
Chingleput area, could record a change in C+/SS+ case cases. The socio-economic improvement, if responsible,
situation, only in later surveys. For example, in the subset could have caused reduction in incidence in all radio-
studied for a longer period [1991, 1994] a significant graphic classes, not confined to X+ cases alone.
decline [2.7% per year] had occurred in the prevalence It is generally recognized that for appreciation of
of SS+ cases [398 to 262 per 100 000]. However, for change with time, C+ case prevalence rate of TB is not
reducing breakdown from among the X+ cases into C+ the appropriate index to rely on. In the Kolin study (26),
cases, a relatively low-key treatment, as followed in the for example, the C+ prevalence rate had been observed
programme could suffice to achieve the objective early to register a high only during the survey years. However,
enough. it was also a crucial observation in the above study that
It is of consequence to programme managers, in their the SS+ cases, detected in a survey, and not confirmed
bid to estimate SS+ case load from ARI, to observe that on culture, were mostly found not to be the real cases. It,
the rate of incidence of SS+ to one per cent of ARI had thus, stands to reason that in considering trend in the
decreased from 74 to 42 per 100 000 in about 7.5 years of Chingleput studies, SS+ cases were considered as cases,
observation [a decrease by over 40%]. The decline in the only when they were C+. The same was the case in NTI
relationship between SS+ incidence and ARI with time longitudinal surveys also. Thus prevalence of smear
in the Indian context is reported earlier from the positivity in a survey, unless supported by culture, is not
Bengaluru rural areas under long-term repeat surveys taken as representative. At the same time, prevalence of
(45). real smear-positive cases, in situations where there is
The findings of the Chingleput area appear to be in considerable pooling of untreated or inadequately treated
line with the overall projections of change made in the cases, is the index which is influenced in an effective
50-year construct of epidemiological situation with a 2.3 control programme. For example, in a situation like India,
per cent reduction annually, in response to a relatively where prevalence is about thrice the annual incidence,
low key programme dispensation (63). One of the most an effective control programme could possibly work by
significant findings from this study concerned the reducing the smear-positive case prevalence. It is in this
incidence of C+ and SS+ cases, from out of those context that the reduction in C+ prevalence cases over
diagnosed as having radiographic abnormality at an time, even earlier to that in SS+ incidence cases, needs to
earlier survey. There was no decline in incidence from be understood. It appears to be due to reduced
42 Tuberculosis
breakdown, and the consequent incidence, specifically Influx of wage earners in younger group and exodus of
from among the X+ cases, through their treatment [a sort those in higher age [possibly considered to be without
of “secondary chemoprophylaxis”], as postulated in the ostensible economic worth] from out of city area, was
foregoing paragraph. It appears possible that the essential demographic feature in the New Delhi city
transmission in the present time did not come down area. This was not observed to be so in the rural areas of
sufficiently largely to be reflected in ARI. It needs to be Bengaluru, possibly causing the difference in the nature
kept in mind that the treatment of SS+ cases was not of epidemiological pooling of cases by age with time,
energetic enough under the routine NTP treatment between the areas
regimens, as pursued in the study area. Even though it There was considerable decline in prevalence of X+
had a salutory effect with regard to the breakdown from cases at later compared to the earlier surveys [Survey I:
X+ class, in the manner of a secondary chemoprophy- 13.2 and Survey VII, VIII: 6.5 and 5.4 per 1000]. The X+
laxis, it could not reduce SS+ case incidence/prevalence cases of earlier surveys had the highest rate of breakdown
as a whole, and consequently the ARI for the area. into C+ cases subsequently, this being the highest risk
group. The reduction in rate of incidence from among
Tuberculosis Trend in an Urban Area X+ cases with time, as observed in Chingleput study was
not observed in New Delhi. Data on SS+ cases as well as
Findings from a study carried out in the New Delhi
ARI were not studied in these surveys.
Tuberculosis Centre area are unique in the sense that it
gives the only trend for an urban area in the country.
Tuberculosis Trend in a Tribal Area
The study was conducted for a sufficiently long span of
30 years, following up the same community seven times The Car Nicobar is an island in the Bay of Bengal, with a
after the first survey (48). The diagnosis in the survey total population of 15 575 residing in 15 villages. An
was based only on culture and X-ray results. All the X+ intensified TB control project was launched there by the
and C+ cases were efficiently treated through the survey Island Administration in 1986 (65,66). All SS+ as well as
period [90% cure rate achieved during 1995 to 1996]. C+ prevalence cases were detected on house-to-house
The findings and comments on the trend are summa- survey and treated adequately. Children aged five years
rized as follows. About a tenth [8%] of the bacillary cases and above were given chemoprophylaxis for six months
had continued as such for about a decade [i.e., between after tuberculin testing and those under four years in age
the last two follow-ups , 1982 to 1991]. This was despite given BCG vaccination. Infection prevalence was 10 per
a good service programme in the area. Of the C+ cases cent among those under 14 years of age [Table 3.12]. The
30 per cent were dead in the period. The proportions prevalence rate of SS+ cases was 4.1 per 1000 and X+
remaining as C+, or, as X+ cases during the above period case, 7.9 per 1000. At the end of nine-month short-course
were significantly lower than observed between earlier chemotherapy 94 per cent of SS+ cases were sputum-
two periods of follow up. The standardized prevalence negative. At a re-survey after a 16-month period, no
rate of C+ cases had not changed over the period, being freshly infected children were detected by the differences
around four per thousand [95% CI 2.54 to 4.84]. of reactions method (29,66). Number of new SS+ cases
However, as in Bengaluru and Chingleput study areas, arising in the area in the period of 16 months was only a
there was a higher C+ prevalence at Survey VIII among third of the previous prevalence, similar to the
population aged 55 years and above, compared to earlier observations from the NTI surveys (39). The intensive
surveys. The peak of C+ cases at Survey VIII in females programme was then discontinued, at a time when there
had shifted to around 45 to 54 years from around 25 to was no observed cumulative prevalence and no fresh
34 years, as seen between Survey I through VI. infection taking place in 16 months. At this point, the
However, a proportional concentration in the number NTP was implemented, leaving the routine DTP to
of cases in higher ages with time, as seen in Bengaluru operate in the area. The survey in the area has been
rural area (2,44), did not occur in the New Delhi area. repeated between 2001 and 2002 (37). The findings are
This was interpreted to be due to a significant reduction shown in Tables 3.13 and 3.14.
in population size in the area, in the age group of 45 years It appears from treatment records available with
and above, compared to that in Survey I, 30 years back. the local health authorities that, over the years, the
Epidemiology 43
Table 3.13: Comparison of notified new sputum smear- the tribal community, back to where their epidemiologi-
positive cases in India [1993-2000] with expected incident cal trend originally was, in fact much worse than it was,
sputum smear-positive cases before 1986. The force of infection of the relatively fresh
Year Diagnosed new Rate [per 100 000] cases diagnosed after 1986, must have caused an
SS+ cases* escalation of ARI as well, the incident cases being more
1993 225 256 25 prone to cause higher transmission of infection in the
1994 226 543 25 community.
1995 264 515 29 Similar reversal of the trend from a tribal community
1996 290 953 31
in Greenland (67) may be recalled in this connection.
1997 274 877 29
1998 278 275 29 Obviously, programmes need to be continued with an
1999 345 150 35 accepted level of efficiency for a long enough time. Lack
2000 349 374 35 of advocacy and priority could be important causes of
Total 2 254 943 25 to 35 attenuation of epidemiological trend in a community.
*Numbers expressed in thousands Trends of reduction in a community, achieved through
SS+ = sputum smear-positive care and effort, as in Car Nicobar, could be rudely halted
Source: reference 13 or reversed, through lack of prioritization at a later stage.
This could be seen even in the most developed countries,
Table 3.14: Tuberculosis situation in Car Nicobar [1986-2002]
as in Japan, for example (68).
Period Prevalence of ARI Prevalence

infection [%] [%/year] of SS+ cases/ Tuberculosis in India: Current Status
among 0-14 year 1000 The estimated TB burden in India in the year 2006,
children without
BCG
published in the WHO Report 2008 (69) are listed in
Table 1.1. The current ARI data in India have also been
1986 10.0 1.53 4.10
recently published (70). In this nation wide study [2000-
2001-2002 25.1 3.80 [3.50] 7.30 [7.10]*
2003] (70), children one to nine years of age in selected
ARI = annual risk of infection; BCG = bacille Calmette-Guerin; clusters of 26 districts in four defined zones of India
SS+ = sputum smear-positive
were subjected to tuberculin testing with 1 TU PPD
Numbers in square brackets indicate ARI calculated from a
standardized prevalence rate of infection RT23 with Tween 80. For the country as a whole, the
* Prevalence of disease significantly higher in 2001-2002 average ARI computed from estimated prevalence was
Source: reference 37 1.5%. The ARI showed regional variations and was
higher in the northern [1.9%] and western [1.8%] zones
programme was not maintained in the island. compared with the eastern [1.3%] and southern [1%]
Investigation and follow-up of cases, diagnosed from zones. The proportion of infected children was found
year-to-year since 1988 in the area, showed only 66 per to be significantly higher in urban than in rural areas
cent of the SS+ cases on register completed treatment in all zones.
and their sputum results were not available. Incomplete
treatment, if taking place in these cases year-to-year,
REVIEW OF RECENT FACTORS THREATENING
could have prevented death, not ensuring sputum
ESCALATION
negativity though. Annual case fatality 3.7 per cent
among the cases on record since 1988, as against the likely
Tuberculosis and HIV/AIDS
rate of over 20 per cent among the cases in an area
without an organized programme (39), the latter taken The reader is referred to the chapter “Tuberculosis human
to represent the natural dynamics of TB. In all likelihood immunodeficiency virus infection” [Chapter 40] for more
this accumulation of cases over the years had returned details.
44 Tuberculosis
Tuberculosis and Multidrug-resistant and oscillating around it, there is a felt need today for forecast-
Extensively Drug-resistant Tuberculosis ing the situation with the help of model constructs. One
needs to construct situational variables owing to
The reader is referred to the chapter “Drug-resistant
introduction of DOTS, the attendant HIV problem, a fast-
tuberculosis” [Chapter 49] for more details.
paced programme expansion along with a changed face
of programme delivery with higher private participation,
ASSESSING TUBERCULOSIS SITUATION
among others. Efforts are underway to construct a model
THROUGH MATHEMATICAL MODELLING
to address the Indian TB situation (74).
Tuberculosis Across the Globe The mathematical model depicted in Appendix
Figure 3.3 and Appendix Table 3.4 prepares the initial
In the global context, the process of mathematically disease state as caused due to programme delivery
estimating the impact of the strategy of DOTS is possible process and the respective efficiency levels of various
now (71-73). Murray (72) has evaluated a range of components under it, with time. The itinerant size of the
extensions to global control strategies in terms of their classes and the fractional changes in them, caused
potential effects on TB incidence and mortality, by
through processes of transfers between classes together
regions of the world, from 1998 to 2030. The impact of
with the directional forces responsible for these, are
each of the likely items of the DOTS strategy are evalua-
expressed in mathematical denominations, called
ted separately and incrementally. They have concluded,
“Symbols” and “Vectors”, respectively. Persuaded by
that globally, 171 million new cases and 60 million deaths
an unavoidably large number of variables, 47 model
are expected in the best possible DOTS scenario and 249
vector states and 26 mathematical equations are
million new cases and 90 million deaths in the worst case
conceived. These are intended to measure the effect of
scenario, by 2028. Uncertainty prevails on outcome
intervention, causing changes in the size of the respective
estimates for Asia. In the model by Dye et al (73), it is
classes, including that of “Cure”. The equations await
shown that the potential effect of chemotherapy deli-
simulation and validation in due course. It could pave
vered as DOTS, on TB, is greater in many developing
the way for an epidemiological statement of the disease
countries now, than it was in developed countries years
state in India, in an ongoing manner, disaggregated to
ago. The potential needs to be realized fully.
state levels.
It is forecast that without greater effort to control TB,
the annual incidence of TB disease is expected to increase
by 41 per cent, between 1998 and 2020 [from 7.4 to 10.6 EPIDEMIOLOGICAL EVALUATION: FUTURE
million cases per year] in view of the HIV/AIDS-TB DIRECTIONS
epidemic. It is envisaged that DOTS would save a greater As estimate on the TB burden and the distribution of the
proportion of deaths than lower the incidence of cases. problem are the basic and important information for the
The proportion of difference is bigger in the presence of planners to have, on which intervention strategies are
HIV- infection. devised and necessary resources deployed. These are
given here based both on Indian survey results, as well
Tuberculosis Modelling in the Indian Context
as on the basis of global consensus statements. These are
The first mathematical model to study the natural trend expressed both in terms of average rates [with range for
of TB in India and on some hypothetical situational 95% CI] and the absolute numbers. Disease rates are also
outcomes created through various efficiency variables presented, after adjusting for under and over diagnosis
of programme delivery was developed at the NTI in 1992 made in the surveys, from which the rates are derived,
(63). However, the model was meant for decision making depending on the survey method used.
on alternatives rather than on forecasting the disease It could be of considerable significance in this context
situation. Further, it also did not make the equations to note that the adjusted rates for culture positive cases
available, in a manner that other set of variables could could be as high as six per thousand and that for
be used in forecasting. Clearly, with the change in the radiologically positive cases, about three per thousand
nature of the programme and in the hypotheses on an average (2). These disease categories, along with
Epidemiology 45
Appendix Figure 3.3: Schematic representation of the proposed model for TB in India
Index r takes three values, namely 1 for RNTCP, 2 for NTP/SCC, and 3
for NTP/CR. Pathways from f4 and f6 to c4 and from f′4 and f′6 to c′4 not shown
[See Appendix Table 3.4 for notations]
Source : Yajnik K, Chakraborty AK, Jochem K. A mathematical model for determining the effect of tuberculosis control programmes
on its prevalence in India. A report submitted to the World Bank, New Delhi Office: 2002.p.1-131 (Unpublished)
46 Tuberculosis
Appendix Table 3.4: Model states

Symbol* Definition of classes
u Uninfected individuals.
n Infected individuals.
v Vaccinated individuals.
cp, c’p TB cases [8 cases, indexed by p, for each of sputum smear-positive type and of other types, that is, sputum smear-
negative and extra-pulmonary type]. 1 = under no allopathic antituberculosis treatment**, 2 = under allopathic
antituberculosis treatment in private sector, 3 = under RNTCP, new case, 4 = under RNTCP, retreatment case, 5 =
under NTP/SCC, new case, 6 = under NTP/SCC, retreatment case, 7 = under NTP/CR, new case, 8 = under NTP/
CR retreatment case
fr, f ’r Treatment failure cases/lost cases [6 cases, indexed by r, each of sputum smear-positive and of other types, that is,
sputum smear-negative and extra-pulmonary]. 1 = RNTCP for new cases, 2 = RNTCP for retreatment cases,
3 = NTP/SCC for new cases, 4 = NTP/SCC for retreatment cases, 5 = NTP/CR for new cases, 6 = NTP/CR for
retreatment cases
rp, r’p Recovered TB cases [cured/treatment completed] [8 cases, indexed by p, for each of sputum smear-positive type
and of other types, that is, sputum smear-negative and extra-pulmonary type]. 1 = recovered without allopathic
antituberculosis treatment, 2 = recovered with allopathic antituberculosis treatment in private sector, 3 = recovered
from RNTCP, new case, 4 = recovered from RNTCP, retreatment case, 5 = recovered from NTP/SCC, new case, 6
= recovered from NTP/SCC, retreatment case, 7 = recovered from NTP/CR, new case, 8 = recovered from NTP/
CR, retreatment case
*A letter in bold lower case indicates a vector of 2K components, 2K being the number of gender-cum-age groups spanning the age
spectrum. For example, ui is the ith component of u. The components of a vector represent the number of members of each class
in the selected gender-cum-age groups at a given time. If the index i has an odd value, the state is for the male gender and if i has
an even value, the state is for the female gender. For example, u[2k – 1] and u2k refer to uninfected males in the [2k–1]th group and
uninfected females in the 2kth group. There is no restriction on the number of gender-cum-age groups or on the age interval of any
group
A lower case letter in italics with two indices q and i corresponding to a bold letter with an index q refers to the ith component of
the vector with index q. The first suffix refers to the vector suffix and the second suffix refers to the number of the gender-cum-age
group. For instance, c32 is the second component of the vector c3 and it refers to the number of new female TB cases in the first age
group in RNTCP
The suffixes i, j, and k are reserved for denoting components of vectors, and suffixes p, q and r are reserved for vectors.
In the case of the last three symbols, an unprimed symbol indicates sputum smear-positive case [current or recovered] and a
primed symbol indicates sputum smear negative or extra-pulmonary cases [current or recovered]
** It is to be noted that all TB cases that are taking any non-allopathic or alternative medical treatment [including ayurvedic, unani
and tribal] are in this group. The members of this group are assumed not to have taken allopathic antituberculosis treatment for one
month or more in public health programme
TB = tuberculosis; RNTCP = Revised National Tuberculosis Control Programme; NTP = National Tuberculosis Programme; SCC =
short-course chemotherapy; CR = conventional regimen
Source : Yajnik K, Chakraborty AK, Jochem K. A mathematical model for determining the effect of tuberculosis control programmes
on its prevalence in India. A report submitted to the World Bank, New Delhi Office: 2002 .p.1-131 (Unpublished)
the estimates of infection reflect the total TB problem and higher risks due to dual infection. The average rates
created through mycobacterial infection. It is the SS+ case for the above categories given in Table 3.7, especially that
who has the obvious priority in the RNTCP because of of SS+ cases and mortality, are conveniently used for the
its infection transmission potential, as well as for causing estimation of the TB burden in the country for the pur-
higher mortality and suffering. Even then changes in all pose of resources mobilization and advocacy. However,
the above disease variables are customarily observed in these have obvious limitations, for the purpose of
studies on epidemiology of TB. Besides, these epidemio- evaluation exercises, as discussed here.
logical classes assume added relevance in the HIV-era. Currently, single target rates, one each for the total
The treatment policy of these categories with or without incidence of TB cases and the other for incidence of SS+
HIV-infection is of concern, given the size of the classes cases, are in use for the country as a whole under the
Epidemiology 47
RNTCP in India, based on Dye’s work [Table 3.7]. These fact presented only in support of the hypothesis of
are based on an estimated relationship between the variability in the epidemiological situation within India.
average ARI for the country and the incidence of SS+ The international experience in evaluating the TB control
cases. This does not appear to be an appropriate approach efforts with either the culture or SS+ results through
at target setting of individual district performance in repeat surveys during a comparatively short time frame,
India, given the wide variation in ARI [Table 3.6], the is not encouraging. Similar has been the Indian
urban rural variations of significance [Table 3.8], the experience too.
variable socio-economic conditions and the likely Of the indices presented, it is, however, possible to
attendant variations in the epidemiological trend. visualize ARI as a potent index for the purpose of
Hence, it is suggested that for ongoing evaluation of intermediate and long-term evaluation of programme
programme efficiency, instead of average rates as in use effect on the epidemiological dynamics. For the ARI to
for the vast country under RNTCP, alternative rates for be thus used, it needs to enjoy the freedom from some
the given areas, corresponding to their identification as confounding influences of socio-economic variables, the
having the best and worst possible disease scenario possible levels of malnutrition in the country affecting
could be more desirable to use. The hypothetical disease tuberculin hypersensitivity measurement, and possibly
situations for the best and worst possible case scenarios, varying levels of exclusion of the BCG vaccinated subjects
as per information available for some areas, are depicted from tuberculin tests employed to measure ARI.
in Appendix Table 3.5 (75). Significant work in the past has paved the way for the
It is true that the type of disease categories used in use of ARI for the intended purpose, as follows:
Appendix Table 3.5 to formulate the hypothesis of the Nutrition states of children ranging from malnutrition
best and the worst possible case scenarios in India, make grades I to III in the proportions as are generally prevalent
it almost impossible to work out their extent, given the in the Indian areas, may not effect the TST reaction sizes
complicated nature of their identification, in various and their interpretation for TB infection prevalence
areas in India, in actual clinical practice or in survey (76,77). Prevalence of grade IV malnutrition does affect
situations. The information in Appendix Table 3.5 is in the appreciation of the skin hypersensitivity (78).
Appendix Table 3.5: Varying epidemiological observations by areas in India
Worst case-scenario Best case-scenario
Areas Chennai slum, Bengaluru area

Wardha district [Urban slum and rural]
Nicobar tribal
Urban-rural distribution High in urban pockets No difference
ARI [%] Around 3.0 1.0
Infection prevalence [%]
Age group 0-4 years > 7 [U], 2-3 [R] 2-4
Age group 5-9 years 22.0 [U], 15.0 [R] 8-12
Disease incidence [per 1000/year] 3.0 [U] 1.0
Type of disease [i] Disseminated forms
[Lymphadenopathy predominant,
4-6/1000]
[ii] Pulmonary TB Pulmonary fibrosis [remnant of primary TB]
[iii] Spinal TB
TB mortality in children [< 4 years age] Very high > 230/100 000 About 50/100 000
U = urban; R = rural; ARI = annual risk of infection; TB = tuberculosis

Res 2004;120:248-75 (reference 3)”
48 Tuberculosis
Appendix Table 3.6: Uses of epidemiology as applicable to tuberculosis situation in India
Summary of epidemiological observations Comments and inference on likely trend Epidemiological rationale of NTP in India
of epidemiological situation in India
1. [a] Tuberculosis is a long-term 1. Two points of observations separa- 1. [a] Tuberculosis programme
epidemic spanning several ted by 10-25 years or more are so should be a long-term prog-
centuries close to each other in the context of ramme. Vertical programmes
[b] Transient changes in the epide- the epidemic curve spanning not suitable. Case finding/
mic curve may occur, e.g., several centuries, that quantitative treatment activities to be
through war, famine etc., but changes in disease rates cannot be carried out as service compo-
the trend resumes its natural measured, unless massive [which is nent of an integrated health
course after their effects unlikely] care delivery system
disappear [secular trend] [b] No quick change in situation to
be expected
[c] No all India repeat sample
survey at small intervals of
10-25 years called for
2. Tuberculosis problem is more or 2. Wide spread tuberculin use has 2. Almost a similar and uniform kind
less spread all over the country. taken place, with the inference that of programme is required all over
Proper sampling required to mea- TB curve is in endemic phase in the the country. No special programme
sure statistically significant area- country. However, there could be was formulated for urban slums, etc.
wise differences. Barring a few differences in the age of epidemic However, the indices for measure-
exceptions, ARI is different from from area to area ment of programme activity [expec-
area to area. There are significant tation] need to be varied, depend-
urban-rural differences in ARI ing on epidemiological situation in
the area, as revealed by ARI studies
3. Prevalence rate of cases was same 3. Disease not likely to be in the 3. In absolute numbers, 80% of the
for the rural and urban areas as per spreading phase: probably on the total problem is distributed in rural
the NSS. It has later on been shown descending limb areas [since 80% of the population
to be higher in the urban areas live in villages]. Hence, TB services
should cover rural areas adequately.
Emphasis needs to be on equitable
spread of programme maintaining
the quality of care. The NTP had an
initial bias in favour of rural areas,
since corrected under the RNTCP,
in view of the concentration of cases
in urban areas
4. About 38% of persons of all ages 4. The wide gap between the rates 4. [a] Presence of 38% of total per-
and both sexes and almost 70% of may mean that the disease is on the sons infected in the community
males above 40 years of age are descending phase may mean that eradication
infected. Prevalence of bacillary cannot be conceived as a goal
cases: 0.4%, mortality rate: 0.05% [b] Also, the large pool of the
to 0.09% infected is of great significance
because of HIV-risk
[c] High infection prevalence and
incidence represents a high
transmission of infection, rela-
ted to smear positive case
prevalence. The HIV preva-
lence would augment the case
incidence. High quality
programme with a fast spread
throughout the country is
advocated
-Contd-
Epidemiology 49
Appendix Table 3.6 -Contd-

5. Prevalence rate of infection and 5. The disease is beyond the peak, —

disease as well as mortality are probably in the descending limb of
more in males than females the curve or endemic phase
6. There is a decreasing trend in the 6. Probably represents a secular trend 6. [a] Programme interference-effi-
infection rate of about 2% per year, of infection rate. Tuberculosis ciencies be augmented to
over a long-term observation for a situation may be on slow downward hasten the decline
period of ranging from 5-25 years trend in some areas and not chang- [b] Surveillance system should be
or more among children [from ing in some other areas. It is logical developed to study infection
longitudinal surveys of NTI]. But the to postulate different epidemio- rate in different parts conti-
same is not seen in the adjoining logical age from area in India, given nually, with provision for strati-
areas of Tumkur, Doddaballapur its vast expanse fication even within districts.
and in the neighbouring state of This could serve as effect-
Tamil Nadu [the last one for nearly evaluation of the programme if
over 15 years] performed over 7-10 years,
area wise.
7. [a] Pulmonary TB is an adult 7. Proportional concentration of 7. Since cases in adults can be easily
disease. Population in 0-19 disease in adults may mean that [a and b] diagnosed by simple tools
years [comprising 50% of total disease is beyond the peak. It is [microscopy] from among sympto-
population] contain only 7% of most likely that the epidemic curve matics, disease among relatively
total prevalence cases. is not on ascending limb. Even as articulate adults is possible to be
Remaining 93% of the cases the population aged 40+ years tackled under a public health prog-
are distributed in population would contain 50% of the cases, the ramme. [Note: 80% of cases are
aged 20+ years public health significance of young aware of symptoms and 50% have
[b] Relatively higher and higher adults between 20-39 years age taken action]
concentration of cases in containing 43% of cases cannot be
higher age groups has occur- over-emphasized, as it happens to
red in later surveys as com- be the most productive segment in
pared to earlier surveys. In later population. Similar is the situation
surveys in Bengaluru rural in females, where the disease
areas, about 80% of cases burden is borne by those in the
were detected among those in reproductive age, nearly half of the
40+ age group. cases in women being in this age
group. May mean that TB is in
declining phase
8. [a] The incidence of smear-pos- 8. [a] This is commensurate with fall 8. The effect evaluation indices follow-
itive cases in the community is in the ARI from 1% to 0.6%. ing intervention need to be area-
observed to have dwindled in May mean that TB is in specific within India, to suit the
23 years in Bengaluru rural declining phase variable epidemiological situations
area from around 65 to 23 per [b] The high ARI with no or small
100 000. This could be the best extent of decline below 3% per
possible case-scenario in India year, marks out India to be one
8. [b] Other areas in India have a ARI of the high prevalence areas,
without change in time e.g., together with the sub- Saharan
Tamil Nadu. African countries
9. There is an evidence of reversal of 9. This is probably related to lowering 9. The antituberculosis measures
a disease trend in Car Nicobar with of priority need to be sustained at a high level
increase in ARI of efficiency over a long time
10. [a] Nearly 10% of all cases of 10. Disease is on downward trend or in 10. [a] Tuberculosis is a major public
crude mortality in the commu- the endemic phase health problem and deserves
nity is contributed by tuber- appropriate priority
culosis deaths
-Contd-
50 Tuberculosis
Appendix Table 3.6 -Contd-

[b] Dramatic reduction in case [b] Programme effectivity in preventing

facility is possible in a short deaths needs to be recorded
time with adequate intervention and highlighted for advocacy
as shown in Madanapalle and purposes
Bengaluru surveys
11. [a] Mortality rate decreasing with 11. Disease is on downward trend or in 11. Better case-holding should be
time from survey to survey, but the endemic phase attempted to save life. Treatment
is still high. services to be widely distributed
[b] Survival rate of cases diag- through integrated delivery appro-
nosed in later surveys were ach. Programme effectivity in pre-
better as compared to in earlier venting deaths needs to be recorded
rounds of longitudinal surveys and highlighted for advocacy
purposes
12. Paediatricians generally report 12. Policy of BCG vaccination to 12. BCG vaccination programme to be
seeing less of military, meningeal or younger children might have been continued in younger population
fulminant forms of TB. Same is the effective in revising the extent as [0-1 year or 0-4 years]
experience of TB specialists, work- well as incidence characteristics in
ing in clinics children, by arresting haemato-
genous dissemination
ARI = annual risk of infection; BCG = bacille Calmette-Guerin; TB = tuberculosis; NTP = National Tuberculosis Programme; RNTCP =
Revised National Tuberculosis Control Programme; NTI = National Tuberculosis Institute, Bengaluru; HIV = human immunodeficiency
virus
Source: reference 2
However, such prevalence is minimal enough in the epidemiological situation and surveillance. The baseline
Indian context to have a bearing on the observation of ARI studies have been completed throughout the country
infection rates through tuberculin test reactions. Thus (71). These would have to be repeated in due time to
protein energy malnutrition [PEM] levels as prevalent obtain a trend in the TB situation, subject to various levels
in India may not affect the infection rates calculations of the intervention-efficiencies. Small population sizes,
and comparison in area and time dimension, unless high as required for infection surveys, make such studies
levels of grade IV malnutrition is present in some specific possible to conduct and they could yield valuable
instances. The varying proportions of the BCG vaccinated information.
children excluded from the test does not affect the Some economic indices in the nature of physical
estimation of infection, as arrived at by testing the quality of life indices [literacy rate, life expectancy at
unvaccinated (79). birth, maternal mortality rate and infant mortality rate],
Moreover, high proportion of the BCG vaccinated as developed from census data, could also be used along
children excluded from the test, could still allow enough with ARI to classify areas for the purpose of applying
unvaccinated children in the community to be tested, and average indices [virtual “targets”] for monitoring. Over
to draw inferences on infection rate and the trend in a comparatively shorter periods of observation of the
community (80). Even the question of appropriate dosage natural dynamics in the NTI longitudinal survey (39) or
of tuberculin antigen to be used in the epidemiological the TRC study in rural Tamil Nadu (35,36), TB appears
setting as in India has been selected carefully. The dose to be having a near steady state in India (2). Evidence is
of 1 TU has been found suitable, as different from the available to permit one to draw the hypothesis that the
international practice of using 2 TU (81). Previous epidemic situation in India is probably on a slow
research in India has, thus, prepared the ground for ARI downward curve of the epidemic. Such evidences could
to be used in this country as an index of measurement of be as follows: declining mortality and case fatality rates
Epidemiology 51
due to TB, decline in meningeal and miliary forms of the assistance of Mr V. Pandu and Ms Savitha Kumar is also
disease, a relatively high prevalence of cases in higher thankfully acknowledged.
ages with a low rate of positive cases in children, and a
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Epidemiology: Global Perspective 55
Epidemiology:
Global Perspective
4
DS Maru, Jason Andrews
INTRODUCTION Case Notification and Passive Case Detection
Tuberculosis [TB] remains the number one cause of adult The most widely available statistics on TB come from
deaths by a curable infectious disease worldwide despite reports of active cases from clinics and hospitals. The
the availability of effective diagnostic, preventive, and advantage of these statistics is that they come directly
curative strategies against Mycobacterium tubercu- from providers treating patients, which can be
losis (1). Indeed, the failure of global public health in coordinated with central surveillance agencies to provide
controlling this epidemic has as much to do with the host reasonably reliable estimates over time. Their accuracy,
and its environment as it does with the microbe. on the other hand, may be compromised in settings
Persistent or rising rates of human immunodeficiency where treatment is primarily through unregulated
virus infection [HIV], poverty, illiteracy, smoking, and private practitioners, where access to care is low, and
malnutrition, together with wars, political uncertainty where diagnostic facilities are wanting. Indeed, in the
and an increasing migratory population patterns, very places where TB may be highest, reporting stan-
provide an ideal host and environment for the survival dards may be poorest. The World Health Organization
and spread of TB. [WHO] endorses DOTS as the key strategy for controlling
This chapter reviews the historical and present and eventually eradicating TB in the guidelines for
epidemiology of this devastating epidemic and discusses National Programmes (2). Accurate recording and
the factors that have been responsible for the divergent reporting are virtues of this system which has gained
pattern of prevalence and mortality trends. acceptance world over. As DOTS expands, it is hoped
that TB detection and treatment will become more
standardized and, consequently, these rates will become
ISSUES IN MEASUREMENT
more accurate.
Evidence-based public health practice requires both the
Active Case Detection
political will to develop data-driven health policy and
the technical capacity to collect sound data. Unfortu- Active case detection requires a much greater investment
nately, these two prerequisites often are lacking in the of resources, and most developing countries do not view
countries most hard-hit with TB. First, some of the key this as a priority strategy. This method has been proposed
parameters that constitute the bedrock of TB control through the following broad measures: [i] active case
policy are defined and some of the challenges in finding through mass miniature radiography and
collecting good data to estimate these parameters are sputum examination; and [ii] contact tracing of close
discussed. contacts of active TB cases (3). Active case finding could
56 Tuberculosis
be undertaken in a periodic fashion, for example, once important in fostering the political will necessary to
in every seven years, or as a single cycle. While the procure the massive funding for the Millennium
primary aim of such programmes is in improving Development Goals [MDGs] (10). Unfortunately, analysis
treatment and detection, they also can serve as strategies of aggregated data may be misleading given the consider-
to improve surveillance. Active case detection could able heterogeneity in the levels and trajectories of the
provide a more accurate estimate of TB epidemiology, innumerable local epidemics.
as well as engage TB control programmes and communi- So, while disease transmission is increasingly a global
ties in broader primary care. However, the experience phenomenon, the fact remains that, even within countries
of active case finding in various contexts and populations and indeed towns, the burden of disease tends to operate
over the past 80 years has been variable, with some in very specific, complex patterns. For example, when
programmes finding great success and having a there is a major outbreak of TB among the most margina-
population-level impact on TB incidence and others lized homeless segments of New York City, most citizens
suffering from high costs, inefficiencies, and the limited of the city are not placed at appreciably greater risk.
sensitivity of chest radiograph and sputum examination Determining incidence rates on city-wide scale may be
(4). Nevertheless, in recognition that additional strategies much less fruitful in assessment, strategy development,
are needed in areas where TB control is failing, such as and monitoring than determining risk among high-risk
settings of HIV prevalence, large scale evaluations of this populations.
tool are currently underway. Especially when assessing global epidemiology, these
Distinct but related approaches include enhanced locally-specific data are either not available or are overly
case finding and contact investigation. Enhanced case cumbersome to interpret. Tuberculosis may be spiralling
finding is a term used to denote a programme that out of count in some countries, but, because their popula-
informs a population about TB symptoms and treatment tion size is small, they have little impact on the numbers
availability, encouraging self-presentation to medical of the global epidemic. So, while 199 countries reported
services rather than individually engaging the patient to the WHO in 2006, 80 per cent of all incident cases of
outside the context of care. Contact investigations can TB were from 22 high-burden countries [HBCs] (11). On
be considered forms of active case finding, whereby the the other hand, many of the African countries with the
close contacts or household contacts of patients highest incidence rates per capita are not on the list of
diagnosed with TB are screened for the disease. The yield HBCs, owing to their small size. As such, setting global
of this approach—and, correspondingly, the cost- TB priorities needs to account for both national and
effectiveness—has been highly variable and is very much highly local epidemiological dynamics.
context- and population-dependent (5). For example, the
tracing of paediatric TB patients has generally found a Mathematical Models and Epidemic Prediction
low yield, despite the fact that TB in children represents Data generated from the above measurement strategies
a recent infection. Secondary case detection rates through
are important not only for enhancing our understanding
routine contact investigation have ranged from two per
of present TB epidemiology, but also in predicting future
cent in the USA, to 12 per cent in India and 61 per cent in epidemics. Mathematical models can provide rigorous
Malawi (6-8). While the utility of this approach continues
prediction of future TB epidemiology, crucial to public
to be evaluated, more recent evidence has suggested that
health planning. While an in-depth treatment of mathe-
contact investigations can be useful in patients with matical models is beyond the scope of this text, the basic
multidrug-resistant TB [MDR-TB] as a means of timely
foundation for even the most complex models is a
identification and treatment of individuals with drug-
modified Susceptible-Infected-Recovered [SIR] model that
resistant infection (9). allows for both latent infection and active disease. A
simple model for illustrative purposes [Figure 4.1A] is
Aggregating Data and Geographical Heterogeneity
modified from Blower (12,13). This is modelled by a series
Aggregating these data from local epidemics and esti- of differential equations as shown in Figure 4.1B.
mating the size of a more conceptual “global epidemic” Essentially, the model allows for individuals in each
is central global public health planning. It is also compartment to flow between each other at constant
Figure 4.1A: A mathematical model for tuberculosis epidemiology.

The letters X, L, T, and R indicate separate compartments between
which an individual in the population flows
Figure 4.2: Changes in tuberculosis mortality rate in Western
Europe, 1750-1980
Reproduced with permission from reference “Murray JF. A thousand
years of pulmonary medicine: good news and bad. Eur Respir J
2001;17:558-65 (reference 19)”
ment from a different path. For interesting applications

of mathematical models to TB epidemiology and
prediction, see references (14-16). The reader is also
referred to the chapter “Epidemiology” [Chapter 3] for
details regarding mathematical modelling as applied to
the Indian scenario.
Figure 4.1B: Mathematical equations underlying the model THE GLOBAL SCENARIO
described in Figure 4.1A. The parameters are defined as:  is the
birth rate; μ is the mortality rate [this can differ between compart- Historical Trajectory
ments; for simplicity not shown]; λ is the “force of infection” which
depends upon the contact rate and the transmissibility of infectious
Prior to the development of effective antituberculosis
active TB in the population; p is the probability that an infection will therapy in the late 1940s, TB was a major public health
rapidly progress to TB [primary progressive TB]; f is the fraction of threat in both developing and developed countries;
primary progressive active TB cases that are smear-positive; q is mortality due to pulmonary TB was 50 per cent and TB
the fraction of endogenous reactivation active TB cases that are meningitis and miliary TB were almost 100 per cent fatal.
smear-positive; w is the rate at which recovered cases relapse;
While there was already a decline in prevalence of TB in
and c is the treatment rate
Source: references 12,13 the developed world prior to the advent of antituber-
culosis treatment [the reasons for which are still being
rates; by varying various parameters, for example, the debated] (17,18), the introduction of specific treatment
treatment rate, one can assess the long-term behaviour with antituberculosis drugs resulted in a precipitous
of the system. A few key assumptions of this kind of reduction in mortality due to TB in the developed world
model are: homogenous mixing; homogenous dynamic [Figure 4.2] (19) and may have further accelerated the
behaviour of individuals within each of the compart- decline in prevalence. However, progress has been much
ments; constant flow rates between compartments that slower in developing countries; although there is a
are independent of the size of individual compartments; paucity of data on TB prevalence and mortality in
additive mortality rates. Additionally, note that there is developing countries prior to the 1990s, when the disease
no age structure and that the system is memory-less in was declared a “global emergency” and surveillance and
the sense that an individual that reached one compart- control efforts became systematized, a snapshot of the
ment from a particular other compartment behaves in global prevalence of TB in 1990 is suggestive; while the
the same way as an individual that reached the compart- prevalence of TB in Europe and the USA was 55 and
58 Tuberculosis
8 per 100 000, respectively, in Africa and South-East Asia

the corresponding figures were 317 and 536 (20). Where
historical data are available, a steady-state in disease,
during the period of TB decline in the West, is revealed;
in India, for example, prevalence of sputum smear-posi-
tive pulmonary TB decreased modestly from 400 per 100
000 in the 1950s to 330 per 100 000 in 1991, and incidence
between 1990 and 2004 was essentially constant (20,21).
Furthermore, global progress in TB control has not
been uniformly smooth. The decline in TB prevalence in
developed countries began to reverse in the 1980s; in the
United States, for example, TB incidence rose steadily
between 1985 and 1992, following 30 consecutive years
of decline (22). This trend has been attributed to
immigration from high-prevalence countries, urban
poverty, HIV, and a response weakened by the percep-
tion that TB was a disease of the past. While TB rates Figure 4.3A: Relative contribution to the global tuberculosis
among the US-born population declined 63 per cent incidence
between 1993 and 2005, it fell by a little over half that
Reproduced with permission from “Central TB Division. Directorate
rate in foreign-born residents of the US over this time General of Health Services, Ministry of Health and Family Welfare,
(23). Many Western European countries have seen similar Government of India. TB India 2008. RNTCP status report. New
trends, while countries in the former Soviet Union are Delhi: Central TB Division. Directorate General of Health Services,
seeing high and rising rates due to poverty, malnutrition, Ministry of Health and Family Welfare, Government of India; 2008
poor living conditions, breakdown in the law and order (reference 24)”
situation and an inadequate health care infrastructure.
GLOBAL TUBERCULOSIS EPIDEMIC: CURRENT sub-Saharan Africa [31%]. As per the estimated number
STATUS of incident cases, 22 countries have been given special
attention. This large excess has partly been ascribed to
The WHO’s 2008 report (11) presents an overview the effect of HIV infection. In 2006, 1.7 million people
regarding the year 2006 data and estimates, basing on died of TB, including 231 000 patients co-infected with
the reports from 202 countries representing 99.9 per cent HIV (11).
of the world’s population. This report (11) provides a
comprehensive insight into the current status and trends
Expansion of DOTS
of the global TB epidemic. In 2006, globally there were
an estimated 9.2 million new TB cases [139 per 100 000] In 1993, the WHO declared TB to be a global health
globally [Figures 4.3A, 4.3B, and 4.3C; Tables 4.1A and emergency; subsequent to this, momentum for DOTS
4.1B] (11,24). Of these, 4.1 million [62 per 100 000] were built up, and the 1990s showed a remarkable expansion
new sputum smear-positive cases. of DOTS coverage throughout the globe. By 2006, DOTS
Tuberculosis prevalence rates appear to be falling has been implemented in 184 countries [93% of the
globally for several years. The TB incidence rate in 2006 world’s population] (11) [Figure 4.4]. Case detection rates
was stable or in decline in all six WHO regions, and followed; from 11 per cent in 1995 to over 50 per cent by
appears to have levelled off for the first time since 1993 2006 (25-27). Data from India show the great speed with
(11). The total number of new TB cases registered slow which this programme has been enacted; from its start
increase because of the continuing increase in the case- in 1997 as national expansion of the Revised National
load in the African, Eastern Mediterranean and South- Tuberculosis Control Programme [RNTCP] to 2006, over
East Asia regions. Majority of the cases [55%] were in a billion Indian citizens came to live in areas covered by
Asia [South-East Asia and Western Pacific regions] and DOTS (24). The Figure 4.5 (11) shows this remarkable
Figure 4.3B: Estimated numbers of new tuberculosis cases [all forms], 2006
TB = tuberculosis
Reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning,
financing WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)”
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report
of the current year available at the URL: http://www.who.int/topics/tuberculosis/en/
Figure 4.3C: Estimated numbers of new tuberculosis cases [all forms] per 100 000 population, 2006
TB = tuberculosis
financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008” (reference 11)”
60 Tuberculosis
Table 4.1A: Estimated tuberculosis burden 2006 in 22 high prevalence countries
Incidence* Prevalence, all Mortality, all HIV prevalence,

forms per 100 000 forms per 100 000 in incident
population per year population per year cases %†
All forms Smear-positive
per 100 000 per 100 000
population per year population per year
1. India 168 75 299 28 1.2
2. China 99 45 201 15 0.3
3. Indonesia 234 105 253 38 0.4
4. South Africa 940 382 998 218 44.0
5. Nigeria 311 137 615 81 9.6
6. Bangladesh 225 101 391 45 0.0
7. Ethiopia 181 82 263 34 0.3
8. Pakistan 378 168 641 83 6.3
9. Philippines 287 129 432 45 0.1
10. DR Congo 392 173 645 84 9.2
11. Russian Federation 107 48 125 17 3.8
12. Vietnam 173 77 225 23 5.0
13. Kenya 384 153 334 72 52.0
14. UR Tanzania 312 135 459 66 18.0
15. Uganda 355 154 561 84 16.0
16. Brazil 50 31 55 4 12.0
17. Mozambique 443 186 624 117 30.0
18. Thailand 142 62 197 20 11.0
19. Myanmar 171 76 169 13 2.6
20. Zimbabwe 557 227 597 131 43.0
21. Cambodia 500 220 665 92 9.6
22. Afghanistan 161 73 231 32 0.0
High-burden countries 177 79 286 32 11.0
* All estimates include TB in people with HIV

† Prevalence of HIV in incident TB cases in adults aged 15-49 years
HIV = human immunodeficiency virus; TB = tuberculosis
Adapted and reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance,
planning, financing. WHO/HTM/TB/2008.393 Geneva: World Health Organization; 2008 (reference 11)”
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of
the current year available at the URL: http://www.who.int/topics/tuberculosis/en/
trend. China, the most populous country in the world Human Immunodeficiency Virus Co-infection
and one of the highest burdens of TB, had similarly The HIV/AIDS epidemic is the major reason for
reached nearly 100 per cent coverage by 2005 (26). increasing host susceptibility patterns in the 1980s and
Assessing the impact of DOTS on global epidemio- 90s and continues to fuel the tuberculosis epidemic
logy is difficult owing to its patchy and sporadic [Figure 4.6]. The HIV is responsible for nearly 10 per cent
distribution with high variability between DOTS of new cases of TB worldwide and more than 30 per cent
programmes, and the lack of hard data as to its real-world of new cases in Africa (27). Widespread HIV/AIDS is a
effectiveness. Mathematical modelling, however, does central reason why the WHO African region remains the
suggest that the epidemiologic potential is quite high, one region that has failed to decrease incidence during
with annual decreases in tuberculosis incidence and the DOTS era; indeed, several African countries have
deaths on the order of 10 per cent; the impact is dam- seen rising incidence rates. A recent study of a high
pened, however, by the HIV epidemic (25). The reader HIV-prevalence community in South Africa found a 2.5-
is referred to the chapter “DOTS: the strategy that ensures fold increase in TB notification [to more than 1400 per
cure of tuberculosis” [Chapter 56] for further details. 100 000, a staggering and unparalleled figure]
Table 4.1B Estimated global tuberculosis burden 2006

Incidence* Prevalence, all Mortality, all HIV prevalence,
forms per 100 000 forms per 100 000 in incident
WHO region All forms Smear-positive population per year population per year cases %†
per 100 000 per 100 000
population population per year
AFR 346 155 547 83.0 22.0
AMR 37 18 44 5.4 6.4
EMR 105 47 152 20.0 1.1
EUR 49 22 54 7.0 3.0
SEAR 180 81 289 30.0 1.3
WPR 109 49 199 17.0 1.2
Global 139 62 219 25.0 7.7
* All estimates include TB in people with HIV

† Prevalence of HIV in incident TB cases in adults aged 15-49 years
HIV = human immunodeficiency virus; TB = tuberculosis; WHO = World Health Organization; AFR = African region; AMR = American
region; EMR = Eastern Mediterranean region; EUR = European region; WPR = Western Pacific region; SEAR = South-east Asian
region
Adapted and reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance,
planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)”
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of
the current year available at the URL: http://www.who.int/topics/tuberculosis/en/
“Tuberculosis and human immunodeficiency virus infection”

[Chapter 40] for more details.
Drug-resistant Tuberculosis
The spectre of MDR-TB has provoked considerable fear
in the public health community in recent years. The
concerns are not without justification: MDR-TB can be
difficult to treat, requires long durations of therapy with
regimens that are orders of magnitude more expensive
than first-line short-course chemotherapy, and carry
Figure 4.4: Number of countries implementing DOTS [out of a
total of 212 countries], 1991-2006 higher rates of mortality.
Reproduced with permission from “World Health Organization. Data presented in the third round of surveys (29,30)
WHO report 2008. Global tuberculosis control: surveillance, coordinated by WHO and the International Union
planning, financing. WHO/HTM/TB/2008.393. Geneva: World Against Tuberculosis and Lung Disease [IUATLD]
Health Organization; 2008 (reference 11)”
between 1996 and 2002 from 77 settings or countries
The World Health Organization updates these data annually.
The reader can access the updated information from the WHO that were collected between 1999 and 2002 indicate that
report of the current year available at the URL: http://www.who.int/ MDR-TB was found in all regions of the world (29). The
topics/tuberculosis/en/ problem of drug-resistant TB has been compounded by
the recent documentation of extensively drug-resistant
concomitant with a 3.5-fold rise in HIV infection in the tuberculosis [XDR-TB] as a global phenomenon (31).
adult population (28). Alarmingly, this trend unfolded The epidemiological aspects related to MDR-TB and
in a community with excellent DOTS coverage, confirm- XDR-TB are exhaustively covered in the chapter
ing the claim that DOTS alone will be an insufficient “Antituberculosis drug resistance surveillance” [Chapter 50]
strategy for containing TB in areas with high rates of HIV and the reader is referred to this chapter for more
infection. The reader is referred to the chapter details.
62 Tuberculosis
Figure 4.5: Contributions to the global increase in the number of new smear-positive cases notified under DOTS made by high-
burden countries, 2005-2006
financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)”
Figure 4.6: Estimated HIV prevalence in new adult tuberculosis cases, 2006
HIV = Human immunodeficiency virus; TB = tuberculosis
financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)”
Figure 4.7: The new Stop TB strategy at a glance

TB = tuberculosis; HIV = human immunodeficiency virus infection; MDR-TB = multidrug-resistant tuberculosis
Reproduced with permission from “World Health Organization. Stop TB Partnership. The Stop TB Strategy. Building on and enhancing
DOTS to meet the TB-related Millennium Development Goals. WHO/HTM/TB/2006.368. Geneva: World Health Organization; 2006
(reference 36)”
64 Tuberculosis
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66 Tuberculosis
Pathology
5
S Datta Gupta, Ruma Ray, SS Gill
He becomes the true discoverer who establishes the truth; and over the bacillus or the bacillus can overwhelm the host.
the sign of truth is the general acceptance. In science, credit At times the battle may stop for years, only to resume
goes to the man who convinces the world, not to the man to later on. All this is reflected in the gross and microscopic
whom the idea first comes appearances of the different organs.
Dubos RJ, Dubos J (1) Tuberculosis infection is spread by aerosol. Therefore,
pulmonary TB is the predominant form of disease. The
INTRODUCTION lung is indeed the primary site of infection in most
instances. Extra-pulmonary TB is commonly a conse-
Tuberculosis [TB] has been known to mankind since quence or accompaniment of pulmonary TB. However,
many years. The aetiology, pathogenesis, clinical features TB affects almost every organ in the body. It would be
and the treatment of TB have been the subject of beyond the scope of this chapter to deal with the
controversy and myths for centuries. However, there was pathology of TB with reference to each and every organ
agreement on one score and that was the observation in detail. Readers are, therefore, referred to the respective
that the disease was associated with a poor prognosis. It chapters concerned with different organ systems that
was hoped that the discovery of the cause of TB marked supplement this chapter.
the end of the scourge, phthisis, struma, phyma, hectic
fever, consumption, ‘white death’, the ‘white plague’, or
CLASSIFICATION
the ‘Captain of all these men of death’ as remarked by
the evangelist John Bunyon. Unfortunately, this did not Tuberculosis is classified into different clinicopatho-
happen. The human immunodeficiency virus [HIV], logical types depending on various factors [Table 5.1].
acquired immunodeficiency syndrome [AIDS] pandemic Though there may be some link in the relationship of
has had a devastating effect on this scenario. Despite the age to the exposure and type of TB, terminology related
emergence of drug-resistant cases, the treatment of TB is to age such as “childhood TB” and “adulthood TB”
the most cost-effective of all cures (2,3). It must be realized should not be used.
that a significant number of TB cases go unreported until Primary TB occurs in persons who have been exposed
death. This underlines the danger of open cases spread- to Mycobacterium tuberculosis for the first time. In areas
ing infection to others. Tuberculosis also constitutes a of the world where TB is highly endemic, primary TB
grave danger to health care professionals (4). usually occurs in children. In countries where substantial
The pathology of TB is essentially similar to most control of TB has been achieved, increasing number of
other infectious diseases. It is the process and the adults lack acquired immunity. When these adults are
consequence of interplay between the bacillus and host infected for the first time, they can manifest the primary
immunity. The relationship between the two can be form of the disease. Primary TB can also occur when
varied, complex and can last life long. The host can win acquired immunity to TB is lost due to senescence or
Pathology 67
Table 5.1: Classification of tuberculosis Virchow [1818] to describe tumours that may ulcerate
and give rise to granulation tissue (6,7). However, the
Based on sequence of events following the first exposure
Primary TB present connotation is different. Granuloma can be
Disease caused by Mycobacterium tuberculosis in a person defined as a focal, compact collection of inflammatory
with no previous exposure cells in which mononuclear cells predominate. Granulo-
Progressive primary TB mas are the result of a persistent non-degradable product
Primary disease which is generally self-limiting may
or organism, or the result of hypersensitivity or both.
progress to give rise to larger lesions
Post-primary TB
Therefore, granulomas may form as a consequence of
Disease which is the result of endogenous reactivation an immunological mechanism or otherwise. Granulomas
[in a person previously exposed to Mycobacterium tuberculo- which are due to a non-immunological mechanism
sis] or exogenous reinfection generally do not reveal a lymphocyte response [e.g., some
Based on location of the foreign body granulomas] whereas those due to
Localized disease an immunological mechanism have a prominent
Pulmonary TB lymphocyte component. There is an almost sequential
Extra-pulmonary TB change due to interplay amongst the causative agent
Disseminated TB
[identifiable or non identifiable], macrophage activity,
Tuberculosis disease process involving more than 2
non-contiguous sites. Disseminated TB can occur in T-cell responses, B-cell overactivity and circulating
primary [early generalized TB] and post-primary [late immune complexes of biological mediators resulting in
generalized TB] forms of the disease. When the lesions a granulomatous inflammation.
are uniform and are of the size of a millet seed [< 2 mm], Granuloma is not a mere collection of inflammatory
the term miliary TB is used
cells but an active site of numerous enzymes and
TB = tuberculosis cytokines involved in the very serious business of
removing the causative agent (8). Morphologically,
occurrence of some specific immune defect. As pointed granulomas invariably show some degree of organi-
out by Rich (5) “resistance is a notoriously fluctuating zation. Centrally, macrophages predominate and are
condition and even though resistance may have been essential constituents of most granulomas because these
previously acquired, it may be overcome by new invasion are sites where an attempt is being made to remove the
of tubercle bacillus”. Progressive primary TB arises when causative agent through phagocytosis. When macro-
there is inadequate immunity. It is most commonly seen phages become activated, the cytoplasm assumes a large,
in infants, adolescents and elderly. pale, eosinophilic or even foamy appearance. The
Post-primary TB, is generally a disease of the adults margins become indistinct so that adjacent macrophages
due to endogenous reactivation or exogenous reinfection seem to form a continuous sheet, akin to the surface
in a patient who has been infected in the past and has epithelium. Such cells are called epithelioid cells and the
retained a degree of acquired immunity. Haematogenous granuloma is known as an epithelioid cell granuloma.
spread of the disease throughout the lungs and to Not all granulomas are of the epithelioid cell type.
multiple organs [miliary TB] may occur in both the Epithelioid cells may fuse to form multinucleated giant
primary and post-primary forms of the disease. cells. Generally, two types of giant cells are identifiable
in TB. In one type, the nuclei are arranged along the
HISTOPATHOLOGICAL APPEARANCE periphery, almost forming a rosette around the central
The histopathological hallmark of TB is a granuloma. cytoplasmic area. This is called the Langhans’ type of
Infact, TB is cited as the classical example of a granulo- giant cell after Theodore Langhans [1868] who critically
matous inflammation. It is, therefore, necessary to briefly evaluated granulomas in TB (5). In the foreign-body type
discuss the features of a granuloma here. of giant cells, the nuclei do not show such a regular
arrangement. The offending foreign-body may or may
Granuloma not be identified within this giant cell. In some lesions
The term granuloma [derived from the diminutive of the associated with multiple discrete granulomas, it appears
Latin term for a grain, granulum] was used by Rudolph as though each granuloma has a single giant cell.
68 Tuberculosis
Sometimes such independent granulomas [if such a term Table 5.2: Aetiology of some granulomatous infections
can be used] appear to coalesce to form confluent granu-
Well recognized agents
lomas. Surrounding the macrophages is a variable cuff Mycobacteria Tuberculosis, leprosy, Buruli ulcer,
of lymphocytes which may be relatively more prominent swimming pool [fish tank] granuloma
in immunologically induced granulomas. Other types of Bacteria Brucellosis, melioidosis, actinomycosis,
inflammatory cells such as eosinophils may also form a nocardiosis, granuloma inguinale,
part of the granuloma. Older granulomas that are healing listeriosis, tularemia
Chlamydiae Lymphogranuloma venereum, trachoma
show fibrosis. Ultimately, the entire granuloma may
Rickettsiae Qfever [Coxiella burnetii infection]
undergo fibrosis, hyalinization, calcification and even Spirochetes [syphilis], pinta, yaws
ossification. The presence of a central area of necrosis Fungi Cryptococcosis, candidiasis,
distinguishes a necrotising granuloma from a non- sporotrichosis, histoplasma, aspergillosis,
necrotising granuloma. The histopathological lesion of blastomycosis, coccidiodomycosis,
chromoblastomycosis, mycetoma
TB is the prototype of a necrotising epithelioid cell
Protozoa Leishmaniasis, toxoplasmosis
granuloma [Figure 5.1] while that of sarcoidosis is a Nematodes Visceral larva migrans [toxocariasis]
classical example of a non-necrotising epithelioid cell Trematodes Schistosomiasis, paragonimiasis,
granuloma. Therefore, it is not uncommon to refer to fascioliasis, clonorchiasis
tuberculoid type and sarcoid type of granulomas. The Viruses Infectious mononucleosis,
causes of granulomatous infection are numerous and are cytomegalovirus, measles, mumps
Foreign body Talc, silica, zirconium
provided in Table 5.2 (9).
The diagnosis of the aetiology of granulomas, on Recently recognized
histopathological grounds, can vary from “accurate” to Bacterium Cat-scratch disease [Bartonella
henselae]
“presumptive” to “impossible”. If the cause is apparent,
Actinomyces Whipples disease [Tropheryma
as in the case of a foreign body or a parasite or fungus or whippeli]
acid-fast bacilli [AFB], then the diagnosis can be made
Idiopathic or suspected but not established
with a reasonable certainty. Newer, sensitive molecular
Measles virus Crohn’s Disease
biological techniques such as the polymerase chain Mycobacterium Primary biliary cirrhosis
reaction [PCR] often resolve the issue. In other instances, Viral Kikuchi’s disease
the diagnosis is at the best presumptive or compatible ? Sarcoidosis
with a clinical suspicion. In many cases, the cause of ? Chronic granulomatous disease of
childhood, orofacial granulomatosis
granulomatous inflammation may not be evident on
[Melkerson-Rosenthal syndrome]
histopathological examination.
Granulomatous Inflammation in Tuberculosis

The characteristic, but not necessarily diagnostic, lesion
in TB is a confluent necrotising epithelioid cell granuloma
(10). Broadly, the microanatomical lesions in TB are
classified into exudative and proliferative lesions.
Exudative lesions are less well-demarcated, comprise of
neutrophils, lymphocytes, macrophages and epithelioid
histiocytes arranged in a loose collection with little
fibroblastic proliferation. These lesions are also described
as soft granulomas and are likely to contain AFB.
Proliferative lesions are well circumscribed with a
lymphocyte cuff surrounding well-aggregated epithe-
Figure 5.1: Photomicrograph showing necrotising [caseating] lioid histiocytes. Plasma cells may be found but
granulomatous tuberculosis lymphadenitis [Haematoxylin and eosin neutrophils are scant. Surrounding fibroblastic prolife-
x 100] ration is more marked [hard granulomas]. Acid-fast
Pathology 69
bacilli are less readily demonstrated. Langhans’ giant

cells are seen in both types but are more common in the
proliferative type. These two types of granuloma are not
specific to a particular type of TB and both lesions are
frequently seen to coexist. The number, size and extent
of these granulomas depend upon the number of
infecting bacilli, mode of spread and amount of
tuberculoprotein discharged into the developing lesion.
It may be mentioned that exudative lesions, sometime
with a predominance of neutrophils, are seen more often
in TB of serous surfaces, such as the meninges and
peritoneum. Sometimes, neutrophils may predominate
in TB lesions in organs with a loose texture [e.g., TB
bronchopneumonia], giving the appearance of a non-
Figure 5.2: Photomicrograph showing extensive hyalinization of
mycobacterial infection. It is in such instances that TB granulomas in tuberculosis [Haematoxylin and eosin x 40]
may be mistaken for an acute inflammation and the
diagnosis can be missed, if Ziehl-Neelsen staining is not
performed. Eosinophils are conspicuous by their absence
in TB except in the gastrointestinal tract lesions.
Mathew Ballie in 1709 and subsequently, Alois
Rudolph Vetter in 1803, compared some of the lesions in
phthisis to cheese (11). This “cheese-like” necrosis on
gross examination of TB lesions is called caseous necrosis.
This term has been extended to microscopy also.
Caseating granulomas are characteristically but not
exclusively found in TB. Caseation necrosis is a
structureless necrosis. It not only implies permanent
tissue destruction, but is also a mechanism for destruction
of Mycobacterium tuberculosis. Within the caseum low
oxygen tension, low pH and local accumulation of fatty
acids inhibit bacillary replication. The caseum can Figure 5.3: Nodular tuberculosis of the lung. Photomicrograph
become inspissated and encapsulated by fibrous tissue showing caseation with calcification [blue] and circumferential
[fibrocaseous granuloma]. The caseous focus can become fibrosis [Haematoxylin and eosin x 30]
completely organized and converted to fibrous scar that
is often calcified or ossified. It may undergo liquefaction The presence of caseation necrosis generally implies that
and cavitation. Liquefaction probably involves proteo- the lesion is active. However, it may be mentioned that
lytic enzymes derived from neutrophils and macro- tubercle bacilli may lie dormant for many years even in
phages which are present within or around the caseous calcified lesions.
focus. Unlike caseous debris, liquefied material is usually Of interest is the recent observation that instead of
teeming with bacilli. Cavitation occurs when the the usual reaction referred to, mycobacterium can give
liquefied area ruptures into an airway and is evacuated. rise to a spindle cell-lesion. These pseudotumours are
Dissemination of bacilli in this manner contributes to the often loaded with bacilli (12). The typical lesions
development of TB pneumonia. The caseous areas can described above are responsible for the tiny tubercles that
become completely organized and converted to fibrous may be visible to the unaided eye. Galen noted tubercles
scar over a period of weeks [Figure 5.2]. These areas may in various animals [tubercle, Latin tuberculum = a
become calcified over several months [Figure 5.3]. After diminutive of tuber, small swelling, e.g., tuberosity] in
several years, the foci may even be ossified [Figure 5.4]. the condition called Hydrops Thoracis. Sylvius noted that
70 Tuberculosis
Table 5.3: Comparison between tuberculosis and

sarcoidosis granulomas
Feature Tuberculosis Sarcoidosis
Epithelioid cells Present Present

Necrosis Usual Not common
Confluent granulomas Usual Discrete
Giant cells in granulomas Multiple Few
Reticulin within granulomas Usually lost Usually
preserved
Acid-fast bacilli May be present Absent
Figure 5.4: Photomicrograph showing bone and marrow in

healed tuberculosis granuloma [Haematoxylin and eosin x 30]
phthisis was accompanied by tubercles. Francisus

Delaboe Sylvius in his Opera Medica in 1679 (11) also
made a description of tubercles. The name TB was
derived for this disease because in 1839, JN Schonlein,
Professor of Medicine at Zurich, suggested that TB be
used as a generic term for all the manifestations of
phthisis (11). In 1869, Richard Morton in his book
[Phthisiologica] named these lesions tubercles (1) and
thus this term has been in use ever since.
Figure 5.5: Photomicrograph showing necrosis in a granuloma
due to sarcoidosis [Haematoxylin and eosin x 200]
DIFFERENTIAL DIAGNOSIS
The histopathological diagnosis of TB lies essentially in Table 5.4: Methods of demonstration of
the demonstration of the characteristic granulomatous mycobacteria in tissues
inflammation and the causative organism. A presump- Culture

tive diagnosis of TB can be made if a necrotising, Modified Ziehl-Neelsen staining
confluent epithelioid cell granuloma is demonstrated. Dieterle staining
Auramine-Rhodamine staining
Unfortunately, not all TB granulomas are necrotising. Immunohistochemistry
Similarly in the list of granulomatous diseases [Table 5.2], Polymerase chain reaction
there are conditions that reveal granulomas identical to
TB. Comparison between TB and sarcoidosis granulomas
is provided in Table 5.3. Both reticulin-rich and reticulin-poor granulomas may
It must be emphasized that there is no single appear- be found in TB, there is nothing more rewarding than
ance or combination of features that can distinguish TB the demonstration of Mycobacterium tuberculosis. Table
and sarcoidosis histopathologically. Schaumann and 5.4 lists some of the possible methods of demonstrating
Asteroid bodies within giant cells may be found in TB. Mycobacterium tuberculosis in tissue samples.
Necrotising sarcoid granulomas [Figure 5.5] are found Appropriate precautions are to be taken and protocols
especially in cutaneous sarcoidosis and are reported even are to be followed for the collection and transport of tissue
in pulmonary lesions (13). The preservation of reticulin samples. It is always necessary to contact the laboratory
in sarcoidosis can be attributed to the lack of necrosis for this purpose. Often invaluable information is lost
and early fibrosis and is a useful distinguishing feature. because of improper collection and transport of samples.
Pathology 71
It is not possible to go into the details of all these techni- staining and are applicable to paraffin sections and
ques here. The reader is referred to the chapter archival blocks. The former requires a fluorescence
“Laboratory diagnosis” [Chapter 10] for more details. The microscope for visualization. The Dieterle stain is less
most frequently employed method is the modified Ziehl- specific due to morphologic similarities of organisms
Neelsen staining. In May 1882, Paul Ehrlich published a with Nocardia and those of cat-scratch disease (14).
paper indicating that tubercle bacilli are not decolourized Immunohistochemical staining lacks the simplicity of
by nitric acid following staining by a mixture of gentian routine stains and is more expensive. Perhaps it would
violet and aniline oil. Hence, the expression “acid-fast” take some more time before this method gains as much
bacilli. Koch accepted this method. Franz Ziehl popularity and acceptance for the demonstration of
recommended that carbolic acid be used instead of organisms as in diagnosis of tumours.
aniline. Freidrich Neelsen recommended fuchsin and Direct detection of Mycobacterium tuberculosis, rapidly,
sulphuric acid instead of gentian violet and nitric acid. is perhaps one of the most significant landmarks in
This is the Ziehl-Neelsen stain [1892] which is widely medicine. Nucleic acid amplification [NAA] based
employed worldwide. Ironically, Paul Ehrlich diagnosed technology (16) is being utilized to detect the AFB.
that he had TB by staining his own sputum sample. He However, things are not so simple in real practice.
spent a year resting in Egypt and returned to Germany Nevertheless, these techniques are definitely a vast
in good health (1). The Ziehl-Neelsen staining is relatively improvement over some of the routinely available
simple, is applicable to paraffin sections and has been in methods. The details of the pros and cons are beyond
use for many years throughout the world. However, with the scope of this chapter.
Ziehl-Neelsen stain, AFB are not always demonstrable In the authors’ institution, due to high prevalence of
and the species of the bacillus cannot be identified. cases of TB [and belief in the dictum: diagnose a rare
False-positive staining due to Nocardia, Legionella disease and you will be rarely right!], in suspected cases,
and Mycobacterium leprae may pose problems. These the demonstration of caseating epithelioid cell granulo-
disadvantages do not in any way undermine the impor- mas is considered sufficient to strongly suggest TB even
tance of this staining and all attempts should be made to if AFB are not demonstrated. Therefore, it is not unusual
demonstrate AFB [Figure 5.6], whenever necessary. to start appropriate therapy following a biopsy report of
Less frequently used methods include fluorescence “granulomatous lymphadenitis compatible with TB”.
with Auramine-Rhodamine staining, Dieterle stain (14),
and immunohistochemistry (15). All these methods are PATHOGENESIS OF TUBERCULOSIS
more sensitive than the conventional Ziehl-Neelsen The lung is the predominant primary site of TB infection
in postnatal life. Mycobacterium tuberculosis is the most
frequent pathogen. In the past Mycobacterium bovis was
a significant pathogen but with the pasteurization of milk
and relative control over bovine TB, infection by
Mycobacterium bovis is now rare. A variety of conditions
are reported to render individuals susceptible or are
associated with an increased risk of TB. Many of these
result in decreased immunity. Some of these include
silicosis, pulmonary alveolar proteinosis, malignant
neoplasm (17) and immunodeficiency disorders among
others [Table 5.5].
The key aspects related to the pathogenesis of TB are
covered in the chapters “Pulmonary tuberculosis” [Chapter
14], “Tuberculosis in children” [Chapter 41], “Immunology
Figure 5.6: Photomicrograph showing acid-fast bacilli in a lymph of tuberculosis” [Chapter 7], “Genetic susceptibility parameters
node [Ziehl-Neelsen staining x 1000]. Note the beaded appearance in tuberculosis” [Chapter 8], and “Genetics of susceptibility
of the acid-fast bacilli to tuberculosis” [Chapter 9].
72 Tuberculosis
Table 5.5: Conditions predisposing to children. Spread of infection to the draining lymph nodes
the development of tuberculosis as well as vascular involvement, mentioned earlier, may
Immunodeficiency disorders affecting CMI including HIV infection lead to dissemination of bacilli from primary complex to
and AIDS almost all tissues through blood and lymphatics. A
Immunosuppressive therapy bacillaemia is, therefore, common at this stage (20,21).
Immunomodulator drugs [e.g. infliximab, etanercept] The initial infection is typically unrecognized though the
Malignant neoplasm [carcinomas of the head and neck, stomach, tubercle bacilli disseminate throughout the body.
intestines and lungs; Hodgkin’s disease, non-Hodgkin’s
Most primary TB infections heal spontaneously with
lymphoma, acute lymphocytic and myelogenous leukaemia]
Silicosis calcification in some of the cases. Repair begins with the
High dose, long-term corticosteroid treatment resorption of caseous material, followed by fibrosis and
Poorly controlled diabetes mellitus dystrophic calcification. A typical primary parenchymal
Chronic renal failure, haemodialysis focus of TB in the lung is characterized by a nodular, often
Connective tissue disorders subpleural, area of necrosis surrounded by fibrosis.
Organ transplantation
Hyalinization and eventual calcification of this nodule is
Intravenous drug abuse, heroin addiction
Tobacco smoking the routine. Microscopic calcification can occur as early as
two months but radiologically visible calcification takes a
CMI = cell-mediated immunity; HIV = human immunodeficiency year or longer. Calcification does not imply a sterile lesion.
virus; AIDS = acquired immunodeficiency syndrome
The most important aspect of primary TB is that the
organisms remain dormant for a variable length of time.
PRIMARY TUBERCULOSIS Resorption of calcium from the lung and lymph node
The following discussion focusses on the pathogenesis lesions occurs subsequently in about one-third of child-
and pathology of primary TB in general. Primary ren with primary complex [see below] over a period of
pulmonary TB will be discussed a little later under years (22). Although the above account of the sequence
“pulmonary TB”. of events briefly describes primary TB in the lungs, the
The earliest foundation of primary TB was actually description in other organs is essentially similar.
laid by Marie-Jules Parrot [1829-1883] in 1876. At a time
Primary Complex
when the understanding of TB was based on several
conjectures, primary TB in children was explained on It can be appreciated that in primary TB there is usually
the basis of what is known as the Parrot’s Law which a unit comprising of the focus of primary TB and the
stated that: “pulmonary TB does not exist in the child infected draining lymph nodes. This is known as the
without involvement of the tracheobronchial gland”. In primary complex of Ranke. Invariably the intervening
other words, this observation implies that primary TB lymphatics between the lesion and the lymph nodes are
includes a prominent lymph nodal involvement. The included as a constituent of the primary complex. The
significance of this was not clear even after the discovery term primary complex as such is used with reference to
of the tubercle bacillus. In 1896, George Kuss [1867-1936] TB and has the advantage that it can be used as a general
brought out a monograph on the pathology of TB due to term implying primary TB without any reference to a
aerogenous infections which included what is under- particular organ. A similar primary complex has been
stood as primary TB. Once again his ideas did not receive described in the case of cryptococcosis (23).
much attention. Eugene Albrecht [1872-1908] in 1907 Over the years, the terms primary complex in the lung
extended the concept of primary TB in childhood to adult and Ghon’s complex [named after Anton Ghon] are used
TB and Hans Albrecht in 1909 confirmed the observations synonymously. The focus of primary infection in the lung
of Kuss and elaborated on Parrot’s law (18). These studies is usually subpleural, in the middle portion [upper region
formed the basis of the observations of Anton Ghon of the lower lobe or the lower portion of the middle lobe
[1866-1936](19). when on the right side] and is known as the Ghon’s focus.
The infection is carried along the lymphatics to the Therefore, the unit of Ghon’s focus and the draining
draining tracheobronchial lymph nodes that enlarge. The tracheobronchial lymph nodes [with the intervening
regional nodes are invariably involved and may be more lymphatics, included by some] is the Ghon’s complex
prominent than the parenchymal lesion especially so in [Figure 5.7]. The term Ghon’s complex should not be used
Pathology 73
Figure 5.8: Photomicrograph showing lymph node with anthracotic

pigment and granuloma [Haematoxylin and eosin x 200]
Figure 5.7: Primary complex in the lungs. Arrow heads indicate

Ghon’s focus in the parenchyma and enlarged tracheobronchial
lymph nodes
to denote primary complex in organs other than the lung.

More details regarding Ghon’s complex will be discussed
in the section on “pulmonary TB”.
In keeping with Koch’s observations in guinea pigs, Figure 5.9: Enlarged pancreatico-duodenal lymph nodes due to
the lesion in primary TB is small, often not discernible; tuberculosis. Areas of caseation are seen
whereas the draining lymph nodes are appreciably
enlarged. This is reflected in Parrot’s Law mentioned
Congenital and Perinatal Tuberculosis
earlier. This is opposite to what is seen in post-primary
TB. Therefore, the presence of an enlarged lymph node The youngest possible contact of TB is the foetus of a
[Figures 5.8 and 5.9] with a correspondingly smaller mother with active TB. Fortunately, the foetus is less
parenchymal lesion is suggestive of primary TB and susceptible to TB in utero in contrast to the vulnerability
serves as a general guideline to distinguish primary and of the newborn infant. Although the cause for this is not
post-primary TB. In post-primary TB the parenchymal apparent, a relative anoxia of foetal tissues may be a
lesion usually overshadows the lesion in the draining reason. Rarely, infection may occur in utero or at birth.
lymph nodes. There are over three hundred cases of congenital TB
The importance of the lung being a common site of reported in the literature (25). The route of infection could
primary TB has already been mentioned. The mucosa of be aspiration of the amniotic fluid [due to TB of the
the gastrointestinal tract is another site of entry of tubercle endometrium, genital tract or placenta] or haemato-
bacilli. However, there are other routes of infection that genous spread. When the route of infection is haemato-
are less common and less easily recognized (24). genous, the bacilli reach the foetus through the placenta
74 Tuberculosis
along the umbilical vein so that a primary complex forms respiration to a comatose TB patient (33). Tuberculosis
in the liver and accompanying portal lymph nodes. has also been described following subcutaneous or
The bacilli may bypass the liver and may be conveyed intramuscular injection. Either the syringe, needle or fluid
via the ductus venosus to the lungs. Widespread to be injected has been contaminated or the medical
involvement of the lungs, hilar and mediastinal lymph attendant has exhaled tubercle bacilli into the patients’
nodes without an associated hepatic lesion indicates skin, which are then introduced by the injection. A
aspiration of the infected amniotic fluid (26), inhalation primary syringe-transmitted infection of a muscle should
of tubercle bacilli from the genital tract or from the room be distinguished from secondary infection of a muscular
air (27). Congenital TB is characterized by a non-immune, haematoma from a patient with TB elsewhere in the body.
non-reactive response. Multiple primary foci or miliary There is a report of 102 children developing primary TB
distribution are common (28,29), and regional lymph at the site of typhoid and paratyphoid A and B [TAB]
node involvement occurs with emphasis on caseation vaccination, transmitted by a school vaccinator who was
and a large number of bacilli. Microscopically, polymor- found to have active TB (34). Primary cutaneous TB has
phonuclear leucocytes predominate but lymphocytes, followed venepuncture (35). As in other situations, it may
epithelioid cells and Langhans’ giant cells are rare. be difficult to differentiate primary TB of the skin from a
Similarly, oral and gastrointestinal infection may secondary one (36).
occur before or at birth from swallowing infected mate- It would not be out of place to mention that bacille
Calmette-Guérin [BCG] inoculation is in essence an
rial. The clinical picture has been well described with
iatrogenic primary infection (3). Primary inoculation TB
symptoms occurring around two to three weeks of life
has been reported following BCG vaccination as a form
(30). Sudden cyanotic attacks have been described
of immunotherapy for malignant melanoma (37).
following few days of the birth. Diagnosis is difficult and
Therefore, it appears that in many countries where BCG
an investigation such as the tuberculin test is unreliable
vaccination is given to the newborn, the commonest
in the first six weeks of life (31). Diagnosis is often delayed
primary TB is cutaneous, and with the draining lymph
and the illness is often fatal. When the lesions are in the
nodes [axillary in most instances] accounts for a frequent
liver, the term congenital TB is appropriate, but for all
primary complex in such cases (38). Perhaps in years to
other cases perinatal TB seems to be a more appropriate
come this form of cutaneous primary complex may be
term. commoner than pulmonary primary complex [provided
the current controversies are sorted out and BCG
Skin
vaccination is widely accepted].
The skin when intact is the best form of protection from
infections. Unfortunately, even a small breach in this Gastrointestinal Tract and Liver
seemingly impenetrable barrier exposes the individual The gastrointestinal tract is one of the sites of primary
to infections. Thus, the skin may provide a site of entry contact between the tubercle bacilli and the host. With a
for tubercle bacilli. Usually there is a history of trauma at significant reduction in the number of cases due to
the site of infection ranging from a dog’s scratch to a major contaminated milk, it is unlikely that the gastrointestinal
road accident. Common sites include exposed areas such tract would be a relatively frequent site for primary TB.
as the face, scalp, knees, legs, feet, hands and forearm. It should be noted that the lack of evidence or inability to
Persons with occupations which involve contact with demonstrate another site of infection often results in a
potentially infective material such as pathologists, mistaken labelling a site of TB as “primary”. Almost
microbiologists, laboratory workers, necropsy attendants, every organ in the gastrointestinal tract is reported to as
butchers, slaughter house workers, cattle handlers and a likely site of primary TB. An associated enlargement of
milkers are all at special risk. Due to its similarity to regional lymph nodes may or may not have been observed.
primary syphilis, cutaneous TB is also known as “tuber- Primary TB has also been described in the oral cavity
culosis chancre”. Regional lymph node enlargement (39). The buccal mucosa is reported to be one of the sites
occurs as in the case of primary complex at other body of primary TB. It may follow dental extraction and result
sites (32). Primary cutaneous TB has been described in a in infection of the tooth socket (40). The primary focus is
doctor eight weeks after he administered mouth to mouth usually small or not easily recognizable whereas the
Pathology 75
lymph node enlargement, mainly submandibular, is primary complex. The likely route of infection in the case
prominent. The tongue is rarely the site of primary of cervical lymph node is considered to be the tonsil (57).
infection (41-43). Secondary TB of the tongue is more However, in most cases, the focus in the tonsil is
frequent and invariably follows TB of the respiratory tract. microscopic and difficult to identify. Exceptionally, the
Isolated reports of primary TB of the oesophagus tonsillar lesion may be readily apparent and ulcerated.
(44,45), stomach (46-48), duodenum (49), ileum (50) and The mucosa over the lymphoid tissue at the pharyngeal
the colon (51) are available. Primary TB of the vermiform entrance may be the site of primary infection (58).
appendix is rare. Most of the cases of TB of the appendix Similarly, the uvula (59), the pharynx (60) and the larynx
are secondary to TB of the ileocaecal region (24). Never- (61,62) have been reported to be the sites of primary TB.
theless, there are cases of apparently primary infection In these instances the infection may follow the common
of the vermiform appendix (24,52,53). An interesting mode of entry that is through inhalation. It is, therefore,
report describes multiple sites of primary TB of the not surprising that the nose (63,64) and the nasopharynx
gastrointestinal tract (54). have been infected primarily (65,66). This forms the basis
It may be mentioned that earlier observations indicate of the Calmette test wherein tuberculin is dropped into
that primary TB of the gastrointestinal tract due to bovine the conjunctiva (5).
TB infrequently involves the lungs. The classical evidence Primary TB can involve the middle ear (67-69). The
of primary infection of the gastrointestinal tract by TB is bacilli are thought to enter the Eustachian tube by
provided by observations following the tragedy at swallowing and regurgitation of the infected amniotic
Lubeck, in Germany. During the period of this disaster, fluid by the foetus. In the Lubeck disaster, some of the
avirulent TB bacillus of the bovine strain [BCG] was victims developed middle ear infection probably by aspi-
employed for immunization by mouth. ration of vomited vaccine into the Eustachian tube (8).
Unfortunately, a contamination of the cultures led Primary TB of the parotid gland (70,71) is thought to
to the accidental administration of virulent human strain occur due to infection of the buccal mucosa at the site of
of TB bacillus to 251 newborn infants. The bacilli were the third molar tooth. Primary TB involving adenolym-
administered orally on three separate occasions during phoma [Warthin’s tumour] of the parotid (5,24) has been
the first 10 days of life. A total of 72 infants died of described.
primary and fatal TB while 175 were reported to be alive
with arrested lesions at the end of four years. An autopsy Genitourinary Tract
study revealed that the alimentary tract was involved The skin of the penis is another rare site of primary TB
in all the cases. The small intestine was most frequently (72-74). In some cases the infection is transmitted
affected [98.3%], while the upper alimentary tract and following circumcision (73) by operators suffering from
the cervical lymph nodes were affected in 78.3 per cent TB. An interesting report (24) records penile TB in 72
of the cases. Interestingly, pulmonary lesions were Jewish infants following ritual circumcision. As apart of
found in 15 per cent of the autopsies. In all probability, haemostasis, the circumcised organ was sucked and in
these lesions were secondary to aspiration because this manner the infection was supposedly transmitted
simultaneous lesions were demonstrated in the mouth, from an infected rabbi to the infants. Some cases may
pharynx or the intestine (5). occur following sexual transmission. Similarly an
Primary TB of the liver is invariably congenital. This infected male may transmit the disease to the female
has already been discussed in the description of partner (24). In general, it appears that the vagina is less
congenital and perinatal primary TB. Cases of primary often the site of primary TB than the penile skin. Infection
hepatic TB are reported from time to time (55,56). It must of the vulva has also been reported.
be emphasized that in adults, the lack of evidence for a
focus of TB elsewhere does not necessarily indicate that Eye
the lesion in the liver is primary TB. Primary TB of the conjunctiva (75-77) and the lachrymal
sac without the involvement of the conjunctiva have been
Head and Neck
described. Lesions probably occur after some minor
Cervical lymph nodes are not infrequently affected by injury or abrasion. Enlarged regional lymph nodes
TB. A proportion of these may reflect a constituent of a [preauricular or submandibular] complete the primary
76 Tuberculosis
complex (24). It may be mentioned that phlyctenular

keratoconjunctivitis may appear as a consequence of
hypersensitivity to proteins to which the individual has
been previously exposed. Thus, phlyctenules may appear
if droplets of coughed sputum containing bacilli or
tuberculoprotein are deposited on the conjunctiva of such
individuals. A rare instance of primary TB of the retina
has been reported (78).
Whether it is necessary to catalogue and compile a
list of sites of primary TB [Table 5.6] is open to debate.
However, this gives an insight into the variety of possible
locations through which the Mycobacterium tuberculosis
can enter the human body. It must be emphasized that
the lung is perhaps the most frequent site of primary TB.
The course of primary TB is generally benign especially
Figure 5.10: Photomicrograph showing epithelioid cell granulomas
with the advent of effective chemotherapy. In a majority adjacent to the wall of a vein in the lung. Invasion of the vein may
no ill effect is felt and infection is recognized by delayed result in disseminated disease [Haematoxylin and eosin x 30]
type hypersensitivity reaction [DTH] reaction to
tuberculin skin testing. There are two more aspects that [Figure 5.10] of virulent TB bacilli from an active caseous
need to be mentioned. Primary TB is invariably source of infection (79,80). The reader is referred to the
associated with haematogenous dissemination or chapter “Disseminated and miliary tuberculosis” [Chapter
generalization. Subsequently, either disseminated/ 34] for further details.
miliary TB may result or seeding of various organs may The characteristic findings of miliary TB include
not be associated with concurrent disease. Later, small, discrete nodules, grey to reddish on cut surface,
depending on the relationship between the host 1 to 2 mm in diameter, distributed evenly throughout
immunity and the mycobacteria that may lie dormant the affected organ. Older lesions, that may be caseous,
for years, TB may manifest in one or more of these organs. tend to be yellowish in colour. The lung, liver, spleen
In a small proportion of cases the primary infection may [Figures 5.11 and 34.1] and bone marrow are most fre-
not heal but progress. quently affected. Even in these organs, tubercles tend
to be larger in the lung and spleen than in the liver and
GENERALIZED [DISSEMINATED] TUBERCULOSIS
marrow. Miliary tubercles at the apical lobes of the lungs
Generalized TB is the occurrence of wide spread visceral may be larger and more numerous, especially in adults.
tubercles due to haematogenous dissemination Pleural and pericardial involvement is common with
bilateral pleural effusions frequently associated with
Table 5.6: List of some reported sites of primary tuberculosis miliary TB. Miliary tubercles may be found studding
other organs such as the kidney, intestine, fallopian
Common
Lung tube, epididymis, prostate, adrenals, bone, meninges,
BCG vaccination [when vaccination is successful in infancy] brain, skin, eye and lymph nodes. Mediastinal lymph
Less common node enlargement occurs in a high percentage of infants.
Tonsil Patients may present with features that point to the
Adenoids involvement of only one organ, such as, meningitis
Probably uncommon
despite disseminated disease.
Ileum [common in era when bovine type of infection was
frequent] All tubercles resulting from acute generalized
Rare dissemination are approximately of the same size and in
Colon, pharynx, duodenum, stomach, uvula, skin, liver [in the same stage of histological spectrum. However,
congenital infection], buccal mucosa, oesophagus, larynx, repeated showers of bacillaemia may yield tubercles of
parotid gland, nasopharynx, tongue, nose, penile skin, con-
different sizes. Histologically, miliary tubercles typically
junctiva, vulva, middle ear, injection site, lacrimal gland, retina
consist of a Langhans’ giant cell with surrounding
Pathology 77
logy of pulmonary TB may include certain features that

have been described earlier. Although the intention is
not to repeat, some aspects of primary TB are included
with special reference to the lung as an organ and also to
provide a basis for understanding further course of
pulmonary TB.
The pathology of pulmonary TB has been elucidated
by a number of studies that included a careful and
detailed examination of lungs obtained at autopsies. In
addition to the elegant studies of Rich (5), Medlar (81)
based his observations on 1332 unexpected deaths in
New York and further evaluated 17000 necropsy records
with reference to pulmonary TB. The Indian perspective
is available from the study based on 1680 autopsies by
Figure 5.11: Photomicrograph showing tuberculosis granuloma Nayak and co-workers at New Delhi (82,83).
in the spleen [Haematoxylin and eosin x 200]
Primary Pulmonary Tuberculosis
epithelioid cells. Depending on the compactness of the
Primary TB has already been dealt with in detail earlier.
arrangement of epithelioid cells and necrosis, miliary
Only certain relevant aspects shall be highlighted here.
tubercles are of two types: cellular and caseating. The
Classical features of a primary complex in the lung [Ghon
cellular form consists of compact epithelioid and giant
complex] are a small [usually less than one centimeter]
cells with very little or no caseation and are known as
often inapparent parenchymal lesion [Ghon lesion or
“hard” tubercles [ordinary miliary tubercles]. The
Ghon focus] coupled with enlarged, ipsilateral hilar and
caseating type consists of loosely formed tubercles with
less commonly paratracheal nodes [Figure 5.7]. The
caseation necrosis. These are known as “soft” tubercles
lymph nodes are generally much larger than the
[acute caseating miliary tubercles]. Acid-fast bacilli are
parenchymal focus. As has been repeatedly indicated,
more likely to be found in soft tubercles. It is not clear
the location of the parenchymal lesion is usually towards
whether one type of granuloma is the precursor of the
the middle of the lung [upper part of the lower lobe or
other.
the lower region of the middle or upper lobe depending
Patients who survive for weeks may show a central
on the side]. Certain sites such as the apical and posterior
area of caseation surrounded by satellite granulomas.
segments of the upper lobe, apical segment of the lower
Eventually healing takes place and the granulomas
lobe or upper portion of right middle lobe are described
undergo progressive hyalinization and calcification. This
as likely sites of primary infection, however, no part of
may give a fine mottling on chest radiographs. Some
the lung is exempt (81). A single Ghon’s complex was
immunosuppressed patients with generalized [dissemi-
identified in 58 per cent and multiple in 16 per cent of
nated] TB may show granulomas that are softer than the
the cases studied by Medlar (81). In one case, five foci
soft tubercles. Giant cells are not found. The epithelioid
were identified, one in each different lobe. In 26 per cent
cells are not well developed and are dispersed. On the
cases, the complex was incomplete because either a
other hand, there is prominent necrosis with numerous
parenchymal or lymph nodal component was not
bacilli. This is also referred to as non-reactive TB.
demonstrated. A typical primary or Ghon’s focus is
single, two millimeters or more in size and located within
PULMONARY TUBERCULOSIS
one centimeter of the pleura of the collapsed lung. Lesions
Pulmonary TB is the most frequent organ TB worldwide. within the lung are relatively uncommon. A majority of
Lungs account for a majority of both primary and post- the primary foci calcify and a minority show caseous
primary forms of TB. Miliary TB invariably affects both necrosis [85% and 15% respectively]. Lymph node
lungs symmetrically. Further, pulmonary TB is a major enlargement is easily identified in a large majority [87%].
source of infection. The following account of the patho- In order to demonstrate the tubercle, it may be necessary
78 Tuberculosis
to make serial slices in about three-fourths of the cases airway can result in laryngotracheal, oral or middle ear
whereas in the remaining the lesions are readily TB. Swallowing infective sputum can also lead to TB
apparent. Bilateral adenopathy is uncommon except with and ulceration of the intestinal mucosa. Ipsilateral hilar
left-sided primary foci (84). Massive lymphadenopathy lymph node spread is especially prominent in primary
is reported (85), especially in the poorly nourished. infections. Perforation of a bronchus by an enlarged
caseous lymph node followed by endobronchial spread
Progression of Tuberculosis can result in massive segmental or lobular pneumonia.
From regional lymph nodes bacilli can disseminate
The natural history of TB in the human host is influenced
by age, sex, mycobacterial virulence, infecting dose, through lymphatics to the pleura, spine and other
viscera. Haematogenous dissemination can occur
natural and acquired resistance, certain host factors
through the thoracic duct after lymph node involvement
resulting in a tendency of the disease to follow a pattern
of progression according to Wallgren’s timetable (86). or by direct extension of the lesion into branches of the
pulmonary vein.
Interplay of these factors and the likely mode of spread
of the bacillus result in different manifestations.
Healing
Early in the course of, disease, tuberculin conversion
after primary infection may result in mild illness. In the Healing of the primary lesions is the rule. The caseous
first few years there is increased susceptibility to miliary focus is gradually replaced by reticulin and collagen
spread and meningitis. Miliary disease and meningitis deposition. Eventually, hyalinization, and calcification
follow within two to nine months in 10 per cent of are common [up to 85%]. Subsequent demonstration of
children under two years of age, although these forms these lesions may be difficult. However, a minority of
can be seen at any age. Segmental lesion [epituberculosis] patients may demonstrate radiologically a residual
is an early sequel in infants and in a minority of hyalinized scar or calcification at the site of the primary
adolescents and young adults generally within two to [Ghon] lesion, in the lung parenchyma and in the hilar
nine months of primary infection. Pleural effusion, which or paratracheal lymph nodes—a combination referred
follows primary TB, is also seen as a sequel of the post- to as the healed primary [Ghon] complex.
primary pulmonary disease. Progression to post-primary
TB is more likely if primary infection is acquired in the Early Generalization
later years of young adulthood than in childhood. In Early generalization or dissemination is an invariable
childhood infection the post-primary disease is delayed
accompaniment of primary pulmonary TB [detailed
until adolescence. Extra-pulmonary organ TB is variable.
above]. The primary infection is accompanied by early
Cervical lymphadenitis may be early but, skeletal and lymphohaematogenous spread within hours or days
renal TB, usually present very late. This progression is
from the site of initial implantation (87). It is felt that
only a broad direction and not absolute.
occult mycobacteraemia is probably common before
acquired immunity and thus may seed many sites in the
Further Changes of the Primary Complex
body especially where the bacillus is favoured to remain
The primary complex may heal or progress further. viable (20). While the sites of these seedings have already
Progression occurs in a small proportion of cases. Early been mentioned, one aspect needs to be highlighted here.
dissemination is common but may not necessarily result Huebschmann [1928] (5) observed a group of nodular
in concurrent illness. lesions in one or both apices of the lung that occasionally
The spread of infection from the primary lesion is by follow primary TB in children. These foci are so small
a variety of ways, such as, direct extension into adjacent that special techniques may be necessary to demonstrate
tissue or by endobronchial, lymphatic or vascular them. These Huebschmann foci heal and cause no further
pathways for a disseminated spread. Endobronchial disease. It is likely that Simon foci which are larger, single
spread of liquefied caseous material is a cause of or multiple apical caseous nodules with a tendency to
ipsilateral or contralateral acinar pneumonia. Implan- calcification are exaggerated form of these smaller foci.
tation of mycobacterium in the mucosa of the upper The importance of Simon foci lies in the pathogenesis of
Pathology 79
post-primary TB (5). In a minority of the cases haemato- commonly affects the anterior segments of the upper
genous dissemination results in miliary TB. lobes and the right middle lobe. Endobronchial TB is a
complication of primary TB in children (89). Residual
Liquefaction and Progressive Primary Tuberculosis bronchostenosis and bronchiectasis may occur as late
complications.
Liquefaction of solid caseous foci is thought to be related
to the onset of DTH with the release of hydrolytic Hilar and mediastinal lymph nodes may very rarely
cause impaired venous return severe enough to cause
enzymes by macrophages (88). Liquefaction may result
superior mediastinal syndrome. Such lymph nodes may
in a caseous mass that may include the enlarged lymph
nodes. Within the liquefied area there are multiplying result in tracheal obstruction at the thoracic inlet, rupture
into the mediastinum and pointing abscess into the
tubercle bacilli and, therefore, there is a risk of transmis-
supraclavicular fossa, erosion of blood vessel, invasion
sion of disease. Due to the liquefactive necrosis there is
extensive parenchymal destruction and cavitation, which of pericardium, compression of or erosion into the
oesophagus and the formation of various fistulae.
is generally a little less than the size of the original
caseous mass. The cavity may communicate with an
airway and thus promote bronchial spread to other parts Epituberculosis
of the lung, larynx and the alimentary tract. An acute Epituberculosis is a rare but more frequent in infants and
fatal bronchopneumonia may result. In some of these
children than in adults. It is a benign lesion appearing as
cases the inflammatory reaction is neutrophilic, like in
a dense homogenous shadow on chest radiographs,
the case of bacterial pneumonia, but AFB are demons- typically wedge-shaped, extending from the hilum to the
trable. Due to such a reaction, the diagnosis may be
pleura. The lesion is frequently large rather sharply
missed. Discharge of the liquefied material through the
defined and has the appearance of an area of consoli-
adjacent pleura results in pleural effusion, pneumothorax dation. Clinical symptoms are few and the shadow
or empyema. Caseous lymph nodes may similarly
generally clears after several months. Residual changes
discharge liquefied contents into the bronchus.
are infrequent and radiographs may show slight
Progressive primary TB directly follows the primary abnormal marking or calcifications. The radiographic
lesion. There occurs an extended primary focus or TB
appearance is relatively dramatic and sinister, in
bronchopneumonia. Cavitation may ensue. Cavitation
contradiction to clinical symptoms and the outcome. It
and progressive primary disease are more likely in has been suggested that this is a non-specific pneumonic
infancy, at puberty and in the elderly. There is a tendency
consolidation that occurs in TB. Hence, Eliasberg and
for progressive primary TB to involve lesions that are
Newland suggested the term “epituberculosis” which
apical. This location is similar to that of post-primary TB. implied a non-tuberculosis consolidation in a TB lung
(5). The current view is that it is either resolving TB
Lobar and Segmental Lesions
pneumonia or an atelectasis produced by obstruction of
As a consequence of spread along the submucosal a bronchus by a TB lymph node or by a primary pulmo-
lymphatics of bronchi, tubercle formation with ulceration nary lesion. A combination of the two is possible. Since
of bronchial mucosa at times is followed by complete the shape of the shadow is highly suggestive of involve-
necrosis of the bronchus. Within the bronchus a cold ment of a portion of lung tissue supplied by a bronchus,
abscess may develop and can be seen on the radiograph Rich studied several cases and found that a caseous lymph
as a rounded or elongated shadow. Bronchial lesions are node had perforated the bronchial wall, discharged its
rare but may result in narrowing of the lumen. Extrinsic contents and resulted in aspiration of the material. It is
compression from enlarged lymph nodes is a relatively understandable that the caseous material is poor in bacilli,
more likely cause of bronchial obstruction. The lobe or otherwise the lesion would be a progressive broncho-
segment subtended by the obstruction may be the seat pneumonia. The resulting consolidation could be partly
of obstructive hyperinflation, atelectasis, secondary [non- due to a “hypersensitive” reaction to contents of the
TB] pneumonia, TB pneumonia, and disseminated intra- lymph node [a positive “pulmonary tuberculin test”, if
alveolar epithelioid cell granulomas. Atelectasis most such a term is acceptable]. The alveoli in such cases would
80 Tuberculosis
resemble pneumonia with epithelioid cells and few or no The great majority of these cases represent recrude-
AFB. There is also sufficient evidence to suggest the scence of dormant tubercle bacilli occurring several years
atelectasis theory and relief of atelectasis by interventional after the primary infection or even decades after primary
bronchoscopy. A combination of aspiration and infection. As has been mentioned earlier, there is a
obstruction by lymph nodal compression may occur. haematogenous seeding of the apical and sub-apical
Since encroachment by an enlarged lymph node is a regions of the lungs, following primary infection. This is
common accompaniment, therefore, these lesions are the endogenous pathway resulting in reactivation TB
common in children (5). (95). However, there is evidence to suggest that a
bronchial spread from an index case may be the route of
Primary Tuberculosis in Adults infection. This is the exogenous pathway resulting in
reinfection TB. The organisms may reach by either
The radiological and other features of adult primary TB pathways (5). Infection with other related species of
are essentially similar to childhood primary disease (90). mycobacteria may also have the same result.
Primary TB poses diagnostic problems in adults (91). The pathological lesions seen in post-primary pulmo-
Prominent hilar and mediastinal glands and caseation nary TB are enumerated in Table 5.7, based on the
are less frequent in adults except in patients with AIDS. findings of Medlar (81), and Nayak et al (82).
Also, bronchial obstruction and dissemination are less
common. As in children, endobronchial TB can compli- Early Lesions
cate post-primary TB in adults. With increasing primary The earliest lesion is probably an apical or subapical
adult TB, endobronchial TB may occur as a sequelae of lobular pneumonia (82). These lesions are not well
adjacent parenchymal disease from which submucosal documented because it is believed that the pneumonia
lymphatic spread leads to mucosal ulceration, hyper- gives way to a granuloma rapidly. An outline of the
plastic polyp formation or fibrostenosis with atelectasis alveolar reticulin framework in the centre of some of
of the subtended lobe (92). these granulomas may suggest such a transition (82).
Post-Primary Pulmonary Tuberculosis Table 5.7: Lesions in post-primary pulmonary tuberculosis
In contrast to primary TB, the localization of post- Pulmonary lesions

primary pulmonary TB is apical or sub-apical. This area Lobular pneumonia
Nodular TB
has been referred to as the ‘vulnerable region’ by Medlar
Small nodule
(81). This site probably relates to the relatively higher Large nodule
oxygen tension in the region resulting from the effect Healed nodules
of gravity on the ventilation-perfusion ratio in the Fibrocaseous TB
upright lung. Presently, evidence suggests that this is With cavity
possibly because of better survival of the bacillus at this Without cavity
Tuberculosis bronchopneumonia
region as the higher oxygen tension has an unfavourable
Bronchial lesions
effect on the macrophage and thereby permits Bronchial inflammation
intracellular growth (93). This may also influence Endobronchial TB
progressive primary disease that is more frequent in Bronchiectasis
the apical and posterior segments of the upper lobe. Whole lung TB
Miliary TB
Higher vascularity and consequently increased oxygen
Complications
tension may determine the preferential multiplication Haemoptysis
of bacilli at other sites also, such as ends of long bones, Aspergilloma
vertebrae and the renal cortex. Similarly, mitral stenosis, Amyloidosis
which results in higher pulmonary arterial pressure and Carcinoma
increased apical blood flow, confers a protective effect. Oral cavity and upper respiratory tract TB
Pleural lesions
The reverse is true for pulmonary stenosis (94). Lowered
blood flow may also be associated with decreased TB = tuberculosis
lymph flow and thus lesser antigen clearance. Source: references 81,82
Pathology 81
It may be mentioned that in 1925, Assmann drew nodules are not related to Ghon’s focus. The location and
attention to the fact that the earliest lesions clearly visible the absence of accompanying enlarged lymph nodes
in clinical TB consist of infiltrates not at the apex, but at should provide a clue. Acid-fast bacilli could be demons-
the sub-apical and infraclavicular region. These infiltrates trated in seven per cent of small nodules and 29 per cent
[Fruhinfiltrat] are known as Assmann infiltrates or foci (5). of large nodules (82).
The histological counterpart of these lesions is not known.
Fibrocaseous Tuberculosis
Nodular Lesions
Fibrocaseous TB includes lesions that reveal well-
Nodular lesions [coin lesions, tuberculomas] are known features of TB such as caseation, consolidation,
localized, well-defined areas of TB wherein the adjacent liquefaction and fibrosis. Grossly, various patterns are
pulmonary parenchyma is usually normal or may show seen. The apical and posterior segments of the upper
some scarring [Figure 5.3]. A small nodule is less than a lobes are predominantly involved (96-98). Lymph node
centimeter in diameter whereas the large nodule is larger involvement is slight in comparison to primary TB.
than a centimeter in diameter. Grossly, nodules are white Retraction of lung parenchyma is associated often with
to yellow in colour and may vary in consistency from pleural thickening. In some cases the lung may have an
soft lesions that are largely necrotic to firm or hard lesions appearance of bronchopneumonia due to consolidation
that are fibrosed [Figure 5.12] or calcified [Figure 5.13]. [Figure 5.14]. At times the caseous areas stand out
Small nodules have a central area of caseation, are amidst the black background of anthracotic pigmenta-
surrounded by epithelioid cells and giant cells and are tion. The most striking feature is the presence of one or
encapsulated by a fibrous wall. Large nodules are similar more cavities [Figures 5.15 and 5.16]. Cavities may
but show more caseation and less encapsulation. Healed assume varying sizes and may be so large as to result
nodules are of the size of small nodules and are fibrosed in a severe loss of lung parenchyma. The wall of the
or hyalinized or calcified. Anthracotic pigment may be cavity may be lined by TB granulation tissue or show
identified in any nodule (82). varying fibrosis. Often the thick walls of cavities seen
Active nodules especially of the small size are on radiographs are found to be accounted for by a rim
predominantly located in the apical and sub-apical of consolidation of the adjacent lung. Communication
regions and may be single or multiple. The reverse is may or may not have been established with a bronchus
true for healed nodules. It appears that small nodules [Figure 5.17]. These findings have implications on
give rise to larger ones and nodular TB may expand to auscultation of the chest. Traversing the wall or the
form fibrocaseous lesions. It may be mentioned that these lumen along fibrous bands, are bronchi and branches
Figure 5.12: Photomicrograph showing healed tuberculosis of the Figure 5.13: Photomicrograph showing healed calcific nodule in
lung with hyalinization and fibrosis [Haematoxylin and eosin x 30] tuberculosis of the lung [Haematoxylin and eosin x 30]
82 Tuberculosis
Figure 5.14: Tuberculosis bronchopneumonia with a

cavity in the left upper lobe Figure 5.15: Specimen of lungs showing
fibrocaseous and cavitary lesions [arrow]
Figure 5.17: Specimen showing tuberculosis cavity in the upper

lobe of the right lung communicating with the bronchus [arrow]
of pulmonary artery. Fortunately in most instances the

Figure 5.16: Close up of cavities in the upper lobe. The lining of chronic process allows the arteries to obliterate. The
the wall is relatively smooth. Note the thickened pleura at the apex caseous material may soften the wall of the arteries
Pathology 83
giving rise to Rasmussen’s aneurysms. These may give in fibrocaseous lesions than in nodular TB. Acid-fast
rise to haemoptysis that may be fatal bacilli were found more frequently in cavitary lesions
Microscopically variable caseous necrosis, extensive [88%] in comparison to non-cavitary lesions [77%] (5).
fibrosis, numerous palisades of epithelioid cells and Smaller cavities may heal. Healing in general results
fibroblasts together with Langhans’ giant cells are seen in fibrosis and cicatrisation extending between the upper
[Figures 5.18, 5.19, 5.20 and 5.21]. Areas of consolidation pole of the hilum and the apex, thus elevating the hilum
may show caseous pneumonia or even a neutrophilic on that side. This causes volume loss on the ipsilateral
response. Microscopic cavities may be identified in such side. Simultaneously the upper mediastinum would be
pneumonic foci. Cavities are lined by necrotic TB granu- pulled towards the side of the lesion distorting the
lation tissue and show fibrosis. Occasional cavities may trachea and giving a characteristic radiological appear-
be lined in part by columnar or squamous epithelium. ance. Modern treatment, however, allows rapid closure
Acid-fast bacilli can be demonstrated more frequently of cavities, which leaves little evidence of disease on chest
Figure 5.18: Tuberculosis of lung. Portions of a bronchus with the Figure 5.19: Pulmonary tuberculosis. Photomicrograph showing
bronchial cartilage and submucosal mucous glands are seen with necrosis and destruction of parenchyma [Haematoxylin and eosin
the epithelioid cell granuloma [Haematoxylin and eosin x 200] x 30]
Figure 5.20: Fibrocaseous tuberculosis of the lung. There is a large Figure 5.21: Photomicrograph showing caseation in tuberculosis
area of caseation with surrounding fibrosis and destruction of of the lung with poor encapsulation and spread [Haematoxylin and
pulmonary parenchyma [Haematoxylin and eosin x 30] eosin x 30]
84 Tuberculosis
Bronchiectasis directly attributable to pulmonary TB

is rare (81). In those instances when this is found it usually
occurs in the upper lobe and is relatively asymptomatic.
Along with bronchostenosis it predisposes to secondary
infection, haemoptysis and atelectasis.
Extension of TB to the pleura is common. Pericardial
TB may follow pleuritis or by lymphatic spread from a
pulmonary focus.
Whole Lung Tuberculosis

Rarely, TB can affect the whole lung. This condition has
a high mortality and results from diffuse bronchogenic
spread or haematogenous dissemination (100).
Figure 5.22: Photomicrograph showing tuberculosis involving a
bronchiole and adjacent alveoli. Rupture into the bronchus may Complications
result in endobronchial spread of the disease [Haematoxylin and
eosin x 30] The reader is referred to the chapter “Complications of
radiographs. Serious complications resulting from
pulmonary TB are uncommon now except when the Pleural Tuberculosis
disease has been neglected and becomes chronic and Pleural effusion is a frequent sequel to primary TB in
progressive. adolescents and adults. It is uncommon in younger
children. It can occur many years after primary infection
Other Lesions as an extension of post-primary TB or as an isolated
Tuberculosis bronchopneumonia and miliary TB are a effusion. Pleural effusion may complicate any TB
consequence of a large dose of virulent organisms pathology of lung or rib cage where the pleura is an
disseminating through the bronchus [Figure 5.22] or the involved bystander.
blood stream [Figure 5.10], respectively. It is obvious that Primary effusion usually occurs on the same side as
the host immunity may be compromised. The lesions the primary complex and hence is a result of contiguous
have been described earlier. affliction. Bilateral pleural effusions or those on the side
opposite to the primary complex should suggest miliary
or disseminated TB. Pleural and subpleural granulomas,
Bronchial Lesions
usually seen on both visceral and parietal surfaces [Figure
Despite being closely associated with the lung paren- 5.23], tend to follow the lymphatics on the visceral surface
chyma, bronchi do not appear to be frequently affected and may be discrete. Diffuse or focal fibrosis may follow.
in pulmonary TB (81). In a majority of cases, the Large caseous or cavitary lesions rupture into the
inflammation is non-specific and typical granulomas pleural space more commonly in post-primary TB and
may not be seen. In some cases endobronchial TB, as cause bronchopleural fistula with empyema. Empyema
discussed under primary pulmonary TB, may follow may heal with a fibrothorax and sometimes as a calcified
post-primary lesions (99) and this is characterized by pleural plaque resulting in a trapped lung [Figure 5.24].
bronchial inflammation, ulceration, granuloma, small These patients may present with functional disability.
pseudopolyps and eventual healing by fibrosis. Histological diagnosis is based on the identification of
Bronchostenosis may give rise to post-stenotic dilatation granulomas [Figure 5.25].
of the bronchus. This should not be confused with The volume and cellular nature of the exudate are
bronchiectasis. The reader is referred to the chapter dictated by the cell-mediated immunity. The fluid is
“Endobronchial tuberculosis” [Chapter 16] for further exudative, serofibrinous and occasionally purulent.
details. Predominant cell type is lymphocyte with few meso-
Pathology 85
Figure 5.25: Tuberculosis of pleura. Photomicrograph showing

epithelioid cell granuloma [Haematoxylin and eosin x 200]
Therefore, treatment of pleural effusion with antituber-

Figure 5.23: Tubercles [arrows] in the lower lobe of right lung. culosis drugs is fully justified.
Thickened pleura can also be seen
ABDOMINAL TUBERCULOSIS
The term abdominal TB generally includes TB of the
gastrointestinal tract and the peritoneum. It is customary
to exclude TB of organs like the kidneys and adrenals
from this list. Isolated TB of organs, such as, the liver is
uncommon. The TB of the intestines accounts for a
majority of such cases [65% to 78%]. Disseminated
abdominal TB has also been observed (101,102).
Intestinal Tuberculosis
The primary form of gastrointestinal TB is extremely rare
and has been discussed earlier. Intestinal TB usually
involves the ileum, ileocaecal region and the adjacent
Figure 5.24: Thickened fibrous pleura due to chronic caecum. Although this disease is chronic and invariably
tuberculosis encasing the lungs presents with symptoms suggestive of an abdominal
disorder. Recurrent intestinal obstruction is an important
thelial cells. Rarely, histiocyte clusters may be seen which presentation. Around one-third to a quarter of the
strongly suggest TB pleural effusion. A neutrophilic patients present with acute abdomen (102,103). Most
response does not rule out TB, though it is necessary to cases of intestinal TB are due to post-primary TB.
demonstrate the organism unequivocally in such cases.
Gross and Microscopic Pathology
Direct microscopy and culture studies often do not reveal
tubercle bacilli. The credit to the description of intestinal TB goes to
Primary pleural TB usually resolves without anti- F. Koenig whose masterly description in 1892 resulted
microbial therapy but when it develops in adolescence in the disease being called “Koenig’s syndrome” (104).
and young adulthood it may carry the risk of post- Grossly, intestinal TB is classified into three types:
primary TB, usually pulmonary within five to ten years. ulcerative [60%], hypertrophic [10%] and ulcerohyper-
86 Tuberculosis
trophic [30%]. Ulcerative lesions indicate a highly

virulent process (105-107). The intestine is indurated with
an increase in mesenteric fat. Ulcers are generally
transverse to the long axis [Figure 5.26]. Circumferential
or annular ulcers are usually less than 3 cm in length
(108,109). The ulcers are superficial and may have
undermined edges. Apparently the disposition of the
ulcers is a reflection of the direction of lymphatics around
the intestine. However, these may be a consequence of
vascular changes (110-112). The base of the ulcer is
covered by necrotic sloughs. On the serosa small
tubercles may be present. Authors feel that it is necessary
to document these lesions in the serosa since in essence
these are lesions of TB peritonitis. However, these are
Figure 5.27: Multiple strictures of the ileum due to tuberculosis
localized lesions and do not result in the usual
with perforation
manifestations of peritonitis that are discussed below.
Perforation of the intestine when present is usually
proximal to a stricture [Figure 5.27]. The hypertrophic
type is characterized by scarring and often mimics a
carcinoma. The ulcerohypertrophic type has features of
the two types described earlier [Figure 5.28]. There is a
thickening of the wall of the intestine. The mucosa may
show very superficial fissures giving rise to a cobblestone
appearance of the mucosa. Small pseudopolyps may be
identified. The ileocaecal region is distorted and the
normal angle as seen on barium films becomes obtuse. It
is important to note that in TB both sides of the ileocaecal
valve are involved leading to its incompetence. This is
unlike the features seen in Crohn’s disease (108,109).
Lymph nodes may be enlarged, but as in other cases of
post-primary TB these may not be prominent. Rarely,
Figure 5.28: Ileocaecal tuberculosis. There is a prominent

thickening of the ileocaecal valve
lymph nodes may assume a large size [Figure 5.29],

giving rise to the condition called tabes mesenterica. It
must be emphasized that the gross appearance of TB can
mimic a variety of conditions. Authors have seen cases
that have very little resemblance to the description
provided above. Surely, if the abdomen is a magic box
to the surgeon, intestinal TB has all the ingredients for a
Figure 5.26: Ileocaecal tuberculosis showing multiple strictures very successful show. Endoscopic diagnosis of colonic
and transverse ulceration TB is possible. In the colon, TB may resemble an
Pathology 87
inflammatory bowel disease [Figure 5.30] with a

prominent mucosal granularity.
Microscopic appearance of intestinal TB is similar to
that of TB elsewhere. Necrotising and non-caseating
granulomas [Figure 5.31] are the hallmark of intestinal
TB. While early lesions show granulomas in the mucosa
and Peyer’s patches, in later lesions any portion of the
intestine may be affected. Pyloric gland metaplasia is not
uncommon. The base of ulcers is lined by inflammatory
granulation tissue. Fibrosis and scaring are variable. In
cases that have undergone chemotherapy, hyalinization
is common. Sometimes the granulomas may be elusive
and certain specimens may not reveal any granuloma.
In fact in some studies granulomas have been Figure 5.31: Ileocaecal tuberculosis showing granulomatous
demonstrated in only 40 per cent of the resected intestinal inflammation in the submucosa [Haematoxylin and eosin x100]
specimens. The clue to the diagnosis is provided by the

identification of granulomas in the lymph node.
In such cases the diagnosis is either not made or at
best presumptive. Acid-fast bacilli can be demonstrated
in six to eight per cent of cases (109). Cultures may
increase the yield ten-fold. In the case of the colon,
histological and bacteriological examinations can provide
diagnosis in 60 per cent of the cases (113). Tuberculosis
in other regions of the gastrointestinal tract reveals the
characteristic granulomas [Figure 5.32].
Figure 5.29: Specimen showing mesenteric

lymph node tuberculosis
Figure 5.32: Tuberculosis of anus. Photomicrograph showing lining

Figure 5.30: Tuberculosis of the colon showing granularity and squamous epithelium and caseating granuloma [Haematoxylin and
ulceration of the mucosa eosin x 200]
88 Tuberculosis
Table 5.8: Differentiating features between intestinal tuberculosis and Crohn’s disease
Feature Tuberculosis Crohn’s Disease
Macroscopic
Anal involvement Rare Relatively common
Serosal tubercles Usually present Not seen
Length of strictures Short [< 3 cm] Long
Internal fistulae Rare Common
Perforation Uncommon Rare
Ulcers Circumferential/transverse Along mesenteric border/
longitudinal serpiginous
Microscopic
Granuloma in intestine/lymph node Present in majority Absent in a quarter
Lymph node granulomas May be only site Absent
Type of granuloma Large, confluent Small, discrete
Caseation Present Absent
Cuff of inflammatory cells Common Usually absent
Fibrosis and hyalinization Can be seen Rare
Fissures beyond submucosa Absent Present
Transmural lymphoid aggregates Not seen Present
Submucosal widening Absent Present
Fibrosis of muscularis propria May be present Not seen
Pyloric gland metaplasia May be seen Absent
Adapted from reference 109
Complications classified into two types: exudative or moist type,

clinically characterized by ascites and the plastic or dry
Haemorrhage, perforation, obstruction, fistula formation
type that is responsible for the typical doughy abdomen.
and malabsorption due to obstruction and blind-loop
syndrome and massive enlargement of mesenteric lymph Cirrhosis may be associated in a small proportion [6%]
nodes [tabes mesenterica] can occur in intestinal TB. of patients with peritoneal TB (114).
On gross examination, multiple, white tubercles are
Differential Diagnosis generally seen. With ascites such lesions may resemble
a metastatic carcinoma. In some cases numerous
Intestinal TB can mimic a variety of diseases. The peritoneal adhesions are identified. Microscopic
common differential diagnosis includes Crohn’s disease examination reveals typical granulomas [Figure 5.33].
[Table 5.8] (109) and ischaemic enteritis. Iscaemic enteritis
Ascitic fluid cytology shows a predominance of
closely resembles TB on gross examination. The presence
lymphocytes. It must be pointed out that on some
of a boggy mucosa due to mucosal and submucosal
occasions the reaction may be neutrophilic mimicking
oedema and the absence of granulomas strongly favour
an acute bacterial peritonitis.
the diagnosis of ischaemic enteritis. Other diseases
include Yersinia enterocolitica, amoebiasis and carcinoma
caecum (111). Syphilis and lymphogranuloma venereum Tuberculosis of the Liver
are curiosities of historical interest. Hepatic involvement by TB is not a rare entity. The
frequency of hepatic changes in lethal cases remains
Peritoneal Tuberculosis
higher than in cases of localized forms of TB. Actual
Peritoneal TB is post-primary and is the result of either involvement of the liver by granulomatous process is
haematogenous spread from a focus elsewhere or due common in fatal cases [Figures 5.34 and 5.35] as opposed
to a spread from an abdominal organ, usually a ruptured to the localized form where non-specific histological
TB lymph node. The lesions in peritoneal TB can be changes predominate.
Pathology 89
Figure 5.35: Granulomatous hepatitis. Photomicrograph showing

epithelioid cell granuloma in the liver parenchyma [Haematoxylin
Figure 5.33: Tuberculosis of omentum. Photomicrograph showing and eosin x 200]
lobules of adipose tissue, epithelioid granulomas with lymphocytic
infiltration [upper panel, left; Haematoxylin and eosin x 60], may yield better results with the presence of hepatic
epithelioid granulomas lymphocytic infiltration, Langhans’ giant cell, granulomas in 30 per cent of cases with TB (116).
foreign body giant cell and fibrosis [upper panel, right; Haematoxylin The liver in TB can have specific and non-specific
and eosin x 100], epithelioid granulomas [lower panel, left; histopathological changes [Table 5.9]. Korn et al (117)
Haematoxylin and eosin, x 400], multiple epithelioid granulomas
have emphasized the occurrence of focal hyperplasia of
with lymphocytic infiltration [lower panel, right: Haemotoxylin and
eosin x 200] Kupffer cells in TB. This refers to localized areas of
Kupffer cell proliferation with dilated sinusoids and
radiation into adjacent sinusoids. Although such lesions
may be the fore runners of microgranulomas, they differ
from microgranulomas in that they are composed of
typical Kupffer cells, have a stellate rather than rounded
configuration and lack characteristic epithelioid cells. On
the other hand, microgranulomas are small aggregates
of epithelioid cells, usually centrilobular in location and
lack giant cells and caseation (117). In fatal cases of TB,
actual involvement by granulomatous process is
common, whereas in localized form the non-specific
changes predominate. The rarer forms of hepatic TB
Table 5.9: Histopathological changes seen in the liver
Specific changes
Figure 5.34: Slice of liver from a patient with miliary tuberculosis Granulomatous hepatitis
showing a large area of necrosis Miliary pattern
Tuberculoma
Non-specific changes
The highest incidence of hepatic TB has been reported
Fatty change
in the miliary form of the disease. In a study of pediatric Spotty necrosis
TB, only 12 per cent of cases showed granulomas in the Portal fibrosis
liver (115). This low incidence can be attributed to the Portal triaditis
inherent drawback of needle biopsy as it samples a very Focal sinusoidal dilation
Kupffer cell proliferation
small portion of the liver. Examination of serial sections
90 Tuberculosis
lesions include TB cholangitis, tuberculoma and TB of

the lymph nodes at the porta hepatis.
GENITOURINARY TUBERCULOSIS
Genitourinary TB usually occurs in the reproductive age
group with a considerable lag period following the
occurrence of primary TB. The disease involves the
urinary tract and the genital tract either singly or in
combination. Due to anatomical considerations, infection
of the urinary tract and the male genital tract in
combination is common.
Urinary Tract
Initially, renal TB granulomas are located in the cortex,
which has a high perfusion rate. Cortical granulomas
may remain dormant and if the host resistance is
favourable, then fibrosis ensues. Highly virulent
organisms or low resistance can cause progression of
the lesion and the necrosis debris may lodge in the loop
of Henle. These produce medullary lesions which can
enlarge, coalesce and produce papillary necrosis. The
larger medullary lesions can persist as localized Figure 5.36: Tuberculosis of the kidney resulting in dilated calyces
tuberculomas or discharge into the draining calyx. and ureter. Caseation can be identified along some of the calyces
Sloughing of the necrotic contents into the calyx leads to
cavity formation. Such cavities have shaggy necrotic
walls with fibrosis of the adjacent renal parenchyma
(118). Tuberculosis may result in changes of pyonephro-
sis with dilatation of calyces [Figure 5.36]. Severe lesions
may destroy the parenchyma fairly extensively [Figures
5.37 and 5.38].
Some observers believe that kidneys can be involved
by ascending infection from the bladder through the
ureteral route. While such ascending infection is not very
common, communication of the caseating granuloma
with the collecting system is usually responsible for the
spread of infection into the distal urinary system, like
pelvis, ureter and urinary bladder. Additionally,
lymphatic spread can occur to contiguous structures.
Tuberculosis ureteritis can lead to stricture formation
as a result of fibrosis. This can lead to obstruction, which Figure 5.37: Tuberculosis of kidney in a child showing distortion
in advanced cases may result in TB pyonephrosis [Figure and caseation necrosis of the upper pole
5.36]. There may be focal or diffuse calcification of the
renal parenchyma. biopsy specimens from 30 patients with pulmonary TB.
Renal amyloidosis can occur in patients with pulmo- Seventy per cent of them had abnormal renal histology
nary TB of long duration. Apart from specific TB process, in the form of cloudy swelling of the tubular epithelial
kidney can show several non-specific changes in cells, focal lymphocytic aggregates, membranous glome-
pulmonary TB. Shah et al (119) examined renal needle rulonephritis, interstitial fibrosis and amyloidosis (119).
Pathology 91
Figure 5.38: Tuberculosis of the kidney. Photomicrograph showing

granulomas including Langhans’ giant cell and renal parenchyma
[Haematoxylin and eosin x 200]
Figure 5.40A: Tuberculosis epididymo-orchitis in a child showing

distortion of the testis and epididymis. Distortion and caseation of
the upper pole of the testis can be seen
Figure 5.39: Tuberculosis cystitis. Metaplastic squamous

epithelium and multiple epithelioid granulomas in submucosa are
seen [Haematoxylin and eosin x 200]
The initial lesions of vesical [urinary bladder] TB are

seen around the urethral orifices. Progressively in
advanced lesion, the whole bladder wall may be Figure 5.40B: Cut-section of testis and spermatic cord from a
patient with tuberculosis epididymo-orchitis
involved. There is granulomatous inflammation and
ulceration of the mucosa [Figure 5.39]. Later on, fibrosis
Male Genital Tract
may lead to urethral stricture formation and reduction
in the bladder capacity. If the infection proceeds from the urinary bladder,
It may be mentioned that treatment of transitional involvement of seminal vesicle, vas deferens and
cell carcinoma of the urinary bladder often involves epididymis can occur. Isolated testicular TB is rare. All
instillation of BCG into the bladder. This may give rise such cases are accompanied by epididymal infection, TB
to BCG granulomas, indistinguishable from TB. epididymo-orchitis [Figures 5.40A, 5.40B and 5.41].
92 Tuberculosis
Female Genital Tuberculosis

Female genital TB is usually secondary to a pulmonary
focus. It may be a component of generalized miliary TB.
Transmission by sputum, used as a lubricant by an
infected partner, has been reported (121).
Pathologically, the fallopian tube is the most common
site of involvement (122,123). The tubes are usually
involved bilaterally. These get seeded during the primary
infection. The lesions get reactivated or clinically
manifested usually after a long latent period. Endo-
metrial TB is related to spread from the fallopian tubes
(124). Less commonly, cervix and vagina are involved,
Figure 5.41: Tuberculosis of the testis. Photomicrograph showing as an extension from the endometrial lesion. Ovarian
semeniferous tubules, granulomas and caseous necrosis infection can also occur from the tubal source. Rarely,
[Haematoxylin and eosin x 100] sexual transmission can cause vulvar ulcers and inguinal
lymphadenopathy in females (125). Frequently, more
than one organ may be involved [Figure 5.43].
Tuberculosis epididymitis can lead to thickening of vas
Gross lesions can be miliary, ulcerative, proliferative
by the granulomatous process. Rarely, cold abscess can
or a combination of these. Fistula formation has also been
also form near the epididymis. Tuberculosis of the
reported. Granulomas are identified usually in the
prostate can mimic a nodular or benign hyperplasia
mucosa of the affected organ [Figures 5.44, 5.45 and 5.46].
clinically [Figure 5.42]. Involvement of multiple sites in
Histopathological confirmation by endometrial curettage
the male genital tract is not uncommon, as reported in
with staining for AFB and culture are necessary for
an autopsy series (118). As concurrent or previous renal
diagnosis. Curettage should ideally be done in the late
TB is seen in many cases (120), genital TB is usually
menstrual cycle. However, it is not necessary to believe
sequelae to a descending infection from the kidney.
that granulomas are identified only in secretory
Penile TB is very rare. As a form of skin TB, it can be
endometrium. Granulomas can be found in any phase
acquired from sexual contact. It can also be a manifes-
of the menstrual cycle and also in hyperplasia of the
tation of either local or haematogenous spread.
endometrium. Cervical biopsy is also useful. Identifi-
cation of necrotising epithelioid cell granulomas with or
Figure 5.42: Tuberculosis of the prostate. Characteristic granulo-

matous inflammation and a prostatic mucosal gland can be
identified [Haematoxylin and eosin x 100] Figure 5.43: Bilateral tuberculosis salpingitis with fibroids
Pathology 93
Figure 5.44: Tuberculosis salpingitis. Note the lining epithelium

and a granuloma [Haematoxylin and eosin x 200] Figure 5.46: Tuberculosis of the uterine cervix. Granuloma and
endocervical glands are seen [Haematoxylin and eosin x 200]
following years of quiescence due to advanced age,

trauma, malnutrition, chronic debilitation and immune
suppression. Tuberculosis meningitis can also result from
miliary spread of the disease. The miliary tubercles in
the leptomeninges are most frequently seen on the lateral
aspect of parietal and temporal lobes on either side of
the Sylvian fissure and along the blood vessels at these
sites.
There are six main parenchymal changes in neuro-
tuberculosis. These are: ventriculitis, border zone
encephalitis, infarction, internal hydrocephalus, diffuse
oedema, and tuberculoma. Ventriculitis is less frequently
encountered than meningitis. In this condition, the
Figure 5.45: Tuberculosis of the endometrium. Photomicrograph
ependymal lining of the ventricles and choroid plexus
showing portions of endometrial glands and granulomas
[Haematoxylin and eosin x 200] show tubercles. Border zone encephalitis is caused by
impingement of the meningeal exudate on the
underlying brain parenchyma. Frequently, there is only
without demonstration of AFB establishes the diagnosis
a glial reaction. Occasionally, the changes may be of
in a considerable number of cases. Caseation has been
inflammatory nature. Infarction is caused by vasculitis
reported to be more frequent in the elderly. Unfortu-
due to inflammation of the vessels in the meningeal
nately, AFB are hardly identifiable in most instances.
exudate. The vessels commonly involved are branches
of the middle cerebral artery, especially the perforating
NEUROTUBERCULOSIS
vessels to the basal ganglia (127). The vascular changes
Neurotuberculosis includes TB of the meninges, the occur in the form of periarteritis, endarteritis, panarteritis,
brain, spinal cord and the nerves. Tuberculosis menin- necrosis and thrombosis. Narrowing or total occlusion
gitis [TBM] is the commonest form of neurotuberculosis of the vessels results in infarction of the zone supplied
and generally develops from the breakdown of a small by the artery.
initial focus in the superficial cortex or leptomeninges. In TBM, hydrocephalus evolves due to the following
This focus discharges caseous material into the cerebro- reasons: [i] blockage of the basal cisterns and
spinal fluid [CSF] (126). Such a focus can destabilize medullocerebellar angles and obstruction to the flow of
94 Tuberculosis
the CSF by the basal exudate; and [ii] interference in the

absorption of CSF by arachnoid granulations.
Macroscopic Features
In TBM, the brain is heavier in weight due to cerebral
oedema. The leptomeninges in the basilar area appear
opaque as the underlying thick exudate fills up the
cisterns. Sometimes, the exudate is found on the surface
of the brain mimicking pyogenic meningitis [Figure 5.47].
The gyri appear flattened with obliteration of sulci.
Superficial blood vessels look congested. Serial slicing
reveals ventriculitis with matted appearance of the
choroid plexus. There may be ventricular dilatation and
areas of infarction in the middle cerebral artery territory.
Figure 5.48: Small tuberculomas of the brain [red arrow heads]
Finding the parenchymal tubercles giving rise to TBM is
difficult task because: [i] the tubercles are frequently of
small size [commonly 3 mm to 5 mm in diameter]. Thus frequent site being the cerebellum. The physical conti-
if the slices are thicker than 3 mm, the lesions may be nuity between a tuberculoma and meningeal exudate is
missed; [ii] the site of origin is frequently a caseous usually not evident, although this has been occasionally
meningeal plaque which is often masked macroscopi- observed (129).
cally by the surrounding meningitis; and [iii] macrosco-
Microscopic Features
pic visualization of caseous nodules is often difficult.
Parenchymal tuberculoma is less frequently seen than Large areas of caseous necrosis feature the leptomenin-
TBM. This may be due to the difference in their patho- geal reaction with a cellular infiltrate consisting
genesis. Usually small tubercles are found in association predominantly of lymphocytes and plasma cells. There
with TBM. While TBM is a typical leptomeningeal may be focal epithelioid granulomas with giant cell
reaction to tubercle bacilli, tuberculoma is the manifesta- reaction [Figure 5.49]. The ependymal lining of the
tion of hypersensitivity to tuberculoproteins in the ventricles reveals ependymitis which resembles the
susceptible individual (128). Generally, tuberculomas inflammatory reaction of meningitis (129). Choroid
[Figure 5.48] favour infratentorial location, the most plexitis may also be evident. In some cases the
Figure 5.47: Tuberculosis meningitis with loss of normal Figure 5.49: Photomicrograph of tuberculosis of meninges
transparency and granularity [Haematoxylin and eosin x 100]
Pathology 95
inflammatory reaction may be polymorphic giving the SKELETAL TUBERCULOSIS

appearance of a pyogenic meningitis. However, in these
Bone and joint TB usually follows a primary pulmonary
cases, numerous AFB are demonstrable.
infection. Less commonly, there can be contiguous spread
Immediately beneath the meningeal exudate, the
from pleura and periaortic lymph nodes. The most
brain shows oedema, perivascular inflammatory
frequently involved site is the vertebral body and this
infiltrate and microglial reaction. In long-standing cases
form of spinal TB is known as “Pott’s” disease. In this
gliosis ensues. If the inflammation is caused by fewer
disease, the classical involvement is of two consecutive
bacilli, complete resolution of the exudate is possible with
vertebrae with destruction of the intervertebral discs. The
treatment. Residual well-circumscribed, small caseous
lower thoracic and upper lumbar areas are common sites
foci may remain following treatment if the bacilli are
of disease. Any other bone or joint can be involved by
abundant.
TB, but weight bearing ones like knee and hip joints are
Histopathologically, tuberculomas show epithelioid
more prone to be affected.
granulomatous response with chronic inflammatory cells
Histopathologically, the presence of a granulomatous
and Langhans’ giant cells [Figure 5.50]. There are areas
inflammation with necrosis is compatible with the
of caseous necrosis. An occasional case shows focal
diagnosis of TB [Figures 5.51 and 5.52]. In the case of the
calcification.
bone, identification of necrotic or dead bone is useful.
The TB abscess consists of pus filled cavities
Special stains can demonstrate AFB in some cases
containing tubercle bacilli. The wall of TB abscess shows
(130,131).
granulation tissue with inflammatory cells. There is
usually a paucity of epithelioid cells or giant cells and
TUBERCULOSIS IN THE IMMUNOCOMPROMISED
the lesion may be misdiagnosed clinically as pyogenic
abscess. The content of the cavity usually shows Tuberculosis is often the sentinel disease warning of HIV
numerous AFB. infection and the development of AIDS. When active TB
Intracranial TBM often extends into the spinal occurs in patients with AIDS, pulmonary TB is almost
meninges. Only in a few cases the inflammation starts in always present and, in up to 70 per cent of the cases extra-
the subarachnoid space from a small subpial tubercle pulmonary disease is associated. The source of infection
[Rich focus] or TB vertebral osteomyelitis. Rarely, there could be recrudescence of latent infection [the
can be spinal intramedullary tuberculomas similar to commonest source], or accelerated progression of newly
intracranial lesions. acquired disease or superinfection of those previously
infected.
Figure 5.50: Tuberculosis of the brain [tuberculoma]. Photomicro-

graph showing epithelioid cell granuloma and Langhans’ giant cells Figure 5.51: Tuberculosis osteomyelitis with necrotic lamellar
[Haematoxylin and eosin x 200] bone and granuloma [Haematoxylin and eosin x 200]
96 Tuberculosis
culoid granulomas with minimal necrosis and few bacilli,

epithelioid cells and Langhans’ giant cells can be seen.
There is, however, the eventual tendency for the cell
aggregates to become smaller. They are more loosely
formed and the lymphocyte collar may not be evident.
Acid-fast bacilli are often found, giant cells are rare and
karyorrhexis [nuclear fragmentation] is often seen
(133-135).
Chest radiograph may be confusing. In a few cases,
the chest radiograph may be normal even in patients with
bacteriologically proven parenchymal TB. This is
especially so in infections caused by Mycobacterium avium
intracellulare complex [MAIC]. Diffuse interstitial pattern
Figure 5.52: Tuberculosis of the synovium. Photomicrograph on chest radiographs can be caused by Pneumocystis
showing necrotising granulomatous inflammation [Haematoxylin jiroveci infection in patients with AIDS and is easily
and eosin x 200] confused with other diseases. A positive blood culture
Impaired cell-mediated immunity [CMI] due to the for Mycobacterium tuberculosis has been observed in up
reduced number of T-cells, specifically, the CD4+ subset to about 26 to 40 per cent cases. Immune anergy with
is considered to be the reason for the higher incidence of loss of tuberculin reactivity is common. The progressive
TB in AIDS. Macrophage and peripheral monocyte loss of tuberculin reactivity appears to coincide with a
function is reduced and consequently there is reduced CD4+ T-lymphocyte count below 300 to 400 per cubic
activation of lymphokines. The cellular arm of immunity millimeter, although very low counts may be associated
is, thus, seriously impaired and the body’s defences with a significant tuberculin reaction at a level of
against intracellular pathogens such as mycobacteria and 5 mm or greater particularly after boosting by a second
other organisms such as Pneumocystis jiroveci become test (133-135).
defective. Tuberculosis itself may cause immunosup- In the terminal stages, when the immune defect is
pression (132). severe, there may be aggregates of macrophages but no
Until a late stage has been reached in the immune granuloma formation with numerous intracellular
impairment, TB presents the usual clinical and pathologic organisms. Disseminated, non-reactive TB with necrosis,
patterns observed in immunocompetent persons. Post- much nuclear debris, many extracellular stainable AFB
primary TB is most often encountered. Only when the and minimal cellular reaction are also seen. Surrounded
immune defect has become severe the presentation by a few histiocytes and lymphocytes areas of naked
becomes atypical and resembles more the pattern of necrosis can be seen. The mechanism of necrosis in the
primary disease (133-135). absence of significant numbers of inflammatory cells is
Hilar and mediastinal lymphadenopathy [often unclear.
bilateral] can occur in up to 60 per cent of adult TB cases
co-infected with AIDS, while this is observed only in
NONTUBERCULOUS MYCOBACTERIAL
three per cent patients without AIDS. Middle and lower
INFECTIONS OF LUNG
zone involvement is more often observed than the usual
upper lobe involvement. Diffuse infiltrates or a miliary The focus of this section is on the pathogenesis and
pattern is apparent in 15 per cent cases and distant pathology of the infections caused by nontuberculous
haematogenous dissemination to unusual sites is mycobacteria [NTM]. Microbiological classification,
common. Pleurisy commonly occurs. The disease, thus, characterization and other details regarding NTM are
resembles primary or progressive primary TB. Cavitation dealt with elsewhere. The reader is referred to the
is less frequent. Therefore, sputum is less frequently chapters titled “The mycobacteria” [Chapter 6] and
positive for AFB. Surprisingly, even in the late stages of “Nontuberculous mycobacterial infections” [Chapter 48] for
immunosuppression, typical compact or ‘hard’ tuber- more details.
Pathology 97
Pathology is present (142,143). Macroscopically the organs are often

enlarged and may be yellow because of the pigment.
The gross and microanatomical knowledge regarding
Recognizable granulomas may not be present or when
NTM disease is incomplete as the number of cases studied
present may be poorly formed. Acid-fast bacilli may be
that have not been modified by previous treatment are
plentiful with minimal or absent inflammatory reaction.
rare. Also many cases have not been studied, as they have
A particular feature of MAIC infection is the occurrence
been passed of as resistant TB or a nodular infiltrative
of aggregates of macrophages filled with many AFB, so
disease. Disease caused by NTM differs from TB in not
called multibacillary histiocytosis, a feature not seen in
causing a defined sequence of primary and post-primary
TB and AIDS. The use of antiviral therapy has permitted
disease (136,137). Haematological dissemination occurs
the repair of CMI which restores a more typical granulo-
only in the immunosuppressed. Radiological patterns of
matous response and an improved clinical response to
MAIC, Mycobacterium kansasii disease and Mycobacterium
antimycobacterial drug therapy. Diagnosis is achieved
xenopi resemble post-primary TB. In Mycobacterium
by blood culture, biopsy examination and culture of tissue
kansasii, the cavities are thin walled. In NTM disease, the
from liver, bone marrow and other organs (140-143).
anterior segments of the upper lobes are more frequently
In the present era, mere identification of AFB in tissue
affected. Spread to contiguous pleura and pericardium
sections would not suffice. It has become a goal of
is rare and spread to the lymph nodes is uncommon.
paramount importance to identify, whenever possible,
Study of a HIV-negative elderly female without other
the species of the mycobacterium and its drug suscepti-
lung disease showed a wide distribution of the lesions,
bility patterns for diagnostic, prognostic, therapeutic and
frequent bronchiectasis, patchy air-space disease, nodules
public health reasons.
and relative infrequency of cavities (138).
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102 Tuberculosis
The Mycobacteria
6
Rajesh Bhatia
INTRODUCTION Table 6.1: Classification of mycobacteria
The generic name Mycobacterium was introduced by Group 1

Lehmann and Neumann in 1896. The organisms were Obligate pathogens
named so because of the mold like [myco: fungus; Mycobacterium tuberculosis
bacterium: bacteria] pellicular growth of these organisms Mycobacterium leprae
in liquid medium (1). The true bacterial nature of these Mycobacterium bovis
Group 2
organisms was, however, soon established. The genus
Skin pathogens
Mycobacterium is the only genus in the family Myco- Mycobacterium marinum
bacteriaceae and order Actinomycetales. The guanine + Mycobacterium ulcerans
cytosine [G+C] ratio in the deoxyribonucleic acid [DNA] Group 3
of mycobacteria is 62 to 70 mol per cent and similar to Opportunistic pathogens
that observed in Nocardia (2). Mycobacterium kansasii
Mycobacterium avium intracellulare [MAIC]
An important character of the mycobacteria is their Group 4
ability to resist decolourization by a weak mineral acid Non- or rarely pathogenic
after staining with one of the aryl-methane dyes. This Mycobacterium gordonae
property of acid fastness is, however, not unique to Mycobacterium smegmatis
mycobacteria because Nocardia species and bacterial Group 5
Animal pathogens
spores are also acid-fast. The genus is better defined on
Mycobacterium paratuberculosis
the chemical structure of the mycolic acids and its Mycobacterium lepraemurium
antigenic structure.
CLASSIFICATION other than tuberculosis [MOTT]. These have been

classified by Runyon (3) into several groups [Table 6.2].
The genus Mycobacterium comprises of more than 50
species, of which several are non-pathogenic environ-
mental bacteria. It has been classified in a variety of ways. MYCOBACTERIUM TUBERCULOSIS
A clinical classification is more practical and is described
Morphology
in Table 6.1.
Mycobacteria other than human or bovine tubercle The tubercle bacilli are slender, straight or slightly cur-
bacilli that cause human disease resembling tuberculosis ved rod shaped organisms measuring two to four μm in
[TB] are called atypical mycobacteria. These are also known length and 0.2 to 0.8 μ in breadth occurring singly, in
as anonymous, unclassified, tuberculoid, paratubercle, or pairs or in small groups. The size depends on conditions
nontuberculous mycobacteria [NTM], mycobacteria of growth and long, filamentous, club shaped and
The Mycobacteria 103
Table 6.2: Runyon classification of nontuberculous mycobacteria
Runyon group Species Disease in humans

I Photochromogens Mycobacterium kansasii Pulmonary disease
Mycobacterium marinum Swimming pool granuloma
Mycobacterium simiae
II Scotochromogens Mycobacterium scrofulaceum Lymphadenitis in children
Mycobacterium gordonae
Mycobacterium szulgai
III Nonphotochromogens Mycobacterium avium Pulmonary disease in
immunocompromised
IV Rapid growers Mycobacterium intracellulare
Mycobacterium xenopi
Mycobacterium chelonae Superficial and systemic diseases
Mycobacterium fortuitum
Source: reference 3
branching forms may sometimes be seen. Mycobacterium linked to a group of long chain fatty acids termed mycolic
bovis is usually straighter, stouter and shorter. However, acid.
no distinction between Mycobacterium bovis and Myco-
bacterium tuberculosis can be made based on morphology. Cultural Characters
The bacilli are non-sporing, non-motile and non-
Growth Requirements
capsulated. In suitable liquid culture media, virulent
human and bovine tubercle bacilli form characteristic Mycobacteria are obligate aerobes and derive energy
long, tight, serpentine cords in which organisms are from oxidation of many simple carbon compounds. Bio-
aligned in parallel. chemical activities are not characteristic and growth rate
The bacilli are Gram positive though they do not take is much slower than that of most bacteria. The generation
the stain readily. These organisms resist decolourization time in vitro is about 18 hours. At the earliest, the growth
by 25 per cent sulphuric acid and absolute alcohol for 10 appears in about two weeks but may be delayed up to
minutes and hence these are called acid and alcohol fast. six to eight weeks. Optimum temperature for growth is
Acid fastness is based on the integrity of the cell wall. 37 °C and growth does not occur below 25 °C and above
Beaded or barred forms are frequently seen in 40 °C. Optimum pH for growth is 6.4 to 7.0. Increased
Mycobacterium tuberculosis while Mycobacterium bovis CO 2 tension [5% to 10%] enhances growth. Human
stains more uniformly. In younger cultures non-acid-fast strains grow more luxuriantly in culture [eugonic] than
rods and granules have been reported. do bovine strains [dysgonic]. The addition of a low
percentage of glycerol to the medium encourages the
Mycobacterial Cell Wall growth of human strains but not that of bovine strains,
The mycobacterial cell wall is complex in nature. It which may infact be inhibited.
essentially distinguishes mycobacteria from other
prokaryotes. Mycobacteria in general give a weakly Culture Media
positive response to Gram stain but are phylogenetically The reader is referred to the chapter “Laboratory diagnosis”
more closely related to Gram positive bacteria (4). It has [Chapter 10] for details on various types of media (5) that
high lipid content which accounts for about 60 per cent are commonly used for cultivation of mycobacteria.
of the cell wall weight. The cell wall has several distinct
layers. The inner layer, overlying the cell membrane is Colony Characteristics
composed of peptidoglycan [murein]. External to the On solid media human type of tubercle bacilli give rise
murein is a layer of arabinogalactan, which is covalently to discrete, raised, irregular, dry, wrinkled colonies which
104 Tuberculosis
are creamy white to begin with and then develop buff gloves, and other such material. The cultures of tubercle
colour. By contrast, the bovine type grows as flat, white, bacilli can be killed by exposure to direct sunlight for
smooth, moist colonies which “break up” more readily three hours while in sputum they can survive for 20 to
when touched. 30 hours. In droplets these may survive for 8 to 10 days.
Tubercle bacilli will grow on top of liquid medium Cultures can be stored for two years in a deep freezer at
as a wrinkled pellicle if the inoculum is carefully floated –20 °C. The organisms are resistant to drying and can
on the surface and the flask left undisturbed otherwise survive for long periods in dried sputum. Ordinary day-
they will grow as floccules throughout the medium. light even passing through glass has a lethal effect on
However, a diffuse growth can be obtained by adding a mycobacteria.
wetting agent such as Tween 80. Virulent strains tend to
form long serpentine cords in the liquid media while Antigenic Structure
avirulent strains grow in a more dispersed fashion. Mycobacteria being complex unicellular organisms,
contain many antigenic proteins, lipids and polysaccha-
Virulence in Animals rides. The exact number of antigenic determinants is
Under natural conditions Mycobacterium tuberculosis unknown. The mycobacterial antigens have been broadly
classified as: [i] soluble [cytoplasmic] and insoluble [cell
infects humans, monkeys, cows, buffaloes, pigs, dogs and
wall lipid bound]; and [ii] carbohydrates or proteins.
occasionally parrots. Under experimental conditions, it
is virulent to guinea pigs and mice and less virulent in Antigens have been extensively used to classify, identify
and type the mycobacteria.
rabbits and avirulent in chicken. Mice are most
commonly used for reasons of cost, convenience, their Soluble Antigens
amenability to genetic manipulations (6). Guinea pigs
Up to 90 soluble antigens are demonstrated by sensitive
exhibit many pathological features similar to those seen
techniques. Soluble antigens are divisible into four major
in humans, but unlike humans they are exquisitely
groups designated as group i to iv [Table 6.3].
sensitive to a progressive pulmonary infection (7).
Rabbits display pathogenicity more characteristic of Polysaccharide Antigens
human disease, ranging from spontaneous healing to Polysaccharide antigens are responsible for the group
caseous and cavitary pulmonary lesions (8). specificity while type specificity is due to protein antigen.
Following infection by tubercle bacilli, delayed hyper-
Susceptibility to Physical and Chemical Agents
sensitivity develops to the protein [tuberculin]. The
The best method to inactivate tubercle bacilli is by heat tuberculins from Mycobacterium tuberculosis, Mycobacterium
and the efficacy of chemical methods are all relative to bovis and Mycobacterium microti appear to be
heat inactivation. The thermal death time at 60 oC is 15 indistinguishable.
to 20 minutes. They are more resistant to chemical agents
than other bacteria because of the hydrophobic nature Biochemical Properties
of the cell surface and their clumped growth. Dyes such Mycobacterium tuberculosis has distinctive biochemical
as malachite green or antibiotics such as penicillins can properties, some of which are utilized for identification
be incorporated into media without inhibiting the growth of various species. The reader is referred to the chapter
of tubercle bacilli. Acids and alkalies permit the survival “Laboratory diagnosis” [Chapter 10] for further details.
of some exposed tubercle bacilli and are used for
Table 6.3: Soluble antigen sharing in mycobacteria
concentration of clinical samples and partial elimination
of contaminating organisms. These organisms can Group Present in Shared with
survive exposure to five per cent phenol, 15 per cent Group i All mycobacteria Nocardia
sulphuric acid, three per cent nitric acid, five per cent Corynebacterium
oxalic acid and four per cent sodium hydroxide. Tincture Listeria
iodine destroys it in five minutes while 80 per cent Group ii Slow growing mycobacteria -
Group iii Rapid growing mycobacteria Nocardia
ethanol does so in two to ten minutes. Thus, 80 per cent
Group iv Individual species None, unique
ethanol is recommended as a disinfectant for skin, rubber
Pathogenesis has been divided into four phage types—A, B, C and I

The first event in the pathogenesis of TB, whether [I stands for intermediate between A and B].
inapparent or overt, is the implantation of bacilli in
Bacteriocins
tissues. The most frequent portal of entry is lungs,
resulting from the inhalation of airborne droplets There is a limited evidence that some strains of myco-
containing a few bacilli that are expectorated by an open bacteria liberate substances that inhibit the growth of
case of TB. Less frequently, the bacilli may be ingested other species. Mycobacterium tuberculosis is divisible into
and lodged in the tonsil or in the wall of the intestine, 11 types by means of bacteriocins produced by rapidly
which may follow consumption of raw contaminated growing mycobacteria.
milk. Finally, third but a rare mode of infection is direct
Immunity and Hypersensitivity
implantation of bacilli into the skin, such as in workers
while handling material containing tubercle bacilli. The Infection with Mycobacterium tuberculosis induces delayed
reader is referred to the chapters “Pathology” [Chapter hypersensitivity [allergy] and resistance to infection
5], “Reactivation and reinfection tuberculosis” [Chapter 47] [immunity]. Unless a host dies during the first infection
for more details. with tubercle bacilli, there is an increased capacity to loca-
Mycobacteria produce no recognized toxins. Various lize tubercle bacilli, retard their multiplication, limit their
components of the bacillus have been shown to possess contiguous spread and reduce haematogenous and
different biological activities which may influence lymphatic dissemination. This can be attributed to the
pathogenesis, allergy and immunity of the disease development of cellular immunity during the initial
[Table 6.4]. infection.
The production and development of lesions and their In the course of primary infection the host also acqui-
healing or progression are determined chiefly by the res hypersensitivity to the tubercle bacilli. This is made
number of mycobacteria in the inoculum and their evident by the development of a positive tuberculin
subsequent multiplication and resistance and hyper- reaction. The reader is referred to the chapter “Immuno-
sensitivity of the host. The essential pathology of TB in logy of tuberculosis” [Chapter 7] for further details on this
infected tissues consists of production, of a characteristic subject.
lesion, the tubercle.
Koch’s Phenomenon
Mycobacteriophages The contrast between primary infection and reinfection
Mycobacteriophages have been used for subdivision of is shown experimentally in Koch’s phenomenon. When
some species of mycobacteria. Mycobacterium tuberculosis a guinea pig is injected subcutaneously with virulent
tubercle bacilli, the puncture wound heals quickly, but a
nodule forms at the site of injection in two weeks. This
Table 6.4: Mycobacterial components as determinants of nodule ulcerates and the ulcer does not heal. The regional
pathogenicity
lymph nodes develop tubercles and extensive caseation.
Cell component Pathogenic effect When the same animal is later injected with tubercle
Cell wall Induces resistance to infection bacilli in another part of the body, the sequence of events
Causes delayed hypersensitivity is quite different. There is a rapid necrosis of the skin
Can replace whole cell in Freund’s adjuvant and tissue at the site of injection, but the ulcer heals
Tuberculoprotein Elicits tuberculin reaction rapidly. Regional lymph nodes either do not become
Induces delayed hypersensitivity
infected at all or do so only after a delay. These differences
Induces formation of epithelioid and giant cells
Polysaccharides Induce immediate hypersensitivity
are attributed to immunity and hypersensitivity induced
Causes exudation of neutrophils from blood by the primary infection. The Koch’s phenomenon has
vessels three components: [i] a local reaction, [ii] a focal response
Lipids Cause accumulation of macrophages and consisting of an acute congestion around the TB foci in
neutrophils tissues and [iii] a “systemic” response of fever which at
Phosphatides Induce formation of tubercles
times may be fatal.
106 Tuberculosis
This effect is not caused exclusively by living tuber- based on production of pigment and rate of growth. The
cle bacilli, but also by killed ones, no matter whether they reader is referred to the chapter “Nontuberculous
are killed by low temperatures or prolonged periods, or mycobacterial infections” [Chapter 48] for further details.
by boiling or by certain chemicals.
MYCOBACTERIA PRODUCING SKIN ULCERS
Laboratory Diagnosis
Two conditions that are associated with skin ulceration
The laboratory diagnosis is based on demonstration and include Mycobacterium ulcerans infection also known as
isolation of tubercle bacilli and no other test is of much Buruli ulcer and infection with Mycobacterium marinum
use. The essential steps for diagnosis are: [i] collection of which causes swimming-pool granuloma. In addition to
specimens; [ii] demonstration of organism; [iii] culture these two, there are some other inoculation-associated
on suitable media; [iv] species identification by various infections.
tests; [v] use of molecular methods; and [vi] antituber-
culosis drug susceptibility testing [wherever possible]. Mycobacterium ulcerans
Microscopy and culture are done in peripheral and
This organism was first described in Australia and was
intermediate laboratories, whereas identification of
given the name Mycobacterium ulcerans in the year 1948.
Mycobacterium tuberculosis and antituberculosis drug
Later, a similar disease was seen in the Buruli county of
susceptibility testing are done in selected referral places.
Uganda and hence the name Buruli ulcer was given.
The reader is referred to the chapter “Laboratory diagnosis”
Epidemiological investigations suggest that the organism
[Chapter 10] for further details.
is inoculated into the skin by thorny vegetation. The
disease has an enormous socio-economic impact and is
Drug Susceptibility Testing
an important public health issue (10).
With the emergence of multidrug-resistance in mycobac- The earliest sign is a discrete firm nodule fixed to the
teria it is essential to perform drug susceptibility testing skin but mobile over deep tissues. It is painless, but may
on the tubercle bacilli isolates as an aid and guide to present with severe itching. If it does not resolve at this
treatment. Drug-resistant mutants continuously arise at stage it progresses to the ulcerative stage which is full of
a low rate in any mycobacterial population. The purpose bacilli. As the disease progresses, the overlying skin
of sensitivity testing is to determine whether the great becomes anoxic and necrotic. Subsequently, skin
majority of the bacilli in the culture are susceptible to ulceration occurs with the escape of liquefied necrotic
the antituberculosis drugs currently in use. Drug tissue and a deep ulcer with undermined edges is formed.
susceptibility testing may be performed directly on the The lesions which may be single or multiple, are more
original specimen or indirectly on a subculture. common on exposed parts of the body, especially limbs.
Four methods of drug susceptibility testing have been The disease is progressive for about three years but then
standardized. These are: [i] absolute concentration an effective immune response develops. Eventually, the
method; [ii] resistance ratio method, [iii] proportion lesion heals but often with extensive fibrosis and
method and [iv] BACTEC-460 radiometric method. The contractures leading to crippling deformities. In general,
reader is referred to the chapter “Drug-resistant chemotherapy has not proved very successful in its
tuberculosis” [Chapter 49] for more details. treatment. Simple excision of the lesion early in the
disease is curative. Physiotherapy is required to prevent
NONTUBERCULOUS MYCOBACTERIA deformities.
The NTM were initially grouped according to speed of
Mycobacterium marinum
growth at various temperatures and production of
pigments (9). More recently, individual species or Mycobacterium marinum is a natural pathogen of cold-
complexes are defined by additional laboratory blooded animals. The skin disease produced is known
characteristics, e.g., nitrate reduction, production of as “swimming-pool granuloma” or “fish tank granu-
urease, catalase and certain antigenic features. The NTM loma” or “fish fancier’s finger”. The organism was
have been classified into four groups by Runyon (3) initially named as Mycobacterium balnei but it was later
found to be identical to the fish tubercle bacillus and was agent in Crohn’s disease in humans (14); however, this
re-named as Mycobacterium marinum. Lesions occur at hypothesis has never been conclusively proven.
sites of injury, which are usually the knees and elbows
of swimming pool users and the hands of the fish REFERENCES
fanciers. The lesion commences as a solitary raised 1. Grange JM. Mycobacterium. In: Greenwod D, Slack S,
watery lesion, but secondary lesions develop along the Peutherer J, editors. Medical Microbiology. New York:
draining lymphatics. Occasionally, tenosynovitis may Churchill Livingstone; 1997.p.200-14.
develop at back. Human infection may occur in epide- 2. Runyon EH. Anonymous mycobacterial in pulmonary
mic form. Infection with Mycobacterium marinum causes disease. Med Clin North Am 1959;43:273-90.
3. Wayne LG, Kubica GP. The Mycobacteria. In: Sneath PHA,
a low-grade tuberculin reaction. The reader is also
Mair NS, Sharpe ME, Holt JG, editors. Bergey’s manual of
referred to the chapter “Cutaneous tuberculosis” [Chapter systematic bacteriology. Baltimore: Williams and Wilkinsons;
25] for further details. 1989.p.1435-57.
4. Brennan PJ, Draper P. Ultrastructure of Mycobacterium
tuberculosis. In: Bloom BR, editor. Tuberculosis: patho-
SAPROPHYTIC MYCOBACTERIA genesis, protection and control. Washington: ASM Press;
1994.p.271-84.
Saprophytic mycobacteria are non-pathogenic acid-fast 5. Petran EI, Vera HD. Media for selective isolation of
bacilli found in milk, butter, water, manure, grass and mycobacteria. Health Lab Sci 1971;8:225-30.
smegma of human beings and animals. Important 6. Orme IM, Collins FM. Mouse model of tuberculosis. In:
features of these mycobacteria are: [i] inability to set up Bloom BR, editor. Tuberculosis: pathogenesis, protection and
a progressive infection in mammals or birds; [ii] profuse control. Washington: ASM Press; 1994.p.113-34.
7. McMurray DN. Guinea pig model of tuberculosis. In: Bloom
growth at room temperature, giving rise to growth in
BR, editor. Tuberculosis: pathogenesis, protection and
two to three days; [iii] optimum temperature is in the control. Washington: ASM Press; 1994.p.135-47.
vicinity of 37 °C but growth at room temperature is also 8. Cosma CL, Sherman DR, Ramakrishnan L. The secret lives
very good; and [iv] extracts and purified protein of the pathogenic mycobacteria. Annu Rev Microbiol
derivative [PPD] prepared from many of these myco- 2003;57:641-76.
9. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley
bacteria may cross-react with PPD-S from Mycobacterium
C, Gordin F, et al; ATS Mycobacterial Diseases Subcommittee;
tuberculosis, resulting in positive skin tests in persons who American Thoracic Society; Infectious Disease Society of
are tuberculin negative. A higher proportion of the America. An official ATS/IDSA statement: diagnosis,
population becomes hypersensitive to mycobacteria treatment, and prevention of nontuberculous mycobacterial
acquired from the environment. diseases. Am J Respir Crit Care Med 2007;175:367-416.
Mycobacterium smegmatis is present in the smegma 10. Sizaire V, Nackers F, Comte E, Portaels F. Mycobacterium
ulcerans infection: control, diagnosis and treatment. Lancet
and contaminates urine samples. It needs to be differen-
Infect Dis 2006; 6:288-96.
tiated from Mycobacterium tuberculosis. It is acid-fast but 11. De Sarkar A, Kaur I, Radotra BD, Kumar B. Impact of
not alcohol-fast. combined Mycobacterium w vaccine and 1 year of MDT on
Mycoabcterium w is a saprophytic, cultivable, non- multibacillary leprosy patients. Int J Lepr Other Mycobact
pathogenic, rapidly growing atypical mycobacterium Dis 2001;69:187-94.
12. Katoch K, Singh P, Adhikari T, Benara SK, Singh HB, Chauhan
listed in Runyon Group IV. Heat-killed suspension of
DS, et al. Potential of Mw as a prophylactic vaccine against
Mycoabcterium w has been tried as an immunomodulator pulmonary tuberculosis. Vaccine 2008;26:1228-34.
in the treatment of leprosy (11). Its efficacy in pulmonary 13. Wells SJ, Whitlock RH, Wagner BA, Collins J, Garry F, Hirst
TB is under evaluation (12). H, et al. Sensitivity of test strategies used in the Voluntary
Mycobacterium avium sub-species paratuberculosis [often Johne’s Disease Herd Status Program for detection of
abbreviated as M.ap], is an obligate pathogenic bacte- Mycobacterium paratuberculosis infection in dairy cattle
herds. J Am Vet Med Assoc 2002;220:1053-7.
rium. It is a slow-growing, fastidious, heat-resistant
14. Shafran I, Burgunder P. Potential pathogenic role of Myco-
organism. It can be characterized rapidly with the help bacterium avium subspecies paratuberculosis in Crohn’s
of molecular techniques. It causes Johne’s disease in disease. Inflamm Bowel Dis 2008 May 28 [Epub ahead of
cattle (13). It has long been suspected as an aetiological print].
108 Tuberculosis
Immunology of Tuberculosis
7
DK Mitra, AK Rai
INTRODUCTION [Figure 7.1]. Each of these phases is determined by the

homeostasis between the bacillary factors and host
Protective immunity and varied clinical manifestations
immune status including both innate and adaptive
of infection with Mycobacterium tuberculosis represent a
immunity [cellular as well as humoral]. First, following
delicate balance between the bacillus and the type as well
inhalation of Mycobacterium tuberculosis, depending on
as magnitude of the immune response elicited by the
their intrinsic microbicidal capability alveolar macro-
host. Host immune response is a broad term reflecting
phages ingest the pathogen and destroy them. However,
complex interactions among various arms of the
bacilli often evade initial destruction by phagocytes and
immunity involving numerous cell types and molecules.
continue to multiply inside them ending in their
This confers a homeostatic balance either in favour of
disruption to cause fresh infection of the bystander
the host, leading to containment of the infection, disease
macrophages. This heralds the second phase, characte-
or in parasite’s favour resulting in failure of containment
rized by recruitment of blood monocytes and other
of infection. Immunity against tuberculosis [TB] needs
inflammatory cells to the primary disease site, the lungs
to be understood not only in terms of sterilising immunity
in most instances. Monocytes ingest the bacilli and
that eliminates Mycobacterium tuberculosis infection at the
differentiate into macrophages, but fail to eliminate them
initial exposure, but also with respect to immunity of
completely. This stage is marked by logarithmic growth
granuloma formation that maintains the steady state
of the pathogens with little tissue destruction. Following
control over the bacillary spread and prevents the
this, antigen specific T-cells are recruited to the pathologic
occurrence of clinical disease. Antituberculosis immunity
site[s] that activate the monocytoid cells leading to their
involves innate as well as adaptive immunity at various
differentiation into either of these two types of giant cells,
levels following Mycobacterium tuberculosis infection. Both
epithelioid and multi-nucleated Langhans’ type giant
of these will be discussed separately here: first the innate
cells. This is the third stage of granuloma formation, which
and then the adaptive one. It should be understood that
aims at walling off the infection from the rest of the body
separating these immune mechanisms is only for the sake
and prevents dissemination of bacilli, thus contains the
of better understanding of the complex cross-talk among
infection. This stage of latency, which disrupts under
diverse cell subsets and bio-molecules and obtaining
conditions of failing immune surveillance and gives rise
reductionist insights into the antituberculosis immunity
to endogenous reactivation of dormant foci culminating
in totality. However, in vivo, the innate and the various
in post-primary TB which is characterized by cessation
components of adaptive immunity are complementary
necrosis [fourth phase]. In summary, after entry into the
and work synergistically in concert.
body, Mycobacterium tuberculosis encounters a series of
host defense mechanisms with final outcome depending
CHRONOLOGY OF IMMUNOPATHOGENESIS OF
on the balance between bacillary growth and extent of
TUBERCULOSIS
host immunity. Essentially, all these phases of TB infection
Pulmonary TB can be marked with four distinct involve various arms of innate and acquired immunity
phases following Mycobacterium tuberculosis infection sequentially in an orchestrated manner.
Immunology of Tuberculosis 109
Figure 7.1: Events during TB infection. Broadly, TB infection is divided into four phases: First phase includes an initial establishment of
Mycobacterium tuberculosis infection in the resident macrophages [alveolar]. This is followed by influx of PMNs, which prevents
Mycobacterium tuberculosis to escape from the innate immune factors. Subsequently, monocytes are recruited to the site of infection/
pathological site [second phase]. Third phase includes granuloma formation. Core of granuloma is made up of multinucleated giant cells
and elongated epithelioid cells. These are surrounded by T-cells. This is aimed at restricting the bacilli from spreading. The fourth and
terminal phase includes dissemination of bacilli. Defective granuloma formation promotes release of bacilli from control of immune
system. Organs/loci targeted by bacilli after dissemination are listed here
DC = dendritic cells; Mφ = macrophages; PMNs = polymorphonuclear leucocytes; TB = tuberculosis
INITIAL ENCOUNTER AND INNATE IMMUNITY [MHC] class II. These antigens presumably serve as the
dominant antigens for CD4+ cells, which start
Mononuclear cells including alveolar macrophages and accumulating in large numbers in lesions during the early
dendritic cells [DCs] play a crucial role during their initial stages of Mycobacterium tuberculosis infection. Recent data
encounter with Mycobacterium tuberculosis by their suggest that probably T-cell dependent acquired
intrinsic or innate defense mechanism[s]. This has been immunity is also critical for protection against
demonstrated by Lurie in animal model where early dissemination and disruption of latency of TB. However,
infection and bacillary multiplication occur in susceptible they may not be so critical for eliminating the initial
rabbits (1). A probable role of DC specific intercellular infection with Mycobacterium tuberculosis (2,3). This
adhesion molecule 3 [ICAM-3] grabbing nonintegrin dynamics of effector immune mechanisms fits well with
[DC-SIGN], a recently discovered type II transmembrane the basic fact that the acquired immunity requires time
protein has been implicated in DC mediated dissemina- to develop and until then innate mechanisms attempt to
tion of Mycobacterium tuberculosis. Subsequently, DCs in either eliminate or control multiplication of the bacilli so
the lymph nodes present some of the early secretory that effective T-cell response eventually may contain the
antigens such as early secreted antigenic target 6 [ESAT6] infection through stable granuloma formation (4). A
and antigen 85 with major histocompatibility complex plethora of clinical and experimental evidence suggests
110 Tuberculosis
an essential role of innate immune responses during an transmembrane proteins with leucine rich repeat motifs
early phase of infection with Mycobacterium tuberculosis. in extracellular domain. Cytoplasmic domains of TLRs
Alveolar macrophages are the first line of cellular are homologous to the signalling domain of IL-1 receptor
elements of initial uptake of aerosolized Mycobacterium [IL-1R] and are linked to signalling molecule IL-1R
tuberculosis, although subsequently DCs and monocytes associated protein kinase [IRAK-1], a serine kinase that
are also involved in the process. Various receptors activates transcription factors of several key
expressed on the phagocytes mediate endocytosis of the immunoregulatory cytokines, such as nuclear factor-
bacilli. Uptake of opsonized bacilli [coated with kappa beta [NF-kB]. Of the several TLRs discovered till
preformed humoral elements like antibodies or comple- date TLR2, TLR4, TLR3 and TLR9 appear to elicit cellular
ment split products] is greatly facilitated by complement response to mycobacterial antigens including the 19-kDa
receptors expressed on macrophages such as lipoprotein and lipoarabinomannan [LAM]. In context
complement receptors [CRs] CR1, CR3 and CR4. Bacillary of CD14, TLR2 binds to LAM, a heterodimer of TLR2
uptake by human macrophages deficient in CRs is found and TLR6 binds to CD19 kDa lipoprotein. The TLR4
to be reduced up to 80 per cent indicating their role in binds to yet undefined heat labile cell associated factor
engulfing Mycobacterium tuberculosis (5). Non-opsonized and TLR9 binds to mycobacterial DNA motifs.
bacilli are engulfed by macrophages through mannose Engagement of TLRs by mycobacterial antigens leads to
receptors [MRs] that recognize the terminal mannose coupling of myeloid differentiation primary response
moieties of mycobacteria (6). Additionally, non- gene [88] [MyD88] and IRAK signalling molecules
opsonized Mycobacterium tuberculosis can be taken up by resulting in multiple signalling events that ultimately
the macrophages through binding to the scavenger translocate transcription factor NF-kB from cytosol to
receptor type A, as blocking CRs and MRs could not nucleus and stimulate the production of various cytokine
completely abrogate the bacillary uptake. Several other required for innate as well as adaptive immune events.
groups of molecules of the innate immune system may Production of cytokines following TLRs induced
also facilitate binding and uptake of Mycobacterium activation of macrophages is important for immunity to
tuberculosis. Collectins, a structurally related group of Mycobacterium tuberculosis. Several cytokines are released,
proteins are important in this regard. Surfactant protein some of which take part in non-specific inflammation,
A enhances the uptake while surfactant D blocks it. and others regulate the functional bias of the relevant T-
Another member of collectins, the plasma factor mannose cells. A brief account of the important cytokines produced
binding lectins is also involved in macrophage uptake by Mycobacterium tuberculosis infected macrophages is
of the bacilli. Fibronectins also facilitate uptake of provided in Figure 7.2. These cytokines eventually induce
Mycobacterium tuberculosis by alveolar epithelial cells further activation of immune cells and lead to a complex
through binding to antigenic proteins (7). Thus, multiple process of immune regulation. Among the pro-inflam-
mechanisms are operational in the uptake of Mycobac- matory cytokines tumour necrosis factor-α [TNF-α],
terium tuberculosis by mononuclear phagocytes giving interleukin-1β [IL-1β], interleukin-6 [IL-6], interleukin-
them a chance to kill the bacilli. However, all these 12 [IL-12], interleukin-15 [IL-15] and interleukin-18
mechanisms only facilitate in their uptake but fail to elicit [IL-18] are important. Each of them plays a distinct role
any immune recognition leading to macrophage in the immune response against TB.
activation. Up-regulation of a battery of surface expressed
and soluble molecules determine the shape of the α
Tumour Necrosis Factor-α
eventual acquired immunity on the surface of macro- This prototype pro-inflammatory cytokine is produced
phages. Toll-like receptors [TLRs] are such family of by macrophages, DCs and Th1 like cells upon infection
molecules on the surface of macrophages that play a and stimulation with Mycobacterium tuberculosis. It plays
critical role in immune recognition of Mycobacterium key roles in macrophage activation, immune regulation
tuberculosis and elicitation of an effective innate immune and particularly granuloma formation by induction of
response. The TLRs are phylogenetically conserved appropriate chemokine receptors on the effector T-cells
molecules mediating the innate immunity and dictating and thus recruiting them to the disease site (8). In mice it
the development of eventual T-cell responses. They are has been shown to be involved in maintaining the latency
Figure 7.2: Summary of the immune response in tuberculosis pathogenesis. After infection, innate immune responses try to put check
on increasing infection. Meanwhile, immature DCs after taking up the antigens, move towards the draining lymph nodes and antigen
recognition and presentation to T-cells occur inside the regional/draining lymph nodes. Recruitment of antigen specific T-cells at the
pathological sites and production of pro-inflammatory cytokines such as tumour necrosis factor-α [TNF-α], interferon-γ [IFN-γ] etc., lead
to granuloma formation to localize the pathogen. Later on, depending on presence/absence of Th1/Th2 skewed response, dissemination
or containment of bacilli occurs
DC = dendritic cell; TLRs = toll-like receptors; ROI = reactive oxygen intermediates; RNI = reactive nitrogen intermediates; IL = interleukins;
Tc cell = T-cytotoxic cell; FAS-FASL = tumour necrosis factor receptor superfamily, member 6 - tumour necrosis factor receptor superfamily,
member 6 ligand; ICAM-1 = intracellular adhesion molecule-1
of TB infection and has been found at the disease site[s]. macrophages and DCs and is found in excess at the
Its role in humans is best evidenced by occurrence of pathologic site[s] of TB. An increased mycobacterial
high incidence of TB among rheumatoid arthritis patients growth and a defective granuloma formation are
when treated with anti-TNF-α antibodies. However, it observed in IL-1β knock out mice (9). Interleukin-6 on
is thought to be a “double edged sword” causing the other hand, may serve as both pro- and anti-
bystander damage of the host tissue and cavity formation, inflammatory cytokines and is found to be present in TB
particularly when present in relative excess in the milieu.
patients (10). Various reports suggest that it may
β and Interleukin-6
Interleukin-1β antagonise either TNF-α or interferon-γ [IFN-γ], both of
Interleukin-1β is another proinflammatory cytokine which are widely believed to be critical for protective
secreted by the Mycobacterium tuberculosis infected immune response against TB.
112 Tuberculosis
Interleukin-12 and Interleukin-18 cytokines are produced as well in TB. Some of these, such
as interleukin-4 [IL-4], interleukin-10 [IL-10] and trans-
Interleukin-12 is the most potent Th1 driving regulatory
forming growth factor-β [TGF-β], are Th2 like cytokines
cytokine produced by infected or stimulated macro-
and their role in the immunopathogenesis of TB has
phages and DCs and thus, plays a crucial role in the
provided the concept of Th1/Th2 paradigm in various
development of protective Th1 type immunity in TB. In
forms of TB. These cytokines are believed to antagonise
TB, IL-12 has been detected in disease sites such as lung the protective and/or containing immunity, thus
infiltrates, pleurisy and granulomas (9,11). Its receptor suppressing the required immunity. Therefore, they have
is also over-expressed in these sites. Children with been implicated in enhanced susceptibility as well as
deleterious mutation of genes encoding IL-12p40 subunit disease severity in terms of clinical manifestation and
and IL-12 receptor are highly susceptible to recurrent the extent of the disease.
nontuberculous mycobacterial infections (12).
Interleukin-18, another pro-inflammatory cytokine is Interleukin-10
important for IFN-γ axis of the T-cell response. High Interleukin-10 is produced by the macrophages after
susceptibility of IL-18 knock out mice to Mycobacterium phagocytosis of Mycobacterium tuberculosis and also by
tuberculosis, bacille Calmette-Guérin [BCG] and the Th2 cells following recognition of duly processed
Mycobacterium leprae strongly suggests a protective role mycobacterial antigens. Mononuclear cells from TB
of this cytokine in TB (13). A close parallelism has been patients, particularly those with disseminated disease,
noted between the concentration of IL-18 and IFN-γ produce copious amounts of IL-10 in vitro in response to
among patients suffering from TB pleural effusion (14). mycobacterial antigens (17). Interleukin-10 transgenic
Protective effect of IL-18 may be mediated by enhanced mice supports better bacillary growth. Also in humans,
production of IFN-γ, another potent effector cytokine for IL-10 production is significantly higher in patients with
macrophage activation leading to killing of the intra- purified protein derivative [PPD] anergy and severe
cellular mycobacteria. forms of TB. Interleukin-10 is well known for its ability
to suppress IFN-γ, TNF-α and IL-12, all of which are
Interferon-γγ critical for eliciting a desired Th1 type immune response
in host’s favour.
A protective role of IFN-γ in TB is beyond doubt. But it
must be remembered that it is not the only terminal Interleukin-4
effector cytokine to confer protection in TB. Mycobac-
The deleterious influence of IL-4 in TB is well known
terial antigen specific in vitro production of IFN-γ by
and is attributed to its suppressive effect on IFN-γ
T-cells from patients represents a surrogate marker of
immunity against TB. However, there exists a great deal production. Mycobacterium tuberculosis infected mice with
of divergence of opinion in this respect among the progressive form of disease shows a significantly higher
researchers and clinicians. In TB, physiologically relevant production of IL-4 (18). Disseminated form of TB, such
sources of IFN-γ are natural killer cells [NK-cells], antigen as miliary TB, is associated with a very high production
specific T-cells [helper and cytotoxic], macrophages of IL-4 by T cells derived from peripheral blood and
themselves, and other relatively rare fine T-cell subsets bronchoalveolar lavage [BAL] fluid following in vitro
such as γδ T-cells and CD1d restricted NKT-cells (15). stimulation (19,20). However, several studies failed to
The IFN-γ is a potent activator of infected macro- reproduce similar observation, which may be due to
phages resulting in potentiation of lytic mechanism[s] variation in the study subjects and methods used for the
responsible for killing of intracellular Mycobacterium detection of IL-4. It is widely believed that IL-4
tuberculosis and enhancement of human leucocyte production is responsible for suppression of Th1 type
antigen [HLA] and co-stimulatory molecules which immune responses against TB. Thus, the host fails to
result in efficient presentation of macrophage processed contain the disease, leading to the development of severe
mycobacterial antigens and elicitation of strong T-cells and disseminated forms of TB.
responses (16). In some recent elegant studies, a splice variant of
In addition to the production of the above pro- IL-4 gene has been detected. This truncated splice variant
inflammatory cytokines, certain anti-inflammatory called IL-4δ gives rise to protein isoform, which inhibits
the immunosuppressive Th2 like function of native Several studies have reported reduced levels of
IL-4. Expression of IL-4δ messenger ribonucleic acid vitamin D among TB patients. Recent clinical trials
[mRNA] was very minimal in the peripheral blood suggest a distinct role for vitamin D in potentiating the
mononuclear cells [PBMCs] of the healthy subjects. On immunity against TB. An interesting element involved
the other hand, it was found to be expressed in in macrophage activation as well as killing of intracellular
significantly higher amount in the thymocytes and BAL mycobacteria is the solute carrier family 11 [proton-
fluid cells from patients with TB. Tissue specific coupled divalent metal ion transporters], member 1
expression of this splice variant and tight correlation with [Slc11a1], and its human orthologue, SLC11A1, formerly
the disease severity suggests a potential immunoregula- known as natural resistance associated macropahge
tory role in pathogenesis of TB. Plausibly, IL-4δ protein [Nramp1]. It is an integral membrane protein
functionally inhibits Th2 skewing of the host immune belonging to a family of metal ion transporter, parti-
response by antagonising the effect of native IL-4 and cularly the iron [Fe++]. Following phagocytosis Slc11a1
facilitates the desired Th1 response. Ratio of IL-4/IL-4δ becomes integrated to the phagosomes and activates
may be useful in monitoring the cytokine polarized macrophages with generation of toxic anti-microbial
immune response among TB patients. radicals, particularly ROIs (24). The Slc11a1 mutant mice
show reduced phagosomal maturation and acidification.
β
Transforming Growth Factor-β In humans, polymorphism of this gene associated with
reduced expression of SLC11A1 is associated with
Transforming growth factor-β also appears to inhibit the
susceptibility to TB in West African population (25).
protective immunity against Mycobacterium tuberculosis
Therefore, genetic variation of this gene may in part
and aggravates the pathology. The TGF-β is also pro-
determine the outcome of Mycobacterium tuberculosis
duced in abundance by TB patients and its expression is
infection.
observed at the pathologic site[s] (21). The TGF-β is a
Generation of ROIs appears to be important for killing
well known inhibitor of T-cell proliferation, IFN-γ pro-
of intracellular bacilli. However, the conclusive proof is
duction, macrophage activation and antigen presentation.
still awaited due to variation among experimental
Moreover, it is also known for its potent host tissue
systems, particularly among mice and human studies. In
damaging effect and fibrosis (22). The TGF-β along with
vitro mycobacteria are resistant to killing by superoxides
IL-10 potently suppresses the Th1 function during TB
and hydrogen peroxides, this may be due to presence of
infection and is thought to contribute to the pathogenesis
LAM on Mycobacterium tuberculosis that can scavenge the
of TB.
ROIs. In mice lacking functional P47 unit of nicotinamide
adenine dinucleotide phosphate [NADPH], which is
IMMUNE EFFECTOR MECHANISMS AGAINST
required for the generation of superoxide ions, early and
MYCOBACTERIUM TUBERCULOSIS
excessive growth of Mycobacterium tuberculosis has been
Activated macrophages are the terminal effector cells demonstrated (26). This points towards an important
responsible for killing of intracellular bacilli in TB. role of ROIs in mycobacterial killing. On the contrary,
Multiple factors are responsible for this activation finally patients suffering from chronic granulomatous disease
resulting in triggering the major lytic mechanisms. [CGD] with a defect in production of superoxide radicals
Among several factors, the most well documented and have not been demonstrated to be susceptible to TB (27).
definitive mediators are IFN-γ and TNF-α. These Therefore, a precise role of ROIs in killing Mycobacterium
cytokines are primarily derived from the Th1 cells and tuberculosis is still not conclusively demonstrated, even
activate the macrophages to induce the intracellular though it is strongly suggested.
messenger molecules, reactive oxygen intermediates Similarly, the role of RNIs still remains inconclusive
[ROIs] and reactive nitrogen intermediates [RNIs] that as well. In vitro infection of macrophages with Mycobac-
are thought to be involved in killing of the intracellular terium tuberculosis leads to up-regulation and excessive
mycobacteria. Also important for macrophage activation production of inducible nitric oxide synthase [iNOS2],
synergistically with IFN-γ and TNF-α is the active which is required for the production of nitric oxide.
metabolite of vitamin D [1,25-dihydroxy vitamin D] (23). Alveolar macrophages obtained from the BAL fluid of
114 Tuberculosis
patients with TB have shown an increased expression of is mediated by the expression of adhesion molecules and
iNOS gene (28). But the precise role of over-expression chemokines. Many of these cell homing molecules are
of iNOS in patients with TB remains uncertain, as post- known to be induced by Mycobacterium tuberculosis. The
translational modification of iNOS is required for intracellular adhesion molecule-1 [ICAM-1], a major
functional activity. adhesion molecule involved in granuloma formation, is
induced by TNF-α, IL-6 and IFN-γ. Chemokines, such as
ACQUIRED T-CELL MEDIATED IMMUNE macrophage inflammatory protein [MIP1-α], regulated
MECHANISM on activation, normal T-expressed and secreted
T-cell mediated immune response is at the hub of immu- [RANTES], monokine induced by interferon γ [Mig], and
nity against Mycobacterium tuberculosis as antibodies fail IFN-γ-inducible protein-10 [IP-10] etc., all associated with
to contain the infection due to its intracellular habitat. inflammation are also induced by the bacilli (32,33). The
Upon initial exposure and recognition of immuno-domi- Th1 cells preferentially recruited by these homing
nant epitopes, naive T-cells are primed and converted molecules, through the release of cytokines promote
into effector and memory T-cells. Effector T-cells contain terminal differentiation of macrophages into giant cells
the initial infectious load. However, dormant foci of like multinucleated and epithelioid types. These acti-
Mycobacterium tuberculosis within macrophages persist vated cells of monocyte/macrophage lineage ultimately
and reactivation of the bacillary foci occurs in the event[s] kill the intracellular Mycobacterium tuberculosis through
of perturbation of a delicate balance of T-cell immunity ROIs and RNIs. Mycobacteria are also capable of
that contained the foci so far (29). Additionally, a fresh inducing caseation necrosis in the centre of the
exogenous infection may also take place. Whatever is the granuloma. Conventionally, TNF-α has been thought to
case, on these subsequent exposures, the memory T-cells be the prime mediator of caseation necrosis. However,
generated during the primary infection elicit a strong Th1 recent findings of caseation necrosis among mice lacking
response and migrate to the site of the pathogen. These functional component of TNF receptor [55 kDa TNF-R]
migrated T-cells are further activated by the processed suggest the existence of other mechanism[s] for this
antigens presented by the local infected macrophages phenomenon. Mycobacterial components such as, LAM
and secrete key effector cytokines, such as IFN-γ and have been demonstrated to activate interstitial
TNF-α, which help in activation as well as terminal collagenase gene and matrix metalloproteinase-9 [MMP-
differentiation of the macrophages into the giant cells. A 9]. These extracellular matrix enzymes probably play a
well-defined architectural aggregation of T-cells and the major role in caseation necrosis. Interestingly, up-
giant cells [both multinucleated and epithelioid types] regulation of MMP-9 has been observed in BAL cells
results in granuloma formation, the immunopathologic recovered from cavitary TB patients (34). Granuloma may
hallmark of TB. An evolution of granuloma occurs be regarded as a localized immune reaction that attempts
through a sequential influx of various types of cells of to wall off the pathogen and prevents its further spread.
the immune system (30). Neutrophils migrate quite early The dormant foci of infection may remain as such for
in this process followed by the monocytes which years or even life-long. However, perturbation of a
differentiate into macrophages within two to three days. delicate balance of immunity with suppression of critical
Chemokines induced in the granuloma begin to recruit mechanism[s] may lead to activation of endogenous foci
T-cells which are activated to secrete cytokines. Among containing dormant mycobacteria. Alternatively, fresh
the T-lymphocyte layer surrounding the granuloma are exogenous infection can also occur. Both of these develop
predominantly of CD4+ type, although CD8+ T-cells are into a clinical disorder such as pulmonary TB. Immune
also present. The T-cell derived cytokines locally trigger response to Mycobacterium tuberculosis continues to play
the macrophages to terminally differentiate into highly a critical role and dictates the clinical outcome of the
active giant cells. Apoptosis of cells, prominently in disease as well. The extent and severity of the disease
epithelioid cells has been demonstrated by terminal appear to be determined by the type and magnitude of
deoxynucleotidyl transferase biotin-dUTP nick end the T-cell response elicited eventually. As Th1 like
labelling [TUNEL] immunostaining (31). Appropriate response is critical for containment of Mycobacterium
positioning of various cell types within the granuloma tuberculosis infection, its robustness and balance between
Th1 and Th2 type of response play an important role to well as severity of their disease. Another major limitation
dictate whether the disease will be of limited extent with of these studies is that all of them looked either at the
localized form such as pulmonary TB or will disseminate soluble and accumulated cytokine level in the peripheral
to give rise to severe forms of disease such as miliary TB, blood or long term in vitro stimulation which might have
multidrug-resistant TB [MDR-TB] [Figure 7.2] (20,35). imposed functional bias on the responding T-cell in terms
of cytokine production.
CD4+ AND CD8+ T-CELLS IN TUBERCULOSIS To address the issue of Th1/Th2 paradigm in TB,
investigators focussed attention to the cells producing
Importance of CD4+ helper T-cells is best demonstrated the cytokines particularly the T-cells derived from the
by significantly higher incidence and occurrence of disease site. Data emanating from these recent studies
severe and disseminated forms of TB among patients co- indicate a possible compartmentalization of T-cell
infected with human immunodeficiency virus [HIV] and mediated immune response among TB patients and a
Mycobacterium tuberculosis (36). It is also suggested by the predominant role of IL-12. Cytokine profile of the pleural
predominant presence of CD4+ helper T-cells in the fluid revealed excess levels of IFN-γ and IL-12 relative to
granuloma outnumbering the CD8+ T-cells. Functionally, their levels in the peripheral blood compartment (37).
mature or memory helper T-cells are of two distinct types, Several investigators have demonstrated a Th1 biased
namely, Th1 and Th2 cells. The Th1 cells preferentially response in the pleural compartment representing the
produce IL-2, IFN-γ and TNF-α to stimulate the cell site of a strong T-cell response of local TB pathology.
mediated immunity which is crucial for containment of To understand the Th1/Th2 phenomenon in TB
Mycobacterium tuberculosis. On the other hand, Th2 cells researchers have studied patients suffering from
are biased to produce more of IL-4, interleukin-13 [IL- disseminated and severe forms of TB. The T-cells from
13], and IL-10, etc., and boost the antibody production, TB patients in the setting of HIV infection showed
particularly of IgE isotype and suppress the Th1 like predominant IL-4 production with excess of IL-10 that is
immunity. The importance of Th1/Th2 paradigm has known to drive the effector T-cell responses towards Th2
been studied in various diseases; the most notable is that and antagonize the Th1 driving cytokine IL-12. Study of
among polar leprosy patients. Tuberculoid leprosy, T-cells from patients with miliary TB provided strong
which is characterized by high degree of T-cell reactivity indication that extent and dissemination of TB tightly
against Mycobacterium leprae is associated with Th1 like correlate with a strong Th2 bias demonstrated by the
polarized cytokine response while lepromatous leprosy, T-cells derived from BAL fluid representing the
hallmarked by T-cell anergy towards Mycobacterium pathologic site of disseminated TB (19). Interestingly,
leprae strongly correlates with dominant Th2 like cytokine IFN-γ production by the T-cells from the BAL fluid could
profile (37). Similar association in TB has been proposed be restored by supplementation with IL-12. Using flow
and subsequently demonstrated by several groups of cytometry based assay of intracellular cytokines, Mitra
investigators. However, conclusive picture is yet awaited. et al (20) have demonstrated that the T-cells from TB
In vitro studies of T-cell proliferation and their cytokine pleural effusion predominantly produce IFN-γ, the Th1
production profile upon antigen stimulation of PBMCs designate cytokine, while the T-cells from BAL fluid of
obtained from TB patients and control subjects support miliary TB patients predominantly produce IL-4, the
the role of cytokine polarized immunity in TB. Cytokine designate cytokine for Th2 response. These elegant recent
profile skewed towards dominant production of the studies with the patients diagnosed on stringent criteria
IL-4 along with lower IFN-γ level was found among TB and specimens from both peripheral as well as the local
patients compared to that of the controls and healthy compartments representing the immune response at the
contacts. At the same time several other groups failed to local pathologic site[s] provided important insights in
observe the same. The reasons for this apparent discre- understanding the dynamics of Th1/Th2 paradigm in
pancy may be the variations of the experimental systems, human TB. The emerging picture of the immune response
use of different antigens, different populations with in TB indicates the importance of polarized cytokine
diverse host genetic factors and importantly, a great deal response and T-cells in a similar way as has been
of variation among the study subjects and the extent as observed in leprosy. Plausibly, a strong Th1 response
116 Tuberculosis
dictates either disease containment or development of CYTOKINES, CHEMOKINES AND GRANULOMA

localized form of disease, such as solitary lesion in FORMATION
pulmonary TB and the pleural effusion. On the other
As discussed previously, granuloma formation is the
hand, a dominant Th2 like response fails to contain the
most important immunopathologic hallmark represent-
disease and, thus leads to the development of severe and
ing immune response containing the infection with
disseminated forms of TB such as miliary TB and
Mycobacterium tuberculosis. Generation of effector T-cells
extensive cavitary disease. Further investigations with
capable of producing pro-inflammatory cytokines that
larger and diverse patient populations are required to
can activate macrophages is one critical element in the
conclusively address these issues.
process of granuloma formation. These cells are
The role of CD8+ T-cells in immunity against TB has
generated through priming of resting memory T-cells by
drawn a relatively less attention from the investigators
captured antigens presented on the surface of antigen
in the felid. However, with recent studies demonstrating
presenting cells [APCs] in the draining lymphoid tissues
susceptibility of the mice lacking MHC class I expression
and then released into the peripheral compartment.
to mycobacterial infection (38), alteration of CD4+/CD8+
Following this, what is critically required is their selective
cells ratio among TB patients, antigen specific in vitro
recruitment at the site[s] of bacillary invasion. Homing
proliferation indicate a definitive role of CD8+ T-cells in
of effector and various other T-cell subsets is mediated
TB pathogenesis. Production of IFN-γ and TNF-α by
by active process of well orchestrated trafficking of
CD8+ T-cells in response to mycobacterial antigens such
T-cells mediated by the groups of molecules, such as
as, ESAT-6 by CD8+ T-cells derived from pleural fluid
selectins, adhesion molecules and chemokines.
of patients suffering from TB pleural effusion have
Chemokines [chemotactic cytokines] are largely respon-
substantiated the role of CD8+ T-cells in the immunity
sible for such well organized recruitment of T-cells
of TB (39). The CD8+ T-cells most probably play an
involved in the granuloma formation (44).
important role in killing the Mycobacterium tuberculosis
A number of chemokines have been found to be
infected target cells initially by [i] TNF receptor
involved in TB. The IL-8 was found to be produced by
superfamily, member 6 [FAS] independent granule
macrophages infected with Mycobacterium tuberculosis
exocytosis pathway releasing lytic molecules such as
(45) and this could be blocked by neutralising antibodies
granulysin (40) and subsequently by [ii] FAS-FAS ligand
against TNF-α and IL-1β, suggesting that IL-8 production
dependent apoptosis of the infected target cells (41). was under the control of these cytokines and is produced
Interestingly, CD8+ T-cells from household contact of early in TB (46). Patients with TB showed higher IL-8
TB patients demonstrated significantly better control of levels in their peripheral blood and BAL fluid (47).
bacillary growth within autologous alveolar macro- Another critical chemokine in TB and granuloma
phages, whereas CD8+ T-cells from the contacts of formation is monocyte chemoattractant protein 1
unexposed subjects failed to do so. Probably, circulating [MCP-1] which is produced by monocyte/macrophage
antigen specific CD8+ effector T-cells expand after and attracts the same (48). In murine models, deficiency
exposure to Mycobacterium tuberculosis and are recruited of MIP1-α inhibited the granuloma formation (49).
to the local site[s] of inflammation in the lungs to play Moreover, MIP1-α level was noted to be significantly
an important role during initial infection (42). This elevated in the serum, BAL and pleural fluids in patients
observation may have implications for vaccine develop- with TB. All these observations indicate an important
ment. In addition to the activation of macrophages by role of this chemokine in human TB (50). Expression of
secreted cytokines, particularly IFN-γ, recent evidences RANTES, an important chemokine responsible for
indicate that CD8+ T-cells can kill mycobacteria directly recruitment of T-cells particularly the Th1 like cells, is
through the cytotoxic T-lymphocyte [CTL] activity (43). also increased in serum and pleural fluid of TB patients.
Therefore, a direct role of CTL in host immunity against Apart from these several other chemokines such as MIP1-
TB, in addition to their macrophage activating property α and MIP1-β, Mig, IP-10 and interferon-inducible T-cell
is well established. However, their precise function still alpha chemoattractant [ITAC] are all found to be elevated
remains to be elucidated. in TB patients, particularly at the local disease site[s] such
as pleural effusion (35). All these chemokines are known usually represented in the peripheral blood in a relatively
to facilitate recruitment of Th1 like effector T-cells via low frequency, less than 10 per cent of total circulating
their binding to the chemokine receptors such as CCR5 T-cell population. Recent data support their role in the
and CXCR3 preferentially expressed on them. These Th1 host response to human TB. Although mice with severe
cell recruiting chemokines are induced on endothelial combined immunodeficiency fail to form granuloma in
cells and macrophages, by the initial pathologic response to challenge with BCG and succumb to death,
onslaught and help trapping the Th1 cell preferentially they can survive such challenge when engrafted with
expressing their respective receptors, following which syngenic lymph node cells depleted of αβ T-cells,
T-cells permeate through vascular barrier and migrate suggesting an important role for Tγδ-cells (51). Recent data
toward the site of pathology under the influence of in patients also substantiate a possible role of γδ T-cells
chemokine gradient formed at the site of bacillary in TB. Mycobacterium tuberculosis reactive Tγδ-cells are
invasion. Inhibition of these chemokines may impair the increased in the peripheral blood of tuberculin positive
granuloma formation. However, due to redundancy of healthy contacts (52,53). Increase in the Tγδ-cells [20% to
chemokine system, the function of a given chemokine 30%] was noted in the peripheral blood of patients with
can be replaced by another member of the chemokine a strong immune reactivity compared to the patients with
family, thus making it difficult to define the precise role disseminated forms of TB, such as extensive pulmonary
of an individual chemokine in TB. Recent investigations or miliary TB. Depletion of Tγδ-cells results in less well-
in TB pleural effusion patients demonstrated that some formed granulomas and increased infiltration of
of the chemokine receptor and/or chemokines can play neutrophils. This indicates that Tγδ-cells are recruited
a definitive hierarchical role in selective recruitment of quite early in the infection with Mycobacterium tuberculosis
Th1 cells at the disease site[s] and delineating such and direct the granuloma formation. Disappearance of
interaction is critical in designing molecular immuno- Tγδ-cells from the peripheral blood of TB patients may
therapeutic strategies. It was found that CXCR3 - ITAC be explained by their early recruitment at the disease
interaction was dominant in selective recruitment of site[s] and FAS-FAS ligand mediated apoptosis.
IFN-γ producing Th1 cells in addition to RANTES –CCR5
and CD11a – ICAM interactions. Interestingly, expression Natural Killer T-cells
of many of these chemokine receptors on the T-cells and
adhesion molecules on the endothelium is influenced by Natural killer T-cells are non-conventional in the sense
TNF-α-the importance of which in TB immunity is well that they bear cell surface markers distinctive of NK-cells
established. in addition to functional TCR. They represent a subset
of T-cells with a distinct lineage and not restricted by
FINE T-CELL SUBSETS WITH AN MHC. They recognize lipid antigens in context of MHC
IMMUNOREGULATORY ROLE like but relatively less polymorphic CD1 molecules (54).
The CD1 molecules are sub-grouped into group I consist-
These are regarded as non-classical T-cells in the sense ing of CD1a, b and c whereas CD1d is the only member
that they either bear non-conventional T-cell receptors of group II so far known. The CD1d restricted NKT-cells
[TCRs] or do not recognize the antigens in context of are heterogeneous in terms of their expression of CD4+/
classical MHC gene products [MHC non-restricted] and CD8+ markers and an important subset of NKT-cells uses
exert an immunoregulatory influence on rest of the restricted set of TCR chain pairs, namely Vα.24/Vβ.11.
T-cells including the effector T-cells. Important among These are called invariant chain NKT-cells [iNKT-cells].
them include γδ T-cells [Tγδ-cells], NK-cells and the The NKT-cells are one of the earliest T-cells to be
regulatory T-cells [Treg-cells]. triggered in an immune response and are known to
produce several immunoregulatory cytokines [IFN-γ, IL-
γδ T-cells
4, IL-10, and TGF-β etc.,] in abundance (55). Through
In contrast to the T-cells expressing TCRs comprising of these released cytokines, NKT-cells are believed to exert
α-β heterodimer, these cells bear functional TCRs on their a strong regulatory effect on the effector T-cell response.
surface made of heterodimer of γ-δ chains. They are The first reported non-protein mycobacterial antigen was
118 Tuberculosis
mycolic acid. Several other lipid antigens of mycobacteria capability of suppressing the other T-cells through
such as LAM, phosphatidyl inositol manoside [PIM], contact dependent as well as contact independent
glucose monomycolate and isoprenoid glycolipids have cytokine mediated pathways. These cells with immuno-
been found to be recognized by NKT-cells when suppressive characteristics are known as Treg-cells
presented by CD1d molecules. Heterogeneity of NKT- [Figure 7.3]. The Treg activity, which is defined by their
cells in terms of release of either Th1 driving IFN-γ or functional suppressive properties, has been found to be
Th2 driving IL-4 or immunosuppressive IL-10 and TGF- enriched within CD4+ T-cells constitutively expressing
β determines the influence that NKT-cell subsets may CD25 [IL-2 receptor α chain]. However, not all the CD4+
impose on the bulk T-cell responses. Selective expansion CD25+ T-cells function as Treg indicating that a precise
and/or activation of NKT-subset[s] may dictate their phenotype of Treg is still awaited. Recent reports strongly
immunoregulatory role. Expansion and preferential indicate that forkhead/winged helix transcription factor
homing of iNKT-cells have been documented in granu- of scurfin family, Foxp3 behaves like a master trans-
loma formation. In addition to their prompt cytokine cription factor essential for development of Treg cells and
releasse, NKT-cells exhibit a potent cytolytic activity both has been proposed and remains till date as the most
by perforin/granzyme and FAS-FAS ligand dependent reliable marker for Treg-cells (56). The CD4+ CD25+
mechanisms. Cytotoxic NKT-cells may be relevant in Foxp3+ cells are maximally [but not completely] enriched
immunity against intracellular microorganism including for Treg activity. The Treg-cells express CTLA4, which
Mycobacterium tuberculosis [Figure 7.3] (54,55). can induce negative signalling through CD80/CD86 co-
stimulatory molecules expressed on the effector T-cells,
Treg-Cells via contact dependent mechanism. In addition, Treg can
Recent experimental evidences strongly suggest the secrete a battery of suppressive cytokines such as IL-10,
existence and role of a unique subset of T-cells with TGF-β which may be responsible for their suppressive
Figure 7.3: Orchestration of effector immune component in building up response against Mycobacterium tuberculosis. Priming of T-cells
for effector functions requires recognition by activated macrophages with stimulation by a battery of potentiating cytokines [IL-12, IL-6,
IL-1β etc.,] released by the infected macrophages. The response of effector T-cells will decide the extreme/polarity of upcoming disease
pathogenesis. Regulatory T-cells [CD4+CD25+FoxP3+ T-cells, natural killer T-cells etc.,] can also modulate the protective effector T cell
responses either in a contact dependent/independent way
IFN-γ = interferon-γ; TNF-α = tumour necrosis factor-α; IL = interleukin; TGF-β = transforming growth factor-β; TCR = T-cell receptor;
NKT = natural killer T-cells; RNI = reactive nitrogen intermediates; ROI = reactive oxygen intermediates; MΦ = macrophage; DC =
dendritic cell
effect on activated T-cells. Immunosuppression by Treg- immune mechanisms are effective as any disruption in
cells essentially requires [i] their expansion and [ii] a these results in reactivation of the persistent dormant
preferential recruitment at the pathologic sites where infection, for example, in HIV infection. The ability of
they are supposed to suppress the T-cells. The Treg-cells Mycobacterium tuberculosis to survive the immune
have been shown to express on their surface a battery of response clearly indicates existence of series of immune
chemokine receptors such as CCR1 and CCR4 that help evasion mechanism[s]. Mycobacteria are capable of
their recruitment. The Treg-cells also express TLR2 producing ammonia and sulphatides which inhibit the
(57,58) and TLR4 (59) which can bind to diverse myco- fusion between phagosomes with lysosomes. In addition,
bacterial pattern recognition molecules like lipids. Recent ammonia prevents alkalization of intralysosomal
reports suggest that TLR2 engagement with myco- contents thus, diminishing the lytic potency of the fused
bacterial component[s] may eliminate Treg-cells thereby phagolysosomes. Inefficient phagolysosomes fail to
stimulating a Th1 response, while TLR4 engagement process the mycobacterial antigens and their presentation
results in persistent expansion and activation of Treg cells to the cognate T-cells. This in turn fails to stimulate
thus, causing immunosuppression (59). The role of Treg repertoire of T-cells optimally leading to weak or no
in human TB has been elegantly demonstrated. immunity against the pathogen. Interestingly, cholesterol
Frequency of Treg is increased in the peripheral blood mediates the phagosomal association of tryptophan
of patients with disseminated form of TB, such as miliary aspartate-containing coat protein [TACO] and prevents
their fusion with lysosomes. Also by retaining TACO and
TB. Their frequency was found to be even more in BAL
intercepting the phagolysosomal fusion mycobacteria
fluid when compared to that of the peripheral blood of
trigger their evasion mechanisms. Lack of TACO
the same patients. This is strongly suggestive of selective
expression on the Kupffer cells of the liver may be
homing or enrichment of Treg-cells at the pathologic site.
responsible to the well-known resistance of liver to
Recently, it has been demonstrated that a greater number
infection by Mycobacterium tuberculosis (61).
of Treg-cells were recruited into the lung in patients with
Mycobacterium tuberculosis infected macrophages are
miliary TB compared with effector T-cells (60). These
relatively ineffective at optimally triggering the T-cell
Treg-cells suppressed the autologous T-cell response to
proliferation and cytokine production. Down-regulation
Mycobacterium tuberculosis through release of IL-10.
of HLA class II expression has been noted among the
These findings strongly indicate the role of Treg-cells in
infected macrophages (62). Infected macrophages are also
modulating the local immune response at the pathologi-
known to secrete immunosuppressive cytokines such as
cal site of TB (60). Further studies are required to
IL-10 and TGF-β (63). Experimental evidences suggest that
substantiate their immunoregulatory role in human TB Mycobacterium tuberculosis infected macrophages are
which shows a remarkable variation in its clinical mani- relatively refractory to the effects of IFN-γ, which is a key
festation. Also critical is to understand the phenomenon mediator in macrophage activation. Recent studies suggest
of their preferential trafficking to the disease site and that recognition of mycobacterial antigens by TLR2 and
capability to modulate the local pathology of TB and the TLR4 differentially regulates either pro- or anti-
extent of the disease. Delineation of the finer details of inflammatory cytokine production by macrophages and
Treg-cell biology among TB patients may offer unique through these cytokines can suppress the immune
molecular therapeutic modalities. recognition. Moreover, mycobacterial interaction with
TLR2 and TLR4 can differentially expand or eliminate the
IMMUNE EVASION BY MYCOBACTERIUM Treg-cells which suppress the effector T-cells (64). All these
TUBERCULOSIS mechanism[s] help the ingested bacilli either to silence or
Mycobacterium tuberculosis can evade and subvert various to evade the immune effector function of the host and help
immune mechanisms adopted by the host to either the pathogen survival.
eradicate or eliminate the infection. Even during the
IMMUNOMODULATORS IN TUBERCULOSIS
phase of latency the bacilli use various immune evasion
strategies to circumvent the effective host immune An extensive role of host immunity in protection, contain-
response that generally contains the infection but fails to ment and pathogenesis of TB and its molecular under-
eradicate them [Figure 7.4]. Clearly, such containing standing has generated a great interest in immunomodu-
120 Tuberculosis
Figure 7.4: Comparative chart showing different components of immune system involved in various stages of infection with Mycobacterium
tuberculosis; primary infection, latency and active disease/pathology. In first exposure, weak host immune status facilitates the survival
and expansion of bacilli and helps in establishment of infection due to delayed immune recognition [primary infection]. The delayed
immune recognition caused by several immune-escape mechanisms adapted by bacilli, develops low level of immunity helping in
establishment of infection. Later on, ensuing effector immune response dictates the disease course. Firstly, protective and eradicative
immune response helps in containment of bacilli leading to persistence of bacilli without any sign of pathology [latent infection]. The tight
balance of pro- and anti-inflammatory factors in restricting the bacilli below a threshold number are the major characteristics of latent
infection. Secondly, a non-optimal [excessive and sub-optimal] immune response developed by host against bacilli may lead to the two
extremes/poles of the disease: [i] contained disease; and [ii] disseminated disease. Excessive or strong immune response facilitates
clearance of bacilli and disease is contained or localized. In this form, the pathology is mostly associated with Th1 like response. On the
other hand, disseminated disease is characterized by Th2 associated weak immune response resulting in bacillary spread
TNF-α = tumour necrosis factor-α; IFN-γ = interferon-γ; IL = interleukin; Treg = regulatory T-cells; Teff = effector T-cells; ↑ = increased;
↓ = decreased
latory approaches for the disease intervention. This is ing factor [GM-CSF] has also been used simultaneously
more true in the face of development of MDR-TB and with IFN-γ (65). Daily low dose administration of
challenges imposed by dual infection with HIV and recombinant IL-2 has been found to activate the immune
Mycobacterium tuberculosis. Several newer approaches to system and may enhance the effect of the drugs in
block certain key molecules responsible for tissue patients suffering from MDR-TB (66). Recent data on the
destruction are gaining attentions for molecular therapy. role of chemokines and their receptors in selective
Proinflammatory cytokines like TNF-α may be a target homing of inflammatory Th1 like cells in TB has opened
for healing of cavitary TB, while TGF-β is thought to be a new avenue to modulate the immune response by
a good candidate for prevention of fibrosis, as it helps controlling selective recruitment of specific subset[s] of
development of fibrotic lesions (63). Role of various other T-cells including the regulatory T-cells [NKT- and Treg-
cytokines in the pathogenesis of TB makes them potential cells] to the pathologic site[s]. Molecular strategies to
targets for intervention. Recent data support the role of modulate the immune response by means of changing
aerosolized IFN-γ in disease resolution among patients the balance of cytokines and chemokines involved in TB
with MDR-TB. Granulocyte, monocyte- colony stimulat- are new fields and require further investigations.
Several agents have provoked interest as candidate by mannose receptors in addition to complement receptors.
adjuvant therapeutic elements. Heat killed preparation J Immunol 1993;150:2920-30.
7. Bermudez LE, Goodman J. Mycobacterium tuberculosis
of other mycobacteria such as Mycobacterium vaccae (67)
invades and replicates within type II alveolar cells. Infect
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granulomatous response. J Immunol 1997;159:3034-43.
to rescue the patients from excessive effect of TNF-α (68).
10. Hoheisel G, Izbicki G, Roth M, Chan CH, Leung JC,
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124 Tuberculosis
Genetic Susceptibility
Parameters in Tuberculosis
8
NK Mehra, Meenakshi Singh
INTRODUCTION factors, such as previous health status, acquired

immunity and variability in the pathogen. Analysis of
Tuberculosis [TB] is no longer restricted to developing
the genetic basis of susceptibility to major infectious
nations, since it has now returned to industrialized diseases is potentially a most complex area. Many
countries due to the acquired immunodeficiency synd- immunogenetic loci influence susceptibility to several
rome [AIDS] epidemic and the emergence of multidrug- infectious agents. A genetic basis for inter-individual
resistant strains of Mycobacterium tuberculosis (1). Most variation in susceptibility to human infectious disease is
people exposed to TB develop effective immunity against also explained through candidate gene studies (8).
the invading bacillus and do not develop disease. A The goal of identification of host genetic factors that
strong host genetic influence has been proposed to be an underlie susceptibility to TB can be approached by two
important factor for the development of disease in a ways: [i] candidate gene studies can be carried out on
limited percentage of the population in a hyperendemic genes of known function that have a possible biological
area. Evidence supporting the role of genetic factors role in the control of infection or disease; and [ii] a second
influencing susceptibility or resistance to TB includes approach utilizes a non-targetted genome-wide linkage
differences in the development of infection and disease analysis, in which increased sharing of chromosomal
among various human racial groups (2,3) and animal regions by affected individuals leads to identification of
strains (4,5) concordance of the disease in monozygotic positional candidates. Recently, development of high
twins (6,7) and familial occurrence of the disease. Clinical throughput genotyping technologies and identification
manifestations of pulmonary TB are due to delayed type of thousands of polymorphic microsatellite markers has
hypersensitivity [DTH] reaction against the Mycobacte- led to the identification of genes [candidate] not pre-
rium tuberculosis rather than direct damage caused by the viously associated with the disease. A better understand-
bacillus. Thus, the final outcome of the disease is the ing of the disease mechanisms and of host-pathogen
result of interaction between the bacillus and host genes interplay could help to identify people at high or low
that govern immune response. risk of infection and provide a basis for early diagnosis
Susceptibility to TB is multifactorial. Host genetic and pre-emptive treatment of susceptible individuals
factors explain partly why some people are resistant and [Table 8.1]. In this chapter, the role of genetic as well as
others susceptible to infection. Rare gene disruptions non-genetic factors in influencing the incidence of TB in
cause fatal vulnerability to certain pathogens, but more a population is discussed.
subtle differences are common and arise from minor
variations in many genes. To predict how much our HOST IMMUNE RESPONSE AGAINST
genetic make up determines the different ways in which MYCOBACTERIUM TUBERCULOSIS
we respond to some infectious agents is a difficult task. Mycobacterium tuberculosis is a classic example of a
This is especially because of the many contributory pathogen for which the protective response relies on cell-
Genetic Susceptibility Parameters in Tuberculosis 125
Table 8.1: Genetic susceptibility to infectious diseases The CD8+ T-cells are non-classically restricted by CD1
molecules. These are non-polymorphic antigen present-
Certain individuals appear to be predisposed to infections;
others are protected ing molecules having structural similarities to MHC
By studying the immune response and the genetic make-up Class I molecules. However, the antigen-binding groove
of these individuals one can get a better understanding of of CD1 is much deeper and more hydrophobic than that
disease mechanism and of host-pathogen interplay in various of MHC class I or II molecules. In contrast to the peptide
diseases
epitopes presented by MHC class I molecules, CD1
Detecting genetic susceptibility facilitates identification of those
at high/low risk of certain deadly infections
present lipids or glycolipids to T-cells (12). A recent study
Genetic susceptibility data may form a basis for early diagnosis provided the first evidence of a recall T-cell response to
and institution of pre-emptive treatment for susceptible a CD-restricted antigen in Mycobacterium tuberculosis
individuals exposed purified protein derivative [PPD] positive
Ideas for rational, genetically targeted approaches to disease subjects. Peripheral blood mononuclear cells [PBMCs]
prevention or effective intervention can be derived
from these subjects proliferated in response to an
isoprenoid glycolipid in contrast to those from PPD-
mediated immunity. This is because the pathogen resides negative subjects, and this proliferation was inhibited by
primarily in a vacuole within the macrophage and thus, anti-CD1c antibody (13). Effector functions of CD1
the major histocompatibility complex [MHC] class II restricted CD8+ T-cells include IFN-γ production and
presentation of mycobacterial antigens to CD4+ T-cells cytotoxic activity, but the target of these cells may not be
is an obvious outcome of infection. It is well documented the macrophages.
that people with defective T-cell responses are at higher The differentiation of T-lymphocytes during immune
risk for developing primary or reactivation TB. priming over the course of disease progression is
The interaction of T-cells and infected macrophages promoted by the cytokine milieu of the host, which
is central to development of protective immunity to includes IL-4, interleukin-6 [IL-6], IL-10, interleukin-12
Mycobacterium tuberculosis. The CD4+ T-cells have an [IL-12], and interleukin-18 [IL-18], among others.
essential role but are supported by other T-cell subsets Although the central role of IFN-γ in the control of Myco-
such as CD8+, γδ T-cell receptor [TCR] positive T-cells bacterium tuberculosis is beyond doubt, other cytokines,
[γδ T-cells], and CD1 restricted T-cells. Tuberculosis in particular tumour necrosis factor-α [TNF-α], trans-
granuloma contains both CD4+ and CD8+ T-cells that forming growth factor-β [TGF-β] participate by regulat-
predominantly participate in the antipathogenic ing the formation and maintenance of the structural
response to contain the infection within the granuloma integrity of granulomas, (14-21), thus influencing the
and inhibit reactivation (9,10). Mycobacteria-specific pathology and disease course.
CD4+ T-cells are typically of the Th1 type, in that they Mycobacterium tuberculosis infected macrophages
are potent interferon-γ [IFN-γ] producers. The IFN-γ plays appear to be diminished in their ability to present
a central role in the activation of anti-mycobacterial antigens to CD4+ T-cells, which would contribute to the
activities of macrophages, which makes it crucial for inability of the host to eliminate a persistent infection.
protection against TB. The Th2 cytokines, such as One mechanism by which Mycobacterium tuberculosis
interleukin-4 [IL-4] and interleukin-10 [IL-10] are scarce, might inhibit recognition of macrophages by CD4+ T-
though not fully absent (11). Apoptosis or lysis of infected cells is by down-regulation of the cell surface expression
cells by CD4+ T-cells may also play a role in controlling of MHC class II molecules. Another mechanism by which
infection. In recent years, CD8+ T-cells specific for antigen presenting cells [APCs] contribute to defective
mycobacterial antigens have been isolated from the T-cell stimulation may be through production of
infected hosts, which point towards their emerging role cytokines, including TGF-β (20,22), IL-6 (21), or IL-10
in anti-Mycobacterium tuberculosis response. The CD8+ (22,23). Production of these cytokines by infected
T-cells, like CD4+ T-cells, can produce IFN-γ, but their macrophages can directly and indirectly affect T-cell
main function is target cell killing via perforin and proliferation and function.
granzyme or tumour necrosis factor receptor super- It is now recognized that CD4+, CD25+ regulatory
family, member 6 - tumour necrosis factor receptor super- T- cells [Tregs] play a central role in the prevention of
family, member 6 ligand [FAS-FASL] pathway. autoimmunity and in the control of immune responses
126 Tuberculosis
by down-regulating the function of effector CD4+ or CD8+ tions and overcrowding have been reported to foster the
T-cells. The role of Tregs in the context of TB infection and development of TB by enhancing the airborne transmis-
persistence is, however, inadequately documented. A sion of Mycobacterium tuberculosis from infectious patients
recent report indicates that the number of Treg cells to susceptible hosts (30). The disease has been well
increase in the blood or at the site of infection in patients documented in restricted environments such as nursing
with active TB (24). This suggests that the presence of Treg homes, prisons and hospices (31).
cells may limit the immunopathology and suppress
cellular immune responses in patients with TB. Malnutrition
Emerging evidence suggests that the human Toll-like
receptors [TLRs] also play an important role in the World Health Organization [WHO] estimates have
activation of innate immunity by Mycobacterium tuber- indicated that poor nutritional status might predispose
culosis. Human TLRs are transmembrane proteins with an individual to TB, but, exactly how malnutrition
a leucine rich repeat in the extracellular domain. Their favours the development of the disease is not clear.
cytoplasmic constituents are homologous to those of the Presumably, various components of the immune system
human interleukin-1 [IL-1] receptor. It appears that including T-lymphocyte function and cell-mediated
distinct mycobacterial components may interact with immunity are impaired. It is also not known which
different members of the TLRs family (25) and that dietary elements [proteins, vitamins, micronutrients] are
Mycobacterium tuberculosis can signal via both human necessary to protect against the occurrence of TB.
TLR2 and TLR4 in a ligand-specific manner. The reader Recently, experimental studies have provided credence
is referred to the chapter “Immunology of tuberculosis” to an important contributory role of protein calorie
[Chapter 7] for further details. malnutrition (32).
Occupation
NON-GENETIC FACTORS INFLUENCING THE
INCIDENCE OF TUBERCULOSIS Workers with silicosis have a greatly increased risk of
developing TB, which reflects the fact that respirable silica
Demographic Factors particles directly impair the function of macrophages,
The risk of acquiring infections is particularly high thereby inhibiting their ability to deal with organisms
between the period of infancy and the early adult age such as mycobacteria (33,34). There is an increased risk
(26), probably because of the compromised or incompe- of TB development among health care workers due to
tent immunity during the early periods and exposure to the concentration of infectious patients in their
newer antigens. In the developing countries, vast environment and only prompt diagnosis and initiation
majority of cases occur between the ages of 15 and 59 of treatment may minimize the risk (35). A recent survey
years, economically the most productive individuals in indicates that low socio-economic status and lack of
the society. In industrialized countries, on the other hand, resources are important risk factors for non-adherence to
TB has been reported mainly in older men (27). The other TB treatment in a poor country such as Nepal (36).
risk factors including individual lifestyle such as
Alcoholism and Cigarette Smoking
alcoholism and cigarette smoking cause severe morbidity
and mortality among TB patients. Due to the inhibitory Tuberculosis is common in alcoholics, which may be due
action of smoke on lung functions, particularly on to the direct effect of alcohol on the host defenses.
macrophages and altered immune response in chronic Mortality and frequency of adverse effects of antituber-
alcoholics, the incidence and severity of pulmonary TB culosis drugs are higher in patients with cirrhosis of liver
have shown a steady increase in several populations (28). who develop active TB. Recent evidence suggests that
The occupation of an individual is yet another important multidrug regimen used to treat TB could be well
factor that may predispose to TB. tolerated in the situation of pre-existing liver dysfunction,
if patients are carefully monitored for side effects (37).
Socio-economic Factors Studies have also shown that tobacco smokers are more
The association between underprivileged sections of the prone to develop TB than non-smokers (38). The smoke
society and TB is well known (29). Poor housing condi- may have inhibitory action on lung defenses, particularly
on macrophages (27). Smoking thereby affects the clinical Racial differences in susceptibility (42), family
manifestations of TB. It has been shown that smokers segregation analyses, association studies, candidate gene
are more likely to have cough, dyspnoea, chest radio- studies (43,44) and genome scan studies (45,46) have all
graph appearance of upper zone involvement, cavity and implicated host genetics as a factor in determining the
miliary appearance and positive sputum culture but are susceptibility or resistance to infectious diseases.
less likely to have isolated extra-pulmonary involvement
than non-smokers (39). Smoking has been found to be Racial Differences
associated with both relapse of TB and its mortality.
Racial differences influence the degree of resistance to
Corticosteroids and Other Immunosuppressive mycobacterial diseases. For example, the African
Agents Americans (45,47) and certain African tribes (48) have
been reported to be particularly more susceptible to
Patients with chronic renal failure or lymphoproliferative
pulmonary TB as compared to Jews, who are relatively
disorders receiving steroids or immunosuppressive drug
immune. Reports from Brailey (49) suggest that the non-
therapy often have suppression of their immune system.
white patients in the age group of one to twenty years
Such individuals have an increased likelihood of
had higher deaths rates from pulmonary TB as compared
developing clinical TB (40).
to white children of the same age group. Similarly, the
Human Immunodeficiency Virus Infection disease prevalence in Gurkhas of Nepal has been found
The reader is referred to the chapter “Tuberculosis and to be higher than other ethnic groups in the same
human immunodeficiency virus infection” [Chapter 38] for geographical area (50).
details on this topic.
Twin Studies
Other Diseases Pulmonary TB has been reported to occur more
Diseases associated with impaired cellular immunity, commonly in twins even when they are living separately
such as leukaemia, lymphoma, disseminated malignancy (6). It has been suggested that the disease expression rate
have all been found to predispose to the development of of TB is significantly higher in monozygotic twins [33.3%]
pulmonary TB. In addition, patients with diabetes than dizygotic twins [15.7%] (51). Among household
mellitus, hypothyroidism and those undergoing contacts, the disease is more likely to occur in siblings
gastrectomy also have an increased risk of developing than in the spouse despite closer physical contact in the
TB, although the mechanisms underlying their latter.
susceptibility are not well characterized (40,41).
ABO and Rh Blood Groups
GENETIC SUSCEPTIBILITY TO TUBERCULOSIS
The natural history of TB is covered in the chapter There are reports indicating that Rh-negative persons are
“Reinfection and reactivation tuberculosis” [Chapter 47] more susceptible to TB than their Rh-positive counter-
Extensive exposure to Mycobacterium tuberculosis in a parts (52). Others have, however, failed to confirm this
hyperendemic area does not always result in disease in observation (53). Incidentally, Chinese with blood group
all individuals. Though environmental and socio- ‘O’ have been found to be more resistant to develop
economic factors are primarily related, numerous studies pulmonary TB than those with other blood groups (54).
have emphasized the importance of host resistance and A significant increase of pulmonary TB in persons with
hereditary susceptibility. Although about one-third of the blood groups ‘O’ and ‘AB’ has also been reported in
world’s population is infected with Mycobacterium sputum positive Danish patients as compared to those
tuberculosis, only around 10 per cent of those who get with group ‘A’ or ‘B’ (55).
infected will ever develop clinical disease (40). Even in
families with similar socio-economic and nutritional IMMUNE RESPONSE GENES
conditions, the disease develops only in a few children
indicating the existence of host genetic factors regulating Genes within and associated with the MHC have been
disease expression or resistance. shown to play a crucial role in governing susceptibility
128 Tuberculosis
to intracellular mycobacterial infections (56). It is now

recognised that MHC gene products play a crucial role
in the immune response by not only providing a context
for the recognition of foreign antigens by T-lymphocytes
but also by controlling the immunoregulatory processes
and final elimination of the cell bound antigen (57). Some
MHC gene products promote efficient T-cell function,
whereas others elicit a poor T-cell response or no response
at all. These MHC products include immune response
[Ir] genes and/or immune suppressive [Is] genes. In
pulmonary TB, the host immune response to Myco-
bacterium tuberculosis is responsible for clinical expression
of the disease rather than damage by the mycobacteria. Figure 8.1A: Human major histocompatibility complex [MHC].
Therefore, an in-depth study of MHC linked genes is Chromosomal location and gene map showing multiple genes on
essential for understanding mechanisms underlying the short arm of chromosome 6 [6p21.3]. The two-way arrow shows
the genetic distance covered by the respective regions on the
disease susceptibility.
chromosome. The circled loci are known to be highly polymorphic
MOLECULAR GENETICS AND ORGANIZATION OF
HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX Class III genes [central genes] placed between class I and
GENES class II regions consist of genes involved in the
Human MHC gene cluster spans a region of about 4000 complement system, tumour necrosis factor [TNF], heat
kb length [4 x 10 6 nucleotides] on the short arm of shock proteins [HSP] and others with non-immune
chromosome 6 in the distal portion of the 6p21.3 band. functions, not directly related to antigen presentation.
Studies on the structural organization of MHC molecules
Major Histocompatibility Complex Class I Genes
have helped in understanding the functional role of MHC
gene products in the host immune response. In the MHC The class I region is the most telomeric part of the MHC
region, a total of 224 genes have been identified, of which complex. Although 36 genes have been defined so far in
128 are assumed to be functional genes and 96 are this region, HLA-A, B and C are the most important since
pseudogenes. More than 40 per cent of the genes have their products have been well defined as ‘classical
one or more assigned immune functions (58). These genes transplantation antigens’. They are characterized by the
are arranged in three distinct sets of molecules, each high degree of polymorphism in most vertebrate species.
comprising of a cluster of Ir genes [Figure 8.1A] (59). The Other human class I genes that show sequence homology
most centromeric segment is the class II region that spans to classical loci include HLA-E, F, G, H, and a set of five
around 1100 kb and contains the human leucocyte MHC Class I related [MIC] genes [MIC A–E]. These have
antigen [HLA]-DP, DQ and DR loci, which are found as reduced expression, restricted to certain tissues such as
pairs, encoding the α and β chains. These chains encode thymus, liver, intestine or placenta, and have low poly-
the heterodimeric class II protein molecules expressed morphism. Of the five MIC genes, only MIC-A and
at the cell surface of antigen presenting cells [macro- MIC-B, situated between the TNF and HLA-B locus are
phages, dendritic cells, Kupffer cells, Langerhans’ cells, expressed. Closely related to these genes lies the haemo-
B-cells, and activated T-cells]. The class I region, on the chromatosis disease candidate gene designated, that
other hand, lies at the telomeric end and contains the regulates iron absorption designated HFE.
classical HLA-A, B and C and related loci, spread over a The HLA-A, B and C molecules are heterodimeric
region of approximately 2Mb. The HLA class I molecules glycoproteins consisting of a MHC-encoded α or heavy
are expressed ubiquitously on almost all nucleated cells. chain of about 45 kDa and a non-MHC-encoded light
The HLA genes that are involved in immune chain [β2- microglobulin] of 12 kDa molecular weight
regulation are mainly in the class I and class II region, [Figure 8.1B]. The α chain is some 350 amino acid residues
which are structurally and functionally different. long and can be divided into three functional regions:
Figure 8.1B: Pictorial view of HLA class II and class I molecular structures showing peptide binding cleft formed between α1 and β1
domains in case of class II, and α1 and α2 domains in case of class I molecules
Figure 8.1C: Location of known ‘pockets’ within the peptide binding region of class II and class I molecules
external, transmembrane and intracytoplasmic. The helices separated by a cleft with a floor composed of a
extracellular portion of the heavy chain is folded into plane of eight antiparallel β-pleated sheets. Dimensions
three globular domains, α1, α2 and α3, each of which of this cleft [2.5 x 1.0 x 1.1 nm] are suited to accommodate
contains stretches of about 90 amino acids encoded by nonamers, but peptides ranging from 10-15 amino acids
separate exons. While the α1 and α2 domain take part in in length, can also bind, depending on how they fold
antigen binding [antigen-binding domains], the α3 (60,61).
domain is essentially conserved. It contains binding sites The amino acid side chains of the peptide are
for the α chain of the CD8 glycoprotein, which is impor- accommodated in a series of pockets named A-F [Figure
tant for recognition of antigens by cytotoxic T-cells. The 8.1C] (62,63). These peptide positions are critical for
outermost domains [α1 and α2] comprise two long α binding to specific pockets of a particular HLA class I
130 Tuberculosis
molecule, hence termed anchors. Pockets A and F lie at DM and DN lie between the DQ and DP loci, and have
the two ends of the peptide – binding groove, are highly very limited polymorphism, if any.
conserved among the various HLA class I molecules and Three-dimensional structural analysis has demons-
accommodate the amino and carboxyl terminal residues, trated that peptides bind to HLA class II molecules in an
respectively. The interactions of the peptide with extended conformation. By contrast to class I bound
conserved residues in A and F pockets, therefore, fix the peptides, the N- and C-termini of class II bound peptides
peptide in the binding groove and play a major role in often extend beyond the binding groove. Three
stabilising the MHC-peptide complex. Although the asparagine residues [α62Asn, α69Asn and β82Asn],
peptide residues P2 and P9 serve as primary anchors, β81His and β61Trp are conserved in all class II molecules
the residues P1, 3, 6 and 7 act as secondary anchors, and and positioned to make hydrogen bonds with the peptide
the P4, 5 and 8 interact with the TCRs. main chain. The α1 and β1 helical regions of most class
II molecules are joined by a salt bridge formed between
Major Histocompatibility Complex Class II Genes [α76Arg, β57Asp] that stabilizes the αβ dimer. The
peptide bound by the class II groove twists along the
The MHC class II region extends over 1000 to 1200 kb
with at least six subregions, termed DR, DQ, DP, DO, length, progressing approximately three residues for each
turn. Successive side chains project from the class II
DN and DM. Structurally, the class II molecules are
bound peptide at regular intervals, many of which are
similar to class I molecules and are expressed as hetero-
dimers on the cell surface with one heavy α chain directed towards the class II molecule. The groove is lined
by series of pockets [P1 to P9] that align the peptide to be
[molecular weight 34 kDa] and one β chain [molecular
read as a single unique determinant by the TCR [Figure
weight 29 kDa] of integral membrane glycoproteins
[Figure 8.1B]. Three-dimensional structural differences 8.1C]. The size of the hydrophobic P1 pocket is controlled
by the Gly/Val dimorphism at position 86 on the β chain.
between the two include an altered position of the
The deepest and the most commonly used binding
immunoglobulin-like β2 domain relative to that of the
α3 domain of class I HLA, and considerable changes in pockets are P1 and P9 followed by P4 and P6.
In addition to the above, two groups of non-HLA
the peptide-binding site. The α and β chains assemble
genes have been identified in the MHC class II region.
non-covalently to create an antigen-binding cleft located
above a conserved membrane proximal structure, which The first group is ABC transporter genes called trans-
porter associated with antigen processing or transporter
can interact with the CD4 molecules on T-cells. Found
of antigen peptides 1 and 2 [TAP1 and TAP2] genes (64).
mainly on cells of the immune system, including B-cells,
macrophages, DCs and thymic epithelium, class II The TAP1 and TAP2 gene products associate as a
heterodimer that is involved in the transport of antigen
molecules display a more limited distribution.
fragments produced in the cytoplasm, into the lumen of
The DR region contains multiple, highly polymorphic
β genes and only one invariant α gene. The conventional the endoplasmic reticulum. The second group is
proteasome related genes that includes low molecular
serologically defined DR molecules [DR1 to DR18] are
mass polypeptide or large multifunctional protease 2 and
coded for by the DRB1 gene, whereas the DR52 and DR53
specificities are encoded by the DRB3 and DRB4 genes, 7 [LMP2 and LMP7] genes. The products of LMP2 and
LMP7 genes are large cytoplasmic proteolytic complex
respectively. The DRB2, DRB6, DRB7, DRB8 and DRB9
molecules that contain multiple catalytic sites. The LMP
are pseudogenes without a first domain exon. The DQ
subregion contains five genes, DQA1, DQA2, DQB1, complex is involved in the production of multiple
peptides simultaneously from the same substrate to
DQB2 and DQB3, of which DQA2, DQB2 and DQB3 are
produce peptides better suited for MHC class I binding.
not known to be expressed. In contrast, both DQA1 and
DQB1 are functional and polymorphic, expressing four
Major Histocompatibility Complex Class III Genes
different types of DQ molecules by different ‘cis’ and
[Central Genes]
‘trans’ combinatorial events. The DP sub-region contains
two α and two β genes, with DPA2 and DPB2 being The central region of MHC has no structural or functional
pseudogenes. The DPB1 shows extensive polymorphism, correlation with the class I or class II region. Presently,
while DPA1 displays limited polymorphism. The DO, at least 39 genes have been located in a 680 kb stretch of
deoxyribonucleic acid [DNA] within this region. This The processing pathway in both situations utilizes
includes genes encoding proteins involved in the highly specialized cell machinery that works most
immune system: the complement genes C4, C2 and factor effectively. The endogenous proteins in the cytoplasm
B [Bf], the TNF-α and TNF-β [lymphotoxin] genes and of the cells are digested into nine to ten amino acid
the heat-shock protein [HSP70] genes. Genes with no peptides by the LMP complex, a distinct subset of the
obvious association with the immune system have also cellular pool of proteasome. Peptides in the cytoplasm
been identified in this region. These include valyl transfer may gain access to the TAP transporter on the membrane
ribonucleic acid synthetase [G7a]. Further, two B-cell of the endoplasmic reticulum [ER] via a specific trans-
associated transcript genes, BAT2 [G2] and BAT3 [G3] porter. Peptides transported into the ER lumen bind to
are novel genes in the class III region that encode large class I molecules, inducing a conformational change that
proline rich proteins with molecular masses of 228 and may facilitate their export to the cell surface. The CD8+
110 kDa, respectively, while the RD gene encodes a cytotoxic T-lymphocytes see this MHC-peptide complex
42 kDa intracellular protein. through the TCR and other co-receptors, subsequently
Apart from the complement components, this region causing killing of the target cell.
also contains two genes coding for synthesis of the steroid In the class II pathway, antigens taken from outside
hormone, 21-hydroxylase [CYP21] genes. The genes the cell by endocytosis are digested by the proteolytic
associate very closely with the C4A and C4B genes. Of enzymes in the endosomal compartment into small
these, the 21B gene [CYP21B gene] is more functional, peptide fragments. The MHC class II molecule with its α
and deficiency of this leads to congenital adrenal and β chains assembles in the ER with the invariant chain
hyperplasia or salt-wasting disease. The CYP21A gene to form a stable trimolecular complex which inhibits the
on the other hand, is most often deleted in certain specific binding of endogenous or self-peptides in the ER. The
HLA haplotypes, particularly the extended haplotype trimolecular complex is efficiently transported out of the
HLA-A1, B8, DR3, SCO1 in Western Caucasians. Such a ER and is targeted to a post-Golgi compartment in the
haplotype is known to be associated with several peripheral cytoplasm. The invariant chain is subse-
autoimmune diseases including type 1 diabetes mellitus. quently cleaved in endosomes, opening up the cleft for
peptide occupancy.
The development of accurate and reproducible high-
BIOLOGICAL FUNCTIONS OF HUMAN LEUCOCYTE resolution DNA-based HLA typing methods have
ANTIGEN significantly improved our capabilities to define HLA
alleles at a single nucleotide difference. Further advanced
The determination of the crystal structure of the human
technologies based on sequencing, mass spectroscopy
MHC class I and class II molecules and the identification
and DNA chips have now opened up a whole new
of the putative peptide binding cleft established that
dimension of studying single nucleotide polymorphisms
MHC molecules are the principal antigen binding and
[SNPs]. Using these procedures, an appreciable number
presenting molecules to the T-cells. Thus, peptide
of ‘novel alleles’ and unique HLA haplotypes have been
antigens alter the HLA molecule by occupying the cleft
discovered in the Indian population (66,67).
to be scrutinized by the T-cell. This concept was first put
forward by Zinkernagel and Doherty (65) who were
HUMAN LEUCOCYTE ANTIGEN AND DISEASE
awarded the Nobel Prize for Medicine in 1996 for their
ASSOCIATIONS
studies of anti-viral T-cell recognition.
The fundamental difference in the above process is The MHC is considered to be associated if one or more
that whereas class I MHC molecules bind ‘endogenous’ alleles are increased or decreased significantly in patients
peptides and eliminate them through the process of when compared with ethnically matched healthy
cytotoxic T-cell killing [inside out mechanisms], the class controls. However, the underlying mechanisms for most
II molecules, on the other hand, bind peptides derived disease associations are still poorly understood.
from ‘external’ sources [exogenous] and present them to Accumulating evidence suggests a direct disease related
CD4+ helper T-cells [outside in mechanism]. role for polymorphic HLA proteins, whereby they
132 Tuberculosis
recognize peptide motif signatures and allow/prohibit a more diffuse, disseminated infection at the other. The
their binding to antigen-binding groove. An increasing pathogenesis of pulmonary TB appears to be due to a
number of HLA-binding motifs are being discovered for detrimental cell mediated immune response to Mycobac-
several autoimmune and infectious agents. One main terium tuberculosis. Several investigators have searched
limitation in identifying primary determinants within the for an association of the disease with either HLA class I
MHC, however, is the linkage disequilibrium that keeps [HLA-A, -B, -C] or class II [HLA-DR, -DQ] antigens.
several genes linked together on a haplotype. Generally,
it is more difficult to demonstrate a negative association Human Leucocyte Antigen Class I Association Studies
of MHC with a disease. These associations vary greatly
among populations and defined ethnic groups. Table 8.2 summarizes the reported HLA class I antigen
associations with pulmonary TB in different populations
IMMUNOGENETICS OF TUBERCULOSIS (70-86). Studies conducted by our group in the population
living in the region of Delhi revealed a significantly
The demonstration of MHC as T-cell restriction element increased frequency of HLA-A2 in pulmonary TB
and its linked Ir and/or Is genes has resulted in a series patients as compared to healthy controls (84). Similar
of HLA and disease association studies at the population association of HLA-A2 with pulmonary TB has earlier
level (68,69). Several workers have demonstrated an been reported in Egyptian patients. Other studies have
association of HLA antigens [or haplotypes] with suggested an association between pulmonary TB and
diseases caused by known infectious agents. These HLA-B15 in North American Blacks and South Chinese,
include hepatitis B virus infection, infectious mono- HLA-B35 in Northern Chinese, HLA-B5 in Egyptians,
nucleosis, viral capsid antigen in Epstein-Barr virus HLA-B8 in Canadians and multiple HLA-A and -B
infection, human T-cell lymphotropic virus III specificities in Russian populations. However, no
[HTLV III] infection and the development of Kaposi’s association of HLA class I antigens with pulmonary TB
sarcoma in patients with AIDS, poliomyelitis, typhoid was reported in Mexican Americans, European
fever, congenital rubella, etc. In most cases, however, a Caucasians and Japanese subjects [Table 8.2]. Studies
clear relationship between HLA antigens and suscepti- carried out in Asian Indians have demonstrated an
bility to infectious diseases has not been established. association of pulmonary TB with B44 in north Indians.
Several explanations can be put forward to explain this Such a heterogeneity in HLA class I association in
lack of association. One of these relates to the complexity different populations may be due to the ethnic variability
of Ir gene effects due to heterozygosity of the MHC gene of the population groups tested. Small number of study
products. Another contributing factor could be ‘disease groups, poor documentation of diagnosis, batch variation
heterogeneity’ because of the multiplicity of epitope in HLA antisera used in these studies may also account
specific antigenic determinants on the infectious agents, for such heterogeneity. It is also possible that the putative
which preclude the detection of the effects of HLA disease susceptibility gene lies in the HLA-class II region
encoded factors as risk factors for infection. This antigenic [DR/DQ locus] rather than the class I.
complexity of the invading pathogen leads to an almost The study reported by Balamurugan et al (86) is an
incomplete recognition of the relevant products of the attempt to delineate HLA class I association in TB on the
HLA system, particularly those in the HLA-D region, basis of a shared ‘sequence motif’ in peptide-binding
which harbours majority of the genes relevant to antigen
pockets of HLA molecules. Although, HLA alleles are
recognition and T-cell interaction.
highly polymorphic, small degree of genetic polymor-
phism may or may not affect peptide presentation and
Population Studies
molecular function. Among genetically related MHC
Among the major infectious diseases, leprosy and TB alleles, each HLA molecule preferentially binds peptides
have emerged as good examples of the role of HLA on with certain anchor residues and then presents it to the
susceptibility to infection. Like in leprosy, TB too follows CD8+ T-cells. However, within these allelic groups, there
a disease spectrum with the localized disease having are shared peptide epitopes and a considerable overlap
limited lung involvement at one end of the spectrum and in peptides binding capacity. Therefore, the need arises
Table 8.2: Association between HLA class I antigens and pulmonary tuberculosis
Study (reference) [Year] Population HLA [RR]*
Rosenthal et al (70) [1973] European caucasoids NA

Lee (71) [1976] Korean ↑B12
Selby et al (72) [1978] Japanese NA
Takata et al (73) [1978] New Foundland ↑B8 [0.44]
Al-Arif et al (74) [1979] North American Blacks ↑B15
Cox et al (75) [1982] Mexican Americans NA
Jiang et al (76) [1983] North Chinese ↓A19 [0.3], ↑B5 [7.4], ↑B27 [3.7]
Hafez et al (77) [1985] Egyptians ↑A2
Hwang et al (78) [1985] North American Blacks ↓B5 [0.26]
Mehra et al (79) [1986] North Chinese ↑A29, ↑B47
Xu et al (80) [1986] South Chinese ↑B44, ↑A11[2.1], ↑B15 [ 2.4], ↓Cw3 [0.3]
Mehra et al (79) [1986] North Indians ↑B12, ↑B44
South Indians ↑B49
Papiha et al (81) [1987] South Indians NA
Khomenko et al (82) [1990] Armenians ↑A19 [3.64], ↑B12 [2.82], ↑B35 [2.77], ↑Cw4
[19.37]
Kazhaks ↓A2 [1.92], ↓A3 [0.29], ↓Cw1 [0.44], ↑B14 [3.20],
↑B35 [2.55]
Moldavians ↓A10 [0.43], ↓Cw9 [0.35], ↑B5 [2.75]
Russians ↑B5 [2.06], ↑B7 [4.84]
Turkmans ↓A3 [0.44], ↓B79 [1.90]
Uzbeks ↑B12 [3.99
Brahmajothi et al (83) [1991] South Indians ↓A19 [0.6] ↓A24[0.4], ↓B17[0.6], ↓B52 [0.4]
↓B57 [0.1], ↓B61 [0.2]
↑A10 [2.8], ↑B8 [3.2], ↑B14 [9.9]
Rajalingam et al (84) [1997] North Indians ↑A2 [1.76]
Goldfield et al (85) [1998] Cambodians ↑B38
Balamurugan et al (86)† [2004] North Indians ↑A3 like supertype, ↓A1 like supertype
* Most of these studies have been conducted on pulmonary tuberculosis patients in different populations. All these studies did not show
consistent and strong association of a particular HLA Class I allele with pulmonary tuberculosis
† disseminated and miliary tuberculosis
HLA = human leucocyte antigen; RR = relative risk; NA = not available
to analyse the functional differences of the ‘peptide in patients with more severe forms of the disease such
presenting MHC class I molecules’. Based on the as miliary, disseminated TB and MDR-TB.
similarities of peptide binding pockets [B and F] and the
preference of identical peptide motifs, Sette and Sidney Human Leucocyte Antigen Class II Association Studies
(87) reported nine different supertypes covering most if Since 1983 several workers have tried to search for an
not all HLA class I alleles. The specificities of the anchor association of HLA class II antigens and alleles with
residues are determined by the amino acid sequences pulmonary TB. The data have been summarized in Table
that constitute the peptide binding pockets as described 8.3 (88-96). The first such report came from north India
by the crystallographic studies (60,61). In the Indian study (94) where a moderate increase of HLA-DR2 was
(86), the class I supertypes were evaluated for their demonstrated in sporadic patients with pulmonary TB.
possible association with TB by comparing the data with This finding was also confirmed in multiplex family
a set of healthy controls belonging to the same ethnic studies suggesting a DR2 linked control of susceptibility
background and socio-economic status. The data to the disease (90). This association was later confirmed
revealed a strong positive association of ‘A3- like’ and a in several other populations, including south Indians and
negative association of ‘A1-like’ supertypes particularly Chinese (79,83,95), Indonesians (93) and Russians (82).
134 Tuberculosis
Table 8.3: Association between HLA class II antigens/alleles and pulmonary tuberculosis
WHO Populations
region
DQA1*0101
DQB1*0402
DQB1*0501
DQB1*0503
DQB1*0601
DPB1*02
DPB1*08
DR10
DQ1
DR2
DR3
DR4
DR5
DR6
DR8
AMR North American Blacks (78) + –
Mexican Americans (75) –
EUR Kazakhs (82) + –

Russians (82) + –
Turkman (82) + –
Uzbeks (82) +
Armenian (82) + –
North Poland (88) +
WPR North Chinese (79) + –

South Chinese (79) +
Hong Kong Chinese (89) –
SEAR North Indians (79,90,91) + +

South Indians (92) + – + – + – + –
Indonesians (93) + + +
WHO = World Health Organization; AMR = American region; EUR = European region; WPR = Western Pacific region; SEAR = South-
East Asian region
However, others could not confirm this association in and no data are available regarding other clinical forms
studies on Hong Kong Chinese (89), Egyptians (77), of the disease including extra-pulmonary disease.
North American Blacks (78), Mexican Americans (75), Therefore, we investigated HLA association with various
as well as in a study on south Indian patients using the clinical subgroups including pulmonary TB, MDR-TB,
technique of restriction fragment length polymorphisms miliary, disseminated TB and lymph node TB. Further,
[RFLP] (96). Except for the study by Sanjeevi et al (96), all molecular subtyping of polymorphic DRB1 alleles has
other studies were based on serological testing of revealed that in addition to the increased occurrence of
expressed HLA antigens on the surface of lymphocytes. DR2 subtypes, a positive association of specific DR6
In 1991, Opelz and co-workers (97) reported that up to subtypes was noticed in different clinical forms of TB,
25 per cent discrepancy has been found in DR typing particularly DRB1*1301 in patients with pulmonary TB
results by serology when compared with the more and MDR-TB and DRB1*1302 in extra-pulmonary TB
sensitive techniques of polymerase chain reaction based [miliary, disseminated TB and lymph node TB]. Although
sequence specific oligonucleotide probe [PCR-SSOP] the DR2 associated haplotype association has been
hybridization. Besides being sensitive, these techniques reported earlier also in pulmonary TB (98), the existence
have allowed definition of molecular subtypes of several of additional DR6 associated haplotypes [both DRB1*13
serologically defined HLA-DR specificities, differing and DRB1*14] in other clinical forms of TB indicates that
even at a single nucleotide level. This has significantly alleles with similar ‘sequence motif’ in the peptide
enhanced our capabilities to identify critical amino acids binding groove may influence susceptibility to
in the MHC binding groove that are relevant in disease Mycobacterium tuberculosis infection and subsequent
causation. Subsequent studies on the possible association development of severe clinical disease.
of HLA class II alleles with pulmonary TB have utilized Data on the clinical and immunogenetic association
the PCR based techniques. for the development of MDR-TB suggest that, in addition
Almost all published studies on HLA association with to poor past compliance to treatment and presence of
TB have been performed in patients with pulmonary TB higher number of cavities in the chest radiographs,
presence of HLA-DRB1*14 allele in patients with HLA- linked susceptibility to pulmonary TB follows a
pulmonary TB acts as an independent predictor for the dominant rather than a recessive mode of inheritance.
development of MDR-TB (99). Also, the development of This is in contrast to the situation in TT leprosy, where
hepatotoxicity during antituberculosis treatment was the data favour a recessive mode of inheritance (102-104).
found to be associated with alleles in this DQ locus, In a recently published meta-analysis (105) [1988
namely DQA1*0102 and DQB1*0201 (100). patients and 2897 controls], a lower risk of thoracic TB
was found in carriers of B13, DR3, and DR7 antigens.
Family Studies Carriers of DR8 were at higher risk for thoracic TB.
The variability of the associated HLA antigens observed Though the risk of thoracic TB tended to be higher in
carriers of DR2 the results were not consistent between
in different ethnic groups indicates that genes controlling
studies.
host response to mycobacteria may be ‘linked’ but not
situated at the HLA class I and class II determinants, and,
High Resolution Analysis of Molecular Subtypes of
therefore, reveal different linkage disequilibria in
HLA-DR2 in Mycobacterial Diseases
different populations. In order to understand the mode
of inheritance or HLA linked control of disease suscep- The population frequency of HLA alleles in the north
tibility, family studies particularly those with at least two Indian population has revealed that two alleles, namely
affected sibs are most informative. Such studies DRB1*1501 and DRB1*1502 constitute greater than 90 per
conducted by us provided the first conclusive evidence cent of the DR2 alleles in this population. Other alleles
for an important role of HLA-linked genes in governing such as DRB1*1506 and DRB1*1602 are represented at
susceptibility to pulmonary TB (90,94,101). Further, the much decreased frequencies. The DRB1*1601 occurred
data collected at the Third Asia-Oceania Histocompati- in only four per cent of DR2 positive healthy controls
bility Workshop involving families from north India, (106). Studies carried out both in north as well as south
south India, Hong Kong and China corroborated these India have indicated a population association of
findings, suggesting an increased sharing of HLA DRB1*1501 [rather than other subtypes of DR2] in
haplotypes by the affected sibs as compared to the patients with TB (107).
unaffected healthy sibs (79). Combined data from these Sequence analysis of the DRB1 first domain residues
studies suggested that DR2-positive haplotypes from the has disclosed that only one amino acid variation can
affected parents showed a non-random segregation discriminate the products of DRB1*1501 from DRB1*1502
among pulmonary TB affected children indicating that and DRB1*1601 from DRB1*1602 [Table 8.4]. Particularly
Table 8.4: Amino acid sequences of molecular subtypes of HLA-DR2*

Serological DR2 Amino acid variation in DRβ1-domain
specificity Subtypes HVR I HVR II
30 31 47 67 70 71 72 74 86
DR15 *1501 Y F F I Q A R A V
*1502 G
*1503 H V
*1504 F V
DR16 *1601 Y F Y F D R R A G
*1602 L
*1603 A
*1604 L
*1605 I
*1606 I A
* Note residue differences in the first and second hyper variable regions [HVRs] in the first domain
of the DRB1 gene. DRB1*1501 differs from *1502 by a single amino acid substitution at position 86
136 Tuberculosis
The report by Singh et al (108) further evaluated all

five different DR2 subtypes based on the V/G dimor-
phism at codon β86 and observed an inverse association
of DR2. The results revealed an inverse association of
DR2 alleles with V86 and G86 as the pulmonary severity
increased from unilateral limited [UL] to bilateral
extensive [BE] lung lesions. Similar inverse relationship
of V86/G86 has also been observed in leprosy as the
disease severity progressed from paucibacillary to the
BL/LL multibacillary leprosy (108).
Knowledge on the three-dimensional crystallography
structure of the human class II HLA molecule has
revealed that residues at position 67 and 86 of the α-helix
of the β-chain are actively involved in the binding of a
foreign peptide [Figure 8.1C]. Accordingly, the peptide
binding and subsequent immune triggering capability
Figure 8.2: Frequency distribution of major DR2 subtypes in of the host depends critically on these single amino acid
pulmonary tuberculosis patients with varying degree of lung lesions variants. It is possible that DRB1*1501 and 1502 alleles
UL = unilateral limited disease; UE = unilateral extensive disease; may be selectively implicated in the presentation of
BL = bilateral limited disease; BE = bilateral extensive disease pathogenic mycobacterial peptides leading to the
development of pulmonary TB.
DRB1*1501 carries valine at amino acid position 86 while
Recently, the amino acid sequence analysis of the
it is substituted with glycine in DRB1*1502. Similarly,
associated HLA-DRB1 genes in tuberculoid leprosy has
DRB1*1601 subtype has the aromatic amino acid phenyl-
alanine at position 67 which is substituted by aliphatic yielded crucial information on critical sites in the peptide-
leucine in DRB1*1602. Studies on pulmonary TB did not binding groove of the DR molecule that affects peptide
favour a preferential involvement of any of these common binding and/or T-cell interaction in immune response
subtypes of DR2 suggesting that the whole DR2 molecule against mycobacteria (109). A large majority of patients
or its closely linked gene[s] may be involved in governing [87%] carry specific alleles of DRB1 characterized by
susceptibility to pulmonary TB and the expression of its positive charged residues Arg13 or Arg70 or Arg71 as
various clinical forms. However, analysis of DR2 subtypes compared to 43 per cent controls conferring a relative
and the differences in radiographic severity based on the risk of 8.8. Thus, susceptibility to tuberculoid leprosy
extent of lung lesions unilateral limited [UL], unilateral involves three critical amino acid positions of the β-chain,
extensive [UE], bilateral limited [BL] and bilateral the side chains of which when modelled on the DR1
extensive [BE] revealed an increased trend in the crystal structure, line a pocket [pocket 4] accommodating
frequency of DRB1*1501 as the pulmonary severity the side chain of a bound peptide. Characteristically,
increased [49% in UL vs 55% in controls 82% in BE vs pocket 4 is formed by the side chains of amino acids α9,
55% in controls] [Figure 8.2]. β13, β70, β71, β74 and β78. Substitutions of any of these can
Similar trends have been observed in leprosy patients. affect the local charge. For example, presence of
A comparison of the distribution of DRB1*1501 in the positively charged Arg at position 13 or Arg at position
two clinical subgroups of patient revealed increased 70 or 71 will probably accommodate the binding of a
occurrence of this allele in lepromatous [BL/LL] leprosy negatively charged residue of the same foreign peptide.
as compared to tuberculoid [BT/TT] patients [81% vs According to the leprosy model, it is likely that
64%]. This is in contrast to the distribution of DRB1*1502 peptides originating from Mycobacterium leprae bind
in these patients. This suggest that a single amino acid preferentially to HLA allelic forms characterized by
difference between the DRB1*1501 [valine] and arginine at positions 13 or 70 and 71 and stimulate parti-
DRB1*1502 [glycine] at codon 86 of the DRβ chain may cular T-cell clones that result in detrimental immune
play an important role in disease manifestation. response as seen in tuberculoid leprosy. Identification
of peptide motifs that bind different allelic forms polymorphic microsatellite markers have made genome-
associated with disease would contribute significantly wide linkage studies possible. This approach has the
to the search for mycobacterial antigenic determinants advantage that no disease model or prior knowledge of
that initiate this response. Similarly, sequence analysis the structure-function or location of the disease gene is
of class II alleles [both DR2 and non DR2] in TB patients required. The chromosomal regions identified by this
can help in the identification of critical amino acid approach are initially much larger than that of an
residues for the binding of Mycobacterium tuberculosis association study. Also, the genome-wide scan has the
derived pathogenic peptide[s] responsible for the advantage that gene[s] of unknown function and those
detrimental or protective immune response. This has not previously suspected as possible candidates can be
potential implications in immune interventions therapies identified. Bellamy (45) has performed genome-wide
in pulmonary TB. screening for TB susceptibility loci [genes] among 136
African families containing 173 independently affected
NON-HUMAN LEUCOCYTE ANTIGEN GENES IN sib pairs. Suggestive evidence of linkage was observed
MYCOBACTERIAL INFECTIONS on two regions of chromosome Xq27 and 15q11. Though
the evidence of linkage did not reach the criteria for
From the above, it follows that HLA associations and genome-wide statistical significance, further support for
relative risk of the concerned HLA antigens and alleles the presence of the loci was obtained using the method
differ in various populations and this can be attributed of common ancestory mapping. Interesting candidate
to the assumption that in polygenic diseases, there can genes in this region are P protein and the HERC2 genes
be more than one pathway and involvement of other on chromosome 15 and CD 40 ligand on the X
genes. The combination of such genes and their polymor- chromosome. Similarly, in the mouse model of TB, a new
phic forms may differ from population to population. locus with a major effect on TB susceptibility, designated
This favours looking at a possible role of non-HLA as susceptibility to TB [sst1] has been mapped to a
polymorphic gene variants such as TAP, TNF-α and 9 centiMorgan [cM] region on chromosome 1 (113). It is
TNF-β, mannose binding lectin [MBL], vitamin D located 10 to 19 cM distal to a previously identified gene,
receptor [VDR], solute carrier family 11 [proton-coupled Slc11a1 that controls the innate resistance of mice to the
divalent metal ion transporters], member 1 [SLC11A1], attenuated bacille Calmette-Guerin [BCG] vaccine strain.
formerly known as natural resistance associated The phenotypic expression of the newly identified locus
macrophage protein [Nramp1] genes and interleukin-1 is distinct from that of Slc11a1 in that sst1 controls
receptor antagonist [IL-1RA]. Further, a genome-wide progression of TB infection in a lung specific manner.
scan of various genes in mycobacterial diseases could Similar genome-wide scans have been conducted in
provide crucial information on the involvement of non- Brazilian patients with TB and leprosy. Non-parametric
HLA genes in governing susceptibility to these diseases. multipoint analysis detected 8 and 9 chromosomal
Amongst the non-HLA genes, combined occurrence regions respectively with provisional evidence for
of TAP2 along with HLA-DR2 and their association with linkage. Three regions [10q26.13, 11q12.3 and 20p12.1]
susceptibility to pulmonary TB has been reported (110). are suggestive of linkage to TB (114).
Similarly, an association with haptoglobin 2-2 phenotype
has been shown in Russian patients (111), although, this CANDIDATE GENES IN TUBERCULOSIS
could not be corroborated in Indonesians (112) and Several candidate genes have been implicated in TB.
Indian patients (81). Genome-wide linkage studies on These include Slc11a1 , MBL, and vitamin D receptor
sibling pairs of families affected with the TB has led to [VDR] genes. The reader is referred to the chapter
the identification of several candidate genes, some of “Genetics of susceptibility to tuberculosis” [Chapter 9] for
which show association with the susceptibility to TB (45). more details.
Genome-wide Linkage Analysis Cytokine Genes and Receptors

The development of high throughput genotyping Experiences on the gene-knock out mice have provided
technologies and the identification of thousands of clues on the potential relevance of genetic polymor-
138 Tuberculosis
Table 8.5: Candidate gene variants associated with susceptibility or resistance to tuberculosis
Candidate genes Chromosome Main function of protein encoded Effect
location
HLA
HLA-DR2
DRB1*1501, *1502 6p21.3 Immune response gene Susceptibility
DQB1 *1601 6p21.3 Immune response gene Susceptibility
Haplotype
DRB1*1501-DQB1*0601 6p21.3 Immune response gene Susceptibility
Non-classical HLA
TAP2 and DR2 6p21.3 Peptide translocation Susceptibility
Non-HLA
MBL 10q21.1 Innate immunity Susceptibility/resistance
VDR 12q12-14 Suppression of inflammation Differential susceptibility/resistance
in males and females
SLC11A1 [{CA}n,823 C/T 2q13 Macrophage activation No association with susceptibility/
TGTG+/del and D543N G/A] resistance
Cytokine genes
TNF-α -238, -308 6p21.3 Pleiotropic, both innate/ acquired No association
immunity
Genome-wide scans Xq27 Suggestive of linkage to tuberculosis
15q11
10q26.13
11q12.3
20p12.1
Innate immunity
TLR2 4q32 Role in pathogen recognition and Susceptibility
innate immunity
TLR4 4q32 Severity of disease
HLA= human leucocyte antigen; TAP = transporter of antigen peptides; MBL = mannose binding lectin; SLC11A1 = solute carrier family
11 [proton-coupled divalent metal ion transporters], member 1, formerly known as natural resistance associated macrophage protein
[Nramp1]; TNF-α = tumour necrosis factor-α; TLR = Toll-like receptor
phisms in cytokine and cytokine receptor genes to developments in modern genetics and genomics have
infectious disease susceptibility in humans. The reader contributed to our understanding of the pathogenic
is referred to the chapter “Genetics of susceptibility to processes that underlie major infectious diseases by
tuberculosis” [Chapter 9] for more details. allowing a more systematic study of the genetic
influences. Identifying HLA and non-HLA genes and
INNATE IMMUNITY TO TUBERCULOSIS: products which are associated with susceptibility or
ROLE OF TOLL–LIKE RECEPTORS resistance to TB could provide important genetic makers
to predict the development or predisposition to TB. An
The reader is referred to the chapter “Immunology of
understanding of the presence of risk conferring and/or
protection genes in the human MHC will be useful for
the development of new epitope based vaccines. The
THE FUTURE
number of candidate susceptibility genes is expanding
The development of TB is the result of a complex inter- rapidly. Moreover, genome-wide linkage analysis is also
action between the host and pathogen influenced by beginning to provide insights into complex disease.
environmental factors. Numerous host genes are likely Advances in SNP typing, microarray technology and
to be involved in this process [Table 8.5]. Recently, bioinformatics will be helpful in the study of infectious
diseases. Hence, these studies may be useful for better 14. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom
management and control of the disease. Thus far, genes BR. An essential role for interferon gamma in resistance to
Mycobacterium tuberculosis infection. J Exp Med 1993;
suggested to have a role in governing susceptibility to
178:2249-54.
TB either act directly and modulate development of the 15. Toossi Z, Gogate P, Shiratsuchi H, Young T, Ellner JJ.
adaptive response [HLA, TAP, VDR], or may bridge the Enhanced production of TGF-beta by blood monocytes from
innate and adaptive responses [SLC11A1, TLR 2, TLR 4, patients with active tuberculosis and presence of TGF-beta
various cytokine genes and their receptors]. This is in tuberculous granulomatous lung lesions. J Immunol
consistent with the idea that an appropriate cell-mediated 1995;154:465-73.
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Genetics of Susceptibility to
Tuberculosis
9
Caroline J Gallant, Tania Di Pietrantonio, Erwin Schurr
INTRODUCTION natives were devastated by TB upon initial exposure and

TB death rates among American natives during the late
There is a significant historical evidence demonstrating
19th century were the highest ever recorded (2).
the importance of host genetic factors in susceptibility to
Abel and Casanova (4,5) describe the genetic control
tuberculosis [TB]. It is thought that the variable pattern
of TB as a continuous spectrum, with simple Mendelian
of TB incidence reflects in part a population’s history of
disease at one end [rare mutations with a strong effect],
exposure to Mycobacterium tuberculosis, the causative
complex polygenic disease predisposition at the other
agent of TB. Infectious diseases, such as TB, that entail a
[polymorphisms with a modest effect], and intermediate
high morbidity and mortality in early life are expected
major susceptibility genes providing the link. High-risk
to select genetic variants that confer resistance.
alleles are rare in a population and explain very little of
Consequently, populations with a long history of expo-
the overall disease prevalence. There is an evidence for
sure to Mycobacterium tuberculosis, such as Europeans,
major gene control of susceptibility in certain populations
compared with populations only recently exposed, such
or epidemiologic contents where gene-environment
as North American natives and sub-Saharan Africans,
interactions can be modelled (6). It is unknown if major
show greater resistance to TB (1,2).
gene effects are rare occurrences limited to specific
epidemiological situations or go undetected due to the
Population Variability in Susceptibility
inherent difficulties in capturing important gene-
to Tuberculosis
environment interactions in common diseases, such as
Two historical events illustrate both population differen- TB. The relative importance of a locus in a public health
ces and inter-individual variability in TB susceptibility. context has been described using the population attribut-
The accidental inoculation of infants with a virulent strain able fraction [PAF] which is defined as the fraction of
of Mycobacterium tuberculosis instead of the live the disease that would be eliminated if the risk factors
attenuated vaccine strain Mycobacterium bovis bacille were removed. It is hypothesized that common modest-
Calmette-Guérin [BCG] in Lübeck, Germany, in 1929 (3) risk variants may account for a greater PAF in complex
provided inadvertent verification that, following uniform diseases than rare high-risk alleles (7). For TB, numerous
infectious exposure, individual variations exist in common genetic variants contributing moderately to
humans regarding susceptibility to TB. Of the 251 susceptibility have been identified but their functional
immunologically naive infants administered virulent relevance and impact at the population level remain
Mycobacterium tuberculosis, four showed no signs of elusive (8-10). It seems likely that the genetic dissection
infection, 72 died of TB within one year of infection, and of TB susceptibility will depend on studying all aspects
175 overcame the infection (3). In comparison to the high of disease pathogenesis and the continuous study in both
survival rate of the German infants, North American animal and human models (11).
144 Tuberculosis
Pathogenesis and Genetic Studies A study (13) of TB patients from the cosmopolitan
urban centre of San Francisco, California, showed stable
The natural history of TB is described in the chapters
associations between genetically distinct strains of
“Pulmonary tuberculosis” [Chapter 14], and “Reactivation/
Mycobacterium tuberculosis and human host populations
reinfection tuberculosis” [Chapter 47]. Understanding the
stratified according to place of birth. The association was
natural history of TB and distinguishing between
shown for both reactivation disease and recent transmis-
infection and disease progression are essential to dissect
sions occurring in San Francisco. The authors (13) extend
the genetic basis of TB (11). Exposure to mycobacteria
that the most important factors maintaining the
usually does not result in clinical disease [Figure 47.1].
association are epidemiological and social. However,
The outcome of exposure depends on a complex inter-
they also suggest that given the stability and longevity
action between environmental factors, including the
of the association, it is possible that Mycobacterium
virulence, genetic make-up and mode of exposure to the
tuberculosis would be allowed to adapt to the genetic,
infectious agent, and both host genetic and non-genetic
cultural and environmental characteristics of specific host
factors (4,12). For example, host genetic susceptibility
populations (13).
could involve a variant affecting the function of a gene
involved in immunity to infection. Non-genetic factors
might include human immunodeficiency virus [HIV] METHODS IN THE GENETIC DISSECTION OF
infection and acquired immunodeficiency syndrome COMPLEX INFECTIOUS DISEASES
[AIDS], advanced age, alcohol abuse, corticosteroids use, Numerous methods have been developed to identify
diabetes mellitus, nutritional status or co-infection with genetic control elements of infectious diseases. Taking a
other pathogens (5). Ultimately, the outcome of exposure forward genetics approach [phenotype-to-genotype],
depends on the ability of the host’s innate and adaptive mendelian or complex inheritance in humans is dissected
immunity to control and clear the infection, which, in using hypothesis-driven or -generating methods both
turn, depends on the genetic background of both the host leading to candidate genes. Complementary studies in
and the tubercle bacilli. animals provide an experimental model of infection,
which has been successful in identifying novel myco-
Host-pathogen Interplay
bacterial susceptibility genes. Candidate genes are
Several recent studies have shown important interactions validated by association studies, mutation detection, and
between the host and genetically heterogeneous Mycobac- finally, functional studies to determine the impact of the
terium tuberculosis strains (12-14). A study investigating polymorphism on gene function and on the phenotype
the influence of strain genetic diversity on the course of of interest (5).
disease in a mouse model of infection showed a marked A key consideration in studying the genetics of
difference in immunopathological events ranging from complex disease is to take into account that a clinical
limited disease and 100 per cent survival with Canetti outcome, i.e., active TB disease, is the synthesis of many
strains to extensive disease and significant earlier intermediate phenotypes. For example, an intermediate
mortality with Beijing strains (14). Another study showed phenotype could be the extent of an acquired immune
that the overexpression of a lipid species produced by response to specific Mycobacterium tuberculosis antigens,
strains belonging to the W-Beijing family inhibited the such as Ag85 (15). Studying intermediate and well-
release of the pro-inflammatory cytokines tumour defined phenotypes increases the chance of identifying
necrosis factor-α [TNF-α], interleukin-6, [IL-6], and the genetic factors contributing to the risk of disease,
interleukin-12 [IL-12] in murine monocyte-derived although to date, few studies have taken this into account
macrophages. The authors propose that Mycobacterium (7). Therefore, when designing a study to understand
tuberculosis strain related differences are important in the genetic susceptibility to TB, it is important to
disease pathogenesis by modifying the host cellular distinguish between infection and disease progression,
immune response and thereby contributing to the primary and reactivation disease, or pulmonary and
diversity of clinical outcomes (12). disseminated TB. Inadequate definition, selection or
Genetics of Susceptibility to Tuberculosis 145
knowledge of the disease phenotype likely explains part MOUSE MODELS

of the poor reproducibility of genetic studies in TB and
Studies involving mouse models have provided impor-
other common diseases.
tant insight into the mechanisms of susceptibility and
Whole-genome scans using linkage analysis are most
resistance to TB. Although Mycobacterium tuberculosis is
successful in identifying genes with strong effects on
not a natural mouse pathogen, inbred strains of mice vary
disease susceptibility. Linkage analyses search within
extensively in their susceptibility to TB (24-26). Moreover,
families for regions of the genome that segregate non-
experimental crosses between susceptible and resistant
randomly with the phenotype of interest (7). Whole-
mouse strains have shown that, as in humans, murine
genome scans have been used to identify susceptibility
disease is under multigenic control (27). Specifically,
loci in several human infectious diseases, including
mouse susceptibility loci identified through whole-
schistosomiasis (16), visceral leishmaniasis and leprosy
genome scanning have expanded our knowledge of the
(9,17,18) but results in TB have been less clear (19,20).
host genetic contribution to Mycobacterium tuberculosis
Whole-genome association studies have long been
infection outcome. In addition, mice with targeted gene
suggested to be a more powerful approach than linkage
deletions have led to the identification of critical media-
analysis to identify common modest-risk genes (7,21).
tors involved in antituberculosis immunity. Novel
However, until recently, the lack of high-density single
susceptibility genes identified through these genetic
nucleotide polymorphism [SNP] maps and limited
studies have subsequently been exploited as human
technological capabilities have inhibited its use (7). To
candidate TB susceptibility genes. A well-documented
date, whole-genome association studies have not been
example is the discovery of the murine solute carrier
used to identify any genes important in infectious disease
family 11 [proton-coupled divalent metal ion transpor-
susceptibility but may be a powerful tool in future
ters], member 1 [Slc11a1], formerly known as natural
studies.
resistance associated macrophage protein [Nramp1] gene
Candidate genes can be identified from linkage hits
whose human orthologue, SLC11A1, was later deter-
in whole-genome scans (22), based on studies of animal
mined to be a susceptibility gene in TB, leprosy and
models in vivo (23) or human cells in vitro, or by compari-
HIV (28-30).
son with human inherited disorders with a related
clinical phenotype (5). Candidate genes are tested by
Solute Carrier Family 11 [Proton-Coupled Divalent
association using population or family-based case-control
Metal Ion Transporters] Member 1 [SLC11A1] Studies
designs. The estimated relative risk of variants for TB in
many of these candidate genes is often small [1.5 to 4] Mendelian segregation analysis in populations of
and many results have been proven difficult to replicate informative crosses between inbred mouse strains
in independent studies. revealed that natural resistance to BCG was under the
A widely used and powerful approach for the study control of a single autosomal dominant gene designated
of infectious disease genetics are experiments in mouse ‘Bcg’. The Bcg gene exists in two phenotypic allelic forms
models. Mouse models have helped uncover numerous in inbred mouse strains: susceptible Bcg s mice are
genes involved in the control of TB infection. Gene-dis- permissive to mycobacterial replication in their reticulo-
rupted mice are useful in that they provide a controlled endothelial organs at the initial phase of infection
approach for the genetic dissection of Mycobacterium whereas Bcgr strains restrict growth of the bacilli (31).
tuberculosis infection. Furthermore, new experimental Chromosomal mapping localized the Bcg gene to the
and analytical tools have facilitated genome-wide proximal portion of mouse chromosome 1 (32), a region
scanning, promoting the identification of new TB genes. overlapping the previously identified Lsh and Ity loci
These advances in TB research have made important which controlled infection with the taxonomically unrela-
contributions to our knowledge of TB susceptibility that ted intracellular pathogens Leishmania donovani (33) and
will lead to increased prevention and maintenance of the Salmonella typhimurium (34). The candidate for the Bcg/
human disease. Selected data will be shortly reviewed Ity/Lsh locus, Slc11a1, was isolated by positional cloning
in the following sections. and found to encode a 12-transmembrane divalent cation
146 Tuberculosis
transporter expressed by professional phagocytes (23). devoid of either cell type have been generated. Despite
Susceptibility to infection was later determined to be the the conflicting results observed in mice lacking B-cells
result of a single, non-conservative, glycine-to-aspartate (44-46), protection against TB is clearly mediated by
substitution at position 169 of the SLC11A1 protein (35). T-cells of the α/β lineage with the possible help of γδ
Although the Slc11a1 gene confers protection against T-cells. Specifically, mutant mice lacking αβ T-cells
the mycobacterial species BCG, Mycobacterium intra- succumb quickly to Mycobacterium tuberculosis infection
cellulare (36) and Mycobacterium lepraemurium (37,38), its (47,48) while those deficient in γδ T-cells survive a low
role in modulating infection with virulent Mycobacterium dose but die when a high inoculum is administered
tuberculosis remains elusive. For example, a number of (47,49). To further dissect the importance of αβ T-cells
groups examining the effects of Slc11a1 on the growth subsets, CD4- and CD8- disrupted mice infected with
kinetics of Mycobacterium tuberculosis following low dose Mycobacterium tuberculosis were tested for increased
infection observed higher bacillary loads in the lungs and susceptibility. Both knockout mouse strains were shown
spleens of Slc11a1s (39,40) animals while others failed to to have increased bacterial burdens (50-52) and earlier
detect any differences (26). In a strain susceptibility mean time to death (50) compared to control animals.
survey, Slc11a1r strains had consistently shorter survival To date, the contribution of CD4+ T-cells in antituber-
times than Slc11a1s mice (25). Concomitant with the culosis immunity has clearly been shown to reside in its
polygenic control of TB, F1 hybrids from resistant and involvement in Th1 cytokine production. However, the
susceptible strains were all resistant to infection whereas function of CD8+ T-cells has not been fully established.
the F2 progeny had random survival times. However, Although a lytic role had initially been ascribed to CD8
the length of survival was independent of the Slc11a1 T-cells, studies involving perforin- and granzyme-
genotype (41). Additional evidence against a role for deficient mice (53,54) suggest that CD8+ protective effects
Slc11a1 in murine TB arose from studies involving may be mediated by other mechanisms including the
congenic Slc11a1r strains (40,42) and Slc11a1 gene deletion synthesis of the cytokine interferon-gamma [IFN-γ] (55).
strains (43). In both instances, the Slc11a1-modified mice
displayed a similar resistance to Mycobacterium Cytokines
tuberculosis as their wild-type counterparts.
The development of Th1 cell-mediated immunity
Mouse Knock-out Studies involving the central cytokine IFN-γ, as well as TNF-α,
and IL-12 has been postulated to be a critical mechanism
Since macrophages are the primary host cells in which
of genetic resistance to Mycobacterium tuberculosis. Mice
Mycobacterium tuberculosis bacilli persist and replicate, a
with a targeted IFN-γ gene deletion exhibit extreme
deficiency in macrophage genes involved in pathogen susceptibility to TB, succumbing to a fulminant and
recognition as well as in macrophage activation and
disseminated form of the disease (56-59). Importantly,
recruitment render the host incapable of containing
the genetic disruption of the IFN-γ receptor 1 [IFN-γr1]
infection with Mycobacterium tuberculosis. Consequently, (60) or IFN-γ-responsive genes including the signal
infection of targeted gene disrupted mice with Mycobac-
transducer and activator of transcription 1 [Stat1]
terium tuberculosis can help to delineate the role of different
(60,61), the nuclear factor-kappa beta p50 [Nfkb1] (62),
cell populations as well as cytokines, chemokines, the interferon regulatory factor-1 [Irf1] (63,64), and the
signalling molecules, receptors and adhesion molecules
interferon inducible protein LRG-47 [Ifi1] (60,65) also
involved in host-Mycobacterium tuberculosis interaction.
produce a severe pathological condition characterized
by early death following Mycobacterium tuberculosis
Cellular Immunity
infection. Since an important effector mechanism of
Control of Mycobacterium tuberculosis infection necessita- IFN-γ is the production of reactive nitrogen inter-
tes cell-mediated rather than humoral immunity and mediates (66), ablation of the nitric oxide synthase
involves a direct interaction between effector T-cells and [Nos2] gene also elicits a highly susceptible phenotype
infected macrophages. To assess the role of T- and (67,68). Similarly, genetic deletion of TNF-α (69-71)
B-cells in Mycobacterium tuberculosis eradication, mice abolishes the hosts’ ability to form functional
granulomas causing rapid mortality following infection immune responses (85-89), their significance in Mycobac-
while a deficiency in its receptor [TNFrsf1a and terium tuberculosis immunity lies primarily in the
TNFrsf1b] (72,73) results in widespread tissue necrosis. generation of protective Th1 responses. In IL-18-deficient
Interestingly, mice with disruptions in other members mice for example, a reduced production of IFN-γ caused
of the TNF superfamily such as lymphotoxin a [Lta] also enhanced susceptibility to mycobacterial infection
display a heightened susceptibility to infection with (90,91). Recently, mice lacking Il-12, Il-18 and Il-23 due
Mycobacterium tuberculosis (74,75). However, the to the double knock-out of Il12b and Il18 were still shown
deletion of a novel TNF superfamily member, LIGHT to synthesize IFN-γ in response to Mycobacterium tuber-
[Tnfsf14], did not affect TB susceptibility (75) whereas culosis, suggesting an IL-12, IL-18 and IL-23-independent
lymphotoxin β [Ltb] or Ltb receptor [Ltbr] deficient IFN-γ production (92). In fact, the proinflammatory
animals were observed by some (74), but not by others cytokine IL-6 has been shown to induce IFN-γ synthesis
(75) to successfully contain the infection. Lastly, since and, in its absence, mice develop high bacillary loads
IL-12 is a potent stimulator of IFN-γ production (76), early in response to an aerosol infection with Mycobacte-
it also plays a critical role in anti-mycobacterial rium tuberculosis (81) and succumb rapidly to a large
immunity. Direct evidence for its mycobacteriostatic intravenous infection (93). Similarly, studies involving
effects arose from studies in mice with a genetic disrup- mice with a targeted disruption of the Il1a and Il1b genes
tion in either the p40 [Il12b] or p35 [Il12a] subunit of (94) or the Il1r gene encoding its receptor (95,96) also
the IL-12 molecule (77,78). Strains deficient in IL-12p35 demonstrated that IL-1 signalling participates in the
survived longer than those lacking p40 possibly due to response to Mycobacterium tuberculosis. However, redu-
an alternative activation by interleukin-23 [IL-23]. Since ced IFN-γ production was observed in IL-1R depleted
IL-12 signals mainly through the STAT4 protein, a mice only.
knock-out of the STAT4 gene obliterated both
IL-12 responsiveness and IFN-γ production, resulting Chemokines
in early death following Mycobacterium tuberculosis Chemokines and their receptors mediate cellular
infection (79). trafficking to and from inflammatory sites, outlining a
Unlike Th1 cell-mediated immunity, the role of the plausible role for these cytokines in granuloma forma-
Th2 response in the host defense against Mycobacterium tion. Functional redundancy among chemokines may
tuberculosis has not been defined. The Th2 cell activation, explain the observation that the genetic deletion of
characterised by IL-4 and interleukin-10 [IL-10] produc- chemokine ligand 2 [CCL2], which is also referred to as
tion, promotes principally humoral immunity and anta- monocyte chemoattractant protein 1 [MCP-1], did not
gonizes the Th1 proliferation pathway. With the excep- drastically diminish resistance to Mycobacterium tubercu-
tion of one study (80), the absence of the Il-4 gene was not losis (97,98). In contrast, an exacerbation of Mycobacterium
shown to alter mycobacterial growth (59,81) while the tuberculosis growth and rapid mortality was observed in
functional deletion of the genes encoding the IL-4 respon- mice deficient in the receptor for CCL2, the C-C chemo-
sive molecules STAT6 and the alpha chain of the IL-4 kine receptor 2 [CCR2], only after a high dose infection
receptor [Il4ra] slightly increased susceptibility to with Mycobacterium tuberculosis (99,100), likely the result
Mycobacterium tuberculosis-triggered disease (82). Further- of the promiscuity of CCR2 for multiple chemokines.
more, a double knock-out of Il4 and Il13, whose gene Interestingly, mutant mice with a disruption in the gene
products both signal through IL-4Rα, did not affect encoding the chemokine receptor CCR5 had increased
mycobacterial replication. Finally, depletion of the Th2- levels of dendritic cells and Mycobacterium tuberculosis
polarising cytokine IL-10 was shown to be associated with bacilli in their lymph nodes, alluding to the role of CCR5
a decreased pulmonary bacterial load in one study (83) in dendritic cellular migration to and from the lymph
while another group failed to observe any difference nodes (101). Furthermore, genetic deletion of CXCR3
(59,84). resulted in impaired and delayed granuloma formation,
Although the interleukin-18 [IL-18], IL-6 and inter- suggesting that CXCR3-signalling is involved in granu-
leukin-1 [IL-1] cytokines regulate both Th1 and Th2 loma regulation (102).
148 Tuberculosis
Adhesion Molecules Although the H-2 genes have been implicated in the
antibody response to mycobacterial antigen (114,115), the
Adhesion molecules are logical TB candidate genes due
generation of a granulomatous inflammatory response
to their involvement in cellular migration. Truncation of
to Mycobacterium tuberculosis does not appear to be under
the intracellular adhesion molecule 1 [ICAM-1] by genetic
H-2 control (116). Nonetheless, carriers of the H-2k haplo-
disruption of the Icam gene did not alter the initial course
type have been shown to display greater susceptibility
of infection (103), although it was shown to be essential
to Mycobacterium tuberculosis than H-2b and H-2d carriers
for granuloma formation and long-term mycobacterial
as evidenced by biological phenotypes such as bacterial
containment (104). Infection of mice deficient in the
burden in the lung (117) and median survival times (25).
complement receptor type 3 [CR3] was indiscernible
Paradoxically, infection with a large inoculum of Myco-
from wild type controls (105) whereas the deletion of
bacterium tuberculosis caused the H-2k haplotypes to be
the CD44 antigen promoted bacterial growth and rapid
associated with a longer duration of survival while
mortality (106).
H-2b and H-2d appear to confer an increase in suscepti-
bility (118).
Pattern Recognition Receptors
To investigate the role of so-called pattern recognition Quantitative Trait Locus Analysis
receptors [PRRs] in Mycobacterium tuberculosis immunity,
Due to the multigenic nature of host resistance to TB,
mice defective in a number of Toll-like receptors [TLR]
quantitative trait locus analysis has been adopted to
as well as in the TLR intracellular adaptor molecule
identify genes involved in disease control. Essentially,
myeloid differentiation factor 88 [MyD88] have been
genome-wide scans are performed on populations of
generated. Studies in mice without functional TLR4 (107)
informative backcross or intercross animals generated
or TLR6 (108) have indicated that these PRRs are not
between strains representing polar ends of a resistance/
involved in mycobacterial clearance. Although one study
susceptibility spectrum. The quantitative trait locii that
suggested that the protective effect of TLR2 is dose-
impact on TB susceptibility are then assigned to specific
related (107), conflicting data exist regarding the rele-
chromosomal regions through the use of sophisticated
vance of TLR2 deficiency in host survival following
algorithms (119,120) and high-density genome-wide
Mycobacterium tuberculosis infection (108,109). Further-
maps.
more, disruption of CD14, encoding a molecule that inter-
The first of the genome-wide scans investigated
acts with both TLR2 and TLR4 (110), did not influence
Mycobacterium tuberculosis triggered weight loss in a panel
susceptibility to TB (107). Deletion of MyD88, whose gene
of backcross animals derived from resistant A/Sn and
product is shared among the TLRs, was shown to pro-
susceptible I/St mice (121). The quantitative trait locii
foundly affect mycobacterial proliferation by one group
were identified in female mice only on a region of
(111) but these results were not corroborated by another
chromosome 3 containing the peroxisomal membrane
study in which differences were undetectable (112).
protein 1 [Pxmp1] gene as well as on an area of proximal
chromosome 9 overlapping the macrophage metallo-
Major Histocompatibility Complex
elastase [Mme1] gene and the IL-10 receptor α-chain
The CD4 and CD8 T-cells interact with the class II and [Il10ra] gene. In addition, suggestive linkages were
class I major histocompatibility complex [MHC], respec- observed on chromosomes 8 and 17 in females and 5 and
tively. Disruption of the latter molecules provided direct 10 in males. Recently, each of these loci was tested for
evidence for their importance in mycobacterial control. linkage to cachexia and survival time in Mycobacterium
Interestingly, mice lacking MHC class II molecules mani- tuberculosis-infected F2 hybrid mice from A/Sn and I/St
fest greater susceptibility than either CD4 (50) or MHC parental strains (122). The quantitative trait locii on
class I deficient animals (48). In fact, some studies chromosomes 3 and 9, designated TB severity 1 [tbs1]
reported that the genetic deletion of the β2-microglobulin and tbs2 respectively, were only suggestively linked to
component of MHC class I causes only a slight difference post-infection body weight loss in F2 mice of both sexes.
in resistance (47) while discordant results showed a Another important susceptibility locus was mapped
highly susceptible phenotype (51,52,113). to a region located only 10 centiMorgan [cM] from the
Sic11a1 gene on mouse chromosome 1. This locus, susceptible to poorly virulent mycobacteria such as
designated sst1 for susceptibility to TB, controlled the environmental nontuberculosis mycobacteria [NTM] and
progression of lung disease caused by virulent Mycobac- BCG vaccine. With the exception of salmonellosis occur-
terium tuberculosis in an F2 population derived from ring in fewer than half the MSMD cases, disease caused
resistant C57BL/6J and susceptible C3HeB/FeJ progeni- by other microorganisms is very rare (127). Several
tor strains (123). Interestingly, C57BL/6J mice, which are patients with the syndrome have been diagnosed with
resistant to infection with Mycobacterium tuberculosis, clinical TB but it is unclear to what extent the mutations
carry both the resistant allele of sst1 and the susceptibility are important in Mycobacterium tuberculosis infection or
allele of Sic11a1. Recently, it has been shown that the disease progression (127-130).
sst1 locus influences susceptibility to another intracellular Five genes have been found to be mutated in patients
pathogen, Listeria monocytogenes (124). Positional cloning with the syndrome. Mutations in the IFN-γ receptor 1
isolated the candidate for sst1, the intracellular pathogen [IFNGR1, OMIM 107470] and IFN-γ receptor 2 [IFNGR2,
resistance 1 [Ipr1] gene, which is thought to encode a OMIM 147569], which encode the two IFN-γ receptor
putative transcription factor. chains, and signal transducer and activator of
Another TB resistance locus, Trl-1, localized on mouse transcription 1 [STAT1, OMIM 600555], an essential
chromosome 1, was shown to be mutually exclusive of signalling component, result in impaired cellular
both Sic11a1 and Ipr1 (125). This locus, which impacted responses to IFN-γ. Mutations in the interleukin-12
on the mean survival time in response to Mycobacterium subunit p40 [IL-12B, OMIM 161561] and interleukin-12
tuberculosis injected intravenously, was identified using receptor β-1 subunit [IL-12Rβ1, OMIM 601604] result in
a panel of F2 mice derived from susceptible DBA/2J and impaired IFN-γ production. The mutations can be
resistant C57BL/6J mouse strains. Importantly, the Trl- classified into three classes of alleles: recessive non-
1 region encompassed several interesting genes including functional; recessive, partially-functional; and dominant-
the chemokine receptor Cxcr4, l10, the Fas ligand [Fasl], negative partially-functional (127). The classes of alleles
the selectin and the neutrophil cytosolic factor 2 [Ncf2] correspond to distinct clinical, immunological and
gene encoding the p67 phox subunit of the NADPH- histopathological outcomes.
dependent oxidase. The Trl-2 locus, which was Individuals with mutations resulting in complete
suggestively linked to the proximal portion of chromo- IFNGR1 and IFNGR2 deficiency lack cellular response
some 7, included Il2, Il12a, and I16 interleukin genes and to IFN-γ. Patients invariably develop BCG and/or NTM
interleukin receptor chain genes, while the interval for disease which is early onset, disseminated and often
Trl-3 on the proximal portion of chromosome 3 did not lethal. All BCG-vaccinated IFNGR1 and IFNGR2
contain any obvious candidate genes. Recently, a Trl-4 deficient patients develop BCG-disseminated disease
locus on chromosome 19 was shown to regulate the (5,127). Mutations leading to partially-recessive IFNGR1
pulmonary replication of Mycobacterium tuberculosis in and IFNGR2 deficiency result in impaired but not
response to a low dose aerosol infection (126). Among abolished response to IFN-γ. The resulting clinical
the genes contained in this region are those encoding phenotype is milder and the prognosis better than for
nuclear factor-kappa beta [NF-kB], NF-kB inducing children with complete IFNGR deficiency (127,131).
kinase α [Ikkα], and the α chain of the cell surface There is a clear correlation between IFNGR1 and
receptor for granulocyte/macrophage colony stimulating IFNGR2 genotype [loss-of-function or hypomorphic
factor [GM-CSFRα]. mutation], the cellular phenotype [complete or partial
defect of response to IFN-γ] and clinical phenotype
GENETIC STUDIES IN HUMAN POPULATIONS [favourable or poor outcome]. From this observation,
IFN-γ-mediated immunity can be viewed as a quantita-
Mendelian Susceptibility to Mycobacterial
tive trait that is critical for the outcome of mycobacterial
Disease [OMIM 209950]
infection (127,131).
The lack or partial deficiency of proteins in the IL-12/ Mutations in STAT1, a critical transducer of inter-
IL-23-IFN-γ axis can lead to a rare syndrome called feron-mediated signals, cause a partially-dominant
mendelian susceptibility to mycobacterial disease deficiency (132). Clinical and cellular phenotypes are
[MSMD]. Individuals with the syndrome are highly similar to patients with partially-recessive IFN-GR
150 Tuberculosis
deficiency (127,133). Complete deficiency of IL-12p40, family-based association study in Moroccan pulmonary
encoded by IL-12β, results in impaired production of TB patients. None of the genetic variants identified in
IFN-γ. Monocytes or dendritic cells from these patients IL-12Rβ1 were loss-of-function or hypomorphic,
are unable to secrete IL-12 upon stimulation and however, two promoter variants were associated with
consequently their lymphocytes secrete less IFN-γ than TB (138). A case-control study in Hong Kong Chinese
those of normal individuals. Patients with complete IL- TB patients (140) found a strong association between a
12Rβ1 deficiency show no cellular response to both IL- IL-12B intron 2 genetic variant and TB susceptibility.
12 and IL-23. The clinical outcome of IL-12 deficient Individuals homozygous for the associated variant had
patients varies from case to case suggesting that alternate an estimated 2.14-fold increased risk of developing TB.
pathways are compensating for the loss of IL-12 In addition, specific IL-12B haplotypes were found to be
signalling. In addition, strictly asymptomatic individuals over-represented in TB patients. No correlation was
with a loss-of-function mutation have been identified. A found between IL-12p70 expression and associated
greater proportion of patients with IL-12/IL-23 genetic polymorphisms (140).
deficiency have a history of severe salmonella disease No associations were found in a Gambian population
than those with IFN-γ deficiency. These findings suggest between IFNGR1 polymorphisms, including one variant
a greater importance of IL-12/IL-23 mediated through previously found associated in a Croatian (141) popula-
IFN-γ independent pathways than IFN-γ in immunity tion, and adult pulmonary TB (142). A study looking at
against salmonella (134). polymorphisms in the IFNGR1 promoter region and
Interleukin-23, a recently identified IL-12 like hetero- either pulmonary or disseminated NTM infection, or
dimer, is composed of IL-12p40 and p19 and binds to a pulmonary NTM infection also failed to show an
heterodimeric receptor composed of IL-12Rβ1 and a association. Two SNPs were reported to influence
novel chain (135). Individuals that are completely or expression but were not associated with increased
partially IL-12p40 or IL-12Rβ1 deficient are also IL-23 or susceptibility (139). Overall, it appears that genes of the
IL-23R deficient. It is possible that the phenotypes seen IL-12/IL-23-IFN-γ pathway are risk factors for TB but
in these individuals result from the disruption of both that the genetic effect is weak. It is possible that the
cytokines (136). A recent study has provided evidence pathway is more important for primary infection during
that IL-23 is important for infection and possibly the
childhood or the development of disseminated TB rather
primary type 1 cytokine. The study showed that
than pulmonary TB (142), a suggestion that deserves
mycobacterium-activated type-1 macrophages secrete IL-
further experimental study.
23 [p40/p19] but not IL-12 [p40/p35]. The macrophages
required IFN-γ as a secondary signal to induce IL-12p35 Interferon-γγ
gene transcription and IL-12 secretion (137).
Although the phenotype-genotype relationship for Given the importance of IFN-γ-mediated immunity in
IFN-γ-mediated immunity against mycobacterial disease MSMD and in animal models of infection, IFNG is a
is relatively clear, the importance of genetic variation in prime TB susceptibility candidate gene. A T to A poly-
the IL-12/IL-23-IFN-γ pathway at the population level morphism was identified in the first intron of IFNG
is less well understood. The extent of cases of rare Mende- where the T-allele is associated with increased in vitro
lian mutations responsible for cases of TB in areas of IFN-γ production. This polymorphism coincides with a
endemicity is unknown, as well as the contribution of putative NF-kb binding site where NF-kb was shown to
more common genetic variants within the IL-12/IL-23- preferentially bind to the T-allele (143). Two studies in a
IFN-γ pathway exerting a more modest effect on the South African population further investigated the role
genetic control of TB (138,139). of the T to A polymorphism in TB [both pulmonary and
meningitis] susceptibility. In a case-control study, the
CANDIDATE GENES polymorphism showed a significant association with TB.
The T-allele was over-represented in the controls and,
Interleukin-12/Interleukin-23/Interferon-γγ
therefore, suggested to confer protection. This result was
[IL-12/IL-23-IFN-γγ] Pathway
replicated in a family-based association study of indivi-
The observation that some IL-12Rβ1-deficient patients duals from the same community (10). These findings
present with TB as the only clinical phenotype led to a were also reproduced in a Sicilian population. The
TT genotype was significantly decreased in TB patients Vitamin D Receptor

compared with the controls (144). In contrast, no asso-
Before the development of antimycobacterial drugs,
ciation between IFNG and TB was found in TB patients
vitamin D was administered with some success to treat
from the Karonga district of northern Malawi (145). The
TB (158). It has since been discovered that the biologically
importance of IFN-γ in Mycobacterium tuberculosis
active form of vitamin D, 1,25-dihydroxyvitamin D3
infection has been questioned as the pathogen interferes
[1,25[OH]2D3], interacting with the vitamin D receptor
with IFN-γ signalling and downregulates the transcrip-
[VDR], acts as an important immunomodulatory
tion of IFN-γ inducible genes (146,147). However, the
molecule (159). Vitamin D plays a role in activating
combined results from human and animal genetic studies
make a strong case for the importance of IFN-γ levels in monocytes and cell-mediated immunity, modulates the
variation of susceptibility to TB. Th1-Th2 host immune response, phagocytosis, and
suppresses lymphocyte proliferation, immunoglobulin
Solute Carrier Family 11 [Proton-coupled Divalent production and cytokine synthesis (160-162). In vitro,
Metal Ion Transporters] Member 1 [SLC11A1] 1,25[OH] 2D 3 restricts the growth of Mycobacterium
tuberculosis in human macrophages (163,164). In addition,
The human orthologue of murine Slc11a1, which confers
results from epidemiologic studies point to a link
susceptibility to specific Salmonella, Leishmania and
between vitamin D deficiency and a higher risk of TB
Mycobacterium species (148), has been tested in numerous
(19,165). This is demonstrated by seasonal variation of
association studies. Initially, SLC11A1 variants were
TB incidence, lower vitamin D serum levels in untreated
found to be associated with TB susceptibility in a West
TB patients, and higher incidence of TB in individuals
African population (149). Individuals with TB were four-
with relatively low serum vitamin D levels (166,167).
times more likely to have a disease-associated SLC11A1
Given that vitamin D exerts its effects via the VDR,
genotype combination than healthy controls (149). These
and that the receptor is present on monocytes and on T-
observations have been replicated in several studies of
and B-lymphocytes (168), several studies have investi-
patients from China, Japan, Korea, Malawi, Guinea-
gated the role of VDR genetic variants in TB suscepti-
Conakry and Cambodia (145,150-154). The independent
replication of SLC11A1 association with TB across bility. Two case-control association studies done in a
different populations makes SLC11A1 the most solidly Gambian population found conflicting results. The earlier
established TB susceptibility gene. Nevertheless, several study reported that the TaqI tt genotype was found to be
studies failed to detect an SLC11A1/TB association over-represented in healthy controls (169). However, in
(155,156) providing strong evidence for genetic a subsequent study, the association was not reproduced
heterogeneity in TB susceptibility. (170) and no individual VDR polymorphism was found
The modest genetic impact of the gene on suscepti- associated with TB susceptibility. The authors explain
bility has been interpreted to suggest that the gene the discrepancy by stating that the previous study might
accounts for only a small proportion of the total genetic have been flawed because of ill-diagnosed TB patients
contribution to susceptibility (9,157). However, an and poorly chosen controls (170). A family-based design
alternative explanation is provided by a genetic study in the same population but different individuals showed
of TB susceptibility in a native Canadian community. a significant “global” association of TB and the polymor-
In this study, it was possible to detect a very strong phisms FokI-BsmI-ApaI-TaqI and FokI-ApaI. Only the FokI
genetic effect [relative risk of 10] of the SLC11A1 region polymorphism has been shown to have functional
on TB (6). Of importance, this strong genetic effect was significance. It is correlated with increased vitamin D-
only detected when gene-environment interactions induced receptor function (171). The authors concluded
were included into the analysis. Despite substantial that their study supports a role for VDR haplotypes,
genetic evidence implicating SLC11A1 in TB rather than individual genotypes, in susceptibility to TB
susceptibility, a causal relationship between specific (170).
SLC11A1 variants and increased TB susceptibility Studies that took into account vitamin D serum levels
remains to be established. or treatment outcome were more successful in detecting
152 Tuberculosis
a significant genetic effect. A small case-control study in susceptibility, whether in infection, disease progression
a Peruvian population found specific VDR polymor- or chemotherapy, before any conclusions can be made.
phisms [TaqI Tt and FokI FF] associated with the time to The reader is also referred to the chapter “Genetic
sputum culture and auramine stain conversion during susceptibility parameters in tuberculosis” [Chapter 8] for
treatment. No VDR polymorphisms were associated with more details on this topic.
susceptibility to progression of pulmonary TB, although
the TaqI t allele was over-represented in the healthy Mannose Binding Lectin
controls compared with the TB patients. It should be
Mannose binding lectin [MBL2] is an important part of
noted that the homozygous tt genotype was virtually innate immunity, which acts in concert with the classical
absent in the population sample. A larger sample size
complement system to opsonize and facilitate phago-
would be needed to demonstrate the effect of the TaqI
cytosis of a variety of microorganisms. For mycobacteria,
polymorphism (172). it binds to the mannose residues in the lipoarabino-
A case-control association study (167) of Gujarati
mannan membrane [LAM] covering the bacteria
Asians/Indians living in west London, England,
(181,182). Several high frequency mutations in the MBL
investigated the interaction between VDR genotype and gene, MBL2 result in complete MBL deficiency in the
serum vitamin D concentrations. The study failed to show
homozygote state. Heterozygous individuals show low
a significant association between VDR genotype and
MBL serum concentrations. The high frequency of these
increased risk of TB. However, a strong association was loss-of-function mutations in several populations
observed between vitamin D deficiency and TB. In
suggests that they may confer an advantage against
addition, the study was able to detect evidence for an
certain infections. Intracellular pathogens, such as
interaction between genotype [either TaqI TT/Tt or FokI Mycobacterium tuberculosis, partly exploit the complement
ff], deficient or undetectable vitamin D serum levels and
system to invade and replicate within host cells. Several
susceptibility to TB (167).
studies have investigated whether mutations leading to
Several other studies have investigated the role of the partial or complete MBL deficiency provide a protective
VDR polymorphisms and TB susceptibility, however, the
effect against TB. Studies in South African, Gabonese,
reports vary considerably in their findings (145,154,
Danish and African-American populations showed
173,174). The findings from the case-control association significant associations between MBL2 genetic variants
studies indicate a potential role of VDR polymorphisms
encoding low serum MBL levels and protection against
in TB susceptibility; however, most of the studies suffer
active TB (23,183-185). In addition, one study found
from a lack of power due to small sample sizes. These significantly lower levels of serum MBP concentrations
findings need to be replicated in larger samples and the
in TB-negative controls compared with fully recovered
functional relevance of the associated polymorphisms
TB patients (186). One study in a population from the
needs to be further studied. Karonga district of northern Malawi showed no
association between MBL2 genotype and TB suscepti-
Major Histocompatibility Complex bility or protection (145). Functional studies on the
interaction between MBL and Mycobaterium tuberculosis
Reports of association between highly polymorphic class
II human leucocyte alleles and TB susceptibility are need to be done to confirm the importance of the MBL in
TB susceptibility.
conflicting and vary among populations. Different
studies have found associations with human leucocyte
Linkage Studies
antigen- [HLA-] DR2 alleles (175-177) and with HLA-
DQB1*0501 (177) and DQB1*0503 alleles (178). Some Complementary to candidate gene studies are genome-
studies failed to detect the HLA-DR2 or DQB1 asso- wide scans, a powerful approach to identify major
ciations (179,180). One study reported HLA-DR3 to be susceptibility loci. A study was performed in 92 sib-pairs
enriched in healthy controls suggesting a protective effect with TB from Gambia and South Africa. Weak evidence
of the antigen. The functional significance of the positive for linkage was detected on chromosome regions 15q and
associations are not known. Further studies are required Xq (19). Expectations that major novel loci had been
to fully understand the importance of the MHC in TB identified were not borne out in a follow-up association
study of the 15q region (8). More recently, a genome scan under oligogenic control: linkage study of the candidate genes
for TB in a Brazilian population found three regions with NRAMP1 and TNFA. Tuber Lung Dis 1997;78:35-45.
10. Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG.
suggestive evidence for linkage: 6q21.32, 17q22, 20p13
Association between tuberculosis and a polymorphic
(20). No subsequent studies on these regions have been NFkappaB binding site in the interferon gamma gene. Lancet
reported. 2003;361:1871-2.
Dissection of the genetic susceptibility to TB using 11. Kaufmann SH. How can immunology contribute to the
both murine and human models has led to the identifica- control of tuberculosis? Nat Rev Immunol 2001;1:20-30.
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Kreiswirth BN, et al. A glycolipid of hypervirulent tuber-
important in antituberculosis immunity. To confirm
culosis strains that inhibits the innate immune response.
current findings, further genetic studies are required that
Nature 2004;431:84-7.
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disease phenotypes. In addition, functional studies are Stable association between strains of Mycobacterium
necessary to understand the importance of critical murine tuberculosis and their human host populations. Proc Natl
antituberculosis mechanisms at the human level and to Acad Sci USA 2004;101:4871-6.
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160 Tuberculosis
Laboratory Diagnosis
10
Rajesh Bhatia
INTRODUCTION may be contaminated with environmental mycobacte-

ria. To facilitate the choice of container, following
Since Robert Koch’s discovery of Mycobacterium tuber-
specifications are recommended for a container: [i] wide-
culosis in 1882, microscopic detection of the bacilli in
mouthed so that the patient can expectorate easily inside
clinical specimens has remained the mainstay of
the container without contaminating it from outside;
tuberculosis [TB] diagnosis in developing nations.
[ii] volume capacity of approximately 25 ml; [iii] made
However, in human immunodeficiency virus [HIV] era
of transparent material in order to observe specimen
microscopic diagnosis has certain drawbacks: [i] a low
volume and quality without opening the container;
clinical sensitivity of the technique in HIV-associated TB;
[iv] screw-capped to obtain a water-tight seal, to reduce
and [ii] lack of access to quality microscopy services in
the risk of leakage during transport; [v] easily-labelled
HIV endemic areas. Recently, a number of exciting
to allow permanent identification; and [vi] rigid, to avoid
technologies are being developed for rapid and improved
breakage during transit.
diagnosis of TB including HIV-associated TB. These
An ideal container is the 28 ml universal container,
include improvements in microscopy, growth-based
which is a heavy glass, screw-capped bottle. This
detection and subsequent strain characterization
container is reusable after thorough cleaning and sterili-
including drug susceptibility testing [DST], antigen
zation. The identification number can be permanently
detection, molecular detection and recently described
engraved on the bottle cap.
interferon-γ release assays [IGRAs].
In TB diagnosis, care must be taken to obtain adequate
and satisfactory specimens. Correct collection and trans-
CLINICAL SPECIMENS: COLLECTION AND
portation of specimens to the laboratory are important
TRANSPORTATION
to ensure that the results are accurate and reliable.
In pulmonary TB, sputum is the specimen of choice. If
TB of any other organ of the body is suspected, specimen Collection Procedure
should be from specific organ or system such as urine
It is best to obtain a sputum specimen early in the
for renal TB and cerebrospinal fluid [CSF] for TB
morning before the patient has eaten, since food particles
meningitis. Mycobacterium tuberculosis is in abundance
in smears make them difficult to examine (1). For collect-
in lesions showing rapid caseation.
ing a good sputum specimen, the patient must be given
clear instructions (2). Aerosols containing mycobacteria
Sputum
may be formed when the patient coughs to produce a
The specimen is collected in a sterile container. It is a sputum specimen. Patients should, therefore, produce
common misassumption that as mycobacterial speci- specimens either outside in the open air or away from
mens are decontaminated before culture, cleanliness of other people and not in confined spaces such as toilets.
the container is not important. Unsterilized containers Because of the intermittent excretion of tubercle bacilli,
Laboratory Diagnosis 161
three specimens should be collected for diagnosis as of the cases and the yield may be greater in infants with
follows: [i] one spot specimen when the patient first extensive disease (5).
attends the health service; [ii] one early morning speci- Gastric lavage should be performed early in the
men [preferably the next day]; [iii] one spot specimen morning, when the patient has been fasting for the
when the early morning specimen is being submitted for preceding eight hours. Securing the specimen at this time
examination. These should not be pooled but should be would minimize the dilution of the bronchial secretions
sent to the laboratory as separate specimens. swallowed during the night by saliva or tears. Inhalation
If a patient has a productive cough, obtaining a of superheated nebulized saline prior to gastric lavage
sputum specimen is a fairly straightforward procedure. has been reported to increase the bacteriologic yield (6).
The patient is given a container on his first attendance. Following insertion of nasogastric tube, the stomach
He should be instructed with demonstration by actual contents are aspirated. Then a small amount of sterile
actions such as: [i] to inhale deeply two to three times; distilled water, [not more than 50 to 70 ml], is instilled
[ii] to cough out deep from the chest; [iii] to open the through the nasogastric tube and the aspirate is added
container and spit the sputum into the bottle; [iv] to avoid to the first collection. As gastric acidity is poorly tolerated
saliva or nasal secretions; and [v] to close the container. by Mycobacterium tuberculosis, the gastric aspirate should
A good sputum specimen should be thick, purulent be immediately neutralized either with 10 per cent
and of sufficient quantity [at least 5 ml]. The details of sodium carbonate [added by dropper] to just pink
the patient’s name, address, age, sex and bottle number [pH 7] indicated by phenol red, or with 40 per cent anhy-
are to be recorded in a form/card and sent to the labora- drous sodium phosphate to green with bromothymol
tory with the specimen. Specimens should be transported blue as an indicator.
to the laboratory as soon as possible after collection. If
the delay is unavoidable, the specimens should be Urine
refrigerated or kept in as cool a place as possible to inhibit
The first few millilitres of urine should be allowed to
the growth of unwanted micro-organisms. If refrigerator flush the external urethra. Thereafter, clean-voided total
is not available and specimen is to be transported in hot
volume of the first early morning urine specimen on three
climate then it should be preserved by adding equal
consecutive days is collected in a sterile container and
volume of one per cent cetyl pyridinium chloride in two transported to the laboratory as early as possible.
per cent saline.
Cerebrospinal Fluid
Collection of Specimens Other Than Sputum
About 5 to 10 ml of CSF should be collected for culture
Fibreoptic Bronchoscopy in a sterile vial.
Fibreoptic bronchoscopy has been extensively used to
ascertain the diagnosis in patients who produce Serous Fluids
inadequate sputum or do not produce sputum at all, and The largest possible volume of pleural, pericardial,
in those with smear-negative pulmonary TB. Various synovial and ascitic fluid is procured for culture and
bronchoscopic specimens such as bronchial washings, 1 ml of 3.8 per cent sodium citrate solution per 4 ml of
brushings, bronchoalveolar lavage [BAL] fluid and specimen or 1 ml of 1:1000 heparin per 50 ml of fluid is
transbronchial lung biopsy have been evaluated and added to prevent clotting of the serous fluid.
found to be useful (3,4).
Tissue
Gastric Lavage
Tissue biopsy specimens of lymph nodes, liver etc., are
Gastric lavage has often been used for the diagnosis of aseptically collected in a vial containing normal saline
pulmonary TB in young children instead of sputum. and transported to the laboratory immediately. Tissue
Young children seldom produce adequate sputum and in formalin should never be sent for culture.
secretions from the respiratory tract are often swallowed. Pus and bronchial secretions should be collected in
Gastric lavage reveals the organism in 30 to 40 per cent sufficient quantities when possible to enable the
162 Tuberculosis
concentration of mycobacteria. Bone marrow aspirates, It has been shown that at least 10 000 bacilli per ml of
which are generally free of rapid growing non-acid fast sputum are required for direct microscopy to be positive.
bacteria, can be directly inoculated onto the Lowenstein- The sensitivity can be further improved by examining
Jensen [L-J] medium. more than one specimen from a patient. Examination of
Urine, CSF, synovial or other fluids which are two specimens will, on an average, detect more than 90
collected aseptically need no decontamination. For other per cent of cases and the addition of a third specimen
specimens, sodium hydroxide in the final concentration increases the percentage to approximately 95 to 98 per
of two per cent in the diluted specimen is the most cent. A negative smear, however, does not exclude the
commonly used liquefying agent and digestant. The diagnosis of TB as some patients harbour fewer numbers
decontaminated specimen is concentrated by sedimen- of bacilli which cannot be detected by direct microscopy.
tation in a refrigerated centrifuge at 3000 g for 30 minutes. A poor quality specimen or smear may also produce
The sediment is used for inoculating media and negative results.
preparation of smears while the supernatant can be used New glass slides should be used for making smears
for biochemical and/or immunological investigations. as acid-fast bacilli [AFB] are not always removed from
the old slides. Only those reagents and diluents should
DIRECT DEMONSTRATION OF MYCOBACTERIA be used which have been shown to be free of environ-
BY STAINING TECHNIQUES mental mycobacteria to avoid false positive smears.
Use of microscopy in diagnosis of TB is of paramount Direct examination is performed by selecting a purulent-
importance, as culture takes a long time before the results looking portion of sputum and spreading it thinly on a
are ready. Microscopy is also helpful in the detection of glass slide with a bacteriological loop or a wooden stick.
open or infectious cases. Stained smears are examined The watery part of sputum is less likely to contain bacilli.
directly from the sputum and after concentration (7). The AFB are seen as bright red rods against the blue,
The tubercle bacilli are Gram positive though they green or yellow background [depending upon the
do not take the stain readily. Mycobacteria retain the counterstain used in staining]. A negative result does not
primary stain even after decolourization with acid- exclude TB. As recommended by World Health
alcohol; hence the term “acid-fast”. A counter-stain is Organization [WHO], before declaring a slide negative
employed to highlight the stained organisms for easier it is essential that at least 100 fields are examined taking
recognition. There are several methods of determining over at least 10 minutes. Smears can be graded according
the acid-fast nature of mycobacteria. In the carbol-fuchsin to the number of bacilli seen [Table 10.1].
[Ziehl-Neelsen] procedure, acid-fast organisms appear
red against a blue background. Other Staining Methods Using Carbol Fuchsin
Acid fastness is based on the integrity of the cell wall.
Beaded or barred forms are frequently seen in Myco- Other staining methods using carbol fuchsin for light
bacterium tuberculosis while Mycobacterium bovis stains microscopy include the cold staining methods [such as,
more uniformly. In younger cultures, non acid-fast rods Kinyoun’s or with Gabett’s solution]. The performance
and granules have been reported. The mycobacterial cell of these techniques might have been overestimated.
wall is complex in nature. It has high lipid content, which Carefully planned studies have shown that the quantity
accounts for about 60 per cent of the cell wall weight. The of bacilli seen with a cold stain method is generally less
cell wall has several distinct layers. The inner layer, than that with the conventional Ziehl-Neelsen [Z-N]
overlying the cell membrane is composed of peptidogly- staining method, which might pose a problem in
can [murein]. External to the murein is a layer of arabino- paucibacillary specimens. The Gabett’s solution has
galactan, which is covalently linked to a group of long advantages only for experienced technicians who have
chain fatty acids termed mycolic acid. These form a dense to stain large numbers of smears, since it consists of only
pallisade, arranged in rope-like structure, which gives two steps [acid and methylene blue combined]. However,
the cell wall its thickness and is largely responsible for the background colour with this method is often not
acid fastness. satisfactory.
Table 10.1: Grades according to the number of bacilli seen Table 10.2: Grades according to the number of bacilli per
with Ziehl-Neelsen staining high power field seen with fluorescent staining
No. of AFB Fields Report No. of bacilli per high power field Grade
None per 100 oil immersion fields Negative Less than 6 per field 1+
1-9 per 100 oil immersion fields Scanty [report 6 to 100 bacilli per field 2+
exact number] More than 100 per field or large clumps 3+
10-99 per 100 oil immersion fields 1+
1-10 per oil immersion field 2+
To increase the sensitivity of microscopic exami-
[examine 50 fields]
> 10 per oil immersion field 3+ nation, various methods for concentrating the bacillary
[examine 20 fields] content of sputum and other clinical specimens are used.
The most widely used method which concentrates the
AFB = acid-fast bacilli
bacilli without inactivating them is Petroff’s method.
Fluorescent Staining Petroff’s Method

Ziehl-Neelsen staining is a time consuming process for In this method, the sputum is incubated with an equal
staining as well as examination. The WHO has recom- volume of four per cent sodium hydroxide at 37 °C with
mended that the maximum number of Z-N smears frequent shaking till it becomes clear. This takes an
examined by a microscopist in a day should not exceed average of 15 to 20 minutes. It is centrifuged at 3000 rpm
20. If more than this number of examinations is for 30 minutes. The deposit is neutralized with dilute
attempted, visual fatigue will lead to a deterioration of hydrochloric acid using neutral red as an indicator. This
reading quality. On the other hand, proficiency in reading deposit can be used for making microscopy, culture and
the Z-N smears can only be maintained by examining at other diagnostic tests.
least 10 to 15 Z-N smears per week, i.e., an average of
Value of Smear Examination in
two to three smears per day. Establishment of
Extra-pulmonary Specimens
fluorescence microscopy is recommended where more
than 50 smears are examined per day, and if electricity Specimens from extra-pulmonary sources, such as urine,
is continuously available. Under such circumstances CSF and other body fluids are centrifuged and the deposit
fluorescence microscopy might be cost-effective. is stained and examined.
Additional requirements in training and economic The benefit of microscopy in these specimens is
considerations [capital investment and maintenance] limited because of their paucibacillary nature and it is,
need to be taken into account before introducing therefore, recommended that the extra-pulmonary
fluorescence microscopy. specimens be referred for culture and other molecular
Fluorescence staining utilizes basically the same techniques.
approach as Z-N staining, but carbol fuchsin is replaced
by a fluorescent dye [auramine-O, rhodamine, auramine- Gastric Washings
rhodamine, acridine orange etc.,], the acid for decolouri- Examination of direct smears of gastric lavage should be
sation is milder and the counterstain, though not avoided, as the results could be misleading. The AFB are
essential, is useful to quench background fluorescence frequently present in food and water and hence in the
(8). Both sensitivity and specificity of fluorescence stomach. There is no way of distinguishing such orga-
microscopy are comparable to the characteristics of the nisms from tubercle bacilli on microscopy and positive
Z-N technique. The most important advantage of the results must be regarded with suspicion.
fluorescence technique is that the slides can be examined
Laryngeal Swabs
at a lower magnification, thus allowing the examination
of a much larger area per unit of time. In fluorescence Direct smear examination of laryngeal swabs is not much
microscopy, the same area that needs examination for useful. A negative result cannot rule out TB and when-
10 minutes with a light microscope can be examined in ever possible, the material obtained should be subjected
two minutes [Table 10.2]. to mycobacterial culture.
164 Tuberculosis
Pus and Thick Aspirates proliferates extremely slowly [generation time 18 to 24

hours]. Further, growth requirements of mycobacteria
Direct smears of pus and other body fluids, should be
are such that they will not grow on primary isolation in
made thin. Thick smears tend to float off the slide and
simple chemically defined media. Hence, culture
even if they are retained, the AFB may be difficult to see
methods for mycobacteria are expensive and require
after staining. Problems may arise if a large amount of
considerable infrastructure and technical expertise.
blood is present in the specimen since blood may
Cultures are very sensitive for the detection of tuber-
sometimes produce acid-fast artifacts.
cle bacilli and may detect as few as 10 to 100 bacilli per
Pleural and Pericardial Fluid ml of sputum. The culture is considered as gold standard
(9). Most commonly used medium is L-J medium. It con-
The pleural and pericardial fluids should be centrifuged tains eggs, asparagine, glycerol and some mineral acids.
and smears should be prepared from the sediment. Again,
these should be thin otherwise they may float off the slide. Cultural Characters
The growth appears in about two weeks but may be
Cerebrospinal Fluid
delayed up to six to eight weeks. Optimum temperature
Smears from CSF are rarely positive and sediment from for growth is 37 °C; growth does not occur below
the CSF should rather be cultured. If a smear is desired, 25 °C and above 40 °C. Optimum pH for growth is 6.4 to
two parallel marks about 10 mm long and 2 mm apart 7.0. Increased carbon dioxide [CO2] tension [5% to 10%]
should be made on a clean glass slide. A loopful of the enhances growth. Human strains grow more luxuriantly
sediment is spread between these marks and the smear in culture [eugonic] than do bovine strains [dysgonic]. The
is allowed to dry. Another loopful of the sediment is then addition of a low percentage of glycerol to the medium
spread over the first. When this is dry, the process may encourages the growth of human strains but not that of
be repeated depending on how much sediment is bovine strains, which may in fact be inhibited.
available. This procedure clearly marks the area to be
searched for AFB. It is desirable that two independent Culture Media
readers examine the smears. The clots should be saved Various types of media that are commonly used have
for culture. been summarized in Table 10.3.
Urine Colony Characteristics

Smears of centrifuged urine deposits are most unreliable On solid media human type of tubercle bacilli give rise
and should be avoided. Nontuberculous mycobacteria to discrete, raised, irregular, dry and wrinkled colonies
[NTM] are sometimes present in the urine, either when which are creamy white to begin with and then develop
it is voided or as a result of poor collection techniques.
The presence of AFB in urine should be viewed with Table 10.3: Media used for the growth
suspicion. of Mycobacterium tuberculosis
Solid media Liquid media

ISOLATION OF MYCOBACTERIA BY CULTURE
Functions
Culture examination, on the other hand, detects fewer Isolation of organism Sensitivity testing
Antigen preparation
bacilli and increases the number of TB cases found, often
Chemical tests
by 30 to 50 per cent. Culture methods provide definitive
diagnosis by establishing the viability and identity of the Examples
L-J medium* Dubos’ medium
organisms. Further, in order to distinguish between
Loeffler serum slope Middlebrook’s medium
different mycobacterial species as well as to perform drug Pawlowsky’s medium [potato medium] Sula’s medium
susceptibility tests, culture examination becomes a Tarshis medium [blood medium] Sauton’s medium
necessity.
* most widely used
Compared to other bacteria, which typically
L-J = Lowenstein-Jensen
reproduce within minutes, Mycobacterium tuberculosis
buff colour. By contrast, the bovine type grows as flat, When the BACTEC 12B vial is inoculated, myco-
white, smooth, moist colonies which “break up” more bacteria, if present, utilize the 14C labelled substrate
readily when touched. [palmitic acid] and release 14CO2. The BACTEC instru-
Tubercle bacilli will grow on top of liquid medium ment measures quantitatively the radioactivity in terms
as a wrinkled pellicle if the inoculum is carefully floated of numbers on a scale ranging from 0 to 999, designated
on the surface and flask left undisturbed otherwise they as the growth index [GI]. The daily increase in GI is
will grow as floccules throughout the medium. However, directly proportional to the rate and amount of growth
a diffuse growth can be obtained by adding a wetting in the medium. When an inhibitory agent is introduced
agent such as Tween 80. Virulent strains tend to form in the medium, inhibition of metabolism is indicated by
long serpentine cords in the liquid media while avirulent reduced production of 14CO2, which in turn is indicated
strains grow in a more dispersed fashion. by decrease in GI. This basic principle is utilized in
The clinical specimen as such, or after concentration, isolation of mycobacteria and drug susceptibility testing
is inoculated onto two bottles of L-J medium and incu- in this method. This system is, at present, standard
bated at 37 °C. Cultures are examined initially after three practice among laboratories in the developed nations as
to four days to rule out the presence of rapid growing a routine method.
mycobacteria and contaminant fungi and bacteria. Several investigators have successfully used BACTEC
Thereafter, cultures are examined twice weekly. A nega- 12B medium for isolation of mycobacteria from blood
tive result is given, if no growth appears after eight to specimens. However, a large quantity of blood cannot
twelve weeks. If growth is obtained, then a Z-N stained be inoculated into 12B medium because it produces turbi-
smear made from the same is examined and routine dity and high background reading. Another approach is
biochemical tests put up. to process the specimen by lysing the blood cells and
All cultures should be examined 48 to 72 hours after concentrating the specimen by centrifugation. The
inoculation to detect gross contaminants. Thereafter introduction of BACTEC 13A medium has eliminated
cultures are examined weekly, up to eight weeks on a the time consuming and potentially hazardous process-
specified day of the week. With doubtful cultures, the ing step by allowing a larger volume [up to 5 ml] of blood
acid-fastness should be confirmed by Z-N staining. A to be inoculated directly into 30 ml of 13A medium (11).
very small amount of growth is removed from the culture The 13A medium can also be used for aseptic collection
using a loop and gently rubbed into one drop of sterile of extra-pulmonary specimens such as bone marrow and
saline on a slide. At this point the ease with which the CSF, which can be directly inoculated [up to 5 ml].
organisms emulsify in the liquid should be noted; as
tubercle bacilli do not form smooth suspensions, unlike Septi Chek Acid-fast Bacilli Method
some other mycobacteria. The smear is allowed to dry, Recently, a novel biphasic-culture approach for detection
fixed by heat and stained by the Z-N method. and isolation of mycobacteria from clinical specimens
has been described. It showed higher mycobacterial
Rapid Culture Methods recovery when this biphasic system was compared with
A constraint faced with the conventional methods using conventional mycobacterial isolation culture techniques
as well as the BACTEC system (11).
egg-based or agar-based media is that they require two
to eight weeks for detection of mycobacteria. In case of
Rapid Liquid Tuberculosis Culture
extra-pulmonary specimens, the time taken may be even
longer. Rapid liquid tuberculosis culture is also known as
A technique for automated detection of bacterial Mycobacteria Growth Indicator Tube [MGIT]. The
metabolism by measuring radioactive CO2 liberated culture is done using manual or automated systems in
during decarboxylation of 14C labelled substrates was which tubes contain enriched Middlebrook 7H9 broth
developed in 1969. This principle was further developed and an oxygen sensitive fluorescent sensor embedded
by several workers, which led to the development of the in silicone on the bottom of the tube. The presence of
BACTEC radiometric system for mycobacteria (10). This oxygen dissolved in the broth quenches emissions from
system is now commercially available. the compound. As the actively growing and respiring
166 Tuberculosis
mycobacteria consume the dissolved oxygen, the sensor two hours reduces nitrate to nitrite which gives a pink
glows indicating mycobacterial growth. This can be or red colour when treated with sulphanilamide and
observed by using an ultraviolet lamp with a wave length N-naphthyl-ethylene diamine dihydrochloride. This
of 365 nm. test differentiates Mycobacterium tuberculosis from
The fully automated version can incubate up to 960 Mycobacterium bovis which does not reduce nitrate.
samples for Mycobacterium tuberculosis. Diagnosis for
sputum positive material is obtained within a week while Tween 80 Degradation [Tween Hydrolysis]
for negative results incubation has to continue for six
The test is carried out by suspending the growth from a
weeks. The culture system has also been used for drug
slope in a mixture of Tween 80-buffer-neutral red at
susceptibility testing for the first-line drugs.
37 oC. The reaction is read at four hours, five days and
These cultures have shown higher rates of
10 days. A pink colour indicates hydrolysis of Tween 80.
mycobacterial isolation and a shorter time-to-detection
Mycobacterium tuberculosis does not produce hydrolysis
compared to cultures on solid media.
of Tween 80. This test is particularly useful in differen-
tiating Mycobacterium scrofulaceum [negative] from
Mycobacteriophage-based Detection Tests
Mycobacterium gordonae and Mycobacterium flavescens
Phage-based tests require limited culture facilities and [positive].
promise rapid results [within 2 days]. Phage tests are
based on the ability of viable Mycobacterium tuberculosis Neutral Red Test
to support the replication of an infecting mycobacterio-
This test detects the ability of a strain to bind neutral red
phage. Plaques of lysed cells in a lawn culture of myco-
in an alkaline buffer solution. Positive tests are obtained
bacteria are counted (12).
with Mycobacterium tuberculosis, Mycobacterium bovis,
Phage-based tests are technically complex to perform
Mycobacterium avium and Mycobacterium ulcerans.
requiring a well-functioning bacteriology laboratory, a
strict incubation protocol and well-trained technicians.
Arylsulphatase Test
They are very labour intensive and some studies also
report a high rate of contamination, making the test and The organism is grown for two weeks in a medium
its results both difficult to perform and to interpret. containing 0.0001 M tripotassium phenolphthalein disul-
phate. The liberation of free phenolphthalein is detected
TESTS FOR CONFIRMATION OF IDENTITY by the red colour produced on addition of an alkali.
Mycobacterium tuberculosis gives a negative test.
Biochemical Properties
Mycobacterium tuberculosis has distinctive biochemical Catalase at Room Temperature
properties, some of which are utilized for identification The test is usually performed by suspending growth in
of various species. Their brief description follows: a mixture of Tween 80-hydrogen peroxide; the appear-
ance of bubbles is interpreted as a positive reaction. The
Niacin Test NTM usually have catalase activity.
All mycobacteria produce nicotinic acid or niacin during
growth. However, only Mycobacterium tuberculosis produ- Catalase at 68 oC
ces niacin in sufficient quantities to give a positive niacin The growth is incubated in phosphate buffer [pH 7] at
test. The niacin production test is today the most exten- 68 °C in a water bath for 20 minutes and cooled to room
sively used in diagnostic mycobacteriology.
temperature. Tween peroxide mixture is then added. The
appearance of bubbles indicates a positive reaction.
Nitrate Reduction
Mycobacterium tuberculosis and Mycobacterium bovis give
Mycobacterium tuberculosis suspended in a buffer negative reaction, while positive reactions are usually
solution containing nitrate and incubated at 37 oC for obatined with several other NTM.
Peroxidase Test Table 10.4: Biochemical tests to differentiate mycobacteria
Isoniazid-sensitive Mycobacterium tuberculosis is Test Mycobac- Mycobac- Nontuberculous

peroxidase positive, while unclassified mycobacteria and terium terium mycobacteria
tuberculosis bovis
isoniazid-resistant strains of Mycobacterium tuberculosis
are peroxidase negative. Production of niacin + – –
Binding of neutral red + + +/–
Hydrolysis of Tween 80 – – +
Nicotinamidase and Pyrazinamidase Activity
Production of enzymes
Mycobacterium tuberculosis has the ability to deaminate Nitrate reduction + – +/–
Arylsulphatase – – –/+
nicotinamide to nicotinic acid and pyrazinamide to pyra-
Catalase
zinoic acid; these properties differentiate Mycobacterium at room temp – – +
tuberculosis and Mycobacterium bovis. at 68 °C – – +
Catalase-Peroxidase Weak + Weak + Strong +
Susceptibility to Pyrazinamide Nicotinamidase + – –
Pyrazinamidase + – +/–
Mycobacterium tuberculosis is sensitive to 50 μg/ml Susceptibility to:
pyrazinamide, while Mycobacterium bovis and other Pyrazinamide + – –
mycobacteria are resistant. Uptake of iron – – –/+
+ = positive; – = negative
Susceptibility to P-Nitrobenzoate
Mycobacterium tuberculosis and Mycobacterium bovis are Identification of Nontuberculous Mycobacteria
inhibited by 500 μg/ml of sodium p-nitrobenzoate in The reader is referred to the chapter “Nontuberculous
L-J medium, while the saprophytes and the unclassified mycobacterial infections” [Chapter 48] for the salient
mycobacteria are resistant. features of NTM and their diagnostic criteria.
Susceptibility to Thiophen-2-Carboxylic ANIMAL INOCULATION

Acid Hydrazide [TCH]
Guinea pig inoculation was once a popular way of
Mycobacterium tuberculosis is usually not inhibited by diagnosing TB but should now be regarded as obsolete.
10 μg/ml of thiophen carboxylic hydrazide; however, It has been clearly demonstrated that the use of this
many Indian strains of Mycobacterium tuberculosis with animal offers no practical advantage over in vitro culture.
low virulence to guinea-pigs are susceptible to TCH. In addition to humane considerations, animal inoculation
Mycobacterium bovis strains are usually susceptible. The is costly and generates many biohazards. However, in
results obtained with these tests have been summarized some laboratories it is still used.
in Table 10.4.
IMMUNODIAGNOSIS
Identification of Mycobacterium tuberculosis Antibody Detection Tests
There is no single reliable test that will differentiate Various antigens have been evaluated for detection of
Mycobacterium tuberculosis from other mycobacteria. antibody to Mycobacterium tuberculosis. The A60 is the most
Nevertheless, the following tests, when used along extensively used antigen for both pulmonary and extra-
with the morphological characteristics, will enable a pulmonary, adult and childhood TB. Immunoglobulin
precise identification of more than 95 per cent of the [Ig] G [IgG] and IgM detection has been evaluated. In
Mycobacterium tuberculosis strains: [i] susceptibility to various studies the sensitivity of these test has ranged
p-nitrobenzoic acid; [ii] niacin production test; between 30 to 100 per cent (13-15). A variety of commercial
[iii] catalase activity at 68 oC/pH 7; and [iv] nitrate kits are available primarily in developing countries.
reduction test [optional]. However, all them lack adequate sensitivity and specificity.
168 Tuberculosis
Tests are also available which use purified antigens no cross hybridization with non-mycobacterial respi-
mainly 38kDa and 30kDa. The former is very specific ratory pathogens (23) with sensitivity equivalent to smear
and the latter is highly immunogenic and more sensitive examination by Z-N staining.
(16-18). Antibody detection by enzyme linked immuno-
sorbent assay [ELISA] or other serological tests are of Polymerase Chain Reaction
limited use since less than 70 per cent of patients produce
Polymerase chain reaction [PCR] is extremely sensitive
specific antibodies in high levels. Moreover, presence of
and specific technique (24). A protocol for detection of
antibody does not indicate current disease or past
insertion element IS6110 was described and it gave a
infection. Accordingly, presence of antigen may be a
positive result in nine out of the fifteen TB pleural effu-
better indicator of the disease than the antibody. How-
ever, antigen quantity in circulation is usually very limited sions, while a PCR for conserved region was positive in
and masked by the antibody and hence difficult to detect. only three of these patients. However, it was also repor-
Though various tests have been attempted (19-21), there ted that when different specimens from the same patient
is none that can be recommended and is widely used. were tested, positive results were obtained intermit-
A recent WHO study found that TB rapid diagnostic tently (25).
tests currently available in the market vary widely in Initially developed PCR could detect as low as 10
performance, with some products showing a high lot- bacilli in the specimen. Recent modifications have
to-lot and reader-to-reader variability. At less than 80 enabled DNA extracted from a fraction of a bacilli to be
per cent, the specificity was poor in the majority of pro- detected after suitable amplification (26).
ducts when tested in TB suspected cases from endemic The DNA ligase functions to link two strands of DNA
settings. Those tests with a better specificity [over 90%] together to continue a double strand segment. The seal
had poor sensitivity, detecting fewer than 40 per cent of can reliably take place only if the ends are complemen-
TB patients. The tests performed even worse in HIV co- tary and are an exact match. In ligase chain reaction
infected samples. The conclusion of a review of several [LCR], the fragmented primers are four in number and
studies showed that none of the assays perform well are added in excess. Results from PCR and LCR tests are
enough even to replace microscopy (22). available in three days as compared to culture which
takes six weeks. Its power can, however, be its greatest
Antigen Detection Test
weakness as even the smallest amount of contaminating
Lipoarabinomannan Urine Test DNA can be amplified, resulting in misleading results.
The test detects lipoarabinomannan [LAM] in urine as a Amplified Mycobacterium tuberculosis Direct Test
surrogate marker for Mycobacterium tuberculosis infection.
Lipoarabinomannan is a component of the TB bacterial The amplified Mycobacterium tuberculosis direct test is
cell wall. The test exists in ELISA and simplified “tube” specific for Mycobacterium tuberculosis complex. It is an
format. Clinical trials to develop a dipstick format are isothermal transcription mediated amplification [TMA]
ongoing. The simplified tube format is apparently robust test in which the target is the mycobacterial 16SrRNA.
and does not require cold chain. The entire process is performed at 42 ºC. The test is highly
specific, and gives result within three hours. This is the
Flow-through Filter Tests first test to be approved by the FDA for smear-positive
These tests rely on detection of Mycobacterium tuberculosis respiratory specimens. Similarly, other PCR test systems
in sputum or body fluids with a polyclonal antibody, that target 16SrRNA including the real time assays have
using a flow-through device. been developed.
Efforts are being made to simplify the nucleic acid
Nucleic Acid Amplification Tests testing systems. In loop mediated isothermal amplifica-
tion [LAMP], Mycobacterium tuberculosis DNA is
Nucleic Acid Probes
amplified directly from clinical samples. A positive
Deoxyribonucleic acid [DNA] hybridization technique result is signalled by a colour reaction visible to the naked
detects small numbers of Mycobacterium tuberculosis with eye.
Overall, sensitivity of nucleic acid amplification tests DRUG SUSCEPTIBILITY TESTING

[NAAT] is higher when test is applied to the respiratory
With the emergence of multidrug-resistance in myco-
samples as opposed to other body fluids (27).
bacteria it is essential to perform DST on the tubercle
GenoType Assays bacilli isolates as an aid and guide to the treatment. Drug-
resistant mutants continuously arise at a low rate in any
Two GenoType assays are commercially available. The mycobacterial population. The purpose of DST is to deter-
first is for TB diagnosis [GenoType Mycobacteria Assay], mine whether the great majority of the bacilli in the
the second for detection of rifampicin and isoniazid culture are sensitive to the antituberculosis drugs curren-
resistance [GenoType MTBDR Assay]. Isolation is tly in use.
commonly done by PCR amplification of the 16S-23S The DST tests should be performed in the following
ribosomal DNA spacer region followed by hybridization
instances: [i] for relapse or retreatment cases; [iii] to
of the biotinylated amplified DNA products with 16
change the drug regimen when drug resistance is
specific oligonucleotide probes. The specific probes are
suspected; and [iii] undertaking drug-resistance surveil-
immobilized as parallel lines on a membrane strip.
lance studies in a region/country.
The DST may be direct [performed on the original
Polymerase Chain Reaction Sequencing
specimen] or indirect [performed on a subculture].
Specific Mycobacterium tuberculosis genetic material is
amplified and sequenced, allowing the DNA to be Direct Method
“read”. This is the gold standard and the most widely
For the direct method, the inoculum is a digested and
used method for defining genetic resistance for drug
decontaminated sputum [or other clinical specimen] in
sensitivity testing. It has been commonly used for
which AFB have been demonstrated in stained smears.
characterising mutations in the rpoB gene in rifampicin-
resistant strains and to detect mutations responsible for In this method, the inoculum is truly representative of
other antituberculosis drugs. Most protocols include the the bacillary population present in the specimen. The
repeat insertion sequence IS6110 as a target for amplifi- advantage of this method is that the drug susceptibility
cation. This sequence is specific of Mycobacterium test results are available along with the culture results
tuberculosis complex and is present in many copies in the [by 3 to 4 weeks].
Mycobacterium tuberculosis genome.
Indirect Test
Identification of Mycobacteria by High Performance The indirect test is used for specimens that are smear-
Liquid Chromatography negative but culture-positive or when the growth in the
Identification of mycobacteria to the species level by control slope of the direct test is inadequate. Further, in
using biochemical and microbiological methods is a time the indirect test, the inoculum is standardized but at the
consuming process. However, in the recent past, several same time is not truly representative and hence there is
newer rapid methods have become available to achieve a chance of selecting a proportion of susceptible or
reliable results. One such rapid method, developed at resistant bacilli from the slope. For this reason, the
the Centers for Disease Control [CDC], Atlanta, USA, is inoculum is prepared by using a representative sweep
the use of high performance liquid chromatography of the entire surface of the growth on the slope.
[HPLC] for the analysis of species-specific mycolic acids There are three general methods used for determining
present in the cell walls of mycobacteria. Extensive work drug susceptibility of mycobacteria by the indirect
with this technique has resulted in a dramatic increase method. These include the absolute concentration
in the usage of this technique by several laboratories. This method also called [MIC method], the resistance ratio
popularity is due to the simplicity and reliability of the [RR] method, and the proportion method. When properly
method and its ability to accurately identify the standardized and performed, all three methods have
mycobacteria from a single test. been shown to be equally satisfactory.
170 Tuberculosis
Absolute Concentration Method are determined by interpreting the point at which the
The absolute concentration method uses a standardized ellipse of inhibition crosses the strip.
inoculum grown on drug-free media and media contain- This is a simple method which does not require
ing graded concentrations of the drug[s] to be tested. sophisticated infrastructure or highly skilled personnel.
Several concentrations of each drug are tested, and It has been shown to be accurate and reproducible and
resistance is expressed in terms of the lowest concen- results become available within five to ten days after
tration of the drug that inhibits growth, i.e., MIC. This primary culture. It, however, requires a higher bacterial
method is greatly affected by inoculum size and by the concentration in the inoculum.
viability of the organisms.
Microscopic-Observation Drug-Susceptibility Assay
Resistance Ratio Method
The microscopic-observation drug-susceptibility
The resistance ratio method compares the growth of
unknown strains of tubercle bacilli with that of a standard [MODS] assay (28-30) facilitates the detection of Mycobac-
laboratory strain [H 37 Rv]. Parallel sets of media, terium tuberculosis, directly from the sputum. This
containing two-fold dilutions of the drug, are inoculated innovative technique utilizes a liquid medium which
with a standard inoculum prepared from both the facilitates faster growth of the TB bacillus and thereby
unknown and standard strains of tubercle bacilli. aids in the early microscopic visualization of characteri-
Resistance is expressed as the ratio of the MIC of the test stic cord formation. Furthermore, incorporation of drugs
strain to the MIC for the standard strain in the same set. allows rapid and direct drug-susceptibility testing
This test is also greatly affected by the inoculum size as concomitantly with the detection of bacterial growth. In
well as the viability of the strains. In addition, any this method, the sputum specimen is subjected to the
variation in the susceptibility of the standard strain also digestion–decontamination procedure using a mixture
affects the RR of the test strain. of two reagents, N-acetyl-L-cysteine and sodium
hydroxide and is directly inoculated into the selective
Proportion Method 7H9 liquid culture medium in 24-well plates. Following
The proportion method enables a precise estimation of concentration by centrifugation, the characteristic cord
the proportion of mutants resistant to a given drug. [microcolonies] formation is detected by light micro-
Several 10-fold dilutions of inoculum are planted on to scopy. Comparison of growth in drug-containing and
both control [drug-free] and drug-containing media; at drug-free wells, susceptible or resistant strains facilitates
least one dilution should yield isolated countable [50 to identification of antituberculosis drug sensitivity. The
100] colonies. When these numbers are adjusted by inverted light microscope that is required for MODS
multiplying by the dilution of inoculum used, the total assay is expensive and may preclude its wide-spread
number of viable colonies on the control medium, and application in resource limited settings.
the number of mutant colonies resistant to the drug In the study reported by Moore et al (31), of 3760
concentrations tested may be estimated. The proportion sputum samples evaluated, 401 [10.7%] yielded positive
of bacilli resistant to a given drug is then determined by cultures for Mycobacterium tuberculosis. The sensitivity of
expressing the resistant proportion as a percentage of MODS assay was 97.8 per cent compared with 89 per
the total population tested. The proportion method is cent for automated mycobacterial culture, and 84 per cent
currently the method of choice. for L-J culture. The MODS assay yielded the culture
results much faster [median time 7 days] compared with
E Test MBBacT system [bioMérieux] and LJ method which
The technique is based on determination of drug required a median time of 13 and 26 days, respectively.
susceptibility testing using strips containing gradients Similarly, drug susceptibility results were also available
of impregnated antibiotics. The E test strip is placed on earlier with MODS assay [median time 7 days] as
the surface of the solid culture medium and MICs a compared with the median time required for MBBacT
measure of the susceptibility of a strain to an antibiotic system [22 days] and L-J method [68 days].
BIOCHEMICAL AND IMMUNOLOGICAL MARKERS Safety precautions in TB laboratories must involve:

[i] provision of safe building and equipment and their
Adenosine deaminase and Interferon-γγ proper maintenance; [ii] education of all staff about safety
Measurement of adenosine deaminase [ADA] is a precautions; and [iii] continuous supervision to ensure
relatively sensitive and specific test for the diagnosis of that these precautions are strictly observed.
TB pleurisy. A recent meta-analysis (32) indicated The focus on biosafety in the TB laboratory should
sensitivity of 0.92, specificity 0.90, positive likelihood be on primary containment measures, which are aimed
ratio 9.03, negative likelihood ratio 0.10, and diagnostic at protecting laboratory staff and the immediate
odds ratio 110.08. environment. These include: [i] proper training in safe
The measurement of IFN-γ levels in pleural effusions laboratory procedures; [ii] adequate information of
is also likely to be a useful tool for diagnosis of TB essentially hazardous techniques and procedures that
pleurisy. A recent meta-analysis (33) demonstrated the require special care; [iii] availability of adequate safety
results as follows: sensitivity 0.89, specificity 0.97, positive equipment and clothing; [iv] preparedness for prompt
likelihood ratio 23.45, negative likelihood ratio 0.11 and corrective action following a laboratory accident;
diagnostic odds ratio 272.7. Another meta-analysis (34) [v] education about their risk of acquiring TB; and
of ADA and IFN-γ measurements for the diagnosis of [vi] periodic monitoring by the medical personnel.
tuberculous pleurisy found both tests to be accurate. The most expensive and sophisticated equipment is
In peritoneal TB (35), IFN-γ and ADA assays showed no substitute for safe techniques and meticulous care.
equal sensitivity of 0.97 and differed marginally in speci- Good hygiene practices and adherence to safety proce-
ficity of 0.97 and 0.94 respectively. For differentiating dures are the responsibility of every laboratory worker.
TB from non-TB ascites, optimal cut-off points were
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The Tuberculin Skin Test 173
The Tuberculin Skin Test

11
VK Chadha, VK Challu
INTRODUCTION of its use as a diagnostic aid. Experimental confirmation

of this fact came very quickly from animal testing. This
The tuberculin skin test [TST] is mainly used to detect
product was later named as old tuberculin [OT].
infection with tubercle bacilli. The test is based on the fact
Sir Robert Koch injected the OT subcutaneously in large
that infection with Mycobacterium tuberculosis produces
doses, which produced systemic reactions including
sensitivity to certain components [sensitins], which are
fever. The OT was gradually replaced by a low dose,
contained in culture extracts called tuberculins. The TST
intradermal test using a purified protein derivative [PPD]
finds its best use among children for detection of
that was well tolerated.
tuberculosis [TB] infection and as a supportive tool for
Clement Von Pirquet (2) observed in 1907 that a tiny
the diagnosis of TB disease. The TST, however, has a
scratch with a little quantity of tuberculin resulted in a
limited value for the diagnosis of TB disease among adults
local reaction at the test site. Subsequently, several
living in areas where TB is highly endemic. The TST has
modifications were made to improve the tuberculin, its
also been used extensively by the epidemiologists for
mode of administration, reading and interpretation of
assessment of TB situation in the community.
the test. Moro (3) in 1908 announced his patch test, where
The usefulness of the test lies not only on proper
tuberculin was incorporated into an ointment that was
technique of administering a specified dose of a standard
smeared onto the skin, with a piece of gauze over it.
tuberculin and reading of the reactions by trained
Around the same time, Charles Mantoux (4) developed
personnel but also in its careful interpretation. The inter-
the intradermal test to be administered by injection as a
pretation of TST is complicated by cross-sensitivity to
measured volume [Mantoux test]. Subsequently, other
tuberculin induced by infection with environmental
test techniques were developed such as Heaf test (5)
mycobacteria or by bacille Calmette-Guerin [BCG]
which used a simple instrument, that caused six spring-
vaccination.
loaded needles to pierce the skin with a drop of undiluted
OT. Similarly, the Tine test (6) was developed as a
HISTORICAL BACKGROUND
disposable multiple puncture test where the tuberculin
It was Sir Robert Koch who first produced a filtrate was introduced into the skin by puncture with four tines
prepared from heat sterilized concentrated broth cultures coated with dried tuberculin. However, the dose of
of human tubercle bacilli, in the late nineteenth century tuberculin administered through these techniques was
(1). This was initially prepared for treatment of TB but subjected to a lot of variation. Therefore, most of these
soon proved ineffective for this purpose. However, the tests have become obsolete and only the Mantoux
observations of Sir Robert Koch that a subcutaneous technique which allowed quantitative measurement has
inoculation in a patient suffering from TB resulted in a stood the test of time and is now the standard method of
local reaction at the inoculation site laid the foundation administration of the TST.
174 Tuberculosis
THE TUBERCULINS saline, to which a detergent called Tween 80 is added. It

had been observed earlier that the tuberculoprotein,
The OT was a crude product that contained a number of
when diluted in the buffered diluent was adsorbed in
extraneous agents including impurities of the culture
varying amounts to glass and plastic of the vials
media and was observed to cause many false reactions.
containing it. This resulted in variation in the potency of
This prompted many to develop a more suitable
different samples of the same batch (11). Therefore, a
preparation in terms of better specificity of the test and
small amount of Tween 80 was added to the diluent as a
consistency of results. Siebert (7) in 1934 showed that
stabilising agent to prevent the absorption of tuberculin
the active principle in the tuberculin reaction was the
to glass surface. As a result, RT23 with Tween 80 was
protein fraction. She made a preparation from heat
found to increase the potency of the tuberculin dilution
concentrated synthetic medium OT by precipitation with
in terms of reaction size and was observed to be three
trichloroacetic acid. It still contained lipopolysaccharides
times more potent compared to RT23 without Tween 80
and nucleic acids. Later, precipitation was accomplished
(12). The seed-lot of PPD RT23 was maintained in India
with ammonium sulphate to obtain a preparation with
by BCG Vaccine Laboratory, Guindy, Chennai. It is
less nucleic acid and polysaccharide content. It was
reconstituted and supplied as ready to use preparation
termed as purified protein derivative [PPD] of tuberculin.
in isotonic buffer solution as 5 ml vials, 0.1 ml corres-
A large batch of PPD was later produced by Siebert in
ponding to ‘1 TU’.
1941, which was termed as PPD-S. It was also called as
Most countries use PPD RT23 with Tween 80, while
mammalian tuberculin and was adopted as the
few others like USA continue to use PPD-S. Some
international standard of tuberculin by the World Health
pharmaceutical companies have also produced PPD from
Organization [WHO] in 1951 (8). All other tuberculins
different strains of Mycobacterium tuberculosis while
are standardized for biological activity against this
employing varying techniques. In India, many such
preparation. One tuberculin unit [TU] of PPD was
products are available in the market. These products are
defined as the activity contained in 0.02 microgram of
not standardized and their sensitivity and specificity vary
PPD (9); ‘5TU’ was defined as the standard dose of PPD-
substantially.
S. The standard dose of any other tuberculin preparation
The sensitins prepared from species other than
is defined as the dose of that product which elicits
Mycobacterium tuberculosis and Mycobacterium bovis [e.g.,
reactions of size equivalent to 5TU of PPD-S [± 20%].
PPD-B derived from Mycobacterium intracellulare, PPD-
The products labelled, as ‘10TU’, ‘50TU’, etc., do not
G from Mycobacterium scrofulaceum and PPD-A from
necessarily contain that many times the activity.
Mycobacterium avium] are used only in epidemiological
In the following years, two batches of tuberculin were
surveys for studying the prevalence of infection with
prepared by Statens Serum Institute [SSI], Copenhagen
environmental mycobacteria, which are usually non-
and labelled as RT-19-20-21 and RT-22 respectively (9).
pathogenic. These sensitins are not used in clinical
It was later observed that the strength of PPD varied from
practice in India.
batch to batch even when different batches were
prepared using similar technique. This necessitated the
IMMUNOLOGICAL BASIS OF TUBERCULIN TEST
production of a large batch, which would also eliminate
the need for repeated and cumbersome process of Individuals infected with Mycobacterium tuberculosis
standardization. Such a large batch of PPD [dry weight respond with delayed type hypersensitivity [DTH] to the
670 g] was prepared in the year 1952, by SSI at the behest TST. In general, the sensitization is induced by natural
of United Nations Children’s Fund [UNICEF] and WHO mycobacterial infection or by vaccination with BCG, a
(10). This batch would meet the requirements of tuber- live attenuated mycobacterial strain derived from
culin for next several years. It was designated as PPD Mycobacterium bovis. Clinically, it is a manifestation of
RT23. It was supplied in freeze-dried form to laboratories previous infection with tubercle bacilli or a variety of
of the individual countries. The dried powder is stored nontuberculous mycobacteria [NTM] (13). The sequence
in the country laboratories and dilutions are prepared of events following exposure to Mycobacterium tuber-
as per requirements using isotonic phosphate buffer culosis are discussed in detail in the chapters “Pulmonary
tuberculosis” [Chapter 14], “Immunology of tuberculosis” Product and Dosage

[Chapter 7], and “Tuberculosis vaccine development: current
The dose of the standard TST was established as 0.02
status and future expectations” [Chapter 64]. The tuberculin
microgram [1 TU] of PPD RT-23 in 0.1 ml of the diluent
sensitivity tends to persist once acquired.
with Tween 80 (8). However, 2 TU of PPD RT-23 is now
The injection of the tuberculin antigen leads to
recommended as the standard dose. A series of studies
migration and proliferation of the sensitized T-cell
conducted in India demonstrated equal sensitivity for
lymphocytes to the test site. These T-cells release
1 TU and 2 TU in detecting true infection with
cytokines and chemokines, which further attract other
Mycobacterium tuberculosis and no change in the potency
lymphocytes and monocytes. These reactions along with
of 1 TU PPD RT-23 with Tween 80 has been observed in
increased permeability of the local blood capillaries lead
India in about four decades of its use (17).
to an induration at the test site (14).
Storage
SKIN CHANGES IN TUBERCULIN SKIN TEST
Tuberculin vials should always be stored at 2 to 8 °C and
The characteristic features of the reaction include a used before the expiry period. Exposure to sunlight and
delayed course reaching a peak more than 24 hours after heat must be avoided (18). The tuberculin should never
injection and an induration with occasional vesiculation be allowed to freeze or kept at temperatures exceeding
and necrosis (14). Some subjects with heavy exposure to 20 °C, except for short periods. The vials once used may
mycobacterial antigens show an immediate erythema- be re-used within a maximum of 48 hours.
tous reaction, maximal at six to eight hours (15).
However, most subjects show little, if any, immediate
Administration of Test
reaction to the intradermal injection of PPD (14). Such
immediate reactions that begin shortly after injection of A special glass syringe was developed for the purpose
tuberculin and disappear by 24 hours are not to be of the test. The 1 ml syringe was graduated to hundredth
confused with DTH. In fact, more emphasis was placed of a milliliter to facilitate exact measurement of 0.1 ml
on measurement of erythema in the early period of the and it was fitted with a 26-gauge platinum needle of half
use of TST. This was found impracticable in subjects with an inch length and 20 degree bevel. A rubber ring was
dark skin and reliance began to be placed more on the provided at the lower end of the piston to make it
size of induration for interpretation of the TST. absolutely air-tight so as to avoid leakage which may
The DTH reaction peaks at 48 to 96 hours with an occur due to pressure that is required to be exerted on
area of erythmatous induration, which resolves in a the plunger for intradermal injection. If the syringe is
week’s time. The size of this induration is, thus, maximal not air tight, the amount of tuberculin injected will not
between 48 to 96 hours after the test (16). Rarely, a giant be precise. The platinum needles were preferred to steel
reaction may occur in extremely sensitive subjects and needles, which are subject to corrosion and hinder
there may be local vesicle formation or ulceration in a painless injection. Therefore, other syringes which may
minority of subjects. In some, the skin test site may lead to leakage should not be used for the purpose. The
undergo necrosis. Lymphangitis may also be observed disposable plastic tuberculin syringes that are now
in few subjects. available are preferred these days, since it is cumbersome
to use glass syringe which required not only proper
THE STANDARD TUBERCULIN SKIN TEST sterilization but also frequent heating of the needle to
red hot. Many brands of disposable syringes are available
The low dose intradermal TST to be administered as in the market, though not all conform to the requirements
Mantoux test has been adopted as the standard especially with respect to leakage. Therefore, the brand
tuberculin test, after extensive studies on various aspects of disposable tuberculin syringe must be selected with
of tuberculin testing and vast experience gained in all caution.
parts of the world. The standard test employs a single Conventionally, the test is given on the mid-volar
batch tuberculin, i.e., PPD RT-23. aspect of the forearm [Figures 12.1 and 12.2] since this
176 Tuberculosis
area is usually hair free. It is given on the left arm by marked with the ballpoint pen and the maximum
convention, to avoid errors in reading. However, right transverse diameter is measured in ‘millimetres’ [mm]
arm may be used in case of any contraindication to use with a transparent ruler. For marking with the pen, the
the left arm. The skin area chosen should be free of scars, ball-point is drawn towards the induration from a point
veins and areas of inflammation. The test site need not 5 to 10 mm away from the margin of the induration until
be sterilized before injection (6). It can be simply cleaned a resistance is felt. The procedure is repeated on the
with soap and water and should be dried before injection. opposite side. The erythema at the test site due to increa-
The skin is lightly stretched and the needlepoint is sed vascular permeability extends beyond the induration
inserted with its bevel facing upward into the superficial and is not considered for interpretation of the test results.
layers of the skin and 0.1 ml of tuberculin is injected The test result should never be recorded as ‘positive’
slowly. Care should be taken to hold the syringe only by or ‘negative’ and must always be recorded in ‘mm of
the barrel and not to touch the plunger before the size’. Induration up to 40 mm in diameter has been
needlepoint has been satisfactorily inserted into the skin. observed in practice. Record should also be made of
A satisfactory test should raise a flat pale pea-sized vesicles, bullae, lymphangitis, ulceration and necrosis at
wheal with clear pits of hair follicles and a well the test site. Besides, the date of testing, date of reading,
demarcated border and without leakage of tuberculin. If details of previous BCG vaccination should also be
the test is unsatisfactory, i.e., the correct amount has not recorded.
been injected or the injection has been made into the A very high degree of inter-reader variation has been
subcutaneous tissue, then another injection can be given observed in measurement of induration sizes and more
either at a sufficient distance from the first injection or commonly, there is a tendency towards under-reading
on the other forearm. The site chosen for the second test (19). Therefore, the health workers need to be appro-
should be appropriately recorded. The subcutaneous priately trained for performing and reading the TST. Each
injection is dome shaped, less pale and is also difficult to trainee performs about 1500 TSTs and readings over a
read. period of six weeks in the assessment phase. The
measurements of indurations by the trainee reader are
Adverse Effects compared against those of standard reader (20,21). Only
In some atopic individuals, an urticarial wheal may those workers who give less than two per cent unsatis-
factory tests qualify as ‘testers’. Similarly, those who
appear within minutes of injection. It usually disappears
achieve a high correlation [of more than 90%] with the
within a few hours. However, occurrence of such an
allergic reaction does not signify the presence of TB standard reader and a minimal intra-reader variation are
considered eligible for reading of the tests.
infection. Systemic allergic reactions seldom occur. The
formation of vesicles, bullae, lymphangitis, ulceration or
necrosis at the test site, which may occur in a proportion SKIN SENSITIVITY TO TUBERCULIN
of children, indicates a high degree of tuberculin The TST gives rise to a DTH reaction in the form of
sensitivity (14). induration at the test site in a sensitized host. The persons
with sensitivity to tuberculin are called as reactors.
Reading of the Test However, not all reactors are infected with tubercle
The TST result is read between 48 to 96 hours after the bacilli. The sensitivity to tuberculin may occur due to
test in good day light, keeping the forearm flexed, by one or more of the following factors.
carefully palpating the site of injection using one finger.
Infection with Environmental Mycobacteria
The induration may be easily recognized as a firm well
circumscribed density. Sometimes, it may present as a Infection with environmental mycobacteria also leads to
soft ill-defined swelling as the addition of Tween 80 has sensitization of the host. The sensitivity induced by these
been found to result in softer reactions. Thus, small generally non-pathogenic mycobacteria cross-reacts with
indurations may be missed if not sought carefully with a tuberculin and is known as ‘non-specific sensitivity’
light touch. The transverse margins of the induration are [NSS]. This NSS is highly prevalent in most parts of India
as in other tropical countries. In a survey conducted by dose of 0.05 ml of the reconstituted freeze-dried BCG-
National Tuberculosis Institute [NTI], Bengaluru [then vaccine [Danish 1331 strain] during early infancy. In a
called Bangalore], about half and two-thirds of the child- study conducted by NTI, about 70 per cent of the children
ren were found to be infected with environmental with BCG scar in the age group up to nine years elicited
mycobacteria by the ages of 10 and 14 years respectively either no reaction or reaction below 10 mm in size, to
(22,23). During the Tuberculosis Prevention Trial (24) at 1 TU of PPD RT 23 with Tween 80 (33). Even in the
Chingleput, 61 per cent of children were found to be immediate post-vaccination period, i.e., during infancy
infected with environmental mycobacteria by the age of and second year of age, same proportion of children
nine years and almost all were infected by the age of elicited reactions below 10 mm. Similar observations have
19 years (24). Therefore, much of tuberculin sensitivity also been made by other investigators in India and Sri
in the community is due to frequent contact with Lanka (34-36). Many factors including administration of
ubiquitous environmental mycobacteria. The distinction a reduced dose of the vaccine, administration during early
between reactions that represent infection with infancy and difficulty in maintaining the standards in
environmental mycobacteria and TB infection is not the vaccination technique might have been responsible
always very clear. However, in general the sensitivity for results obtained in the NTI study under programme
induced by environmental mycobacteria results in conditions.
smaller reactions to tuberculin than from true infection In another study, comparing the tuberculin reaction
sizes among children with BCG scar compared to those
with Mycobacterium tuberculosis (25).
without BCG scar, a higher proportion of reactions in
Bacille Calmette-Guerin Vaccination the range of 4 to 13 mm was observed among the former
(37). However, the proportion of children with larger
It was observed in European countries, during the early reactions that signify natural infection with tubercle
1950s, that the tuberculin sensitivity among school bacilli was similar in the two groups. That the BCG
children, when vaccinated with BCG resembled that vaccination does not influence the tuberculin sensitivity
induced by natural TB infection (26). It was also observed due to natural infection with tubercle bacilli has also been
to remain stable for a number of years. This led to the observed in other places where BCG is given in infancy
general belief that tuberculin test is of no value among (38-40). Therefore, it may be inferred that the BCG
vaccinated populations, to detect natural infection with induced sensitivity to tuberculin is generally weaker than
tubercle bacilli. However, during the Mass BCG the sensitivity induced by infection with tubercle bacilli.
Vaccination Programme in India, tuberculin reactions It has also been confirmed experimentally that the
due to BCG induced sensitivity were found to be smaller sensitivity to heterologous sensitins is weaker than to
than those due to true infection with Mycobacterium homologous sensitins. Nevertheless, it must be remem-
tuberculosis (27). During the Tuberculosis Prevention Trial bered that the absence or presence of weak sensitivity
at Chingleput (24), post-vaccination tuberculin sensitivity does not imply that vaccination is ineffective. The degree
was found highly satisfactory when full dose [0.1 ml] of of protection conferred by BCG has been found unrelated
BCG was administered under controlled conditions. It to the extent of tuberculin sensitivity induced by it (31).
was observed to peak at 2.5 months after which it began
Infection with Mycobacterium tuberculosis
to wane with time. Similar waning between three months
and six years after vaccination was observed in The specific tuberculin sensitivity induced by infection
other countries (28-30). Thus, BCG induced sensitivity with Mycobacterium tuberculosis is more pronounced
may vary in intensity from very weak to about the same compared to the NSS induced by infection with
level as natural infection, in different population groups. environmental mycobacteria or BCG vaccination, as
It depends not only on the strength of vaccine but also explained above. Therefore, most of the individuals
the way it is handled and administered as well as on the harbouring TB infection usually elicit a larger reaction
age of vaccination and time interval between vaccination to tuberculin. However, in general, the probability that
and tuberculin testing (24,27,29-32). a skin reaction to tuberculin is due to infection with tuber-
Under Universal Immunization Programme [UIP] in cle bacilli rather than due to infection with environmental
India, multipurpose health workers administer a reduced mycobacteria or BCG vaccination increases as the size
178 Tuberculosis
of reaction increases. This probability is also increased reactions. Some of the small reactions may also be due
in the presence of history of contact with a sputum smear- to needle trauma. The peak on the right with the reactions
positive case of TB. Similar is the case as the time since spread around it, i.e., from 15 to 28 mm represents the
BCG vaccination elapses. Nevertheless, it is difficult to reactions due to infection with Mycobacterium tuberculosis.
distinguish the sensitivity induced by Mycobacterium Such a distribution with two modes is called ‘bimodal
tuberculosis and Mycobacterium bovis. In India, infection distribution’. The peak on the left is called as first mode
due to Mycobacterium bovis is rare because of the practice and the peak on the right is called as second mode. The
of boiling milk before consumption. point at which the two subgroups meet is called anti-
mode. The majority of the reactions above the antimode
SEPARATION OF REACTIONS DUE TO signify infection with Mycobacterium tuberculosis and
INFECTION WITH TUBERCLE BACILLI FROM majority of reactions below this are considered due to
REACTIONS DUE TO OTHER CAUSES other causes (43). This has been consistently reported
The tuberculin reaction sizes recorded among apparently from the results of tuberculin reactions among confirmed
healthy individuals during population based surveys cases with sputum smear-positive TB. The distribution
when plotted as frequency histograms have shown that of reactions in such patients has been found symmetrical
there are two main sub groups of individuals in any and lies on the same size scale as the subgroup on the
community, one consisting of those ‘infected with right side of the distribution among apparently healthy
Mycobacterium tuberculosis’ and the rest having no individuals.
tuberculin sensitivity or sensitivity due to other causes. The antimodes as obtained during epidemiological
The frequency distribution of reaction sizes usually surveys have been found to vary between 10 to 15 mm
shows two peaks (24,37,41-55). An example is illustrated in different parts of India. Many a times, it is difficult to
in Figure 11.1. In this figure, the peak on the left with the find a definite cut-off even from tuberculin surveys due
reactions spread around it, i.e., from 0 to 14 mm to some degree of overlapping around the antimode,
represents generally the group of uninfected individuals between the infected group and the rest. The overlap
or individuals with tuberculin sensitivity due to cross- around the antimode increases in areas with high
Figure 11.1: Frequency distribution of tuberculin reaction size among Indian children one to nine years of age [n = 5370]
Data source: National Tuberculosis Institute, Bengaluru, India
prevalence of non-specific tuberculin sensitivity and the a greater proportion of individuals show suppression of
subgroups cannot be clearly discerned. In fact, for any test reactions as the CD4+ counts decline (59). A transient
cut-off point, some true infections will be missed and supression of sensitivity has also been observed in acute
some others falsely included. In general, as the cut-off viral infections as well as after vaccination with live virus
point moves to the left, there is an increase in sensitivity vaccines. The DTH may be impaired among persons
of the test at the expense of specificity and vice versa. receiving corticosteroids and other immunosuppressive
Practically, it is not feasible to conduct tuberculin surveys agents (60).
all over the country to find suitable cut-off points in The false-negative reactions may also be observed
respective areas. In clinical practice, it is best to consider among infants below three months of age, due to
other circumstances also to decide on the significance of immature immune system (58). Similarly, false-negative
the reactions, such as history of contact, presence of reaction may be observed during the window period,
symptoms, among others. since the sensitivity to tuberculin is evident only after
four to eight weeks of infection with Mycobacterium
FALSE-POSITIVE AND FALSE-NEGATIVE tuberculosis. The tuberculin reactivity also tends to wane
REACTIONS with time in some individuals (61). However, the
reactivity may be recalled by repeat infection or even by
The false-positive reactions may be observed as seen
repeat tuberculin testing. The tuberculin sensitivity is
above due to tuberculin sensitivity induced by infection
also suppressed in old age, due to generalized
with environmental mycobacteria or BCG vaccination.
suppression of cellular immunity (62).
However, the errors can be minimized with careful
Sometimes, a non-significant reaction may be due to
interpretation. False-positive reactions may also occur
a general inability to respond [anergy]. If such a possi-
due to testing with high dose of tuberculin and repeat
bility is suspected, then it may be desirable to test for
testing, and due to reading errors by untrained and
DTH to some other antigens to which the individual is
inexperienced readers.
likely to have been exposed, e.g., candida, tetanus toxoid.
It is also important to recognize that a non-significant
A failure to respond to any of such antigens suggests a
reaction does not always exclude the presence of TB
non-functioning immune system which may be respon-
infection or disease. The most common reason of a false-
sible for a false non-significant reaction to tuberculin.
negative result is the poor technique of administering or
reading the test, besides improper storage of tuberculin.
INTERPRETATION OF TUBERCULIN TEST
The tuberculin reaction may be suppressed in the
presence of immunosuppresion. The size of induration The interpretation of the test is influenced not only by
has been observed to be diminished among children who the size of induration but also by the purpose of the test
are suffering from TB disease, especially those suffering as well as the consequences of false classification. Based
from disseminated TB (56,57). The sensitivity of the test on the descriptions given in the previous sections and
among bacteriologically confirmed cases of pulmonary the experience gained during various tuberculin studies
TB has been found to be around 80 per cent and the in India, the following general guidelines [Table 11.1]
remaining about 20 per cent of the cases do not manifest may be followed while interpreting tuberculin test
a significant reaction (52,53,55,58). This is because a few results. Not all reactions to tuberculin are attributable to
sensitized circulating T-cells are available to participate infection with Mycobacterium tuberculosis. Larger the size
in the reaction, since most of these may be collected in of induration at the test site, higher is the probability of
the TB lesions. The mean reaction size of TST has also presence of infection with Mycobacterium tuberculosis.
been found to decrease with increasing grade of This is supported by the observation that TB morbidity
undernutrition (48). Tuberculin induration size may increased with the size of induration (63). Almost all
similarly be diminished in the presence of a co-existing reactions with induration of 15 mm or more in size may
immunosuppressive disorder, such as malignancy, be considered attributable to infection with tubercle
Hodgkin’s disease and sarcoidosis. During human bacilli, irrespective of the presence or absence of BCG
immunodeficiency virus [HIV] infection, though scar. The formation of vesicles, bullae or necrosis at the
tuberculin sensitivity is not affected at the initial stages, test site indicates high degree of tuberculin sensitivity,
180 Tuberculosis
Table 11.1: Interpretation of the tuberculin test positive case of pulmonary TB or presence of symptoms
or clinical findings suggestive of TB. The probability of a
Size of induration 15 mm and above
Signifies infection with tubercle bacilli, irrespective of BCG reaction in this range attributable to infection with
vaccination status tubercle bacilli is relatively higher among children
Size of induration 10 to 14 mm without BCG scar compared to those with scar. However,
Could be attributable to one or more of the following: higher the age of the child, lesser the probability of the
Cross-sensitivity induced by environmental mycobacteria reaction attributable to BCG.
BCG induced sensitivity
As noted above, the tuberculin reaction may be
Infection with Mycobacterium tuberculosis
Size of induration 5 to 9 mm suppressed in the presence of certain conditions. This
Majority of such reactions are attributable to cross-sensitivity does not mean that the test should not be carried out in
induced by environmental mycobacteria and/or BCG the presence of those conditions. The size of induration
vaccination depends upon the degree of immunosuppression and
Could be attributable to infection with tubercle bacilli in the
the level of immunodeficiency should be considered
presence of immunosuppresive conditions
Size of induration less than 5 mm while interpreting tuberculin reactions. Also, there
Indicates absence of any type of mycobacterial infection should be a minimum time gap of eight weeks between
except in individuals with severe degree of immunosup- exposure and performing TST, since infection with
pression tubercle bacilli may be missed if the test is carried out
BCG = bacille Calmette-Guerin during the ‘window period’.
The interpretation of TST also depends on the purpose
and thus, presence of infection with Mycobacterium of the test. In case the test is used for screening apparently
tuberculosis (13). The reactions with induration of less than healthy children for subjecting to further investigations
5 mm size usually indicate lack of tuberculin sensitivity, for diagnosis of TB, it is more desirable to have a higher
and thus, absence of infection. Simple trauma of the sensitivity by deciding on a lower cut-off point at 10 mm,
needle has been observed to give rise to induration so that most of those excluded are not infected. For a
usually in the range of 1 to 4 mm NTI, Bengaluru, decision on preventive chemotherapy, it is desirable to
unpublished data]. However, some individuals infected have a higher cut-off point of 15 mm, to be more specific
with Mycobacterium tuberculosis but suffering from severe so that most of those put on chemoprophylaxis are
degree of immunosuppression may show induration in definitely infected. Though chemoprophylaxis is not
this range. Among children without a BCG scar, the routinely recommended in India, it may be considered in
majority of reactions with indurations in the range of 5 special situations, e.g., HIV positive contact of a case with
to 9 mm are attributable to cross-sensitivity to environ- TB. Under the Revised National Tuberculosis Control
mental mycobacteria. Some of these children might Programme [RNTCP], of the Government of India, every
actually have been vaccinated with BCG but do not show asymptomatic child under the age of six years in contact
the BCG scar (64,65). Thus, in a proportion of children with smear-positive case is started on preventive
without BCG scar, the indurations in this range may be chemotherapy (66). This is because the tuberculin test may
attributable to BCG vaccination. Among children with not be available at every place and there is high risk of
BCG scar, the reactions with indurations in this range such children acquiring TB infection. It is also well known
may be attributable to BCG vaccination and/or infection that the risk of developing active TB disease is maximum
with environmental mycobacteria. in the period immediately following acquisition of
The reactions in 10 to 14 mm range require most infection especially among children (67).
careful interpretation as these could be attributable to
Interpretation of Tuberculin Skin Test Among
infection with tubercle bacilli or due to cross sensitivity
Human Immunodeficiency Virus Infected Persons
to environmental mycobacteria and/or BCG-induced
sensitivity. An induration in this size range is more likely All HIV-seropositive individuals should be assessed for
to be attributable to infection with tubercle bacilli among the presence of active TB. Once active TB is excluded,
high-risk contacts e.g., infants of mothers suffering from TST should be performed as soon as possible since the
TB, individuals with history of contact with smear- reliability of the test can diminish as the CD4+ T-
lymphocyte count declines, especially to less than was not observed when the test was repeated after 18
200/mm3 (59). A good proportion of the HIV-infected months (77). However, the time of disappearance of
persons may even be anergic. Studies indicate that the boosting effect could not be ascertained. In another study,
probability of a significant induration to the tuberculin boosting was observed within three weeks of the first
test indicative of TB infection is significantly lower test (78). Therefore, previous history of the individual
among HIV-infected persons compared to HIV- taking the test should always be ascertained while
uninfected (68). Therefore, some countries advise a lower interpreting the test result.
cut-off point for diagnosing latent TB infection (69,70). Repeating the test with a higher dosage may result
However, it remains to be proved that a lower cut-off in larger reactions which are actually attributable to non-
point will increase the sensitivity of the test. Nevertheless, specific sensitivity or BCG induced sensitivity (22,23).
irrespective of the test results, patients with evidence of Therefore, a repeat test with a higher dose is of no value
old healed TB on chest radiograph or with a past history for detection of infection with tubercle bacilli.
of active TB and also those with a previously documented
history of a positive TST result may be considered as
DETECTION OF NEWLY INFECTED PERSONS
infected for all practical purposes. Similarly, those with
a history of recent exposure to a sputum positive case The TST does not distinguish between past and new
may be considered as infected. infection. As stated above, the incidence of disease among
The TST only detects the presence or absence of TB recently infected is much higher compared to the
infection. The presence of infection is not synonymous incidence among previously infected, especially in the
with disease. Thus, TST should never be the sole criteria paediatric age group (49). Therefore, detection of newly
for diagnosing TB. infected individuals may be important in some situations,
e.g., among children who showed a reaction of less than
REVERSION, BOOSTER PHENOMENON AND 10 mm at an earlier test but have been exposed to a smear-
CONVERSION positive case thereafter. For detection of such new infec-
In elderly subjects and many adults, the percentage of tion occurring in the intervening period between the two
significant reactors to tuberculin declines with age. Loss tests, there should be a significant increase in reaction
of tuberculin reactivity over time has been termed skin size. Studies conducted by the NTI (79,80) have shown
test reversion and is estimated to occur at a rate of five per an increase of 14 mm and above among those infected
cent per year in a healthy population (61,71). This is during the intervening period when two tests were
attributed to a specific waning of cell-mediated immunity conducted one-and-half to three years apart. In clinical
for tuberculin antigen rather than to a generalized anergy practice, it would be more useful to consider an increase
or a diminished cutaneous reactivity of the elderly patients of 10 mm between the two tests as indicative of new
(72,73). Loss of lymphocyte blastogenic capacity has been infection. There should be a minimum period of eight
shown to be responsible for skin test reversion (74). weeks between exposure and the second test. This applies
It is usually unnecessary to repeat the TST unless the to BCG vaccinated as well as unvaccinated children.
test injection or reading was performed unsatisfactorily. It needs to be emphasized that a simple ‘tuberculin
The repeat test should be given at a different site within conversion’ from a non-significant reaction at first test
one week of the first test (75). This is because the small to a significant reaction at a subsequent test does not
amount of tuberculin injected for the first test can boost necessarily signify new infection. Such ‘conversion’ may
the size of the second test though it per-se does not be attributable to a number of factors besides true fresh
sensitize the individual. This boosting results from ‘recall’ infection, e.g., boosting of tuberculin sensitivity on
of sensitivity induced by infection with environmental account of previous test and infection with environ-
mycobacteria or BCG vaccination, that had waned by mental mycobacteria in the intervening period. The risk
the time of first test. In a study conducted by NTI (76), of developing TB has been found to be highest among
the boosting effect was observed when the test was those who have a larger increase in reaction size between
repeated after two months. The boosting phenomenon tests conducted at a reasonable time interval (81).
182 Tuberculosis
HEALTH CARE WORKERS AND TUBERCULIN TEST Tuberculin Skin Test, Tuberculosis and Sarcoidosis
The reader is referred to the chapter “Tuberculosis in health Patients with sarcoidosis frequently manifest tuberculin
care workers” [Chapter 45] for more details. anergy (89). In areas where TB is highly endemic this
may not always be true. In a study from India (90), it
BACILLE CALMETTE GUERIN TEST was reported that the TST in patients with sarcoidosis
has a high specificity but a poor sensitivity for TB. The
Some medical practitioners use BCG vaccination for authors also suggest that while a negative TST in the
detection of TB infection by assessment of local reactions. general population is a sensitive test for sarcoidosis, a
However, the interpretation of BCG test has not been positive TST among sarcoidosis patients is a specific test
standardized since the number of injected viable and for indicating TB. A positive TST in a patient suspected
dead organisms is highly variable. Moreover, the vaccine to suffer from sarcoidosis should, therefore, be an
has not been prepared for eliciting tuberculin sensitivity. absolute indication for a thorough work-up for TB.
Therefore, BCG test is not recommended to be used for
detecting TB infection. NEWER TUBERCULINS
Though more specific than old tuberculin, PPD is not a
EPIDEMIOLOGICAL USES OF TUBERCULIN TEST fully species-specific antigen and results in wide cross-
The TST has been put to maximum use by epidemiolo- reactivity to sensitivity induced by environmental
gists to study the epidemiological situation of TB in the mycobacteria and BCG vaccination. Further attempts are
community. The tuberculin surveys are often conducted thus being made by various scientists to develop newer
in a representative sample of children without BCG scar tuberculins, which are more species-specific. One of the
and based on the frequency distribution of tuberculin improvizations that has been made is to avoid heating
reaction size, the prevalence of infection in the study since heat can denature protein content of the PPD.
group is estimated. Prevalence represents a cumulative Recent developments in the manufacture of purer tuber-
effect of the infection acquired by the study group in all culins include use of methods, such as electrophoresis
their years of exposure. The average annual risk of infec- and chromatography. The experimental assays with
tion [ARI] is mathematically derived from the estimated some of these products designated by different codes,
prevalence using appropriate statistical formula (82,83). e.g., T-1327 and T-1456 are under progress and none has
The ARI is defined as the average probability of yet been produced on a large scale (81-83).
acquiring new TB infection over the course of one year.
It expresses the overall impact of the prevalence of infec- THE FUTURE
tious cases in the community as well as the efficiency of For nearly a century, the TST was the only method of
TB control activities. Any change in the epidemiological detecting TB infection. The new millennium has witnes-
situation of TB is first reflected in a change in ARI rates. sed introduction of the newer diagnostic methods for TB
The tuberculin surveys to estimate ARI are also relatively such as interferon-γ release assays [IGRAs]. The initial
simpler to conduct compared to disease surveys. These experience with the IGRAs indicates that they are
are generally carried out among young children since proving to be more reliable than the TST in detecting TB
the results obtained reflect relatively recent situation. The infection (91,92). The reader is referred to the chapter
trends in ARI obtained by repeating tuberculin surveys “Diagnosis of latent tuberculosis infection: recent advances
at an interval are also used to study the impact of TB and future directions” [Chapter 12] for more details.
control activities (84-88). The epidemiological studies
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186 Tuberculosis
Diagnosis of Latent Tuberculosis

Infection: Recent Advances and
Future Directions 12
Madhukar Pai, Rajnish Joshi, Shriprakash Kalantri
INTRODUCTION drugs (8), mainly through non-profit agencies and public-

private partnerships. The new Global Plan to Stop TB,
Approximately one-third of the world’s population is
2006-2015 (9), released in early 2006 places a great deal
estimated to be infected with Mycobacterium tuberculosis
of emphasis on the development of new tools for TB
(1,2). This enormous pool of individuals with latent
control. In this chapter the advances and emerging
tuberculosis infection [LTBI] poses a hurdle for global
technologies in the diagnosis of LTBI are described (4,10-
tuberculosis [TB] control, because it is from this vast reser-
15). The focus is primarily on a novel group of T-cell
voir that new TB cases will emerge in future. Between eight
based cytokine assays that have shown promise in several
and nine million people develop TB disease each year,
clinical studies.
and about two million die from TB every year (1,2). Despite
this tremendous global burden, case detection rates
CURRENT APPROACH TO DIAGNOSIS OF
continue to be low (2). Conventional TB diagnostic
TUBERCULOSIS INFECTION: THE TUBERCULIN
approaches utilize tests such as sputum smear microscopy,
SKIN TEST
sputum culture, chest radiographs, and tuberculin skin
test [TST] also known as Mantoux test. These tools have Infection with Mycobacterium tuberculosis, in most
been in use, almost unchanged, for almost a century. individuals, is contained by the host immune defenses,
Because of the limitations of these tests, particularly in and the infection remains latent. This state is called
areas affected by the human immunodeficiency virus “LTBI”. In LTBI, the Mycobacterium tuberculosis bacilli that
[HIV] epidemic, there is an urgent need for more rapid, persist in asymptomatic individuals can reactivate and
accurate and convenient diagnostic tests (3-5). cause active disease in about five to ten per cent of those
After a prolonged period of neglect, there has been a infected over a lifetime (16). Because of the risk of
recent resurgence of interest in developing new tools for progression from latent infection to active disease,
TB control. The active involvement of agencies such as targeted testing and treatment for LTBI is a key compo-
the Stop TB Working Group on New Diagnostics [one of nent of TB control in many low incidence, high-income
the Working Groups of the International Stop TB Partner- countries (17). For example, countries such as the United
ship], the Foundation for Innovative New Diagnostics States actively screen and treat selected high risk groups
[FIND], a non-profit agency dedicated to developing new [e.g., close contacts] for LTBI (18). In contrast, LTBI testing
diagnostics for neglected diseases, and the TB Diagnostics and treatment is not routinely done in high incidence,
Initiative of the Special Programme for Research and resource limited countries, such as India.
Training in Tropical Diseases [TDR], World Health Until recently, the only diagnostic test available to
Organization [WHO], have led to renewed interest in detect LTBI was the TST. First introduced in 1890, the
the development of new tools for TB diagnosis (6). Similar TST is probably the oldest diagnostic test in clinical use
efforts are ongoing to develop new TB vaccines (7) and (19). Figures 12.1 and 12.2 show the Mantoux technique
Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 187
Figure 12.1: Administration of the tuberculin skin test Figure 12.2: Reading of the tuberculin skin test
TU = tuberculin units TU = tuberculin units
Source: US Centers for Disease Control and Prevention, Atlanta, Source: US Centers for Disease Control and Prevention, Atlanta,
GA (www.cdc.gov) GA (www.cdc.gov)
used to administer and read TST. The TST detects cell- in individuals with depressed immunity, e.g., HIV
mediated immunity [CMI] in the form of a delayed-type infection and other immunosuppressive conditions, e.g.,
hypersensitivity [DTH] response to the purified protein due to medications such as corticosteroids and tumour
derivative [PPD]. The PPD is a crude cocktail of several necrosis factor-α [TNF-α] blockers, advanced TB, cancer
antigens, many of which are shared among Mycobac- and malnutrition (20-22). Table 12.1 shows the
terium tuberculosis, Mycobacterium bovis bacille Calmette- common causes of false-positive and false-negative TST
Guérin [BCG], and several nontuberculous mycobacteria results.
[NTM]. As a result, the TST has lower specificity in In addition to known limitations with accuracy, the
populations with high BCG coverage and NTM exposure administration and reading of TST also poses problems—
(20-22). The sensitivity of TST may be low due to anergy inter- and intra-reader variability [i.e., reproducibility]
188 Tuberculosis
Table 12.1: False-positive and false-negative tuberculin skin test results
TST result Possible reasons for such a result Individuals who are likely to have such a result
False-positive BCG vaccination Individuals who received BCG vaccination in the past, especially if
they were vaccinated after infancy, or if they received repeated BCG
vaccinations
NTM Individuals who were exposed to NTM or had infection or disease with
NTM species [e.g., Mycobacterium avium]
False-negative Anergy HIV infection, certain viral infections [e.g., measles], live virus
vaccinations, immunosuppressive medications, such as steroids,
patients on cancer chemotherapy, malnutrition, elderly, renal failure,
severe TB disease, lymphoma or leukaemia
Recent TB infection Individuals who were recently infected [within the past 10-12 weeks]
Very young age Children younger than 6 months
Technical reasons Inadequate dose of PPD or poor quality PPD, poor Mantoux technique,
early or late reading
BCG = bacille Calmette-Guérin; NTM = nontuberculous mycobacteria; TB = tuberculosis; PPD = purified protein derivative; HIV =
human immunodeficiency virus
is a concern, trained personnel are required for adminis- emergence of the field of comparative genomics. In
tration and reading, and patients have to be seen a second addition, the advent of proteomics has greatly enhanced
time for the purpose of reading the results (22). In some our ability to identify and clone highly specific proteins.
settings [e.g., homeless individuals and intravenous drug Because of such advances in molecular biology and
users], patients often do not come back for the reading genomics, for the first time, an alternative to the TST has
of the skin test. Also, when TST is repeated [e.g., annual emerged in the form of a new class of in vitro assays that
testing of health care workers], boosting, conversions, measure interferon-γ [IFN-γ] released by sensitized T-
and reversions can occur, and, these can complicate the lymphocytes after stimulation with Mycobacterium
interpretation of serial skin testing (20). Despite these tuberculosis antigens (25-29). These assays are now called
limitations, the TST is still widely used because of its IFN-γ release assays [IGRAs]. Interferon-γ is a cytokine,
ability to predict active disease in latently infected and a classic marker of Th-1 type cellular immune
individuals, and the fact that trials have shown that response. The biological rationale for T-cell based IGRAs
treatment of LTBI with isoniazid for six to nine months, is shown in Figure 12.3 (30). T-cell based IGRAs for LTBI
diagnosed on the basis of TST results, reduces the risk of actually belong to a larger family of cytokine-based
active disease by about 60 per cent (17,23,24). This strong assays that can be used to detect cellular immune
experimental evidence has resulted in targeted skin response to a variety of antigens [Figure 12.4]. As shown
testing and LTBI treatment programmes in developed in Figure 12.4, several factors including host, microbial
countries (17). A major advantage of the TST is its low exposure and disease, can impact the results of these
material cost, and the fact that it does not require any cytokine assays. In contrast to the TST, cytokine-based
laboratory infrastructure. This is a key consideration for assays probably detect only some components of the
developing countries such as India. cellular immune response. For example, IGRAs detect
only one cytokine [IFN-γ], while the TST probably detects
INTERFERON-GAMMA RELEASE ASSAYS: a more complex immune response involving more than
BIOLOGY AND DEVELOPMENT one type of cytokine.
Early versions of IGRAs used PPD as the stimulating
The successful sequencing of Mycobacterium tuberculosis antigen, but these tests have been replaced by newer
and Mycobacterium bovis genomes, and the development versions that use antigens that are more specific to
of genomic tools such as deoxyribonucleic acid [DNA] Mycobacterium tuberculosis than PPD. These antigens
microarrays and genome-wide scans, has led to the include early secreted antigenic target 6 [ESAT-6], culture
Figure 12.3: Biological rationale for T-cell based assays for tuberculosis infection
TNF-α = tumour necrosis-α; IFN-γ = interferon-γ; IL = interleukin
Reproduced with permission from “Andersen P, Munk ME, Pollock JM, Doherty TM. Specific immune-based diagnosis of tuberculosis.
Lancet 2000;356:1099-104 (reference 30)”
Figure 12.4: Factors that can affect T-cell based assays of cellular immunity
TNF-α = tumour necrosis factor-α; IFN-γ = interferon-γ; IL = interleukin; TB = tuberculosis; PBMC = peripheral blood mononuclear cells;
PPD = purified protein derivative; ELISA = enzyme linked immunosorbent assay; ELISPOT = enzyme linked immunospot; PCR = polymerase
chain reaction; RD = region of difference; ESAT = early secreted antigenic target; CFP = culture filtrate protein; BCG = bacille Calmette-
Guerin
190 Tuberculosis
Figure 12.5: Overview of the QuantiFERON-TB Gold® In Tube assay technology

IFN-γ = interferon-γ
Reproduced with permission from Cellestis Limited, Carnegie, Australia (www.cellestis.com)
filtrate protein 10 [CFP-10], and TB7.7 [Rv2654]. The Immunotec, Oxford, UK]. The QFT-G assay is available
ESAT-6 and CFP-10 are encoded by genes located within in two formats, a 24-well culture plate format [approved
the region of difference 1 [RD1] segment of the by the US Food and Drug Administration [FDA] (32)],
Mycobacterium tuberculosis genome; they are more specific and a newer, simplified In Tube format also FDA approved
than PPD because they are not shared with any of the and now the most widely used format (29). Figure 12.5
BCG vaccine strains or certain species of NTM, e.g., shows the QFT-G In Tube assay format. The T-SPOT.TB
Mycobacterium avium (30,31). This is because the RD1 test [Figure 12.6] is currently CE marked for use in Europe,
region is deleted in all BCG vaccine sub-strains and in and is likely to receive FDA approval in future. In India,
several species of NTM (31). Thus, the use of such specific the QFT-G In Tube assay kit is available, although mostly
antigens in an ex vivo assay format is a key feature of used in research settings (33-35).
IGRAs. As seen in Figure 12.7 (29), the two commer-
cially available IGRA kits differ in many aspects. The
COMMERCIALLY AVAILABLE INTERFERON- T-SPOT. TB assay requires purified peripheral blood
GAMMA RELEASE ASSAYS TESTS AND THEIR mononuclear cells [PBMC], and uses a sensitive enzyme-
LABORATORY CHARACTERISTICS linked immunospot [ELISPOT] technology to detect
Within a short span of less than 10 years, two IGRAs have IFN-γ producing T-cells [as “spot-forming cells”]. In
been developed into commercial kits: the QuantiFERON®- contrast, the QFT-G assay requires whole blood, and uses
TB Gold® [QFT-G] [Cellestis Ltd, Carnegie, Victoria, the enzyme-linked immunosorbent assay [ELISA]
Australia] assay, and the T-SPOT.TB® test [Oxford technology to detect the amount of IFN-γ released into
Figure 12.6: Overview of the T SPOT-TB® assay technology

TB = tuberculosis
Reproduced with permission from Oxford Immunotec, Oxon, UK (www.oxfordimmunotec.com)
the supernatant [measured as international units measures of exposure to Mycobacterium tuberculosis in low
per mL]. In general, the ELISPOT technology is more incidence settings, and less cross-reactivity due to BCG
complicated and involves more steps, including separa- vaccination than the TST. The IGRAs that use at least
tion and counting of PBMCs. The ELISPOT-based test two RD1 antigens [e.g., ESAT-6 and CFP-10] appear to
also costs more than the ELISA-based test. However, be at least as sensitive as the PPD-based TST for active
there is some evidence that the ELISPOT-based test is TB. In the absence of a gold standard for LTBI, active TB
less prone to indeterminate results [due to lack of is used as a surrogate for LTBI. Figure 12.8 (14) shows
response to mitogen control] than the ELISA-based whole forest plots of sensitivity and specificity [for active
blood assay (36). Indeterminate QFT-G results have been disease] from studies that used the research or
reported in groups such as HIV-infected individuals (37), commercial versions of the QFT-G and T-SPOT.TB assays
individuals with other immunocompromising conditions (41-53). Overall, the plot shows high specificity [> 95%]
(38), and in children (39). It is possible that the whole- in most of the studies. Sensitivity, on the other hand, is
blood assay is more affected by conditions that result in lower and variable [70%-97%]. Figure 12.8 also suggests
decreased T-cell counts. that the QFT-G assay may be slightly more specific but
less sensitive than the ELISPOT assay. Recently published
WHAT IS KNOWN ABOUT INTERFERON-GAMMA head to head comparisons of these two commercial
RELEASE ASSAYS TEST PERFORMANCE? assays lend support to this observation (36,52).
Several studies have been published on IGRAs, including Given the lack of a gold standard for latent infection,
some from India. The available research evidence on the sensitivity and specificity of IGRAs for LTBI cannot
IGRAs [Table 12.2], reviewed extensively elsewhere be directly estimated, and there is some concern that
(10,14,25-29,32,40), suggests that IGRAs have higher sensitivity for LTBI might be less than that of the TST,
specificity than TST, better correlation with surrogate especially in high-risk populations (32). Besides high
192 Tuberculosis
to be useful in low-endemic, high income settings [i.e.,

countries that usually implement targeted LTBI screening
and treatment programmes] where cross-reactivity due
to BCG adversely impacts the utility of TST.
CURRENT INTERNATIONAL
RECOMMENDATIONS AND GUIDELINES
The US Centers for Disease Control and Prevention [CDC]
published its guidelines on the QFT-G assay in December
2005 (32). The CDC recommended that QFT-G may be
used in all circumstances in which the TST is currently
used, including contact investigations, evaluation of
immigrants, and serial testing of health care workers (32).
The guidelines suggest that QFT-G can be used in place
of [and not in addition to] the TST (32). In 2005, the CDC
also published its updated guidelines for preventing the
nosocomial transmission of TB in health care settings (54).
These guidelines suggest that QFT-G can be used in place
of the TST for infection control surveillance, and
conversion [i.e., new infection] has been defined as change
from a negative to a positive result (54).
The UK National Institute for Health and Clinical
Excellence [NICE] TB guidelines were published in 2006
(55). These guidelines recommend a two-step [hybrid]
strategy for LTBI diagnosis: initial screen with TST, and
those who are positive [or in whom TST may be unreli-
able] should then be considered for IGRA testing, if
available, to confirm positive TST results (55).
Overall, these currently available recommendations
should be viewed as interim guidelines that will require
updates as new evidence rapidly accumulates on the
accuracy and role of IGRAs. For example, there are no
published studies that have used the hybrid strategy
Figure 12.7: Comparison of the two commercially available
recommended by NICE (55). This approach, although
interferon-gamma assays
ELISA = enzyme linked immunosorbent assay; ELISPOT = enzyme reasonable, is yet to be validated in clinical practice. Also,
linked immunospot; PBMC = peripheral blood mononuclear cells; there is limited evidence on the use IGRAs in serial
ESAT = early secreted antigen; CFP = culture filtrate protein testing of health care workers. The current CDC recom-
Reproduced with permission from “Rothel JS, Andersen P. mendation (54) on the use of the diagnostic threshold
Diagnosis of latent Mycobacterium tuberculosis infection: is the for conversion does not take into account the possibility
demise of the Mantoux test imminent? Expert Rev Anti Infect Ther
2005;3:981-93 (reference 29)”
of misclassifying non-specific IFN-γ changes as true
conversions (35).
specificity, other potential advantages of IGRAs include
AREAS OF CONTROVERSY AND
logistical convenience, avoidance of poorly reproducible
DIRECTIONS FOR FUTURE RESEARCH
measurements such as skin induration, need for fewer
patient visits, and the ability to perform repeated [serial] The body of literature supporting the use of IGRAs has
testing without inducing the boosting phenomenon. exploded (25-29,32,40). However, several unresolved and
Overall, because of its high specificity, IGRAs are proving controversial issues still remain. Several ongoing and
Table 12.2: Comparison of tuberculin skin test and interferon-gamma release assays
Performance and operational characteristics TST IGRA
Estimated sensitivity in patients with active TB 75%-90% lower in immunocompromised 75%-95% [inadequate data in
populations immunocompromised populations;
but appears promising]
Estimated specificity in healthy individuals 70%-95% lower in BCG-vaccinated, 90%-100% [maintained in BCG
with no known TB disease or exposure especially if BCG is given after infancy vaccinated]
Cross-reactivity with BCG Yes Less likely
Cross-reactivity with NTM Yes Less likely, but limited evidence
Association between test-positivity and Moderate to strong positive association Insufficient evidence
subsequent risk of active TB during follow-up
Correlation with Mycobacterium Yes Yes [correlated better with exposure
tuberculosis exposure than TST in some, but not all, head-
to-head comparisons]
Benefits of treating test-positives based Yes No evidence
on randomized controlled trials
Reliability and reproducibility Moderate and variable Limited evidence but appears high;
no evidence on within subject
variability during serial testing
Boosting phenomenon Yes No
Potential for conversions and reversions Yes Insufficient evidence
Adverse reactions Rare Rare
Material costs Low Moderate to high
Patient visits Two One
Laboratory infrastructure required No Yes
Time to obtain a result 2 to 3 days 1 to 2 days, but longer if run as
batches
Trained personnel required Yes Yes
TST = tuberculin skin test; IGRA = interferon-gamma release assay; TB = tuberculosis; BCG = bacille Calmette-Guérin; NTM =
nontuberculous mycobacteria
Adapted with permission from “Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part
1. Latent tuberculosis. Expert Rev Mol Diagn 2006;6:413-22 (reference 14)”
new studies should help to clarify the role of these assays with large TST reactions [> 15 mm, and, therefore, high
in various settings, and resolve some of the controversies. likelihood of infection], about one-third were negative
One area of considerable confusion is discordance by the QFT-G In Tube assay (58). In a study (34) from
between TST and IGRA and their interpretation. Several Sevagram, India, 11 per cent of individuals with TST
studies have shown discordance between TST and IGRA >15 mm were negative by the QFT-G In Tube assay. While
results; discordance estimates have ranged between 10 such discordance could be due to false-positive TST, it
to 40 per cent in most studies. While some discordance, plausible that IGRAs are less sensitive than TST in
especially the type where TST is positive but IGRA is detecting LTBI, or IGRAs may detect only a subset of all
negative, was probably due to prior BCG vaccination in those with LTBI [i.e., those with recent, persistent
certain studies (43,56,57), other studies found no clear infection versus remote infection which has been cleared
explanations for discordance (34,58). Research is needed spontaneously or after treatment].
to determine the biological basis for discordance, Discordance of the reverse type [i.e., TST negative
especially when discordance is extreme. For example, a but IGRA positive] has also been documented (34,59-61);
recent study from South Africa found that among those they are largely unexplained. Future studies, therefore,
194 Tuberculosis
Figure 12.8: Forest plots of sensitivity and specificity from studies that used research or commercial versions of the QuantiFERON-TB
Gold and T-SPOT.TB assays with RD1 antigens
*Not all studies reported data on specificity
Point estimates of sensitivity and specificity from each study are shown as solid circles. Error bars are 95% confidence intervals [CI]
QFT-G = QuantiFERON-TB Gold; ELISPOT = enzyme linked immunospot [T-SPOT.TB]
Adapted with permission from “Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part
1. Latent tuberculosis. Expert Rev Mol Diagn 2006;6:413-22 (reference 14)”
should perform thorough analyses of correlates of high incidence settings (34,59,65). The basis for this
discordance, including a description of discordance due phenomenon is unclear. Variations in BCG vaccination
to variability of TST and IFN-γ values around their practices might be a relevant factor. Also, in high incidence
thresholds [cut-points]. It is important to acknowledge settings, it is possible that IGRAs detect recent [effector]
that both TST and IGRAs results are continuous measures, as well as remote [memory] T-cell responses. Further, in
and, therefore, thresholds are needed to interpret them as such settings, there are several factors that might modu-
dichotomous [positive or negative] outcomes. At least late immune responses, such as malnutrition, BCG
some of the observed discordance could be due to minor vaccination, NTM exposure, leprosy, helminthic, and
variations around the TST and IFN-γ thresholds, as tropical infections that impact the Th1/Th2 immune
shown in a large study from India (62). balance. These issues underscore the importance of studies
The association between surrogate markers for TB from high incidence countries (34,46,48,49,59).
exposure and IGRA results appears to be stronger and There are few studies on the performance of IGRAs
better defined in low TB incidence (56,57,60,61,63,64) than in vulnerable subgroups including immunocompro-
mized individuals [e.g., HIV/AIDS, and those on immu- Another area of controversy is the kinetics of T-cell
nosuppressive medications such as TNF-α blockers], responses during and after treatment for latent and active
patients with extra-pulmonary TB, contacts, children, and TB. As reviewed elsewhere (25,26), some studies have
health care workers. At present, it is difficult to make shown declining responses after treatment, whereas
strong clinical recommendations in these high risk others have shown unchanging, fluctuating, or increasing
groups. responses during treatment. Therefore, it is not clear if
In immunocompromized individuals, IGRAs might these tests have a clear correlation with bacterial [antigen]
have a higher proportion of indeterminate results [mostly burden, and therefore can be used for monitoring
due to lack of T-cell response to mitogen, a potent stimu- response to LTBI and active TB treatment. Variations in
lant of T-cell response] and this may indicate underlying incubation periods, antigens [proteins vs peptides], and
anergy (37,38,66). Recent studies suggest that IGRAs may assay formats might explain some of the discrepancies
be promising in individuals with HIV infection (37,48,67), (25,26).
contacts (56,57,60,61,63), children (33,39,49,68), and A recent study from India (70) showed that IGRAs
health care workers (34,35,69), but this requires may offer interesting insights into T-cell kinetics after
confirmation in larger studies. LTBI treatment. In an environment with ongoing, inten-
For periodic testing of health care workers, IGRAs sive nosocomial exposure, Indian health care workers
may have important advantages: they might eliminate had strong IFN-γ responses [measured using QFT-G]
the need for two-step testing protocol at baseline, avoid when LTBI was diagnosed, and continued to have
sensitization and boosting, and may minimize interpre- persistently elevated responses, even after six months of
tational difficulties that often hamper serial TST screen- isoniazid treatment for LTBI. It is possible, although
ing. However, there are virtually no data on the long- unproven as yet, that persistence of infection and/or re-
term reproducibility of IGRAs, particularly within- infection [or repeated exposure] might account for this,
subject variability in serial testing, where conversions and and raises concerns about efficacy of conventional
reversions can occur (35). Without data on longitudinal preventive therapy in high incidence settings with recur-
changes and biological variability, the results of serial rent exposure (70). Further research is needed to study
IGRA testing are hard to interpret. Currently, there is no T- cell kinetics during LTBI treatment, and determine
consensus as to what an IGRA “conversion” is. Prelimi- the effect of repeated exposures on host cellular immune
nary data from a recent cohort study in India suggests responses, particularly in high incidence settings. The
that IGRAs conversions are strongly correlated with TST availability of standardized, commercial T cell-based
conversions when stringent thresholds were used for IGRAs such as QFT-G and T-SPOT.TB might greatly
both tests; however, it is still not clear how much IFN-γ facilitate such novel investigations.
levels must increase in order to be considered a true Can IGRAs be used to diagnose active TB disease?
“conversion” (35). This study showed that conversions, The CDC guidelines recommend the use of the QFT-G
reversions, and non-specific variations occur with serial assay for diagnosing infection with Mycobacterium
IGRA testing, as they do with TST (35). Although IGRAs tuberculosis, including both LTBI and active disease (32).
are often thought of as tests that produce simple yes/no According to these guidelines, persons who have positive
results, the data suggest that these tests are threshold IGRA results, regardless of symptoms or signs, should
dependent. Analogous to the TST, different thresholds be evaluated for TB disease before LTBI is diagnosed (32).
may be appropriate for different populations, or clinical It is important to note that currently available IGRAs
settings [e.g., threshold for diagnosis vs conversion]. To assays cannot distinguish between active disease and
meaningfully interpret repeat IGRA results, the optimal LTBI, and this may pose problems for diagnosing active
thresholds to distinguish new infections from non- disease in countries with high burden of LTBI. It is,
specific variations must be determined. Therefore, therefore, important to interpret the results in a specific
longitudinal studies of serial testing will be of great clinical context. In an individual being investigated for
interest. Such studies should concurrently perform serial suspected TB disease, a positive result may be due to
TSTs, in order to provide a baseline for comparison with active TB or irrelevant concurrent LTBI. However, a
changes in IFN-γ responses over time. negative IGRA result may represent a useful ‘rule out’
196 Tuberculosis
test, particularly in low incidence settings (26). However, new diagnostics, vaccines, and drugs, is currently being
a negative test, particularly if there is underlying addressed by several global health agencies, non-profit
immunosuppression, should not preclude further groups, industry, funding agencies, public-private
investigation or treatment if the clinical suspicion is high. partnerships, and academic institutions. In this context,
The negative predictive value of IGRAs for active TB the emergence of IGRAs is a much anticipated, welcome
requires further evaluation. development that has, for the first time, increased the
Another important unresolved issue is whether range of diagnostic tools available for LTBI.
IGRAs have the ability to identify latently infected Detection and treatment of LTBI is an important
individuals who are most likely to progress to active component of TB control efforts in low incidence [high
disease, and, therefore, most likely to benefit from income] settings. Until recently, the TST was the only
preventive therapy. Although there are limited data, tool available to detect LTBI. The most important
based on one small African study (71), of an association breakthrough in recent years has been the development
between IFN-γ response to ESAT-6 and subsequent of IGRAs. Because of their high specificity and logistical
progression to active TB among contacts of TB patients, convenience, IGRAs might replace the century-old TST
the association between IGRA positivity and progression in selected low incidence, high-income settings in the
to active disease is largely unknown. Long-term cohort next decade. Research during the next few years will help
studies are needed to address this critical issue. settle unresolved issues, and define the exact role for
Lastly, a limitation of IGRAs, particularly for high these assays in clinical and public health settings. Further
burden, resource limited countries, is their higher mate- refinement [e.g., inclusion of additional antigens to
rial and equipment costs and the need for laboratory increase sensitivity] and standardization of these
infrastructure and trained personnel (27). The IGRAs commercial assays will also occur, and that will enhance
require equipment such as ELISA or ELISPOT readers, their utility and applicability.
and also technicians skilled in running such immuno- At this time, the role for IGRAs in low income, high
logical assays. Such resources are not easily accessible in burden settings [e.g., India] is rather limited. Simplifi-
developing countries where even quality sputum smear cation of the test format and reduction of costs might
microscopy services are often lacking. Economic enhance applicability in such settings, particularly in
evaluations are needed to better delineate the role of selected subgroups such as HIV-infected individuals,
IGRAs in public health and routine clinical settings children, and other high-risk groups [e.g., household
(40,72). It is possible that, at least in some settings [i.e., contacts]. In addition, IGRAs may serve as useful tools
high income countries], the advantages of a more to investigate the transmission dynamics and epidemio-
convenient and specific blood test might outweigh the logy of TB in various settings (35,70,75). Until IGRAs
higher costs. It is also possible that hybrid strategies that become widely accessible, the TST will continue to be a
combine TST and IGRA might be more cost-effective useful, simple, low-cost tool in developing countries
(55,73,74). Cost and requirement for laboratory support where BCG vaccination is given in infancy [and, there-
are obviously very important issues in developing fore, has limited impact on TST results (21,22)] (27).
countries such as India. However, if IGRAs are shown to be more predictive of
active TB than the TST in large cohort studies, then the
IMPLICATIONS FOR RESOURCE-LIMITED use of IGRAs can be expected to be expand exponentially,
HIGH BURDEN COUNTRIES with the potential to revolutionize our approach to LTBI
diagnosis and treatment.
Tuberculosis continues to be a major public health Recent studies from India have shown that the TST
problem worldwide. Despite the enormous global and QFT-G produce fairly comparable results (33-35).
burden of TB, case detection rates continue to be low, Also, several Indian studies, including large nation-wide
compromising TB control, particularly in areas with high tuberculin surveys, have shown that prior BCG
HIV prevalence. The portfolio of currently used TB diag- vaccination does not significantly affect the TST results
nostic tools relies on century old tests with several known (76-79). Also, a 15-year follow-up of 280 000 subjects in
limitations. The long felt need for new tools, including the South Indian BCG vaccine trial showed that TST
response is significantly associated with long-term tuberculosis and drug resistance. Expert Rev Mol Diagn
development of active TB (80). Thus, all these studies 2006;6:423-32.
16. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a
suggest that the TST is a useful test for LTBI in the Indian
positive tuberculin reaction in childhood and adolescence.
milieu, particularly because of the low cost, relatively Am J Epidemiol 1974;99:131-8.
easy accessibility, and because BCG does not significantly 17. American Thoracic Society. Targeted tuberculin testing and
affect TST specificity. Future Indian studies should help treatment of latent tuberculosis infection. Am J Respir Crit
to settle the debate on whether IGRAs should replace Care Med 2000;161:S221-47.
the TST. For now, it is probably a good strategy to keep 18. Horsburgh CR Jr. Priorities for the treatment of latent
tuberculosis infection in the United States. N Engl J Med
both TST and IGRAs on the LTBI diagnostic menu, and
2004;350:2060-7.
select the appropriate test based on the population, the
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purpose of testing, and the resources available. Clin Infect Dis 1993;17:968-75.
20. Menzies D. Interpretation of repeated tuberculin tests.
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200 Tuberculosis
Roentgenographic
Manifestations of
Pulmonary Tuberculosis 13
Sima Mukhopadhyay, Ashu Seith
INTRODUCTION chiectasis can be detected by CT. The newer multidetector

CT scanners [MDCT] are useful in delineating length of
Tuberculosis [TB] is a major public health problem in
the stenotic segments. Lymphadenopathy which is a
the developing countries (1). With the advent of the
common feature in pulmonary TB can be detected and
human immunodeficiency virus [HIV] infection and the
nature of the lymph nodes can be characterized by CT.
acquired immunodeficiency syndrome [AIDS], the
Pleural pathology [i.e., effusion, empyema, thickening,
clinical presentation of TB is changing. Lungs are the
calcification, etc.,] and underlying bony changes in
most common and often the first site of involvement in
empyema are well evaluated by CT. Miliary lesions in the
TB. Early diagnosis and treatment of pulmonary TB is
lungs are well shown by CT, especially high resolution
extremely important for ensuring cure. Imaging plays a
CT [HRCT], even when the plain film is normal. The CT
very important role in the diagnosis and follow-up of
has a definite role in symptomatic Mantoux positive
patients with pulmonary TB.
patients with a normal plain chest radiograph. In a study
from Korea (2), chest CT findings in 41 children with
IMAGING MODALITIES
confirmed pulmonary TB were reviewed retrospectively.
Chest Radiograph In 37 per cent patients, CT gave additional information
which altered clinical management (2). The HRCT is also
In a patient suspected to have pulmonary TB, postero- useful in predicting the activity of TB by demonstrating
anterior [PA] view of the chest is the first imaging evidence of bronchogenic spread and characterising the
modality and is mostly adequate for diagnosis and pulmonary lesions seen on plain radiographs.
subsequent follow-up of such patients. Lateral view of
the chest is necessary to confirm findings of the PA view Ultrasonography
or to evaluate inadequately visualized areas in a selected Ultrasonography can be used to evaluate pleural
group of patients. Apicogram of the chest is needed if pathology. Pleural aspiration and biopsy can be safely
the lesion is partially obscured by the medial end of the performed under ultrasonography guidance. Ultrasono-
clavicle and the nearby ribs in a PA view of the chest. graphy can also be used to evaluate hepatosplenomegaly
and abdominal lymphadenopathy in patients with TB.
Computed Tomography Additionally, lesions of the pelvic organ scan be
Computed tomography [CT] can give important diagnosed in female patients using ultrasonography.
information in patients with pulmonary TB and may
Magnetic Resonance Imaging
identify foci in the lungs undetected on a plain film. Occult
cavitation may be detected particularly when obscured Magnetic resonance imaging [MRI] can be used to
by pleural effusion, bones or diaphragm. Bronchial evaluate mediastinal and hilar lymphadenopathy. It is
stenosis or occlusion and nature and extent of bron- equally accurate as CT in this regard.
Roentgenographic Manifestations of Pulmonary Tuberculosis 201
IMAGING IN PULMONARY TUBERCULOSIS

Pulmonary TB can be considered under two broad
headings as follows: [i] primary TB, and [ii] post-primary
TB. The reader is referred to the chapter “Reactivation
and reinfection tuberculosis” [Chapter 47] for more details.
Though radiographically primary and post-primary
TB are different in the nature of the lesion, site of involve-
ment, lymphadenopathy and pleural involvement, often,
there is a considerable overlap in the findings observed
in both the forms.
PRIMARY TUBERCULOSIS
Primary disease now accounts for 23 to 34 per cent of all
adult cases of TB (3). A large number of paediatric Figure 13.1: Chest radiograph [postero-anterior view] showing an
patients are asymptomatic at presentation and even in ill-defined area of consolidation [arrow] in the right lower lobe in a
symptomatic patients, early diagnosis by bacteriology is child with primary tuberculosis
hampered by the difficulty in obtaining suitable sputum
samples (4). A positive tuberculin skin test [TST] and an lack of systemic toxicity, associated lymphadenopathy
abnormal chest radiograph are the only clues to the and/or failure to respond to conventional antibacterial
diagnosis in this group. therapy may help in predicting TB aetiology (5).
Primary TB may involve one or more of the following There is no predilection for a particular form of
structures, i.e., lung parenchyma, lymph nodes, tracheo- regional involvement within the lungs. While different
bronchial tree and pleura. However, chest radiograph workers have documented predilection for the upper
may be normal in up to 15 per cent. Radiographic features lobe or lower lobe, no regional preference has been
in primary pulmonary TB are shown in Table 13.1. reported by others. Right sided predominance has been
noted in many series. For practical purposes, primary
Table 13.1: Radiographic features in primary TB can cause consolidation in any lobe (5). In adults with
pulmonary tuberculosis primary TB, the lesion is often seen in the lower lobe.
Parenchymal consolidation Cavitation of the parenchymal lesion is rare in
Tuberculoma children but can be seen in seven to twenty-nine per cent
Miliary tuberculosis adults with primary TB (6,7). Endobronchial spread is
Lymphadenopathy rare since cavitation is uncommon.
Airway involvement
Computed tomography is superior to plain chest
Pleural effusion
radiographs in demonstrating the parenchymal changes.
Consolidation is seen as a homogeneous soft tissue
Parenchymal Involvement attenuation lesion with air bronchogram or areas of
breakdown within. Parenchymal changes are better
Consolidation
appreciated on HRCT (8). Computed tomography is
The primary parenchymal lesion is typically seen as an superior to MRI in the demonstration of pulmonary
area of consolidation. The lesion is usually single, of parenchymal changes.
variable size, often less than 2 cm in diameter, homo- In a series of 2677 patients with pulmonary TB seen
geneous with ill-defined margins [Figure 13.1]. The lesion at the Paediatric Tuberculosis Clinic at the All India
may involve the entire lobe due to endobronchial Institute of Medical Sciences [AIIMS] hospital, New
obstruction (5). Consolidation abutting a fissure may Delhi, over a period of 29 years, 50 per cent had primary
show sharp margins. Consolidation of pulmonary TB is pulmonary complex. Of these, 39 per cent had only
often indistinguishable from bacterial pneumonia. But parenchymal lesion without lymphadenopathy (9).
202 Tuberculosis
Figures 13.2: Chest radiograph [postero-anterior view] [A] and CECT of the chest [B], showing well-defined, single, oval
lesion in the left upper lobe [arrow] with cavitation within the mass, suggestive of a tuberculoma
Tuberculoma probably an interval of about six weeks or more between

dissemination of bacilli and positive findings on a chest
A tuberculoma is a persistent mass-like opacity which
radiograph. When the lesions increase in size, they appear
may be seen either in primary or post-primary TB. It is
as tiny, discrete, pinpoint opacities, evenly distributed
seen in seven to nine per cent of patients with tuber-
throughout both the lungs with some basal predomi-
culosis. It is a round or oval lesion, most commonly seen
nance. This is thought to be due to gravity dependent
in the upper lobes, more often on the right side. Small
increase in the blood flow to the lung bases (10) [Figure
discrete lesions in the immediate vicinity of the main
13.3A]. Even distribution of nodules is seen in 85 per cent
lesion [satellite lesions] may be seen in as many as 80 per
of cases while 15 per cent show asymmetric dissemination
cent of the cases (10). Tuberculomas range from 0.5 to
(16). Initially, the foci are about 1 mm in diameter. If not
4 cm or more in diameter, though majority are less than
treated, the foci may reach 3 to 5 mm in size and become
3 cm in size. Cavitation is seen in 10 to 50 per cent of
confluent, presenting a “snow-storm” appearance (10).
cases. Majority remains stable over a long time (5)
Associated lymphadenopathy is seen more commonly
[Figures 13.2A and 13.2B]. On CT, usually tuberculoma
in children [95%] than in adults [11%]. Affected lymph
appears as a nodule with a regular and smooth outline.
nodes are mostly seen on the right side, in paratracheal
Calcification within the nodule or satellite nodules
location. Associated parenchymal consolidation is also
around the periphery of the dominant nodule is found
more common in children (15). In a series from a teaching
in 20 to 30 per cent of the lesions. Cavitation may also be
hospital at New Delhi (9), of 2677 paediatric patients with
seen [Figure 13.2B]. Tuberculomas show ring-like or
pulmonary TB, miliary and bronchopneumonic forms
central curvilinear enhancement (11-13).
were seen in three per cent patients.
In a case of miliary TB, CT, especially HRCT, plays an
Miliary Tuberculosis
important role in establishing the diagnosis (17). Often in
Dissemination of organisms via the haematogenous route the appropriate clinical setting, a patient with miliary TB
leads to miliary TB in the lungs and other organs (14). may have a normal chest radiograph. The HRCT can detect
Miliary TB is mostly a feature of primary TB, although it miliary nodules with or without lymphadenopathy even
may be seen in post-primary disease also. Radiographi- when a chest radiograph is normal [Figure 13.3B].
cally detectable miliary TB occurs in one to seven per With treatment radiographic clearance is seen in two
cent of patients of all forms of TB (3,6,15). In the initial to six months. Some of the patients with miliary TB may
period following haematogenous dissemination, the chest develop acute respiratory distress syndrome [ARDS](18).
radiograph is usually normal. During this period, the foci The reader is referred to the chapter “Tuberculosis and
are too small to be identified radiographically. There is acute lung injury” [Chapter 36] for more details.
Figure 13.3: Chest radiograph [postero-anterior view] [A] and HRCT ot the chest [B], showing bilateral, diffuse, tiny,
discrete, pinpoint opacities, suggestive of miliary tuberculosis
Lymph Node Involvement and 10 to 43 per cent adults (6,7) with primary TB. This
is usually associated with a parenchymal component.
Radiographically visible lymphadenopathy is a common
When associated with parenchymal lesion, lymph nodes
feature of primary TB, especially in children. Lymph-
draining that area are enlarged [Figure 13.4]. Typically,
adenopathy is seen in up to 96 per cent children (11,13)
the involvement is unilateral. Right hilum and right
paratracheal areas are the most commonly involved
areas. Less commonly, subcarinal, azgyo-oesophageal
and aortopulmonary window regions are involved
[Figure 13.5]. A recent study has reported the subcarinal
region as the most frequently involved site seen in 90 of
the 92 patients (19). Bilateral adenopathy occurs in up to
31 per cent of cases (4,11). Right sided predominance of
lymphadenopathy is postulated to be due to the predomi-
nance or right sided parenchymal lesions and due to the
fact that right sided nodes drain the entire right lung
along with left lower lobe.
Lymphadenopathy may be the sole finding in
primary TB. Occurrence of isolated lymphadenopathy
Figure 13.4: Chest radiograph [postero-anterior view] showing right decreases with increasing age (4), being seen in up to
parahilar consolidation [black arrow] with enlarged ipsilateral hilar 49 per cent of children aged under three years, in nine
and paratracheal lymph nodes [white arrows] per cent of children aged four to fifteen years and only
Figure 13.5: CECT of the chest of three different patients showing necrotic right paratracheal nodes [arrow] [A], necrotic right hilar
and subcarinal nodes with rim enhancement [arrow] [B] and homogeneously enhancing right paratracheal nodes [arrow] [C]
204 Tuberculosis
rarely in adults (20-22). In the study reported by metastases from testicular tumours, head and neck
Mukhopadhyay and Gupta (9), 50 per cent of the 2677 squamous cell carcinoma and Crohn’s disease (23).
subjects with paediatric pulmonary TB had primary Calcification is uncommon, seen in 10 to 21 per cent
complex. Of these 32 per cent had only lymphadeno- children with TB and is never present in children less
pathy, 29 per cent had parenchymal and lymph node than six months of age (13,19) [Figure 13.6].
involvement while 39 per cent had only parenchymal Disease activity in mediastinal TB lymphadenopathy
lesions (9). was assessed by CT and correlated with biopsy findings
Computed tomography is more sensitive than a chest in a study of 49 Korean patients (25). Findings of central
radiograph for detection and characterization of intra- low attenuation and peripheral enhancement on CT
thoracic lymphadenopathy (23,24). Variable post- suggested active disease while homogeneous and
contrast CT appearances of TB lymph node involvement calcified nodes suggested inactive disease. Since low
have been described [Table 13.2]. Peripheral rim enhance- attenuation areas within the nodes pathologically
ment with or without central low attenuation is the correspond to areas of caseation necrosis and may be a
commonest pattern. Such nodes are 0.5 to 5 cm in dia- reliable indicator of disease activity (25).
meter. Rim enhancement may be: [i] uniform, thin, Mediastinal and hilar nodes are equally well demons-
complete enhancing rim; [ii] thick, irregular, complete trated on MRI. Focal areas of necrosis are seen as areas
or incomplete, peripheral rim; or [iii] conglomerated of increased signal intensity on T2-weighted images (16).
group of nodes showing peripheral and central areas of Three patterns of MRI appearances of TB nodes have
rim enhancement [Figures 13.5A and 13.5B]. With CT- been described: [i] relatively homogeneous nodes,
histologic correlation, excised nodes exhibiting this hyperintense on both T1- and T2-weighted images;
pattern of enhancement have been found to contain [ii] inhomogeneous nodes with peripheral hypointense
complete central necrosis in association with a highly and central hyperintense areas with strong peripheral
vascular, inflammatory, capsular and perinodal reaction enhancement; and [iii] homogeneously hypointense
(13,23). There may be diffuse perinodal fat plane nodes on both T1- and T2-weighted images [Figure 13.7].
obliteration. Non-homogeneous enhancement of the Type 2 lymph nodes were the most common and
lymph nodes has also been described. These nodes are were seen in symptomatic patients suggesting active
1.5 to 3.5 cm in diameter. This is also a relatively frequent disease (26).
manifestation of TB. Andronikou et al (19) described
‘ghost-like’ ring enhancement in a group of matted nodes Airways Involvement
as the most common pattern of enhancement rather than Airways involvement is caused either by extrinsic
discreet rim-enhancement of a single large node.
compression by the enlarged lymph nodes or due to
Homogeneous enhancement in nodes of a size less than
endobronchial TB. The resultant narrowing leads to
2 cm in diameter is not frequently seen [Figure 13.5C]. segmental or lobar atelectasis. This is frequently seen in
Sometimes, lymph nodes may not show any enhance-
primary TB in children below two years of age and is
ment.
less common in older children [9%] (20) and adults [18%]
Though peripheral rim enhancement pattern can (6,9). Atelectasis in primary TB characteristically affects
suggest a diagnosis of TB in the appropriate clinical
the anterior segment of an upper lobe or the medial
setting, it is, however, not pathognomonic of TB. Similar
segment of the middle lobe. In adults such atelectasis is
pattern can be seen in malignant adenopathy, especially less commonly seen than in children; the usual site of
Table 13.2: Contrast-enhanced computed tomography involvement is anterior segment of the upper lobes and
findings in tuberculosis intrathoracic lymphadenopathy may simulate bronchogenic carcinoma (27).
Peripheral rim enhancement with or without central low On HRCT bronchial compression by enlarged nodes
attenuation as well as endobronchial involvement is well detailed.
Non-homogeneous enhancement Acute tracheo-bronchial TB manifests on HRCT as
Homogeneous enhancement irregular or smooth bronchial wall thickening associated
No enhancement with luminal narrowing (28).
Figure 13.6: NCCT [A] and CECT of the chest [B] of two different patients showing
calcification in paratracheal nodes [arrow]
The airway abnormality can be better delineated with Complications may rarely be seen in the form of
the recent multislice scanners which provide excellent empyema, bronchopleural fistula, empyema necessitates
reconstructions obtained in multiple planes as well as or bone erosion. With healing, residual pleural thickening
the endoscopic view. or calcification may remain [Figure 13.10].
Ultrasonography is a useful investigation in the
Pleural Involvement evaluation of pleural effusion [Figure 13.11], pleural
Pleural effusion as a manifestation of TB is particularly thickening and empyema. In a patient with small pleural
common in adolescents and young adults [6% to 38%] effusion, chest radiograph may be normal, but ultra-
and usually reflects primary TB. Pleural effusion is sonography can demonstrate small amount of effusion.
uncommon in young children with primary TB and if Effusion or empyema can be repeatedly evaluated by
present, is very small in quantity. ultrasonography without radiation to the patient.
Pleural effusion is most commonly unilateral, non- Computed tomography plays an important role in
loculated and moderate to large in quantity. Contralateral complicated pleural involvement in TB by demonstrating
shift of the mediastinum is seen in patients with large extent of disease, site and amount of loculations in
effusions [Figure 13.8]. At times the effusion may be empyema, effusion, status of the underlying rib and lung
subpulmonary in location and produces apparent pathology and helps in planning the management. On
elevation of the ipsilateral dome of the diaphragm. A contrast enhanced CT, loculated empyema is seen as an
lateral decubitus radiograph will show the fluid shift encysted pleural collection of fluid with smooth,
along the lateral chest wall [Figure 13.9]. enhancing surrounding pleura [Figure 13.12].
Figure 13.7: T1 [A] and T2 [B] weighted magnetic resonance images showing pre and paratracheal
nodes [arrows] that appear mildly hyperintense compared to muscle
206 Tuberculosis
Figure 13.8: Chest radiograph [postero-anterior view] of two different patients showing massive left sided free pleural
effusion [arrows] with contralateral mediastinal shift [A]; right sided free as well as loculated pleural effusion [arrows] [B]
Figure 13.9: Chest radiograph [postero-anterior view] showing an opacity in the left lower zone [asterisk] with apparent elevation of the
left dome of the diaphragm [arrow] suggestive of subpulmonary effusion. Left lateral decubitus view of the same patient [B] showing the
diaphragm [asterisk] to be in normal place. The subpulmonary fluid has now settled along lateral chest wall [arrows]
Figure 13.10: Chest radiograph [postero-anterior view] [A] showing ill-defined opacity all along the lateral chest wall [arrows] with loss of
volume of left hemithorax. CECT of the chest of the same patient [B] showing loss of volume, dense and thick peripheral pleural
thickening with calcification [arrows]
usually complete within two to six months. Clearance is

slower in older than in younger patients.
Atelectasis secondary to nodal compression may
disappear with the regression of enlarged lymph nodes
or perforation of the node into the bronchus provided
the bronchial occlusion did not persist too long (10).
However, with bronchostenosis, the collapse is often
persistent.
With appropriate treatment, most often there is a
complete resolution of pleural effusion. However,
residual pleural thickening or calcification may persist
[Figure 13.10].
Figure 13.11: Ultrasonography of the chest showing POST- PRIMARY TUBERCULOSIS

significant right sided pleural effusion [asterisk]
Majority of post-primary TB occurs as a result of
reactivation of a focus of infection acquired in earlier life.
Occasionally, the disease results from initial infection by
virulent organisms in individuals who have been
vaccinated with bacille Calmette-Guerin [BCG]. A
minority of cases represent exogenous reinfection.
Several radiographic patterns can be identified in post-
primary TB and one or more of the patterns can be seen
[Table 13.3].
There is considerable overlap between primary and
post-primary TB on a chest radiograph. But the following
points favour post-primary TB: [i] predilection for upper
lobe involvement; [ii] propensity for cavitation; and [iii]
rarity of lymphadenopathy (5).
Figure 13.12: CECT of the chest showing loculated empyema
[asterisk] surrounded by thick enhancing pleura [arrows] Parenchymal Disease
Exudative Lesion
Follow-up of Primary Tuberculosis
Consolidation which is patchy or confluent in nature can
On follow-up evaluation, two-thirds of patients show
occur in specific anatomic regions, i.e., the apical and
complete clearance of parenchymal lesions. Resolution
posterior segment of an upper lobe or the superior
may require six months to two years time. Associated
lymphadenopathy takes more time to resolve as
compared to the parenchymal lesion. It is important to Table 13.3: Radiographic features in post-primary
pulmonary tuberculosis
recognize that a paradoxical worsening of radiographic
findings is common in both parenchymal and extra- Local exudative lesion
parenchymal TB in the first three months of follow-up Local fibroproductive lesion
Tuberculoma
despite adequate therapy (29). In a series of 252 paediatric
Cavitation
patients with TB, consolidation resolved completely Bronchogenic spread
within two years in all cases, 18 per cent had parenchy- Miliary tuberculosis
mal scarring, 11 per cent had parenchymal calcification Bronchostenosis
and nodal calcification was seen in six per cent cases (20). Pleural disease
On treatment, radiographic clearance of miliary TB is Other complications
208 Tuberculosis
segment of a lower lobe. The consolidation is hetero- Fibroproductive or Fibroproliferative Lesion

geneous and ill-defined. Often, more than one segment
The ill-defined exudative lesion is replaced by more
is involved [88%] [Figures 13.13 and 13.14]. Bilateral
sharply defined medium to coarse reticular and nodular
upper lobe involvement is seen in 32 to 64 per cent cases.
opacities [Figure 13.15]. Healing occurs by replacement
Cavitation occurs in about 45 per cent cases (6). The lesion
of TB granulation tissue by fibrous tissue resulting in a
resolve completely with appropriate treatment. At times,
considerable loss of volume [Figure 13.16]. In patients
the disease worsens initially but subsequently clears.
with a significant volume loss of the affected area of the
Exudative lesion if not treated properly may lead to lobar
lung, elevated diaphragm, tracheal and hilar retraction
or total lung consolidation with rapid destruction. But
may be seen. In 41 per cent cases an apical opacity or
even with inadequate therapy, exudative lesion may
apical cap results from pleural thickening, subpleural
regress and become fibroproductive. Lymphadenopathy
is very uncommon and is seen in five per cent cases (6).
Figure 13.15: Chest radiograph [postero-anterior view] showing

Figure 13.13: Chest radiograph [postero-anterior view] showing coarse, sharply defined opacities mainly in left upper lobe
massive right upper lobe consolidation [asterisk] in a patient with suggestive of parenchymal fibroproliferative lesion [asterisk]
post-primary tuberculosis

volume loss of right upper lobe, extensive fibrosis both upper lobes,
Figure 13.14: HRCT of the chest of another patient showing consoli- elevated right hilum, residual cavities [arrow] and bronchiectatic
dation involving apical segment of right lower lobe [asterisk] changes in the left lung [asterisk]
atelectasis and extrapleural fat deposition. Mixed or thick, and smooth or internally nodular [Figures 13.17
exudative and fibroproductive lesion is the commonest and 13.18]. A thick-walled cavity with healing may
finding and is seen in 79 per cent cases. Pure exudative progressively become thin walled and ultimately balloon
or fibroproductive lesions are uncommon (6). into a large emphysematous space (30), although
they usually resolve with or without scarring. This prog-
Cavitation ression is well demonstrated on HRCT (13). The cavitary
With lysis of semisolid caseous material, the liquefied disease usually involves the apical and/or posterior
caseous material may be expelled from the centre of the segments of the upper lobes in 83 to 85 per cent and the
lesion into the bronchial tree with a resultant cavity superior segments of the lower lobes in 11 to 14 per cent
formation. Cavitation in an area of consolidation is a patients (31).
distinct feature of post-primary TB and indicates likely Air-fluid level is not very common in a TB cavity and
active disease [Figures 13.17 and 13.18]. Cavitation may is seen in 9 to 22 per cent of uncomplicated cases (5). As
be seen on chest radiographs in 40 to 87 per cent patients a rule, there is a fairly wide opening of the bronchus into
sometime during the course of their disease. Size of the a TB cavity. The cavities are mostly situated in the upper
cavity is variable [few mm to several cm] depending on lobe, posterior segment and are peripherally located. The
the extent of caseation and extrusion. Multiple cavities draining bronchus is usually basal in position and has a
are more common [54% to 76%] than a single cavity (6). downward course. The basal position of the entering
The wall of an untreated TB cavity may be variably thin bronchus, its downward course and its free communi-
Figure 13.17: Chest radiograph [postero-anterior view ] [A] and HRCT of the chest [B] showing a thick walled cavity
[arrow] in the left upper lobe with surrounding fibroproliferative lesions. Miliary lesions are seen in rest of the lungs
Figure 13.18: Chest radiograph [A] and HRCT of the chest [B] showing a large thick walled cavity [asterisk] with surrounding
consolidation [black arrow] and contralateral nodules [white arrows] in another patient with post-primary tuberculosis
210 Tuberculosis
cation with the cavity tend to keep the TB cavity empty

(32). Tuberculosis cavity may be complicated by intra-
cavitary fungal ball [“mycetoma” or commonly
“aspergilloma”].
In patients with dense fibrosis, consolidation, or
architectural distortion, cavity may not be visible on a
chest radiograph. The CT is extremely helpful in
detecting a cavity and intracavitary fungal ball through
the dense lung.
Tuberculosis Bronchopneumonia
Tuberculosis cavity may communicate with the
bronchial tree resulting in endobronchial spread of the
liquefied caseous material. Similar spread may occur Figure 13.19: Chest radiograph [postero-anterior view] showing
occasionally from intrabronchial rupture of caseous extensive bilateral bronchopneumonic tuberculosis
material of a lymph node. Bronchial dissemination
causes multiple poorly defined parenchymal acinar peribronchial and centrilobular regions and the pattern
nodules in the same lobe or in other lobes of either lung, is known as “tree-in-bud” appearance as seen in HRCT.
predominantly in the dependent areas [Figure 13.19]. “Tree- in- bud” lesion which was first described by Im
Extension of the disease through surrounding air spaces et al (33) is a combination of centrilobular nodules and
may result in acute confluent pneumonia, indis- branching linear structures [Figures 13.20 and 13.21].
tinguishable from causes other than TB. The presence These lesions are a result of bronchogenic spread of
of an open cavity or fairly discrete nodules in other parts infection causing impaction of caseous material in the
of the lung suggests TB as the probable aetiological terminal or respiratory bronchioles and are considered
cause (10). an important sign of activity (33). The appearance,
Endobronchial spread is seen in a chest radiograph however, is non-specific and can result from any
in 19 to 58 per cent (22) and by HRCT in up to 98 per condition that causes plugging of small airway with
cent (27) cases. The nodules are distributed in the fluid or exudates (11). While 70 per cent of such lesions
Figure 13.20: HRCT of the chest of two different patients, illustrating the typical “tree-in-bud” nodules [arrow],
in a bronchovascular distribution [arrow]
Figure 13.21: HRCT of the chest [A] showing middle lobe consolidation with cavitation [asterisk] and bronchogenic spread to the right
lower lobe. There is also bronchostenosis of the middle lobe bronchus [black arrow]. Coronal multiplanar reconstruction [B] shows
middle lobe consolidation with volume loss [white arrow]
clear completely, 30 per cent may have parenchymal least six months and repeated negative sputum cultures
scarring, residual nodules and calcification (10). are the best indicators of an inactive lesion (6). It is also
suggested that the cases should be reported as
Airway Involvement [Bronchostenosis] “radiographically stable” rather than “inactive” (6).
Bronchostenosis occurs in 10 to 40 per cent of patients The HRCT has a definite role in prediction of activity
with active TB by direct extension from adjacent of parenchymal lesions. The presence of thick-walled
lymphadenitis, endobronchial spread of infection or cavities, consolidation and centrilobular nodules indicate
lymphatic dissemination to airways. The CT can depict active disease. Ground glass opacities may also be seen
the bronchial abnormality in 93 to 100 per cent of cases around active lesions. Amongst these, centrilobular
(34) [Figure 13.21]. lesions without evidence of surrounding broncho-
vascular distortion or fibrosis were the most common
Pleural Effusion and reliable CT findings in active TB. On HRCT, charac-
Pleural effusion is mostly seen in primary TB but may teristic findings of bronchogenic spread are reported in
occur in six to eighteen per cent patients with post- more than 94 per cent of cases (34,35) [Figures 13.20 and
primary disease (6). Pleural effusion in post-primary TB 13.21]. Whereas, thin-walled cavities, fibrotic bands and
is usually small and typically seen as a loculated effusion well-defined nodules are seen in inactive disease [Figure
associated with parenchymal disease. Frank TB 13.22]. Some workers suggest that these findings should
empyema is less common. Residual pleural thickening be described as ‘stable’ rather than ‘inactive’, because of
and calcification may also occur (5). Pneumothorax may the possibility of future recrudescence of latent bacilli in
occur due to rupture of a cavity into the pleural space. such residual cavities. The CT picture can, however, be
equivocal and clinical correlation in this regard is
Evaluation of Activity of Tuberculosis on Imaging imperative. The CT cannot always accurately predict the
One should never be dogmatic about the activity of a TB disease activity. Well-defined nodules can also be seen
lesion on a single radiograph. Typical exudative lesion in patients with inactive TB and in such cases ascertaining
on a chest radiograph may remain unchanged even on activity on HRCT may be difficult (11,36,37).
adequate therapy and the patient may still be sputum Evaluation of activity in nodes is difficult, though
culture negative. On the other hand, a typical fibrocavi- presence of low attenuation areas has been suggested as
tary lesion may look inactive but show active granulo- a sign of activity. However, this sign is of limited
matous inflammation and contain viable tubercle bacilli reliability as enhancement patterns of the nodes can be
(10). Radiographic stability of a lesion for a period of at quite variable as discussed previously (25).
212 Tuberculosis
Figure 13.22: Chest radiograph [postero-anterior view] [A] and HRCT of the chest [B] showing extensive
destruction of right lung with volume loss and fibro-bullous changes [asterisk]
In pleural TB, fibrothorax with diffuse pleural

thickening and calcification, but without pleural effusion
on CT, suggests inactivity (28).
SEQUELAE AND COMPLICATIONS OF

TUBERCULOSIS
A variety of sequelae and complications can occur in
pulmonary TB.
Parenchymal Complications
Parenchymal complications include thin-walled cavities,
fibrotic bands, cicatrization, end-stage lung destruction
and aspergilloma. Residual thin-walled cavities may be Figure 13.23: Mycetoma in a tuberculosis cavity. CT of the chest
seen in both active and inactive disease. After antituber- showing loss of volume of right upper lobe with a cavity. Soft tissue
culosis chemotherapy, the TB cavity may disappear; mass seen inside the cavity is caused by fungus ball [arrrow]
occasionally, the wall becomes paper-thin and an air-
filled cystic space remains [Figure 13.22]. Serial imaging Bronchciectasis in post-primary TB can develop most
helps determine the stability or activity of pulmonary commonly due to destruction and fibrosis of lung
disease (38). The characteristics of residual fibrosis parenchyma, resulting in retraction and irreversible
include grooving, calcification and retraction of the bronchial dilatation or due to cicatricial bronchostenosis
adjoining parenchyma. These changes can be extensive secondary to localized endobronchial tuberculosis,
and result in considerable destruction of the lung paren- resulting in obstructive pneumonitis and distal
chyma. Cavities and bronchiectasis may be colonized by bronchiectasis [Figure 13.24]. Most of the post-primary
Aspergillus species forming an aspergilloma [Figure TB lesions are in the apical and posterior segment of
13.23], or other organisms. Haemoptysis is clinically most upper lobes, hence these are common sites for
important consequence of these sequelae. bronchiectasis. Since bronchial drainage is adequate
from these sites, usually symptoms are minimal
Airway Complications
[bronchiectasis sicca] (10). Bronchostenosis may result
Airway complications include bronchiectasis, tracheo- in persistent segmental or lobar collapse [Figures 13.25,
bronchial stenosis, and broncholithiasis (38). 13.26, and 13.27], lobar hyperinflation or obstructive
Figure 13.24: Chest radiograph [postero-anterior view] [A] and CT of the chest [B] of the same patient showing collapse of left lower
lobe with cystic bronchiectasis, loss of volume of left hemithorax [arrow] and herniation of right lung to the left [asterisk]
pneumonitis. Broncholithiasis is an uncommon compli- Vascular Complications

cation of pulmonary TB and is defined as the presence
Vascular lesions include pulmonary or bronchial
of calcified or ossified material within the lumen of the
arteritis and thrombosis, bronchial artery dilatation, and
tracheobronchial tree.
Rasmussen aneurysm (38). Vascular complications in
pulmonary TB can result in massive haemoptysis which
Pleural Complications
may be life-threatening and often needs emergency
Pleural complications include chronic empyema, embolotherapy. At times in post-primary TB,
fibrothorax, bronchopleural fistula, and pneumothorax. pulmonary arteries and veins in an area of active TB
Fibrothorax with pleural thickening and calcification infection may show vasculitis and thrombosis. Arteries
results in a significant loss of thoracic volume (38) [Figure near chronic TB cavities frequently show endarteritis
13.10]. obliterans. There is an increase in the number and

Figure 13.25: Chest radiograph [postero-anterior view] showing a dense opacities in right upper lobe with elevated horizontal fissure
triangular opacity through the heart suggestive of left lower lobe and right hilar adenopathy, suggestive of collapse consolidation of
collapse [arrow] the right upper lobe [arrow]
214 Tuberculosis
size of bronchial artery branches [Figure 13.28]. patients who had previous primary TB, HIV infection
Occasionally, an artery lies contiguous with the fibrous significantly impairs cellular immunity and leads to
capsule of a cavity and undergoes localized dilatation, reactivation TB (39).
known as Rasmussen’s aneurysm [Figure 35.3]. It is The radiographic manifestations of tuberculosis in
seen as an enlarging mass or rapidly enlarging patient with AIDS depend upon the degree of immuno-
consolidation due to haemorrhage. This is seen in four suppression. Early in HIV disease, clinical presentation
to five per cent of autopsy cases in patients with chronic of TB is similar to that observed in immunocompetent
TB (10). individuals and upper lobe infiltrates, cavities and
bronchogenic spread may be evident. At this stage
TUBERCULOSIS AND HUMAN infection is confined to the lungs in more than 75 per
cent of cases. In more advanced AIDS, radiographic
IMMUNODEFICIENCY VIRUS INFECTION
findings are often atypical including diffuse infiltrates,
Patients with HIV infection are more prone to develop multiple pulmonary nodules or masses and significant
an overwhelming disease process of primary TB. In mediastinal lymphadenopathy (40). The infiltrates may
Figure 13.27 Chest radiograph [postero-anterior view] [A] showing volume loss of left upper lobe [asterisk].
HRCT of the chest of the same patient [B], in addition, reveals narrowing of the left main bronchus [arrow]
Figure 13.28: HRCT of the chest [A] showing extensive fibrocavitary lesions in the right upper lobe [white arrow]. Selective
bronchial artery angiogram [B] reveals a hypertrophied intercosto-bronchial artery supplying the region [black arrow]
be quite extensive, fairly rapidly progressive and 5. McAdams HP, Erasmus J, Winter JA. Radiologic manifesta-
randomly distributed in upper and lower lobes. Cavita- tions of pulmonary tuberculosis. Radiol Clin North Am
1995;3:655-78.
tion is rare in the advanced stage of AIDS. The reader is
6. Woodring JH, Vandiviere HM, Fried AM, Dillon ML,
also referred to the chapter “Tuberculosis and human Williams TD, Melvin IG. Update: the radiographic features
immunodeficiency virus infection” [Chapter 40] for more of pulmonary tuberculosis. AJR Am J Roentgenol
details. 1986;146:497-506.
7. Choyke PL, Sostman HD, Curtis AM, Ravin CE, Chen JT,
Godwin JD, et al. Adult-onset pulmonary tuberculosis.
FAMILY SURVEY Radiology 1983;148:357-62.
It is essential to survey the family members who stay in 8. Buxi TB, Sud S, Vohra R. CT and MRI in the diagnosis of
tuberculosis. Indian J Paediatr 2002;69:965-72.
close contact with a patient of pulmonary TB (41). All
9. Mukhopadhyay S, Gupta AK. Imaging in childhood tuber-
contacts should have a chest radiograph taken and all culosis. In: Seth V, editor. Essentials of tuberculosis in
those below 12 years of age should undergo tuberculin children. New Delhi: Jaypee Brothers Medical Publishers;
testing to detect asymptomatic contacts with latent TB 1997.p.240-63.
infection. In our experience with 2677 children with 10. Fraser RG, Pare JA, Fraser RS, Genereux GP. In: Diagnosis of
diseases of the chest. Vol.II. 3rd ed. Philadelphia: W.B.
pulmonary TB, there was a positive family history of TB Saunders and Company; 1989.p.882-933.
in 30 per cent patients. Radiographic screening of 300 11. Lee JY, Lee KS, Jung KJ, Han J, Kwon OJ, Kim J, et al.
adult contacts of children with primary pulmonary Pulmonary tuberculosis: CT and pathologic correlation. J
complex showed active pulmonary lesions in four to five Comput Assist Tomogr 2000;24:691-8.
per cent of those screened (9). The reader is referred to 12. Lee KS, Song KS, Lim TH, Kim PN, Kim IY, Lee BH. Adult-
onset pulmonary tuberculosis: findings on chest radiographs
the chapter “Tuberculosis in children” [Chapter 41] for more and CT scans. AJR Am J Roentgenol 1993;160:753-8.
details. 13. Leung AN. Pulmonary tuberculosis: the essentials. Radiology
1999;210:307-22.
RADIOGRAPHIC FOLLOW-UP SCHEDULE 14. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary
The American Thoracic Society and Centres for Disease Dis 2005; 5:415-30.
Control (41) recommend the following radiographic 15. Weber AL, Bird KT, Janower ML. Primary tuberculosis in
schedule. In patients with a negative sputum mycobac- childhood with particular emphasis on changes affecting the
tracheobronchial tree. AJR Am J Roentgenol 1968; 103:123-
terial culture, a repeat chest radiograph is indicated at 32.
two months of treatment; another chest radiograph is 16. Reed MH, Pagtakhan RD, Zylak CJ, Berg TJ. Radiologic
considered as desirable at the end of treatment. In features of miliary tuberculosis in children and adults. J Can
patients with a positive sputum mycobacterial culture, Assoc Radiol 1977;28:175-81.
repeat chest radiographs at two months and at the 17. Pipavath SN, Sharma SK, Sinha S, Mukhopadhyay S, Gulati
MS. High resolution CT [HRCT] in miliary tuberculosis
end of treatment are considered desirable [but not [MTB] of the lung: correlation with pulmonary function tests
essential] (42). and gas exchange parameters in north Indian patients. Indian
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14
VK Vijayan, Sajal De
INTRODUCTION have been coughed out by ‘open’ [sputum-positive]

pulmonary TB patients who have received no treatment,
Pulmonary tuberculosis [TB] is a chronic infectious
or have not been treated fully. The initial contact with
disease caused by Mycobacterium tuberculosis (1). Other
the organism results in few or no clinical symptoms or
mycobacteria can also produce pulmonary TB and these
signs. The tubercle bacillus sets up a localized infection
include Mycobacterium africanum and Mycobacterium bovis.
in the periphery of the lung. Four to six weeks later,
Usually, patients with pulmonary TB who have cavitary
tuberculin hypersensitivity along with mild fever and
lesions are an important source of infection. These
malaise develops. In the majority of patients, the process
patients are usually sputum smear-positive. Coughing
is contained by local and systemic defenses. Rupture of
produces tiny infectious droplets. Usually, one bout of
the sub-pleural primary pulmonary focus into the pleural
cough produces 3000 droplet nuclei and these can stay
cavity may result in the development of TB pleurisy with
in the air for a long period of time. Ventilation removes
effusion.
these infectious nuclei. Mycobacterium tuberculosis can
Less commonly, tubercle bacilli may be ingested and
survive in the dark for several hours. Direct exposure to
lodge in the tonsil or in the wall of the intestine. This
sunlight quickly kills these bacilli. Of the several factors,
form of TB occurs following the ingestion of contami-
determining an individual’s risk of exposure, two factors
nated milk or milk products. Rarely, TB can occur as a
are important. These include the concentration of droplet
result of direct implantation of the organisms into the
nuclei in contaminated air and the length of time that air
skin through cuts and abrasions. This form of TB is a
is breathed. The risk of transmission of infection from a
health hazard faced by health care workers and labora-
person with sputum smear-negative pulmonary TB and
tory staff who handle materials infected with
miliary TB is low and with extra-pulmonary TB is even
Mycobacterium tuberculosis. These lesions were termed
lower. However, infection with Mycobacterium bovis is
“prosector’s warts” (2). Interestingly, Laennec, the
rare in India because milk is often boiled before use. Even
inventor of the stethoscope, acquired TB in this fashion
though nontuberculous mycobacteria [NTM] are
which eventually led to his death (2).
harmless, some can cause human disease especially in
immunocompromised individuals (2). Primary Tuberculosis
From the implantation site, the organisms disseminate
NATURAL HISTORY OF TUBERCULOSIS
via the lymphatics to the regional lymph nodes. The
The cardinal event in the pathogenesis of TB, whether lesion at the primary site of involvement, draining
inapparent or overt is the implantation of Mycobacterium lymphatics and the inflamed regional lymph node
tuberculosis in the tissues. Lung is the most frequent portal constitute the primary complex. When the primary site of
of entry [Figures 14.1A and 14.1B]. The organism enters implantation is in the lung, it is called Ghon’s focus. The
the lung from the inhalation of air borne droplets which draining lymphatics and the involved lymph nodes
218 Tuberculosis
Figure 14.1A: Chest radiograph [postero-anterior view] showing a Figure 14.1B: Chest radiograph [postero-anterior view] of the same
cavity in left upper zone [arrow]. Sputum culture was positive for patient at 24 months of follow-up. The patient had received six
Mycobacterium tuberculosis months short-course chemotherapy. The left upper zone cavity has
disappeared
together with Ghon’s focus constitute the primary complex present era in patients with human immunodeficiency
[Ghon complex]. In children, the lymph node component virus [HIV] infection. Caseation necrosis at the Ghon’s
may be much larger than the Ghon’s focus. focus may lead to liquefaction. Expectoration of the
Having secured entry, the tubercle bacilli then liquefied material can leave a cavity with shaggy
disseminate via the haematogenous route to other parts margins in the pulmonary parenchyma which may be
of the lung and many organs of the body. Thus, primary apparent on the chest radiograph.
TB is a widely disseminated infection. This fact is often Mediastinal and tracheobronchial lymph nodes may
not realized by clinicians. Most of these metastatic foci produce compression of the adjacent bronchus. If this
heal. However, some of these metastatic foci may obstruction is complete, the lung distal to the site of
remain dormant and may reactivate at a later date when bronchial obstruction becomes atelectatic [epitubercu-
the host resistance decreases. The subsequent course of losis] (3). If the obstruction is incomplete, it may act as a
the events varies considerably. In most of the patients, “ball-valve” and results in obstructive emphysema. The
the primary complex resolves without becoming clinically inflamed caseous lymph nodes may erode through the
apparent. This occurs when the immune status of the walls of the bronchus and result in bronchogenic dissemi-
host is good, and healing occurs by fibrosis and nation. Bronchial mucosal involvement may result in TB
calcification. In a minority of patients, progressive bronchitis. In a patient with overwhelming infection, large
primary TB due to the extension of the inflammatory number of Mycobacterium tuberculosis may gain access to
process at the site of the primary focus can occur. In the the circulation and result in miliary and meningeal TB.
lung, this can present as an area of consolidation [TB In majority of the patients, the initial focus of infection
pneumonia]. This form of the disease was often subsides. Cicatrization, scar formation and often
encountered in the prechemotherapeutic era and was calcification develop. Repeated episodes of extension of
termed “galloping consumption” or “pneumonia alba” infection followed by healing and fibrosis may result in
[white pneumonia]. This form is encountered in the the formation of “onion skin” or “coin lesion” (2).
Post-primary Tuberculosis tuberculin conversion (2). However, this presentation

is not commonly seen these days.
Rarely, the primary lesion may progress directly to the The patient may develop symptoms insidiously and
post-primary form, characterized by extensive caseation some may remain asymptomatic. Usually patients with
necrosis and cavitation. More commonly, the primary pulmonary TB present with constitutional and respi-
lesion remains quiescent, and may remain so for decades ratory symptoms (3). Constitutional symptoms include
or for the remainder of the individual’s lifetime. The tiredness, headache, weight loss, fever, night sweats and
precise mechanism[s] underlying this phenomenon have loss of appetite. The classic symptoms and signs of TB
not yet been clarified as yet. However, reactivation or were noted in a significantly higher proportion of the
reinfection TB may occur due to old age, malnutrition, younger group than elderly: fever [62% versus 31%],
malignant disease, HIV infection and acquired immuno- weight loss [76% versus 34%], night sweats [48% versus
deficiency syndrome [AIDS], use of immunosuppressive 6%], sputum production [76% versus 48%], and haemop-
drugs and intercurrent infections. tysis [40% versus 17%] (5). Clinical manifestations of TB
While reactivation can occur at any site, post- in HIV infected patients vary and generally depend
primary TB classically involves the apical and posterior upon the severity of immunosuppression. In early stages
segments of the upper lobes, or, the superior segment of of HIV disease, clinical presentation of TB tends to simu-
the lower lobes in more than 95 per cent of the cases. late that observed in persons without immunodeficiency.
Balasubramanian et al (4) have critically reviewed the Fever is often present in the late afternoon or evening,
pathway to the apical localisation in TB and proposed and is low-grade at the onset and becomes high-grade
the integrated model for the pathogenesis of TB. with the progression of disease. Weight loss may precede
Post-primary lesions are different from primary the symptoms. Some patients may remain afebrile.
lesions in that, local progression and central caseation Associated laryngeal TB can result in hoarseness of the
necrosis are much more marked in post-primary TB as voice. Amenorrhoea can occur in severe diseases. The
compared to primary TB. Tuberculosis cavities are most common respiratory symptom of pulmonary TB is
cough which lasts for three or more weeks. Cough may
abundant sites for the growth of Mycobacterium tuber-
be dry or productive. It is nearly impossible to differen-
culosis as the temperature in them is optimal, there is
tiate cough due to pulmonary TB from cough due to other
abundance of oxygen and various nutrients derived from
respiratory diseases including smoking, and it is often
the cell wall are readily available. The bacilli in the wall
passed off as a smoker’s cough. Sputum may be mucoid,
of the cavity gain free access into the sputum and are
mucopurulent, purulent or blood-tinged and is usually
expectorated. Such patients are said to have “open
scanty. Haemoptysis, although observed in many
tuberculosis” and are infectious to the community. If
diseases, is an important and often the presenting
these bacilli are aspirated from the cavity to other parts
symptom of pulmonary TB. Furthermore, TB is the most
of the lung via the bronchi, many secondary pulmonary common cause of haemoptysis in India. Severity of
lesions develop. Early in the illness, TB cavities are haemoptysis in pulmonary TB varies from blood-stained
moderately thick walled, usually have a smooth inner sputum to massive haemoptysis. Massive haemoptysis
surface, lack an air-fluid level and are surrounded by an usually results from rupture of a bronchial artery (1).
area of consolidation. Later, in the chronic phase of the Chest pain may be dull aching in character. Acute chest
disease, the wall may become thin, and the cavities may pain can occur in TB pleurisy or in pneumothorax; with
appear spherical. severe pain occurring at the height of inspiration. In
diaphragmatic pleurisy, pain is referred to the ipsilateral
SYMPTOMS shoulder when central part of the diaphragm is involved.
Occasionally chest pain can occur from fracture of ribs
Pulmonary TB is a disease of protean manifestations due to violent coughing. Breathlessness results from
and can mimic many diseases. Previous accounts extensive disease or if complications such as bronchial
referred to the development of erythema nodosum, obstruction, pneumothorax or pleural effusion occur.
phlyctenular conjunctivitis and fever at the time of Localized wheeze can occur due to endobronchial TB or
220 Tuberculosis
because of the pressure of enlarged lymph nodes on the muscles in front of the thorax. A light tap over the
bronchus. sternum produces fibrillary contractions, at some
distance off, in the pectoral muscles.
PHYSICAL SIGNS High-pitched [tubular] bronchial breathing can be
heard in patients with TB pneumonia. Bronchial
A thorough general physical examination should be done
breathing can be low-pitched [cavernous] if there is an
in all patients with pulmonary TB. Anaemia and cachexia
underlying cavity in the lung or an open pneumothorax.
may be observed in severe cases. Tachycardia can occur
A special type of high-pitched bronchial breathing with
and is usually proportional to the fever. Digital clubbing
an “echo-like” quality [amphoric breathing] is indicative
occurs rarely in advanced cases and with superadded
of a large cavity with smooth walls or a pneumothorax
suppuration. There can be an increase in the respiratory
communicating with a bronchus. It resembles the sound
rate. Extra-pulmonary TB foci such as cold abscess,
produced by blowing across the mouth of a bottle and
enlarged cervical and mesenteric lymph nodes, defor-
consists of one or more low-pitched fundamental tones
mity or localized immobility of the spine, epididymitis,
and a number of high-pitched overtones. Vocal fremitus
etc., can be discovered on general physical examination.
is increased when lung is consolidated or contains a large
In addition, general physical examination may also reveal
cavity near the surface. Vocal fremitus is diminished
phlyctenular conjunctivitis or keratitis. Further, signs of
when the corresponding bronchus is obstructed and is
meningeal irritation and focal neurological signs may be
absent when there is pleural effusion or thickening. The
apparent in patients with extra-pulmonary focus in the
presence of fine crepitations, especially post-tussive
nervous system. Associated signs of protein energy
crepitations, is an important sign of TB infiltration. A
malnutrition such as anasarca, change in hair colour and pleural rub is characteristic of pleurisy.
leuconychia may occur. Adult patients with chronic Hippocratic succussion is the splashing sound which
disease can present with lower body-mass index [BMI]. can be heard when a patient who has both air and fluid
Respiratory system examination may reveal displace- in the pleural cavity is shaken or moved suddenly. Post-
ment of the trachea and the heart depending on the tussive suction, a sucking noise resembling that produced
underlying pathology. Asymmetrical abnormalities of by an India-rubber ball that is springing open again, can
the chest wall such as retraction, fibrosis or collapse and be heard after a coughing, over a cavity in the lung when
prominence in pleural effusion, emphysema or pneumo- its walls are not too rigid. It occurs due to re-entry of air.
thorax may be observed. Undue prominence of the
clavicular head of the sternocleidomastoid muscle [Trail’s DIAGNOSIS
sign] on one side may be indicative of apical fibrosis due
to TB. Mobility of any part of the chest wall may be The diagnosis of primary and post-primary forms of
restricted on the affected side. A dull percussion note pulmonary TB involves detection and isolation of
can occur as a result of consolidation, collapse of the lung, Mycobacterium tuberculosis (6-12). In addition, identifi-
or thickened pleura or extensive infiltration of the lung cation of the mycobacterial species and determination
due to TB. A stony dull note can be elicited over a pleural of their susceptibility to antimycobacterial drugs are
effusion or empyema. Hyperresonance on percussion is required for management.
encountered in pneumothorax. Cracked-pot sound may
be elicited in cases where percussion is practiced over a Tuberculin Skin Test
cavity which communicates with bronchus of moderate Tuberculin skin test [TST] is useful for the detection of
size and is most distinct when the mouth is open. It infection with Mycobacterium tuberculosis which leads
results due to a sudden expulsion of air through a to the development of sensitivity to certain antigenic
constricted orifice. It has a hissing character, combined components of the organisms called “tuberculins”.
with a clinking sound like that produced by shaking coins Intracutaneous injection of tuberculin results in a classic
together. It is a rare finding. Cracked-pot sound is often delayed [cellular] hypersensitivity reaction. A delayed
produced in healthy children when percussion is hypersensitivity reaction to tuberculin may indicate
performed during crying. Myotactic irritability or myoi- previous natural infection with NTM or vaccination with
dema can occur due to hyperirritability of malnourished bacille Calmette-Guérin.
Haematology frequently atypical, particularly in the late stage of HIV

Haematological abnormalities in pulmonary TB include infection, and include non-cavitary disease, lower lobe
anaemia, leucocytosis, leucopenia, purpura, leukaemoid infiltrates, hilar lymphadenopathy and pleural effusion.
reaction and polycythaemia vera.
Radiology
Standard posterior-anterior and lateral radiographs of
the chest should be obtained in patients who have signs
and symptoms suggestive of pulmonary TB. The initial
radiological manifestations include parenchymal
infiltration with ipsilateral lymph node enlargement.
Hilar or mediastinal lymph node enlargement in TB is
usually unilateral and this lymph nodal enlargement
persists longer than the parenchymal lesions.
Calcification of the lymph nodes and the lung lesions
could occur several years after infection. In adults, the
lesions may be patchy or nodular infiltrates and may
occur in any segment. Dense and homogeneous lesions
with lobar, segmental or subsegmental distributions are
also encountered frequently [Figures 14.1A, 14.1B, 14.2,
14.3A, 14.3B and 14.4]. Cavitation, often multiple, occurs
in immunocompetent individuals, but is rare in
Figure 14.3A: Chest radiograph [postero-anterior view] showing
immunocompromised individuals. The X-ray features of extensive parenchymal infiltrates in the right lung. Few scattered
pulmonary TB in HIV-seropositive patients are infiltrates are also seen in the left lung. The patient had multidrug-
resistant pulmonary tuberculosis
Figure 14.2: Chest radiograph [postero-anterior view] showing Figure 14.3B: Chest radiograph [postero-anterior view] of the same
extensive parenchymal lesions in the left lung. Few scattered lesions patient taken a year later showing pneumothorax on the right side
are also seen in the right lung. The sputum smear and culture were and a large cavity in the left lung. The patient did not respond to
positive for Mycobacterium tuberculosis treatment and died
222 Tuberculosis
are evenly distributed throughout the lung. Computed

tomography more accurately defines the group of lymph
nodes involved, their extent and size. The lymph nodes
with central low attenuation and peripheral rim
enhancement, especially with contrast, strongly suggest
a diagnosis of mycobacterial infection. Complications of
TB, such as post-TB bronchiectasis, aspergilloma etc.,
are better diagnosed with the help of a CT.
Other radiographic findings in pulmonary TB include
atelectasis and fibrotic scarring with retraction of the hila
and deviation of the trachea. Unilateral pleural effusion
may be the only radiographic abnormality in pleural TB.
Rarely, chest radiographs may be normal especially in
patients with endobronchial TB and HIV infection. It is
important to compare the current chest radiographs with
previous radiographs done months or years earlier, so
that subtle changes can be detected. Progression of lesions
on serial chest radiographs indicates active disease.
Apical-lordotic or oblique view of, chest may aid in
visualization of lesions obscured by bony structures or
Figure 14.4: Chest radiograph [postero-anterior view] of a patient the heart. Contrast-enhanced CT [CECT] and magnetic
with sputum smear-negative and culture-positive pulmonary resonance imaging [MRI] of the chest may be useful in
tuberculosis defining intrathoracic lymph nodes, nodules, cavities,
More typical post-primary TB with upper lobe infiltrates cysts, calcification and vascular details in the lung
and cavitations is seen in the earlier stages of HIV parenchyma. Bronchial stenosis or bronchiectasis can
infection. be defined by bronchography and CT of the chest. Fluoro-
Computed tomography [CT] is more sensitive than scopy may be useful in the detection of the mobility of
chest radiograph in detecting subtle parenchymal thoracic structures.
changes and mediastinal involvement. Primary TB
Fibreoptic Bronchoscopy
typically appears as air-space consolidation with hilar
or mediastinal lymphadenitis. Post-primary TB most Patients with positive skin tests and abnormal chest
commonly appears as nodular and linear opacities at the radiographs compatible with TB pose diagnostic
lung apex. The CT findings of early bronchogenic spread problems and therapeutic dilemma [to treat or not to treat
of post-primary TB include centrilobular nodules [2 to 4 for TB] to chest physicians. Microbiologic confirmation
mm] or branching linear structures. These findings of TB among sputum smear-negative is increasingly
correspond to caseous material filling the bronchioles important because of an increasing incidence of smear
(13), and this is referred as “tree-in-bud” appearance. negativity, especially among immunocompromised
Cavitations usually occur at the centrilobular area and hosts. Fibreoptic bronchoscopic studies provide various
may progress to a larger coalescent cavity. The CT can types of specimens [aspirate, brush, lavage fluid and
document miliary disease even when chest radiograph biopsy] for early diagnosis of sputum smear-negative
is normal. The CT findings of early miliary dissemination pulmonary TB. An early diagnosis of TB is possible in
commonly include ground-glass opacification with nearly one-third of sputum smear-negative pulmonary
barely discernible nodules. On high-resolution computed TB, if different bronchoscopic procedures are employed
tomography [HRCT], miliary TB typically shows fine, instead of a single procedure alone during bronchoscopy
nodular or reticulonodular pattern with nodules (14-17). The overall yield of bronchoscopy is greater than
involving both intralobular interstitium, interlobular 90 per cent, especially when culture were included in
septa and subpleural, and perivascular regions. Nodules analysis (18). Examination and culture of post-broncho-
scopy sputum also had high diagnostic yield [93%] (19). tuberculosis can be isolated from blood, gastric aspirate,
The topical anaesthetic agents that are used during bronchial washings, BAL fluid, pleural fluid, pus,
bronchoscopic procedure had inhibitory effect on cerebrospinal fluid, urine, bone marrow biopsy and other
mycobacteria. Therefore, these agents should be carefully tissue biopsy specimens. All diagnostic specimens should
used. Bronchoscopic examination may show normal be collected before the patient is given antituberculosis
bronchial mucosa to ulcerative lesions, granulomatous treatment.
lesions, and ulcerative-granulomatous tumour-like Sputum microscopy is the earliest and quickest
lesions and residual fibrotic stenosis. Because of high procedure for the preliminary diagnosis of pulmonary
mortality in miliary TB, it is imperative that the diagnosis TB. Patients should be instructed that the material
is confirmed as quickly as possible. In miliary TB, bron- brought out from the lungs after a productive cough.
choscopy is diagnostic in 73 to 83 per cent of cases (20). Patients should be instructed not to submit the naso-
The yield of bronchoscopy for diagnosis of pulmonary pharyngeal discharge and saliva. The patient should
TB in HIV infected patients is similar to that in patients rinse his/her mouth with water before specimen
without HIV infection and transbronchial biopsy collection to remove materials that interfere with the
provides incremental diagnostic information (14). In culture results. Sputum collection should be done in an
paediatric patients the gastric lavage is superior to isolated, well-ventilated area. Sputum specimen should
bronchoalveolar lavage [BAL] for bacteriologic confirma- be collected in a wide-mouth, rigid container with tight-
tion of pulmonary TB. The overall bacteriologic yield was fitting screw tops. If the patient cannot produce sputum,
34 per cent while gastric lavage alone was positive in 32 deep coughing may be induced by inhalation of an
per cent of the cases (21). aerosol of warm hypertonic [3% to 15%] saline. Sputum
Indications for bronchoscopy as a diagnostic tool for containers should be examined in each patient. The bacilli
pulmonary TB may include: [i] patients suspected of can be stained with basic fuchsin dyes [Ziehl-Neelsen or
having pulmonary TB with negative smears and in Kinyoun method] or with a fluorochrome [auramine-
whom treatment must be started due to clinical status; rhodamine] staining. The positive predictive value of a
[ii] suspicion of associated neoplasia; [iii] selected patients properly performed smear is more than 90 per cent for
with negative cultures; and [iv] lack of material being pulmonary TB.
obtained by simpler methods. However, it has been
demonstrated that sputum induction is a safe procedure DIFFERENTIAL DIAGNOSIS
with a high diagnostic yield and high agreement with Tuberculosis can practically involve all organs of the
the results of fiberoptic bronchoscopy for the diagnosis body and can simulate most of the diseases. Diseases
of pulmonary TB in both HIV-seronegative and HIV- which are to be differentiated from pulmonary TB are
seropositive patients. Sputum induction was well listed in Table 14.1. However, by no means this list is
tolerated, involved low-cost, and provided the same, if exhaustive.
not better, diagnostic yield compared with bronchoscopy
in the diagnosis of smear-negative pulmonary TB (22,23). Bacterial Pneumonia
In a decision analysis model to assess the overall utility
Bacterial pneumonia, especially occurring in the upper
of BAL in clinically suspected sputum smear-negative
part of the lung, may mimic TB. In acute pneumonia,
pulmonary TB, it has been suggested that, in a region of
symptoms occur suddenly and a raised white blood cell
high TB prevalence, empirical treatment is the best course
count may point to the diagnosis. If sputum is negative
of action (17).
for Mycobacterium tuberculosis, antibiotics which have no
effect on Mycobacterium tuberculosis can be given for seven
Diagnostic Mycobacteriology
to ten days. A rapid fall in temperature may occur follow-
The definitive diagnosis of pulmonary TB is made by ing treatment with antibiotics if the lesion is due to acute
the isolation and identification of the infecting organism. pneumonia. The patient may be re-evaluated after a
All patients presenting with cough and sputum for more course of antibiotics with a chest radiograph which may
than three weeks must have their sputum examined for show clearance of the lesions in acute pneumonia.
Mycobacterium tuberculosis. In addition, Mycobacterium However, it should be noted that shadows may look
224 Tuberculosis
Table 14.1: Differential diagnosis of pulmonary stic feature of actinomycosis is the demonstration of
tuberculosis “sulphur granules” in sputum, pus or tissue specimens.
Infections These are usually yellow and consist of aggregated micro-
Bacterial pneumonia organisms. Aspergillus is responsible for four types of
Lung abscess pulmonary manifestations, viz: allergic broncho-
Fungal and miscellaneous bacterial infections pulmonary aspergillosis [ABPA], aspergilloma, chronic
Bronchogenic carcinoma
necrotizing pulmonary aspergillosis and invasive
Bronchiectasis
Bronchial asthma aspergillosis. Allergic bronchopulmonary aspergillosis
Sarcoidosis is characterized by asthma-like symptoms, eosinophilia,
Pneumoconiosis fleeting pulmonary infiltrates, a positive immediate skin
Cardiovascular disease test response to aspergillin, elevated serum IgE and anti-
Congenital abnormalities
Aspergillus IgG antibodies. Aspergilloma occurs in
Other diseases
Hyperthyroidism
patients with pre-existing TB or other cavities and these
Diabetes mellitus patients can have high serum IgG antibody titres of
Aspergillus. Invasive aspergillosis usually occurs in
smaller after the antibiotic course if there is collapse of immunocompromised patients. Blastomycosis can be
the part of the lung or pneumonia due to obstruction of diagnosed by demonstration of yeast-like organisms with
a bronchus. Pneumonia due to Pneumocystis jiroveci is a highly refractile cell wall and multiple nuclei in sputum
common in patients with AIDS. If the sputum exami- samples. Patients with coccidioidomycosis can be
nation is non-contributory, BAL fluid examination for diagnosed by showing spherules in the sputum stained
Mycobacterium tuberculosis and Pneumocystis jiroveci cysts with Gomori’s or Papanicolaou’s stains. Cryptococcosis
is indicated (17,24). can be identified by staining the biological specimens
with India ink and demonstration of doubly refractile
Lung Abscess cell wall, the presence of budding and the clean capsule.
Viable organisms in macrophages can be seen in
Patients with lung abscess often produce foul-smelling histoplasmosis. Candidiasis can occur in pulmonary TB
purulent sputum. Clubbing of fingers is a prominent patients with immunodeficiency.
feature in these patients. Peripheral blood examination
reveals neutrophilic leucocytosis. Ziehl-Neelsen staining Bronchogenic Carcinoma
is negative for Mycobacterium tuberculosis.
A solid round tumour in the chest radiograph may be
Fungal and Miscellaneous Bacterial Infections difficult to distinguish from a well-circumscribed TB
lesion. Both bronchogenic carcinoma and pulmonary TB
The important fungal diseases of the lung that may mimic cause weight loss, cough, blood-streaked sputum and
pulmonary TB include aspergillosis, blastomycosis, fever. Bronchogenic carcinoma may also cavitate.
coccidioidomycosis, cryptococcosis, and histoplasmosis. Bronchogenic carcinoma can produce post-obstructive
Other miscellaneous bacterial infections can also simulate pneumonitis and lung abscess. The patient with broncho-
pulmonary TB and these include nocardiosis and genic carcinoma is usually a chronic smoker and sputum
actinomycosis. Nocardia micro-organisms are common will be negative for Mycobacterium tuberculosis. Confir-
bacterial inhabitants of soil. Examination of sputum or mation of diagnosis requires bronchoscopic biopsy in
pus reveals crooked, branching, beaded, Gram-positive these patients.
filaments. Most Nocardia microorganisms are acid-fast
in direct smears if a weak acid is used for decolourisation. Bronchiectasis
The organisms often take up silver stains. Actinomycosis
is an indolent, slowly progressive bacterial infection Patients with bronchiectasis have a long history of
caused by a variety of Gram-positive, non-spore forming respiratory symptoms, especially since childhood. They
anaerobic or microaerophilic rods. The most characteri- produce purulent sputum. Clubbing of fingers is a
prominent sign and coarse bubbling crepitations can be when enlarged left atrium compresses the left recurrent
heard on auscultation. Sputum examination is negative laryngeal nerve [Ortner’s syndrome] and this may be
for Mycobacterium tuberculosis. The middle and lower mistaken for hoarseness due to TB. Radiographic abnor-
lobes [or lingula on the left side] are commonly involved malities seen in haemosiderosis due to long-standing
in bronchiectasis. The CT of the chest and bronchography mitral stenosis can be confused with miliary TB.
will aid in the diagnosis. Haemoptysis can also occur in patients with primary or
secondary pulmonary arterial hypertension and in severe
Bronchial Asthma pulmonic stenosis. Careful examination of the heart and
Patients with bronchial asthma often manifest wheezing. appropriate investigations [electrocardiogram and
echocardiogram] will help in the differential diagnosis.
They often give history of allergy to inhalants or
ingestants. However, a localized wheeze can occur in TB
Congenital Abnormalities
if a bronchus is obstructed by an enlarged lymph node
or if there is TB bronchitis. Bronchial asthma can be Dermoid cysts, arteriovenous fistulae and hamartomas
diagnosed by demonstrating reversibility in pulmonary may require differentiation from pulmonary TB.
function after inhalation of bronchodilator aerosols. Sequestration of the lung may produce difficulty in
diagnosis, if associated with bronchiectasis or purulent
Sarcoidosis sputum and fever. Bronchoscopy, aortography, CT and
sputum examination can facilitate the diagnosis.
Sarcoidosis usually presents with bilateral hilar
lymphadenopathy and pulmonary infiltration. It can also
present with pulmonary infiltrates or nodular lesions Other Diseases
without mediastinal lymphadenopathy. In these Hyperthyroidism and diabetes mellitus can have
situations it is difficult to differentiate these lesions from symptoms such as loss of weight, easy fatigability and
pulmonary TB, especially miliary TB. These patients often malaise which can be mistaken for the constitutional
have negative tuberculin test and the sputum is negative symptoms associated with TB. Appropriate investiga-
for Mycobacterium tuberculosis (25). Almost every organ tions will facilitate the diagnosis.
of the body can be involved in sarcoidosis and the tissue
biopsy reveals non-caseating epithelioid cell granulomas.
PRACTICAL APPROACH TO THE DIAGNOSIS OF
ACTIVE PULMONARY TUBERCULOSIS
Pneumoconiosis
Occupational exposure to silicon dioxide, asbestos, coal Even in a country like India where TB is highly endemic,
dust, beryllium, ferrous oxide, etc., and hypersensitivity diagnosis of active pulmonary TB can be a diagnostic
reactions to organic inhalants can cause pulmonary dilemma. The following criteria would indicate active
infiltration that may mimic pulmonary TB. Conglomerate pulmonary TB. These include: [i] clinical signs of infection
masses and even cavitation can occur in silicosis. and features of TB toxaemia [fever with evening rise,
Sometimes TB develops in a patient with silicosis [silico- night sweats, malaise, weight loss, etc.]; [ii] progressive
tuberculosis]. Coal miners suffering from rheumatoid radiographic changes; [iii] microbiological or histo-
arthritis can develop round shadows in the lung pathological evidence of TB infection; and [iv] response
resembling TB. Some patients with pneumoconiosis to therapeutic trial with antituberculosis treatment. Of
develop progressive massive fibrosis. A carefully elicited these, microbiological or histopathological evidence
occupational history and absence of Mycobacterium [Figure 14.5] is conclusive and the remaining are
tuberculosis in the sputum help in the diagnosis. suggestive.
Cardiovascular Diseases TREATMENT

Haemoptysis can occur in patients with mitral stenosis. The reader is referred to the chapter “Treatment of
In addition, hoarseness of voice occurs in mitral stenosis tuberculosis” [Chapter 52], for more details.
226 Tuberculosis
8. American Thoracic Society. Diagnostic standards and

classification of tuberculosis in adults and children. Am J
Respir Crit Care Med 2000;161:1376-95.
9. Schluger, Rom WN. Current approaches to the diagnosis of
active pulmonary tuberculosis. Am J Respir Crit Care Med
1994;149:264-7.
10. Shinnick TM, Good RC. Diagnostic mycobacteriology
laboratory practices. Clin Infect Dis 1995;21:291-9.
11. Steingart KR, Ramsay A, Pai M. Optimizing sputum smear
microscopy for the diagnosis of pulmonary tuberculosis.
Expert Rev Anti Infect Ther 2007;5:327-31.
12. Manjunath N, Shankar P, Rajan L, Bhargava A, Saluja S,
Shriniwas. Evaluation of polymerase chain reaction for the
diagnosis of tuberculosis. Tubercle 1991;72:21-7.
13. Im JG, Itoh H, Lee KS, Han MC. CT- pathology correlation of
pulmonary tuberculosis. Crit Rev Diagn Imaging 1995;36:227-
85.
14. Kennedy DJ, Lewis WP, Barnes PF. Yield of bronchoscopy
for the diagnosis of tuberculosis in patients with human
immunodeficiency virus infection. Chest 1992;102:1040-4.
15. Vijayan VK, Paramasivan CN, Sankaran K. Comparison of
bronchoalveolar lavage fluid with sputum culture in the
diagnosis of sputum smear negative pulmonary tuberculosis.
16. Chawla R, Pant K, Jaggi OP, Chandrashekhar S, Thukral SS.
Fibreoptic bronchoscopy in smear negative pulmonary
tuberculosis. Eur Respir J 1988;1:804-6.
17. Mohan A, Pande JN, Sharma SK, Rattan A, Guleria R,
Figure 14.5: Pulmonary tuberculosis. Photomicrograph showing Khilnani GC. Bronchoalveolar lavage in pulmonary tuber-
bronchial cartilage with ossification [thin arrow], marrow culosis: a decision analysis approach. QJM 1995;88:269-76.
development [asterisk] and bronchial mucosal glands [upper panel, 18. Mohan A, Sharma SK. Fibreoptic bronchoscopy in the
left; Haematoxylin and eosin x 60], bronchial tissue exhibiting diagnosis of sputum smear-negative pulmonary tuberculosis:
epithelioid granulomas [arrow heads], lymphocytic infiltration, acini current status. Indian J Chest Dis Allied Sci 2008;50:67-78.
of bronchial mucosa [upper panel right; Haematoxylin and eosin x 19. de Gracia J, Curull V, Vidal R, Riba A, Orriols R, Martin N, et
60; lower panel right; Haematoxylin and eosin x 200] and alveoli al. Diagnostic value of bronchoalveolar lavage in suspected
with anthracotic pigment [thick arrow] [lower panel, left; pulmonary tuberculosis. Chest 1988;93:329-32.
Haematoxylin and eosin x 60] 20. Pant K, Chawla R, Mann PS, Jaggi OP. Fibrebronchoscopy in
smear-negative miliary tuberculosis. Chest 1989;95:1151-2.
REFERENCES 21. Somu N, Swaminathan S, Paramasivan CN, Vijayasekaran
D, Chandrabhooshanam A, Vijayan VK, et al. Value of
1. Ducati RG, Ruffino-Netto A, Basso LA, Santos DS. The bronchoalveolar lavage and gastric lavage in the diagnosis
resumption of consumption-a review on tuberculosis. Mem of pulmonary tuberculosis in children. Tuber Lung Dis
Inst Oswaldo Cruz 2006;101:697-714. 1995;76:295-9.
2. Grange JM. Mycobacteria and human disease. London: 22. Conde MB, Soares SL, Mello FC, Rezende VM, Almeida LL,
Arnold; 1996. Reingold AL, et al. Comparison of sputum induction with
3. Miller FJW. Tuberculosis in children. Edinburgh: Churchill fiberoptic bronchoscopy in the diagnosis of tuberculosis:
Livingstone; 1982. experience at an acquired immune deficiency syndrome
4. Balasubramanian V, Wiegeshaus EH, Taylor BT, Smith DW. reference center in Rio de Janeiro, Brazil. Am J Respir Crit
Pathogenesis of tuberculosis: pathway to apical localisation. Care Med 2000;162:2238-40.
Tuber Lung Dis 1994;75:168-78. 23. Anderson C, Inhaber N, Menzies D. Comparison of sputum
5. Alvarez S, Shell C, Berk SL. Pulmonary tuberculosis in elderly induction with fiberoptic bronchoscopy in the diagnosis of
men. Am J Med 1987;82:602-6. tuberculosis. Am J Respir Crit Care Med 1995;152:1570-4.
6. Enarson DA, Grosset J, Mwinga A, Hershfield ES, O’Brien R, 24. Sharma SK, Pande JN. Fiberoptic bronchoscopy. Indian J
Cole S, et al. The challenge of tuberculosis: statements on Chest Dis Allied Sci 1988;30:163-5.
global control and prevention. Lancet 1995;346:809-19. 25. Sharma SK, Mohan A, Guleria R, Padhy AK. Diagnostic
7. Crofton J, Horne N, Miller F. Clinical tuberculosis. New Delhi: dilemma: tuberculosis? or, sarcoidosis? Indian J Chest Dis
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Lower Lung Field Tuberculosis
15
G Ahluwalia, SK Sharma
INTRODUCTION view of the proximity of the lesion to hilum, the term

‘hilar and perihilar TB’ was also used by a few authors
Classically, the post-primary pulmonary tuberculosis
(17,18). However, Ostrum and Saber (16) suggested that
[TB] is a disease located predominantly in the upper
various terms used by different authors were infact
lobes. Since Laennec’s era, lower lung field TB was
referring to the same entity.
considered a rarity. In fact, Laennec himself opined that
The lower lung field is defined as the area on the
TB hardly ever developed in the middle or lower lobes
postero-anterior [PA] chest radiograph, which extends
of the lungs (1). Throughout the 19th century, most of
below an imaginary horizontal line traced across the
the authors were of the view that involvement of the
hilum and includes the parahilar regions. A standard PA
lower lung field from TB was an irrelevant issue (2,3).
chest radiograph is ordinarily sufficient for the diagnosis
However, there was a school of thought holding a diver-
of pulmonary TB. Since lateral films of the chest are
gent view. In 1886, Kidd stated that “the apex of lower
available very infrequently, it is difficult to identify the
lobe is very prone to TB disease and may be attacked
exact topographic location of the lesion, i.e., whether the
before the apex of the upper lobe” (4). Subsequently, two
disease is confined to the lower lobe only or is present in
years later, Fowler stated that “the upper and posterior
the middle lobe and lingula as well. Therefore, the term
part of the lower lobe is a spot only second in point of
‘lower lung field TB’ has come into vogue. In a PA
vulnerability to the apex itself’” (5). Except these two
radiograph of the chest, lower lung field includes the
early documentations, the literature is silent over the
middle lobe and lingula in addition to the lower lobe.
occurrence of lower lung field TB till the first quarter of
the 20th century. Subsequently, many authors (6-11)
PREVALENCE
concluded that lower lung field may be the site of pulmo-
nary TB in specific situations which one encounters rather The prevalence of lower lung field TB has ranged from
frequently. Therefore, a high index of suspicion is the 0.003 to 17 per cent. In fact, Ross (19) reported a high
key to the diagnosis of lower lung field TB. prevalence of 18.3 per cent in their series. The reason for
the wide variation in the prevalence is probably due to
TERMINOLOGY OF LOWER LUNG FIELD confusion in the terminology used [basal, parahilar,
TUBERCULOSIS lower lobe, lower lung field] and selection bias
[hospitalized or ambulatory patients].
It is important to understand the meaning of the term The prevalence of lower lung field TB in studies
‘lower lung field TB’. In the earlier reports (4-11), the reported from India has been observed to be higher than
term ‘basal TB’ was frequently used. However, with the that reported in western studies [Table 15.1]. This may
advent of lateral radiographs of the chest, the term ‘lower be due to the fact that a majority of Indians tie their
lobe TB’ had been used by various authors (12-16). In clothes [women their sari and men their loin cloth] tightly
228 Tuberculosis
Table 15.1: Prevalence of lower lung field tuberculosis of patients with lower lung field TB were less than 40 to
years old while Parmar (24) reported that 46 per cent of
Study (reference) Year No. of Prevalence
pulmonary of lower lung the patients were less than 20 years of age. However,
TB field TB Tripathy and Nanda (25) did not find a similar distri-
cases [%] bution in their study. Unlike previous reports, Chang
Colton (7) 1928 2335 0.003
et al (28) have observed that lower lung field TB is no
Ross (19) 1930 60 18.3
longer a disease of the young.
Du Fault (8) 1932 365 0.27
Associated Conditions
Reisner (20) 1935 4494 0.68
Hamilton and Fredd (12) 1935 349 2.9 Lower lung field TB appears to be more common in
Viswanathan (21) 1936 638 6.4 patients receiving corticosteroid treatment, patients with
Romendick et al (22) 1944 2354 2.7 hepatic or renal disease, diabetes mellitus, pregnancy,
Segarra et al (23) 1963 10962 0.85 silicosis and kyphoscoliosis (23,28,30-32).
Parmar (24) 1967 1455 3.4
Symptoms
Tripathy and Nanda (25) 1970 707 5.1
Mathur et al (26) 1974 5072 0.63 The duration of symptoms may be less than two weeks,
Berger and Granada (27) 1974 386 7.0 although the mean duration is twelve weeks (28). Most
Chang et al (28) 1987 1276 5.1 series report symptoms for less than six months
Wang et al (29) 2006 520 15.8 (23,27,28). Tripathy and Nanda (25) have observed that
about 20 per cent of patients reported within two weeks
TB = tuberculosis
and 70 per cent of patients within six months in their
series of 36 cases.
around the upper abdomen and this results in impaired Cough with variable amounts of expectoration is the
movement of diaphragm. This theory has been most frequent symptom (21,23,25). Mathur et al (26)
substantiated by Viswanathan (21), who studied the reported cough in 100 per cent cases. Many workers have
diaphragmatic movements on the radiographic screen noted haemoptysis as an important symptom (8,11,12,20-
in subjects accustomed to tight lacing around their waists. 24). Tripathy and Nanda (25) noted haemoptysis in
It has been suggested that the resultant impaired nearly two-thirds of the cases, while Romendick et al (22)
movement of diaphragm leads to costal type of breathing noted it in 75 per cent of cases.
[as in females], which leads to decreased ventilation, The general toxic manifestations of TB infection such
retarded blood circulation and lymphatic flow in lower as fever, chills, malaise, weakness and anorexia are also
lung fields, thus making them more vulnerable to TB. frequently present. Segarra et al (23) reported these
symptoms in about 40 per cent of their cases whereas
PATHOGENESIS Tripathy and Nanda (25) reported them in 86 per cent of
Besides the above cited palusible mechanisms (20,21), their cases.
the most common pathogenetic mechanism of lower lung
Signs
field TB is the ulceration of a bronchus by a lymph node
affected by TB with spillage of TB material into the The physical signs vary with the extent and character of
bronchus. Most authors have proposed that lower lung the lesions. Patients with extensive involvement of the
field TB occurs as a continuum of primary TB or soon lungs have pronounced signs of the underlying lesion.
after in the post-primary phase (23,24). However, patients who have involvement of a relatively
small area, especially those in whom the lesion is limited
to the apical segment of lower lobe, physical signs may
CLINICAL FEATURES
be scanty or even absent. However, physical signs are
In most studies (9,19,23,30), female preponderance and encountered more often in patients with lower lung field
predilection for patients under the age of 40 years has TB than in those with the classical form of upper lobe
been reported. Segarra et al (23) reported that 89 per cent pulmonary TB (27).
Lower Lung Field Tuberculosis 229
INVESTIGATIONS
Sputum Examination
Although sputum examination is the simplest way to
diagnose lower lung field TB, isolation of Mycobacterium
tuberculosis is difficult on smear or culture examination
(27,28). However, the diagnostic yield of sputum exami-
nation is better in patients with cavitary lesions (33).
Chest Radiograph
More than half of the cases of lower lung field TB have
right lung involvement, whereas one-third have left lung
involvement. Bilateral lesions are reported in 10 per cent
of the cases (24,25,30).
The radiographic findings in lower lung field TB
differ significantly from those found in upper lobe Figure 15.2: Chest radiograph [postero-anterior view] showing
disease (20). The most frequent radiographic finding is cavitary lesion in the right lower zone
consolidation, which is more confluent and extensive
than that found in upper lobe TB (33) [Figure 15.1]. lung field TB (23,25,34,35). Other radiological features
Cavitary lesions are also frequently seen, which may be include evidence of atelectasis or solitary mass with
single or multiple and may lie within an area of consoli- intrathoracic lymphadenopathy.
dation (27,28) [Figure 15.2]. Cavities may be large [3 to 4 The radiological features also have a prognostic value.
cm in diameter]. The presence of tension cavities [thin- The outcome is unfavourable in patients with lower lung
walled with fluid] is also a radiological feature of lower field TB who have lung collapse or pulmonary consoli-
dation in the chest radiograph (33,35).
Bronchoscopy
The early diagnosis of lower lung field TB is important
for prevention of severe sequelae. Fibreoptic broncho-
scopy is the preferred diagnostic modality for the
diagnosis of lower lung field TB. Abnormal broncho-
scopic findings in lower lung field TB include ulcerative
granuloma, mucosal erythema, submucosal infiltration
and fibrostenosis [Figure 15.3].
Fibreoptic bronchoscopy provides a higher diagnostic
yield than sputum examination, especially in patients
who present with radiographic findings of pulmonary
consolidation, lung collapse or solitary mass (22,33).
Fibreoptic bronchoscopy is also important in assessing
the severity of endobronchial lesions in lower lung field
TB. The outcome is unfavourable in patients with lower
lung field TB when fibreoptic bronchoscopy reveals
fibrostenosis or ulcerative granuloma. If severe fibro-
stenosis is present, early surgical intervention should be
Figure 15.1: Chest radiograph [postero-anterior view] considered to prevent damage of the lung distal to the
showing consolidation in the right lower zone obstruction (27,33).
230 Tuberculosis
details. Long-term follow-up is recommended to

diagnose possible relapse after the completion of
treatment. In India, patients with lower lung field TB
receive DOTS under the Revised National Tuberculosis
Control Programme [RNTCP] of the Government of
India. The reader is referred to the chapter “Revised
National Tuberculosis Control Programme” [Chapter 63] for
more details.
Tracheobronchial stenosis is an important compli-
cation of lower lung field TB leading to permanent damage
of lung distal to the obstruction. Since the outcome is poor
in patients with lower lung field TB, when fibreoptic
bronchoscopy findings show fibrostenosis or ulcerative
granuloma, these patients should be followed-up closely.
Figure 15.3: Mucosal erythema and submucosal infiltration The non-invasive methods such as chest radiograph and
observed during fibreoptic bronchoscopy in a patient with right lower flow-volume loops on pulmonary function testing are
lung field tuberculosis. Bronchoalveolar lavage revealed insensitive for detecting or monitoring tracheobronchial
Mycobacterium tuberculosis stenosis. In these patients, close follow-up with fibreoptic
bronchoscopy is necessary if chest radiograph shows no
MANAGEMENT significant improvement or clinical features that suggest
progression of endobronchial lesions after antituber-
Lower lung field TB presents a definite problem in diag- culosis therapy for a few months. Surgical intervention
nosis because of its location and radiographic findings. is indicated if re-examination with fibreoptic broncho-
Moreover, when TB is confined to lower lung field, it scopy shows no significant improvement or worsening
often masquerades as pneumonia, lung cancer, bron- of endobronchial involvement. However, if severe
chiectasis or lung abscess, thereby, delaying the correct fibrostenosis is present, early surgical intervention in the
diagnosis. The shift in age-distribution from the young form of sleeve operation is indicated before permanent
to the aged and non-specific clinical features adds sequelae such as damage of lung distal to the obstruction
another challenge in the diagnosis of lower lung field and respiratory failure occur (27,33).
TB (33,35). Therefore, TB should be considered a diag-
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Intern Med 1935;56:258-80. 34. Perez-Guzman C, Torres-Cruz A, Villarreal-Velarde H,
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232 Tuberculosis
Endobronchial Tuberculosis
16
SS Dhillon, NA Hanania
INTRODUCTION cent of patients with active TB (24-28). However, in recent

studies, a lower prevalence rate has been reported, which
Endobronchial tuberculosis [TB], which refers to the
is most likely due to the timely and more effective
involvement of trachea and bronchi, was first described
chemotherapy received by patients with TB (5-9). In fact,
in 1689 by an English physician, Richard Morton (1).
the current prevalence rate may be as low as 0.18 per
However, it remained mainly a post-mortem diagnosis
cent in areas where TB is not endemic (29). The difference
and was infrequently reported until the advent of
in prevalence between autopsy and bronchoscopy
bronchoscopy in the late 1920s (2-4). Subsequently, the
studies is likely due to the inclusion of microscopic
natural history of endobronchial TB was described in
involvement of airways in autopsy data that is not
large clinical and pathological series (2-4). Following the
detected by bronchoscopy (23). Endobronchial TB is
introduction of effective chemotherapy for TB, reports
mostly seen in patients between 21 to 40 years of age
on endobronchial TB decreased dramatically to the extent
and rarely in those 60 years or older (12,19,23). The
that no cases were reported in several large studies on
majority of studies report a female preponderance
the bronchoscopic evaluation of patients with TB (5-9).
(4,12,14,19,23,30). This may be due to the fact that the
More recently, several case series of patients with
implantation of organisms from infected sputum occurs
endobronchial TB have been published (10-20) and the
easily in women who tend to voluntarily suppress their
interest in this topic has re-emerged.
cough because of socio-cultural and cosmetic reasons
(19,31,32). Small airways in women may also contribute
EPIDEMIOLOGY
to the observed difference in prevalence.
The exact prevalence of endobronchial TB is not known.
In autopsy studies on patients with TB, the reported PATHOPHYSIOLOGY
prevalence has ranged from three per cent (21) to 72 per
cent (22) although most series report a rate of about 40 per Mechanisms of Endobronchial Infection
cent (23,24). This variation in prevalence rate may be due Five potential mechanisms for the spread of endo-
to the difference in severity of cases of TB studied and/or bronchial infection with TB have been suggested (3).
the extent of tracheobronchial tree evaluation (23). For
example, in a study published in the pre-chemotherapy
Extension from the Lungs by Direct Infiltration
era, more than 30 per cent of the patients with endo-
bronchial TB had concomitant pulmonary TB for a Direct spread probably occurs when bronchi in the
duration of more than two years, a fact that may explain immediate neighbourhood of an infected lung are
the high prevalence of endobronchial TB noted (23). involved. In general, tracheobronchial ulceration is more
Based on previously published bronchoscopic commonly seen adjacent to areas of extensive and
studies, endobronchial TB was reported in 10 to 20 per progressive parenchymal TB (23).
Endobronchial Tuberculosis 233
Implantation of Organisms from Infected Sputum Four of these patients had ulcerating endobronchial
granulomas. Direct perforation of TB lymph nodes into
The finding of endobronchial disease on the wall of
the bronchi is relatively uncommon in adults, especially
bronchi opposite the opening of a diseased lobe is likely
now in the post-chemotherapy era (38,39).
due to the implantation from infected material passing
In summary, although different mechanisms for the
over the mucous membrane. Auerbach (23) observed the
endobronchial spread of TB have been described, implan-
presence of gross airways ulcerations on the same side
tation of the organisms from infected sputum is likely
where cavities in the lung were present. These cavities
the most frequent mechanism in adults.
are a potential source of bacilli causing the endobronchial
involvement. However, in some cases, cavity formation
Macroscopic Appearance
may follow the diagnosis of endobronchial TB, pointing
to the possibility of other mechanisms (15). In addition, The earliest bronchoscopic sign of endobronchial TB is
the absence of endobronchial involvement in cases the finding of erythematous mucous membranes.
where large cavities are present argues against this Discrete tubercles may have a rough granulated appear-
mechanism (33). ance to the naked eye or may lead to shallow ulcers of
the mucous membrane that progress to deep ulcers
Haematogenous Dissemination involving the bronchial wall. Formation of extensive
granulation tissue may occasionally result in a tumour-
Haematogenous spread is possible but very rare, as
like growth into the lumen of the bronchus mimicking a
endobronchial TB is not commonly described in miliary
neoplasm. In most cases where ulcers are deep, healing
TB (23).
will be complicated by stenosis secondary to extensive
fibrosis. Bronchial stenosis may also result from oedema
Lymphatic Spread
or from extrinsic compression by a lymph node (23). On
This mechanism involves retrograde passage of the rare occasions, post-obstructive pneumonia, lung abscess,
tubercle bacilli through lymphatics from bronchioles and obstructive emphysema and subsequent bronchiectasis
sub-segmental bronchi to the main-stem bronchus. may develop distal to this stenosis (23).
Peribronchial infection of the lymphatics may be seen Autopsy studies suggest that ulcers are more common
histologically in some cases. However, the data by in region of the carina and posterior surface of the
Auerbach (23) suggests that in most cases the infection tracheobronchial tree (23). The size of these ulcers varies
starts in the submucosal region and progresses towards from 1 to 5 mm and their long axes are usually parallel
the adventitia. Only in few cases, infection is limited to to the cartilaginous rings (23). Ulcers may progressively
or starts from the adventitia, where lymphatics are coalesce leaving the cartilage partially exposed at the base
located. This fact argues against the lymphatic spread as of the ulcer (23).
a common mechanism. Endobronchial TB may be an integral part of the
parenchymal lung involvement with TB but this involve-
As a Part of the Primary Infection ment is overlooked, as smaller airways cannot be
accessed by bronchoscopy. Diffuse stenosis of small
In certain cases of primary TB a lymph node erodes into
a bronchus. The lymph node becomes attached to the bronchi distal to the fourth generation mimicking
bronchiolitis obliterans has been described (40).
bronchial wall because of the ongoing inflammatory
changes and, thus, the infection spreads through the
Microscopic Appearance
walls of the bronchus to the mucosal lining. This
mechanism is predominantly seen in children (34,35). Small, oval and round foci of epithelioid giant cell
Chang et al (36) reported endobronchial involvement in tubercles, with or without a central zone of caseation
12 of the 16 patients with intrathoracic TB lymphadeno- within the wall especially in the subepithelial region and
pathy. Baran et al (37) found endobronchial abnorma- in the region of mucous glands, are the early microscopic
lities in 15 of the 17 patients with intrathoracic TB findings with endobronchial TB. In advanced cases, these
lymphadenopathy in the absence of parenchymal lesions. foci are also present in the adventitia and in rare occasions
234 Tuberculosis
they may only be seen in the adventitia (23). Involvement Simultaneous involvement of other organs has been
of the cartilage is usually limited to very extensive cases. reported. Auerbach, hypothesized that endobronchial TB
Rupture of one of these submucosal foci results in represents a tendency towards the development of “tract
ulceration and gradual destruction of the wall of tuberculosis”. Concomitant intestinal and laryngeal
bronchus. The zone of caseation is usually surrounded involvement with TB was noted in 82 and 60 per cent of
by vascular granulation tissue and is occasionally autopsy cases respectively (23). However, these findings
covered by a pseudomembrane formed by fibrin exuded have not been reported in more recent studies and were
from capillaries in this granulation tissue. During the limited to older studies which included patients with
process of healing, granulation tissue replaces the inner progressive TB of a long duration.
zone of caseation and regenerating epithelium from all
sides will eventually cover the ulcer. Connective tissue LABORATORY AND RADIOLOGIC INVESTIGATIONS
ultimately replaces the cells and capillaries within the
granulation tissue. If this process is extensive and Sputum Examination
involves most of the circumference of the airway, stenosis
will eventually occur. Sputum smear for Mycobacterium tuberculosis has a low
yield [15% to 20%] (10,12) for the diagnosis of endo-
bronchial TB. This may be because expectoration of
CLINICAL COURSE
sputum is difficult due to mucus entrapment by proximal
The clinical presentation of endobronchial TB is variable. bronchial granulation tissue (10). Furthermore, ulceration
In adults, it may occur as primary or reactivation TB. of the involved mucosa may be necessary for obtaining
However, in children, it is usually a complication of a positive sputum smear (12). Thus, a negative sputum
primary TB. The onset of endobronchial TB may be acute smear does not exclude the diagnosis.
mimicking asthma, pneumonia and foreign body
aspiration (3,29,41,42) or insidious, simulating lung Chest Radiograph
cancer (10,43-47). Symptoms may start years after the Endobronchial TB usually co-exists with extensive
diagnosis and treatment of pulmonary TB (48). A barking pulmonary parenchymal or intrathoracic lymph node
cough has been reported in the majority of patients. involvement. However, 10 per cent to 20 per cent of the
Dyspnoea, chest pain, fever, generalized weakness, patients have a normal chest radiograph (10,12,25,30,53-
weight loss and haemoptysis may also be present (10,12). 58). Chest radiograph may show patchy infiltrates (15),
Sputum production is variable; bronchorrhoea [> 500 ml/ evidence of collapse [25% to 35%] or consolidation [35%
day] has been reported in rare cases (49). Physical to 60%] (10,12). Other radiological features include
examination may reveal diminished breath sounds or a hyperinflation, cavity formation, pleural effusion, miliary
localized wheeze (3,30). Wheezing is classically low- infiltrates and mediastinal lymphadenopathy (10,15).
pitched, constantly present, and heard over the same area
of the chest wall (2), but may disappear as the airways
Computed Tomography
become progressively narrowed. Partial airway obstruc-
tion may on rare occasions act as a one-way valve leading Computed tomography [CT] of the chest is an important
to distal air-trapping (3). Expectoration of bronchial tool for evaluation of endobronchial TB. While the
cartilages (50,51) and fistula formation between the right findings are non-specific, it may show endobronchial
and left main bronchi have also been described (52). involvement of both large and small airways. In fact, in
Bronchial stenosis is the most important complication some studies the endobronchial involvement is more
of endobronchial TB. It may present with slowly progres- pronounced in small airways than large airway (59-62).
sive shortness of breath years after the diagnosis and These CT findings have been well correlated with
treatment of pulmonary TB. Respiratory failure, difficult corresponding pathological findings by Im et al (61).
endotracheal intubation, need for tracheostomy and Findings on CT of endobronchial disease in small airways
death by suffocation may occur as a consequence of may include: poorly-defined nodules, centrilobular
tracheal stenosis (15). nodules, bronchial wall thickening and “tree-in-bud”
appearance [Figure 16.1] (59-61). All these findings are wall of the involved bronchus by the adjacent consoli-
best visualized on high resolution CT [HRCT ] (60). dation or of the inner wall by the absence of intraluminal
Centrilobular lesions reflect solid caseation material air. It is extremely difficult to differentiate endobronchial
within or around the terminal or respiratory bronchioles. TB from bronchogenic carcinoma by CT, and therefore,
Terminal tufts of the “tree-in-bud” may represent the bronchoscopy is ultimately needed. However, CT has the
lesions within the bronchioles and alveolar ducts, while advantage of revealing areas of the airway beyond the
the stalk may represent a lesion that affects the last order stenosis as well as the length of stenosis and the extent
bronchus within the secondary lobule [Figure 16.1] (61). of peribronchial soft tissue, lymph nodes involvement
The CT may also show stenosis or obstruction of the (20,66). Thus, CT complements bronchoscopy in evaluat-
major airways. A peribronchial cuff of soft tissue may be ing these patients and can also be used to monitor
seen (62,63). During the active TB stage, irregular and response to treatment (66).
circumferential luminal narrowing may be visualized. While it is very helpful, radiologic findings of endo-
However, during the fibrotic stage, wall thickening is bronchial TB are non-specific and can be seen in other
much less prominent and an equal distribution of smooth diseases. Conditions that may show bronchial wall
and irregular narrowing occurs (64,65). The CT may on thickening and luminal narrowing on CT, like
occasion show enlarged lymph nodes in the mediastinum sarcoidosis, amyloidosis, relapsing polychondritis and
and other parenchymal lesions, such as segmental
tracheopathia osteoplastica, should always be kept in
collapse, collapse with multiple low density areas,
mind (64). Evolving radiologic techniques such as
cavities and round low density lesions which most likely
multiplanar and 3D helical CT images with
represent mucoid impaction distal to obstruction (62,63).
reconstruction [virtual bronchoscopy] may play a better
An intra-luminal lower density polypoid mass with
role in evaluating the tracheobronchial tree in
narrowing may sometimes be seen in a bronchus (62).
endobronchial TB (64,65,67,68).
While the CT is extremely accurate in detecting focal
bronchial lesions, it is inaccurate in predicting whether
Spirometry
the lesion is endobronchial, submucosal or outside the
airway (62,63). In addition, it may not be possible to The most common abnormality seen on spirometry in
accurately assess the thickness of the bronchial wall in endobronchial TB is restriction. Lee and Chung (20)
many cases because of the loss of silhouette of the outer evaluated spirometry findings in 68 patients and
Figure 16.1: CT scan of the chest showing “tree-in-bud” pattern seen [arrows] in endobronchial tuberculosis [A]. This pattern refers to
peripheral, small centrilobular, and well-defined nodules that are connected to linear, branching opacities that have more than one
contiguous branching site, thus, resembling a “tree-in-bud” [arrows] [B]. In histopathologic studies, the “tree-in-bud” appearance correlates
well with the presence of plugging of the small airways with mucus, pus, or fluid; dilated bronchioles; bronchiolar wall thickening; and
peribronchiolar inflammation
236 Tuberculosis
demonstrated a restrictive abnormality in 47 per cent, Salkin and colleagues (24) presented one of the earliest
obstructive abnormality in 5.9 per cent, mixed in 23.5 serial follow-up data and documented the progression
per cent, and normal spirometry in 23.5 per cent of the of bronchial ulceration to polyp formation and stenosis
patients. The flow-volume loop abnormalities classically in three to six months. Bronchostenosis develops in 50 to
seen in patients with upper airway obstruction are rarely 90 per cent of patients despite effective therapy (10,19).
seen in endobronchial TB. Unlike patients with bronchial This complication which can present years after diagnosis
asthma, patients with endobronchial TB do not and therapy may involve the trachea or main-stem
have increased bronchial hyper-reactivity to inhaled bronchi. Ip and colleagues (10) showed that stenosis
histamine (69). developed in all but one of the 12 patients who had a
follow-up bronchoscopy within eight to forty-nine
Bronchoscopy months of completing antituberculosis therapy. Eight of
Bronchoscopy is the gold standard for diagnosis of these patients were asymptomatic including one who
endobronchial TB. The diagnosis can be missed in some had severe stenosis of the left main-stem bronchus.
cases with normal chest radiograph if bronchoscopy is Several bronchoscopic classifications of endobron-
not considered (70,71). Unlike pre-chemotherapy era chial TB have been proposed (14,19,20,73). The most
where tracheal ulcerations were commonly seen, most recent classification by Chung and Lee (19) describes
of the recent bronchoscopy series report more common seven forms of bronchoscopic findings [Figure 16.2] (19).
involvement of the main-stem and upper lobe bronchi Chung and Lee (19) studied 81 patients with endobron-
(12,16). Endobronchial biopsies usually reveal the classic chial TB who underwent serial bronchoscopy to examine
histological features of TB. These range from non-necrotic the predictive value of this classification. Bronchoscopic
epithelioid cell granulomas with no acid-fast bacilli [AFB] examination was initially performed every month until
to necrotic granulomas with abundant AFB. Bronchial there was no subsequent change in the endobronchial
brushings obtained along with biopsy increase the lesions followed by an examination every three months
diagnostic yield (72). until the completion of antituberculosis chemotherapy.
Bronchoscopy has been useful in learning about the Seven forms of bronchoscopic findings are described
natural history and progression of endobronchial TB. below.
Figure 16.2: Classification of endobronchial tuberculosis by bronchoscopic findings. Top: A, actively caseating type; B, oedematous-
hyperaemic type; C, fibrostenotic type; and D, tumorous type. Bottom: E, granular type; F, ulcerative type; and G, non-specific bronchitic
type
Reproduced with permission from “Chung HS, Lee JH. Bronchoscopic assessment of the evolution of endobronchial tuberculosis. Chest
2000;117:385-92 (reference 19)”
Non-specific Bronchitic Endobronchial Tuberculosis covered with caseous material. This endobronchial mass
may occlude the bronchial lumen and is frequently
Only mild mucosal swelling and/or hyperaemia are seen
mistaken for lung cancer. The prognosis of tumorous
on bronchoscopy in this form. The prognosis is overall
good and all cases resolve within two months of treatment. endobronchial TB is grave and the most unpredictable.
Seventy per cent of patients in this report (19) had fibro-
Granular Endobronchial Tuberculosis stenosis at the end of treatment. More tumorous lesions
can appear subsequently at different segmental bronchi.
In this form, the bronchoscopic appearance mimics The above classification closely correlates to the
scattered grains of boiled rice, and the underlying microscopic changes seen in endobronchial TB. Non-
bronchial mucosa shows severe inflammatory changes. specific bronchitic endobronchial TB corresponds to the
Only 20 per cent of the cases develop fibrostenosis.
initial lesion, which presents as simple erythema and
oedema of the mucosa with lymphocytic infiltration of
Oedematous-hyperaemic Endobronchial Tuberculosis
the submucosa. This is followed by submucosal tubercle
In the oedematous-hyperaemic form, severe mucosal formation which produces erythema, granularity
swelling with surrounding hyperaemia causing and partial bronchial stenosis, seen at bronchoscopy,
narrowing of the bronchial lumen is seen. Patients with caused by considerable congestion and oedema of the
these findings have poor prognosis as 60 per cent of cases mucosa. These represent the granular and oedematous-
develop fibrostenosis within two to three months after hyperaemic type, respectively. With more progressive
treatment, and 30 per cent progress to complete disease, caseous necrosis with formation of TB granulo-
obstruction of the bronchial lumen. mas at the mucosal surface is seen and constitutes the
actively caseating endobronchial TB. When the inflam-
Actively Caseating Endobronchial Tuberculosis
mation progresses through the mucosa, an ulcer, which
Caseating endobronchial TB is the most commonly seen may be covered by caseous material, is formed and this
form and bronchoscopy shows swollen and hyperaemic represents the ulcerative class. Finally, the bronchial
mucosa that is diffusely covered with whitish cheese- mucosal ulcer may evolve into hyperplastic inflam-
like material. Luminal narrowing at diagnosis is usually matory polyps, and the endobronchial tuberculous lesion
seen whether granulation tissue is present or not. A heals by fibrostenosis, explaining the next two stages seen
significant improvement of bronchial stenosis is seen on bronchoscopy.
with treatment, although 65 per cent of patients progress On rare occasions, TB lymph nodes may rupture into
to fibrostenosis. a bronchus (74). In the early stage, the lymph node may
be seen as a greyish-yellow mass protruding through the
Ulcerative Endobronchial Tuberculosis mucosa sometimes obstructing the lumen. The bronchial
This form is characterized by the presence of ulcers in wall may show haemorrhage and granulation tissue
the tracheobronchial tree. The prognosis is generally formation. A fistula may subsequently develop in the
good as most of the cases will completely resolve within bronchial wall with caseous material protrusion. The
three months of treatment. mucous membrane then becomes less inflammed and
evacuation of the node occurs. The opening then
Fibrostenotic Endobronchial Tuberculosis gradually closes and fibrosis with scarring of the
In the fibrostenotic form, a marked narrowing of the bronchial wall followed by bronchial stenosis may
bronchial lumen due to fibrosis is seen and patients show subsequently develop. Perforation of a lymph node into
no response to treatment. Progression of fibrosis despite the lumen of a bronchus may present as a pigmented
treatment may result in complete obstruction of the mass or stenotic bronchus with black pigmentation
bronchial lumen two or three months after treatment. overlying the mucosa (11,39,44,47,75,76). This pigmen-
tation is likely from the anthracotic material in lymph
Tumorous Endobronchial Tuberculosis nodes and has been termed “anthracofibrosis” (76).
Tumorous endobronchial TB class is characterized by the Chung and colleagues (76) demonstrated that 60 per cent
presence of an endobronchial mass whose surface is often of patients whose bronchoscopy showed bronchial
238 Tuberculosis
narrowing and black pigmentation had active TB. occurs in one to seven per cent of patients with pulmo-
Endobronchial TB should be strongly considered when nary TB. It is more commonly seen in patients with
such findings are encountered on bronchoscopy. diabetes mellitus, pregnancy, chronic renal disease and
All forms of endobronchial TB lie between the two malignancy. Endobronchial involvement has been
ends of the spectrum of healing and fibrostenosis. The reported in up to 75 per cent of these patients (89-95).
extent of disease progression (14) and formation of Therefore, there should be a low threshold to perform a
granulation tissue (11) are important determinants of the bronchoscopic examination in such patients. The reader
different forms and outcome. Bronchial stenosis is is referred to the chapter “Lower lung field tuberculosis”
inevitable in the presence of progressive disease. There- [Chapter 15] for further details.
fore, prompt diagnosis including timely bronchoscopy
and efficacious treatment are of paramount importance Elderly
in order to minimize the progression to bronchial steno- About 15 per cent of elderly patients with pulmonary
sis. The concern of worsening of TB and asphyxiation as
TB have concomitant endobronchial TB (45). Many of
a result of aspiration of caseous particles to opposite lung
these cases are diagnosed during a work-up for lung
as a result of bronchoscopy should not be a limiting factor cancer, or non-resolving pneumonia (44,45). The
to perform a bronchoscopy. These complications have
pathogenesis of endobronchial TB in the elderly is
not been described recently, despite the large number of
believed to be similar as in other age groups. Cough is
bronchoscopies performed on such individuals the most commonly observed symptom. Other symp-
(10,16,23).
toms, such as dyspnoea, haemoptysis, chest pain and
Bronchography hoarseness of voice may be present. Constitutional
symptoms, such as anorexia, weight loss and fatigue are
Bronchography was once used for the definitive
usually present in most of the patients. Endobronchial
diagnosis and preoperative evaluation of bronchial
appearances are similar to those described in younger
stenosis (27,77). However, with widespread availability subjects. Bronchial stenosis occurs in about 60 per cent
and imporvements in the CT scan this procedure is rarely
of elderly patients with endobronchial TB (45).
performed now.
Human Immunodeficiency Virus Infection
Endobronchial TB is not uncommon in patients with
Presence of an endobronchial mass should always raise human immunodeficiency virus [HIV] infection. In one
the suspicion of malignancy or TB co-existing with study, six out of 25 HIV-positive patients with TB who
malignancy (78), infection with nontuberculous myco- underwent bronchoscopy had endobronchial TB (96).
bacteria [NTM] (79-85), sarcoidosis (86), actinomycosis Endobronchial TB may be a part of primary infection in
(87) and papillomatosis (88). Presence of airway stenosis patients with HIV, and hilar and mediastinal lymph-
may be seen in other conditions. Focal stenosis may be a adenopathy is commonly seen on chest radiograph (96-
result of previous endotracheal intubation, or various 99). Other radiological findings described in these
systemic diseases that may involve the airways, such as patients include a normal chest radiograph, a miliary
Crohn’s disease and Behcet’s syndrome (88). Diffuse pattern and a small pleural effusion. Pulmonary
stenosis of the central airways may be seen in Wegener’s infiltrates are rare (96). The findings on bronchoscopy
granulomatosis, relapsing polychondritis, tracheobron- are similar to those observed in HIV-negative patients,
chopathia osteochondroplastica, amyloidosis, papillo- although the tumorous form has been more commonly
matosis, and rhinoscleroma (88). reported (96-98). Because the tumorous form is likely to
be caused by the erosion of a lymph node into a bronchus
SPECIAL SITUATIONS (19), the higher prevalence of mediastinal and hilar
lymphadenopathy in patients with HIV-associated TB
Lower Lung Field Tuberculosis
may explain why this finding is not uncommon in such
Tuberculosis involving the right middle lobe, lingular patients. Lymph node perforation into the airway in
division of left upper lobe and both lower lobes (89,90) HIV-associated TB has also been described by
bronchoscopy (96,99). Bronchial stenosis has not been Antituberculosis Treatment

reported in HIV-associated endobronchial TB.
Treatment of endobronchial TB is similar to the treatment
of pulmonary TB. The reader is referred to the chapter
Indian Experience
“Treatment of tuberculosis” [Chapter 52]. The addition of
Few case reports have been published describing inhaled streptomycin (107,109,110) and inhaled isoniazid
endobronchial TB in Indian adults (100-102). A large (111) to the standard therapy has improved outcomes in
study (103) reporting the bronchoscopic findings in 85 some studies but their efficacy in large randomized,
Indian children with active TB has been published. In controlled trials has not yet been evaluated.
that study, the prevalence of endobronchial TB was 9.4
per cent (103). In a series published by Parmar (93), 42 Corticosteroids
per cent of the 50 patients with lower lobe TB from a
Corticosteroids have been used empirically with
sanatorium in Amritsar were thought to have endo-
antituberculosis medications in some cases to prevent
bronchial TB based on clinical and radiographic findings,
bronchial stenosis (10,12,19). Lee and colleagues (12) felt
although it was confirmed in five of the 13 patients who
that corticosteroids may suppress the barking cough but
underwent a bronchoscopic examination. In a study
may not alter the course of the disease or prevent
assessing the usefulness of bronchoalveolar lavage in the
bronchostenosis. Hypersensitivity reaction associated
diagnosis of sputum smear-negative pulmonary TB from
with antituberculosis medications is another situation
New Delhi, endobronchial TB was not described in any
where corticosteroid therapy may be beneficial
of the 50 adult HIV-negative patients (104).
(41,112,113). Local endoscopic injection of corticosteroids
in endobronchial tuberculous lesions has been described
Endobronchial Involvement by
in one case report (114).
Nontuberculous Mycobacteria
Some studies have suggested a positive role for
Endobronchial involvement with NTM is rare and mostly corticosteroid therapy in children with lymph node TB
seen in patients with HIV (79-85). Most cases respond to causing bronchial obstruction (115-117). However, the
therapy without any residual stenosis. benefit of corticosteroids in this situation remains
speculative (10,15) and a recent randomised trial in adults
TREATMENT with endobronchial TB failed to show any beneficial
effect (118).
Before the introduction of streptomycin and para-
aminosalicylic acid [PAS] for clinical use, the treatment
of endobronchial TB lesions involved painting the small Bronchoscopy
ulcers directly with caustic soda or silver nitrate to Bronchoscopic procedures are helpful in relieving
enhance fibrosis (3,105). These methods, however, caused stenosis if used alone or in combination with chemo-
more fibrosis due to their effect on the surrounding therapy depending on the clinical situation in sympto-
normal tissue (3,105). Salkin et al (24) demonstrated that matic patients. Lee and colleagues (12) advocated
many of the endobronchial TB ulcers heal when the curettage with forceps during bronchoscopy for the
parenchymal disease is adequately treated. Effective drug removal of the pseudomembrane. Dilatation of the
therapy and preventive measures have altered the narrowed airway can be achieved with the use of dilators,
natural history of endobronchial TB (106,107). A high balloons or using the bronchoscope itself. Balloon
clinical index of suspicion and prompt bronchoscopy are dilatation is usually successful when the stenotic segment
essential for the early diagnosis of this condition, as it is short (14, 119,120). Repeated dilatation of the stenotic
can present several years after the actual treatment of segment may be required (23,100). Removal of tissue by
pulmonary TB (48,108). forceps and carbon dioxide [CO2] laser, or neodymium-
Treatment options currently available for patients yttrium aluminium garnet [Nd-YAG] laser is useful in
with endobronchial TB are listed below. some situations (121-123). Following tissue removal and
240 Tuberculosis
dilatation, patency of the stenotic area can be In conclusion, endobronchial TB is a frequently

maintained by the placement of self-expanding metallic undiagnosed complication of pulmonary TB. It is often
stent (124-127). Potential complications of such overlooked as bronchoscopy, which is the key for
procedures include perforation, injury, stent migration diagnosis, is not always performed in these patients (136-
and re-stenosis due to granulation tissue formation 138). The presentation of endobronchial TB may precede,
(127,128). Endoluminal dilatation and stenting is occur concomitantly or occur up to 17 years after the
currently recommended as first-line intervention for diagnosis and treatment of pulmonary TB (121).
managing tracheobronchial stenosis due to TB (126). Bronchoscopy should be considered in any patient with
a history of pulmonary TB and symptoms suggestive of
Surgery endobronchial involvement. Treatment involves
antituberculosis treatment along with bronchoscopic
In the early part of last century, collapse therapy by procedures or surgery as indicated. The role of adjuvant
inducing a pneumothorax, phrenic nerve paralysis or corticosteroids is unclear at this time.
thoracoplasty [surgical removal of several rib bones from
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Tuberculosis Pleural Effusion
17
AN Aggarwal
INTRODUCTION a lymph node] into the pleural space. Supportive

evidence comes from the operative findings of Stead and
The frequency of tuberculosis [TB] as a cause of pleural
co-workers (17), who could demonstrate such a focus in
effusion depends on the prevalence of TB in a particular
lung contiguous to the pleura in 12 of 15 patients with
population. In many regions of the world where TB is
TB pleuritis; the remaining patients had parenchymal
more common, TB pleural effusion maintains its position
TB, although this focus was not adjacent to the pleura.
as the leading inflammatory pleural disease (1-8). In fact,
More recently, such foci have been demonstrated on
pleural disease is one of the most common extra-pulmo-
thoracic computed tomography [CT] in patients with TB
nary involvement in TB in developing countries (9,10).
pleural effusion (18). Possibly, rupture of such a focus
The increasing prevalence of human immunodeficiency
allows the tubercular protein to enter the pleural space
virus [HIV] infection in some of these geographical
and generate hypersensitivity responsible for most
locations may be an additional factor explaining the
clinical manifestations. Pleural effusions may also be seen
higher frequency of TB pleural effusion (4,7). The entity
with direct contiguous spread of the disease to the pleura
is relatively uncommon in the developed world where
or by haematogenous spread (11). Occasionally, it can
prevalence of TB is low (11-14). For example, in the USA
also occur as a complication of thoracic vertebral tuber-
the incidence of TB pleural effusion has been estimated
culosis with paravertebral cold abscess. Tuberculosis
to be only about one in 1000 cases. Furthermore, in the
osteitis of the rib may also be associated with pleural
USA, TB pleural effusion accounts for approximately one
effusion.
in every 30 cases of TB and this ratio has remained
One might speculate that the intense pleural inflam-
constant even after the advent of the acquired immuno-
mation and consequently increased vascular perme-
deficiency syndrome [AIDS] epidemic (12). However,
ability would provide an obvious and satisfying
there is some evidence that these low figures may be an
explanation for fluid retention. However, at least in
underestimation of the true disease burden in the general
animal models, no significant alterations in vascular
population (15).
permeability have been demonstrated (19). It is now
believed that the intense inflammatory reaction obstructs
PATHOGENESIS AND IMMUNOLOGY
the lymphatic pores in the parietal pleura, causing
Tuberculosis may affect the pleura at different stages of proteins to accumulate in pleural space with subsequent
pulmonary or systemic disease by various mechanisms. retention of fluid (19,20).
Tuberculosis pleural effusion may represent a manifesta- Delayed hypersensitivity, rather than a TB infection
tion of either primary infection or reactivation of latent per se, plays an important role in the development of TB
disease, the latter being more common (16). Pleural pleural effusion. This explains the poor rate of isolation
effusion is believed to occur secondary to the rupture of of mycobacteria from pleural fluid samples from these
a subpleural caseous focus in the lung [or less commonly patients [vide infra]. Pleural effusion has been shown to
246 Tuberculosis
develop in non-sensitized animals that have received cells blood-recruited monocytes determine this early stage
from immunized animals. Similarly, on administration of with the predominant expression of pro-inflammatory
anti-lymphocyte serum, pleural effusion does not develop chemokines interleukin-1 [IL-1], interleukin-6 [IL-6] and
in sensitized animals (19,21). Tuberculosis pleural fluid tumour necrosis factor [TNF]. In animal models, after
is also rich in several potentially immunoreactive cells the initial neutrophil-rich phase, macrophages
and substances that contribute to the vigorous local cell predominate in the pleural fluid from second to fifth day
mediated immune response (22,23). Mycobacterial (31). Neutrophils in pleural space appear to secrete a
antigens enter the pleural space and interact with T- monocyte chemotaxin that recruits monocytes to the
lymphocytes previously sensitized to mycobacteria, pleural space and helps in granuloma formation (31). In
resulting in delayed hypersensitivity reaction and addition, mesothelial cells may also play an important
accumulation of fluid. Several investigators have role. Animal models have shown that mesothelial cells
demonstrated T-lymphocytes specifically sensitized to stimulated with BCG or IFN-γ produce macrophage
protein[s] of Mycobacterium tuberculosis in TB pleural fluid inflammatory protein and monocyte chemotactic
(24-27). The concentration of such lymphocytes in pleural peptides, and that these two proteins account for more
fluid is nearly eight-fold than that found in the peripheral than 75 per cent of the mononuclear chemotactic factor
blood (26). It is not clear whether this represents in the TB pleural fluid (32,33). After three to four days,
sequestration of these cells from peripheral blood into in the following intermediary stage, lymphocytes are the
prominent cell in the pleural fluid (34). They are mostly
pleural space, or local expansion in the pleural cavity. In
T-cells comprising CD4+ helper cells as well as CD8+
addition, these lymphocytes show greater responsiveness
cytotoxic cells with a CD4+/CD8+ ratio of about 4.3, and
to purified protein derivative [PPD], and when co-
so-called unconventional cells including T-cell receptor
cultured with PPD, produce far greater levels of cytokines
double-negative [DN] αβ T-cells and γδ T-cells [Figure
than do peripheral blood lymphocytes (25,28). The ratio
17.1] (35,36). A strong promoter of macrophage activation
of CD4+ [helper-inducer] to CD8+ [suppressor/
and granuloma formation, IFN-γ, together with TNF-α
cytotoxic] lymphocytes is also much higher in TB pleural
are the predominant cytokines at this stage. Initially these
fluid as compared to peripheral blood [3:4 vs 1:7] (22,29).
lymphocytes do not respond to PPD. However, reactivity
Patients with TB pleural effusion have significantly
is restored over the next few days, and parallels the
higher interferon-γ [IFN-γ] levels in their pleural fluid reactivity of lymphocytes in the peripheral blood (37).
than in peripheral blood, thus exhibiting localization of Lymphocyte activation can occur in the pleura of some
predominantly T-helper cell type 1 [Th1] type immunity patients who fail to react to cutaneous PPD, a fact that is
in the pleural space (29,30). explained by the presence in the circulation of suppressor
Based on experimental evidence, the sequence of cells that inhibit response in the skin; these suppressor
immunological processes involved in TB pleuritis has cells are apparently lacking in the pleural fluid (24).
recently been described in terms of a three-stage pattern Helper T-cells in pleural fluid express a battery of homing
of cellular and granulomatous tissue reactions. receptors such as CD11a, CCR5 and CXCR3, which are
Experimental data suggest that neutrophils are the first important in modulating cell trafficking and recruitment
cells responding to mycobacterial protein in the pleural to pleural space and tissue (36). The late phase of TB
space. When intrapleural bacille Calmette-Guerin [BCG] pleural effusion is characterized by an equilibrated and
is administered to previously BCG-sensitized animals, sustained CD4+/CD8+ cell-based response with
the resultant pleural fluid is rich in neutrophils in the persistent IFN-γ release and consequent granuloma
first 24 hours (31). The accumulation of pleural fluid and formation that is modulated by the release of Th1-cells
inflammatory cells is markedly decreased in neutropenic [Figure 17.1] supporting interleukin-12 [IL-12] and
animals, and appears to be restored by intrapleural counter-regulatory anti-inflammatory cytokines such as
injection of neutrophils. Any trigger mechanism that interleukin-10 [IL-10] and transforming growth factor-β
allows access of mycobacterial protein to the pleura will [TGF-β]. Recent data also suggest a hierarchial role of
set off a rapid mesothelial-cell initiated and interleukin- CXCR3+ T-cells and crucial role of chemokines in the
8 [IL-8] mediated polymorphonuclear neutrophil cell selective recruitment of Th1 like cells in TB pleural
influx, within a few hours. In addition, macrophages and effusion (38).
Tuberculosis Pleural Effusion 247
Figure 17.1: Enrichment of Th1-like antigen-specific memory cells in tuberculosis pleural effusion and DTH sites [a] Frequency of naive
[CD45RA+] and memory [CD45RA–] helper [CD4 gated] T-cells in peripheral and pleural compartments of 19 tuberculosis patients. Inset
shows one representative FACS histogram of naive and memory T-cells in peripheral blood lymphocytes [solid line] and pleural fluid
[dotted line], respectively; [b] lymphoproliferative response of peripheral and pleural fluid-derived T-cells from nine tuberculosis patients
to Mycobacterium tuberculosis [EA = Erdman’s antigen]. Error bar depicts mean ± SEM; [c] profile of intracellular designate polarized
cytokines [gamma interferon and interleukin-4] in peripheral and pleural helper T-cells following in vitro stimulation; and [d] statistical
representation of frequencies of Th1 like and Th2 like T-cells in peripheral and pleural compartment of 19 patients with tuberculosis
pleural effusion. Cells were gated on CD45RA– helper subset
Reproduced with permission from “Mitra DK, Sharma SK, Dinda AK, Bindra MS, Madan B, Ghosh B. Polarized helper T cells in tubercular
pleural effusion: phenotypic identity and selective recruitment. Eur J Immunol 2005;35:2367-75 (reference 36)”
Recent studies have improved our understanding of proteoglycan complex and lipoarabinomannan, can
the immunological pathways involved in TB pleuritis. stimulate macrophages to produce TNF-α, which
After phagocytosing mycobacteria, macrophages act as regulates granuloma formation (39). Activated pleural
antigen presenting cells and present TB antigen to macrophages can also produce IL-1 which along with
T-lymphocytes. This results in activation of T-lympho- TNF-α is involved in lymphocyte activation (40). On
cytes and subsequent promotion of macrophage exposure to mycobacterial antigens, pleural T-lympho-
differentiation and granuloma formation. Some compo- cytes produce IFN-γ, which is an important activator of
nents of the mycobacterial cell wall, such as protein/ macrophage killing capacity, as well as interleukin-2
248 Tuberculosis
[IL-2] which is a regulator of T-cell proliferation (40,41). weakness, weight loss, anorexia and fatigue. Physical
Cytotoxic cell activity could be an additional defense examination usually provides only non-specific signs of
mechanism. The CD4+ and natural killer cells present in pleural effusion, including dullness to percussion and
pleural fluid of these patients demonstrate cytotoxic the occasional demonstration of a pleural rub at
activity when stimulated with PPD (42,43). auscultation. Untreated, this effusion will usually resolve
On the other hand, there is also a strong evidence spontaneously.
that infectious invasion of the pleural space actually
occurs at a substantial, albeit variable degree. At thoraco- RADIOLOGY
scopy, even with negative fluid studies, extensive
Tuberculosis pleural effusion is unilateral in more than
inflammatory granuloma formation and fibrin deposits
90 per cent instances, and usually small to moderate in
with unexpected abundant recovery of mycobacteria are
size, although it may occupy the entire hemithorax
a common finding (44). Also, the increasingly emerging
(46,49,50). Although conventionally regarded as a rare
evidence of a preferred association of TB pleurisy with
cause of massive pleural effusion, recent data suggest
reactivated TB in Western populations may be interpre-
that TB may represent more than 10 per cent of all cases
ted in favour of true infectious mechanisms (16). Thus,
of large pleural effusion in high prevalence areas (51,52).
the concept of exudative pleurisy representing exclu-
In up to half of these patients, co-existing parenchymal
sively delayed hypersensitivity may not hold true.
disease can be demonstrated by conventional chest
Infectious as well as immunological mechanisms are
radiographs (46,49). In such patients, the pleural
obviously closely interrelated and operative in complex
effusion is almost always on the side of the parenchymal
patterns.
infiltrate and invariably indicates active parenchymal
disease [Figure 17.2]. In three-fourths of such cases, the
CLINICAL MANIFESTATIONS
parenchymal disease is located in the upper lobe, sug-
Tuberculosis pleural effusion is typically a disease of gestive of reactivation TB (53). In the remaining patients,
young men (45,46). Patients with post-primary pleural the parenchymal disease involves the lower lobe and
effusion secondary to reactivation tend to be older than resembles primary disease. It is likely that even in cases
those with progressive primary pleural effusion (16). The with no radiographic evidence of parenchymal involve-
clinical presentation of TB pleural effusion may vary from ment, the effusion is associated with a subpleural focus
an acute illness simulating bacterial pneumonia to an of infection. If carefully searched for, thoracic CT can
indolent disease first suspected on a chest radiograph in demonstrate this subpleural focus in many such patients
a patient with minor constitutional symptoms. Tubercu- (18,54). Computed tomography is more sensitive than
losis pleuritis occurs as an acute illness in about two- chest radiography, showing parenchymal disease in
thirds of cases, with symptoms often of less than a over 80 per cent of cases. Almost half of these patients
month’s duration (47-49). In fact, the illness often mimics have smooth pleural thickening exceeding 1 cm on a
bacterial pneumonia with parapneumonic effusion (49). thoracic CT; involvement of mediastinal pleura is
As a general rule an acute illness is more likely to occur uncommon (54).
in younger and the more immune-competent patients. Classically, TB pleural effusion associated with acute
Older patients more frequently present with an insidious symptoms and the absence of radiographically evident
onset of symptoms (48). Tuberculosis pleuritis is a more parenchymal lung disease has been felt to represent
chronic process in patients with reactivation disease than primary infection. By contrast, TB effusion that is
in those with classic pleuritis. Non-productive cough associated with an indolent course and with parenchy-
[70%] and chest pain [75%] are the two most common mal lung disease on the chest radiograph has been seen
symptoms at presentation (49). If both cough and pleuri- more frequently in older patients and has been consi-
tic chest pain are present, the pain usually precedes the dered to be a manifestation of post-primary [reactivation]
cough (48). Despite the frequency of pleuritic chest pain, disease (55) [Figure 17.2]. However, such a clear-cut
a pleural friction rub is unusual. The patient is usually distinction between primary and reactivation disease
febrile, but absence of fever does not rule out the disease cannot always be made with confidence based solely on
(49). Other systemic manifestations include night sweats, chest radiography (55).
Figure 17.2: Chest radiograph [postero-anterior view] of a woman being investigated for pulmonary tuberculosis showing a right sided
mid zone lesion [A]. Sputum examination was non-contributory, but bronchoalveolar lavage showed presence of acid-fast bacilli. During
the course of her evaluation, she developed ipsilateral exudative pleural effusion [B]. Both pulmonary and pleural lesions responded to
antituberculosis therapy
Conventional chest radiography requires fluid evaluation, almost 20 per cent of TB pleural effusions
amounts of at least 200 ml to become detectable as will defy a definitive diagnosis. A brief diagnostic
blunting of the costophrenic angle in standard projec- approach is outlined in Figure 17.3.
tions. Thoracic ultrasonography may detect much smaller
effusions. Specific advantages of ultrasonography Sputum Examination
include more precise volumetry than by chest radio-
Only a minority of patients with TB pleural effusion are
graphy, localization of septae, membranes and pleural sputum smear-positive for acid-fast bacilli [AFB].
thickening, along with its clinical versatility for bedside
Sometimes, AFB can be demonstrated even in patients
diagnosis and in addition intervention guidance on
with no radiographic evidence of pulmonary involve-
demand. ment (59). Sputum cultures grow mycobacteria in 30 to
50 per cent of patients having both pulmonary and
DIAGNOSIS pleural TB (49,60). However, cultures are positive in less
than five per cent of patients with isolated TB pleural
The step-wise diagnosis of TB pleural effusion is
effusion (61). The yield of sputum cultures obtained after
essentially the same as for any other exudative pleural
sputum induction may be much higher even in patients
effusion. An initial diagnostic thoracocentesis is always
with no apparent radiological parenchymal lesions (62).
indicated. The diagnosis of TB pleural effusion can be
difficult because of the low sensitivity of various
Tuberculin Skin Test
diagnostic tools. No single laboratory test has 100 per
cent sensitivity and specificity for diagnosis of TB pleural In populations with a low prevalence of TB infection, a
effusion. Most patients undergo a battery of investiga- positive tuberculin skin test [TST] in a patient with
tions, and the diagnosis is often established after careful exudative pleural effusion strongly suggests the diag-
consideration of clinical features and results of several nosis of TB, whereas the diagnostic value of a positive
laboratory parameters (55-58). Despite a comprehensive test in countries with a high prevalence of TB is lower.
250 Tuberculosis
Figure 17.3: Algorithm for diagnosis of tuberculosis pleural effusion

TB = tuberculosis; ADA = adenosine deaminase; AFB = acid-fast bacilli; ATT = antituberculosis treatment;
PCR = polymerase chain reaction; +ve = positive; – = negative
The TST is positive in majority of patients, but a negative even more common in HIV-infected patients (64). This
test does not rule out the diagnosis. About 30 to 50 per anergy to PPD appears to be due to an antigen-specific
cent patients can demonstrate a negative skin test at extrapleural immunosuppression. Although pleuritis is
initial evaluation (46,49,63). Such negative tests may be considered to be related to a delayed hypersensitivity,
circulating adherent cells in the acute phase of the disease other disorders associated with pleural inflammation and
may suppress the specifically sensitized T-lymphocytes infiltration are associated with decreased shedding of
in the peripheral blood and in the skin [but not in the mesothelial cells in the pleural cavity, and numerous
pleural fluid], accounting for the negative results in these mesothelial cells can sometimes be found in some
patients (24). Anergy may occasionally result from patients with pleural TB (78). Presence of eosinophils in
pleural compartmentalization of PPD-sensitized lympho- a significant number in the fluid makes the diagnosis of
cytes occurring in the early phase of infection, resulting TB unlikely, except in patients having a hydropneumo-
in a relative depletion of these cells in the circulation. If thorax due to a previous thoracocentesis (79,80). It is
the patient is not anergic or immunosuppressed, the skin reasonable to assume that effusions containing more than
test will almost always become positive within eight 50 per cent of these cells are of a non-TB aetiology.
weeks of the development of the symptoms. Pleural fluid smear for AFB is positive in less than 10
per cent instances in most reports, while mycobacteria
Pleural Fluid Analysis can be cultured from pleural fluid in 10 to 70 per cent
cases (47,50,60,61,63,81-84). In one study, steroid use,
The pleural fluid in TB pleuritis is invariably a serous
[serosanguinous in less than 10%] exudate. Frequently, concurrent TB involving another site, increased
neutrophils and decreased glucose levels in pleural fluid
the pleural fluid protein level exceeds 5 g/dl (63,65).
were predictive factors for culture positivity (85). Sensi-
Chemical analysis of the fluid is otherwise of a limited
value. Although in the past it was observed that the tivity of mycobacterial cultures is improved if pleural
fluid is transported in heparinized containers, bedside
pleural fluid glucose was reduced in most patients with
inoculation of pleural fluid is substituted for laboratory
TB pleural effusion (66), more recent studies show that
majority of patients have a pleural fluid glucose of more inoculation, or if liquid culture media and/or a radio-
metric [e.g., BACTEC] system are used (86-88).
than 60 mg/dl (49,61). A low pleural fluid pH was once
thought to be suggestive of TB pleural effusion, but
Pleural Biopsy
subsequent reports have not confirmed this (67-69).
Glucose and pH values are in general not substantially A closed parietal pleural biopsy can be performed using
different from exudates due to other aetiologies, and their a Cope or Abram needle. The demonstration of parietal
diagnostic significance has probably been over-estimated pleural granulomata on histopathological examination
in the past. is suggestive of TB pleuritis; caseation necrosis and AFB
In most patients, the pleural fluid differential cell are not always present (65). Although other disorders
count reveals more than 50 per cent lymphocytes. In a such as fungal diseases, sarcoidosis and rheumatoid
series of 49 patients, only five had fewer than 50 per cent arthritis may produce granulomatous pleuritis, more
lymphocytes in the pleural fluid (49). In fact, the over- than 95 per cent of patients with this histopathological
whelming predominance of lymphocytes on prepara- picture have TB. The initial biopsy reveals granulomas
tions examined cytologically can sometimes result in a in 50 to 97 per cent patients with TB pleural effusion
misdiagnosis of lymphoma (70). The percentage and (50,60,61,63,81,83,89). The yield increases if multiple
absolute numbers of CD4+ T-lymphocytes in pleural biopsies are performed (90-92). However, if properly
fluid are higher than in the blood (71-74); by contrast, obtained, even a single high quality sample should be
the percentage and number of B-lymphocytes are enough to obtain a diagnosis (92,93). Mycobacteria can
significantly lower (25,26,75). However, the separation be cultured from pleural biopsy specimens in 33 to 80
of lymphocytes into T and B subsets is not useful diag- per cent cases (50,60,61,63,83,89,94). When culture of
nostically. In patients with symptoms of less than two- biopsy specimen is combined with microscopic exami-
week duration, the fluid may reveal predominantly nation, the diagnosis can be established in up to 95 per
polymorphonuclear leucocytes (48). If serial thoracente- cent instances (95). Even when granulomata are not
ses are performed, the differential count will reveal a shift demonstrated, the biopsy specimen should be examined
to predominantly small lymphocytes (49). The fluid for AFB. In less than 10 per cent of cases, organisms may
rarely contains more than five per cent mesothelial cells, still be demonstrated when no granulomas are present
although the finding is not diagnostic (76,77). Several in the biopsy (49,60). A visceral pleural biopsy obtained
252 Tuberculosis
through video-assisted thoracoscopic surgery [VATS] can higher the pleural fluid ADA, the more likely the
sometimes yield diagnosis in patients with a negative diagnosis of TB. Essentially, all reports from the West
parietal pleural biopsy (96). have been very positive in finding that pleural fluid ADA
level is useful diagnostically (103). Early reports from
Adenosine Deaminase Asia were much less positive, though more recent reports
Adenosine deaminase [ADA] is an enzyme involved in have been more favourable (104). It is not clear whether
the purine catabolism. It catalyses the deamination of these differences represent methodologic differences or
adenosine to inosine and of deoxyadenosine to true ethnic variation. Some of the differences could also
deoxyinosine. Adenosine deaminase is found in most be explained by differences in methodology used for
cells, but its chief role concerns the proliferation and ADA estimation, as well as delays in transportation and
differentiation of lymphocytes, especially T-lymphocytes. processing of pleural fluid samples. It is well known that
For this reason ADA has been looked on as a marker of ADA levels in pleural fluids maintained at ambient
cell-mediated immunity, which encompasses the delayed temperatures, and without the use of specific additives,
hypersensitivity reaction. The ADA activity correlates to decrease with passage of time (105). Several investigators
CD4+ T-lymphocyte cell infiltration in the pleura and from India have reported the use of pleural fluid ADA
the fluid (97). Determination of pleural fluid ADA level in the diagnosis of TB effusions (106-121). Overall, the
appears to be a promising marker in the diagnosis of TB sensitivity and specificity of the test in diagnosis of TB
pleural effusion because of the ease, rapidity, and cost- are not as good as in Western studies [Table 17.1].
effectiveness of the assay. Estimation of ADA is However, based on epidemiological and Bayesian consi-
performed using a simple colorimetric method that is derations, positive predictive value of pleural fluid ADA
quite suitable for use in the field setting (98). Recently, in the diagnosis of TB pleural effusion should be far better
meta-analyses have shown that ADA estimation is in geographical regions with a higher prevalence of TB
reasonably accurate in diagnosing TB pleural effusion as a cause of pleural effusion [Figure 17.4] (99). Hence,
(99,100). However, the results of ADA assays should be elevated ADA can provide a reliable basis of diagnosing
interpreted in conjunction with clinical findings and the TB pleural effusion in such areas (122). It also appears
results of conventional investigations. It appears that that ADA is a poor discriminator when used as a single
pleural fluid ADA in excess of 70 IU/l is highly sug- investigation, but may be more useful when results are
gestive of TB pleuritis, whereas a level below 40 IU/l interpreted in conjunction with clinico-radiological data
virtually rules out the diagnosis (101,102). In addition, and results of other investigations (100,123).
Table 17.1: Performance of adenosine deaminase estimation in the evaluation of

tuberculosis pleural effusion in Indian patients
Cases/controls Cut-off [IU/l] Sensitivity Specificity
Raj et al (106) 30/25 40 1.000 –

Sinha et al (107) 22/14 30 1.000 1.000
Sinha et al (108) 37/16 30 1.000 1.000
Chopra et al (109) 37/27 – 0.892 0.852
Gilhotra et al (110) 30/43 40 1.000 0.907
Gupta et al (111) 36/57 50.8 1.000 0.941
Subhakar et al (112) 62/18 38 0.984 1.000
Kaur et al (113) 21/52 30 0.667 0.923
Prasad et al (114) 21/26 30 1.000 1.000
Nagaraja et al (115) 30/18 50 1.000 1.000
Maldhure et al (116) 83/42 40 1.000 0.348
Singh et al (117) 41/43 – 0.902 0.870
Ghelani et al (118) 54/27 40 0.722 0.593
Parandaman et al (119) 25/9 47.3 0.760 0.714
Nagesh et al (120) 20/40 50 0.550 0.550
Sharma et al (121) 48/27 35 0.833 0.666
Interferon-gamma
Interferon-γ is produced by the CD4+ T-lymphocytes in
patients with TB pleural effusion in response to mycobac-
terial antigens (131,132). In fact, the concentration of
Mycobacterium tuberculosis in pleural liquid correlates
with the amount of IFN-γ (133). Patients with pleural
effusion may have up to 25-fold higher IFN-γ levels in
the pleural fluid as compared to their peripheral blood,
suggesting homing of Th1 cells in the pleural fluid from
the peripheral blood and enrichment of pleural space
with Th1 cytokines (30). The IFN-γ can be estimated either
by enzyme-linked immunosorbent assay [ELISA] or
radioimmunoassay [RIA]. Estimation of pleural fluid
IFN-γ levels is reported to be useful in differentiating TB
from other pleural fluids [Figure 17.4] (99). A number of
Figure 17.4: Effect of prevalence on the operating characteristics reports have demonstrated that IFN-γ levels in patients
of pleural fluid adenosine deaminase [ADA] and interferon-γ [IFN] with TB pleurisy are high, with sensitivity and specificity
for diagnosis of tuberculosis pleural effusion. The curves depict ranging from 90 to 100 per cent (102,132-145). However,
post-test probability of pleural tuberculosis after knowing positive proper comparison of results from different studies is
[top] or negative [bottom] results of ADA [inner curves] or of IFN not possible due to differences in methods of estimation
[outer curves] for different pre-test probabilities of disease
Adapted with permission from reference 99
and units used for quantification. Although the test is
promising, it is expensive and still not widely available.
There are several isoforms of ADA, but the prominent The cost of performing a single IFN-γ test in India is, in
ones are ADA1 and ADA2, which are coded by different fact, equivalent to the cost of a complete course of anti-
gene loci (124). The ADA1 isoenzyme is found in all cells, tuberculosis treatment for such patients, and therefore,
with the highest concentration found in lymphocytes and does not appear to be a cost-effective investigation for
monocytes, whereas ADA2 isoenzyme is found only in differentiating TB from non-TB pleural effusions (146).
monocytes (125). The ADA2 is the predominant isoform Recently, meta-analyses (99,147) have demonstrated the
in the TB pleural fluid, accounting for approximately 90 utility of estimation of pleural fluid IFN-γ in the diag-
per cent of total ADA activity, whereas ADA1 is elevated nosis of TB pleurisy.
in empyema (126). This would suggest that ADA2 is a
more efficient marker of TB pleural effusion and has been Serodiagnosis
shown to be increased in TB pleural effusions (126-128).
In pleural fluids with a high ADA level, a ADA1:ADA2 Till date only a few studies are available on the immuno-
ratio less than 0.45 is highly suggestive of TB, whereas a diagnosis of TB pleural effusion (118,148-159). Both
ratio greater than 0.45 may be seen in malignancy, mycobacterial antigens and their antibodies have been
empyema, and other conditions (117,129). The measure- estimated in pleural fluid and/or serum using ELISA
ment of ADA2 is almost 10 times more expensive than based techniques to assess their utility in the diagnosis
estimation of total ADA. Although determination of this [Table 17.2]. The sensitivity reported in most studies is
ratio may increase the diagnostic accuracy of ADA much less than desirable. The problem of false-positive
estimation in TB pleural fluids, in clinical practice the results has also been troublesome in other studies
difference in the use of total ADA and isoform ADA2 (149,157,158,160). The kaolin agglutination test, which
may not be significant (130). In fact, there may be an detects antituberculophospholipid antibodies, may also
advantage in the measurement of total ADA because of provide equivalent sensitivity and specificity, while
its low cost and rapid turnover. Activity of ADA1 is deter- being much simpler (161). The origin of antibodies to
mined by subtracting ADA2 measurement from total mycobacterial antigens in pleural fluid of these patients
ADA activity. is not clear. Levy and co-workers (162) found close
254 Tuberculosis
Table 17.2: Evaluation of tuberculosis antigens and anti- Thoracoscopy

bodies in the diagnosis of tuberculosis pleural effusion
Thoracoscopy, often considered the ‘gold standard
Study (reference) Sensitivity Specificity procedure’ for the diagnosis of TB pleuritis, may have a
Antibody in Samuel et al (148) 0.683 1.000 role in evaluation of pleural effusions undiagnosed by
pleural fluid Murate et al (149) 0.226 0.949 less invasive investigations. The diagnostic accuracy of
Caminero et al 0.500 1.000 this procedure is greater because multiple selected
(150,151) biopsies can be obtained, which have a higher yield both
Ghelani et al (118) 0.907 0.333
on microbiologic as well as histopathological exami-
Chierakul et al (152) 0.254 0.904
Kunter et al (153) 0.841 0.730 nations (168-170). The endoscopic appearance of pleural
Yokoyama et al (154) 0.500 0.938 TB is well described. It is characterized by greyish-white
Kaisermann et al (155) 0.764 0.963 granulomata covering the entire parietal and diaphrag-
Antibody in Caminero et al (150) 0.550 1.000 matic pleura, and in particular, the costovertebral gutter
serum Caminero et al (151) 0.533 1.000
(171,172). However, lesions have often lost their specific
Arora et al (156) 0.900 0.950
Chierakul et al (152) 0.463 0.596
appearance by the time of thoracoscopy and may mimic
Kunter et al (153) 0.591 0.811 a simple inflammatory process. In addition, the
Antigen in Samuel et al (148) 0.488 1.000 examination itself may be difficult because of numerous
pleural fluid Baig et al (157) 0.600 0.800 bands and adhesions. Complication rates for thoraco-
Ramkisson et al (158) 1.000 0.983 scopically guided pleural biopsy are minimal, and similar
Dhand et al (160) 0.800 0.381
to closed pleural biopsy (170-172). Apart from cost
Banchuin et al (159) 0.115 1.000
Antigen in Banchuin et al (159) 0.000 1.000 concerns, the performance of thoracoscopy is limited by
serum availability of equipment, and of personnel with exper-
tise to perform this procedure.
correlation between pleural fluid and serum levels,
reflecting passive diffusion. Other investigators have Nucleic Acid Amplification Techniques
demonstrated higher titers of antibodies in pleural fluid,
Various nucleic acid amplification methods that have
indicating local accumulation (163). Assays based on
been used in the diagnosis of mycobacterial infection
detection of tuberculostearic acid [TSA] in pleural
include target amplification techniques such as
aspirates have not yielded encouraging results (164).
polymerase chain reaction [PCR], strand displacement
Further work needs to be done before immunodiagnostic
amplification, and transcription mediated amplification,
techniques can be recommended for routine use in the
as well as probe, primer amplification techniques such
diagnosis of TB pleural effusions.
as ligand chain reaction and Q-Beta replicase amplifica-
tion. Polymerase chain reaction, the most widely used
Lysozyme
of these techniques, is based on the amplification of
Lysozyme is a low molecular weight bacteriolytic protein mycobacterial deoxyribonucleic acid [DNA]. In respira-
distributed extensively in organic fluids. Its estimation tory specimens, the PCR can be performed rapidly and
in pleural fluid has been proposed as a useful test in the has a diagnostic yield comparable to that of culture (173).
diagnosis of TB pleural effusion. Mean lysozyme levels Polymerase chain reaction offers the option of referring
in TB pleural fluid have been reported to be higher than the sample, rather than the patient, to a specialized centre
in other exudative effusions (101,165-167). However, or laboratory. This procedure has also been used to detect
there is so much overlap that the levels themselves are mycobacterial DNA in pleural fluid (119,120,174-187).
not diagnostic. Pleural fluid to serum lysozyme ratio of Its sensitivity in the diagnosis of TB pleural effusion
more than 1 or 1.2 can differentiate better between TB ranges from as low as 17 per cent to as high as 100 per
and non-TB pleural fluids (164,166,167). A more recent cent, depending on the patients selected, genomic
report (102) has, however, not reproduced these good sequence amplified, and the procedure used in the
results. extraction of DNA [Table 17.3]. Specificity ranges from
Table 17.3: Pleural fluid polymerase chain reaction in the diagnosis of tuberculosis pleural effusion
Study (reference) Cases/Controls Sequence amplified Sensitivity Specificity

de Wit et al (174) 53/31 336 bp repetitive sequence 0.811 0.774
de Lassence et al (175) 15/10 IS6110 sequence 0.600 1.000
Gene coding 65 kD antigen 0.200 1.000
Verma et al 176) 38/29 150 bp sequence 0.632 0.931
Querol et al (177) 21/86 IS6110 sequence 0.809 0.977
Tan et al (178) 10/13 IS6110 sequence 0.700 1.000
MPB64 fragment 0.700 1.000
Villena et al (179) 33/98 IS6110 sequence 0.424 0.990
Seethalakshmi et al (180) 22/– IS6110 sequence 0.409 -–
Mitarai et al (181) 36/39 Amplicor kit 0.273 0.976
Martins et al (182) 19/11 MPB64 fragment 0.684 0.909
Parandaman et al (119) 30/20 IS6110 sequence and TRC4 1.000 0.850
Villegas et al (183) 42/98 IS6110 sequence 0.738 0.898
Reechaipichitkul et al (184) 36/62 16S-23S rRNA gene spacer sequence 0.500 0.613
Nagesh et al (120) 20/40 150 bp sequence 0.700 1.000
Lima et al (185) 16/29 IS6110 sequence 0.313 0.966
Kim et al (186) 9/92 Amplicor kit 0.333 1.000
Moon et al (187) 57/54 Amplicor kit 0.175 0.981
TRC = insertion element like repetitive sequence
61 to 100 per cent. The parameter that determines the biopsy specimens can be useful when employed in
sensitivity of PCR is probably the number of bacilli in combination with microbiological and histological
the sample of pleural fluid analysed. Series with a pleural examinations (194).
fluid culture positivity of as high as 69 per cent report Although these techniques are promising, the high
more than 80 per cent sensitivity of PCR (177). The PCR cost and the technology involved in the procedure do
may be positive in 100 per cent of culture-positive TB not permit the routine diagnostic use of PCR at present
pleural fluids and only in 30 to 60 per cent of culture- (195).
negative pleural fluids (174-176,179-181,184,187). The
lower sensitivity is most likely attributable to the NATURAL HISTORY
inefficient recovery of genomic DNA from the charac-
teristically low number of mycobacteria in patients with In the short-term, TB pleural effusion seems to be a self-
pleural TB. Genomic sequences present in multiple copies limited inflammatory process in most instances. The
in mycobacteria give better results than sequences natural history of untreated TB pleuritis and effusion is
present in only a single copy (174-176). Contamination usually complete absorption of fluid and apparently
of samples by mycobacterial DNA in the laboratory complete restoration of the patient’s health to normal
environment is partly responsible for the low specificity. [although some degree of pleural fibrosis may be evident
Few investigators have also evaluated the value of pathologically or radiologically]. However, the likelihood
various nucleic acid extraction and amplification of subsequent development of pulmonary TB is high; for
techniques in formalin-fixed and paraffin-embedded example, in one study (196) from the pre-chemotherapy
pleural tissue samples (188-194). Although specificity of era on 2816 members of the Finnish army with pleural
these techniques is high, approaching 100 per cent in effusion followed up for seven years, 43 per cent develo-
several instances, sensitivity was seen to be low [47% to ped active TB during the follow-up period. Confirmatory
90%]. However, in these studies, nucleic acid ampli- evidence was provided in another study on 141 American
fication techniques resulted in a similar or higher military personnel who had presented with pleural
positivity as compared to histological examination or effusion and a positive tuberculin skin test; nearly two-
culture of pleural biopsy specimens. Thus, PCR of pleural third subsequently developed some form of TB (197). In
256 Tuberculosis
this study, isolation of mycobacteria from pleural fluid three months of start of medications, which eventually
or size of pleural effusion were not correlated with resolve on the same treatment (211).
subsequent appearance of active TB. Thus, the long-term Even after successful completion of treatment, nearly
prognosis in patients who have TB pleurisy is determined 10 per cent patients may have a residual restrictive
by its prompt recognition and the early initiation of ventilatory defect on pulmonary function testing (212).
effective therapy, which lowers the risk of subsequent Mild degree of pleural fibrosis may be present on chest
disease (198). radiographs a year after therapy is begun in up to 50 per
cent of patients (63). With the strict definition of fibro-
TREATMENT AND ITS RESPONSE thorax as a pleural membrane of at least 5 mm thickness
extending across major portions of the hemithorax, a
The goals of therapy in patients with TB pleural effusion
figure of around five per cent is perhaps the more realistic
are: [i] prevention of subsequent development of active
and widely accepted rate of this complication. The
TB; [ii] relief of symptoms; and [iii] limitation of pleural
presence of fibrosis is not related to the initial pleural
fibrosis.
fluid findings and is of limited clinical significance,
although a higher pleural fluid glucose may be associated
Antituberculosis Treatment
with increased residual pleural thickening (213,214). A
Patients with TB pleural effusion respond well to faster resolution of pleural effusion during the initial
treatment with standard short-course antituberculosis phase of treatment may decrease the occurrence of
therapy (199,200) and DOTS is preferred. Under the significant pleural thickening (215). The correlation
Revised National Tuberculosis Control Programme between radiographic and functional sequelae [as
[RNTCP], of the Government of India, patients with assessed by pulmonary function testing] is poor (212).
massive or moderately severe pleural effusion receive
Category I treatment, while patients with small and Corticosteroids
unilateral pleural effusion receive Category III treatment. Evidence regarding efficacy of systemic corticosteroids
The reader is referred to the chapters “Treatment of tuber- in the treatment of TB pleuritis remains insufficient
culosis” [Chapter 52], and, “Revised National Tuberculosis (216,217). Three randomized, double-blind, placebo-
Control Programme” [Chapter 63] for more details. This controlled trials have been completed, but all had
form of treatment is well accepted by patients, and has a important methodological differences. There was no
relapse rate of less than three per cent (201). Because benefit with the use of systemic corticosteroids in two
patients with TB pleural effusion have low mycobacterial controlled studies in which therapeutic thoracocentesis
burden, less intensive regimens may also prove effective was also performed (218,219). However, the duration of
(202,203). With treatment, patients generally become fever and the time required for fluid resorption were
afebrile within about two weeks, and the pleural effusion decreased in a third study in which no therapeutic
resolves within two months (204). Lung functions thoracocentesis was performed (220). Administration of
continue to improve even after completion of therapy corticosteroids did not influence residual pleural
(205). There appears no medical reason to confine these thickening in any of these studies. Based on these data,
patients to bed, and patients need to be isolated only if routine use of corticosteroids cannot be recommended
their sputum smear examination demonstrates AFB. and should only be used if acute symptoms, such as fever,
In some patients, the pleural effusion may worsen chest pain, or dyspnoea, are disturbing to the patient. If
after antituberculosis treatment is initiated. In this needed, corticosteroids should be prescribed only after
situation, the possibility of a wrong diagnosis must be the institution of appropriate antituberculosis treatment.
considered, but paradoxical worsening can also occur Patients can start therapy with 0.5 to 0.75 mg/kg body
with a correct diagnosis and appropriate antituberculosis weight of prednisolone [or equivalent] daily until acute
medications (206). One hypothesis is that these para- symptoms have subsided, with rapid tapering thereafter.
doxical responses are related to isoniazid-induced lupus
pleuritis (207). New pleural effusion may occasionally Surgery
arise on the contralateral side as well (208-210). Similarly, In general, surgical procedures have no place in the
new parenchymal lesions may also be noticed within routine management. Therapeutic thoracocentesis is only
indicated if the patient has a moderate-sized or larger likely to be anergic on (231,233). The AFB can be demons-
pleural effusion producing significant breathlessness. In trated on pleural fluid smears in six to fifteen per cent
fact, routine serial therapeutic thoracenteses, or and on pleural biopsy specimens in 44 to 69 per cent cases
continuous pigtail catheter drainage, does not alter the (230,232,234). The AFB smears are more likely to be
course of illness or the development of residual pleural positive when CD4+ T-lymphocyte counts fall below 200
fibrosis (221,222). Early surgery for pleural thickening is cells/mm3 (232). Pleural fluid and/or biopsy cultures
also not recommended, as the thickening decreases with grow mycobacteria in 30 to 50 per cent cases (230,233-
treatment. A recent study also suggests that instillation 235). Despite the impaired T-lymphocyte function,
of a fibrinolytic agent into a loculated collection may help pleural biopsy specimens show granulomatous
in subsequent reduction of pleural thickening (223). inflammation in 44 to 88 per cent cases (230,234,235). The
Although medical thoracoscopy can open intrapleural role of PCR, and measurements of ADA, lysozymes, or
loculations, completely evacuate the pleural fluid, and IFN-γ in the diagnosis of TB pleural effusion in these
to some extent produce effective debridement, no patients is still not clear.
controlled study has so far proven the value of these Management guidelines for these patients are similar
efforts. to those for other patients, and standard four-drug
antituberculosis treatment is the treatment of choice (236).
HUMAN IMMUNODEFICIENCY VIRUS The clinical and microbiologic response to treatment in
CO-INFECTION these patients appears to be similar to that in patients
not infected with HIV. Most HIV-infected patients with
It appears that co-infection with HIV is the main factor
TB pleural effusion respond favourably to standard
responsible for the increase in TB pleurisy in the West
treatment, with mortality rates less than 10 per cent after
and in Africa (224,225). Pleural effusion is seen in six to
an average follow-up of more than two years (230,237).
twenty-eight per cent of HIV-infected patients with TB
Patients with poor or absent tissue reaction on pleural
(226-228). These patients tend to develop pleural effusion
biopsy histology appear to have a less favourable res-
in early stages of immunosuppression and the frequency
ponse to therapy and higher mortality (233). Paradoxical
of pleural effusion is higher in patients with CD4+ T-
reactions or immune reconstitution inflammatory
lymphocyte counts exceeding 200 cells/mm3 (229).
syndrome [IRIS] are much more common in patients with
Pooled estimates from several reports reveal that TB is
HIV-TB co-infection (238).
responsible for almost a quarter of all pleural effusions
seen in patients with HIV infection, and that the condition
PLEURAL EFFUSION DUE TO NONTUBERCULOUS
is second only to bacterial parapneumonic effusions in
MYCOBACTERIA
terms of frequency (226). In addition to the delayed
hypersensitivity phenomenon, persistence of mycobac- As with pulmonary disease, the vast majority of cases of
teria in the pleural space as result of failure of immune pleural mycobacterial infection are caused by Mycobac-
system has been proposed as an alternative explanation terium tuberculosis; only occasional cases are related to
for the higher incidence of pleural disease in these nontuberculous mycobacteria [NTM] (239,240). Pleural
patients (230). It is not clear if the higher rate of pleural effusions without parenchymal disease analogous to the
disease reflects a greater burden of pleural mycobacteria post-primary pleural effusion with Mycobacterium
or dysregulation of immune function in the pleural space. tuberculosis do not occur. Approximately five per cent of
Affected patients usually are symptomatic for longer patients with parenchymal disease due to either
periods, have additional symptoms [fever, dyspnoea, Mycobacterium avium-intracellulare complex [MAIC] or
night sweats, fatigue, diarrhoea, etc.,] and more com- Mycobacterium kansasii have an associated small pleural
monly have hepatomegaly, splenomegaly and lymph- effusion (240). About 15 per cent patients with paren-
adenopathy than patients who are HIV-seronegative chymal disease due to Mycobacterium intracellulare have
(231,232). The diagnostic approach in patients with HIV marked pleural thickening as well (240). In patients with
infection is largely similar to other patients with TB AIDS and disseminated disease due to MAIC, pleural
pleural effusion, although the performance of some fluid cultures are sometimes positive for MAIC (241).
individual diagnostic tests is different. Patients are more However, it is not clear whether these NTM are actually
258 Tuberculosis
responsible for the pleural effusion. Even in immunocom- mycobacteria on culture. Pleural fluid cell counts usually
petent patients one must be cautious regarding the exceed 100 000/mm3, with virtually all cells being
interpretation of isolation of NTM from pleural fluid. It neutrophils (245). The pleural fluid has low glucose
has been suggested that NTM cultured from pleural fluid [usually below 20 mg/dl] and high protein concentration
should not be considered aetiologic, unless there is evi- [usually more than 5 g/dl], and is acidic [with pH usually
dence of the same organism infecting other tissues (242). below 7.20]. Anaerobic and aerobic cultures should also
be performed to exclude concomitant bacterial and
mycobacterial infection.
TUBERCULOSIS EMPYEMA
The principles of treatment, pleural space drainage,
Tuberculosis empyema is an entity distinct from, and and antimicrobial chemotherapy are similar for bacterial
much less common than, TB pleural effusion. In contrast and TB empyema. Difficulties specific to management
to delayed hypersensitivity leading to pleural fluid of TB empyema include the inability of the trapped lung
accumulation in a TB pleural effusion, TB empyema is to re-expand adequately and failure to achieve thera-
characterized by chronic, active mycobacterial infection peutic drug levels in pleural fluid, which can lead to drug
resistance (245,249). It is, therefore, important to use
of the pleural space. It usually represents the failure of a
multiple drugs at their maximum tolerated dosages.
primary TB effusion to resolve and subsequent prog-
Pleural drainage is indicated for large empyemas and
ression to a chronic suppurative form, and may develop
mixed empyemas, especially if there is a bronchopleural
in fibrous scar tissue resulting from pleurisy, artificial
fistula. Because intensive chemotherapy coupled with
pneumothorax, or thoracoplasty (243). In addition, TB
serial thoracocentesis can be curative at times, this
empyema can also occur due to extension of infection
approach should be attempted initially (250). In addition
from intrathoracic lymph nodes or a subdiaphragmatic
to standard antituberculosis treatment, patients usually
focus, or haematogenous spread (244). In TB empyema
require surgery (251). Surgical procedures include
the pleural contamination is massive, the pleural fluid is
standard decortication, decortication limited to the
purulent, and it is common to find mycobacteria on direct
parietal sides of the empyema collection, thoracoplasty,
smear examination or culture of pleural fluid (245).
muscle flap, plombage, parietal wall collapse, open
Tuberculosis empyema represents nearly 20 per cent of
drainage, or resection of the entire lung along with the
all cases of empyema seen in high prevalence countries
empyema (244). Most patients have associated significant
like India (246).
pulmonary parenchymal involvement (245). The status
In many patients with chronic TB empyema, the of the underlying lung should be determined before
inflammatory process may be present for years with a planning any surgery, because presence of massive
paucity of clinical symptoms (243,247). This prolonged fibrotic lesions, cavities, or bronchiectasis can make
asymptomatic course is largely related to the marked surgery difficult or inadvisable. Ideally, antituberculosis
pleural thickening that isolates the tubercle bacilli to medications are given for two to four months
the empyema cavity. Patients are often diagnosed only preoperatively and the sputum should be negative for
after a routine chest radiograph or after development AFB for two months prior to surgery. Morbidity and
of complications, such as bronchopleural fistula or mortality related to surgery continue to be high
empyema necessitans. Other patients may present with (245,252,253). It must be stressed that such surgery is
low-grade fever, night sweats and constitutional extremely complex and challenging, and should only be
symptoms, such as fatigue and weight loss. Patients often undertaken by experienced thoracic surgeons. As with
have respiratory symptoms for several months prior to other forms of chronic empyema, surgery can help in
diagnosis (248). postoperative improvement of lung function (254).
The typical radiological findings of chronic TB Presence of bronchopleural fistula, chronicity of the
empyema include a moderate to large loculated pleural lesion and presence of disease in the underlying and/or
effusion with pleural calcification and thickening of the contralateral lung contribute to a poorer outcome with
overlying ribs (18). Diagnosis is confirmed after treatment (251). The relative lung volume of the affected
thoracocentesis by finding grossly purulent fluid that is side, as well as the volume of empyema, can help predict
smear- positive for AFB and subsequently grows the quantum of improvement in lung function after
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268 Tuberculosis
Silicotuberculosis
18
Praveen Aggarwal
INTRODUCTION fibrogenic potential. Factors which can modify the

exposure response to airborne silica include the presence
Silicosis is a major occupational lung disease which
of other dust particles. For instance, the mixed dust
remains a problem in both industrialized and developing
pneumoconiosis in foundry workers probably represents
countries. Tuberculosis [TB] contributes significantly to
the modification of the response to silica in the presence
the morbidity and mortality of patients with silicosis
of other dusts which contaminate many foundries (8).
(1-3). In order to have a proper understanding of
Host factors probably also contribute to the clinical
silicotuberculosis, it is important to discuss briefly about
picture of silicosis. There may be an association between
silicosis.
exposure to silica dust [and/or silicosis] and the presence
SILICOSIS of progressive systemic sclerosis (9,10). Genetic factors
may also influence the body’s response to silica exposure
Silicosis, one of the most common forms of pneumo- though there are inconsistent reports regarding this
coniosis, is an ancient disease which probably dates from (11,12). The clinical presentation of silicosis is usually
the Stone Age. Pneumoconiosis is defined as a condition grouped into three types (13) as described below.
characterized by an accumulation of dust in the lung
parenchyma and the tissue reaction to it (4). Silicosis Chronic Silicosis
develops from the inhalation of silica particles.
Chronic silicosis is the commonest form of silicosis which
The industries involved in silicosis include quarry-
occurs after many decades of exposure to relatively low
ing and rockbreaking, sandblasting, construction and the
levels of silica. It is usually seen in industries with
founding of ferrous and non-ferrous metals. The exact
rigorous environmental control procedures. This form
prevalence of silicosis in India is not known. Several
of silicosis is characterized by gradually progressive
studies have been carried out in persons working in high-
dyspnoea, dry cough and evidence of progressive fibrosis
risk industries. Most of these studies have utilized
of both lungs on a chest radiograph. The course of this
radiographic findings to make a diagnosis of silicosis.
form of silicosis is often compatible with a normal life
Gupta et al (5) from Rohtak reported radiologic evidence
span (14).
of silicosis in 28.3 per cent of stone-cutters. When the
study was extended, silicosis was evident radiologically
Acute Silicosis
in as many as 35.2 per cent of 227 stone-cutters (6). In
slate pencil workers of Madhya Pradesh, silicosis was Acute silicosis occurs after exposure to a very high
reported in 57 per cent workers (7). concentration of dust over a few months and is usually
The main determinants of silicosis are exposure to rapidly fatal within years (14). Currently, sandblasters
silica dust, its duration and the level, the size, distribution and silica flour mill workers are the two groups
and respirability of airborne particles, and their considered at high risk of developing acute silicosis.
Silicotuberculosis 269
Accelerated Silicosis and lower zones of the lungs is more frequent in

accelerated silicosis.
Accelerated silicosis occurs after a few years of exposure
to silica and is associated with rapidly progressive Bronchoalveolar Lavage
features of dyspnoea and pulmonary fibrosis.
Bronchoalveolar lavage shows increased number of total
Radiographic Findings cells in patients with silicosis as compared to normal
subjects. This increase is due to an increase in both
The radiological features of silicosis [Table 18.1] are lymphocytes and alveolar macrophages. However, the
variable and range from diffuse fine rounded regular proportion of alveolar macrophages is significantly
nodularity resembling miliary TB to coarser irregular lower, whereas lymphocytes are significantly higher in
nodules or extensive fibrosis resembling progressive patients with silicosis than in control subjects (15,16).
massive fibrosis. In early stages, upper zones of the lungs
are more commonly involved as compared to the lower Complications
zones. The involvement of lymph nodes by chronic Tuberculosis is the most frequent complication of silico-
silicosis is fairly characteristic, with a tendency towards sis. Other complications include oesophageal compres-
peripheral calcification, which produces the so-called egg- sion, left recurrent laryngeal nerve palsy, atelectasis,
shell appearance [Figure 18.1]. The hilar and mediastinal pulmonary artery hypertension, chronic respiratory
groups are most often affected, but other thoracic and failure, recurrent chest infections, lung abscess, chronic
extrathoracic nodes may also be affected. The visceral cor-pulmonale, pneumothorax, hydropneumothorax,
pleura is often diffusely thickened by fibrosis with perforation of the bronchial tree by the calcified lymph
occasional focal calcification. Involvement of the middle nodes and lung cancer (14,17).
Table 18.1: Radiographic findings in patients with silicosis SILICOTUBERCULOSIS

Multiple nodular shadows Epidemiology
Reticular pattern
Conglomerate nodular shadows and large opacities Much of the information about the association between
Cavitation silicosis and TB was documented by clinical observations
Egg-shell calcification involving hilar and mediastinal lymph nodes and autopsy reports in the early part of the 20th century,
Extensive fibrosis
and later by epidemiological surveys conducted in
different parts of the world.
In a study from Spain, the incidence of TB was found
to be 150.1 [±30.9] cases per 100 000 miners per year
between 1971 and 1985 (18). This incidence was three
times that in the general population in that area. Studies
from Hong Kong revealed a 27 per cent incidence of TB
over five years among a group of 679 patients with
silicosis (3). In a study from China, TB was diagnosed in
as many as 43 per cent patients with silicosis when
followed over a period of 18 years (19). Of these, 55.1 per
cent cases of TB were identified when silicosis was first
diagnosed. Tuberculosis was the major cause [62.1%] of
deaths in these patients. However, over the years, the
mortality from TB has reduced possibly because of better
surveillance and treatment. In another study, TB
accounted for 11.8 per cent deaths in patients with
silicosis (20). It has also been shown that in small indus-
Figure 18.1: Chest radiograph [postero-anterior view] tries where the environmental conditions are poor, the
showing egg-shell calcification in the hilar lymph nodes prevalence of silicosis and silicotuberculosis is high (21).
270 Tuberculosis
In a recent study (22), the mortality data over 40 years because atypical mycobacteria are encountered
was analysed in 200 silica-exposed persons. Of 200 infrequently in the general population (3).
persons, 99 died during this period. Pulmonary TB was
responsible for 10 deaths of which nine had silicosis. The Influence of Tuberculosis on the Progression of
standardized mortality ratio for pulmonary TB in the Silicosis
studied population was much higher compared to that Animal experiments suggest that concomitant exposure
in the general population, indicating that silicotuber- to silica has an unfavourable influence on the course of
culosis has a greater mortality compared to TB without induced TB (31,32) and that more fibrosis is produced
underlying silicosis (22). The prevalence of pulmonary by silicosis and TB combined than by either of these
TB is closely associated with age and service duration of acting alone. Although clinical evidence is limited, such
the workers (23), as well as the severity of underlying a synergistic effect of silicosis and TB in producing more
silicosis (24). proliferative fibrous reaction appears to be substantiated
From India, a few studies are available which have by general clinical impression (13). Moreover, TB may
shown a higher incidence of TB in patients with silicosis. complicate simple silicosis as well as advanced disease
In 1949, Sikand and Pamra (25) reported TB in 28.6 per (28). It has been postulated that TB infection might contri-
cent of patients with silicosis. Other workers have bute to the development of massive fibrosis in patients
reported three to seven times higher incidence of TB in with silicosis (33-35).
persons with silicosis compared to those without silicosis
among persons working at the same place (5,6). Overall, Pathogenesis
it appears that TB occurs in as many as 20 to 25 per cent
Several pathogenetic processes are common to TB and
of all silicosis patients in their lifetime.
silicosis which may be synergistic in producing more
Tuberculosis is one of the important predictors of
fibrosis and in enhancing susceptibility to mycobacterial
mortality in patients with silicosis. For the same radio-
infection or reactivation of a latent focus of infection. The
logical extent of silicosis, the mortality risk is higher than silica particles are phagocytosed by the alveolar
expected if TB develops (26,27). It appears that the macrophages. Inside these cells, silica particles are
relative risk of death from TB is three- to six-fold greater engulfed in phagolysosomes. Silica has the capacity to
in patients with silicosis than in the general population. cause damage to the cell membranes which leads to the
Epidemiological and experimental studies also death of the macrophages with re-exposure of the other
suggest that the exposure to silica dust, even in the macrophages to the same particles. Prior to their death,
absence of radiological silicosis, may be responsible for the macrophages become activated and secrete
the increased rate of pulmonary TB (2,28). interleukin 1β [IL-1β] and tumour necrosis factor-α
It is generally agreed that the prevalence rate of TB [TNF-α] (36). These cytokines are responsible for
in the general population at a given point in time deter- fibroblast activation and fibrosis. The TNF-α also
mines the incidence of infection in patients with silicosis. stimulates neutrophils to release oxidants which produce
Better control of TB in a population has an important local damage.
influence on decreasing the risk of TB in patients with It has been postulated that both humoral and cell-
silicosis (29). mediated immune responses are inhibited in silicosis.
The distribution and prevalence of different species Cell-mediated immunity is important to contain the
of mycobacteria in the general population also determine mycobacteria, and its alteration could facilitate infection
the incidence of mycobacterial diseases in patients with with mycobacteria. Lung fibrosis occurs in both diseases
silicosis. In a study by Bailey et al (13), Mycobacterium and may interfere with the clearance of dust-laden
kansasii and Mycobacterium avium-intracellulare were alveolar macrophages or mycobacteria-laden material
reported in 12 of the 22 cases of silicosis with mycobac- from the lung. Lymphatic obstruction causes macro-
terial infection. Cowie et al (30) reported atypical phages to accumulate in the interstitial tissues resulting
mycobacteria in 14 per cent of 234 gold miners. On the in local fibrosis (34).
other hand, no case of atypical mycobacterial infection Another hypothesis for the unexplained incidence of
was reported in the study from Hong Kong (3). This is pulmonary TB in patients with silicosis is through the
surface coordination of iron by dust particles (37). By this

process, the body iron is adsorbed by the silica crystals
in the lung. Indeed, low serum iron has been observed
among people exposed to silicates (38). Evidence that iron
is complexed on the silicate dust can be found by the use
of specific stains for iron or by measurement of the iron
content of lungs in which silicate content is increased
(39). This iron can be mobilized from the silicate surface
by a strong iron chelator. Mycobacteria are dependent
on iron for growth and produce the iron chelators,
namely, mycobactin and exochelin to mobilize the metal
from body stores; indeed iron is considered a virulence
factor for mycobacteria. It has been hypothesized that
silicate particles act as a reservoir of iron which can be
used by the mycobacteria thereby, explaning the
increased incidence of TB among those who inhale silica
dust (37). The iron made available from silicato-iron
complexes may activate dormant tubercle bacilli by a Figure 18.2: Chest radiograph [postero-anterior view]
showing tuberculosis cavity in a patient with silicosis
mechanism similar to the effect of iron repletion (40).
Clinical Features surround pre-existing silicotic nodules. Presence of a

cavity in a nodule is usually indicative of TB [Figure 18.2]
The manifestations of TB in patients with silicosis are (41,42) though large fluid-filled cavities have been
similar to those in general population. However, since reported in silicosis also (43). Tuberculosis cavities in
malaise, fatiguability, dyspnoea and night sweats occur patients with silicosis are usually not traversed by large
in silicosis also, at times, it may be difficult to detect vessels possibly due to vascular obstruction frequently
superimposed TB clinically. seen in these patients (44). Additional suggestive findings
include rapid changes in the radiographic picture,
Diagnosis
development of pericardial or pleural effusion, or onset
The diagnosis of active TB in patients with silicosis of bronchial stenosis, especially of the right middle lobe
demands a high degree of suspicion [Table 18.2]. From (41). Computed tomography [CT] of the chest may be
the point of view of radiology, it is usually quite challeng- useful in some patients (44).
ing to differentiate abnormalities in the chest radiograph Establishing the diagnosis of pulmonary TB in a
of a patient with silicosis who has superimposed TB. patient with silicosis by bacteriological methods is often
Tuberculosis can be suspected in patients with silicosis difficult (41,45). Therefore, more frequent sputum
when the radiographic abnormalities are seen in the examination for acid-fast bacilli is recommended (45).
apical area of either of the lungs. These abnormalities The need for mycobacterial culture is more important in
include poorly demarcated infiltrates of variable size that areas where there is a high prevalence of nontuberculous
do not cross the lung fissures (41). These opacities may mycobacterial infection.
Distinguishing this disease from miliary TB is
Table 18.2: Features suggestive of tuberculosis in patients particularly important as some patients have both
with silicosis conditions. Previous recommendation was to treat all
Apical location patients with any possibility of miliary TB with anti-
Cavitation tuberculosis treatment (46). It is suggested that sputum
Rapidly changing opacities examination, fibreoptic bronchscopy, bronchoalveolar
Pleural effusion
lavage and transbronchial lung biopsy should be
Pericardial effusion
performed in all patients to facilitate accurate and early
272 Tuberculosis
diagnosis and, thus, obviating the need for a therapeutic under the Revised National Tuberculosis Control
trial of antituberculosis treatment (47). Programme [RNTCP] of the Government of India. The
reader is referred to the chapter “Revised National
Treatment Tuberculosis Control Programme” [Chapter 63] for more
Presently, empirical treatment with antituberculosis details.
drugs is often necessary because of the serious
consequences of not treating miliary TB, if the diagnosis Prevention
is not obvious despite a bronchoscopic examination and As TB is quite common in patients with silicosis, there is
bronchoalveolar lavage. a strong case for considering antituberculosis chemo-
Previously, the success rate of the treatment of TB in prophylaxis in patients with silicosis. The currently
patients with silicosis was reported to be lower than that accepted regimen of administering isoniazid for six to
in patients without silicosis (45,48,49). It has been
twelve months has been shown to be highly effective in
postulated that the intense fibrotic reaction and vascular
individuals without silicosis but has been associated with
obstruction seen in patients with silicosis makes it
appreciable risk of hepatic toxicity, particularly in older
difficult for the drugs to reach their target. However, most
age groups (56). Poor compliance is a common problem
of these studies were conducted at time when new
with the chemoprophylaxis regimens and is inevitably
effective antituberculosis agents were not available.
related to their long duration (57). Therefore, it is impor-
Based on the results of these studies, those miners
tant to develop shorter chemoprophylaxis regimens for
working in the South African gold mines who were
patients with silicosis. In a preliminary study, the rate of
diagnosed to have pulmonary TB were excluded by law
development of active TB in patients with silicosis has
from further underground work. This regulation was
been shown to be reduced to half when they were given
based on experimental evidence from animal studies that
the pulmonary resistance to infection by mycobacteria rifampicin for 12 weeks, isoniazid and rifampicin for 12
is impaired in direct proportion to its total silica dust weeks, and isoniazid for 24 weeks (3). However, this
load, and the belief that TB can never be cured in patients figure is less than that seen in individuals without
with silicosis (30,50,51). silicosis, when isoniazid alone is used as prophylactic
However, it was shown later that once the febrile agent (57). This suggests that the local immune response
phase of the disease subsides on treatment with is less efficient in subjects with silicosis, probably because
antituberculosis drugs, the return to underground work of direct impairment of macrophage function by free
did not adversely affect the treatment outcome as silica (45,58). Further, the trials on prophylaxis suggest a
reflected by the relapse rate which may be same need to develop a regimen which would prevent the
(30,52,53), or a little higher in patients with silicosis than occurrence of TB in a majority of patients with silicosis.
in those without silicosis (54). As in pulmonary TB, most At present, the Centers for Disease Control and Preven-
of the relapses in patients with silicotuberculosis occur tion recommends isoniazid prophylaxis for one year to
within first two years after stopping the drugs but the all patients with silicosis who are tuberculin positive.
risk of relapse may continue indefinitely after completion Besides chemoprophylaxis, engineering measures to
of treatment (30). In several recent trials, the efficacy of a reduce or eliminate the exposure to silica dust are
short-course chemotherapy has been established in important in reducing the incidence of both silicosis and
patients with silicotuberculosis (30,52-54). However, a silicotuberculosis. There is a strong evidence to support
few studies have suggested the need for a longer duration the view that silica dust control is associated with a major
of antituberculosis treatment (55). reduction in risk of TB in silica-exposed patients (59).
Treatment of silicotuberculosis is similar to the An active surveillance of the workers should be
treatment of TB elsewhere in the body. The reader is carried out in both pre-employment and post-employ-
referred to the chapter “Treatment of tuberculosis” [Chapter ment periods. This involves performing periodic chest
52] for more details. Long-term follow-up is recom- radiographs and tuberculin skin tests. Careful clinical
mended to diagnose possible relapse after the completion investigations and close follow-up of tuberculin con-
of treatment. In India, patients with TB receive DOTS verters are essential to reduce the risk of TB.
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Abdominal Tuberculosis
19
M Tewari, SP Sahoo, HS Shukla
INTRODUCTION Table 19.1: Classification of abdominal tuberculosis
Abdominal tuberculosis [TB] includes TB of the gastro- Gastrointestinal tuberculosis

intestinal tract, peritoneum, omentum, mesentery, lymph Ulcerative
nodes and other solid intra-abdominal organs like liver, Hypertrophic
Hypertrophic or hyperplastic
spleen and pancreas. It is one of the most common forms
Sclerotic or fibrous
of extra-pulmonary TB (1,2). Diffuse colitis
Mycobacterium tuberculosis, Mycobacterium bovis and Peritoneal tuberculosis
nontuberculous mycobacteria [NTM] can cause Tuberculosis of the peritoneum
abdominal TB. With widespread pasteurization of milk Acute tuberculosis peritonitis
and the strict control of TB in dairy herds, abdominal TB Chronic peritoneal tuberculosis
caused by Mycobacterium bovis is rarely seen in the present Ascitic form
Encysted [loculated] form
era and Mycobacterium tuberculosis is the most frequently
Fibrous form
isolated organism. Classification of abdominal TB is listed
Adhesive type
in Table 19.1. Plastic type
Tuberculosis of the mesentery and its contents
PERITONEAL TUBERCULOSIS Mesenteric adenitis
Mesenteric cyst[s]
Epidemiology Mesenteric abscess[es]
Bowel adhesions
Tuberculosis peritonitis constitutes four to ten per cent
Rolled-up omentum
of all patients with extra-pulmonary TB and has been Tuberculosis of the solid viscera
estimated to occur in 0.1 to 3.5 per cent of patients with Liver, biliary tract and gall bladder
pulmonary TB (1,5-11). Pancreas
Spleen
Pathogenesis Miscellaneous
Retroperitoneal lymph node tuberculosis etc.
Activation of long-standing latent foci of TB infection of
the peritoneum or haematogenous spread of bacilli from Based on references 3,4
an active pulmonary lesion results in the development
of TB peritonitis. Contiguous spread of infection from
Clinical Presentation
an intestinal lesion or fallopian tube is a relatively infre-
quent mechanism. Very rarely, TB peritonitis has been Clinical presentation of TB peritonitis is detailed in
described as a complication of peritoneal dialysis (12). Table 19.2 (1,6-11).
276 Tuberculosis
Table 19.2: Clinical presentation of tuberculosis peritonitis Congenital hydrocoele may be present in a male child
due to the processus vaginales becoming filled with the
Variable Frequency [%]
peritoneal fluid. Umbilical herniation due to increased
Abdominal swelling 65-100 abdominal pressure is a common observation (2-4). The
Abdominal pain 36-93 rolled-up greater omentum infiltrated with tubercles may
Weight loss 37-87
Diarrhoea 9-27
be felt as a transverse solid mass in the abdomen.
Ascites on physical examination 51-100 Encysted [loculated] form The clinical presentation of
Abdominal tenderness 65-87 encysted TB peritonitis resembles that of the ascitic form.
Ascitic peritonitis 92-100
Patients often present with localized abdominal swelling.
Fibroadhesive peritonitis without ascites 0-8
Anaemia 48-68 Diagnosis is difficult and is often made retrospectively.
Positive tuberculin test 55-100 A child with a suspected mesenteric cyst or a female with
Abnormal chest radiograph 37-63 a suspected ovarian cyst, for example, may undergo a
Associated active pulmonary tuberculosis 4-21 laparotomy and an encapsulated collection of fluid may
Data are derived from references 6-11 be discovered. In some patients, intestinal obstruction
Adapted from reference 1 may develop late in the disease.
Fibrous form Widespread adhesions may cause coils of
Tuberculosis of the Peritoneum
intestine especially in the ileal region to be matted
Acute Tuberculosis Peritonitis together and distended. These matted coils may act as
“blind-loop” leading to the development of steatorrhoea,
Tuberculosis peritonitis may have an onset closely malabsorption syndrome and abdominal pain. The
resembling acute abdomen and such patients may often disease may present as acute or subacute intestinal
be subjected to emergency surgery (2-4). In this setting, obstruction. On physical examination, the adherent loops
when the abdomen is opened, straw-coloured fluid may of intestine and the thickened mesentery may be felt as
be present and tubercles may be found scattered over lump[s] in the abdomen.
the peritoneum and greater omentum. Sometimes, in
addition to acute abdominal symptoms, ascites may be Tuberculosis of Mesentery and Its Contents
clinically demonstrable making the diagnosis of
Purulent form of TB peritonitis is rare and is often secon-
peritonitis reasonably evident (2-4). dary to TB salpingitis. Tuberculosis pus may be present
amidst the mass of adherent intestines and omentum.
Chronic Tuberculosis Peritonitis
Cold abscess, entero-cutaneous and entero-enteric
Most often, persons between 25 and 45 years of age are fistulae can develop (3,4).
affected and a slight female preponderance has been Patients with mesenteric lymph node TB may present
observed (1,6-11). Abdominal pain and swelling are the with general symptoms of TB toxaemia and abdominal
most common presenting symptoms. Symptoms of TB pain. Enlarged mesenteric lymph nodes may be felt as
toxaemia such as fever, weight loss and night sweats are lump[s] in the abdomen, usually in the right iliac fossa
often present. In about a quarter of the patients, an (3,4). Uncommonly, the presentation may mimic acute
abdominal mass may be felt (1,6-11). Three varieties of appendicitis. Tuberculosis pseudomesenteric cyst has
chronic TB peritonitis have been described, namely, also been described (3). Sometimes, calcified mesenteric
ascitic, encysted [loculated], and fibrous forms. lymph nodes may be evident on a plain radiograph of
the abdomen.
Ascitic form Ascitic form of TB peritonitis often has an
insidious onset. History of fatigue, weight loss, fever, GASTROINTESTINAL TUBERCULOSIS
anorexia, facial pallor, and abdominal distension are
frequently present. Abdominal pain is usually absent. Epidemiology
Sometimes, considerable abdominal discomfort, diar- Gastrointestinal TB, though rare in industrialized
rhoea or constipation may be present. On physical countries, continues to be a common problem in the
examination, abdomen may be distended and dilated developing countries. Although exact estimates are not
veins may be apparent coursing beneath the skin. available, presently, gastrointestinal TB is less commonly
Abdominal Tuberculosis 277
encountered than in the pre-antibiotic era (1,2). Reliable the lymphoid follicles become infiltrated and inflamma-
epidemiologic data on abdominal TB are lacking from tion extends throughout the submucosa. Eventually, the
India. Incidence of isolated intestinal TB in unselected epithelial layers above the Peyer’s patches ulcerate giving
autopsy series from India has been reported to vary from rise to characteristic histopathologic appearance of
0.02 to 5.1 per cent (13,14). In Delhi, 0.8 per cent of all ulcerative TB enteritis. Gastrointestinal TB can be of
hospital admissions were reported to be due to intestinal ulcerative, hypertrophic, ulcerohypertrophic, diffuse
TB (15). In India, TB has been reported to be the cause in colitis and sclerotic forms.
three to twenty per cent of patients with intestinal
Ulcerative form The ulcerative form of intestinal TB
obstruction (16). About five to seven per cent of all gastro-
usually occurs in adult patients who are malnourished.
intestinal perforations [excluding appendix perforations]
There is induration and oedema of the diseased segment
have been reported to be due to TB (17).
of the intestine with an increase in serosal fat. Tuberculo-
Pathogenesis sis ulcers can be solitary or multiple and usually lie
transverse to the long-axis of the gut girdle ulcers.
Gastrointestinal TB can occur primarily or it can be Longitudinal or irregularly shaped ulcers may occa-
secondary to a TB focus elsewhere in the body (1,2). sionally be seen. Areas of normal appearing mucosa may
Ingestion of milk or food material contaminated with be found amidst the diseased segment skip lesions. The
Mycobacterium bovis can result in primary intestinal TB. ulcers are of varying depth extending from the submucosa
This form of the disease is rare in the present era. Infection to muscularis propria or even serosa. As TB ulcers are most
more often reaches the abdomen by: [i] swallowing of often horizontally located, healing and fibrosis result in
infected sputum containing the bacilli; [ii] haemato- stricture formation napkin ring strictures and lead to
genous dissemination from a focus of active pulmonary obstructive symptoms. Adhesions between the bowel
TB, miliary TB, or silent bacteraemic phase of primary loops prevent free perforation but promote formation of
TB; and [iii] spread of the disease from infected adjacent
intestinal fistula. Severe haemorrhage due to endarteritis
viscera. The organism may disseminate in the bile from
is rare. The related mesenteric lymph nodes enlarge and
a hepatic granuloma (2,3).
may caseate to form mesenteric abscesses.
Tuberculosis of Small Bowel and Colon Hypertrophic form Unlike the ulcerative form, hyper-
trophic intestinal TB commonly occurs in young patients
Pathology who are relatively well nourished. Caecum is the most
Any region of the gastrointestinal tract from mouth to commonly affected site. Hypertrophic intestinal TB
anus can be affected by TB. Ileocaecal area is commonly occurs due to a low volume infection by less virulent
affected site (18-21). The striking prediliction for this organisms in a host with good resistance and wound
region is thought to be due to the abundance of lymphoid healing capacity. This form is characterized by extensive
tissue [Peyer’s patches]. Increased physiological stasis, inflammation and fibrosis that often results in the
increased rate of fluid and electrolyte absorption and adherence of bowel, mesentery and lymph nodes into a
minimal digestive activity permitting greater contact time mass. This mass may occasionally appear to be an
between the organism and the mucosal surface in the exophytic neoplasm from the mucosal surface. On
ileocaecal area render this region more vulnerable to the histopathological examination, lymphoid follicular
development of intestinal TB. The vulnerability of overgrowth and hyperplastic germinal centre with infil-
ileocaecal region has also been attributed directly to tration by eosinophils, lymphocytes, plasma cells and
Peyer’s patches and the associated microfold-cells giant cells are present. Caseation, though not always
[M-cells]. The bacille Calmette-Guérin [BCG] has been present in the gut, is often seen in the mesenteric lymph
shown to be phagocytised by the M-cells and transported nodes. Caseation may occasionally be absent in tuber-
to the antigen presenting cells in the Peyer’s patches culosis granulomas. These non-caseating granulomas
without any evidence of epithelial inflammation (22). may be difficult to distinguish from those seen in Crohn’s
Often, intestinal lesion starts as crypt abscess, followed disease. Confluence of the granulomas, relative absence
by infection of Peyer’s patches. As the disease progresses, of cracks and fissures and submucosal oedema are
278 Tuberculosis
important findings that favour the diagnosis of TB (23). Symptoms Abdominal pain is the most common
Das and Shukla (24) experimentally produced hyper- symptom and is present in almost all the patients (1,18-
trophic tuberculosis by intraperitoneal inoculation of 21). The pain is most commonly located in right lower
infective tissue into guinea pigs. Inspite of non-specific quadrant of the abdomen, though a significant propor-
histology, acid-fast bacilli [AFB] could be demonstrated tion of patients may complain of diffuse, central,
in the gut and mesenteric lymph nodes in all four guinea epigastric or left lower quadrant pain. The pain, parti-
pigs. While in a similar experiment, Crohn’s disease cularly in patients presenting with intestinal obstruction
tissue failed to produce any lesion (24). has a cramp-like or colicky character. Pain may be diffuse
or dull in character, especially when the peritoneum or
Ulcerohypertrophic form Ulcerohypertrophic form of
mesenteric lymph nodes are involved. Sometimes,
intestinal TB displays characteristics of both forms of the
abdominal pain may be severe. Tuberculosis duodenitis
disease.
may produce distress mimicking duodenal ulcer disease.
Diffuse colitis Another much less common form of Tuberculosis of the appendix mimics acute appendicitis.
intestinal TB is diffuse colitis, which is endoscopically Diarrhoea occurs in 11 to 20 per cent of the patients
very similar to ulcerative colitis. Diffuse colitis cannot (1,18-21). Liquid to semisolid stools are passed six to eight
be easily distinguished from ulcerative colitis on the basis times a day. Mucus is usually present. Blood or frank
of mucosal appearance alone. pus may be passed rarely. Diarrhoea is almost always
Sclerotic form Sclerotic variety is associated with associated with intestinal ulceration, although it can
sometimes occur in the absence of any mucosal disease
stricture that can be solitary or multiple (23).
and is thought to occur due to a generalized inflamma-
Entero-enteric, entero-vesical and entero-cutaneous
fistulae can occur. In the gastrointestinal tuberculosis, tory response. Diarrhoea alternating with constipation
has been described in 8.8 to 20 per cent of the patients
luminal narrowing is often caused by adjacent TB
(1,18-21).
lymphadenitis that results in traction, diverticula
formation, narrowing, fixation and sinus tract formation. Weight loss is a common complaint. Anorexia
contributes to marked diminution of food intake. Patients
Clinical Features may also present with features of malabsorption.
Decreased total absorptive area due to extensive ulcera-
Demographic characteristics and clinical features of tion, lymphatic obstruction or bacterial overgrowth are
abdominal TB are summarized in Tables 19.3 and 19.4. thought to be the causes of malabsorption. Bacterial
Abdominal TB is a chronic illness with protean overgrowth secondary to stagnant loop syndrome is
manifestations. Although the disease can affect any age found in 15 to 20 per cent patients presenting with
group, subjects in the age group between 20 to 40 years intestinal TB and obstruction (1,18-21). Other abdominal
are most often affected and slight female preponderance symptoms include moving lump in the abdomen, nausea,
has been described (1,18-21). vomiting, malaena, and constipation.
In the series reported by Bhansali (20), 171 patients Fever has been reported in 40 to 70 per cent of the
complained of insidious onset of illness. The remaining patients (1,18-21). Menstrual abnormalities have been
139 patients presented with acute manifestations. Of described in nearly one third of the female patients (1,18-
these 139 patients, 92 [66.2%] presented with intestinal 21).
obstruction, 23 [16.6%] presented with perforation while
19 patients [13.6%] had a presentation simulating Signs Most patients appear ill and malnourished.
peritonitis and in five patients [3.6%] the presentation Examination of the abdomen generally reveals tender-
mimicked acute appendicitis. In these patients, the ness most frequently in right iliac fossa. A palpable
cardinal presenting feature was abdominal pain. In 56 abdominal mass may be present. The mass is due to
of these 139 patients [40.3%], the acute episode was the hyperplastic caecal TB, lymph node enlargement
first manifestation of tuberculosis, while the remaining and rolled-up omentum. The classic “doughy
83 patients [59.7%] gave a history of chronic intermittent abdomen” has been described in only six to eleven per
abdominal pain in the past (20). cent patients in Indian studies [Table 19.3]. Abdominal
Table 19.3: Demographic characteristics and symptoms at presentation in patients with abdominal tuberculosis
Variable Das and Shukla (19) Bhansali (20) Singh et al (21)

[n = 182] [n = 310]* [n = 145]
Place of study Allahabad Mumbai Banaras
Duration of study [years] 7 13 5
Male : Female 1:2.6† 1:0.9 1:2
Symptoms [%]
Fever 44.2 49.2 66.2
Abdominal pain 94.0 100.0 88.3
Vomiting 69.6 29.9 55.2
Constipation 46.7 40.5 24.1
Diarrhoea 11.1 15.4 20.7
Diarrhoea alternating with constipation 8.8 11.4 20.0
Weight loss 35.0 25.6 21.4
Anorexia 44.4 ND 71.7
Cough 8.8 ND 11.0
Moving lump in abdomen 28.8 ND 26.2
Borborygmi 25.5 ND ND
Postprandial distress 27.2 ND ND
Abdominal distension 45.0 ND 41.4
Menstrual abnormalities‡ 35.6 [n = 132] 14.6 [n = 160] 35.0 [n = 97]
Dysphagia ND ND 0.7
Bleeding per rectum ND ND 4.8
* Of the 310 patients included in the study, break-up of symptoms at presentation was provided for 254 chronic cases. Of these 254
chronic cases, 171 presented with a chronic ailment and 83 presented with acute on chronic disease
† While the overall male:female ratio was 1:2.6, it was 1:8.5 in patients with hyperplastic ileocaecal tuberculosis [n = 38] 1:3 in patients
with ascites [n = 20]: 1:2.8 in patients with stricture of ileum [n = 50]; 1:1.5 in those with mesenteric lymphadenitis and 1:1.5 in those with
chronic miliary tuberculosis peritonitis [n=48]
‡ Numbers in square brackets indicate the number of female patients in the study
ND = not described
distension with increased peristaltic activity is generally Oesophageal Tuberculosis

associated with intestinal obstruction [Figure 19.1]. There Tuberculosis of oesophagus is very rare. In an autopsy
may be free intestinal perforation when signs of study, oesophageal TB accounted for 0.2 per cent of the
peritonitis may be apparent. cases (25). Oesophageal involvement usually occurs due
Figure 19.1: Intestinal tuberculosis. Abdominal distenstion due to distended bowel loops,
everted umbilicus [white arrow] and visible peristalisis [black arrow] can be seen
280 Tuberculosis
Table 19.4: Physical signs at presentation in patients with abdominal tuberculosis

[n = 182] [n = 310]* [n = 145]
Anaemia 56.5 29.0* ND
Malnutrition 45.6 21.7† ND
Peripheral lymphadenopathy 1.6‡ 9.0§ ND
Features of intestinal obstruction 51.0 30.0 50.0
Abdominal tenderness 65.9 62.6 ND
Distension of abdomen 58.2 81.3ll 41.4
Doughy feel of the abdomen 6.0 ND 11.7
Visible peristalsis 35.1 66.2ll 31.7
Ascites 18.6 1.9 20.0
Rigidity/guarding 8.7 31.7 ND
Lump abdomen 28.6¶ 59.1** 31.0††
All values are shown as percentages

* 90 of the 310 cases had haemoglobin less than 60 per cent
† 55 of the 254 chronic cases were in a state of malnutrition
‡ Cervical lymphadenopathy
§ Cervical, axillary and inguinal lymphadenopathy
ll Described in 139 of the 310 patients with acute presentation
¶ In 18.5% of the patients, right iliac fossa mass was present. Other sites included umbilical region [4.2%], epigastrium [3.2%], right
hypochondrium [1.6%]. A vague mass was palpable in 1.1% of the cases
** Abdominal lump was described in 101 of the 171 [59.1%] patients with chronic presentation. In 80 of them [46.7%], the mass was
located in the right iliac fossa and was due to hyperplastic ileocaecal tuberculosis; in 19 [11.1%], it was due to lymphadenopathy and in
two [1.2%], the mass was due to rolled-up omentum
†† The lump was situated in the right iliac fossa
ND = not described
to direct extension of infection from adjacent affected has been reported (33,34). Symptoms are non-specific and
structures, such as mediastinal lymph nodes or the lung include abdominal pain, nausea, vomiting, gastrointesti-
(26-29). Less frequently, oesophageal involvement occurs nal bleeding, fever and weight loss (35,36). Ulcerative
in the absence of TB elsewhere in the body (30). Upper form is the commonest and is encountered in 80 per cent
part of the oesophagus is more often involved than the of patients with gastric TB (35,36). The ulcers are found
lower part. Patients commonly present with dysphagia on the lesser curvature of the stomach. Very rarely, fistu-
and odynophagia. Pulmonary aspiration can occur in lous communications with adjacent organs may be
patients who go on to develop tracheo-oesophageal or evident. Gastric TB often is not suspected until the time
broncho-oesophageal fistula. Mild, rarely massive of surgery and is usually a retrospective diagnosis.
haematemesis due to aorto-oesophageal fistula has been
described (31,32). However, none of these findings are Duodenal Tuberculosis
specific to oesophageal TB, and endoscopic biopsy is
Duodenal TB is a rare form of gastrointestinal TB (21,37-
mandatory for confirmation of the diagnosis.
40). In the series described by Singh et al (21), duodenal
involvement occurred in five of the 145 patients [3.4%]
Gastric Tuberculosis
with abdominal TB. Usually patients present with
Gastric TB is also rare due to the presence of gastric acid obstructive symptoms or with non-specific dyspeptic
and the paucity of lymphoid tissue in stomach. In an symptoms. Fever and weight loss may be present. The
autopsy series of TB patients, an incidence of 0.6 per cent obstruction is more often due to extrinsic compression
rather than luminal obstruction. Extrinsic obstruction tructive jaundice have all been described (46). Pancrea-
may be caused by lymph nodes or adhesions. Very rarely, tic TB may present as acute or chronic pancreatitis or
patients may develop obstructive jaundice. Endoscopic may mimic malignancy (47,48). Investigations generally
biopsy has been found to have a low diagnostic yield. do not contribute to the diagnosis and confirmation of
the diagnosis is sometimes not possible even at operation.
Tuberculosis of Appendix Fine-needle aspiration cytology [FNAC] and biopsy may
Incidental TB involvement of the vermiform appendix be helpful in differentiating TB from carcinoma,
is fairly common in patients with active ileocaecal TB lymphoma, sarcoidosis or chronic pancreatitis.
(1), but the incidence of isolated TB of the appendix is
rare even in areas where TB is highly endemic (41). In SPLENIC TUBERCULOSIS
India, TB has been reported in two per cent of all appen-
Tuberculosis involvement of the spleen can occur due to
dicectomies (42). The clinical features of TB appendicitis
disseminated or miliary form of the disease [Figure 19.2]
may be very vague, with the disease being diagnosed
(49-51). In developed countries, the disease is most
only on abdominal exploration. Very rarely, appendi-
commonly encountered in human immunodeficiency
cular perforation may be the presenting feature (43).
virus [HIV] seropositive individuals. Fever, left upper
Anal Tuberculosis quadrant abdominal pain, weight loss and diarrhoea are
common features (49-51). Multiple TB abscesses have
Anal and perianal TB are rare but pose diagnostic been described in patients with HIV infection (51,52).
problems clinically. These lesions are mostly ulcerative, Clinically, these patients may manifest with spleno-
although lupoid, verrucus and miliary lesions have been megaly or hepatosplenomegaly and can present with a
described (44). The TB ulcers are shallow with bluish fever of unknown origin. Rarely, isolated splenic TB may
undermined edges and progress very slowly. Associated occur in immunocompetent individuals (53-55). The
inguinal lymphadenopathy may be present. Tuberculosis clinical presentation may mimic splenic abscess due to
fistula-in-ano and perianal abscess may be present. other causes. Associated vertebral TB with a psoas
Tuberculosis fistula-in-ano should be considered when abscess may facilitate involvement of the spleen by
multiple or recurrent fistulae are seen along with inguinal contiguous spread. In earlier days, pre-operative diag-
lymphadenopathy (45). Anal lesions of Crohn’s disease, nosis was often difficult and used to be confirmed on
squamous cell carcinoma, lymphogranuloma venereum histopathological examination of the splenectomy
and syphilis can be differentiated by histopathological specimens. However, with the availability of modern
examination. imaging techniques, splenic TB lesions are increasingly
being recognized.
HEPATOBILIARY TUBERCULOSIS
The reader is referred to the chapter “Granulomatous

hepatitis” [Chapter 20] for more details.
PANCREATIC TUBERCULOSIS
Pancreatic TB is rare. It is often associated with miliary

TB and occurs more often in immunocompromised
patients (46). Pancreatic TB is most often the result of
lymphohaematogenous dissemination or direct spread
from other adjacent organs. The clinical manifestations
are protean and depend on the site and extent of disease.
Anorexia, malaise, low-grade fever, weight loss, night Figure 19.2: Splenic tuberculosis. Extensive areas of
sweats, malaena, pancreatic mass or abscess or obs- caseation necrosis can be seen
282 Tuberculosis
Splenomegaly can also occur in TB patients with Table 19.5: Diagnostic criteria of abdominal tuberculosis
haematological abnormalities, such as pancytopenia,
Histopathological evidence of caseating granulomas, acid-
myelodysplasia, acute leukaemia, chronic myeloid fast bacilli
leukaemia (56-59). In some patients splenomegaly is Presence of Mycobacterium tuberculosis in sputum, tissue or
thought to contribute to the haematological abnormali- ascitic fluid
ties, as it has been reported that splenectomy resulted Clinical, radiological or operative evidence of proven
resolution of these abnormalities (60,61). tuberculosis elsewhere with good therapeutic response
Good therapeutic response to antituberculosis treatment
ABDOMINAL TUBERCULOSIS IN PATIENTS WITH Based on reference 64

HUMAN IMMUNODEFICIENCY VIRUS INFECTION
AND ACQUIRED IMMUNODEFICIENCY SYNDROME gastrointestinal TB, barium meal studies, endoscopy with
The epidemic of acquired immunodeficiency syndrome biopsy, exploratory laparotomy are potentially helpful
[AIDS] has been accompanied by a resurgence of TB. The in confirming the diagnosis. Biopsies are preferred from
incidence of extra-pulmonary TB is about 50 per cent in ulcer margins. Culture of the biopsy material increases
patients with AIDS, whereas, it is 10 to 15 per cent in the diagnostic yield. Diagnostic criteria for abdominal
patients without HIV infection (2,11,62). Fee et al (63) TB (64) are summarized in Table 19.5.
compared the presentation of abdominal TB in 43
patients infected with HIV and 35 patients without HIV Haematology and Serum Biochemistry
infection. Fever, weight loss, and extra-abdominal There is a varying degree of anaemia, leucopenia with
lymphadenopathy were more common in patients with relative lymphocytosis. The erythrocyte sedimentation
HIV infection, whereas ascites and jaundice were more rate [ESR] is increased. Raised ESR was reported in 50 to
frequent in patients without HIV infection. Intra-abdomi- 100 per cent patients in several studies (1,5-11,18-21).
nal lymphadenopathy and visceral lesions, visualized on However, ESR was found to be normal in many
computed tomography [CT], were more common in histologically proven patients with abdominal TB
patients with HIV infection, whereas ascites and omental (1,5-11,18-21). Serum albumin levels tend to be
thickening were more frequent in patients without HIV depressed. Serum transaminase levels tend to be normal.
infection. Disseminated TB was present in 93 per cent of Serum alkaline phosphatase may be raised (1,5-11,18-21).
the HIV infected patients, compared with 31 per cent of Laboratory investigations are non-specific and do not
those without HIV infection. In HIV-seropositive contribute to the diagnosis.
patients, abdominal TB appears to be a manifestation of
disseminated disease and results in significant mortality. Tuberculin Skin Test
A positive tuberculin skin test [TST] has been reported
ABDOMINAL INVOLVEMENT IN NONTUBERCULOUS
in 55 to 100 per cent patients with abdominal TB (1,5-
MYCOBACTERIAL INFECTION
11,18-21). However, in areas where TB is highly endemic,
Abdominal involvement is uncommon in patients with positive TST neither confirms the diagnosis of abdominal
nontuberculous mycobacterial [NTM] infections. Occa- TB nor excludes it.
sionally, intra-abdominal infection and disseminated
disease caused by NTM have been described. The reader Imaging Studies
is referred to the chapter “Nontuberculous mycobacterial
Chest Radiograph
infections” [Chapter 48] for more details.
Associated pulmonary TB has been described in 24 to 28
DIAGNOSIS per cent of patients with abdominal TB [Table 19.6].
Abdominal paracentesis and ascitic fluid examination,
Plain X-ray Abdomen
laparoscopy with biopsy, needle biopsy of the perito-
neum, diagnostic laparotomy are useful in confirming Plain radiograph of the abdomen may show calcified
the diagnosis of TB peritonitis. In patients with lymph nodes or calcified granulomas in the spleen, liver
Table 19.6: Evidence of associated pulmonary tuberculosis in patients with abdominal tuberculosis

[n=182]* [n=310] [n=145]
Active pulmonary TB 15.1 10.6 16.6
Pleural effusion 6.9 ND ND
Healed or calcified pulmonary TB 5.8 14.2 3.4
Total 27.8 24.8 20.0

* Chest radiograph was done in 86 of the 182 patients
ND = not described; TB = tuberculosis
and pancreas (65). Other radiographic features include and recording images in real time as the contrast moves
dilated loops with fluid levels, dilatation of terminal through] followed by barium enema is useful for
ileum and ascites. Pneumoperitoneum may be evident evaluation of intestinal TB. Increased transit time with
in patients with intestinal perforation. hypersegmentation and flocculation of barium is one of
the earliest signs of intestinal involvement. Localized
Barium Studies areas of irregular thickened folds, mucosal ulceration,
Barium contrast studies have been the most useful dilated segments and strictures may be seen [Figures
investigation for the diagnosis of intestinal TB till 19.3A and l9.3B]. The ulcers may be linear or stellate and
recently. Although the radiological features of intestinal are situated along the circumference of the wall. Rarely,
TB are non-specific, several findings are highly there may be deep ulcers with fistulae. The ileocaecal
suggestive of the disease. Enteroclysis [a fluoroscopic valve may be thickened initially and gives a broad
procedure to evaluate the small intestine, done by triangular appearance with the base towards the caecum.
inserting a tube through the nose to the duodenum, This is referred to as the inverted umbrella sign or
infusing radiocontrast, like barium and air through it Fleischner’s sign. Other features include rapid transit and
Figure 19.3A: Barium meal follow through study showing grossly

dilated terminal ileum [black arrow], stricture in the ileocaecal region
[white arrow], contracted caecum and part of the ascending colon
[asterisk] suggestive of ileocaecal tuberculosis with ascending colon Figure 19.3B: Enteroclysis study showing multiple
involvement strictures [arrows] in the jejunum
284 Tuberculosis
lack of barium retention in an inflamed segment of the usually arise from the serosa of the small bowel and are
small bowel because of extreme irritability due to due to high fibrin content of the exudative ascitic fluid.
ulceration [Stierlin’s sign] and persistent narrow stream They are considered to be diagnostic of abdominal TB
of barium in the bowel suggestive of stenosis [string sign]. (65). But this finding may be observed in patients with
Both Stierlin’s and string signs are also seen in Crohn’s malignant ascites also (67). Loculated ascites probably
disease and hence not specific for TB. Barium meal follow represents walled-off peritoneal inflammation. Fluid
through findings in intestinal TB have been classified into collection in the pelvis produces thick septae and can
four groups (66) as presented in Table 19.7. mimic ovarian cysts. Interloop ascites gives rise to
In patients with oesophageal TB, common radio- characteristic club sandwich appearance of alternating
graphic features on barium oesophagogram include echogenic and echo-free layers of the bowel wall and
ulcerative oesophagitis, stricture, pseudotumour masses, interloop fluid (68). Mesenteric thickening is better
fistulous communication with airway, sinus tract detected in presence of ascites and is often seen as the
formation, and traction diverticulae. In patients with stellate sign of bowel loops radiating out from its root.
duodenal TB, barium studies usually reveal segmental Enteritis with diffuse mural thickening is non-specific
narrowing of the duodenum. Hypertrophic type most and must be distinguished from Crohn’s disease (69). In
commonly mimics neoplasm while the ulcerative type intestinal TB, bowel wall thickening is usually uniform
mimics peptic ulcer disease. Widening of “C” loop of and concentric as opposed to the eccentric thickening at
duodenum due to lymphadenopathy may simulate
the mesenteric border seen in Crohn’s disease and the
superior mesenteric artery syndrome.
variegated appearance seen in malignancy. This may be
difficult to appreciate on ultrasonography. Lymphoma
Abdominal Ultrasonography
of the bowel remains an important differential diagnosis.
Abdominal ultrasonography often reveals a mass made Lymphadenopathy may be discrete [Figure 19.4] or
up of matted loops of small bowel with thickened walls, matted. There is a predilection for periportal, peripan-
diseased omentum, mesentery and loculated ascites (65). creatic and mesenteric locations. Calcification and
However, these findings are not specific for TB. Fine heterogeneous echotexture may also be seen (70).
septae may be seen in the ascitic fluid. These strands
Table 19.7: Barium meal follow through findings in

intestinal tuberculosis
Group I Highly suggestive of intestinal tuberculosis if one or

more of the following features are present
Deformed ileocaecal valve with dilatation of terminal
ileum
Contracted caecum with an abnormal ileocaecal valve
and/or terminal ileum
Stricture of the ascending colon with shortening and
involvement of ileocaecal region
Group II Suggestive of intestinal tuberculosis if one of the
following features is present
Contracted caecum
Ulceration or narrowing of the terminal ileum
Stricture of the ascending colon
Multiple areas of dilatation, narrowing and matting of
small bowel loops
Group III Non-specific changes
Features of matting, dilatation and mucosal thickening
of small bowel loops
Group IV Normal study Figure 19.4: Ultrasonography of the abdomen showing extensive
hypoechoic lesions in the retroperitoneum suggestive of lymph-
Based on reference 66
adenopathy [N]
include, thickened bowel loops and ascites. Balthazar et

al (72) described preferential thickening of the medial
caecal wall with an exophytic mass engulfing the
terminal ileum associated with massive lymphadeno-
pathy as characteristic findings in TB. This florid response
was observed in patients who had AIDS (72). Short
segments of homogeneous circumferential or eccentric
mural thickening [Figures 19.7A and 19.7B] with normal
intervening bowel associated with ileocaecal involve-
ment strongly suggest TB (66). Granulomas or abscess
in the liver, pancreas and spleen may be seen [Figure
19.8]. In most of the patients with splenic TB, multiple
hypoechoic foci [< 2 cm] may be evident on contrast
enhanced CT of the abdomen [Figures 19.9A, 19.9B, 19.10,
Figure 19.5: CECT of the abdomen showing marked ascites

[asterisks] and streakiness of the mesentery [arrows]
Although caseation of lymph node is common in TB,

necrosis within the metastatic lymphadenopathy may
have a similar appearance (71).
Abdominal Computed Tomography

Abdominal CT is better than ultrasonography for
detecting high density ascites [Figure 19.5] (65). Abdomi-
nal CT also detects retroperitoneal, peripancreatic, porta
hepatis, mesenteric and omental lymph node enlarge-
ment; caseation necrosis in the lymph node may appear
as low attenuating, necrotic centres and thick, enhancing Figure 19.7A: CECT of the abdomen showing ileocaecal
tuberculosis with stricture in the ileocaecal region [arrow]
inflammatory rim (65) [Figure 19.6]. Other CT findings
Figure 19.7B: CECT of the abdomen showing caecal tuberculosis.

Figure 19.6: CECT of the abdomen showing extensive Thickening of the caecal wall due to inflammation can be seen
retroperitoneal lymphadenopathy [arrows] [arrow]
286 Tuberculosis
Figure 19.8: CECT of the abdomen showing multiple, low

attenuation lesions in the liver
Figure 19.9B: CECT of the abdomen showing solitary, low
attenuation lesion in the spleen [arrow]
Ascitic Fluid Examination

The serum-ascitic fluid albumin gradient is less than 1.1
in more than 90 per cent of the patients (1,5-11,74,75).
Ascitic fluid white blood cell count is usually 150 to 4000
cells/mm3 and consists of lymphocytes predominantly.
For unknown reasons, neutrophilic response has been
observed in the ascitic fluid in patients with TB peritonitis
associated with peritoneal dialysis (12). Red blood cells
may be found often in the ascitic fluid. Ascitic fluid
reveals AFB in less than three per cent of the cases (1,5-
11). In most of the studies (1,5-11), ascitic fluid culture
for Mycobacterium tuberculosis is positive in less than 20
per cent of the patients. Singh et al (6) reported that the
Figure 19.9A: CECT of the abdomen showing multiple,
low attenuation lesions in the spleen [arrows] yield of ascitic fluid culture was as high as 83 per cent
when one liter of fluid was concentrated by
centrifugation and then cultured.
19.11 and 19.12] (51). Occasionally, a large solitary splenic Adenosine deaminase [ADA] activity in ascitic fluid
tuberculoma has been described (62). is a sensitive and specific marker for TB (76-78). The
In addition to ascites, mesenteric infiltration, omental reader is also referred to the chapter “Tuberculosis pleural
masses peritoneal enhancement or thickening and dis- effusion” [Chapter 17] for a detailed discussion on ADA
organized masses of soft tissue densities may be seen. estimation. When a cut-off value of 32 IU/l is chosen,
Most of the features can be seen individually in a variety the specificity and sensitivity of ascitic fluid ADA
of conditions like peritoneal mesothelioma, carcino- estimation are found to be 95 and 98 per cent, respectively
matosis and peritonitis of any form (73). However, when (76-78). In low protein ascites, false-negative results are
a combination of these findings is associated with lymph- more frequent (77). In patients with HIV infection and
adenopathy and mural thickening of ileocaecal region, TB peritonitis, the ADA levels may be lower (77).
it would favour a diagnosis of TB. False-positive ADA result has also been reported in
Figure 19.10: Abdominal tuberculosis. CECT of the abdomen showing multiple low attenuation lesions [black arrows] in the spleen
[A,B]; ascites [white arrows], [B,C]; dilated bowel loops [asterisk] [C,D]; and extensive retroperitoneal lymphadenopathy [D], [square]
Figure 19.11: Ultrasonography showing a large, regular hypoechoic lesion [arrow] located peripherally along the inferior aspect of the
spleen [A]. CECT of the abdomen of the same patient shows a large irregular hypodense lesion [arrow] in the inferior aspect of the
spleen suggestive of an abscess [B]
Reproduced with permission from “Sharma SK, Smith-Rohrberg D, Tahir M, Mohan A, Seith A. Radiological manifestations of splenic
tuberculosis: a 23-patient case series from India. Indian J Med Res 2007;125:669-78 (reference 51)”
288 Tuberculosis
Figure 19.12: Ultrasonography showing multiple large hypoechoic lesions [arrows] [A]. CECT of the abdomen of the same patient
shows multiple large hypodense lesions seen within the spleen [B] [arrows]
Reproduced with permission from “Sharma SK, Smith-Rohrberg D, Tahir M, Mohan A, Seith A. Radiological manifestations of splenic
tuberculosis: a 23-patient case series from India. Indian J Med Res 2007;125:669-78 (reference 51)”
patients with malignant ascites (76,79). The level of Polymerase Chain Reaction
interferon-γ [IFN-γ] in ascitic fluid is significantly higher
in TB peritonitis than in malignancy and cirrhosis (79). The scope of molecular biological methods in the diag-
Using an optimal cut-off point of 112 pg/ml, IFN-γ was nosis of abdominal TB is being explored. Anand et al
useful in distinguishing TB ascites from non-TB ascites (83) have used polymerase chain reaction [PCR] assay
(76). Estimation of both ADA and IFN-γ levels is simple, on endoscopic biopsy specimens to diagnose intestinal
rapid and non-invasive with high sensitivity and TB in a patient with chronic diarrhoea. The patient was
specificity. However, estimation of IFN-γ is almost twice treated with antituberculosis drugs with complete
expensive than ADA test. Thus, ADA is particularly resolution of endoscopic abnormalities. The PCR can
useful in developing countries where more sophisticated be used to complement the diagnosis of TB in proces-
and expensive tests such as laparoscopy may not be sed and paraffin embedded tissue materials, especially
available (76). in situations where a definite conclusion cannot be
obtained by conventional methods (83,84). However,
Serodiagnosis empirical antituberculosis treatment is justified in
patients with clinical and histological features highly
Conventional histopathological and microbiological suggestive of peritoneal TB, even in cases with
methods are often inadequate for diagnosing abdomi- negative results from microscopy, culture and PCR
nal TB. In these instances, immunodiagnostic procedures analysis (85).
seem to have a major role to play, even if they are only
moderately sensitive. However, the results of various Scintigraphy, Positron Emission Tomography
serological techniques are variable due to uncertainty of
antibody response to mycobacteria, poor reproducibility Radionuclide scintigraphy detects serosal inflammation
and lack of specificity (80). The serum CA-125 level that and peritonitis. Gallium67 citrate is superior to Indium111
is normally elevated in ovarian malignancy is also raised labeled leucocytes for detecting areas of abdominal
in some patients with abdominal TB. The level falls with disease (86). 18Fluorine fluorodeoxyglucose positron
antituberculosis treatment. This at times leads to emission tomography [18FDG-PET] has been found to be
diagnostic difficulty in patients with abdominopelvic useful in the diagnosis of peritoneal TB (87). Exact role
mass with or without ascites mimicking an ovarian of these modalities is not clear at present and they should
malignancy (81,82). not be used indiscriminately.
Endoscopy Peritoneal Biopsy
Colonoscopy Blind percutaneous peritoneal needle biopsy and open

parietal peritoneal biopsy under local anaesthesia are also
Colonoscopy is the easiest and most direct method for useful procedures for confirming the diagnosis of
establishing the diagnosis of TB colitis and when abdominal TB (19-21,93). These techniques are relatively
combined with directed colonoscopic biopsy, it has a safe, although blind needle biopsy can cause fatal bowel
clear advantage over radiographic approaches (88-90). perforation. Shukla et al (93) carried out open peritoneal
On colonoscopy, the ileocaecal valve may be oedematous biopsy by a grid iron incision in right iliac fossa under
or deformed [Figure 19.13]. Nodules, ulcers, pseudopoly- local anaesthesia and reported 80 per cent diagnostic
poid folds and strictures may be seen. Ulceration is the accuracy. The needle biopsy of peritoneum has an added
most common finding and is observed in the ileocaecal limitation that an involved part of peritoneum may not
region. However, as with most diagnostic procedures in be obtained (94).
intestinal TB, endoscopic findings are not pathogno-
monic. Tuberculosis granulomas are found in the sub-
Laparoscopy
mucosa, hence multiple and deep biopsies will increase
the diagnostic yield (88-90). A combination of histology Direct inspection and biopsy of the peritoneum are
and culture of the biopsy material can establish the perhaps the most effective method of diagnosing TB
diagnosis in 80 per cent of the cases (88-90). peritonitis [Figure 19.14]. Laparoscopy alone will
facilitate an accurate presumptive diagnosis in 80 to 95
per cent of patients (1,89,95). Laparoscopy biopsy
specimens may reveal AFB in 75 per cent and caseating
granulomas in 85 to 90 per cent patients (1,8,95,96).
Characteristic laparoscopic findings include multiple,
yellowish-white miliary nodules over visceral and
parietal peritoneum, erythematous, thickened and
hyperaemic peritoneum, turbid ascites and adhesions.
Chances of perforation are high when patients with
fibroadhesive peritoneal TB are subjected to laparoscopy.
Figure 19.13: Colonoscopy showing oedematous and

deformed ileocaecal valve [arrow]
Fine-Needle Aspiration Cytology

In patients with palpable masses, FNAC has been shown
to have a high diagnostic accuracy (91,92). In patients
with lymphadenopathy, abscesses, and focal lesions of
the viscera, FNAC confirms the diagnosis (70).
Lowenstein-Jensen culture of the FNAC material increa-
ses the yield further. The FNAC during colonoscopy is
likely to add to the diagnostic yield in patients with Figure 19.14: Laparoscopy showing multiple peritoneal tubercles.
ileocaecal or colonic TB (91). Biopsy confirmed the diagnosis of peritoneal tuberculosis
290 Tuberculosis
In these patients, use of open exposure of the peritoneum

to introduce the laparoscope will significantly reduce the
risk of perforation (1). The safety of laparoscopy has been
well established in both HIV and non-HIV patients with
suspected TB peritonitis.
TREATMENT
Management of patients with abdominal TB includes
medical treatment and conservative or radical surgery
wherever appropriate.
Medical Treatment
Earlier, patients with abdominal TB have been treated
with antituberculosis drug regimens of eight to twelve
months duration (97,98). However, recent evidence
suggests that six month short-course chemotherapy
regimens are effective in the treatment of all forms of
abdominal TB (99). The reader is referred to the chapter
“Treatment of tuberculosis” [Chapter 52] for more details. Figure 19.15: Resected specimen of the small intestine
showing tuberculosis ulcers and perforation [arrow]
In India, majority of patients with abdominal TB get
treated with DOTS using standardized intermittent with end-to-end anastomosis is recommended (97).
treatment regimens under the Revised National Tuber- Hypertrophic ileocaecal TB requires a limited ileocaecal
culosis Control Programme [RNTCP] of the Government resection with a five-cm margin from a visibly abnormal
of India. A decade of experience with the RNTCP tissue or a limited right hemicolectomy and end-to-end
suggests encouraging results (100,101). anastomosis (103). Perforating ulcers are treated by
excision of the perforated segment with primary
Corticosteroids anastomosis.
The role of corticosteroid treatment in patients with Acute intestinal obstruction, perforation and perito-
abdominal TB is not well established and these should nitis are treated conservatively, if possible. Operation
not be routinely administered to all patients. undertaken during the acute stage carries a high morta-
lity rate. However, surgery is essential when conserva-
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294 Tuberculosis
Granulomatous Hepatitis
20
Vineet Ahuja, SK Acharya
INTRODUCTION hemisphere, tuberculosis [TB] is the most common cause

in India.
Granulomas in the liver may be found incidentally and Hepatic granulomas usually represent a generalized
perplex the clinician, but more often reflect an underlying disease process and have been described in five to ten
clinically relevant disease. The search for an aetiology of per cent of needle liver biopsy specimens (2,4). The causes
granulomas usually suggests a systemic disorder rather of hepatic granulomas are listed in Table 20.1. However,
than primary liver disease. Granulomas represent the this list is by no means exhaustive. The relative frequency
inflammatory response of the mononuclear phagocytic of occurrence of hepatic granulomas in some of the
system to the presence of a foreign antigen. An extremely published studies is shown in Table 20.2. In many studies,
diverse array of inciting agents can result in the formation TB and sarcoidosis have been the two most common
of granulomas in the liver. These granulomas often have causes of hepatic granulomas [Table 20.2]. With the
a common histopathological pattern but may sometimes advent of the human immunodeficiency virus [HIV]
differ in detail (1-4). However, in spite of an extensive infection and the acquired immunodeficiency syndrome
work-up and evaluation, the aetiology remains obscure [AIDS], hepatic granulomas due to rare causes such as
in 10 to 25 per cent patients with hepatic granulomas nontuberculous mycobacteria [NTM], cryptococcosis,
etc., are being increasingly encountered (1-4).
and these patients have been labelled as having
“granulomatous hepatitis” (2-6). Table 20.1: Common causes of hepatic granulomas
The word “hepatitis” implies that there is hepatic cell
Infections
destruction. However, in most patients with hepatic Bacterial: Brucella, Salmonella
granulomas, hepatic destruction is seldom seen. Mycobacterial: Tuberculosis, Leprosy, NTM
Therefore, several workers have proposed that the term Rickettsiae: Q fever
“granulomatous hepatitis” should be avoided and have Spirochaetal: Syphilis
Fungal: Histoplasma, Coccidioidomycosis, Cryptococcosis
suggested “hepatic granulomatous disease” or “hepatic
Parasitic: Schistosomiasis
granulomas” as alternatives (3,4,7). Viral: Hepatitis C, Cytomegalovirus
Sarcoidosis
AETIOLOGY Primary biliary cirrhosis
Hodgkin’s disease
Hepatic granulomas have varied aetiology and show AIDS related opportunistic infections
Drugs: Carbamazepine, chlorpromazine, chlorpropamide,
considerable geographic variation. There are numerous
phenylbutazone, procainamide
causes of hepatic granulomas, both infective and non-
infective. While the occurrence of sarcoidosis, primary AIDS = acquired immunodeficiency syndrome; NTM = nontuber-
culous mycobacteria
biliary cirrhosis and fungal disease is high in the Western
Granulomatous Hepatitis 295
Table 20.2: Major causes of hepatic granulomas in various case series
Variable Guckian and Neville Klatskin (9) Cunnigham Ferrell (11) Kanel and Sabharwal
Perry (8) et al (1) [n = 565] et al (10) [n = 35]* Reynolds (3) et al (12)
[n = 63] [n = 54] [n = 77] [n = 202] [n = 51]
Tuberculosis 53 2 12.4 10.4 2.5 25.2 55

Sarcoidosis 12 54 38 10.4 20 27.2 1.9
Primary biliary cirrhosis ND 19 10.4 6.5 22.8 0† 0
Malignancy 5 1.4 4.4 7.8 8.5 3.5 7.8
Unknown 20 10 6.5 31.2 20 17.3 12

ND = not described
* Patients with epithelioid cell granulomas only
† Patients with primary biliary cirrhosis were excluded
PATHOLOGY formed granulomas occurs in patients with haematological

malignancies and AIDS (3). Bile granulomas have been
Hepatic granulomas are the result of a cell mediated
described in areas of cholestasis. Lipogranulomas can be
immune response by hepatic reticuloendothelial system
seen in fatty liver. Microgranulomas can sometimes occur
to antigen or foreign substances (1-4).
in patients with AIDS, cytomegalovirus [CMV] hepatitis
Histopathological features of hepatic granulomas
and can occur along with other types of granulomas.
depend on the aetiology. Generally, hepatic granulomas
Klatskin (9) estimated that in a patient with one
consist of pale-staining epithelioid cells with surrounding
granuloma in the needle biopsy specimen, the entire liver
lymphocytes. Sometimes, the foreign body or infecting
would contain about 15 million granulomas assuming
organism can be identified within the granuloma. Central
that there is a generalized distribution. Hepatomegaly
area of caseation necrosis, foreign body and Langhans’
is, therefore, commonly observed in patients with
giant cells can also be seen. Fibrous capsule and hyaline
granulomatous liver disease (1-4,16-18).
change representing healing may also be found.
Several morphological types of hepatic granulomas
have been described [Table 20.3]. Epithelioid granulomas CLINICAL PRESENTATION
are often encountered in patients with TB [Figure 20.1],
Clinical presentation of patients with hepatic granulomas
sarcoidosis, primary biliary cirrhosis among other
depends on the causative disorder. These patients often
conditions. Caseating [necrotizing] granulomas have been
present with pyrexia of unknown origin [PUO]. Mild to
classically associated with TB. Fibrin ring granulomas
moderate hepatomegaly, which is usually non-tender,
with a characteristic “doughnut” appearance occur in
is common. When the disease is due to TB, sarcoidosis,
Q fever and have been described in several other
associated peripheral mediastinal lymphadenopathy,
conditions (13-15). Granulomatoid reaction with poorly
erythema nodosum, clinically apparent jaundice may be
found. In some conditions such as Hodgkin’s lymphoma
Table 20.3: Morphological types of hepatic granulomas
and primary biliary cirrhosis where hepatic granulomas
Epithelioid cell granulomas are an incidental finding, jaundice may be prominent.
Caseating [necrotizing] granulomas
Non-caseating granulomas
Fibrin ring granulomas LABORATORY ABNORMALITIES
Granulomatoid reactions with poorly formed granulomas
Bile granulomas In a patient with PUO, marked elevation of serum alka-
Lipogranulomas line phosphatase [SAP] [3 to 6 times the normal] with
Microgranulomas mild elevation of serum transaminases [2 to 6 times the
296 Tuberculosis
Table 20.4: Clinical syndromes of hepatobiliary

tuberculosis
Congenital tuberculosis
Primary hepatic tuberculosis
Disseminated/miliary tuberculosis
Tuberculoma
Tuberculosis of the biliary tract
Drug induced hepatic failure
Granulomatous hepatitis
Tuberculosis pylephlebitis
pulmonary TB, is usually clinically silent. Occasionally,

local signs and symptoms may be prominent in hepatic
TB, and may constitute the initial or sole presenting
feature of the disease. Using needle biopsy specimen,
epithelioid granulomas can be demonstrated in hepatic
TB in 80 to 100 per cent of cases; caseation necrosis in 30
to 83 per cent and acid-fast bacilli [AFB] in up to 59 per
cent of cases (2-4).
Congenital Tuberculosis
Hepatic involvement is very common in congenital TB
and has been recently incorporated into the diagnostic
criteria for this condition (19). When an infant born to a
mother with active TB manifests hepatomegaly, jaundice
Figure 20.1: Granulomatous hepatitis. Photomicrograph showing and failure to thrive, congenital TB should be considered
a well-defined epithelioid granuloma [arrow], Langhans’ giant cells,
in the differential diagnosis. The reader is referred to the
ballooning and fatty degeneration [asterisk] of hepatocytes [A],
[Haematoxylin and eosin × 200]. Epithelioid granuloma and chapter “Tuberculosis in pregnancy” [Chapter 30] for details
Langhans’ giant cells [arrow] are also seen amidst hepatocytes on this topic.
showing ballooning degeneration [B] [Haematoxylin and eosin
× 400] Primary Hepatic Tuberculosis
normal], well preserved hepatic synthetic function, Primary hepatic TB is said to occur when there is involve-
normal prothrombin time, serum albumin and a normal ment of the hepatobiliary tract by TB without apparent
to slight increase in serum bilirubin should arouse a involvement elsewhere, or, only with local lymph node
suspicion regarding the presence of hepatic granulomas and splenic involvement (18). Some workers have called
(2-4). Anaemia and elevated erythrocyte sedimentation this condition “local hepatic tuberculosis” (18,19). Cinque
rate may be found. Peripheral blood eosinophilia may et al (20) suggested that the tubercle bacilli reach the liver
suggest Hodgkin’s disease, parasitic infestation and drug via the portal vein as opposed to miliary TB where the
sensitivity (2-4). organism reaches the liver via the hepatic artery. Alvarez
and Carpio (21) reported clinical and histopathological
DIFFERENTIAL DIAGNOSIS features of 130 patients with localized hepatic TB seen
over a 20-year period at Manila, Philippines. The disease
Hepatobiliary Tuberculosis
was more common in males and most patients were in
Tuberculosis involvement of the hepatobiliary system the 11 to 30 years age range. Most of them were sympto-
can occur in several ways [Table 20.4]. Liver involvement matic for one to two years prior to the time of confir-
in TB, though common both in pulmonary and extra- mation of the diagnosis. The paper described two major
forms of clinical presentation. A hard, nodular liver with

fever and weight loss mimicking cancer was observed
in 65 per cent of the patients. In the remaining 35 per
cent patients, chronic recurrent jaundice mimicking
extra-hepatic obstruction was observed. Percutaneous
liver biopsy [positive in 48 of 71 patients; 67%] and
laparoscopy [positive in 49 of the 53 patients; 92%] were
the main methods of confirmation of the diagnosis. On
laparoscopy, hepatic lesions appeared as cheesy white,
irregular nodules. Hepatic calcification was evident in
49 per cent of the patients. In patients with jaundice,
serum aminotransferases were elevated in more than 90
per cent and SAP was elevated in 100 per cent patients.
Figure 20.2: Granulomatous hepatitis. Photomicrograph showing
In those without jaundice, serum aminotransferases were ballooning degeneration of hepatocytes [asterisk] and caseation
elevated in about five per cent and SAP was elevated in necrosis [arrow] [Haematoxylin and eosin × 400]
60 per cent patients. Overall, 12 per cent patients died in
this series (21).
[ii] multiple, miliary, micronodular and low-density
In the series reported by Essop et al (22), hepatic TB
lesions with miliary calcifications; [iii] singular, low-
was confirmed in 96 patients presenting with the features
of liver disease, only 14 of whom had other concomitant density mass with multiple flecked calcifications; [iv]
multiple cystic lesions; and [v] multiple micronodular
hepatic pathology. Although respiratory symptoms
and low-density lesions fusing into multiloculated cystic
occurred in 74 per cent of cases, these were over-
shadowed by the abdominal manifestations which mass or “cluster” sign. Balci et al (24) reported the
spectrum of MRI features in 18 patients with a histo-
included pain in the right hypochondrium, abdominal
pathological diagnosis of granulomatous hepatitis.
distension, firm, tender hepatomegaly, splenomegaly
and ascites. Icterus was observed in 11 cases [only one of Diffuse nodular liver involvement was visualized in all
patients. Nodules were consistent with granulomas and
whom had concurrent hepatic pathology] and liver
were 0.5 to 4.5 cm in diameter. Caseating granulomas
failure was found in 10 patients. A surgical presentation
occurred in three patients. Coagulation abnormalities were of intermediate and high signal intensity on T2-
weighted images and low signal on T1-weighted images.
were noted in 26 patients [24 with low prothrombin index
Non-caseating granulomas revealed intermediate signal
and 2 with moderately raised fibrinogen degradation
products]. The characteristic serum profile included on T1- and T2-weighted images and increased enhance-
ment in arterial phase images with persisting enhance-
hyponatraemia [64%], raised SAP [3%] and γ-glutamyl
ment in late phase images.
transferase [77%], hypoalbuminaemia [63%] and hyper-
gammaglobulinaemia [83%]. Transaminase levels were Most patients respond to antituberculosis treatment.
For patients with obstructive jaundice, in addition to
moderately elevated in 78 per cent of the cases. Hepatic
antituberculosis treatment, biliary decompression should
imaging techniques were frequently misleading. Chest
radiographs were normal in 25 per cent of cases. Liver be performed either by stent insertion during endoscopic
retrograde cholangiopancreatography, by percutaneous
biopsy was the most useful aid to correct diagnosis which
transhepatic biliary drainage or by surgical decompres-
was suspected clinically in only 47 per cent of cases.
Histopathologically, AFB, caseation [Figure 20.2] and sion whenever feasible (25).
granulomas were seen in nine, 83 and 96 per cent of cases,
Disseminated and Miliary Tuberculosis
respectively. The overall mortality was 42 per cent (22).
Yu et al (23) have described computed tomography Hepatic involvement is a common finding in patients
[CT] in hepatic TB in 12 cases. The findings included: with disseminated and miliary TB (17). Granulomas has
[i] multiple nodular lesions in the subcapsule of liver; been reported in 75 to 100 per cent patients in autopsy
298 Tuberculosis
series (26-28) and in 25 to 100 per cent needle biopsy three per cent. In these patients, symptoms and signs
specimens in patients with miliary TB (17,29,30). Miliary attributable to the biliary ducts are seldom found. Only
lesions are small 1 to 2 mm epithelioid granulomas. The three of the 45 patients [6.7%] reported by Stemmerman
reader is also referred to the chapter “Disseminated and (39) manifested clinical jaundice, and hepatomegaly was
miliary tuberculosis” [Chapter 34] for more details. evident only in one-third of them. However, evidence of
TB of other organ systems draining into the portal
Pulmonary Tuberculosis circulation [e.g., caseous TB mesenteric lymphadenitis,
intestinal TB, and TB peritonitis] was observed in 41 of
Up to two-thirds of the patients with pulmonary TB have
been shown to have evidence of hepatic involvement the 45 patients in this series (39). Biliary stricture (40)
and cholangitis (2) due to TB have also been described.
(2,4,16). In patients with pulmonary TB, hyperglobuli-
naemia is frequently present and mild hyperbilirubi-
Tuberculosis of Gall Bladder
naemia may occasionally be present (30). Serum amino-
transferase levels are usually normal. Kupffer cell hyper- Gall bladder is an uncommon site of involvement by TB.
plasia is often present (16,31,32). Most cases occur in association with other organ
involvement. Rarely, isolated TB of the gall bladder can
Tuberculoma occur (41,42) and is usually a retrospective diagnosis,
becoming evident on histopathological examination of
Sometimes, hepatic TB lesions can present as masses
the cholecystectomy specimen. Management consists of
larger than 2 mm in diameter (33). Symptoms of fever,
malaise and weight loss are common. Occasionally, administration of antituberculosis treatment (2,31,41,42).
abdominal pain and diarrhoea may occur. Hepatomegaly
Hepatobiliary Tuberculosis in Patients with
is frequently present. Jaundice and a palpable abdominal
Human Immunodeficiency Virus Infection and
mass are uncommon presenting signs. Obstruction to bile
Acquired Immunodeficiency Syndrome
flow due to compression at the porta hepatis by a tuber-
culoma has been postulated to be the cause of jaundice. Hepatobiliary involvement is very common in patients
Bleeding into a solitary tuberculoma presenting as an with HIV infection and AIDS (7). Both, Mycobacterium
acute abdomen and progressive anaemia have also been tuberculosis and NTM can cause the disease (2,31). In
reported (34). Consistent with a pattern characteristic of patients with AIDS, it is important to distinguish hepatic
space occupying lesions of the liver, serum transaminases granulomas due to TB from other causes.
are normal or only slightly elevated; SAP levels are
moderately elevated. On liver scan and arteriography, Other Hepatic Lesions
these lesions may mimic the appearance of a primary
Granulomatous hepatitis has been described in 12 to 28
or metastatic carcinoma. They may also be confused with per cent patients receiving bacille Calmette-Guerin [BCG]
pyogenic or amoebic liver abscess (31,35). While blind
vaccination (43-45). Clinically, constitutional symptoms,
percutaneous needle biopsy was not very helpful in the
hepatomegaly, mildly elevated serum transaminases,
diagnosis (31,36), aspiration cytology at the time of bilirubin and moderately elevated SAP levels are present.
laparoscopy was more useful in confirming the diagnosis
Focal defects or non-homogeneous uptake on technetium
(37). Most often these lesions resolve with effective
liver scan may be present. On histopathological exami-
antituberculosis treatment. nation, granulomas, hepatocellular necrosis, lympho-
histiocytic aggregates and Kupffer cell hyperplasia have
Tuberculosis of Bile Ducts
been described (43-45). Direct effect of viable BCG bacilli
Tuberculosis of the bile ducts is uncommon. The disease and hypersensitivity reaction have been proposed as the
is thought to result from rupture of tubercles in the underlying pathogenetic mechanisms (46).
periportal region into the walls of contiguous biliary Amyloidosis has been described in 10 per cent of
ductules or by primary infection of bile ducts (38). patients with concomitant hepatic TB which may
Stemmerman (39) found TB of the biliary ducts in 45 of occasionally present as marked hepatomegaly (28). Most
1500 autopsies and estimated the incidence to be of these patients have long standing advanced disease
frequently involving the intestinal tract (28,47). Nodular giant cells are not common and necrosis is not present.
regenerative hyperplasia had been described in TB and Sometimes epithelioid cells may surround the inter-
several other disorders such as collagen vascular lobular bile ducts undergoing non-suppurative destruc-
disorders [e.g., systemic lupus erythematosus, rheuma- tion. Liver granulomas may also be seen in primary
toid arthritis, progressive systemic sclerosis], antiphos- sclerosing cholangitis (14).
pholipid antibody syndrome, macroglobulinaemia,
among others (48,49). In Bantus of Africa, haemosiderosis Drugs
of the liver has often been described (50). Whether these
Many drugs have the potential to produce hepatic
are mere associations or the cause/effect of TB needs granulomas [Table 20.3] that may be eosinophil rich (57).
further clarification.
Pyrazinamide which is given for the treatment of TB has
Hepatobiliary TB can rarely present as hepatic failure
also been implicated as a cause of granulomatous liver
(51). Severe degree of immunosuppression following disease (58,59).
liver transplantation also predisposes to the development
of hepatic TB (52). Chronic Hepatitis
Sarcoidosis Hepatitis C Infection

Sarcoidosis is a multisystem granulomatous disorder of Chronic hepatitis C virus [HCV] infection has recently
unknown aetiology. In patients with sarcoidosis, hepatic been recognized as an aetiological cause of hepatic
granulomas are widely distributed in the liver; very often granulomas (60). Hepatic granulomas have been
in the portal and periportal regions. Often, hepatic described in up to 10 per cent patients with chronic HCV
involvement seems incidental, but a few patients may infection. Development of hepatic granulomas following
present with signs and symptoms of hepatic dysfunction. interferon treatment has been reported in patients with
In some patients, the clinical presentation may resemble HCV infection (61). A recent multicentre study (60)
primary biliary cirrhosis (52). evaluated a total of 725 liver biopsies from 605 patients
The granulomas are numerous enough to make it with chronic HCV infection to identify an association
unlikely that could be missed in a liver biopsy sample of between the presence of granuloma and response to
even moderate size (53). Central necrosis in these interferon treatment and also to see whether interferon
granulomas is less frequent than in TB and they contain treatment leads to the formation of hepatic granulomas.
abundant reticulin. The granulomas are made of In eight patients, hepatic granulomas were detected in
epithelioid cells [often with a thin rim of lymphocytes] the initial liver biopsies. Four patients had repeat
and giant cells, some of them containing stellate [asteroid] biopsies, and all had hepatic granulomas again. The
bodies. The granulomas may show characteristic prevalence of hepatic granulomas in patients with
clustering which is also seen in the lymph nodes. As the chronic hepatitis C was calculated to be 1.3 per cent. The
granuloma ages, there may be deposition of collagen in presence of granulomas was not found to be a predictor
a lamellar manner at the periphery of granuloma. of response to interferon therapy. The development of
Sarcoidosis may present with chronic cholestasis, hepatic granulomas during interferon therapy was also
destruction of interlobular ducts and limiting plates may not found to be a common phenomenon in this study.
be evident in liver biopsy specimens (54-56). Hence, the clinical relevance of finding hepatic granulo-
mas in HCV infected patients still needs further studies.
Primary Biliary Cirrhosis Development of systemic sarcoidosis many years after
interferon-α treatment for chronic HCV infection has also
In the early stages, the hepatic granulomas in patients
been documented (62).
with primary biliary cirrhosis may be indistinguishable
from sarcoidosis. The granulomas are epithelioid and are
Hepatitis B Infection
most often found in the portal tracts. Lymphocytes are
scattered within the granuloma. Plasma cells are often Tahan et al (63) studied the prevalence of hepatic
present in perigranulomatous location. Multinucleated granulomas in 663 patients with chronic hepatitis B virus
300 Tuberculosis
[HBV] infection, to determine its significance regarding of abundant epithelioid cells with scattered lymphocytes.
treatment outcome. Hepatic granulomas were found in Multinucleated cells may be present and these granulo-
10 cases [1.5%]. Of these, four responded to interferon mas are most often present in the parenchyma. It is
therapy, two dropped out, and four were non- seldom possible to identify the bacilli even when special
responders. This study (63) concluded that hepatic stains are used. The lepromatous type granuloma is
granuloma is a rare finding in chronic HBV infection and inflammatory in nature and consists of histiocytes with
its presence does not seem to predict the response to clear to foamy cytoplasm. Lymphocytes are infrequent
interferon therapy. and multinucleated giant cells are not present. These
granulomas can be seen within the portal tracts or the
Brucellosis
parenchyma and contain abundant numbers of acid-fast
Brucella suis, Brucella abortus, Brucella melitensis and organisms identified by Fite stain. The intermediate type
Brucella canis cause granulomatous reaction in the liver. granulomas consist of epithelioid cells with only scanty
Brucellosis is acquired by contact with cattle, goats, dogs number of lymphocytes. Giant cells are seldom seen.
or by ingestion of unpasteurized dairy products. The
infection presents as undulating fever with remissions Schistosomiasis
and relapses. Excessive weakness and depression are
present during the acute illness. The diagnosis is made Hepatic granulomas are caused by Schistosoma mansoni
by brucella serology and positive reactions in titres of and Schistosoma japonicum. The granulomas are quite
1:320 or more are considered diagnostic. The most disease specific and ova may be seen in the centre of the
reliable method of establishing the diagnosis is by blood granuloma. Presence of eosinophils may point to
or bone marrow culture. parasitic aetiology (4).
Systemic Mycoses Hodgkin’s Lymphoma

Histoplasma capsulatum and Coccidioides immitis usually Hepatic granulomas have been described in eight to
infect humans by inhalation of organisms with primary seventeen per cent patients with Hodgkin’s disease
infection occurring in the lungs. Chronic pulmonary (64,65). The presence of hepatic granulomas does not
lesions develop in a few and rarely there is a widespread appear to be related to disease outcome or prognosis in
dissemination to other organs including the liver. The Hodgkin’s lymphoma.
hepatic reaction to these fungi is usually by granuloma
formation (2-4). Typhoid Fever
Histoplasma usually colonizes in immunosuppressed
patients but occasionally immunocompetent individuals Hepatic granuloma is a rare complication of typhoid
may also be affected. The disease usually manifests as fever. A report has described two cases of typhoid fever
fever with hepatosplenomegaly and oral ulcers. with hepatic, splenic and bone marrow granulomas (66).
Commonly there is an associated adrenal involve-
ment with Addison’s disease. Liver usually contains Q Fever
granulomatous lesions, sometimes with central casea- Fibrin ring granulomas are often present in patients with
tion necrosis resembling TB. Use of special stains like Q fever. These granuloma contain a ring-like array of
methenamine silver, Hotchkiss-McManus stain makes fibrin [stainable with phosphotungstic acid-haematoxy-
identification easier although the organism can often be lin] producing a “halo” effect around a central empty
found in the granuloma by haematoxylin and eosin space (2-4). These granulomas have also been described
staining. Diagnosis is best confirmed by culture of the in allopurinol hypersensitivity, CMV hepatitis,
organisms from blood, bone marrow, sputum and oral leishmaniasis, toxoplasmosis, hepatitis A and systemic
ulcer scrapings (2,4). lupus erythematosus (2-4).
Leprosy Acquired Immunodeficiency Syndrome

Three types of granulomas have been described in Several conditions result in hepatic granulomas in
patients with leprosy (3). The tuberculoid type, consists patients with AIDS (4,15,16,57). These are listed in
Table 20.5. The diagnosis is confirmed with histopatho- Anti-mitochondrial antibodies may be helpful in the
logical and microbiological examination of the liver diagnosis of primary biliary cirrhosis. Elevated serum
biopsy specimen. angiotensin converting enzyme levels may suggest a
diagnosis of sarcoidosis.
Idiopathic Granulomatous Hepatitis Liver biopsy is essential for the diagnosis. Biopsy
Despite extensive investigations, 10 to 25 per cent of material must be subjected to microbiological and histo-
pathological examination. Type and location of granulo-
patients are labelled as having “idiopathic” hepatic
mas may offer a clue to the aetiology. Special stains may
granulomas (2-6,67). Idiopathic granulomatous hepatitis
is a condition characterized by recurrent fever and be required to identify infectious agents. Examination
under polarized light may help in visualizing foreign
granulomas in the liver and other organs where other
bodies.
causes of hepatic granulomas have been carefully
excluded (5,68,69). Patients are usually in the age range
of 16 to 60 years. The prominent symptom is fever, which TREATMENT
is often relapsing in character, although continuous and When the investigations are conclusive, treatment should
remittent fever patterns have also been described. Forty- be directed towards the aetiological agent. In a country
four per cent of patients first presented as PUO in one like India, when the aetiological cause of granulomatous
series (5). Other symptoms, include malaise, chills, hepatitis is unclear, a therapeutic trial with antituber-
weight loss, abdominal pain, anorexia, night sweats, culosis agents is often given. If this fails, then cortico-
nausea, jaundice, diarrhoea and abdominal distension. steroid treatment may be tried.
The natural history of the disease is marked by multiple In the study of idiopathic granulomatous hepatitis
remissions and exacerbations. Response to corticoste- reported by Zoutman et al (5), the disease resolved
roids is usually dramatic (5,68,69). spontaneously in seven patients, two patients responded
with less than three months of oral corticosteroids or
DIAGNOSIS indomethacin treatment and seven patients required
steroid treatment for two years or longer to maintain
Patients with hepatic granulomas must be thoroughly
asymptomatic state.
investigated for a possible aetiological cause. Detailed
history must be obtained specifically focusing on
exposure to an infectious source, and occupational or PROGNOSIS
environmental agents including drugs. Several labora- Outcome of hepatic granulomatous disease depends on
tory tests are often employed in the work-up of a patient the underlying cause. In the study of TB hepatitis
with granulomatous hepatitis. Cultures of blood, body reported by Essop et al (22), age below 20 years, acute
fluids and biopsy material must be done keeping in mind presentation, presence of coagulopathy and a high mean
the common infectious causes of hepatic granulomas. caseation score were found to be predictors of a poor
outcome. Drug-related granulomas often resolve when
Table 20.5: Causes of hepatic granulomas in patients with the offending agent is withdrawn (59). The presence of
acquired immunodeficiency syndrome
hepatic granulomas in patients with Crohn’s disease,
Mycobacterium tuberculosis Hodgkin’s disease and primary biliary cirrhosis is
Mycobacterium avium-intracellulare complex thought to indicate a better prognosis (69-71).
Cytomegalovirus
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Toxoplasmosis REFERENCES
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304 Tuberculosis
Neurological Tuberculosis
21
PS Mathuranath, K Radhakrishnan
INTRODUCTION diagnosis and management of chronic meningitis and

single, small, contrast enhancing brain lesions are also
Neurological tuberculosis [TB] comprises five to ten per
detailed. Spinal TB is covered in the chapter “Skeletal
cent of the cases of extra-pulmonary TB and occurs more
tuberculosis” [Chapter 23].
frequently in children (1,2). With the emergence of TB as
Indian investigators have contributed considerably
an increasingly common secondary infection in patients
to the understanding of the pathogenesis, pathology,
with human immunodeficiency virus [HIV] infection and
diagnosis and treatment of neurological TB (8-12). Last
acquired immunodeficiency syndrome [AIDS], there is
two decades have witnessed major changes in several
a resurgence of neurological TB across the globe,
aspects of neurological TB. These include a change in
including in the developing countries (3-5). Even with
the clinical picture of neurological TB with an increasing
the modern day antituberculosis treatment, neurological
number of cases with atypical presentation and an
TB continues to have a high morbidity and mortality rate,
alarming increase in the number of patients with multi-
especially in children (6,7). The fact that the neurological
drug-resistant tuberculosis [MDR-TB]. Intense research
TB is responsible for two to ten per cent of
is being carried out for discovering an accurate serologi-
hospitalizations is a testimony to this fact (2).
cal marker for early diagnosis of neurological TB. Wide-
Neurological TB may be classified into three clinico-
spread availability and utilization of computed tomo-
pathological categories: tuberculosis meningitis [TBM],
graphy [CT] and magnetic resonance imaging [MRI],
tuberculoma, and arachnoiditis, which is also referred
have facilitated an early diagnosis of complications.
to as TB radiculomyelitis [TBRM] [Table 21.1]. In
addition, there is the less common clinicopathological
entity of TB abscess. In this chapter, TBM, intracranial TUBERCULOSIS MENINGITIS
tuberculoma and TBRM are described. In addition, Tuberculosis meningitis, which accounts for 70 to 80 per
cent of cases of neurological TB, is still an important
Table 21.1: Classification of neurological tuberculosis
public health problem in developing countries (2,13). In
Tuberculosis meningitis spite of its common occurrence, extensive research and
Tuberculosis arachnoiditis
widespread public awareness, there is often a delay in
Basal
Opticochiasmatic the diagnosis and institution of specific therapy for TBM.
Spinal This is unfortunate as the promptness with which
Tuberculoma antituberculosis treatment is initiated is the single most
Intracranial important physician-controlled factor influencing the
Spinal prospects for recovery without serious neurological
Tuberculosis abscess
sequelae.
Neurological Tuberculosis 305
Pathogenesis The leptomeningeal reaction is characterized by a

serofibrinous exudate lying between the pia and arach-
A majority of cases of TBM are caused by Mycobacterium
noid intermixed with areas of caseous necrosis [Figure
tuberculosis. Isolated cases of meningitis caused by bovine,
21.1]. The cellular exudate consists predominantly of
avian and nontuberculous mycobacteria [NTM] have also
lymphocytes and plasma cells with infrequent epithe-
been documented (2). Central nervous system [CNS] TB
lioid cells and giant cells. The proliferative arachnoiditis
is invariably secondary to TB elsewhere in the body. It is
is most marked at the base of the brain, most prominent
generally believed that the critical event in the develop-
in the area of the optic chiasma. As the process of
ment of meningitis is the rupture of a subependymally
opticochiasmatic arachnoiditis becomes more chronic, it
located tubercle [Rich focus] resulting in the delivery of
may progress and encircle the brainstem to involve the
infectious material into the subarachnoid space (14). In
function of other cranial nerves.
the bacteraemic phase of primary lung infection,
Ependymitis is almost a constant feature of TBM and
metastatic foci can get established in any organ, which
may even be more severe than the meningeal reaction.
can undergo reactivation active after a variable period of
The choroid plexus may show varying degrees of
clinical latency. Whether the critical subependymal
inflammatory process. The terminal portion of the
tubercle develops during primary haematogenous
internal carotid artery and proximal middle cerebral
dissemination or due to secondary haematogenous
artery in the Sylvian fissure are the vessels most
spread from an area of extra-cranial extra-pulmonary TB
frequently involved by vasculitis with inflammation,
is still a matter of dispute.
spasm, constriction and thrombosis. The meningeal veins
Several co-morbid conditions such as intercurrent
traversing the inflammatory exudate show varying
viral infections, advanced age, malnutrition, alcoholism,
degrees of phlebitis and thrombosis. The brain
HIV/AIDS, use of corticosteroids and other immunosup-
parenchyma immediately underlying the meningeal
pressive drugs may compromise cellular immunity of
exudate as well as the subependymal region shows a
the host leading to reactivation of a latent infection.
variable degree of oedema, perivascular inflammation
However, a majority of cases of TBM occur in the absence
and microglial reaction. A majority of infarcts occur in
of any clinically demonstrable extra-cranial infection or
the territory of the middle cerebral artery.
overt disturbance in host immune function.
Hydrocephalus develops in the majority of patients
Pathology with TBM who have been symptomatic for more than
The pathology of TBM comprises of: [i] inflammatory two to three weeks (2,15). In the majority, it is a com-
meningeal exudate; [ii] ependymitis; [iii] vasculitis; [iv] municating hydrocephalus due to the blockage of the
encephalitis; and [v] disturbance of cerebrospinal fluid basal cisterns by the exudate in the acute stage and
[CSF] circulation and absorption [Table 21.2].
Table 21.2: Pathology of tuberculosis meningitis

Meningitis
Inflammatory leptomeningeal exudate
Caseous necrosis
Proliferative opticochiasmatic arachnoiditis
Vasculitis
Arteritis
Phlebitis
Ependymitis and choroid plexitis
Encephalitis
Cortical
Subependymal
Vasculitis and infarction
Hydrocephalus Figure 21.1: Tuberculosis meningitis. The meningeal blood vessels
Communicating show vasculitis. They are surrounded by granulomas with epithelioid
Obstructive cells and necrosis [Haematoxylin and eosin × 250]
306 Tuberculosis
adhesive leptomeningitis in the chronic stage. Less partial loss of vision is a major complication of the
frequently, the hydrocephalus is obstructive due to either disease. The mechanisms for this may include arteritis
narrowing or occlusion of aqueduct by ependymal or compression of the anterior visual pathways due to
inflammation or by a strategically placed brainstem hydrocephalus or tuberculoma. Ethambutol toxicity too
tuberculoma, or at the outlet foraminae of the fourth may contribute to the visual impairment. The frequency
ventricle. Hydrocephalus is more frequent and severe in of optic nerve involvement in clinical reports varies from
children than in adults. four to thirty-five per cent (2,17), although visual evoked
Udani and Dastur (10) described a pathological entity potentials testing has shown disturbance in over 50 per
predominantly seen in the pediatric age group, desig- cent of patients examined in the acute stage of the disease
nated as TB encephalopathy, characterized by diffuse (18). The clinical presentation of TBM as documented at
brain oedema, perivascular myelinolysis and haemor- a teaching hospital in North-west India is shown in
rhagic leucoencephalitis with little evidence of menin- Table 21.3 (17).
gitis. They ascribed the syndrome to hypersensitivity In untreated cases, adhesions in the basal brain
reaction to tuberculoproteins. Clinical and pathological progress and result in extensive cranial nerve palsies,
distinction of this entity from Reye’s syndrome, acute internal carotid constriction and stroke, increasing
disseminated encephalomyelitis and acute haemorrhagic hydrocephalus with tentorial herniation, pupillary
leucoencephalitis will be difficult. There is little evidence abnormalities, pyramidal signs and progressive
for the existence of TB encephalopathy without deterioration in the consciousness state. The terminal
meningitis. illness is characterized by deep coma and decerebrate or
decorticate posturing. Without treatment, death usually
Clinical Features occurs in five to eight weeks.
According to the severity of the illness, patients with
In developing countries, TBM is still a disease of child- TBM can be categorized into three or four clinical stages
hood with the highest incidence in the first three years
of life (2,13). Recent contact with TB, when elicited, can Table 21.3: Percentage frequency of presenting symptoms
be found in 70 to 90 per cent of children with TBM (16). and signs in 232 patients with tuberculosis meningitis seen
The disease usually evolves gradually over two to six at Postgraduate Institute of Medical Education and Research,
weeks although an acute onset of illness can occur in 50 Chandigarh*
per cent of children and in 14 per cent of adults (16). The Clinical presentation %
prodromal phase is non-specific and usually lasts two to Symptoms
three weeks with a history of vague ill-health, apathy, Fever 78.4
irritability, anorexia and behavioural changes. As a part Altered sensorium
of the prodrome, headache, vomiting or fever may occur Semiconscious 29.3
in 13 to 30 per cent of patients and heralds the onset of Unconscious 23.3
meningitis. Focal neurological deficits and features of Seizures 21.5
raised intracranial tension may precede signs of menin- Behavioural changes 12.9
geal irritation. Focal or generalized convulsions are Signs
encountered in 20 to 30 per cent of patients sometime Neck rigidity 64.2
during the course of illness and are particularly common Papilloedema 33.6
in children and the elderly. The underlying mechanism Abducens nerve palsy 18.5
could include hydrocephalus, tuberculoma, cerebral Hemiplegia 18.5
oedema, and hyponatraemia due to syndrome of Facial nerve palsy 17.7
inappropriate antidiuretic hormone [SIADH] secretion. Optic atrophy 11.6
Decerebration 11.2
Cranial nerve palsies can occur in 20 to 30 per cent of
Abnormal movements 6.5
patients, the sixth nerve involvement being the most
Oculomotor nerve palsy 6.0
common (2,8,16,17). Choroidal tubercles 3.4
Exudate around the optic chiasma is the central
feature of the pathology in TBM. Hence, complete or * Data from reference 17
Table 21.4: Clinical staging system for Neurosciences [NIMHANS] in Bengaluru [earlier called
tuberculosis meningitis Bangalore], in south India (26).
Stage Description
Although HIV infected patients are at an increased
risk for TBM, the HIV status does not alter the clinical
1 Conscious and rational, with or without neck stiffness,
manifestations, CSF findings and response to therapy
but no focal neurological signs or signs of hydro-
cephalus (5,22,25,27). However, CSF examination may frequently
2 Conscious but confused or has focal signs, such as be normal in HIV-seropositive subjects with TBM (23).
cranial nerve palsies or hemiparesis In such patients, radiographic clues to the diagnosis of
3 Comatose or delirious with or without dense neurological neurotuberculosis include multiloculated abscess,
deficit
cisternal enhancement, basal ganglia infarction and
4 Deeply comatose with decerebrate or decorticate
posturing communicating hydrocephalus, which are not the
findings associated with the more commonly encoun-
Adapted from references 19,20
tered CNS lymphoma or toxoplasma encephalitis.
Extra-meningeal TB is seen more often [65% to 77%] in
[Table 21.4] (19,20). The clinical staging helps to optimize patients co-infected with HIV and TB compared to HIV-
therapy [e.g., addition of dexamethasone to antituber- seronegative individuals [9%] (22,28). Likewise, an
culosis drugs] and to predict the prognosis. The prognosis associated tuberculoma may be present in more than half
of TBM is determined by the clinical stage at the time of of HIV infected patients with TBM (5). Neurological TB
initiation of treatment.
can also be the initial presentation of AIDS (29). Bishburg
During the last two decades, the picture of TBM has
et al (24) noted that intravenous drug abusers with AIDS
changed in developed countries with an increasing
were more likely to develop TB of the CNS and TB brain
number of atypical cases (15,16). Atypical presentations
abscesses.
of TBM include acute meningitic syndrome simulating
pyogenic meningitis, progressive dementia, status
Diagnosis
epilepticus, psychosis, stroke syndrome, locked-in-state,
trigeminal neuralgia, infantile spasm and movement Tuberculosis meningitis should be differentiated from
disorders (2,17,21). The factors that are thought to be res- other causes of subacute and chronic meningitis [Table
ponsible for this changing pattern include delay in the 21.5]. Early and accurate diagnosis of TBM can substan-
age of onset of primary infection, immunization, prob- tially reduce the morbidity and mortality, especially in
lems related to immigrant populations and HIV infection children. Diagnosis of TBM is based on history, neuro-
(22,23). logical symptoms, signs and CSF findings. Supporting
features include radiological evidence from CT or MRI,
Tuberculosis Meningitis and Human such as basal exudates, hydrocephalus, infarcts, tuber-
Immunodeficiency Virus Infection culomas and gyral enhancement. However, the diagnosis
One of the major causes for re-emergence of TB in the of TBM is fraught with difficulties because demonstra-
west has been the HIV epidemic. The CNS involvement tion of Mycobacterium tuberculosis in CSF is difficult and
is five times more frequent in HIV-seropositive compa- is often time-consuming.
red to HIV-seronegative patients (22,24). Berenguer et al
Table 21.5: Differential diagnosis of
(22) reported that 10 per cent of 455 patients co-infected tuberculosis meningitis
with both TB and HIV developed TBM. Yechoor et al (25)
Partially-treated bacterial meningitis
observed that 20 of the 31 patients [65%] identified as
Cryptococcal meningitis
definite or probable TBM over a 12-year period were co- Viral meningoencephalitis
infected with HIV. Neurotuberculosis, either alone or Carcinomatous meningitis
associated with other opportunistic infections, was found Parameningeal infection
in 35 of the 100 HIV-seropositive patients seen over seven Neurosarcoidosis
years at the National Institute for Mental Health and Neurosyphilis
308 Tuberculosis
Exposure to TB is important supportive evidence, TBM are seen on CT as multiple areas of hypodensity
especially in children. In a retrospective analysis spread secondary to ischaemia. Serial CT imaging is very
over 20 years of 38 children with CNS TB, Farinha et al helpful in assessing the course of tuberculomas and
(30) reported presence of epidemiological evidence for hydrocephalus. Gadolinium enhanced MRI is superior
TB in 71 per cent. Evidence of TB outside the CNS with to the CT in detection of basal meningeal enhancement
appropriate microbiological, radiological or histopatho- and small tuberculomas. Contrast enhanced MRI has
logical proof, a positive tuberculin skin test [TST] in the been found to be superior to contrast enhanced CT in
absence of a previous subclinical infection or bacille the detection of diffuse and focal meningeal granulo-
Calmette-Guérin [BCG] vaccination, and a resolution of matous lesions. The MRI is also superior to CT in deli-
the symptoms and signs of TBM after initiation of neating focal infarcts of the basal ganglia and
antituberculosis treatment are also important supportive diencephalon. Furthermore, MRI is superior to CT in
features for a diagnosis of TBM. defining the presence, location and extent of associated
brainstem lesions. Interestingly, in a very large
Investigations retrospective series of more than 500 Filipino children,
Routine laboratory studies are rarely helpful in Lee (33) found cranial sonography a very useful
diagnostic tool for intracranial TB, especially in children
establishing the diagnosis of TBM. Elevated erythrocyte
below the age of two years.
sedimentation rate [ESR], anaemia and lymphocytosis
are not seen in majority of the patients.
Radiological Studies Tuberculin skin test [TST] with purified protein deriva-
Chest radiograph The chest radiographs reveal findings tive [PPD] has been reported to be positive in 40 to 65
consistent with pulmonary TB in 25 to 50 per cent of adult per cent of adults and in 85 to 90 per cent of children
patients and 50 to 90 per cent of children with TBM seen with TBM in western studies (15,16,30,31). However, TST
in western countries (31). lacks specificity in developing countries because of the
possibility of previous sensitization to environmental
Neuroimaging Plain radiograph of the skull is no longer mycobacteria and BCG vaccination.
a diagnostic tool for any form of neurotuberculosis. The
CT or MRI of the brain may reveal thickening and Interferon-Gamma Release Assays
enhancement of basal meninges, hydrocephalus,
Recently, interferon-gamma release assays [IGRAs] have
infarction, oedema [often periventricular], and mass
been found to be useful for detecting infection with Myco-
lesions due to associated tuberculoma or TB abscess.
Common sites of exudates are basal cisterna ambiens, bacterium tuberculosis. The reader is referred to the chapter
“Diagnosis of latent tuberculosis infection: recent advances
suprasellar cistern and Sylvian fissures. Bhargava et al
and future directions [Chapter 12]” for more details.
(32) classified exudates as: [i] mild, when cisterns were
obliterated but not enhanced; [ii] moderate, when the
Cerebrospinal Fluid Study
cisterns were outlined by high attenuating exudates; and
[iii] severe, when attenuating exudates enlarged the Cytology and biochemistry Clear CSF with moderately
cisterns. Hydrocephalus is the single most common raised cells and protein and low glucose constitute the
abnormality and is reported in 50 to 80 per cent of the typical CSF picture of TBM. However, these characteri-
cases. The degree of hydrocephalus generally correlates stics are shared by other forms of chronic meningitis and
with the duration of disease. Enhancements of basal partially treated pyogenic meningitis. In TBM, the
meninges [60%] followed by cerebral infarction [28%], leucocyte count is usually between 100 to 500 cells/μl,
most frequently in the middle cerebral artery territory, but rarely can exceed 1000 cells/μl. Median leucocyte
are other common findings. Bhargava et al (32) demons- counts in various reports range from 63 to 283 cells/μl.
trated the presence of hydrocephalus [83%], cerebral Predominantly, lymphocytes are increased in the CSF,
infarction [28%] and tuberculoma [10%] on CT in patients although in the acute stage a polymorphonuclear res-
with TBM. Vasculitis and thrombosis associated with ponse is not unusual. This response is transient and is
replaced by lymphocytic reaction in the course of days reported a higher yield of AFB with examination of four
to weeks. Occasionally, the cell count may be normal. CSF smear samples [37% in the first, and a further 25%,
Rarely, the CSF may be haemorrhagic because of 19% and 3% in the second, third and fourth samples,
fibrinoid necrosis of vessels. A negative cytology for respectively].
malignant cells in the CSF is essential for the diagnosis Lowenstein-Jensen [L-J] culture of CSF takes four to
of TBM. eight weeks to isolate the organisms because of the slow
The CSF protein is generally between 100 to 200 growth of mycobacteria. The reported positivity of CSF
mg/dl. In the presence of co-existing spinal meningitis culture ranges from 25 to 70 per cent of cases, but is less
and spinal block, the values can exceed 1 g/dl and the than 50 per cent in most reports. In many Indian reports,
fluid may be xanthochromic. If allowed to stand, a pellicle the yield has been much lower, around 19 per cent (2,17).
or cobweb may form, indicating the presence of fibrino- The yield can be increased by using liquid culture media,
gen. The pellicle is highly suggestive but not pathogno- such as Septi-Chek AFB system, and Middlebrook 7H9
monic of TBM. The CSF protein has been reported to be instead of the conventional L-J medium. The isolation
normal in some patients with AIDS and TBM (22,34). rate of Mycobacterium tuberculosis is higher from cisternal
The CSF glucose level is abnormal in majority of cases, and ventricular CSF than lumbar CSF (37), but in routine
being less than 40 per cent of the corresponding blood practice, CSF is seldom collected from the ventricles.
glucose level. Median glucose levels are reported to be Similar to AFB smear examination, repeated cultures of
between 18 to 45 mg/dl. In patients with TBM, CSF CSF samples increased the sensitivity from 52 per cent
glucose levels are never undetectable as in patients with for the first culture up to 83 per cent after four cultures
pyogenic meningitis. Low CSF chloride level was (20). In patients with disseminated and miliary TB with
previously considered to be a non-specific marker for CNS involvement, cultures from extra-neural sites such
TBM. It is actually a reflection of co-existent serum hypo- as the sputum, lymph node and bone marrow may be
chloraemia and is presently not considered to be helpful positive.
in discriminating between TBM, bacterial and viral
Immunological tests As the CSF picture in patients with
meningitis. Thomas et al (17) observed the classical TB
TBM can be variable and non-specific, there is urgent
pattern in 66.8 per cent; pseudopyogenic pattern in
need for a reliable and rapid test to diagnose TBM. In
14.5 per cent; and normal CSF in five per cent of the cases.
the Indian context, the difficulty in differentiating TBM
Patients with miliary TB and CNS involvement can
from partially treated pyogenic meningitis is an added
sometimes present with a normal CSF profile and absence
problem.
of neurologic signs. An acellular CSF may also be found
Several tests have been devised for these reasons and
in elderly patients suffering from TBM (28). Such cases
they are broadly divided into direct tests that measure
are usually diagnosed by the findings on neuroimaging
the chemical components or antigens of Mycobacterium
(35,36).
tuberculosis and indirect tests that measure the components
Microbiological tests A negative Gram stain, negative of the host response to Mycobacterium tuberculosis. The
India ink stain and a sterile culture for bacteria and fungi specificity of immunodiagnosis depends on the
are pre-requisites for the diagnosis of TBM. Demons- specificity of the antigens or antibodies used. Non-
tration of acid-fast bacilli [AFB] in the CSF by microscopy availability of a clear cut gold standard has hampered
is the most crucial part of the investigation and the rate the validation of the usefulness of newer diagnostic tests
of detection varies in different reports from 12.5 to for the diagnosis of TBM. As the yield of conventional
69 per cent (27,30). The yield of CSF smears by Ziehl- methods such as culture is low when applied to the CSF
Neelsen staining and auramine staining is low, ranging in patients with suspected TBM, these methods cannot
from four to forty per cent in various reports and is found be considered to be a gold standard against which
to be a function of the volume and the number of samples immunodiagnosis or other tests can be compared with
of CSF. Centrifuging the CSF [10 to 20 ml] for 30 minutes tests such as enzyme linked immunosorbent assay
and thick smear examination from the pellicle and repeat [ELISA], a significant overlap between the results of
CSF examination enhance the detection rate. Kennedy patients with and without TBM necessitates specification
and Fallon (20) in a series of 52 patients with TBM of a cut-off point to separate positive from negative test
310 Tuberculosis
results. When establishing such a cut-off, there is usually treatment. Though antimycobacterial antibodies were
a trade-off between sensitivity and specificity. With present in 70 per cent patients, the immune complexes
regard to immunoassays, it is also important to were not formed probably because of the non-availability
understand that the sensitivity of any immunoassay of antigen 5 in optimal concentration. Patil et al (50)
depends on standardization and evaluation of the assay detected immune complexes in the CSF in 60 per cent
system, whereas specificity depends on the type of the and antimycobacterial antibodies in 55 per cent and both
probe employed in the system (38). Furthermore, false- in 82 per cent patients with suspected TBM.
negative results of antigen detecting immunoassays can
Other indirect measures of host response Adenosine deami-
also result from masking of the antigens by specific
nase, an enzyme produced by T-lymphocytes, is elevated
circulating antibodies.
in the CSF of 60 to 100 per cent of patients with TBM
Mycobacterial antibodies Antibodies against glycolipids (52-54). However, false-positive results have been
and proteins isolated from Mycobacterium tuberculosis, reported in other forms of meningitis. The CSF lympho-
BCG, PPD, antigen 5, and lipoarabinomannan have all cyte transformation assay, detection of anti-BCG
been used as a supporting test in the diagnosis of TBM. secreting cells in CSF, leucocyte migration inhibition
Radioimmunoassay, ELISA, and immunoblot methods assay, and T-cell immunoblotting are other tests used as
have all been used to detect these antibodies. Various indirect evidence of host response to Mycobacterium
authors have reported sensitivity ranging from 61 to 90 tuberculosis. The bromide partition test (55) is not
per cent and specificity ranging from 58 to 100 per cent routinely used these days.
with these antibodies (39-44). Assay of antibodies against
Biochemical detection of mycobacterial products Detection of
Mycobacterium tuberculosis antigens has a better sensitivity
tuberculostearic acid [TSA], a structural component of
and specificity than PPD or BCG. Recent antibody targets
Mycobacterium tuberculosis has been reported to have a
have included antibodies against A-60 antigen. They
sensitivity of about 75 per cent and specificity of 96 per
have shown a greater sensitivity in sera [95%] compared
cent (56). Requirement of complex instrumentation is a
to CSF and a greater specificity in the CSF [100%] com-
major limitation to its wide application. Detection of
pared to the sera (45,46).
3-[2’-ketohexyl] indoline has also been used as an
Mycobacterial antigens There are many reports of detection evidence of Mycobacterium tuberculosis infection (57).
of mycobacterial antigens using ELISA and latex particle
Molecular methods Amplification of the Myobacterium
agglutination (12,47-49). Antigen detection has been
tuberculosis specific deoxyribonucleic acid [DNA]
shown to be more specific than antibody assays. Rabbit
sequences by polymerase chain reaction [PCR] has been
immunoglobulin [IgG] raised against BCG, culture
evaluated as a means of rapid diagnosis of neurotuber-
filtrate antigen, antigen 5, and immunoabsorbent affinity
culosis (58-62). The use of primers derived from the
column-purified antigen have all been used for antigen
insertion sequence IS6110, which is a multiple repetitive
detection. The diagnostic yield is considerably improved
element in the genome of the Mycobacterium tuberculosis
by performing both antigen and antibody assays (42,50).
complex, has yielded amplification of high analytical
Other mycobacterial antigen targets have included the
sensitivity.
35kDa antigen (51). Unfortunately, many assays showing
One-step amplification used in conventional methods
early promise in highly controlled studies do not perform
has a low sensitivity, which is attributed to the low copy
with high sensitivity and specificity in clinical practice.
numbers of the DNA template that could be extracted
Circulating immune complexes Circulating immune comp- from CSF samples of patients with TBM. In comparison,
lexes in the serum and CSF of patients have been used in two-step nested amplification can enhance the sensitivity
the diagnosis of TBM by isolating these complexes and by several folds. Using this technique, Liu et al (60)
confirming the presence of mycobacterial antigens and detected Mycobacterium tuberculosis genome in 19 of the
antibodies by ELISA test. Mathai et al (42) demonstrated 21 [90.5%] patients with clinically suspected TBM.
antigen 5 in the immune complexes of CSF in 30 per cent The PCR has the advantage of being the only available
of their patients with TBM. The antigen concentration in technique besides AFB smear test, which can confirm
the immune complexes declined during the course of the diagnosis of TB on the same day. While sensitivity of
CSF smear microscopy in TBM is nine per cent, the of precautions to avoid DNA contamination. More
sensitivity of PCR for the CSF specimens is 48 per cent recently, microscopic observation drug susceptibility
(63). In some studies, PCR was more sensitive than L-J [MODS] assay has also been found to be useful in the
culture and, hence, could be considered a superior rapid diagnosis of TBM and multidrug-resistant TB
method. The PCR can be applied to the CSF obtained (68,69).
after initiation of antituberculosis treatment. The PCR Thus, even though there are many recently intro-
for Mycobacterium tuberculosis is not affected by the duced rapid diagnostic methods for TBM, most of them
presence of other infecting bacteria as may occur in an lack the required combination of reproducibility, high
immunocompromised host. sensitivity and specificity. A negative test, does not
However, in some reports, the sensitivity of PCR was exclude TBM and many immunodiagnositc tests show
not much higher than that of mycobacterial culture. false-positive results in other forms of meningitis. Unless
Hence, a negative PCR, like culture, cannot exclude the stringent measures are adopted to prevent cross
diagnosis of TBM (64). False-negative PCR results are contamination in laboratories, false-positive results could
attributed to several factors, like prior treatment, pre- limit the use of PCR.
sence of inhibitory factors to PCR in the CSF, extremely
low bacterial numbers in the CSF, small volume of CSF Treatment
tested, and the method of DNA extraction. When per- Once the disease has been diagnosed, the decision
forming PCR, samples that may have large quantities regarding initiation of antituberculosis treatment is the
of bacteria, such as sputum, should not be simulta- most important step in the management of TBM. Though
neously tested because of the high risk of cross a delay in the commencement of therapy should be
contamination and hence, higher false-positivity. Even minimized, adequate evidence favouring the presence
in PCR-positive cases, culture remains important for of TBM should be gathered before starting therapy, as
testing drug sensitivity, especially with the emergence antituberculosis treatment is both potentially toxic and
of drug-resistant strains (65). is required for a long period.
In a comparative study, Shankar et al (59) found PCR Confirmation of the diagnosis, either by PCR or by
to be more sensitive than antibody assay. Comparing immunological methods is seldom possible in every case,
antibody assay, immune complex assay and PCR, because of the limited facilities available in the develop-
Miorner et al (66) found that antibody immunoassays were ing countries. Apart from the investigations, there are
non-specific. They also reported that detection of myco- indirect evidences of the disease being TBM, especially
bacterial immune complexes strongly correlated with in countries with a high prevalence of TB infection. These
infection and was positive in 64 per cent of TBM cases, include, clinical diagnosis of chronic meningitis; a history
PCR was positive in 54 per cent of cases. All culture- of pulmonary TB, especially if inadequately treated;
positive and 74 per cent of culture-negative samples were exposure to a patient with pulmonary TB; evidence in
found to be positive when immune complex assay was the chest radiograph of an old TB lesion; a persistently
combined with PCR (60). Thus, a combination of tests elevated ESR; a positive TST and CT or MRI evidence of
may be more useful than a single test in arriving at basal meningitis and/or its sequelae. Though none of
treatment decisions. An inherent defect in many of the the above information in isolation is sufficient, a combi-
older studies stems from the lack of a gold standard, a nation of these factors should raise the suspicion of a
problem of circularity [using the clinical diagnosis of TBM diagnosis of TBM. Following this, a CSF study is manda-
to validate the tests and subsequently recommending the tory if there is no contraindication for a lumbar puncture.
tests to substantiate the clinical diagnosis], small sample If suspicion of TBM is high then antituberculosis
size and the lack of reproducibility of the tests (67). Kox treatment should be initiated at the earliest. The pros and
et al (63) have suggested that the PCR could detect cons of initiating antituberculosis treatment before the
Mycobacterium tuberculosis up to six weeks after starting confirmation of the diagnosis should be carefully
treatment. The sensitivity of PCR in CSF samples seems weighed in each patient. However, the most important
to be better than that of culture and the specificity is principle of therapy is that antituberculosis treatment
comparable, but depends on scrupulous implementation should be initiated when the disease is suspected. It
312 Tuberculosis
should not be delayed until proof of diagnosis of TBM concentration of this agent, has now been abandoned,
has been obtained (15). as this has not improved the outcome (82).
The following situations can be considered as separate
management issues in TBM. Treatment Regimens
There are no convincing randomized, controlled clinical
Uncomplicated Tuberculosis Meningitis
trials to suggest that any particular regimen is superior
It is important to stage TBM patients according to one of in the treatment of TBM. However, enormous clinical
the clinical stages described earlier before the initiation experience has accumulated to recommend some treat-
of treatment (19,20,70). Primary management of this ment regimens (2,15,16,83,84). It is advisable to
condition is with first-line antituberculosis agents. commence a four-drug regimen. The recommended
Experimental studies indicate that meningeal drugs are isoniazid, rifampicin, pyrazinamide and
permeability is enhanced by non-ionization of a drug, ethambutol or streptomycin. Ethambutol is preferred
small molecular weight, low protein-binding, and high over streptomycin because of its better CSF penetration.
lipid solubility of the unionized moiety (71-73). Isoniazid Though a drug susceptibility result is preferred prior
is non-protein bound and rapidly penetrates into CSF, to, or, soon after starting the treatment, it is seldom
whether or not the meninges are inflammed, to give practical, especially in the developing countries. Unless
concentrations more than 30 times the minimum inhibi- there is a very high suspicion of drug-resistant organism
tory concentration [MIC] for Mycobacterium tuberculosis in a particular patient, the proposed four-drug-regimen
(74-76). is generally effective. After two months of treatment,
Rifampicin is highly protein bound and only up to pyrazinamide and ethambutol [or streptomycin] are
20 per cent is available to penetrate into the CSF. Though stopped and isoniazid and rifampicin are continued.
peak plasma levels are achieved at around four hours Pyridoxine is usually administered along with anti-
following administration of the drug, the maximum CSF tuberculosis treatment to reduce the risk of isoniazid-
concentration, which is 10 per cent of the plasma related peripheral neuropathy.
concentration, is achieved only at eight hours (77). Even In India, patients with TBM get treated with DOTS
this concentration is only marginally above the MIC under the Revised National Tuberculosis Control
(77,78). However, in spite of these facts clinical expe-
Programme [RNTCP] of the Government of India and
rience suggests that rifampicin is almost equally effective
receive Category I treatment. Patients receive treatment
in both TBM as well as pulmonary TB.
for six months; in individual patients, there is a provision
Pyrazinamide has excellent penetration into the CSF,
for extending the treatment on a monthly basis for a
which is uninfluenced by the state of the meninges. In
further period of three to six months. The reader is
view of its unique sterilizing activity and the significant
referred to the chapters “Treatment of tuberculosis”
reduction in relapse rates (79,80), it is highly recom-
[Chapter 52] and “Revised National Tuberculosis Control
mended in the treatment of TBM.
Programme” [Chapter 63] for more details.
Ethambutol penetrates into the CSF only when the
meninges are inflamed. Accurate estimates of its con-
Duration of Treatment
centration in CSF are unavailable. In contrast, ethiona-
mide at a dose of 250 mg crosses both the healthy and The optimum duration of treatment for TBM is unknown
inflamed meninges and attains a CSF concentration that (85). Longer duration of treatment possibly lowers the
is comparable to that of serum and is well above the MIC relapse rates, though the cost, risk of toxicity and chances
for Mycobacterium tuberculosis (81). of poor compliance are greater. The only evidence-based
The concentration of streptomycin in CSF varies with recommendation possible is that a minimum of six
the severity of the disease. As the meningeal inflamma- months of treatment is necessary. In a large series of
tion reduces, its penetration declines. With a daily dose 95 children treated with a four-drug regimen, with 96
of 750 mg, its concentration in CSF is only slightly above per cent of cases presenting in the MRC stage 2 or 3, a
the MIC for Mycobacterium tuberculosis (81). Intrathecal high rate of success and a mortality of as low as 16 per
route of administration, which can provide better cent was achieved (6), while in yet another large series
of 781 cases of TBM, nearly all patients with relapse had and elevated pressures resolved significantly faster in
received less than six months of therapy (86). The corticosteroid recipients. Two of the studies (97,100)
maximum duration of treatment has varied. The National stratified participants by severity and found no benefit
Institute for Health and Clinical Excellence [NICE] (87) in either mild or severe disease, but significant benefit
and the American Thoracic Society [ATS], Centers for for patients with intermediate disease. Studies with
Disease Control and Prevention [CDC], and Infectious longer regimens [4 weeks to ‘months’] demonstrated
Diseases Society of America [IDSA] (88) guidelines significant beneficial effects while those with shorter
recommend 12 months of treatment for uncomplicated regimens [2 to 4 weeks] did not. Dexamethasone at 8 to
TBM. Although 18 to 24 months treatment was recom- 12 mg/day (97,98,100) or prednisolone of equivalent dose
mended in the past, there is substantial evidence to (103,104) was effective and had fewer side effects than
suggest that a duration ranging between six to twelve higher doses.
months may be adequate (89,90). According to In addition to these studies, a comprehensive review
Humphries (83), patients in clinical stage 1 or 2 can be in 1966 (105) and a large Chinese study in 1984 (106)
treated for nine or twelve months, while those in clinical also provided some evidence to recommend use of
stage 3 or 4 should be preferably treated for at least 12 steroids to reduce mortality in patients with clinical stage
months and often for 18 months. 2 and 3 but found no benefit in those with clinical stage
Additional factors that need to be considered prior 1 of the disease. In a randomized prospective study,
to initiation of treatment include age, co-existent renal Kumaravelu et al (107) from India [n = 47] reported that
or hepatic disease and pregnancy. One of the most the addition of dexamethasone to antituberculosis
common drug-induced side effect during the treatment treatment resulted in better outcome in patients who
of tuberculosis is development of hepatotoxicity (91). It had severe disease at three months. Girgis et al (97) from
is practically impossible to differentiate drug-induced Egypt found that corticosteroids also reduced the
hepatotoxicity from coincidental viral hepatitis that is morbidity and complications, if administered early in
highly prevalent in developing countries. The reader is the course of treatment. However, they reported no
referred to the chapter “Antituberculosis treatment induced benefit with steroids in patients with very advanced
hepatotoxicity” [Chapter 54] for more details. disease [stage 3 or 4].
A greater clinical and radiological improvement, a In a randomized, double-blind, placebo-controlled
significant reduction in CSF tumour necorsis factor- trial [n = 545] from Vietnam, Thwaites et al (108) studied
alpha and a negligible side-effect profile with an whether adjunctive treatment with dexamethasone
adjunctive thalidomide therapy of childhood TBM in reduced the risk of death or severe disability after nine
South African children with stage 2 disease in a recent months of follow-up. In this study, 545 patients were
report, has drawn attention to this agent (92). randomly assigned to groups that received either
dexamethasone [n = 274] or placebo [n = 271]. It was
Role of Corticosteroids observed that treatment with dexamethasone was
The role of corticosteroids in the treatment of TBM has associated with a reduced risk of death. However,
been a subject of intense and interesting debate for many dexamethasone treatment did not result in a significant
decades, with both proponents (93,94) and opponents reduction in the proportion of severely disabled patients
(95,96) for its use. Administration of corticosteroids has [18.2% among survivors in the dexamethasone group vs
been found to be most beneficial in patients with compli- 13.8% in the placebo group] or in the proportion of
cations of TBM. The role of steroid therapy in majority patients who had either died or were severely disabled
of these situations remains to be established. after nine months. The treatment effect was consistent
Seven trials of various degrees of rigor have investi- across subgroups that were defined by disease severity
gated the effects of corticosteroids on TBM (97-103). Five grade and by HIV status.
of these seven trials, including the best-analysed (97) Published evidence also favours the use of cortico-
clearly demonstrated an advantage of adjunctive steroids in the management of children with TBM, as it
corticosteroid therapy over standard therapy for survival, has been shown to decrease mortality, long-term neuro-
frequency of sequelae or both. The CSF abnormalities logical complications and permanent sequelae (97,109)
314 Tuberculosis
It may also be useful in the management of complications may not be reflected in the improvement in CSF para-
of TBM, such as raised intracranial pressure, cerebral meters. Any clinical worsening during treatment
oedema, stupor, focal neurological signs, spinal block, warrants neuroimaging to rule out complications, such
hydrocephalus and basal opticochiasmatic pachymenin- as hydrocephalus, tuberculoma, TB abscess or arteritis
gitis [Table 21.6]. The recommended daily dose of predni- leading to infarction. Vigilance should also be maintained
solone is 0.75 to 1 mg/kg/day in adults and 1 to 2.5 mg/ to detect the development of antituberculosis treatment
kg/day in children. induced hepatotoxicity, ethambutol induced optic
neuritis and streptomycin induced vestibulopathy. These
Drug-resistant Tuberculosis Meningitis complications develop at varying intervals and are dose
related.
The reader is referred to the chapter “Drug-resistant
A repeat CSF examination may not be required in
tuberculosis” [Chapter 49].
patients showing a steady clinical improvement. How-
Treatment of Tuberculosis Meningitis Associated with ever, in patients showing neither clinical improvement
Human Immunodeficiency Virus Infection nor deterioration, CSF parameters should be monitored
along with neuroimaging, if required. In those patients
Treatment of CNS TB in patients with HIV infection is showing deterioration in clinical status, neuroimaging
the same as in patients without HIV infection (110). The should precede a CSF examination.
reader is referred to the chapter “Tuberculosis and human
immunodeficiency virus infection” [Chapter 40] for further Complications of Tuberculosis Meningitis
details on this topic. Hydrocephalus, tuberculoma and rarely TB abscess are
important complications of TBM that require surgical
Monitoring Therapy interventions [Table 21.7]. Both hydrocephalus and
Once antituberculosis treatment is initiated, the mono- tuberculoma can develop after initial improvement with
nuclear pleocytosis in CSF may briefly become antituberculosis agents and can contribute to clinical
polymorphonuclear. At two months of antituberculosis deterioration.
treatment CSF glucose levels normalize in almost all
patients. Normalization of CSF protein level takes Table 21.7: Complications of tuberculosis meningitis
between four to twenty-six months, with a median period
Raised intracranial pressure, cerebral oedema, stupor
of eight months (16). The CSF cell counts normalize in
Basal meningitis with cranial nerve palsies
one-third of the patients by 16 months and in almost all
Focal neurological deficits
patients by three years (16).
Hydrocephalus
Clinical improvement in the form of abatement of
fever and decrease in meningeal signs occurs over a Tuberculoma
variable period of time. However, clinical improvement Tuberculosis abscess
Opticochiasmatic pachymeningitis resulting in visual loss
Table 21.6: Possible indications for corticosteroids in Tuberculosis arteritis and stroke
tuberculosis meningitis Endocrine disturbances
Clinical Hypothalamic disorder leading to loss of control of blood pressure
Clinical stages 2 and above and body temperature
Evidence of raised intracranial pressure Diabetes insipidus
Focal neurological deficits suggesting arteritis
Syndrome of inappropriate antidiuretic hormone secretion
Radiological Internuclear ophthalmoplegia
Cerebral or perilesional oedema
Hemichorea
Hydrocephalus
Infarcts Spinal block
Opticochiasmatic pachymeningitis Spinal arachnoiditis
Ventriculomegaly in TBM need not always be due higher magnetization transfer ratio in the wall of the
to hydrocephalus. Cerebral atrophy can also cause pyogenic abscess compared to that in the tuberculosis
ventriculomegaly. Moderate to severe hydrocephalus is abscess.
often associated with features of raised intracranial Surgical aspiration of the abscess or excision of a
pressure. In children with TBM, hydrocephalus is almost multiloculated abscess may be required as these lesions
always present after six weeks of illness (32). Early harbour TB bacilli and their thick capsules are often
drainage of hydrocephalus by vetriculoperitoneal or impervious to antituberculosis agents. Draining the
ventriculoatrial shunt has been recommended (70,111, abscess decreases the mycobacterial load. Development
112). High protein content or raised polymorphonuclear of fulminant TB meningitis following surgical excision
cell count in CSF often increases the chances of shunt of TB abscess remains a problem (117).
complication. In such situations, external ventricular
drainage may have to precede the shunt surgery. Morta- CHRONIC MENINGITIS
lity appears to be related to the severity of hydrocephalus Definition and Aetiology
(70). Patients in clinical stage 3 and 4, unlike those in
clinical stage 1 and 2 often have a poor outcome despite Chronic meningitis is defined as the clinical syndrome
shunt surgery. There is no convincing evidence to characterized by symptoms and signs of meningitis or
recommend subarachnoid or intraventricular use of meningoencephalitis developing in a subacute or chronic
hyaluronidase for hydrocephalus and optochiasmatic fashion associated with CSF abnormalities and persisting
arachnoiditis (113). for at least four weeks (118,119). In general, chronic
Other common complications of TBM include arteri- meningitis has an insidious evolution and a gradual
tis causing stroke, and opticochiasmatic arachnoiditis progressive course. Sometimes chronic meningitis may
causing visual loss. Early institution of antituberculosis begin relatively acutely and may become chronic later
treatment helps in preventing the occurrence of these on. Chronic meningitis is a potential manifestation of
complications. Treatment for these conditions has been several infectious and non-infectious diseases [Table
disappointing. Steroids have been recommended for the 21.8] (119,120).
prevention of these complications. The reader is referred As the aetiology of chronic meningitis is diverse, these
to the chapter “Endocrine implications of tuberculosis” patients require a thorough diagnostic evaluation to
[Chapter 39] for discussion on SIADH and diabetes establish the cause. Partially treated pyogenic meningitis
insipidus. often needs to be differentiated from chronic meningitis.
Tuberculosis abscess is an uncommon manifestation In our country, majority of patients with chronic
of CNS TB, most often occurring as a complication in meningitis are presumed to have TBM and are treated
patients with reduced immune resistance who are often accordingly. A detailed account of various aetiological
on antituberculosis therapy for systemic or CNS TB. It is causes of chronic meningitis is beyond the scope of this
characterized by an encapsulated collection of pus chapter. However, the diagnostic and therapeutic
containing viable tubercular bacilli without evidence of approach in patients with chronic meningitis will be
the classic TB granuloma. It must be distinguished from discussed briefly.
a granuloma with central caseation and liquefaction Tuberculosis is the most common cause of chronic
mimicking pus. It develops in the brain parenchyma meningitis in the developing world, where TB is highly
although intraventricular (114) and subdural (115) sites endemic. By contrast, in areas with a low prevalence of
have also been reported. Differentiation from pyogenic TB, the scenario may be different. In a study from Mayo
abscess can often be difficult and presence of indirect Clinic (121), sarcoidosis [31%] and metastatic adenocarci-
evidence of TB, culture of the aspirate or response to noma [25%] were the most frequent causes of chronic
antituberculosis treatment may be needed. Recently, meningitis.
Gupta et al (116) reported that elevated lipid and lactate
Clinical Evaluation
levels if accompanied by an elevated amino acid levels
favour a pyogenic abscess over a TB abscess on magnetic The history is critical to distinguish partially treated
resonance spectroscopy. They also found a significantly pyogenic meningitis and TBM [which may present as
316 Tuberculosis
Table 21.8: Causes of chronic meningitis Diagnostic Evaluation

Infectious causes Chest radiograph, bronchoscopy with transbronchial
Mycobacterium tuberculosis lung biopsy, open lung biopsy, and lymph node or liver
Partially-treated bacterial meningitis
biopsy may help in identifying systemic diseases.
Cryptococcus neoformans
Treponema pallidum Neutrophilic CSF pleocytosis may occur in chemical
Borrelia burgdorferi meningitis, systemic lupus erythematosus, bacterial
Candida [Actinomycetes, Listeria, Nocardia] and fungal [Aspergillus,
Brucella Candida, Zygomycetes] meningitis. Eosinophilic
Leptospira icterohaemorrhagiae
CSF pleocytosis favours a parasitic aetiology. Low
Coccidioides immitis
Histoplasma capsulatum glucose in the CSF is non-specific and can occur in a
Aspergillus variety of infectious and non-infectious causes of chronic
Toxoplasma gondii meningitis. The CSF should be exhaustively searched for
Actinomyces specific aetiologic clues utilizing the currently available
Nocardia
facilities.
Zygomycetes
Larva migrans In a retrospective study (122) of patients with chronic
meningitis [n = 168] seen during the period 1986 to 1992
Non-infectious causes
at the Sree Chitra Tirunal Institute for Medical Sciences
Neoplasms
Sarcoidosis and Technology [SCTIMST], Thiruvanananthapuram
Vasculitis [earlier called Trivandrum], India, chest radiographs
Connective tissue disorders revealed evidence of pulmonary TB in 12.5 per cent; CSF
Systemic lupus erythematosus smear or culture were positive for Mycobacterium tuber-
Behcet’s disease
culosis in 16 per cent; and CSF ELISA for Mycobacterium
Vogt-Koyanagi-Harada syndrome
Chronic benign lymphocytic meningitis tuberculosis antigen or antibody was positive in 59 per
Mollaret’s meningitis cent of the patients.
Drug and chemical exposure: iodophendylate dye, sulphona-
mides, isoniazid, ibuprofen, and tolmentin Neuroimaging Studies
acute onset chronic meningitis], chronic meningitis with Contrast enhanced CT or MRI of the head, in addition to
remissions and exacerbations; and recurrent meningitis revealing hydrocephalus and parenchymal lesions, may
[Mollaret’s meningitis]. Useful aetiological clues such as demonstrate meningeal enhancement. In the study from
a known systemic disease, immunocompromised state, the Mayo Clinic (121), MRI with gadolinium contrast was
exposure to drugs and infectious agents [such as Borrelia, the most useful diagnostic imaging technique demon-
Treponema, Leptospira and Brucella] can be obtained from strating meningeal enhancement in 15 of 32 patients
a carefully taken history. Physical examination may [47%] while only two of 32 [6%] CT showed meningeal
reveal a systemic disease, erythema nodosum [which enhancement. In the study (122) from SCTIMST,
may occur in TB, sarcoidosis, histoplasmosis, coccidio- Thiruvananthapuram, India, CT was abnormal in 62 per
idomycosis], erythema chronicum migrans [Lyme cent of the 168 patients with chronic meningitis.
disease], oral and genital ulcers [Behcet’s disease],
Meningeal Biopsy
pulmonary abnormalities [suggestive of TB, sarcoidosis,
fungal infections], heart murmurs [bacterial endocarditis] Despite numerous diagnostic advances, the cause of
and splenomegaly [lymphoproliferative diseases, brucel- chronic meningitis frequently remains a diagnostic
losis]. Ophthalmoscopic examination may show choroid dilemma. Few patients eventually require a lepto-
tubercles, sarcoid granulomas or uveitis [Behcet’s disease, meningeal biopsy, with or without sampling of under-
Vogt-Koyanagi-Harada syndrome]. Granulomatous lying cortex through suboccipital and pterional
myositis [tender, nodular muscles and proximal craniotomy. In a recent study, a definitive aetiologic
weakness] may be found in sarcoidosis. diagnosis of chronic meningitis was made in 16 of
41 biopsies [39%] (121). In patients in whom meningeal INTRACRANIAL TUBERCULOMAS

enhancement was present on CT or MRI, a diagnosis was
obtained in 80 per cent, while only nine per cent of non- Definition and Pathology
enhancing regions were diagnostic. Therefore, contrast Tuberculoma is a mass of granulation tissue made up of
enhanced CT or MRI findings provide valuable assistance a conglomeration of microscopic small tubercles [Figure
in predicting the yield and selecting the site for biopsy. 21.2]. A tubercle consists of a central core of epithelioid
cells surrounded by lymphocytes. Giant cells are
Management scattered among epithelioid cells. The centre of the
In patients with inconclusive clinical and laboratory data tuberculoma becomes necrotic, forming caseous material,
concerning the aetiology of chronic meningitis, the while the periphery tends to be encapsulated with fibrous
decision between empirical therapeutic trial and tissue. There may be liquefaction of the caseous material
meningeal biopsy is critical. The clinical presentation, resulting in the formation of a TB abscess.
especially the pace of progression of course of the disease The size of cerebral tuberculomas is highly variable.
will often dictate the choice. Antituberculosis treatment In most cases their diameters range from a few mm to 3
is indicated early in the course of chronic meningitis in a to 4 cm (123). Intracranial tuberculomas in patients under
patient whose clinical condition shows deterioration. If the age of 20 years are usually infratentorial, but
PCR, serological tests and culture of the CSF for supratentorial lesions predominate in adults. Solitary
Mycobacterium tuberculosis are all negative, TST continues tuberculomas are more frequent than multiple lesions.
to remain non-reactive even after re-testing at two weeks,
and no clinical response occurs, then antituberculosis Epidemiology
treatment may be stopped after six weeks. The decision In the early decades of the twentieth century, cerebral
to empirically use potentially toxic antifungal, drugs such tuberculoma was a common lesion, accounting for 20 to
as amphotericin-B, in chronic meningitis is more difficult. 40 per cent of all intracranial tumours (124). Since then
In the absence of a positive proof for a fungal aetiology the incidence of tuberculoma has declined dramatically
the following situations may warrant such a strategy: in industrialized nations. In 1972, Maurice-Williams (125)
[i] a host with neutropenia or compromised cell-mediated from Great Britain reported a frequency of 0.15 per cent.
immunity; [ii] presence of unequivocal clinical evidence Ramamurthi and Varadarajan (8) noted that the tuber-
or culture or biopsy proven systemic fungal disease, and culomas formed 20 per cent of all intracranial tumours
[iii] a patient with obscure chronic meningitis, hypo- at Chennai [then called Madras] in the 1950s. Although
glycorrhachia and progressive neurological deterioration
inspite of antituberculosis treatment.
A well-preserved patient with undiagnosed chronic
meningitis and a static or slowly progressive course is a
candidate for meningeal biopsy, especially when the
neuroimaging studies suggest an enhancing lesion
accessible through a pterional or suboccipital craniotomy.
Empirical corticosteroid therapy in chronic meningitis
is inappropriate because it can result in the rapid
progression of an undiagnosed fungal disease. Of the
168 patients with chronic meningitis who were
treated with antituberculosis drugs at the SCTIMST,
Thiruvananthapuram, India (122), 19 per cent required
ventriculo-peritoneal shunt for symptomatic hydro-
cephalus. In this study (122), 19.6 per cent patients died.
Figure 21.2: Tuberculoma. Photomicrograph showing granulo-
At one and half years follow-up, 44 per cent of patients matous reaction with epithelioid cells, Langhans’ giant cells [arrows]
were fully functional, the remaining 36 per cent of and central necrosis, characteristic of a tuberculoma [Haematoxylin
patients had significant neurological sequelae. and eosin x 250]
318 Tuberculosis
the frequency has decreased in the last two to three quite variable; homogeneous, patchy, serpentine and ring
decades, tuberculomas still constitute about five to ten enhancement, have all been observed. Unless treated
per cent of intracranial space occupying lesions in the with steroids, oedema is nearly always present and can
developing world (2,126). be quite marked. These CT findings are non-specific and
may simulate the appearance of gliomas, metastasis,
Diagnosis abscess, cysticercosis and fungal granulomas. In a study
from Saudi Arabia (126), the initial diagnosis based on
The CT and MRI have facilitated the diagnosis and
the CT appearance was wrong in 80 per cent of cases.
assessment of intracranial tuberculomas. The
characteristic CT and MRI finding is a nodular enhancing The rupture of a parenchymal tuberculoma or tubercu-
loma en plaque of the meninges [Figures 21.6A and 21.6B]
lesion with a central hypointensity (127) [Figures 21.3A,
can result in TBM. In a study reported by Bhargava et al
21.3B, 21.4 and 21.5]. The pattern of enhancement can be
(32), tuberculomas occurred in 10 per cent of patients
with TBM. Brainstem tuberculomas, although uncom-
mon, constitute two to eight per cent of all intracranial
tuberculomas and are more commonly seen in children
(128). Ventricles form a relatively rare site for the
tuberculoma (129).
Management
In the past, management of tuberculoma was mainly
surgical (130). With the availability of CT and MRI, a
trial of antituberculosis treatment without pathological
confirmation has been tried (127,131,132). Short-course
chemotherapy may be adequate for the treatment of
tuberculoma (133), although its efficacy is not yet
established. Corticosteroids are helpful in selected
patients who have cerebral oedema and are symptomatic.
Figure 21.3A: Contrast-enhanced T1-weighted MRI showing a Tuberculomas begin to decrease in size within the first
round, well-defined lesion with central hypodensity [arrow] and
two months of antituberculosis treatment. Paradoxical
surrounding oedema and conglomerate lesions
expansion of intracranial tuberculomas during anti-
tuberculosis treatment for neural or extra-neural TB has
been observed (134,135). Although the exact mechanism
is unclear, it is thought to have an immunological basis.
Surgery is still indicated for large lesions producing
midline shift and severe intracranial hypertension,
expanding lesions during antituberculosis treatment,
when clinical and neuroimaging findings favour alter-
nate possibilities such as glioma or metastasis and
when the expected improvement is not forthcoming in
the clinical and CT picture during follow-up of medical
treatment.
Therapeutic trial with antituberculosis treatment in
patients with a solitary lesion suspicious of a tuberculoma
is a widely accepted option. However, many workers
Figure 21.3B: Repeat MRI of the same patient showing complete
advise a CT-guided excision biopsy for lesions larger than
disappearance of the lesions after eight months of antituberculosis 2 cm in size, as these lesions could have a varied
treatment aetiology.
Figure 21.4: MRI of the brain [T2-weighted image, axial view] showing characteristic appearance of a tuberculoma [A]. Close-up view of
the lesion showing central hyperintense area [solid arrow] suggestive of caseation necrosis; surrounding hypointense rim [white arrow
head] of fibrousis capsule; and a significant perilesional white matter oedema [black arrrow head]
Figure 21.5: MRI of the brain [T2-weighted image, axial view] showing multiple tuberculomas [white arrows] and basal meningeal
enhancement [black arrows] suggestive of tuberculosis meningitis [A]. Magnetic resonance spectroscopy of the largest lesion
showing a large lipid peak with reduced n-acetyl aspartate peak compatible with tuberculoma [B]
320 Tuberculosis
from India (136-139). The enhancing lesion is less than

two centimeters, but may show considerable oedema
around it. A majority of them resolve over a six-to-twelve-
week period without any specific therapy other than
anticonvulsant medication. These lesions have been
described under various names, such as “disappearing
CT lesions” (138), “appearing and disappearing CT
lesions” (136) and “solitary microlesions in CT” (140),
but are currently called single, small, enhancing lesions
[SSEL] (141,142).
Aetiology
Because of the exclusive geographical distribution, an
infection, such as TB [Figure 21.7], focal encephalitis,
microabscess, or infestation [cysticercosis] was suspec-
ted to be the aetiologic agent for SSEL. Currently, there
Figure 21.6A: Contrast enhanced T1-weighted coronal MRI is fairly a convincing evidence to incriminate cysticer-
showing an en plaque enhancing lesion with oedema [arrow] in a cosis as the major cause of SSEL. Epidemiologically, the
patient with tuberculoma en plaque with meningitis reported occurrence of SSEL corresponds with the
endemicity of cysticercosis. For example, in Kerala, where
cysticercosis is non-existent, SSEL is encountered only
in subjects who have lived outside Kerala. Serologically,
Ahuja et al (139) showed that a significant proportion of
patients with SSEL had positive serology for cysticercosis
compared to healthy control subjects. Radiologically,
most of SSEL on high resolution imaging, such as MRI,
show pathognomonic features of cysticercosis [Figures
21.8A and 21.8B]. The biopsy studies by Chandy et al
Figure 21.6B: The lesion and oedema decreased while the patient
was on antituberculosis treatment. Ipsilateral dilatation of lateral
ventricle is also seen. The CSF data supported the diagnosis of
tuberculosis meningitis and PCR was positive
SINGLE, SMALL, ENHANCING BRAIN LESION ON

COMPUTED TOMOGRAPHY AND SEIZURES
Definition
Figure 21.7: MRI of the brain [post-gadolinium T1-weighted, axial
Patients with seizures, who showed ring enhancing view] showing ring enhancing lesions in the brain [black arrow]
single CT lesions, have been described almost exclusively and cervical cord [white arrow]
the end of three months, the reduction in size or total

resolution of the lesion was comparable in both the
groups. There was no statistically significant difference
between the albendazole or placebo groups. Natural
involution of the cyst may account for the spontaneous
resolution of lesions (145).
Neuroimaging
Rajashekhar et al (146) compared clinical and CT data of
six consecutive patients with histologically proven
tuberculomas and 25 consecutive patients with histo-
logically verified cysticercus granulomas. Evidence of
raised intracranial pressure and a progressive focal
neurological deficit was seen only in patients with
tuberculomas. On CT, all tuberculomas were greater than
Figure 21.8A: Contrast enhanced CT in a 17-year-old girl showing 2 cm in size and majority were irregular in outline. In
small enhancing ring lesion with a mural nodule [arrow] and contrast, all cysticercous granulomas were less than
surrounding oedema. The findings are suggestive of cysticercosis
20 mm and majority were regular in outline. Only
in the early dying stage
tuberculomas were associated with a midline shift on
CT. The authors (146) concluded that based on clinical
findings [evidence of raised intracranial tension and a
progressive neurological deficit] and CT appearance
[size, shape and association with a midline shift] it is
possible to distinguish these two entities in a majority of
patients presenting with seizures and SSEL.
Management
Management of a patient with seizure and SSEL poses
many problems. A series of Consensus Meetings held
under the auspices of Neurological Society of India made
the following recommendations in 1994 (147).
First Visit
If the patient did not have a contrast enhanced CT, then
Figure 21.8B: The T1-weighted contrast enhanced MRI image [left
panel] showing a small enhancing ring lesion [arrow] and a zoomed
the study needs to be done. Plain CT has no place in the
T-2 view [right panel] of the same patient showing the lesion [arrow] management of this disorder. After a careful neurological
and systemic evaluation, routine blood tests and chest
(143) from Vellore in south India showed evidence of radiograph should be performed. If a subcutaneous
cysticercosis in 12 of 15 patients with SSEL. nodule is detected, it should be biopsied. Reliable
immunological diagnostic tests are available only in
Follow-up certain selected institutions and the reports from
A majority of these lesions disappear without any specific elsewhere should not be relied upon. Lumbar puncture
therapy. Padma et al (144) carried out a double-blind, need not be performed as a routine. Treatment should
randomized, placebo-controlled study by comparing the be started with an anticonvulsant drug, usually pheny-
resolution of SSEL on CT in 40 patients who received toin or carbamazepine. If the patient is neurologically
albendazole and 35 patients who received placebo. By normal and seizure free, a follow-up CT is done at three-
322 Tuberculosis
months; if neurological symptoms or signs or seizures to 90 per cent have been observed. Clinical stage 3 and 4
recur then a follow-up CT is done at four to six weeks. are usually accompanied by very high morbidity and
mortality. In a multivariate analysis of 199 Chinese
Second Visit patients with TBM, Humphries et al (82) showed that only
Contrast enhanced CT of the head is repeated. If CT the age and the stage of presentation affected the outcome
shows the lesion to be of the same size as before, smaller and with respect to the disease stage and the mortality
than before, the oedema is less and the patient is seizure raises from none to four per cent in stage 1, to 22 to 30 per
free, anticonvulsant drugs are continued. If the CT shows cent in stage 2, to 78 to 79 per cent in stage 3 or 4.
enlargement of lesion, but the lesion is still less than
2 cm in size with no shift or ventricular compression, Age
then, albendazole is started and anticonvulsant drugs The outcome of TBM, particularly in children, is often
are continued. If the CT shows lesion larger than two poor irrespective of the region where they live. Extremes
centimeters with shift or compression of ventricle or of age have poorer outcome; children below three years
gyri, there are two options: biopsy of the lesion or and adults above 50 years of age generally have a poor
institution of antituberculosis treatment. All biopsies prognosis (30,82). Highest mortality due to intracranial
should be open biopsies with stereotaxic localization, TB has been observed in patients above 50 years of age
whenever feasible. (148).
Third Visit Cerebrospinal Fluid Parameters

Third visit is scheduled at three months after the second Though earlier studies suggested that lower glucose
visit for patients receiving anticonvulsant drug alone and levels in CSF had a poorer outcome, more recent studies
at six to eight weeks for those receiving albendazole and with larger number of patients have failed to show any
antituberculosis treatment. If the repeat enhanced CT correlation between CSF sugar levels and the clinical
shows either enlargement or no change in the size of the outcome (16). The only CSF parameter that correlated
lesion, a biopsy should be done to establish the diagnosis. with a poor outcome was high protein levels [greater than
Those who have responded to anticonvulsant therapy 2 g/l], as it was associated with a more advanced stage
or albendazole and antituberculosis treatment by a of the disease at presentation.
decrease in size or disappearance of the lesion should be
followed-up at three to six monthly intervals. Anti- Neuroimaging of the Head
convulsant drugs are continued till the time the lesion
disappears, calcifies and/or if the patient remains seizure Patients with dense exudates in the basal cisterns and
free for one to two years. visual loss due to organized exudates over optico-chias-
matic region respond poorly to treatment (32). Similarly,
patients with diencephalic infarcts and angiographic
PROGNOSIS AND OUTCOME OF INTRACRANIAL
evidence of narrowing in the middle or anterior cerebral
TUBERCULOSIS
arteries have higher morbidity (2,148). It is also important
The most important factor determining the outcome of to note that diencephalic infarcts give rise to syndrome
intracranial TB, as mentioned earlier, remains early of inappropriate antidiuretic hormone secretion, which
diagnosis and prompt initiation of antituberculosis is a poor prognostic indicator.
treatment. The following factors have been found to
influence the prognosis of TBM. Others Variables
Poor outcome has also been associated with raised
Clinical Stage of the Disease
intracranial pressure with hydrocephalus and infection
When antituberculosis treatment and corticosteroids are with drug-resistant mycobacterial strains. Children who
initiated before patient’s progress beyond clinical stage 1 have not received BCG vaccination also have a poor
or early stage 2 disease, high cure rates ranging from 85 outcome. Infection with HIV does not seem to alter the
prognosis of TBM, except in patients with CD4+ T- culosis treatment, four had an excellent outcome while
lymphocyte counts below 0.2 × 109/l (22,25). These one died.
patients have reduced survival even otherwise (22).
In a recently published study of 65 patients from TUBERCULOSIS RADICULOMYELITIS
Lucknow, India (149), neurological sequelae were
observed in 78.5 per cent patients [cognitive impairment Tuberculosis radiculomyelitis is a form of spinal TB and
in 55%, motor deficit in 40%, optic atrophy in 37% and may develop in one of the three ways: [i] as a primary
other cranial nerve palsy in 23%]. Logistic regression TB lesion; [ii] as a downward extension of TBM; and
analysis revealed that focal motor deficit at admission [iii] as a secondary extension from vertebral TB. The first
was the most important predictor of neurologic deficits two varieties of TBRM are discussed here briefly. Wadia
at one year follow-up. and Dastur (9) suggested TBRM as a generic term to
include cases designated as arachnoiditis, intradural
Sequelae spinal tuberculoma or granuloma and spinal cord
complications of TBM.
The sequelae that have been identified following
intracranial TB occur in patients with advanced disease
Pathology and Clinical Features
[late clinical stage 2 or beyond], and especially in children
[Table 21.9]. On an average, about 20 to 25 per cent of Although common in clinical experience in India, TBRM
children with TBM suffer some sequelae. In a series from is less reported in literature. Hernandez-Albujar et al (152)
a teaching hospital from North-west India (17), only 58 identified 74 cases of TBRM in the published literature
of the 170 surviving patients [34%] with TBM were left from 1966 to 1999. Pathologically, it is characterized by
with no sequelae. In the west, permanent neurological extensive, copious and tenacious exudates that may
sequelae was noticed in 47 to 80 per cent of children with occupy the entire space between the spinal dura mater
TBM, with motor disorders [25% to 27%], visual loss and the leptomeninges that may encase the cord and
[20%] and cognitive and behavioural changes [17% to impinge on the roots. Clinical features include a subacute
40%] being the three of the commonest consequences in to chronic progressive flaccid paraparesis, often in the
long-term follow-up studies (30,150). presence of a positive Babinski’s sign, that is frequently
Intracranial tuberculomas generally grow without preceded by root pains, paraesthesias, bladder distur-
causing the tissue destruction that usually accompanies bances and focal muscle wasting. Secondary TBRM may
a malignant tumour. Therefore, they tend to resolve follow TBM during the acute stage but can also occur
with minimum residual deficits. Conservative medical after a variable periods of months to years (153). Further-
management seems to result in superior functional more, it is known to occur in patients with TBM on
recovery. Choudhury (131) reported that 17 [68%] of 24 inadequate or adequate antituberculosis treatment
patients treated conservatively showed complete regimens (154,155). Lumbosacral region is the most
recovery, while only two patients [8%] had significant commonly affected site in TBRM that is primary or
residual neurological problems. In the series reported by follows TBM, although cervical involvement is not
Gropper et al (151), of the five patients with tuberculoma unknown. In contrast, TBRM secondary to vertebral TB
who underwent surgical excision followed by antituber- is relatively more common in the dorsal region.
Investigations
Table 21.9: Sequelae of tuberculosis meningitis
In most patients with TBRM, if the lumbar puncture is
Psychological or psychiatric disturbances
Visual defects not a dry tap, CSF shows lymphocytic pleocytosis,
Hearing defects [often drug-induced] hypoglycorrhachia and characteristically, a very high
Focal neurological deficit protein level [probably secondary to a CSF flow block].
Endocrine disturbances These findings may persist despite sterilization of CSF.
Seizures
Although in practice, CT myelography or contrast MRI
Intracranial calcification
of the spine is often preferred over the conventional spinal
324 Tuberculosis
myelography in patients with TBRM, Chang et al (153),

in their comparison of these modalities of imaging found
conventional myelography to be the primary radiological
method for diagnosis of suspected TBRM, particularly in
those cases that are characterized by chronic adhesive
changes. In patients with active intrathecal inflammatory
process or with myelopathy, they reported gadolinum
enhanced MRI to be optimal [Figures 21.9, 21.10 and
21.11]. In contrast to this observation, Gupta et al (156)
favoured MRI as the primary imaging modality for
screening patients with suspected intraspinal TB,
regardless of the stage of the disease, an opinion that
may find wider acceptance in view of the non-invasive
Figure 21.10: Contrast enhanced MRI in a patient with spinal pachy
nature of the investigation and the recent advances in arachnoiditis showing post-gadolinium enhancement of clumped
spinal MRI technology. The CT myelography has no nerve roots after emergence from spinal forimina [1]; in spinal canal
superiority over contrast enhanced MRI, except perhaps [2]; and at emergence from spinal forimina [3]
in cases with extensive vertebral tuberculosis. The MRI
features of TBRM include loculation and obliteration of
the spinal subarachnoid spaces, loss of outline of the
spinal cord in the affected region, clumping or matting
of the nerve roots in lumbar region, a syringomyelic cavity
[as a late complication] and nodular, thick, linear
intradural and meningeal enhancement on gadolinum
enhanced MRI. Spinal meningeal enhancement in the
Figure 21.9: Contrast enhanced MRI in a patient with spinal pachy Figure 21.11: Contrast enhanced MRI in a patient with spinal pachy
arachnoiditis showing post-gadolinium enhancement of meninges arachnoiditis showing post-gadolinium enhancement of anterior
[arrow] [A]; and nerve roots [arrow] [B] in a patient with spinal pachy spinal nerve root [arrow] [A] and clumped nerve roots in spinal
arachnoiditis canal [arrow] [B]
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Professor and Head, Department of Radiology, Sree Chitra A clinical study of 232 cases. J Assoc Physicians India
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330 Tuberculosis
Tuberculosis and Heart

22
SS Kothari, A Roy
INTRODUCTION acute pericarditis (6,7), two per cent of cardiac tamponade

(8) and zero to one per cent of constrictive pericarditis
Cardiovascular involvement is a relatively uncommon
(9,10). However, with emergence of the global pandemic
manifestation in patients with tuberculosis [TB] and has
of the acquired immunodeficiency syndrome [AIDS],
been described in one to two per cent of patients (1). It
these numbers are likely to increase again (11).
mainly affects pericardium, but very rarely myocardium,
Tuberculosis pericarditis is the predominant form of
the valves and large arteries are involved. Although
cardiovascular TB. Before the advent of antituberculosis
cardiovascular involvement is always secondary to TB
treatment, TB pericarditis carried a grave prognosis. The
elsewhere in the body, it may be the only clinical
reported mortality rate in TB pericarditis is more than
manifestation of TB. Mycobacterium tuberculosis is the
80 per cent during the acute phase of illness and still more
usual infecting agent. Cardiovascular TB caused by
at a later stage due to constrictive pericarditis (12-14).
nontuberculous mycobacteria [NTM] has been documen-
With the advent of modern multiple drug short-course
ted in patients with human immunodeficiency virus
treatment, the mortality rate in patients with TB
[HIV] infection (2).
pericarditis has decreased but still remains worrisome
TUBERCULOSIS PERICARDITIS with reported death rates of three to seventeen per cent
in the pre-HIV era (15,16) and as high as 27 per cent in
Pericardial TB may present as acute pericarditis, chronic HIV-seropositive patients (17).
pericardial effusion, cardiac tamponade or pericardial
constriction. Hence, TB should always be considered in
Pathogenesis
the differential diagnosis of pericardial disease. In
developing countries where the disease is highly Pericardial involvement most commonly results from
endemic, TB is an important cause of pericardial disease direct extension of infection from adjacent mediastinal
(3-5). Tuberculosis pericarditis, caused by Mycobacterium lymph node or through lymphohaematogenous route
tuberculosis, is found in about one per cent of all autopsied from a focus in lungs, kidneys, or bones. The TB peri-
cases of TB and in one to two per cent of cases of carditis has following stages: [i] dry stage; [ii] effusive
pulmonary TB (1). In India, TB is responsible for nearly stage; [iii] absorptive stage; and [iv] constrictive stage
two-thirds of the cases of constrictive pericarditis (3,4). (18). The disease may progress sequentially from first to
Overall, TB accounts for 60 to 80 per cent of cases of acute fourth stage or may present as any of the stages. The
pericarditis in the developing countries. However, factors that lead to a dominant exudative inflammation
recently published literature suggests that, in the in some patients or fibrosis in others are not known (19).
developed world, TB is a relatively rare cause of peri- While acute pericarditis appears to be a primary
cardial disease in HIV negative, immunocompetent hypersensitivity response to tuberculoprotein[s], chronic
persons and accounts for two per cent of the cases of effusion and constriction reflect granuloma formation
Tuberculosis and Heart 331
and fibrosis. Epithelioid granulomas, Langhans’ giant black race as compared to whites in the western world
cells and caseation necrosis are evident on histopatho- (1,23,24). The clinical features depend on the stage and
logical examination (20). The T-lymphocytes, in addition severity of the disease. The pericarditis is often insidious
to activated macrophages, are important in granuloma in onset and presents with fever, malaise and weakness.
formation. The accompanying exudative pericardial fluid Attention to the diagnosis is drawn by presence of
may contain polymorphonuclear leucocytes in the initial pericardial rub, vague chest pain or cardiomegaly on
one to two weeks, but later on, it is predominantly chest radiograph. Dyspnoea, non-productive cough and
lymphocytic with high protein content. In 80 per cent of weight loss are common symptoms. Chest pain,
the cases, the fluid is straw coloured or sero-sanguinous, orthopnoea and ankle oedema occur in nearly 40 to 70
and may be grossly bloody resembling venous blood at per cent of patients (1,22,25). Chest pain is usually
times (1). Very rarely, severe inflammation may result pleuritic in nature and is characteristically relieved by
in pyopericardium due to TB (21). The amount of peri- sitting up and leaning forward. This manoeuvre relieves
cardial fluid may vary from 15 to 3500 ml (22). increased pericardial tissue tension due to inspiration and
Development of cardiac tamponade due to TB truncal extension and also splints the diaphragm (26).
pericarditis depends on the rapidity of collection of Pain radiation to shoulder and jaw can mimic angina
pericardial fluid. It may occur with small amount of rarely. Radiation of pain to trapezius ridge through the
pericardial fluid collected rapidly and may not occur even phrenic nerve is virtually pathognomonic of pericardial
with a slowly accumulating large pericardial effusion. pain (26). However, TB pericarditis may also present with
Fibrinous exudates, pericardial effusion and thickening an acute illness in 20 per cent of the cases (5). The reported
of pericardium from fibrosis [especially the visceral layer] frequency of various symptoms in different series is
result in features of effuso-constrictive pericarditis within shown in Table 22.1 (1,24,25,28,29).
weeks of development of TB pericarditis. Continued Fever, pericardial rub and systemic congestive failure
inflammation and fibrotic activity may lead to chronic are important signs that are commonly seen [Table 22.2].
constrictive pericarditis [CCP]. With effective Exudative pleural effusion is seen in nearly half the
antituberculosis treatment, the pericardial effusion may patients. The typical features of pericardial effusion and
resolve without development of CCP in nearly half the constrictive pericarditis are described below.
patients (5). Many patients with CCP, however, have no
history of previous TB pericarditis. Complete obliteration Pericardial Effusion
of pericardial space by a fibrotic constricting shell results Patients with TB pericarditis may develop chronic
in impairment of cardiac function. In chronic cases the pericardial effusion with mild or severe constitutional
inflammatory process may extend into myocardium symptoms (1,25). Patients may also present acutely with
resulting in myonecrosis and muscle atrophy. The cardiac tamponade and may manifest severe distress,
constriction at times may be patchy and localized to retrosternal compression, tachycardia and raised jugular
certain areas, like mitral or tricuspid annulus (23). The venous pressure [JVP] with blunted y descent. In patients
space around transverse and oblique sinus is often spared with cardiac tamponade, the heart sounds are usually
from fibrosis, and therefore, some degree of left atrial distant. A pericardial rub may be heard despite signi-
enlargement commonly occurs in CCP. ficant pericardial effusion being present. Pulsus para-
doxus [inspiratory decline of systolic blood pressure of
Clinical Features more than 10 mm Hg] is the hallmark of bedside
Tuberculosis pericarditis can develop at any age but diagnosis.
commonly occurs in the middle age. In the series,
Subacute Effusive-Constrictive Pericarditis
reported by Strang et al (16) more than 80 per cent patients
were older than 35 years with nearly half of them being This subacute stage of TB pericarditis is also termed as
more than 55 years old. Like other forms of TB, it is more subacute “elastic” pericarditis. It has features of both
common in patients who are immunosuppressed. pericardial effusion and constriction. The fluid-fibrin
However, the majority of patients do not have any other layer leads to relatively elastic compression of heart,
co-morbid conditions. It is more common among the which has been compared to “wrapping the heart tightly
332 Tuberculosis
Table 22.1: Clinical symptoms in patients with tuberculosis pericarditis
Variable Hageman et al (24) Rooney et al (25) Fowler (1) Komsuoglu et al (27) Yang et al (28) Reuter et al (29)
[n = 44] [n = 35] [n = 19] [n = 20] [n = 19] [n = 162]
Weight loss ND 85 40 ND 32 79
Night sweats 14 37 58 10 ND 62
Chest pain 39 57 76 40 37 27
Cough 48 85 94 50 47 90
Haemoptysis ND 17 14 ND ND ND
Dyspnoea 80 74 88 60 84 86
Orthopnoea 39 66 53 ND ND 38

n = number of patients; ND = not described
Table 22.2: Physical signs in patients with tuberculosis pericarditis
Variable Hageman et al (24) Rooney et al (25) Fowler (1) Komsuoglu et al (27) Yang et al (28) Reuter et al (29)
[n = 44] [n = 35] [n = 19] [n = 20] [n = 19] [n = 162]
Fever 73 97 83 NA 58 75
Tachycardia [> 100/min] 68 94 83 73 47 74
Pulsus paradoxus 45 23 71 33 11 27
Ankle oedema 64 49 39 24 42 38
Raised JVP 70 46 61 47 68 78
Pericardial rub 41 37 84 ND 32 ND
Cardiomegaly 90 85 95 98 79 ND
Pleural effusion ND 71 58 10 42 38
Hepatomegaly 68 63 65 67 26 62
Ascites 34 3 ND ND 26 ND
Pulmonary infiltrates ND ND ND ND 42 ND

n = number of patients; JVP = jugular venous pressure; ND = not described
with rubber bands” (30). The haemodynamics of the non- Chronic Constrictive Pericarditis
rigid fibroelastic form of constrictive pericarditis In hearts with CCP, the inflow of blood is impeded due
resembles tamponade because the fibroelastic constric- to thickened unyielding pericardium, especially in the
tion compresses the heart throughout the cardiac cycle, late diastole. Thus, patients usually present with
and respiratory changes in intrathoracic pressure are symptoms of systemic and pulmonary venous
transmitted to the cardiac chambers (30). Thus, the congestion. Abdominal swelling [from ascites or
pattern of ventricular filling is similar to cardiac hepatomegaly] and peripheral oedema are the most
tamponade rather than constrictive pericarditis and common presenting symptoms. Dyspnoea and ortho-
includes a systemic venous waveform with a dominant pnoea are also present in nearly half the patients requiring
x descent or equal x and y descent, an inconspicuous early surgical intervention (31). Cardiac output is mildly
diastolic dip in the ventricular waveforms, an inspiratory reduced at rest. These patients have compensatory
dip in systemic venous and right atrial pressures, and tachycardia to maintain cardiac output. Since more than
presence of pulsus paradoxus. This stage can develop 75 per cent of diastolic filling occurs in the first 25 per
within weeks of TB pericarditis. With effective antituber- cent of the diastole, shortening of diastole does not reduce
culosis treatment, the disease may resolve in some stroke volume much but helps in augmenting cardiac
patients, but, commonly chronic constriction supervenes output. Other clinical signs include raised JVP with rapid
(5,16). y descent [Friedrich’s sign], which further increases on
inspiration [Kussmaul’s sign]. Pulsatile hepatomegaly, three weeks (33). However, a more protracted course,
ascites, with an impalpable apex or systolic retraction of large pericardial effusion or cardiac tamponade are not
the precordium [Broadbent’s sign] are also seen infrequent in idiopathic or viral pericarditis. On the other
commonly. A pericardial knock that occurs 0.11 to 0.12 hand, TB pericarditis may have an acute onset. The
seconds after the second heart sound may be present; differentiation of TB pericarditis from idiopathic or viral
murmurs are uncommon. In an Indian study (32), pericarditis may present a diagnostic dilemma.
atrioventricular regurgitation was present in 78 per cent
of patients with CCP on Doppler examination, but an Diagnosis
audible murmur was present in only two of the 33
Chest Radiograph
patients. In general, presence of cardiomegaly, third and
fourth heart sounds, significant mitral or tricuspid Cardiomegaly has been commonly reported in various
regurgitation, and severe pulmonary hypertension favour published series on TB pericarditis. It was present in 40
the diagnosis of restrictive cardiomyopathy. of 44 patients described in one study (24) and in 190 of
Other atypical manifestations include clinical presen- the 193 patients in another (16). Active pulmonary TB
tation with ascites that is disproportionate to the has been reported in nearly 30 per cent patients with
peripheral oedema [ascites precox] which may TB pericarditis (1,16,34,35). However, pericarditis may
masquerade as primary liver disease. Sometimes, patients be the only manifestation of extra-pulmonary TB in
may also present with subtle signs, such as like fatigue, several patients. Reduced cardiac pulsations on
without obvious clinical findings of CCP. These patients fluroscopy has been reported in 76 per cent patients (24).
with “occult” constrictive pericarditis often manifest Pleural effusion has also been frequently described and
may be bilateral in some patients (25). Pericardial
pericardial thickening on radiological imaging. The
calcification [Figures 22.1A and 22.1B] commonly occurs
clinical signs of constrictive pericarditis may become
around the annulus and has been observed in 15 per
evident on fluid challenge in such patients. These patients
cent patients in Indian series and in about 75 per cent
improve with pericardiectomy. Other patients may
patients in Western series (3,23).
present with congestive splenomegaly and protein losing
enteropathy resulting in hypoproteinaemia. Rarely,
Electrocardiogram
nephrotic syndrome due to CCP has been described (31).
Cardiac cirrhosis may also develop after many years of The most common electrocardiogram [ECG] findings in
hepatic venous congestion. patients with TB pericarditis are presence of low voltage
The disease worsens gradually and in chronic cases, complexes and T-wave inversion with or without ST-
significant myocardial atrophy occurs due to extension segment changes [Figure 22.2]. One of these findings is
of inflammation and possibly disuse of cardiac muscle. present in over 90 per cent patients (24,25). In a recent
These patients have suboptimal results and higher study of 88 patients with TB pericarditis, presence of low
mortality with pericardiectomy (23). voltage in the extremity and/or precordial leads cor-
related with the presence of greater than 750 ml of
Differential Diagnosis pericardial fluid. However, no ECG parameters were
predictive of cardiac tamponade (36). The presence of
The differential diagnosis of pericardial disease involves
classical ST-segment elevation of acute pericarditis is rare
a number of conditions, such as idiopathic, viral, or,
and is seen in two to nine per cent of patients (24,25).
infectious pericarditis and pericarditis due to neoplasia,
collagen vascular disorders and uraemia among others.
Pericardial Fluid
The aetiological diagnosis in pericarditis is often
established on the basis of “guilt by association”. The pericardial fluid is usually straw coloured or
Majority of patients with idiopathic or viral peri- serosanguinous and has a high protein content. The cell
carditis have acute onset with characteristic chest pain. count is high with predominance of lymphocytes and
Pericardial effusion may be small or absent. Idiopathic monocytes. In the initial weeks, predominantly polymor-
or viral pericarditis is a self-limited illness lasting two to phonuclear leucocytes may be seen and very rarely TB
334 Tuberculosis
Figure 22.2: Three-channel recording of a 12-lead electrocar-

diogram at 25 mm/s in a child with chronic constrictive pericarditis.
Limb leads show a low-voltage graph and non-specific T-wave
inversion in leads V4-V6. Left atrial enlargement is also evident
may cause a purulent pericarditis (21). A smear of

pericardial fluid rarely identifies acid-fast bacilli [AFB]
on Ziehl-Neelsen [Z-N] staining. Flurochrome staining
Figure 22.1A: Chest radiograph [postero-anterior view] showing is a more sensitive technique for identifying mycobacteria
moderate cardiomegaly, dense, plaque-like calcification of the
than conventional Z-N staining (37). Culture of peri-
pericardium in the anterior and inferior atrioventricular groove. Right
basal pneumonitis and pleural effusion are also seen. Extensive cardial fluid grows Mycobacterium tuberculosis in about
calcification of hilar, anterior mediastinal and right paratracheal 50 to 60 per cent cases using Lowenstein-Jensen [L-J] or
lymph nodes is indicative of tuberculosis double strength Kirchner medium (16,25). However, the
major drawback is that six to eight weeks are needed for
the cultures to yield results. Newer radiometric culture
techniques like BACTEC yield quicker results. Applica-
tion of polymerase chain reaction [PCR] to the pericardial
fluid (38) and tissue (39) has also been found to be useful
in the diagnosis of TB pericarditis. Elevated pericardial
fluid adenosine deaminase [ADA] [cut-off > 40 IU/l,
sensitivity 87%, specificity 89%]; and interferon-γ
[IFN-γ] [cut-off > 50 pg/ml, sensitivity 92%, specificity
100%] have been found to be useful for the diagnosis of
TB pericardial disease (29). However, a recent study (40)
demonstrated that ADA, which is produced by activated
macrophages and lymphocytes may also be raised in
malignant effusions. The authors (41) proposed that
simultaneous measurement of lysozyme, which is raised
in TB effusions, along with ADA may help in distinguish-
ing TB pericardial effusion from malignant pericardial
effusion.
Pericardial Biopsy
Pericardial biopsy is another useful method for con-
firming the aetiology of pericarditis and it gives results
earlier than pericardial fluid culture. Tissue can be
obtained by open biopsy or percutaneously using a
Figure 22.1B: Chest radiograph [lateral view] of the same patient. bioptome (41,42). Pecutaneous biopsy is taken from
Pericardial calcification [arrow] is better appreciated in this view multiple sites and has been shown to be safe in a selected
group of patients, including children. Histopathological evidence. Pericardial fluid often contains fibrinous
examination of pericardial tissue may be diagnostic of exudates. Rarely, these exudates may appear as a fleshy
TB in 70 per cent of cases when performed prior to tumour that disappears with antituberculosis treatment
initiation of therapy (16). However, it is important to note (44). Thickened pericardium and pericardial effusion are
that in some patients with culture positive TB, histo- seen in the effusive-constrictive stage. Pericardial
pathology may show non-specific changes. Thus, a non- thickening is best visualized anteriorly over the right
specific histopathological change in the pericardial ventricular free wall. Transoesophageal echocardio-
biopsy does not exclude TB (16). The pericardial tissue graphy is superior to transthoracic echocardiography in
culture also provides an additional source for isolating the detection of pericardial thickening. The normal
Mycobacterium tuberculosis and increases the diagnostic pericardium is a thin, bright line of 1.2 [± 0.8 mm]. In
yield (16,42). one study (45), the pericardium in patients with
constrictive pericarditis measured 9.8 [± 1.6 mm].
Echocardiogram Pericardial thickness as measured by transoesophageal
echocardiography was found to have an excellent
The echocardiogram is highly sensitive and specific for
the diagnosis of pericardial effusion and cardiac correlation with the measurements obtained by electron
beam computed tomography (46). When a value of 3
tamponade [Figure 22.3]. When 1 cm of posterior echo-
mm was used as a cut-off for defining pericardial thick-
free space is evident in systole and diastole, with or
without fluid accumulation elsewhere, the pericardial ness as measured by transoesophageal echocardio-
graphy, the sensitivity and specificity of this technique
effusion is classified as ‘small’. When a posterior clear
for CCP were calculated to be 95 per cent and 86 per
space of 1 to 2 cm is maintained in systole and diastole,
the effusion is classified as ‘moderate’. In ‘large’ cent, respectively (46).
The other findings in CCP include abrupt flattening
pericardial effusions, a clear space of 2 cm or more is
of mid to late diastolic movement of the left ventricular
evident; or an anterior and posterior clear space can be
seen in systole and diastole (43). posterior wall on M-mode, reflecting a sudden decline
in diastolic filling (47). Other M-mode features include
Collapse of right atrial and right ventricular free wall
rapid early closure of the mitral valve and, uncommonly,
in diastole by pericardial fluid and exaggerated respira-
tory variation in atrio-ventricular valve flow velocities premature pulmonary valve opening from increased
right-sided diastolic pressures. A diastolic septal bounce
are diagnostic of tamponade and may precede clinical
is also commonly seen. Diastolic septal motion is
controlled by the pressure gradient across the septum.
The abrupt bounce may be caused by sudden changes in
the transseptal gradient during diastole, when filling is
particularly rapid (48). Additional echocardiographic
abnormalities include mild atrial and inferior vena cava
[IVC] dilatation.
Doppler studies also help in diagnosing CCP and
differentiating it from restrictive cardiomyopathy. The
mitral flow velocities show more than 25 per cent
respiratory variation [decrease with inspiration], most
pronounced in the first heartbeat after inspiration from
apnoea (49). Similarly, an expiratory increase in diastolic
flow reversal [> 25%] of the hepatic venous flow velocities
is suggestive of CCP. Tissue doppler velocities are usually
Figure 22.3: Two-dimensional echocardiogram in parasternal long preserved in CCP and this feature helps to distinguish it
axis view of a child with tuberculosis pericardial effusion from restrictive cardiomyopathy wherein tissue velocities
RV = right ventricle; LV= left ventricle; PEff = pericardial effusion are commonly impaired.
336 Tuberculosis
Cross-Sectional Imaging Cardiac Catheterization

Cross-sectional imaging with computed tomography Cardiac tamponade or CCP due to any cause produces a
[CT] or magnetic resonance imaging [MRI] is very similarly elevated right, left atrial [or pulmonary arterial
useful in the diagnosis of CCP and in distinguishing it wedge], right and left ventricular end-diastolic pressures.
from restrictive cardiomyopathy in difficult cases. The These pressures are within 5 mm Hg of each other [Figure
diagnostic hallmark is the presence of pericardial 22.6]. The other classical haemodynamic criteria
thickening with or without calcification [Figure 22.4]. favouring CCP over restrictive cardiomyopathy (52) are
Additionally, CT is useful in demonstrating mediastinal a right ventricular systolic pressure less than or equal to
lymphadenopathy [Figure 22.5]. While CT scores over 50 mm Hg and a ratio of right ventricular end-diastolic
MRI in detection of minimal amounts of pericardial pressure to right ventricular systolic pressure greater than
calcification, MRI provides better soft tissue characteri- or equal to 1:3. If all these three criteria are met the
zation (50). Pericardial thickening of more than 3 mm probability of correctly diagnosing CCP is over 90 per
is usually considered abnormal. Often a localized cent. If one or none of these criteria is present then
process, pericardial thickening is most frequently seen probability of having CCP is less than 10 per cent. How-
over the right ventricle. In a study of 29 patients (51), ever, one-fourth of patients could not be classified by
MRI was found to be 88 per cent sensitive and 100 per these haemodynamic criteria (53).
cent specific, with a diagnostic accuracy of 93 per cent Measuring respiratory variation in ventricular
for detecting CCP. However, pericardial thickening can haemodynamics during catheterization is another useful
criteria for the diagnosis of CCP (49,53). As a manifes-
be seen without constrictive physiology. Similarly, in a
tation of ventricular interdependence, respiratory
small percentage of patients with constrictive physio-
discordance occurs in peak right ventricular systolic
logy, no pericardial thickening can be identified. There-
pressure and left ventricular systolic pressure. In CCP,
fore, it is important to search for additional findings
right ventricular systolic pressure increases with
suggestive of CCP like tubular shaped ventricles,
inspiration while left ventricular systolic pressure
enlarged atria, focal contour abnormalities of the ventri-
simultaneously decreases. Wedge pressure declines more
cles, dilated IVC, ascites and pleural effusion on CT or than the left ventricular diastolic pressure during
MRI (50). inspiration, and the reduction in mitral flow translates
into the observed reduction in left ventricular systolic
pressure. These criteria have 100 per cent sensitivity and
95 per cent specificity for the diagnosis of CCP (53). In
restrictive cardiomyopathy, both right and left ventri-
cular systolic pressure decrease concordantly with
inspiration (53).
Treatment
Once diagnosis of TB pericarditis is established, prompt
initiation of antituberculosis treatment is mandatory.
Recommended therapy consists of four drug regimens
consisting of isoniazid, rifampicin, pyrazinamide and
ethambutol or streptomycin for two months followed by
isoniazid and rifampicin for next four months. Some
physicians prefer to administer longer duration of
treatment. However, no randomized controlled trials
have compared different durations of antituberculosis
Figure 22.4: Sagittal reconstruction of a contrast enhanced CT of
the chest showing shell-like thickening [11 mm] of the pericardium drug regimens in TB pericarditis. Similar duration of
[arrow] in a patient with tuberculosis pericardial effusion. treatment is recommended for HIV-seropositive patients,
Echocardiography did not reveal any evidence of constriction though patients with NTM infection may require longer
Figure 22.5: Tuberculosis effusive-constrictive pericarditis. Chest radiograph [postero-anterior view] showing cardiomegaly [A]. CT of
the chest of the same patient [mediastinal window] showing pericardial effusion along with well-defined pericardial thickening [arrows] [B]
and mediastinal lymphadenopathy [arrow] [C]. The lymph nodes show the characteristic peripheral rim enhancement with central attenuation.
Repeat CT after completion of antituberculosis treatment showing significant regression in pericardial effusion and thickening [D] and
mediastinal lymphadenopathy [E]
338 Tuberculosis
overall favourable status. In a subsequent randomized

controlled trial with a factorial design by the same group
(16): [i] immediate, complete, open surgical drainage of
pericardial fluid versus percutaneous pericardiocentesis
as required; and [ii] prednisolone versus placebo, double-
blind, as a supplement to six months of antituberculosis
treatment, the authors (16) reported that open drainage
eliminated the need for repeat pericardiocentesis. They
also observed that prednisolone reduced the risk of death
from pericarditis and the need for repeat pericardio-
centesis, and was associated with a higher proportion of
patients with an overall favourable status. In both trials,
prednisolone was used for a period of 11 weeks of
antituberculosis treatment in a dosage of 40 to 60 mg/
day for four to six weeks and tapered over the next five
weeks. The authors (54), recently reported results of 10
years follow-up of the same cohort. Multivariate survival
Figure 22.6: Left and right ventricular pressure tracing at paper analysis [stratified by type of pericarditis], adjuvant
speed of 100 mm/s and 100 mm Hg gain [each small square = 5 prednisolone treatment reduced the overall death rate
mm Hg]. Early [thick arrow] and late [thin arrow] diastolic pressures after adjusting for age and sex, and substantially reduced
of the two ventricles are similar [30 mm Hg] and markedly eleva-
the risk of death from pericarditis.
ted. Right ventricular systolic pressure is also elevated to 60 to
65 mm Hg
In another trial (17) in HIV-seropositive patients with
LV = left ventricular pressure tracing; RV = right ventricular pressure TB pericarditis, there was a significant reduction in all
tracing cause mortality with use of steroids at 18 months of
follow-up (17). Therefore, unless contraindicated, it
duration of therapy. The reader is referred to the chapter appears appropriate to recommend steroids in all
“Treatment of tuberculosis” [Chapter 52] for more details. patients with TB pericarditis and pericardial effusion
Under the Revised National Tuberculosis Control along with antituberculosis treatment (55). The higher
Programme [RNTCP] of the Government of India, dose of prednisolone is due to concurrent use of rifam-
pericardial TB is categorized as serious form of extra- picin which influences corticosteroid metabolism.
pulmonary TB and is treated with Category I DOTS
treatment. The reader is referred to chapter “Revised Pericardiocentesis and Pericardiectomy
National Tuberculosis Control Programme” [Chapter 63] for Pericardiocentesis is life saving in patients with cardiac
more details. tamponade and also provides an opportunity to confirm
the aetiology of the pericardial effusion. This can be
Role of Adjuvant Corticosteroid Treatment
performed percutaneously and by open surgical
In controlled clinical trials, the addition of prednisolone drainage. The latter method abolishes the need for repeat
to antituberculosis treatment has been shown to reduce pericardiocentesis but does not reduce subsequent
mortality and the need for repeated pericardiocentesis mortality or need for pericardiectomy (16). Furthermore,
in patients with TB pericarditis and effusion (5,16). open surgical drainage requires general anaesthesia
In a double-blind comparison of prednisolone vs unlike percutaneously performed procedure, but
placebo as an adjuvant to six months of antituberculosis provides an opportunity to obtain pericardial tissue for
treatment in patients with active TB constrictive peri- histopathological examination. Reuter et al (56) from
carditis (5), addition of prednisolone increased the rate South Africa studied 233 patients with TB pericardial
of clinical improvement, reduced the risk of death from effusion and reported that these patients responded well
pericarditis and the need for pericardiectomy, and was to closed pericardiocentesis and a six-month course of
associated with a higher proportion of patients with an antituberculosis treatment.
Chronic constrictive pericarditis requires pericardiec- and serological studies (62). There is no consensus
tomy, which is preferably avoided in the subacute stage regarding the role of antituberculosis treatment in patients
when a plane of cleavage has not clearly developed (56). with Takayasu’s arteritis. However, patients with
However, pericardiectomy can be done after two to four evidence of active tuberculosis should be treated with
weeks of chemotherapy and should not be unduly antituberculosis treatment and corticosteroids.
delayed if indicated. Various approaches to pericardiec-
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342 Tuberculosis
Skeletal Tuberculosis
23
S Bhan, HL Nag
INTRODUCTION the attachments of the articular cartilage which may

become displaced in the joint.
Existence of “tuberculosis-like” disease has been known
Sometimes the synovium may be infected first and
since time immemorial. Evidence of osteoarticular tuber-
the bone becomes infected secondarily. Usually, there is
culosis [TB] has been found in pre-historic humans (1).
a low-grade synovial infection with moderate increase
In immunocompetent individuals, the osteoarticular
in joint fluid and formation of tubercles and fibrin
involvement occurs in 10 per cent of patients with extra-
deposits. Caseation necrosis of the synovium and the joint
pulmonary TB (2). Commonly, TB affects the spine and
capsule is rare. When a destructive caseating lesion of
the hip joint; other sites of involvement include knee joint,
foot bones, elbow joint and hand bones; rarely, it also the bone penetrates into the joint, the synovium too gets
affects the shoulder joint (3-5). affected. Two classical forms of the disease have been
described: granular and exudative [caseous] that involve
the bone and synovium. Though both the patterns have
SKELETAL TUBERCULOSIS
been observed in patients with skeletal TB, one form may
Skeletal TB occurs due to haematogenous spread and predominate.
affects almost all bones. The disease process can start
either in the bone or in the synovial membrane. Types
Thereafter, it spreads to other structures in a short time. Osseous Granular Type
Typically, an active focus forms in the metaphysis [in
children] or epiphysis [in adults] and the inflammation In the osseous granular type, the bone involvement
extends peripherally along the shaft to reach the occurs at metaphysis or epiphysis often following
subperiosteal space. The inflammatory exudate may trauma. The onset is insidious. Hydrarthrosis of the
extend outwards through the soft tissues to form cold adjacent joint is non-specific and appears following
abscess and sinuses. Frequently, secondary infection exertion. Constitutional symptoms are rare. Overlying
occurs through the sinus tract. The epiphyseal plate is soft tissues are slightly warm and tender. Muscle atrophy
not destroyed as the cartilage is resistant to destruction appears rapidly.
by the TB inflammatory process. The granulation tissue
Osseous Exudative [Caseating] Type
can, however, invade the area of calcified cartilage and
interfere with longitudinal growth. Metaphyseal Onset of the osseous exudative [caseating] type is more
infection reaches the joint through subperiosteal space rapid. Constitutional symptoms, muscle pain and spasm
by penetrating the capsular attachment. In adults, the are more marked. The overlying soft tissues are warm,
inflammation can spread up to the subchondral area and swollen, indurated and tender. When the caseous mate-
enter the joint at the periphery where synovium joins rial penetrates into the joint, a severe destructive arthritis
the cartilage. Destruction of the subchondral bone loosens ensues.
Skeletal Tuberculosis 343
Synovial Granular Type infection spreads and destroys the epiphyseal cortex, the
intervertebral disc and the adjacent vertebrae. It may
The synovial granular type is characterized by inter-
spread beneath the anterior longitudinal ligament to
mittent joint effusion with little or no pain. Later, joint
reach neighbouring vertebrae. The vertebral body
effusion occurs more frequently and becomes persistent.
becomes soft and gets easily compressed to produce
Constitutional symptoms are mild and muscle atrophy
either wedging or total collapse. Anterior wedging is
gradually sets in. This form of synovitis can continue for
commonly seen in the thoracic spine where the normal
a long time without involving the bone. Rarely, the
kyphotic curve accentuates the pressure on the anterior
synovial granular form may get converted into caseous
part of vertebrae. In the cervical and lumbar spine, the
form and the patient may experience increase in the local
centre of gravity is posteriorly located due to lordotic
and constitutional symptoms.
curve and, therefore, wedging is minimal.
A single large caseating lesion of the vertebral body
Synovial Exudative [Caseous] Type
is rare. This type of lesion remains isolated and calcifies
The synovial exudative [caseous] type has an acute onset centrally, appearing as a sequestrum. In this form,
with marked local and constitutional symptoms. Over- mechanical strength of vertebral body is reduced to lesser
lying soft tissues are very tender. The joint movements extent and deformity may not occur. Adjacent interver-
are painful and regional lymph nodes are enlarged. tebral disc is affected gradually.
Abscess and sinus formation is common. Tuberculosis infection starting in the posterior bony
arch and transverse processes is uncommon. With
Prognosis healing, the exudate is resorbed, osteoporosis decreases
and density of body gradually increases to normal. When
The availability of modern antituberculosis drugs has
the intervertebral discs have been completely destroyed,
changed the outlook of patients with bone and joint TB.
the adjacent bodies fuse with each other.
In the granular form of disease, healing is possible
without residual joint scarring and ankylosis. Effective Formation of Cold Abscess
antituberculosis treatment combined with resection of
large caseous destructive foci ensures early healing and Vertebral TB develops as an exudative lesion due to
prevents the spread of infection into joint and soft tissues. hypersensitivity reaction to Mycobacterium tuberculosis.
In recent years, the occurrence of multidrug-resistant The exudate consists of serum, leucocytes, caseous mate-
tuberculosis has, however, become a matter of concern. rial, bone fragments and tubercle bacilli. It penetrates
ligaments and follows the path of least resistance along
SPINAL TUBERCULOSIS fascial planes, blood vessels and nerves, to distant sites
from the original bony lesion and forms a swelling
Spinal TB is the most common form of skeletal commonly called as “cold abscess”.
involvement. In the cervical region, the exudate collects behind
prevertebral fascia and may protrude forward as a
Pathology of Spinal Tuberculosis retropharyngeal abscess. The abscess may track down
in mediastinum to enter into the trachea, oesophagus or
Infection of Bone
the pleural cavity. It may spread laterally into the
Lower thoracic and lumbar vertebrae are the most sternomastoid muscle and form an abscess in the neck.
common sites for spinal TB followed by middle thoracic In the thoracic spine, the exudate may remain
and cervical vertebrae. Usually, two contiguous vertebrae confined locally for a long time and may appear in the
are involved, but several vertebrae can be affected and radiographs as a fusiform or bulbous paravertebral
skip lesions may also be seen. The infection begins in the abscess. Tension may force the exudate to enter into the
cancellous area of vertebral body, commonly in epiphy- spinal canal and compress the spinal cord. Rarely, a
seal location and less commonly in the central or anterior thoracic cold abscess may follow the intercostal nerve to
area of vertebral body. Tuberculosis infection produces appear anywhere along the course of nerve. It can also
an exudative reaction with marked hyperaemia. The penetrate the anterior longitudinal ligament to form a
344 Tuberculosis
mediastinal abscess or pass downwards through medial Table 23.1: Mechanisms underlying the development of
arcuate ligament to form a lumbar abscess. Pott’s paraplegia
The exudate formed at lumbar vertebrae most com- Extrinsic or mechanical causes
monly enters the psoas sheath to manifest radiologically During active disease
as a psoas abscess or clinically as a palpable abscess in Cold abscess [fluid or caseous material]
the iliac fossa. Abscess can gravitate beneath the inguinal Granulation tissue
ligament to appear on the medial aspect of thigh. It can Sequestrated bone and disc fragments
Pathological subluxation or dislocation of vertebra
spread laterally beneath the iliac fascia to emerge at the
Following healing of lesions
iliac crest near the anterior superior iliac spine. Some- Pressure of ridge of bone anterior to cord
times an abscess forms above the iliac crest posteriorly. Fibrosis of dura matter
Collection can follow the vessels to form an abscess in Gliosis of cord
Scarpa’s triangle or gluteal region, if it follows femoral Intrinstic or non-mechanical causes
Spread of tuberculosis inflammation through the dura to
or gluteal vessels respectively.
meninges and eventually to the spinal cord
Rare causes
Paraplegia Spinal tumour syndrome
Thrombosis of anterior spinal artery
While neurological complications of spinal TB are rarely
encountered in developed countries, their incidence Adapted from reference 11
remains quite high in the developing world. Paraplegia
is the most serious complication of spinal TB and its
occurrence is reported to be as high as 30 per cent in material, pus and the granulation tissue. Recovery in
patients with spinal TB (6,7). Neurological involvement these cases is favourable. Late onset paraplegia occurs
is common when the dorsal spine is involved because: due to long-standing persistent mechanical causes. These
[i] diameter and space of the spinal canal are smallest in include internal gibbus, severe kyphotic deformity, dural
the dorsal region; [ii] the abscess remains confined under fibrosis and stenosis of spinal canal. Prognosis in these
tension and is thereby forced into the spinal canal; cases is much less favourable (13).
[iii] tuberculosis infection is common in this area; and
[iv] the spinal cord terminates below the first lumbar Clinical Features
vertebra.
Spinal TB, once a disease of children and adolescents, is
Paraplegia due to spinal TB has been known for a
very long time. It is also known as Pott’s paraplegia. It can now often seen in the adults. Majority of the patients are
under 30 years of age at the time of diagnosis.
be of early or late onset (8-11). Early onset paraplegia
Constitutional symptoms, such as weakness, loss of
develops during the active phase of infection. Paraplegia
of late onset can appear many years after the disease has appetite and weight, evening rise of temperature and
night sweats, generally occur before the symptoms
become quiescent even without any evidence of reacti-
related to the spine manifest.
vation. Most commonly paraplegia develops due to
mechanical pressure on the cord, but in a small number
Vertebral Disease
of patients, it may occur due to non-mechanical causes
as well. The mechanisms underlying the development A young child may be disinclined to play and may not
of Pott’s paraplegia are listed in Table 23.1. Frequently, complain of anything else. Localized pain over the site
more than one of these mechanisms may be operative in of involvement is the most common early symptom and
a given patient. the pain may worsen with activity or unguarded
The fact that paraplegia can sometimes recover even movements. Pain may be referred along the spinal nerves
after many years suggests that the inflammatory exudate to be misdiagnosed as neuralgia, sciatica or intra-
and the resultant oedema may temporarily inhibit the abdominal pathology. As the infection progresses, pain
nerve cell function (12). In most cases, early onset para- increases and paraspinal muscle spasm occurs. Relaxa-
plegia results from cord compression due to multiple tion of muscles during sleep permits painful movements
causes and these include inflammatory oedema, caseous which may cause the child to cry during night [night cries].
Patient walks carefully to avoid sudden jerks which [paraplegia in flexion] with complete loss of conduction
can exacerbate the pain. With the involvement of cervical in pyramidal and extrapyramidal tracts. The sense of
spine, head may be held with hands. Muscle spasm obli- position and vibration is the last to disappear. In severe
terates normal spinal curves and all spinal movements cases, spasticity disappears and flaccid paralysis, sensory
become restricted and painful. Careful palpation, percus- loss and loss of sphincter control [areflexic paraplegia]
sion or pressure will reveal tenderness over the affected can develop.
vertebrae. Sometimes a boggy, dusky thickening of skin Rarely, the cord compression may be so sudden and
may be seen over the affected area. In patients presenting complete that the patient presents with sudden onset of
late, when vertebral wedging and collapse have occurred, flaccid paralysis simulating the picture of spinal shock.
a localized knuckle kyphosis becomes quite obvious This may occur due to rapid accumulation of TB pus and
especially in the dorsal spine. Occasionally, patients with caseation, pathological dislocation of vertebra and
dorsal spine involvement present very late with an exten- ischaemia of cord due to thromboembolic phenomenon.
sive destruction of multiple vertebrae. These patients have Rarely, presenting features may simulate the features of
deformity of thoracic cage with a large gibbus. spinal tumour syndrome. These features occur due to
localized tuberculoma, granuloma or peridural fibrosis
Cold Abscess producing partial or complete block without any patho-
Local pressure effects, such as dysphagia, dyspnoea, or logy being visible on radiographs. Such cases should be
hoarseness of voice may occur due to a retropharyngeal differentiated from lathyrism in endemic areas since
abscess. Further, dysphagia may also occur due to a lathyrism also presents as pure motor paraplegia of
mediastinal abscess. Flexion deformity of the hip insidious onset. However, patients with lathyrism will
develops due to a psoas abscess. The abscesses may be not reveal block to cerebrospinal fluid flow on lumbar
visible and palpable if they are superficially located. puncture, myelography and magnetic resonance imaging
Therefore, in addition to the physical examination of the [MRI].
bony lesion, a careful search for the presence of cold Clinically, the severity of paraplegia has been
abscess in the neck, chest wall, groin, inguinal areas and classified into four grades (14-16).
thighs can be rewarding. Grade I Negligible paraplegia The patient is unaware
of the neurological deficit but examination reveals clonus
Paraplegia and extensor plantar response.
Rarely, paraplegia may be the presenting symptom. But, Grade II Mild paraplegia The patient is aware of
in a majority of cases, the diagnosis of TB of the spine is weakness and difficulty in walking but manages to walk
already established when paraplegia develops. Spon- with or without support.
taneous twitching of muscles in lower limbs and clumsi- Grade III Moderate paraplegia The patient is bedridden
ness in walking due to muscle weakness and spasticity
and cannot walk due to severe weakness. Examination
are the earliest signs of neurological involvement. With
reveals paraplegia in extension and sensory deficit in less
passage of time, paralysis progresses through various
than 50 per cent.
stages. These include muscle weakness, spasticity,
incoordination, difficulty in walking and paraplegia in Grade IV Severe paraplegia Features of grade III with
extension. Subsequently, paraplegia in flexion, sensory flexor spasm or paralysis in flexion or flaccid paralysis
loss and loss of sphincteric control occur. Exaggerated and sensory deficit of more than 50 per cent.
deep tendon reflexes, clonus, and extensor plantar reflex The higher the grade of paralysis, more severe is the
can be elicited. Anteriorly located motor tracts in the compression of cord and poorer is the prognosis for
spinal cord are in close proximity to the disease process recovery of neurological deficit.
and are sensitive to pressure effect. Therefore, the motor
functions are affected first due to the cord compression. Radiological Features
Increasing compression of cord produces uncontrolled On an average, involvement of 2.5 to 3.8 vertebrae has
flexor spasms. In later stages, limbs remain in flexion been described (17-19). There are mainly four sites of
346 Tuberculosis
infection in the vertebra: paradiscal, central, anterior and

appendicial. The most common site of vertebral
involvement is paradiscal. The appendicial type includes
the involvement of pedicle, lamina, spinous process and
transverse process. Nearly seven per cent of patients may
show skipped lesions (17-19). Some of the vertebral
bodies may become eroded not necessarily due to the
disease process per se, but due to the pressure effect of
the paravertebral cold abscess.
Radiologically, paradiscal infection first appears as
demineralization with indistinct bony margins adjoining
the disc [Figure 23.1]. Gradually, the disc space narrows
signifying either atrophy of disc tissue due to lack of
nutrition, or, prolapse of nucleus into the soft necrotic
vertebral body. The disc space may eventually disappear Figure 23.1: Plain radiograph of the lumbosacral spine [lateral view]
and vertebral bodies reveal an enlarging area of showing early changes of paradiscal involvement of L2 and L3
destruction and wedging. Rarely, disc space may remain vertebrae, indistinct bony margins of adjacent vertebrae along with
intact for a long time. It takes about three to five months loss of disc space [arrow]
for the bony destruction to become visible on a
radiograph. More than 30 per cent of mineral must be mediastinal widening. An abscess arising below the
removed from the bone for a radiolucent lesion to be attachment of diaphragm forms a psoas abscess and in a
discernable on the plain radiograph. Computed good quality radiograph appears as a bulge of the lateral
tomography [CT] and MRI allow identification of bony border of the psoas muscle shadow. A long-standing,
lesions including prevertebral and paravertebral abscess tense paravertebral abscess [usually in the dorsal spine]
shadows at an early stage [Figures 23.2, 23.3, and 23.4]. may produce concave erosions along the margin of verte-
Abscess in the cervical region presents as a soft tissue bral bodies [aneurysmal phenomenon]. Canal compromise
shadow between the vertebral bodies, pharynx and and cord status are best demonstrated by CT or MRI
trachea. Early detection of an abscess in the area of [Figures 23.5 and 23.6].
seventh cervical to fourth dorsal vertebrae requires a Central type lesion starts in the centre of the vertebral
good quality radiograph. Abscess in the dorsal spine area body. Infection at this site probably reaches through
produces a typical fusiform shape [bird-nest appearance] Batson’s venous plexus or through branches of posterior
and a large abscess in this region may appear as vertebral artery. A lytic area develops in the centre of
Figure 23.2: Chest radiograph [postero-anterior view] showing left sided empyema [arrow]. CECT of the chest [sagittal reconstruction]
[B] and [C] showing destruction of vertebral body [black arrow], paraspinal cold abscess [white arrow] and left sided empyema [asterisk]
Figure 23.3: Plain radiograph of the dorsolumbar spine [antero-

posterior view] [A] showing the involvement of D10 and D11
vertebrae, narrowing of intervening disc and paravertebral abscess Figure 23.5: CT [transverse section through the body of C7
[arrows]. CT of the dorsal spine [B] showing bilateral psoas vertebra] showing its destruction and anterior compromise of canal
abscesses [arrows] by bony fragments [arrow]
logically, it is seen as a shallow excavation on anterior or

lateral surface of vertebral body. Similar excavations will
also appear due to the aneurysmal phenomenon in
patients with paradiscal type of lesion and a long-
standing, tense, paravertebral abscess.
Tuberculosis of the posterior elements of vertebra is
not detected in its early stage in the plain radiographs.
In the late stage of disease, the erosive bony lesions of
posterior elements can be seen in the radiographs. How-
ever, CT or MRI is invaluable in detecting these lesions
at an early stage. Paravertebral abscess shadow may be
present but the disc space remains intact. Sometimes
more than one lesion may be present in vertebral column
with one or more healthy vertebrae intervening between
Figure 23.4: CECT of the lower abdomen showing hypodense the diseased vertebrae [called skip lesions].
collections [asterisks] in bilateral psoas muscles [bigger on the left In late stages, anterior wedging or vertebral collapse
side] in a patient with disseminated tuberculosis. The adjacent results in the development of kyphotic deformity.
vertebral body appears normal Sometimes this deformity can be very severe. Destruction
of vertebral body on one side can produce lateral
the vertebral body and may gradually enlarge resulting deviation and rotation similar to that seen in patients
in the ballooning out of the vertebral body mimicking a with hemivertebra, especially when the disease affects
tumour. In the later stages of advanced destruction, a the lower dorsal and lumbar spine [Figure 23.7]. On very
concentric collapse occurs almost resembling vertebra rare occasions, a vertebral body may dislocate anteriorly
plana. In this type of lesion, the disc space is either not due to destruction of the pedicles.
affected or affected minimally and paravertebral shadow The severity of a gibbus can be predicted with 90 per
is also usually not well-marked. Therefore, this type of cent accuracy using the following formula (20)
lesion should be differentiated from a tumour or Calve’s y = a + bx where:
disease. y = final angle of gibbus
Anterior type lesion occurs when the infection starts a = constant with a value of 5.5
in front or on sides of the vertebral body beneath the b = constant with a value of 30.5
anterior longitudinal ligament and periosteum. Radio- x = amount of initial loss of height of vertebral body
348 Tuberculosis
Figure 23.6: MRI of the dorsolumbar spine. Sagittal view showing profound destruction of D10 and D11 vertebrae with anterior compression
of the cord [A] [arrow]. Sagittal spin-echo T1 weighted image showing hypointense L1 and L2 vertebral bodies, intervening disc and an
epidural soft tissue component at L1 level [B][arrow]. The bodies of L1 and L2 vertebrae and epidural soft tissues are brightly enhanced
in T2-weighted image [C] [arrow]
Amount of initial loss of height of vertebral body is

calculated as follows.
Height of vertebral body on lateral radiograph is
divided into 10 equal parts. Loss of height of all
contiguous affected vertebrae is then added
together to get the value of ‘x’.
Differential Diagnosis
Usually, clinical presentation and radiological findings

of spinal TB are characteristic. However, in doubtful
cases, clinical examination and radiological investiga-
tions including CT or MRI will help in making an accu-
rate diagnosis. In a very small percentage of cases, biopsy
of the diseased vertebra for histopathological and
microbiological examinations may be required to confirm
the diagnosis. However, some conditions [Table 23.2]
Figure 23.7: Plain radiograph of the lumbosacral spine [antero-
posterior view] showing mild scoliotic chage due to the relative
may mimic TB of the spine and these conditions need to
destruction of one side of vertebra involving L2 and L3 levels be differentiated from spinal TB, especially in patients
[arrows] with atypical clinical presentation.
Table 23.2: Conditions resembling spinal tuberculosis Table 23.3: Indications for surgery in patients with spinal
tuberculosis regardless of paraplegia
Developmental defects like hemivertebra, Calve’s disease,
Schmorl’s nodes and Scheuermann’s disease Doubtful diagnosis where open biopsy is necessary
Infections like pyogenic osteomyelitis, enteric fever, brucellosis, Failure to respond to antituberculosis drugs
mycotic infections and syphilis Radiological evidence of progression of bony lesion and/or
Benign neoplasms like haemangioma, aneurysmal bone cyst, paraspinal abscess shadow
giant cell tumour Imminent vertebral collapse
Primary malignant tumours like Ewing’s tumour, chordoma, Prevention of severe kyphosis
osteosarcoma, fibrosarcoma, chondrosarcoma, multiple Instability of spine and subluxation or dislocation of vertebral body
myeloma and lymphoma
Secondary neoplastic deposits
Langerhan’s cell histiocytosis
transversectomy with decompression. If a large gap is
Paget’s disease left behind after debridement, adequate bone grafting
Traumatic fracture must always be done. Anteriorly placed grafts provide
Hydatid disease good stability and heal well. An additional use of metallic
implants and titanium cage filled with cancellous bone
Management grafts may be required when nearly whole of the
vertebral body has been removed during debridement.
Surgical prevention of severe kyphotic deformity
Antituberculosis drug treatment for skeletal TB is requires extensive panvertebral operative procedures.
essentially the same as for TB elsewhere in the body. These consist of anterior debridement, anterior interbody
However, there is a difference of opinion regarding the fusion and posterior fusion of the affected vertebrae
duration of drug therapy. Though many orthpaedicians (15,24). It has also been suggested that, a severe deformity
favour 18 to 24 months of antituberculosis drug treat- in the presence of active disease should be an absolute
ment (21,22), short-course chemotherapy for nine months indication for debridement, correction and stabilization
has also been shown to be equally effective in patients since late correction of TB kyphosis is difficult and
with disease caused by drug-susceptible microorganisms dangerous. Correction of a fixed spinal curve and severe
in whom the diagnosis has been established early (23). kyphosis is a formidable surgical undertaking and should
The DOTS should be administered as it takes care of only be done in selected patients by a specially trained
compliance and cost and is associated with lesser adverse surgeon (25).
events. Community DOT providers facilitate adminis- Formerly, posterior spinal fusion by the methods of
tration of drugs in non-ambulatory patients. The reader
Hibbs [fusion between laminae, articular facets and
is referred to the chapters “Treatment of tuberculosis”
spinous processes] and Albee [fusion between spinous
[Chapter 52] and “Revised National Tuberculosis Control
processes with tibial cortical graft] were frequently used.
Programme” [Chapter 63] for more details.
Fusion was successful because posterior elements were
seldom involved in disease process. However, by these
Antibiotics
interventions, progression of lesion in body was not
Persistently draining sinuses are often secondarily affected. Posterior spinal fusion is now rarely used except
infected and, therefore, appropriate antibiotic[s] should to reinforce an anterior spinal fusion in regions of greatest
be administered along with antituberculosis drugs after stress at junctional areas like cervicothoracic and
culture and sensitivity testing. dorsolumbar junctions; and for panvertebral fusion in
children who are at risk of developing severe kyphosis.
Surgery
Cold Abscess
Efficacy of antituberculosis treatment has significantly
reduced the need for operative intervention. Indications With antituberculosis treatment, a small cold abscess will
for adjunct surgery in patients with spinal TB lesions per heal along with the bony lesion. Tense and large cold
se [regardless of paraplegia] are listed in Table 23.3. abscesses are usually located in the neck, chest wall, iliac
Common operative procedures include anterolateral fossa, lumbar triangle, inguinal region and thigh. These
decompression with interbody bone grafting or costo- abscesses are frequently painful and tend to burst and
350 Tuberculosis
form sinuses. Therefore, these abscesses must be drained Table 23.4: Indications for surgical treatment in patients
as early as possible by the standard surgical approach with spinal tuberculosis and paraplegia
which depends on the location of the abscess. Most sur- Absolute indications
geons do not use a drain after evacuation of abscess for Onset of paraplegia during conservative treatment
fear of sinus formation. Paravertebral abscess need not Surgery is not performed for pyramidal tract signs but delayed
be drained on its own but should be evacuated at the till motor weakness is evident
Paraplegia getting worse or remaining stationary despite
time of debridement of bony lesion when indicated.
adequate conservative treatment
Persistence or complete loss of motor power for one month
Paraplegia despite sufficient conservative treatment
Paraplegia accompanied by uncontrolled spasticity of such
Three schools of thought exist in the treatment of Pott’s
severity that reasonable rest and immobilization are impossible
paraplegia. One of the views is that immediate operative or there is a risk of pressure necrosis of skin
decompression of the cord by extensive anterior debride- Severe paraplegia of rapid onset. This usually indicates severe
ment results in maximum improvement in the shortest mechanical pressure but may also be due to vascular
possible time (26). According to these workers, operation thrombosis. Surgery is not helpful when thrombosis causes
should be performed at an earliest because they feel that paraplegia
Severe paraplegia, paraplegia in flexion, flaccid paraplegia,
the TB infection can penetrate into the dura matter and
complete sensory loss or complete loss of motor power for
infect the cord making recovery impossible. This view more than six months. All these are indications for immediate
recommends early radical anterior debridement, surgery without trial of conservative treatment
decompression and arthrodesis in all patients with Pott’s
Relative indications
paraplegia, except in patients with spinal tumour synd- Recurrent paraplegia even with paraplegia that would cause
rome and those with paraplegia resulting from posterior no concern in the first attack
spinal disease. Paraplegia with onset in old age to avoid hazards of immobi-
The second view favours initial treatment with lization
immobilization or complete bed rest. If this does not Painful paraplegia. Pain may be due to spasm or root
compression
produce improvement and recovery within a specified Complications such as urinary tract infection and stones
time period then the surgical decompression of the spinal
cord is performed (9,10,27-29). The widely accepted Rare indications
Posterior spinal disease
indications for surgical treatment are listed in Table 23.4. Spinal tumour syndrome
The third view proposes the “middle path Severe paralysis from cervical disease
regimen”(6) and advocates rest and antituberculosis Severe cauda equina paralysis
treatment for four weeks and surgical decompression if
Adapted from references 28 and 29
there is no improvement in the neurological deficit by
this time. This regimen is useful for developing countries
if the radiographs are normal. Following decompression
with limited resources.
with or without bone grafting, bed rest for a period of 10
Treatment of paraplegia in severe kyphosis is by
to 12 weeks is indicated. Thereafter, the patient is
excising internal gibbus through anterolateral approach
gradually mobilized with a suitable brace.
or by anterior transposition of cord through laminec-
Reactivation or reinfection may result in a relapse in
tomy. Anterolateral decompression is a surgery of lesser
a small percentage of cases and may be complicated by
magnitude compared to anterior decompression and is
neurological involvement. In such situations, early
preferred in resource limited settings. Details of surgical
operation and administration of appropriate antituber-
techniques are beyond the scope of this chapter. How-
culosis drugs are indicated.
ever, it must be pointed out that obtaining adequate
surgical exposure of junctional areas of spine is difficult
TUBERCULOSIS OF HIP JOINT
and this type of surgery must be undertaken only by
experienced and well-trained surgeons. Tuberculosis of the hip joint occurs in about 15 per cent
Laminectomy and intraspinal exposure must be of all cases of osteoarticular TB and is the next common
deferred if the neurological deficit is non-progressive or form after spinal TB.
Pathology
Tuberculosis of the hip joint almost always starts in bone
and the initial focus is in the acetabular roof [Figures 23.8
and 23.9], femoral epiphysis, proximal femoral
metaphysis or greater trochanter. Rarely, the initial focus
may be in the synovial membrane and the disease may
remain as synovitis for a few months. In these patients,
the diagnosis may be considerably delayed. Tuberculosis
of the greater trochanter may involve the overlying
trochanteric bursa. Since the head and neck of femur are
intracapsular, a bony lesion here invades the joint early
and later spreads to involve the acetabulum as well.
When the disease starts in the acetabulum, symptoms
related to joint involvement appear late [Figure 23.10].
Extensive destruction may result in pathological Figure 23.8: Plain radiograph of the hip joint showing lesions
dislocation of the hip joint. A cold abscess forms in the [arrows] at the acetabulum in a six-year-old boy at the beginning of
treatment
joint, may perforate the capsule and extend anywhere
around the hip joint. It may perforate the thinned
acetabular floor to form an intrapelvic abscess. stage subsides, pain and muscle spasm become less
severe and muscle atrophy develops.
Clinical Features Classical untreated TB of the hip joint passes through
Tuberculosis of the hip frequently affects the children. following three clinicopathological stages and each stage
Constitutional symptoms may precede the joint has a definite pattern of clinical deformity.
symptoms. Pain around the hip joint or along the thigh
or inner aspect of the knee joint. Particularly on weight Stage of Synovitis [Stage I]
bearing, is usually the first symptom. The patient limps This stage is the earliest manifestation of disease. Intra-
while walking and avoids weight bearing on the affected synovial effusion and exudate distend the joint capsule.
side. During the acute stage, muscle spasm is severe. At The hip joint assumes a position of flexion, abduction
night, relaxation of muscle spasm and unguarded move- and external rotation. During this stage, capacity of the
ments produce night cries. All movements of the hip joint hip joint is maximum. Limb appears lengthened but there
are painful and limited to a variable degree. As the acute is no real lengthening. This is the stage when the disease
Figure 23.9: Plain radiograph of the hip joint showing early tuberculosis lesion at the acetabulum [circle] in a 34-year-old man
which was missed initially [panel A]. Same lesion, three months later [rectangle] when treatment was started [B]
352 Tuberculosis
is seldom diagnosed since similar physical findings are

seen in traumatic synovitis, non-specific transient
synovitis, rheumatic disease, low-grade pyogenic
infection, Perthes’ disease and spasm of iliopsoas muscle
due to an abscess in its sheath or nearby inflammed
lymph nodes. In such situations, clinical and radiological
examinations must be repeated at two to three weeks
intervals till a definitive diagnosis has been made.
Stage of Early Arthritis [Stage II]

As the capsule thickens by fibrosis and contracts, and
damage to the articular surface progresses, the hip joint
assumes a position of flexion, adduction and internal
rotation. Limb appears short but true shortening may
not be present and if present is not more than one
centimetre. All movements of the hip joint remain painful
and limited.
Stage of Advanced Arthritis [Stage III]

The capsule becomes further destroyed, thickened and
contracted along with advanced bony destruction
producing true shortening of the limb. The joint move-
ments become more restricted and the flexion, adduction,
internal rotation deformity may become severe. With
further destruction of the acetabulum, femoral head,
capsule and ligaments, the joint dislocates with the
destroyed head coming to lie proximally and posteriorly
in wandering or migrating acetabulum. Instead of
proximal migration sometimes protrusio acetabuli can
develop with destruction of medial wall of acetabulum.
Radiological Features
In the earliest stage, radiographs may reveal diffuse
decalcification of upper end of femur. Osteolytic bony
focus of infection may be visible in the acetabulum or
femur a little later and this lesion may be seen to be
enlarging on sequential radiographs. Soft tissue swelling
may be evident on the radiograph, but ultrasonography
Figure 23.10: Plain radiograph of the hip joint of the patient shown is useful at this stage to confirm soft tissue swelling. Late
in Figure 23.9 showing increase in the size of the lesion [square] stages of the disease will reveal increasing destruction
despite five months of treatment [A]. Destruction of acetabulum of acetabulum, wandering acetabulum, small atrophic
and granulation tissues [arrows] are seen better in transverse femoral head, subluxation or dislocation of the femoral
section in MRI [B]. Biopsy confirmed the diagnosis of tuberculosis.
head. Seven different types of radiological appearances
Radiograph at 13 months of treatment showing regression of lesion
with extension into the hip joint [square] limiting the movements have been described in advanced stage of TB arthritis of
[C] hip joint (30) and are described below [Figure 23.11].
Figure 23.11: Different radiological types of the hip joint tuberculosis
Normal Type
The disease is mainly synovial. There may be cysts in

the femoral neck, head or acetabulum, but there is no
gross destruction of subchondral bone and the joint space
is normal.
Perthes’ Type
Most patients are under five years of age. The whole
femoral head is sclerotic and differentiation from Perthes’
disease can be difficult though metaphyseal changes seen
in the classical Perthes’ disease are not seen.
Dislocating Type
Subluxation or dislocation of the femoral head occurs.
Figure 23.12: Plain radiograph of the hip joint showing the
This is mainly due to capsular laxity and synovial hyper- “protrusio acetabuli” type of hip involvement
trophy and not due to accumulation of pus. Results are
better after open relocation of the hip joint. Atrophic Type
The femoral head is irregular and the joint space is
Wandering Acetabulum, Protrusio Acetabuli,
narrow. It is seen almost exclusively in adults and the
Mortar and Pestle Type
results of treatment are poor and the condition almost
These appearances occur due to the erosion of sub- always progresses to fibrous ankylosis [Figure 23.13].
chondral bone [Figure 23.12]. Results of surgery are These radiological appearences in general also
generally poor in these types of TB of the hip joint. correspond to the duration of the disease before diagno-
354 Tuberculosis
Figure 23.13: Plain radiograph of the hip joint [antero-posterior

view] showing marked atrophy of head and neck of femur [A]. Figure 23.14: Plain radiograph of the hip joint [antero-posterior
Radiograph of the hip joint [lateral view] of the same patient showing view] showing good healing of the lesion involving superior portion
extensive involvement of upper shaft of the femur [B] of acetabulum following antituberculosis treatment
sis. In the normal, Perthes’, dislocating and atrophic

types, the mean duration of symptoms varies from four
to seven months. In wandering acetabulum, protrusio
acetabuli and mortar and pestle types, the mean
duration of symptoms is usually longer, ranging from
10 to 14 months.
Management
In patients with TB of the hip joint, the prognosis depends

on the stage of disease when treatment is initiated.
Antituberculosis drug therapy started at stages I and II
of the disease may allow an almost or near normal hip
joint at the end [Figures 23.14 and 23.15]. The deformities
Figure 23.15: Plain radiograph the hip joint [antero-posterior view]
should also be corrected as early as possible, or else
of the patient shown in Figure 23.8, showing healed lesion [square]
fibrous ankylosis in the position of deformity will occur. at completion of treatment. The patient recovered with a good
Neglected cases will eventually have a markedly defor- function of the hip joint
med hip joint and a short limb. The shortening is partly
due to gross bony destruction and partly due to growth pain. It also maintains joint space, minimizes chances of
arrest at proximal femoral epiphysis. Occasionally, if the development of wandering acetabulum and prevents
limb has been immobilized for more than one year, pre- dislocation. In the presence of abduction deformity,
mature fusion of distal femoral epiphyseal plate can traction should be applied to both limbs to stabilize the
result in shortening. pelvis. Otherwise, traction to the deformed limb alone
Antituberculosis drugs should be administered in would further increase the abduction deformity. In stage
adequate dosages for a sufficient length of time along I and II, a prolonged period of traction [up to 12-weeks]
with supportive measures to improve the general health. may be required. Traction should be continued till disease
Skin traction is usually required initially in all cases. activity is well-controlled, hip movements improve and
Traction corrects deformity, relieves muscle spasm and become pain free and muscle spasm does not recur.
Gentle hip mobilization and sitting in bed for short arthrodesis [Brittain’s arthrodesis] (32). Now-a-days, with
periods are started during the period of traction. For the effective antituberculosis treatment being available, a
next 12 weeks, non-weight bearing walking is allowed direct intra-articular fusion between the raw surfaces of
with crutches followed by another 12 weeks period of femoral head and acetabulum is performed when
partial weight bearing. Unprotected weight bearing arthrodesis is indicated.
should not be permitted early since chances of collapse Excision arthroplasty of the hip joint (33) [Girdlestone
and deformity of the acetabulum and femoral head may arthroplasty] consists of excision of head and neck of
persist till bones have become fully calcified after control femur along with debridement. Postoperatively, 10 to
of infection. Drainage of the cold abscess should be done 12 weeks of traction is required and this is followed by
without undue delay to prevent sinus formation. gradual weight bearing. The limb becomes shorter by
In patients with stage II disease, partial synovectomy about two centimeters in addition to the preoperative
and curettage of large or enlarging osteolytic lesions in shortening and the joint also becomes unstable. But this
the acetabulum [Figure 23.10] and femoral head should procedure offers the advantage of retaining a good range
be done. At operation, the hip joint should not be disloca- of movements; the patient can even squat and sit cross-
ted in order to remove all TB tissue. After curettage, large legged.
lesions may be filled with cancellous grafts. Curettage Replacement arthroplasty, which has been so
of extra-articular lesions prevents spread of infection in successful in osteoarthritis and rheumatoid arthritis, is
the joint if done early enough. Postoperatively, the
also now being performed in selected patients. For this
regimen of traction, non-weight bearing mobilization,
procedure the disease must be clinically healed for over
partial weight bearing and then unprotected weight
five years.
bearing are followed as described above.
In patients presenting with advanced arthritis, or
TUBERCULOSIS OF KNEE JOINT
stage III disease, the aim is to achieve fibrous ankylosis
in a functional position. Traction is applied first and if Knee joint is the third common site for osteoarticular TB.
indicated, limited operative procedure of partial synovec- It accounts for more than 10 per cent of cases of
tomy and curettage of extra-articular lesions and joint osteoarticular TB.
debridement are done. Once the deformities are corrected
and operative wound has healed well, a plaster spica is Pathology
applied. Immobilisation in the plaster is continued for In the past, the knee joint involvement was mainly a
six to nine months followed by partial weight bearing disease of children presenting as “synovial type”.
for another six months. Unprotected weight bearing is Presently, it is increasingly being seen in adults and
usually possible after about 12 to 18 months from the presents as an osseous metaphyseal lesion which spreads
beginning of treatment. to the joint. The synovial type of infection is a low-grade
Corrective osteotomy of proximal femur at a level just inflammation. The synovial membrane becomes conges-
above the lesser trochanter is required in patients ted, oedematous and is studded with tubercles. The
presenting with ankylosis in an unacceptable position. synovial fluid is increased. It is thin, watery, opalescent
Further, with corrective femoral osteotomy, a painful, and contains flakes of fibrin and an increased number of
fibrous ankylosis may be converted into a painless, bony mononuclear cells. Healing at this stage leaves the
ankylosis. synovial membrane thickened with fibrosis and the
Arthrodesis to achieve bony ankylosis and painless articular surfaces remain largely intact. If healing does
hip joint is done after about 20 years of age when proxi- not occur and the infection persists, the granulation tissue
mal femur has no more potential for longitudinal growth. forms and the synovial space is obliterated by fibrous
In the era prior to the availability of antituberculosis adhesions. The granulation tissue erodes the cartilage,
drugs, extra-articular arthrodesis was done due to fear invades the subchondral bone, capsule and cruciate
of reactivation of infection if the joint was opened. Two ligaments. When initial infection starts in metaphysis, it
popular methods of arthrodesis were iliofemoral produces an acute exudative infection with caseation
arthrodesis [Hibb’s arthrodesis] (31) and ischiofemoral necrosis. This lesion can invade the joint to produce
356 Tuberculosis
granulation tissue and extensive destruction of the premature closure of neighbouring growth plate can
articular cartilage [Figure 23.16]. Sinus formation can occur and in this situation, the limb becomes shorter.
occur [Figure 23.17]. Wasting of thigh and calf muscles
occurs early in this type of infection [Figure 23.18]. Clinical Features
A low-grade synovial infection stimulates osteo- The synovial type of infection is insidious in onset and
genesis and ossification centers in adjoining tibia and starts as intermittent episodes of synovial effusion. The
femur. These bones may become longer than on the affected joint remains normal in appearance and function
opposite side. If infection is not controlled early, a during each remission. Excessive activity and strain tend
Figure 23.16: Tuberculosis synovitis with osteomyelitis. Photomicrograph showing synovial lining, chronic
inflammatory changes and small necrotic bone spicules [arrow] [upper panel, left: Haematoxylin and
eosin, x 100], epithelioid granuloma with lymphocytic infiltration [arrow] [upper panel, right; Haematoxylin
and eosin x 200], caseation necrosis, Langhans’ giant cells [arrow], foreign body giant cells [lower
panel, left; Haematoxylin and eosin, × 400] and caseation necrosis, giant cells [arrow] and lymphocytes
[lower panel, right; Haematoxylin and eosin × 400]
Figure 23.17: Clinical photograph showing healed tuberculosis Figure 23.18: Clinical photograph showing early quadriceps
sinus and flexion deformity of the left knee joint at eight months of wasting due to tuberculosis synovitis in the right knee joint
treatment
to precipitate effusion. Aspirated joint fluid is not

abnormal except for the presence of some mononuclear
cells. At this stage, other causes must be considered in
the differential diagnosis. These include meniscal tear
and synovitis due to trauma, rheumatic fever, rheuma-
toid arthritis and pyogenic arthritis, osteochondritis
dessicans, chondromalacia patellae, haemarthrosis, villo-
nodular synovitis and synovial chondromatosis. In
doubtful cases, synovial biopsy for histopathological and
microbiological investigations are necessary. When a
patient presents with recurrent or persistent knee joint
swelling of insidious onset, a possibility of TB must be
considered. Caution must be exercised while adminis-
tering intra-articular corticosteroids in such patients as
Figure 23.19: Clinical photograph showing hamstrings spasm due
a flare-up of TB can occur.
to tuberculosis synovitis leading to early flexion deformity of the
Gradually, the attacks of synovitis become more left knee joint
intense and presistent. The synovium and capsule
become palpably thickened and tender. This feel of subluxation of tibia, painful fibrous ankylosis, abscess
swelling of the knee joint in synovial TB is classically and sinus formation become evident.
described as “doughy swelling” [Figure 23.18]. At first,
the muscles, particularly hamstrings develop spasm, Radiological Features
atrophy and contractures may develop later. The biceps In the first stage of intermittent synovitis, radiographs
femoris muscle pulls the leg in deformity of flexion are normal [Figure 23.20]. In the next stage of persistent
[Figure 23.19], abduction and external rotation. If this synovitis, radiographs show generalized osteoporosis,
deformity persists, capsular contracture occurs and tibia loss of definition of articular margins [Figure 23.21].
gradually subluxates posteriorly. The synovial fluid is Occasionally, marginal erosions are also seen. Thickened
thin, opalescent and contains a large number of synovium and capsule may cast soft tissue shadow. In
mononuclear cells and flakes of fibrin. When healing patients with advanced disease, radiographs may reveal
takes place in the early stage of intermittent synovial marked narrowing of the joint space and the joint appears
effusion, the knee joint may almost remain near normal.
Healing in the later stages leaves behind thickened and
fibrotic synovial membrane and capsule. Intra-articular
adhesions lead to fibrous ankylosis.
In the form commonly seen in adults, metaphyseal
focus of infection spreads to the joint. Inflammatory signs
develop suddenly and include severe pain, muscle
spasm, local warmth, tenderness and restriction of
movements. Constitutional symptoms are present and
include fever, anorexia and night sweats. Destruction is
greater and abscess and sinus formation are frequent.
Gradual of ossification may result in bony enlargement,
most notably in the medial femoral condyle, and valgus
deformity of the knee joint. A premature epiphyseal
fusion results in retardation of longitudinal growth. In
advanced cases, characteristic “triple deformity” of Figure 23.20: Plain radiograph of the knee joint [antero-posterior
flexion, abduction, external rotation and posterior view] in a patient with tuberculosis synovitis showing normal bones
358 Tuberculosis
Figure 23.21: Sequentially taken plain radiographs of the left knee joint in a 54-year-old man, showing stage of synovitis with the knee
in flexion before initiation of treatment [A and B]. Three months later, while on treatment, juxtaarticular rarefaction of bones in early
arthritis stage is evident [C and D]. The radiograph taken at the completion of treatment showing ankylosed knee joint approximately at
100° flexion despite skeletal traction [E]
grossly disorganized. Osteolytic cavities and TB of the material obtained may facilitate confirmation of
sequestra in bones may also be evident in an advanced the diagnosis. In the stage of intermittent effusion,
stage of the disease and, the classical triple deformity administration of standard antituberculosis treatment
[Figure 23.22] is seen. When the clinical presentation is alone may be sufficient. Traction is useful in all stages of
atypical, and the findings on the plain radiograph do the disease in children and only in the stage of persistent
not support the clinical features, an MRI of the knee joint synovitis in adults. Preoperative traction is used in the
can be helpful [Figure 23.23]. acute fulminating form and surgery is deferred till the
acute stage of disease has been controlled. Traction is
Management also necessary in the postoperative period following
In the early stages of synovial disease, a synovial biopsy synovectomy and debridement. Simple skin traction is
adequate in patients with minimal flexion deformity. But,
and histopathological and microbiological examination
in cases where triple deformity has developed, the double
traction technique should be used. It consists of applying
both horizontal and vertical tractions from a pin passed
in proximal tibia. But traction has its limitations in
correction of deformity in patients with advanced disease
of the knee joint [Figure 23.21E]. Double traction helps
in correction of deformity and prevents posterior
subluxation of tibia. With quiescence of acute local signs,
intermittent, gentle active and passive knee bending
exercises are started. Gradual mobilization and weight
bearing are started with clinical and radiological
improvement. Clinical improvement is indicated by
improvement in local and constitutional symptoms. Re-
ossification of radiolucent areas and increased density
of joint margins are signs of radiological improvement.
In the early period of mobilisation, a bivalved plaster
Figure 23.22: Plain radiograph of the knee joint in a patient with
advanced knee joint tuberculosis. Antero-posterior view showing
cast or brace can be used to prevent recurrence of flexion
gross destruction of bones, lateral subluxation, flexion deformity deformity. If synovitis persists despite of adequate
and tricompartmental involvement can be seen [A]. Lateral view antituberculosis treatment for three months, an open
[B] of the same patient showing flexion deformity arthrotomy and subtotal synovectomy are indicated. The
Figure 23.23: Plain radiograph of the left knee joint in an 18-year-old boy with a history of significant injury who developed pain and
stiffness in the left knee joint not responding to symptomatic treatment, showing rarefaction [small oval] [A], and patellofemoral sclerosis
[large oval] [B]. MRI [sagittal section] of the same patient showing infective changes affecting epiphyseal part of the femur more than tibia
[C]. Biopsy confirmed the diagnosis of tuberculosis
main objective is the removal of infected tissues to render Healing of the wound after surgery in patients with
the chemotherapy more effective. advanced arthritis is often slow and wound dehiscence
Moderately advanced disease, in addition, requires may occur. This is because, the capsule, subcutaneous
debridement with removal of loose bodies and debris. tissue and the skin [that is often scarred] may also be
Excision of pannus covering the articular cartilage and affected by the disease process.
curettage of superficial cartilage erosions and osseous
necrotic foci are also done. If large metaphyseal lesions TUBERCULOSIS OF ANKLE AND FOOT
are present, they are exposed through a window at a
Tuberculosis of the ankle joint and foot accounts for less
distance from joint, curetted and packed with cancellous
than five per cent of all cases of osteoarticular TB. Tarsals
bone grafts. Postoperatively, traction must be continued
and the ankle joint are usually involved together in TB.
for at least six weeks in order to prevent or to correct
This occurs due to spread of the TB infection through
flexion deformity and avoid compressive forces acting
intercommunicating synovial channels or along soft
against the articular surface. Thereafter, the knee joint
tissue planes. The extent of bony involvement and the
must be protected in a bivalved plaster cast or brace and
clinically evident swelling around the ankle joint and foot
the weight bearing is started slowly and cautiously. The
are more extensive than what is discernible on the plain
range of knee joint flexion is likely to remain limited to
radiograph.
moderate or significant extent. In patients with advan-
ced or progressive destructive arthritis or a painful
fibrous ankylosis, arthrodesis may be required. During Pathology
surgery, sufficient bone is removed to overcome Tuberculosis of the ankle joint and foot most commonly
deformity and expose normal cancellous bone and a starts as synovitis which may be either due to infection
compression device is used to obtain rapid fusion (34). of the synovium or less often due to inflammatory
Whenever possible, arthrodesis must be deferred till the response to an adjacent focus of TB in the bone. Usually,
completion of growth in distal femur and proximal tibia. the disease presents as synovial disease or extra-synovial
With arthrodesis, the knee joint remains stable and allows soft tissue disease associated with a bony focus. The
long hours of standing and walking. However, disease spreads fast to involve several joints and is
arthrodesis does not allow flexion of the knee joint and clinically characterized by early occurrence of signs of
the leg remains sticking out while sitting. inflammation. Sometimes, a central bony focus may
360 Tuberculosis
remain clinically quiescent for some time or may produce

low-grade symptoms for some weeks. Local inflam-
matory signs develop late, only after the cortex has been
penetrated and when the adjacent soft tissues and
synovium are involved.
The most commonly affected bone is calcaneum,
followed in frequency by talus, first metatarsal, navicular
and medial two cuneiform bones. Certain bones appear
to be predisposed to TB at different ages. In infants,
metatarsals are most often affected. Tarsal bones in
children and bones of the ankle joint in adults are Figure 23.25: Clinical photograph of a young girl showing mid-
frequently involved. Talus is most often affected in old foot swelling [A] [arrow] extending up to ankle [B] [arrow] due to
age. Multiple lesions, abscess and sinus formation are tuberculosis arthritis involving right foot and ankle joint
common in adults. On the other hand, fulminating
synovial disease is more common in children. A meta-
usually starts at dorsolateral aspect of tarsal areas and
physeal focus in tibia can involve the growth plate and
with the spread of infection it extends towards tarsometa-
produce deformity of the ankle joint. An infective focus
tarsal joints.
can develop in the epiphysis and destroy a part of it. In a
In the less common type of disease, which starts as a
child, intramedullary extension of the bony focus may
central bony focus, usual clinical features include dull
precede the perforation of cortex.
aching pain of a few weeks duration. The foot may
Clinical Features appear deceptively normal. A careful clinical examina-
In the common variety of synovial disease, the onset is tion may reveal minimal swelling, tenderness and
insidious. The clinical presentation includes pain, limp, warmth. Sometimes, a sinus may form adjacent to the
local warmth, tenderness and a diffuse doughy swelling bony lesion [Figure 22.26].
[Figures 23.24 and 23.25]. The soft tissue swelling is
initially intermittent; subsides with rest and reappears Radiological Features
with walking. Eventually, the swelling becomes An isolated destructive lesion may be seen in tarsal bones,
persistent, pain increases and movements of the ankle commonly in calcaneum and talus [Figure 23.27]. In small
joint become restricted. The boggy and tender swelling tarsal and metatarsal bones and phalanges, single
Figure 23.26: Clinical photograph of the left foot showing healed

Figure 23.24: Clinical photograph of the left ankle joint showing tuberculosis sinus [arrow] overlying the bony lesion which
doughy swelling [arrows] due to tuberculosis arthritis responded well to treatment
Figure 23.27: Plain radiograph of the calcaneum [axial view] [A] showing lytic lesion [arrow] in a patient with histopathologically
proven calcaneal tuberculosis. The lytic lesion [arrow] is evident in the posterior part of the calcaneum in the lateral view [B]
intraosseous lesion usually first produces expansion of

bone. Early diffuse osteoporosis is a prominent feature.
Early radiological signs, before bony destruction becomes
evident, are narrowing of joint space, cortical irregu-
larities and minimal destruction of cortical margins. In
late stages of the disease, radiographs show complete
obliteration and disorganization of joint, large bony
lesions and soft tissue swelling.
In selected clinical situations where either the diag-
nosis is not clear or radiological features are inconclusive,
MRI is helpful. This will show the extent of the bony as
well as soft tissue lesions [Figures 23.28 and 23.29].
Management
Synovial biopsy may be needed at times for confirmation
of diagnosis. Antituberculosis drugs should be given in
appropriate dosages for adequate length of time. Plaster
of paris cast is used to give rest to the affected area. The
ankle joint should be immobilized in 10° equinus
position. This allows ankylosis, if at all it occurs, to
develop in functional position. Immobilization and non-
weight bearing should be continued till the disease
becomes quiescent as evidenced by improvement in local
signs. When treatment is started early, this conservative
treatment will produce either completely normal or
functionally normal ankle joint in over 80 per cent of the
Figure 23.28: Plain radiograph of the right foot of the patient shown
cases.
in Figure 23.25 antero-posterior [A] and oblique [B] views showing
An extensive, long-standing synovial disease requires loss of outline of individual tarsal bones. An MRI [sagittal section]
arthrotomy and synovectomy. Along with synovectomy, of the right foot shows involvement of talus, navicular, calcaneum,
pannus should be carefully peeled off the articular and cuboid by tuberculosis [C, D, E, and F]
362 Tuberculosis
involvement of shoulder joint by TB occurs more

frequently in adults than children (35-37).
Pathology
Tuberculosis of the shoulder joint seldom begins in the
synovium and the clinical presentation as synovitis is
rare. Commonly, the disease starts as an osseous lesion
in the humeral head or glenoid. The joint is involved early
and is filled with granulation tissue. Capsular contracture
and fibrous ankylosis occur early and, therefore, stiffness
and limitation of movements also appear early. Small
osseous foci gradually enlarge and become confluent.
Subsequently, a large fibrocaseous cavity forms which
may lead to deformity of the humeral head and glenoid.
This common variety of TB of the shoulder joint is
considered to be a dry and atrophic type, and hence the
name caries sicca. Swelling, abscess and sinus formation
occur rarely. In children, osseous lesion may start in
metaphyseal region of humerus and interfere with the
Figure 23.29: Plain radiograph of the foot showing no lesions in longitudinal growth.
antero-posterior [A] and lateral [B] views. But MRI reveals extensive
tuberculosis involvement of the mid-tarsal bone in the sagittal Clinical Features
[arrow] [C] and transverse [arrow] [D] sections
The onset is insidious, the early symptoms are non-
specific and include sensation of heaviness or muscle
cartilage. The articular cartilage tends to survive for long
weakness. Pain on movements of the shoulder joint,
periods and destroyed articular cartilage heals by
appears next and progressively worsens. Muscle spasm
formation of fibrocartilage.
fixes the shoulder joint in adduction. Examination reveals
An isolated bony lesion should be curetted and large
painful limitation of all movements of the shoulder joint
cavities should be packed with bone grafts. This ensures
especially external rotation and abduction. In early stages
early healing and prevents spread of disease into the joint
of the disease, some swelling, thickening and tenderness
and adjoining bones. An extensive destruction of one or
in soft tissues around the shoulder joint may be present.
multiple tarsal bones requires complete excision of the A marked wasting of deltoid and supraspinatus muscles
affected bone. Any portion of tarsus can be excised from may occur. Axillary lymph nodes may be enlarged and
the level of neck of talus proximally to metatarsal bases rarely a cold abscess may be present.
distally by two transverse saw cuts. The cut bone surfaces In early stages, TB of the shoulder joint has to be
are approximated and cast applied. This results in a differentiated from periarthritis of the shoulder joint. In
shortened but a well-functioning foot. the advanced stage, rheumatoid arthritis must be
When the joint destruction is so extensive that a considered in the differential diagnosis. In rheumatoid
functional joint can not be expected, arthrodesis of ankle arthritis, the marked soft tissue swelling and synovial
or subtalar joint alone or together can result in a painless effusion occur. In doubtful cases, synovial biopsy should
albeit stiff foot. The technique of arthrodesis is beyond be submitted for microbiological and histopathological
the scope of this chapter. examinations.
TUBERCULOSIS OF THE SHOULDER JOINT Radiological Features

Tuberculosis of the shoulder joint is relatively rare. It Diffuse osteoporosis is an important radiological feature
accounts for only one to two per cent of all cases of in early stages. Later, some soft tissue swelling occurs
osteoarticular TB. In contrast to TB at other skeletal sites, and cortical margins become indistinct. Osteolytic
osseous lesions, narrowing of the joint space and

deformity of the humeral head and glenoid develop in
the late stages of the disease [Figure 23.30]. Rarely,
pathological subluxation or dislocation of the shoulder
joint may develop [Figures 23.31 and 23.32].
Management
In patients with a doubtful diagnosis, a synovial biopsy
should be performed early to confirm the diagnosis.
In addition to the general measures, the affected
shoulder joint should be immobilized in plaster spica for
Figure 23.32: Plain radiograph of the shoulder joint [antero-

posterior view] showing pathological superior migration and
osteoporosis of the right humeral head [arrow] in treated
tuberculosis arthritis of the right shoulder joint
three months. Currently, removable polythene brace is

commonly used for this purpose. Immobilization of the
joint should be in functional position in the event of
eventual healing with ankylosis. The optimum position
for immobilization is 80° abduction, 30° forward flexion
and 30° of internal rotation. Usually, fibrous ankylosis
occurs. Patient can perform routine activities due to
compensatory movements at the scapulothoracic level.
Figure 23.30: Plain radiograph of the shoulder joint [antero- Tuberculosis of the shoulder joint responds well to
posterior view] showing late tuberculosis arthritis with destruction antituberculosis treatment. Occasionally, despite
of the humeroscapular joint
adequate antituberculosis treatment, fibrous ankylosis
of the shoulder joint remains painful and has to be
distinguished from a relapse. In selected cases with
fibrous ankylosis, surgical arthrodesis of the glenohume-
ral joint in the optimum functional position is helpful.
This relieves pain and provides a stable joint. A shoulder
spica or internal fixation with metallic implants is
necessary for the success of arthrodesis. Shoulder spica
is to be continued for two to three months till the radio-
logical confirmation of arthrodesis. Subsequently, limb
is supported on a sling after removal of the spica. Gradual
physiotherapy is started to encourage the scapulothoracic
movement.
An alternative to arthrodesis is available for patients
with a painful shoulder joint due to TB. In the procedure
known as excision arthroplasty of the shoulder joint, the
Figure 23.31: Plain radiograph of the shoulder joint [antero-
diseased tissues are removed by thorough debridement,
posterior view] showing pathological dislocation and a large cold
abscess in axilla [arrow]. Patient had multiple sinuses located and the affected bony parts are removed from proximal
posteriorly humerus and glenoid. The resultant pseudoarthrosis
364 Tuberculosis
preserves the movement at the shoulder joint. However, joint tenderness, boggy oedema of periarticular tissues
this procedure may render the joint unstable. Possibility and increased synovial effusion occur [Figure 23.33].
of development of future relapses of the disease is also Swelling is most easily appreciated at the back of the
another risk with this procedure. All major surgical elbow on both sides of the olecranon and triceps tendon.
procedures are to be undertaken under the cover of Wasting of arm and forearm muscles occurs early.
antituberculosis drugs. Supratrochlear or axillary lymph nodes are enlarged in
about one-third of the cases. In advanced untreated
TUBERCULOSIS OF ELBOW JOINT disease, discharging sinuses may be present.
Tuberculosis of the elbow joint accounts for about two
Radiological Features
per cent or less of all osteoarticular TB. Children are less
often affected as compared to adults. In the early stage of the disease, bones around the joint
show generalized osteoporosis and the articular margins
Pathology become fuzzy and irregular [Figure 23.34]. Osteolytic
bony lesions can be seen in the olecranon, coronoid, distal
The disease commonly begins as an osseous focus in the
humerus or radial head [Figure 23.35]. In the late stage
olecranon, coronoid, lower end of the humerus or upper
of the disease, marked joint space narrowing and destruc-
end of the radius in order of decreasing frequency. These
tion of articular margins appear. Rarely, due to marked
caseous bony lesions involve the joint to produce destruc-
tion of cartilage and pannus formation. At this stage, if destruction of ligaments and bones, the elbow joint may
healing occurs, the eventual outcome will be a fibrous develop pathological posterior dislocation. As the disease
ankylosis. If caseous arthritis continues for a long period, heals, fibrous ankylosis develops more frequently than
discharging sinuses also develop. Tuberculosis starting bony ankylosis.
as a synovial disease is uncommon in the elbow joint.
Management
Clinical Features
If the disease starts from an osseous focus or has
Disease is generally insidious in onset and produces pain, progressed to an advanced stage of arthritis, clinical and
muscle spasm and limitation of movements. Generalized radiological features are usually diagnostic. In the stage
Figure 23.33: Clinical photograph with arms abducted [A] and held by the side [B] showing a doughy swelling at the left elbow joint, more
marked on lateral and posterior aspects. Flexion of the elbow joint and muscle wasting in the arm are also evident
Figure 23.34: Plain radiograph of the elbow joint, antero-posterior [A] and lateral [B] views showing generalized rarefaction, fuzziness of
joint surfaces [rectangles]. Plain radiograph [antero-posterior view] [C], [lateral view] [D] of the patient shown in Figure 23.33 showing
soft tissue swelling and fuzziness of joint surfaces [circles] [C and D]
secondary infection with pyogenic bacteria is likely. In

these cases, a broad spectrum antibiotic should also be
administered.
In all stages of the disease, with or without operative
intervention, the elbow joint should be immobilized for
about three months in a plaster cast or removable poly-
thene brace. When the disease is unilateral, immobiliza-
tion of the elbow joint in 90° flexion and forearm in the
midprone position is recommended to avoid the develop-
ment of ankylosis in non-functional position. After
removal of splintage, overuse of the joint should be
avoided for further six to nine months. Functionally,
satisfactory range of movements at the elbow joint is
retained in a majority of the cases. Results, however, also
Figure 23.35: Plain radiograph of the elbow joint [lateral view] depend on the stage and extent of the disease and joint
involved by tuberculosis showing lytic lesion in olecranon [arrow] destruction when treatment is started. The results are
and loss of joint space with flexion deformity
much better in the early stage disease of synovitis and in
of synovitis and during early stages of the joint unicompartmental disease. In advanced arthritis with
destruction, differentiating TB of the elbow joint from involvement of all compartments of the joint, the usual
rheumatoid arthritis can be difficult. In doubtful cases, end result is fibrous ankylosis in a majority of patients.
an open biopsy of the synovium should be done to The bony ankylosis is uncommon.
ascertain a definitive diagnosis. A localized destructive lesion near the joint [usually
The principles underlying the management of TB of in the olecranon or coronoid] should be curetted early to
the elbow joint are similar to those applicable to TB of eradicate a source of future relapses and extension of
other synovial joints. Antituberculosis drugs form the disease into the joint. Synovectomy and joint debride-
mainstay of therapy. In cases where sinuses have formed, ment are indicated in patients with early arthritis, when
366 Tuberculosis
response to chemotherapy and immobilization is not the infected tenosynovitis (38,39). Abscess and sinus
adequate. formation are common.
When advanced arthritis has healed with elbow joint
in tight fibrous anklylosis or anklyosis in unacceptable Clinical Features
position, a good and functionally useful range of move-
The onset of the disease is insidious. Exacerbation of pain
ments at the elbow joint can be regained with excision by movements is the early symptom. Soft tissue swelling,
arthroplasty. The surgery should be deferred till growth
tenderness and limitation of flexion and extension
is complete and should not be done in persons engaged
movements at the wrist joint occur later. In progressive
in heavy manual work. The surgery consists of removing disease with destruction of bones and ligaments,
an “inverted V-shaped” segment of the lower end of
subluxation or dislocation of radiocarpal joints occurs.
humerus with the apex of “V” reaching the olecranon
This gives rise to a marked deformity and further limita-
fossa. Supracondylar ridges, epicondyles and collateral tion of movements. Abscess and sinus formation are
ligaments should be carefully preserved. Upper end of
frequent in advanced disease. Extension of disease to
the ulna [rarely along with upper end of the radius] should
flexor and extensor tendon sheaths produces a localized
be sparingly trimmed and allowed to slide in the boggy swelling and difficulty in movements of fingers.
“inverted V-gap” in the humerus. After seven to ten days
A monoarticular rheumatoid arthritis may be difficult
of operation, movements of active and assisted active
to differentiate from TB.
flexion, extension, supination and pronation are started.
Night splint should be used for three months. Light Radiological Features
work without splint is allowed three months after the
surgery (19). In the early stages, radiographs show demineralization
In heavy manual workers, arthrodesis of the elbow of bones, bony erosions and some reduction of the joint
joint is indicated when the joint has become extensively space. Osteolytic bony lesions in the radius and carpal
disorganized. For unilateral disease, a position of 90° of bones may be seen. In advanced stages of the disease,
flexion is desirable. For bilateral cases, one elbow joint joint spaces of both wrist and intercarpal joints become
should be placed in 110° flexion to enable the hand to obliterated. Bony destruction and even subluxation or
reach mouth and face and the other in 65° flexion to dislocation of the wrist joint may occur [Figures 23.36
attend to personal hygiene. The optimum position is best and 22.37].
decided after a trial immobilization of the elbow joint in
plaster cast for few weeks before operation. The surgical
technique of arthrodesis of the elbow joint is beyond the
scope of this chapter.
TUBERCULOSIS OF WRIST JOINT

Tuberculosis of the wrist joint is rare and is seen mainly
in adults.
Pathology
The most common site of initial focus of TB in the wrist
joint is in the distal radius and capitate. The disease
spreads to involve the wrist and intercarpal joints. Less
often, the disease starts from a primary focus in the
synovium and infection soon gets disseminated to Figure 23.36: Post-treatment radiograph of the wrist joint [antero-
posterior view] [A] showing ankylosed wrist, gross destruction of
intercarpal and wrist joints. Infection then spreads to
carpals, loss of intercarpal and radiocarpal joints. Mild volar
involve both flexor and extensor tendon sheaths. Still less subluxation of carpals with loss of radiocarpal joints can be seen in
commonly, the infection may spread to wrist joint from the lateral view [B]
is doubt regarding the diagnosis. With the availability

of better imaging modalities for an early diagnosis,
effective drugs, use of better orthopaedic splintage and
surgical intervention is rarely required (38,39).
Arthrodesis of the wrist joint is the treatment of choice
to minimize the disability in patients where wrist joint
has dislocated due to the advanced destruction, in
patients with painful fibrous ankylosis or ankylosis in
non-functional position [e.g., flexion]. Thorough debride-
ment and arthrodesis are also useful for painful wrist
joint with a history of recurrence of infection. Arthrodesis
of both wrist and intercarpal joints is performed together
from a dorsal approach. The diseased tissue, synovium
and articular cartilage are removed as far as possible and
Figure 23.37: Plain radiograph of the right wrist, antero-posterior joint spaces are packed with cancellous grafts. In the
[A] and lateral [B] views of a patient who has received a full course Darrach’s procedure, a large cortico-cancellous graft is
of antituberculosis treatment showing bony ankylosis [rectangles]
placed in a trough made in distal radius, lunate, capitate
of distal radioulnar, radiocarpal and intercarpal joints
and proximal part of the third metacarpal. Along with
this, the distal end of ulna should be excised to provide
Management useful range of pronation and supination. Optimum
Tuberculosis of the wrist joint is quite likely to be mis- position of the wrist joint arthrodesis is in 10° to 15° of
diagnosed as monoarticular rheumatoid arthritis and, dorsiflexion.
therefore, it is essential to confirm the diagnosis with
synovial biopsy. TUBERCULOSIS OF SACROILIAC JOINT
Subsequent to an early diagnosis, the patient should Sacroiliac joint is a true synovial joint. This joint is
be treated with DOTS. Periodic follow-up with imaging involved in two to five per cent cases of osteoarticular
is required. If indicated, the continuation phase may be TB (40).
extended and this practice of extension of treatment
should be individualized. More clinical trials are required Pathology
to say definitely about the efficacy as well as duration of
antituberculosis treatment. A prolonged splintage in Tuberculosis of the sacroiliac joint may start in the
plaster cast or polythene splint with wrist in 10° synovium, in lateral masses of sacrum or ilium. Infection
dorsiflexion and in midprone position is always required. can either start at these sites or occur as an extension of
Splintage should be gradually discarded during daytime TB from ipsilateral hip joint and lumbosacral area of
but night splint is used for nearly one year. Heavy spine. Destructive caseous lesions form and destroy the
physical work should be avoided for 18 to 24 months in joint. Abscess formation is common and the abscess may
order to avoid collapse of the bones and minimizing the present dorsally or inside the pelvis. Intrapelvic extension
risk of development of deformity. The combination of can lead to severe visceral lesions making the prognosis
modern antituberculosis treatment and proper splintage quite serious. Dorsal abscess or its extension along the
are adequate in nearly two-thirds of the patients. Good iliac crest is likely to result in sinus formation. These
functional range of movements can be regained with sinuses heal with difficulty. Superadded bacterial infec-
these if the treatment is started at an early stage of the tion through the sinuses is common.
disease. Gross fibrous ankylosis occurs in one-third of
Clinical Features
the patients.
Synovectomy of the joint or tendon sheaths [if Sacroiliac TB is rare in infancy and childhood and affects
involved] and curettage of bony lesions are indicated in adults more frequently. The females are affected more
patients not responding to treatment or whenever there frequently than males [male:female ratio = 2:5].
368 Tuberculosis
Concomitant TB infection at some other site is present in infection and juxta-articular bony lesions should be
about half the patients. In patients with a poor general considered in the differential diagnosis. The CT and MRI
health and nutritional status, bilateral sacroiliac joint are of great value in detecting early joint erosions, cavita-
involvement is common. tion and abscess.
The onset of the disease is insidious and it may follow
trauma or pregnancy. Pain over the affected joint is the Management
main symptom. It is referred to groin and less commonly
Tuberculosis of the sacroiliac joint is difficult to diagnose
in the sciatic nerve distribution. Pain worsens on lying
in the early stages, as the clinical manifestations are
either supine or on affected side. Prolonged standing and atypical. Also, it responds slowly and less favourably to
walking also aggravate pain. Sitting on the buttock on
antituberculosis treatment and surgery becomes
affected side is painful, whereas sitting on opposite
necessary quite often. In the pre-chemotherapeutic era,
buttock relieves pain. Bending forwards with the knee TB of the sacroiliac joint was commonly encountered in
joints in extension produces tension on the hamstrings
patients with generalized severe infection and the
and exacerbates the pain, but, bending forwards with
mortality was high in these patients.
the knee joints in flexion is less painful as this manoeuvre Standard antituberculosis treatment and general
relaxes the hamstrings. Sudden jerks, coughing and
supportive therapy are initiated. Surgical intervention
sneezing also worsen the pain. Localized tenderness and
is indicated in patients not responding to drugs and in
some boggy swelling or abscess are present. Stressing those with recurrence of infection or when the diagnosis
the involved sacroiliac joints by any one of the following
is in doubt. It consists of debridement of joint, freshening
three manoeuvres increases pain: [i] distraction of both
of joint margins and packing the area with adequate bone
sacroiliac joints by simultaneous pressure on both grafts to achieve arthrodesis. Post-operative bed rest is
anterior superior iliac spines; [ii] stressing the sacroiliac
required for about three months followed by gradual
joint with forced flexion, abduction and external rotation
mobilization in a lumbosacral belt or plaster jacket till
of ipsilateral hip joint [Faber’s test]; and [iii] by performing clear bony fusion of the joint is evident radiologically.
the Gaenslen’s test of rotating the ilium on sacrum. In the
Gaenslen’s test, the hip on the unaffected side is first firmly
TUBERCULOSIS AT RARE SITES
flexed to fix the pelvis and lumbosacral junction. The
affected hip is then hyperextended thereby rotating the Sternoclavicular Joint
corresponding ilium forwards. This stresses the
inflammed ligamentous structures about the sacroiliac Tuberculosis of the sternoclavicular joint is rare.
joint and produces pain. Frequently, the disease may be misdiagnosed to be low-
Rectal examination is important to detect intrapelvic grade pyogenic infection, rheumatoid arthritis, multiple
abscess. In advanced disease, large cold abscesses and myeloma or metastases. The disease usually starts in the
sinuses may be present. bone at the medial end of clavicle and presents with a
painful swelling of an insidious onset. The swelling may
Radiological Features be warm, tender and boggy. A cold abscess and a sinus
can form in late stages of the disease. Radiographic
In the early stages, the plain radiographs are normal. The
examination of this joint is very difficult; MRI is useful
earliest radiological evidence is in the form of haziness
to detect early erosion and soft tissue swelling. Biopsy is
or loss of definition of joint margins. Thereafter, an
necessary if the diagnosis is in doubt. Response to
irregularity of the articular surface with areas of erosions
antituberculosis treatment is usually good.
may become evident. If the disease is controlled at this
early stage, the joint space narrowing and sclerosis of
the joint margins occur. Progressive destruction causes Acromioclavicular Joint
marked cavitation in the bone and narrowing of the joint Acromioclavicular joint is also a rare site for TB and the
space. Healing of advanced disease occurs by bony disease may start from the lateral end of clavicle or
ankylosis and increased density of the joint margins. acromion and spreads to the joint. Clinical features
Ankylozing spondylitis, rheumatoid arthritis, pyogenic include pain and swelling of an insidious onset. The
diagnosis is often missed. Antituberculosis treatment inferior or superior angle of scapula. Pain and occa-
often yields satisfactory results. sionally swelling are the presenting clinical features. This
is another bone where radiological evaluation is difficult.
Symphysis Pubis CT or MRI can be helpful to detect early lesion of the
disease in scapula. Treatment is with antituberculosis
Tuberculosis of symphysis pubis is rare. The disease
usually begins in pubic bone and spreads to symphysis. drugs.
Localised pain and sometimes abscess and sinuses are
Clavicle
presenting features. Radiological assessment of this area
reveals osteolytic areas in pubic bones and destruction Tuberculosis of the clavicle without involvement of
of margins of pubic symphysis. Concomitant TB lesions acromioclavicular or sternoclavicular joint is rare.
in sacroiliac joint are not uncommon and some of these Children are most often affected. Presenting clinical
patients may develop displacement of symphysis. features include painful swelling of clavicle with or
Treatment is essentially with antituberculosis drugs. Cold without cold abscess or sinuses. Radiograph shows any
abscess may require antigravity aspiration. one of the following types of appearances: diffuse
thickening and honeycombing, multiple cystic cavities
Ilium, Ischium and Ischiopubic Ramus and sequestra formation similar to pyogenic infection.
The mainstay of management is antituberculosis
Isolated TB lesions are rarely seen in one of these bones.
treatment. The role of surgery is limited. Biopsy may be
Usual presenting features include pain, swelling,
tenderness, cold abscess and discharging sinuses. done to confirm the diagnosis. Debridement may be
helpful in patients with slow or no response to drugs.
Radiologically these lesions show varying number of lytic
Large sequestrum should be removed surgically. If neces-
areas and some of these lesions may contain sequestra.
Superimposed pyogenic infection will produce sclerosis sary, a part of clavicle can be excised without loss of
function (41).
around lytic areas. One must be aware of these conditions
in order to diagnose them at an early stage. Treatment is
with antituberculosis drugs. Exploration and debride- TUBERCULOSIS TENOSYNOVITIS AND BURSITIS
ment of bony lesions is indicated in the following situa- Tuberculosis of the tendon sheaths and bursa is rare. Any
tions: [i] patients with doubtful diagnosis; [ii] disease not synovial sheath or bursa can be affected but tendon
responding to antituberculosis treatment; and [iii] sheaths around hand are more commonly affected as
recurrent disease. compared to other sites.
Sternum and Ribs Tuberculosis Tenosynovitis

Tuberculosis very rarely involves the sternum and ribs. Hand is the most common site of involvement. People
Often, the disease is not diagnosed till sinuses have who work with cattle are predisposed to disease caused
formed. Nearly one-third of patients will have detectable by Mycobacterium bovis. Infection can also reach the
TB lesion in lungs or other parts of the skeleton. Radio- tendon sheath by haematogenous route or from
logical assessment of both these sites is very difficult and neighbouring affected bone and joint. The disease usually
may reveal irregular destruction and cavities. The starts as a simple inflammation of the tendon sheath with
diseased ribs may be thickened very much or expanded serous exudate and fibrinous deposits covering the inner
with “punched out” erosions. Surgery is not required surface. Gradually, the tendon sheath thickens and the
routinely in these patients. However, it may be done to exudate becomes seropurulent. With movement and
establish the diagnosis or for the removal of sequestrum. friction, the broken villi and fibrinous exudate get
Response to antituberculosis treatment is good. moulded to resemble rice bodies mimicking rice bodies
sometimes seen in rheumatoid arthritis. The tendon
Scapula sheath may undergo caseation necrosis and the exudate
The scapula is another rare site for TB. Infection may penetrates the soft tissues to form sinuses. Rarely,
start in the angle of acromion, spine, neck of scapula and necrosis of underlying tendons may occur. With healing,
370 Tuberculosis
the sheath becomes fibrotic. The infection spreads in the common presenting features include pain, swelling of
sheath to involve all areas from muscle to tendinous bone with warmth, tenderness, boggy soft tissue swelling
insertion. Paratendon and fascial structures are involved and regional lymphadenopathy. In late cases, abscess and
by the spread of disease. Tuberculosis tenosynovitis of sinus formation occur. A high index of suspicion is
the common sheath of forearm flexor tendons distends required for the diagnosis. Radiographs show irregular
the sheath both proximally and distally up to flexor cavities and areas of destruction with little surrounding
retinaculum. This produces a dumb-bell shaped swelling, sclerosis [Figures 23.38 and 23.39]. This commonly
classically known as compound palmar ganglion. Cross fluc- produces a honeycomb appearance. Some of the cavities
tuation can be demonstrated between the swelling may contain feathery sequestra. After sinus formation,
proximal and distal to flexor retinaculum. superadded bacterial infection produces marked sclerosis
The clinical course of TB tenosynovitis is slow and and occasionally sequestration of cortical bone
insidious. Presenting features include pain, swelling, resembling pyogenic chronic osteomyelitis. Differential
tenderness, weakness of grip and limitation of move- diagnosis includes chronic pyogenic osteomyelitis,
ments. The latter is minimal to start with but progres- Brodie’s abscess and tumours. Biopsy for histopatho-
sively worsens with adherence of tendons. Spontaneous logical and microbiological investigations may help in
tendon rupture and sinus formation are uncommon and the diagnosis. Occasionally, a presumptive diagnosis can
occur as late complications. Fever and general constitu-
tional symptoms are unusual until neighbouring bone
and joint have been involved.
Management in early stage consists of antitubercu-
losis treatment and immobilization. In extensive and long
standing disease, surgical resection of the diseased tissue
followed by immobilization should be done. Function
becomes better after radical excision. If tendon has
become necrotic, it should be excised and tendon grafting
should be done. When infection has spread to bone and
joint, especially the wrist joint, wide excision, debride-
ment and arthrodesis will give best functional result.
Tuberculosis Bursitis Figure 23.38: Plain radiograph of the forearm antero-posterior [A]
and lateral [B] views showing tuberculosis osteomyelitis of entire
Bursa over greater trochanter, subdeltoid bursa and pes
ulna at the beginning of treatment [arrows]
anserinus bursa are known to develop tuberculosis. All
are rare lesions. Clinical presentation includes mild pain,
localized swelling and tenderness. Differentiation from
rheumatoid arthritis, ganglion and synovial tumours can
be difficult and biopsy may be required for an accurate
diagnosis.
Tuberculosis bursitis responds well to antituber-
culosis drugs. Large swellings may require aspiration.
TUBERCULOSIS OSTEOMYELITIS
Tuberculosis of the bone alone can occur without
involvement of the joint (42). Any bone can be affected
Figure 23.39: Plain radiograph of the forearm antero-posterior [A]
but long tubular bones are rarely involved. These are and lateral [B] views of the patient shown in Figures 23.38A and
often diagnosed and treated like bacterial chronic 23.38B showing healed TB osteomyelitis of ulna at completion of
osteomyelitis (37). Usually, adults are affected. The treatment [arrows]
be confirmed on the basis of favourable response to like a graft and nearly complete restoration of osseous
antituberculosis drugs. structure occurs.
Tuberculosis osteomyelitis of short tubular bones, like In refractory cases involving long and short tubular
phalanges, metacarpals and metatarsals is more often bones or in the presence of abscess around the involved
seen and is predominantly a disease of children. The bone, excision of the granulation tissue and infected bone
disease process starts in the medullary cavity causing should be done. Concomitant presence of bacterial infec-
patchy destruction. The entire diaphysis sequestrates due tion in the same osseous lesion, usually through sinuses,
to a combination of two interrelated pathological pro- causes a delay in healing. A short-course of additional
cesses. First, the periosteum becomes lifted up due to antibiotic should be given to control bacterial infection.
granulation tissue. This results in the formation of
involucrum and consequently sequestration of diaphysis TUBERCULOSIS INFECTION OF
occurs. Secondly, because of deficient anastomosis of the PROSTHETIC JOINT
osseous arteries in childhood, the thrombosis caused by As the prosthetic joint replacement is increasingly being
TB pathology leads to sequestration of diaphysis. Rarely, done globally, several reports documenting TB of the
the sequestrated diaphysis may be extruded before prosthetic joint have been published (45-48). Prosthetic
involucrum formation. As a result, gross shortening of joint TB may develop due to the reactivation of the TB
the bone occurs. The bone becomes thickened and spindle arthritis for which prosthetic replacement was per-
shaped. Usually, these patients present with gradual and formed. These patients present with slowly progressive
almost painless swelling of one of the phalanges of hand joint pain. Diagnosis requires a high index of suspicion.
and foot. Constitutional symptoms are usually absent Arthrocentesis must be done and specimens must be
and the bone may be minimally tender. Radiological obtained from multiple sites for mycobacteriological
features of sequestration of diaphysis and subperiosteal studies. Eradication of TB focus is not possible without
new bone formation are diagnostic. 18Fluorine fluoro- removing the prosthesis. Treatment consists of removal
deoxyglucose positron emission tomography [18FDG- of the prosthesis followed by appropriate antituber-
PET] [Figure 23.40] has been found to be useful in culosis therapy.
localizing TB disease in inaccessible or obscure sites. It
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Musculoskeletal Manifestations
of Tuberculosis
24
Ashok Kumar, AN Malaviya
INTRODUCTION These data show that RA is much more common than

TB arthritis. Moreover, RA is just one of the several
Tuberculosis [TB] of the musculoskeletal [MSK] system
idiopathic inflammatory arthritides. The incidence
is an important form of extra-pulmonary disease. With
figures quoted above did not include spondyloarth-
increasing numbers of extra-pulmonary TB cases, it is
ritides, juvenile idiopathic arthritis, psoriatic arthritis,
expected that the global burden of MSK-TB would
systemic connective tissue diseases and other less
increase. Rheumatologists, especially in ‘high burden’ TB
common causes of inflammatory arthritides. Thus,
regions of the world would be expected to diagnose and
despite high incidence of TB in the world, rheumatolo-
manage such cases.
gists would still be seeing much bigger numbers of
patients with RA than patients with TB arthritis. This
EPIDEMIOLOGY
would be true even for so-called ‘high burden’ countries.
Published data suggest that MSK involvement is seen in Yet, TB arthritis remains a curable condition if diagnosed
about two per cent of patients with all forms of TB and and treated early. Therefore, rheumatologists should
in 10 per cent of the patients with extra-pulmonary TB; have a high index of suspicion with emphasis on early
associated pulmonary TB being present in 50 per cent of diagnosis and treatment.
these patients (1-3). It is of interest to compare the burden Generally, MSK-TB is classified into TB of the spine
of MSK-TB with that of rheumatoid arthritis [RA]. The [which constitutes nearly 50% of all MSK-TB] and the
average incidence rate of RA was approximately 26 cases TB of the peripheral joints (6). Various rheumatic
per 100 000 population per year with rates varying from syndromes resulting from TB are listed in Table 24.2 (7).
3.8 to 75.3 (4,5). On this basis the comparative figures for Tuberculosis of the spine and peripheral joints has been
RA and MSK-TB are summarized in Table 24.1. covered in the chapter “Skeletal tuberculosis” [Chapter 23].
Table 24.1: Comparative rates of incidence of musculoskeletal tuberculosis and

rheumatoid arthritis
Disease MSK-TB RA
World High burden countries
Average incidence [per 100 000

population per year] 2.88 3.7 26
Incidence range [per 100 000
population per year] 0.04- 11.68 1.36-11.68 3.8-75.3
MSK-TB = musculoskeletal tuberculosis; RA = rheumatoid arthritis

374 Tuberculosis
Table 24.2: Rheumatic syndromes resulting from cytotoxic drugs, corticosteroid therapy [including local
tuberculosis depot-preparation of steroid injections] (15), intravenous
Invasive TB arthritis substance abuse (16), human immunodeficiency virus
Poncet’s disease [para-infective TB arthritis] [HIV] infection and acquired immunodeficiency
TB soft tissue rheumatism syndrome [AIDS] (17) also predisposes to TB. Bone TB
Iatrogenic rheumatism but not TB arthritis has been reported in patients having
TB osteomyelitis
received anti-tumour necrosis factor agents [e.g.,
Pott’s spine
infliximab and etanercept] for the treatment of rheumatoid
TB = tuberculosis arthritis (18). Local factors related to joint integrity and
Reproduced with permission from “Malaviya AN, Kumar A,
health [e.g., pre-existing joint or bone disease, joint, bone
Muralidhar R, Pande I. Rheumatological manifestations of
tuberculosis–a short review. J Indian Rheumatism Assoc
trauma, including surgical trauma] appear to play an
1994;2:145-8 (reference 7)” important role in the reactivation of disease (19,20).
Consideration of local risk factors for MSK-TB is of great
In this chapter, the focus will be on Poncet’s disease [para- importance to rheumatologists, especially from the stand-
infective TB arthritis]; TB soft tissue rheumatism; and point of pre-existing systemic rheumatic diseases (21,22).
iatrogenic rheumatism, especially from the perspective It is not uncommon to see MSK-TB [arthritis, osteomyelitis]
of rheumatologists. in patients who already have an underlying inflammatory
joint disease [e.g., systemic lupus erythematosus, Sjögren’s
AETIOPATHOGENESIS AND PATHOLOGY syndrome, gout, osteonecrosis of the hip due to sickle-cell
disease and prosthetic joint] (23-27).
The reader is referred to the chapter “Skeletal tuberculosis”
[Chapter 23] for details regarding TB of the spine
CLINICAL SETTING FOR SUSPECTING
peripheral joints.
TUBERCULOSIS ARTHRITIS
It has already been mentioned above that TB arthritis
is not as common as idiopathic inflammatory arthritis In majority of the cases [nearly 85%], TB of the joint
[prototype RA]. But, it is potentially a ‘curable’ condition, manifests as chronic monoarthritis involving large and
which the rheumatologists cannot afford to overlook. There- medium weight bearing joints, hip and shoulder being
fore, it becomes mandatory to be aware of the clinical the most common sites (3,6,28). Therefore, in persons
settings where TB arthritis should be high on the list of with TB risk-factors or those from high-burden regions
differential diagnoses. In endemic regions of the world presenting with chronic monoarthritis, TB arthritis
extra-pulmonary TB including its MSK form, is a disease should be the first consideration till excluded with
of children, juveniles, young and middle-aged adults (3,8- appropriate investigations. Uncommonly, TB arthritis
10). On the other hand, in non-endemic regions it mainly can present as a polyarticular or oligoarticular disease.
affects people in older age group with compromised host However, this clinical form is mostly restricted to
defence [e.g., neglected inmates of homes for elderly, debilitated children or the elderly in high-burden regions
poor and homeless people from inner city, prisoners and with a background of close contact with TB, or in other
jail inmates, alcoholics, racial and ethnic minorities and immunocompromised settings mentioned above.
immigrants from high-TB burden countries] (3,11,12). Rheumatologists would rarely be confronted with TB
Among immigrants from high TB burden countries, as osteomyelitis, which in adults most commonly involves
in their native countries, MSK-TB occurs primarily in long bones [femur, tibia and ulna]. In children, the
children, and young and middle-aged adults who common sites include short [e.g., phalanges] or small
commonly present with a solitary osteolytic lesion in the bones [carpals, tarsals] and closely resemble the so-called
axial skeleton distant from the initial focus strongly ‘spindle-like’ swelling, typically seen in psoriatic arthritis
indicative of reactivation of a metastatic focus (12). and other spondylarthropathies or arthritis of the wrist
Immunosuppressed state due to diabetes mellitus, or midfoot region. In early stages, TB dactylitis spares
malnutrition, other debilitating illnesses [chronic renal the adjacent joint leaving the articular margins intact.
failure, pneumoconiosis, liver cirrhosis, disseminated This can be easily appreciated in a plain X-ray, which is
cancer], haemodialysis (13,14), immunosuppressive and often helpful in diagnosis [Figures 24.1 and 24.2].
Musculoskeletal Manifestations of Tuberculosis 375
culosis of the spine is an important differential diagnosis

in certain types of back pain. Depending upon the presence
or absence of symptoms considered red flags for possible
serious spinous pathology, rheumatologists classify back
pain as ‘specific’ and ‘non-specific’ (29,30). The red flag
symptoms for back pain include constitutional symp-
toms, non-mechanical nature of pain that is characteri-
stically acute, severe and persistent without precipitants,
pains at night, pain worse in the morning, hyperexten-
sion of spine and walking. Involvement of thoracic spine
presenting as pain on coughing or sneezing is also
considered red flag symptom for spinous pathology.
This is also seen in ankylosing spondylitis where thoracic
cage involvement is very common. Presence of
Figure 24.1: Multifocal tuberculosis dactylitis widespread neurologic features, localized tenderness in
Reproduced with permission from “Malaviya AN, Kotwal PP. Arthritis the spine without structural deformity, onset under
associated with tuberculosis. Best Practice Res Clin Rheumatol 30 or above 50 years of age, often in an immunocompro-
2003;17:319-43 (reference 6)” Copyright [2003] Elsevier
mised host [glucocorticoids, HIV, cytotoxic drugs,
debilitating underlying illness, etc.], favour the diagno-
sis of serious spinous pathology. It is also to be noted
that ‘specific’ back pain under the red flag category
includes inflammatory back pain seen in spondyl-
arthropathies and ankylosing spondylitis as well as
‘sinister’ back pain caused by infection [e.g., TB] or
neoplasm. The former has typical features of inflam-
matory rheumatic disease including duration of spinal
discomfort for at least three months, spinal morning
stiffness, age less than 40 years, insidious onset of
symptoms, and no relief from pain with rest, but
improvement with exercise (31). These features are
generally not seen in ‘sinister’ back pains caused by
neoplasms and infection [TB spine]. However, even in
TB spine occasionally the symptoms may resemble those
of inflammatory back pain (31). In endemic areas, back
Figure 24.2: X-ray of right hand of an 11-year-old girl with tuberculo- pain due to TB spine is most often seen in children and
sis dactylitis of the proximal phalanx in the right middle finger. Note young adults. However, in developed countries it is more
the prominent periosteal reaction and soft tissue swelling adjacent often seen in older age with a mean of approximately 50
to the proximal interphalangeal joint. Spindle-shaped swelling near years (3). Therefore, as a rule, in any specific back pain
the proximal interphalangeal joint may clinically resemble arthritis
of that joint causing diagnostic confusion. The joint margin is
TB spine should be one of the diagnostic considerations,
preserved indicating that in early stages tuberculosis dactylitis especially if other risk factors are present.
spares the adjacent joint, the articular margins remain intact Tuberculosis infection of soft tissue may present as
Reproduced with permission from “Malaviya AN, Kotwal PP. Arthritis bursitis, tenosynovitis, myositis, or fasciitis [Figure 24.3].
associated with tuberculosis. Best Practice and Res Clin Rheumatol However, these are uncommon presentations of MSK-
TB. Their clinical resemblance with local and focal soft
Radioisotope bone scan may reveal ‘hot spots’ in the tissue inflammatory disorders may cause delay in
metaphysis, diaphysis of a short bone in hand or foot diagnosis (32). However, in patients with pre-existing
that favours the diagnosis of TB osteomyelitis. Tuber- systemic rheumatic diseases, and other risk factors
376 Tuberculosis
current history of extra-pulmonary TB (35). However,

Poncet’s concept of ‘tuberculosis rheumatism’ was rather
broad and non-specific that tended to include all forms
of polyarthritis associated with active or inactive TB,
associated with a family history of TB or, evidence of
foci of TB in any joint before, coincident with, or following
a polyarthritis (36). The lack of diagnostic precision and
specificity in this broad description led to unrelated
diseases getting labelled as ‘Poncet’s disease’ and the
concept became controversial. For the present, “tuber-
culosis rheumatism” [Poncet’s disease] is defined as a
polyarthritis associated with extra-pulmonary TB in
which there is no evidence of bacteriologic involvement
Figure 24.3: Tuberculosis tenosynovitis of the extensor tendon of
of the joints themselves (37-42).
the hand with skin ulceration [A] and healed lesion after anti-
tuberculosis drug treatment [B].
Reproduced with permission from “Malaviya AN, Kotwal PK. Arthritis Pathogenesis
associated with tuberculosis. Best Practice Res Clin Rheumatol
Pathogenesis of Poncet’s disease is uncertain. Most
workers believe it to be a ‘reactive arthritis’ due to hyper-
discussed above, appearance of these soft tissue mani- sensitive immune response against tuberculoprotein (37-
festations should raise the suspicion of soft tissue TB. 42). It is known that mycobacteria are arthritogenic.
Injection of heat killed and desiccated Mycobacterium
CHANGING CLINICAL PATTERN OF tuberculosis in oil [complete Freund’s adjuvant] in animals
TUBERCULOSIS ARTHRITIS can produce a chronic synovitis resembling rheumatoid
arthritis (43). Interestingly, bacillus Calmette-Guérin
As discussed elsewhere in the book, all forms of extra-
[BCG] immunotherapy given in cancer patients has been
pulmonary TB are seen in endemic countries. Generally,
shown to produce arthritis as an adverse effect, possibly
TB arthritis is more common among children, juveniles
caused by a similar adjuvant effect (44). Molecular
or young adults typically presenting as chronic
mimicry between mycobacterial antigens and host tissues
monoarthritis of the weight-bearing joints (3,33).
resulting in immunologic cross-reactivity has been
However, in non-endemic countries it is generally a
implicated in its causation. Thus, antigenic similarity
disease of older age with involvement of non-weight
between a fraction of Mycobacterium tuberculosis and
bearing joints presenting as oligoarthritis indicative of
human cartilage has been demonstrated (45) as has been
an immunocompromised host status (3,33,34). In recent
the mycobacterial heat shock protein [HSP65] that cross-
years, this trend is changing even in developing countries
reacts with human HSP (46). A T-cell mediated cross-
where presentation with oligoarthritis of non-weight-
reactive autoimmune response might also be operative
bearing joints in older patients is common (3,32). It has
in the pathogenesis of Poncet’s disease. Increasing reports
already been mentioned above that an immuno-
of Poncet’s disease in HIV infected persons have brought
compromised state due to an increasing incidence of
out the complexities of the relationship between host and
diabetes mellitus, wider use of immunosuppressive
pathogen leading to paradoxical activation of some
drugs including glucocorticoids, malnutrition, HIV,
immune responses causing immune-mediated tissue
substance abuse, alcoholism and a host of other factors,
lesions (47). Since Poncet’s disease apparently occurs only
is the likely cause for this change in pattern of the disease.
in a small proportion of patients with active TB, a genetic
predisposition might be involved. In one of the Poncet’s
REACTIVE [PARA-INFECTIOUS] ARTHRITIS
disease patients investigated by the authors’ group, the
[PONCET’S DISEASE]
human leucocyte antigen [HLA] haplotype was DR2,
In 1887, Poncet described inflammatory arthritis in the DR4. It is interesting to note that genes coding for this
joints of the hands and feet in 12 patients with a past or allele are associated with RA and may also influence the
immune response to mycobacterial antigens. The DR4+ ARTHRITIS ASSOCIATED WITH ADJUVANT
patients are hyperresponsive to mycobacterial antigens MYCOBACTERIAL TREATMENT OF URINARY
(48). Poncet’s disease might result from a genetically BLADDER CANCER
determined HLA-linked hyper-responsiveness to
Use of BCG as an adjuvant in the therapy of bladder
mycobacterial antigens disseminating into the joint
cancer for stimulating T-cell-mediated immunity is now
spaces (49). This issue needs further studies.
a standard practice. Interestingly, 0.4 to 0.8 per cent of
A number of case reports and small series have been
these patients develop inflammatory polyarthritis
published describing patients with this disease (37-
following intravesical administration of BCG (55). In
42,50,51). Poncet’s disease has been mainly a disease of
approximately one-fifth of the patients, the disease
juveniles or young adults with a slight female prepon-
simulated spondyloarthritis with lower limb asym-
derance. These patients present with fever and consti-
metrical inflammatory arthritis with sacroiliitis that was
tutional symptoms associated with acute or subacute
associated with HLA-B27 (55). In another study (44),
symmetrical peripheral inflammatory polyarthritis
synovial biopsy showed development of an inflamma-
predominantly involving the large joints [the knee being
tory synovitis predominantly comprising of T-
the most common, followed by ankle and wrist]
lymphocytes that resolved spontaneously within 14 days.
(37-42,50,51). Small joints may be affected in a
Thus, arthritis associated with adjuvant BCG treatment
symmetrical fashion resembling RA, but asymmetrical
of bladder cancer appears to be the human counterpart
involvement is also frequently seen. Joint effusions are
of ‘adjuvant arthritis’ routinely produced in experimental
not uncommon. Some of the patients have oligoarticular
animals by injecting complete Freund’s adjuvant
presentation (37-42,50,51). Several other workers have
containing heat-killed Mycobacterium tuberculosis. The T-
also described it as a pauciarticular symmetrical arthritis
cell cross-reactivity between mycobacteria and human
predominantly involving the large joints in the
proteins could be the most likely common aetiological
extremities (37-42,50,51). Lymph nodes are the most
factor between all these three forms of reactive arthritis
common extra-pulmonary site of TB (37-42,50-52). The
with HSP65 as the main candidate cross-reactive antigen.
cervical, supraclavicular, axillary mediastinal and
Besides 50 per cent homology with human HSP the
retroperitoneal lymph nodes are often enlarged with
mycobacterial HSP also has homologies with
demonstrable caseous granulomas. Hilar and paratra-
proteoglycan and HLA-DR (55).
cheal lymphadenopathy with or without pulmonary
infiltrates may be encountered (37-42,50-52). Patients of
PANNICULITIS ASSOCIATED WITH TUBERCULOSIS
Poncet’s disease presenting with fever, polyarthritis and
TB lymphadenitis may also develop pleural or The term “panniculitis” has been given to non-suppu-
pulmonary TB during the course of their illness (51). rative inflammation in the subcutaneous fat [i.e., panni-
The existence of this entity, however, has been culus] (56,57). Some forms of panniculitides have been
questioned (53) and the concept still remains contro- considered to have TB aetiology. It is not uncommon for
versial because the search for active TB foci in these joints patients with panniculitis to present with arthralgias or
has not always been rigorous (49). Some patients frank arthritis, often associated with a characteristic
clinically suspected of Poncet’s disease, on careful periankle inflammatory oedematous lesion with
diagnostic work-up were proven to have polyarticular overlying skin showing ecchymotic purplish discoloura-
TB arthritis (54). tion and scaling. Other large and small peripheral joints
Poncet’s disease is mainly a “diagnosis of exclusion” may also be affected transiently. Rheumatologists often
in a patient with polyarthritis associated with docu- see such patients due to the presence of arthritis. The
mented active TB. Investigations usually demonstrate most common form of panniculitis in clinical practice is
non-specific findings with negative autoimmune erythema nodosum [EN] which is a form of septal
serology. The synovial fluid shows inflammatory panniculitis without vasculitis (56-58). It has a strong
characteristics with no microbiological evidence of TB. gender bias, seen much more often in young women.
The arthritis in Poncet’s disease is said to resolve Clinically, it is characterized by acute or subacute
completely with antituberculosis therapy. appearance of a few tender erythematous nodules on the
378 Tuberculosis
anterior tibial surface that are better palpated than be seen with EI including Bazin’s disease (63-65). There-
visualized. The overlying skin shows indurated fore, with rising incidence of extra-pulmonary TB, vague
inflammation. Healing starts within a few days with arthralgias, arthritis and especially ankle-periankle
softening of the nodules that become less palpable. The arthritis associated with induration and inflammatory
skin colour changes to an unusual ecchymotic purplish oedema with lesions of panniculitis need to be carefully
discolouration associated with scaling of the skin. worked up with TB as a distinct possibility.
Usually, the healing is complete in four to six weeks
without suppuration or scarring. In addition to the MSK UNUSUAL PRESENTATIONS OF
symptoms and the nodules on the lower leg, fever, MUSCULOSKELETAL TUBERCULOSIS
malaise, leucocytosis, are other common features. The
Literature is replete with a variety of unusual presen-
EN is considered to be a form of hypersensitivity reaction
tations of MSK-TB. Thus, a non-healing ulcerative mass
mainly after primary contact with the implicated
of the elbow in a 69-year-old woman resembling synovial
aetiological factors. These include streptococcal and
sarcoma, which on histopathology showed TB synovitis
upper respiratory infections, acute onset of sarcoidosis,
(66). A 51-year-old woman’s left hip pain was because
and inflammatory bowel disease. Other less common
of left trochanteric bursitis due to TB (67); a sterno-
aetiological factors include TB, histoplasmosis,
clavicular mass in a haemodialysis patient was proven
coccidioidomycosis, psittacosis and other rare infections;
to be TB arthritis on culture (14); another patient had
oral contraceptives, several other drugs [sulphonamides,
bilateral sternoclavicular joint TB (68). Four cases have
aspartame, bromides, iodides], and pregnancy (58).
been reported in the world literature with TB arthritis
Another form of panniculitis that has close clinical and
causing Baker’s cyst (69). Injury-related TB [injury
morphologic resemblance to EN is called erythema
tuberculosis] among immigrants from ‘high burden’
induratum [EI]. It is a form of lobular panniculitis
areas (19), TB arthritis of the right great toe (70); TB of
associated with vasculitis of medium- or small-sized
the lower end of the fibula in a young patient presenting
blood vessels in the panniculus. It has often been labelled
with symptoms of pain and swelling over the outer aspect
as ‘nodular vasculitis’ (59). The patients usually have no
of the right ankle (71), foot pain in a patient with spinal
constitutional symptoms and appear otherwise healthy.
TB due to TB arthritis of midtarsal joints (72), sternal TB
In contrast to EN, EI occurs without any gender bias.
that developed following sternotomy performed for
Despite its close clinical resemblance to EN, unlike EN
coronary artery bypass graft surgery (20), have all been
the commonest site of the nodules is on the calves rather
reported. The TB dactylitis may resemble sickle cell
than the shin. Also, unlike EN, EI lesions may breakdown
anaemia and lytic lesions of neuroblastoma, Langerhans’
and ulcerate or heal with scar. A proportion of patients
cell histiocytosis and leukaemia (73). The TB oesophageal
with lesions clinically and histopathologically indis-
ulcer has been described as an unusual presentation of
tinguishable from EI shows an adjacent suppurative or
Pott’s disease (74). Rare cases of multifocal skeletal TB
granulomatous panniculitis. This presentation, called
have also been described. The disease may also resemble
Bazin’s disease, is considered rather specific for TB (56,60).
RA (75). Unusual manifestations of osteoarticular TB
Recent studies have shown that a significant number of
have also been reported (76).
these patients have a form of cutaneous TB; typically
seen in young patients; the lesions being labelled as
MUSCULOSKELETAL DISEASE ASSOCIATED
‘tuberculid’ (47,60). Histopathology usually confirms the
WITH NONTUBERCULOUS MYCOBACTERIA
diagnosis of TB but in others it may require confirmation
with other investigations, such as polymerase chain Musculoskeletal TB caused by nontuberculous myco-
reaction [PCR] (61). Response to antituberculosis bacteria [NTM] is uncommon but not rare. Most common
treatment is usually satisfactory. Therefore, distinction mycobacterial species to cause such problems is
between EN and EI is crucial for appropriate treatment Mycobacterium kansasii (77-79), although other NTM, such
(60,62). It is important to note that the inflammatory as Mycobacterium xenopi (80,81), Mycobacterium marinum
arthritis/periarthritis of ankle often associated with (82,83), Mycobacterium avium intracellulare, Mycobacterium
peripheral polyarthritis characteristic of EN, may also chelonei (84), and Mycobacterium fortuitum (85) have also
been implicated. For some reasons, synovial sheath spinal TB [Figure 24.3]. On the other hand, for detailed
infection is much more common than infection of the anatomical evaluation and for distinguishing different
osseous tissue (86). Predisposing factors are discernible densities of tissues [fibrous tissue, abscess, meninges,
in most cases and may include history of trauma spinal cord, etc.,] magnetic resonance imaging [MRI]
[including puncture wound], surgery, glucocorticoid with contrast is considered superior (97). The
therapy, plaque psoriasis, a pre-existing MSK disease, characteristic ‘Phemister’s triad’ is considered rather
immunocompromised conditions, such as diabetes melli- typical of TB. Three components of the triad are: [i] juxta-
tus, haemodialysis, renal transplantation, Hodgkin’s articular osteoporosis; [ii] peripherally located osseous
disease, and HIV infection (76,86,87). Occasionally, erosions; and [iii] gradual narrowing of the joint space
arthritis due to NTM has also been reported in non- (98-100). On the other hand, in the course of RA and
immunocompromised host (88). Arthritis and bursitis pyogenic arthritis, the joint space narrowing occurs early.
due to Mycobacterium kansasii has been described in a For soft tissue TB, the ultrasonography is the method of
patient with systemic lupus erythematosus [SLE] (78,89). choice as it shows the extent and degree of involvement.
An unusual form of arthritis due to NTM on exposure to On the other hand, the MRI shows the extent of soft
contaminated marine life has been described (90,91). tissue, osseous and joint involvement (98). One of the
Recently, a case of tenosynovitis due to Mycobacterium other typical features of TB aetiology of the bones that
marinum in association with Still’s disease was described have a relatively superficial cortical surface [e.g.,
(82). metacarpals, metatarsals, phalanges, tibia and ulna] is
the presence of lytic lesions surrounded by reactive
ANTITUBERCULOSIS TREATMENT INDUCED subperiosteal new bone formation (86). It needs to be
ARTHRALGIAS emphasized that despite these advances, the ‘gold
standard’ for the diagnosis of TB of the MSK system still
Patients initiated on antituberculosis therapy may often
remains histopathological and/or microbiological
complain of polyarthralgias in the initial stages with
confirmation; definitive treatment cannot be instituted
occasional actual polyarthritis (92-96). It is usually a
before confirming the diagnosis (98).
transient self-limiting condition that does not require
treatment or, at the most may require symptomatic
DIAGNOSIS
control of pains. Most commonly incriminated drug is
pyrazinamide. The exact mechanism of these symptoms A high index of suspicion is required for making the
is not known. Hyperuricaemia is common in patients diagnosis of MSK-TB. The clinical presentation and the
taking pyrazinamide but gouty arthritis is rare. Use of characteristic pattern of joint involvement should arouse
allopurinol should be individualized depending upon the suspicion of MSK-TB. Imaging of the lesion and
the severity of arthralgias along with elevation of serum confirmation of the diagnosis by histopathological and
uric acid to twice the upper limit of the normal. Interes- microbiological techniques then follow. Adequate tissue
tingly, ethambutol also causes mild hyperuricaemia but biopsy of the representative lesion is the quickest method
does not cause joint pains. These adverse events are much of confirming the diagnosis of TB. Synovial biopsy is
more common with daily as compared with intermittent usually satisfactory with more than 90 per cent yield (35).
administration of antituberculosis drugs. Synovial fluid smear for acid-fast bacilli [AFB] is positive
in 20 to 40 per cent of cases, while culture could yield a
IMAGING OF MUSCULOSKELETAL TUBERCULOSIS positive result in up to 80 per cent cases (3).
Imaging in patients with skeletal TB is covered in detail
Indications for Synovial Biopsy
in the chapter “Skeletal tuberculosis” [Chapter 23]. Certain
key issues related to imaging in MSK-TB are described The issues concerning procurement of adequate tissue
here to supplement the content covered in the chapter for histopathological diagnosis of skeletal TB are
“Skeletal tuberculosis” [Chapter 23]. Among the various discussed in the chapter “Skeletal tuberculosis” [Chapter
available imaging techniques, computed tomography 23]. The indications for a synovial biopsy in patients with
[CT] is superior in depicting the degree of bony MSK-TB from a rheumatologist’s perspective is discussed
destruction and facilitating image-guided biopsy for below.
380 Tuberculosis
When clinical evaluation and routine investigations 12. Houshian S, Poulsen S, Riegels-Nielsen P. Bone and joint
fail to provide a diagnosis, synovial biopsy is the logical tuberculosis in Denmark: increase due to immigration. Acta
Orthop Scand 2000;71:312-5.
next step. It is usually the only definitive method of 13. Courtman NH,Weighill FJ. Systemic tuberculosis in
diagnosing infection with fastidious organisms including association with intra-articular steroid therapy. J R Coll Surg
TB. An absolute indication for synovial biopsy is a chronic Edinb 1992;37:425.
inflammatory monoarthritis where synovial fluid 14. Fukasawa H, Suzuki H, Kato A, Yamamoto T, Fujigaki Y,
examination including microbiological studies may have Yonemura K. Tuberculous arthritis mimicking neoplasm in
a hemodialysis patient. Am J Med Sci 2001;322:373-5.
failed to give a definitive diagnosis. Another strong 15. Binymin K, Cooper RG. Late reactivation of spinal tuber-
indication for synovial biopsy would be a patient with culosis by low-dose methotrexate therapy in a patient with
persistent disease activity in a single joint. rheumatoid arthritis. Rheumatology [Oxford] 2001;40:341-2.
16. Belzunegui J, Rodriguez-Arrondo F, Gonzalez C, Queiro R,
Martinez de Bujo M, Intxausti JJ, et al. Musculoskeletal
TREATMENT
infections in intravenous drug addicts: report of 34 cases with
Treatment consists of administration of standard analysis of microbiological aspects and pathogenic
mechanisms. Clin Exp Rheumatol 2000;18:383-6.
antituberculosis drugs. Many workers suggest nine
17. Jellis JE. Human immunodeficiency virus and joint and bone
months of treatment for extra pulmonary TB including tuberculosis. Clin Orthop 2002;398:27-31.
MSK-TB (101). The reader is referred to the chapter 18. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J,
“Treatment of tuberculosis” [Chapter 52] for more details. Schwieterman WD, et al. Tuberculosis associated with
infliximab, a tumor necrosis factor alpha-neutralizing agent.
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384 Tuberculosis
Cutaneous Tuberculosis
25
M Ramam
INTRODUCTION carried out in India. Information on the epidemiology of

the disease is, therefore, based on hospital records and
Cutaneous tuberculosis [TB] is an ancient disease. Cuta-
suffers from the usual drawbacks of such data.
neous lesions of TB were described long before Robert Cutaneous TB accounts for 0.11 to 2.5 per cent of all
Koch identified Mycobacterium tuberculosis. The first patients with skin diseases seen at hospitals located in
description of cutaneous TB is attributed to Laennec (1) different parts and this figure seems to be constant for
in 1826 who described his own prosector’s wart that all regions of the country (24-36). In a study from
followed an injury sustained while performing an Vishakapatnam (24), cutaneous TB constituted 0.025 per
autopsy on a patient with spinal TB. Mycobacterium cent of all patients with TB and 15 per cent of all patients
tuberculosis was first demonstrated in tissue sections of with extra-pulmonary TB. One study (34) found that
lupus vulgaris by Demme (2) in 1883. In 1886, Reihl and cutaneous TB was associated with TB in other organs in
Paltauf (3) established that the prosector’s wart was a 22.1 per cent of patients. The organs affected most
TB lesion. Apple-jelly nodules in lupus vulgaris were first commonly were lungs, followed by bones, abdomen,
described in 1888 (4) and tuberculids in 1896 (5). central nervous system and the heart. Most studies reveal
a male preponderance and a significant proportion of
EPIDEMIOLOGY those affected are children (24-36). The disease is more
common in the poor. In a study from Chandigarh (34),
World Scenario about 70 per cent of the patients had developed the
Cutaneous TB appears to have been frequently disease in spite of having been vaccinated with bacille
encountered by dermatologists all around the world Calmette-Guérin [BCG]. Patients who had not been
during the early part of this century and comprised 0.1 vaccinated were more likely to have TB in another organ
to 2.6 per cent of the total number of dermatology patients than those who had received BCG vaccine (34).
in various hospitals at different periods of time (6-22).
CLINICAL FEATURES
Some workers had suggested that cutaneous TB was
uncommon in the tropics and ascribed this difference to Cutaneous TB presents in a variety of ways. The
the abundant sunshine and consequent high levels of presentation is determined by the host immune response,
vitamin D in the skin (9,23). However, this view appears the route of inoculation and the previous sensitization
erroneous as evidenced by the numerous reports of of the host to the Mycobacterium tuberculosis. The clinical
cutaneous TB from India (24-36). varieties of cutaneous TB can be divided into three broad
groups [Table 25.1].
Indian Scene Lupus vulgaris is the most common variety reported
No systematic survey for the prevalence and incidence from India followed by TB verrucosa cutis and
of cutaneous TB in the community appears to have been scrofuloderma. The other types are distinctly rare.
Cutaneous Tuberculosis 385
Table 25.1: Clinical varieties of cutaneous tuberculosis indolent, asymptomatic, gradually progressive, firm
plaque with central clearing and peripheral activity
Lesions developing in those not previously exposed to
Mycobacterium tuberculosis [Figure 25.2]. In some cases, the progressing border of
Tuberculosis chancre the plaque reveals translucent, erythematous papules
Acute miliary tuberculosis of the skin that show a residual yellowish brown colour when
Lesions developing in previously sensitized hosts blanched with a glass slide, the so-called apple-jelly
Lupus vulgaris
nodules. Though this term is associated with lupus
Tuberculosis verrucosa cutis
Scrofuloderma
vulgaris, it may be seen in other granulomatous diseases
Tuberculids including sarcoidosis and leprosy. Further, apple-jelly
Lichen scrofulosorum nodules are often obscured by the hyperkeratosis and
Papulonecrotic tuberculids crusting of lupus vulgaris. Thus, this is not a particularly
Erythema induratum useful sign. As the lesion progresses, there is central
Erythema nodosum
healing with scarring while the periphery continues to
Tuberculosis Chancre spread [Figure 25.3]. The lesion may be atrophic or may
Tuberculosis chancre develops at the site of inoculation

of Mycobacterium tuberculosis in a previously non-
sensitized host. The bacillus enters the skin following
minor wounds and abrasions. It may also gain entry
following trauma, injections, circumcision and ear
piercing. A non-descript papule or nodule develops at
the site followed by crusting and ulceration. Spontaneous
healing may occur but lesions usually proceed to lupus
vulgaris. The regional lymph nodes are enlarged and
may break down to form a discharging sinus in three to
six months. Acid-fast bacilli [AFB] can be demonstrated
and grown from early lesions. Skin biopsy reveals
necrosis, infiltration by neutrophils and numerous AFB
in early lesions. Later, epithelioid cell granulomas
develop accompanied by the disappearance of the bacilli Figure 25.1: Miliary tuberculosis of the skin. Chest radiograph
from the lesion. demonstrated bilateral miliary lesions. Polymerase chain reaction
[PCR] from skin lesions detected mycobacterial DNA
Acute Miliary Tuberculosis of the Skin
Miliary TB develops following the haematogenous
dissemination of Mycobacterium tuberculosis (37). It may
follow measles or other viral exanthems (38). The skin
lesions of miliary TB present as pustules, vesicles and
papules that have a non-specific appearance and lack
any diagnostic features [Figure 25.1]. Constitutional
symptoms are usually severe and the patient is usually
gravely ill. The diagnosis may be suspected if the patient
is known to have TB in another organ system. Mycobacte-
rium tuberculosis can be demonstrated in the lesions.
Lupus Vulgaris
Lupus vulgaris is probably the most common manifes- Figure 25.2: Lupus vulgaris. Central scarring and peripheral
tation of cutaneous TB. Classically, it presents as an activity in a long-standing lesion
386 Tuberculosis
underlying focus. It has also been reported as a rare

complication of BCG vaccination (40,41) [Figure 25.5].
The regional lymph nodes may be slightly enlarged but
do not show any evidence of TB. In some patients, the
presence of broad, atrophic scarring indicating the
possibility of a previous TB infection of the regional
lymph nodes may be noted [Figure 25.6]. Less commonly,
the regional lymph nodes draining a lesion of lupus
vulgaris may show active scrofuloderma. Most patients
with lupus vulgaris are well preserved and do not have
constitutional symptoms even when lesions are extensive
and multiple. The tuberculin skin test [TST] is positive
in almost all patients. Skin biopsy reveals epithelioid cell
granulomas in the upper dermis abutting the epidermis
Figure 25.3: Lupus vulgaris. Annular plaque with erythematous
and scaly papules at the periphery and a relatively clear centre
Figure 25.5: Lupus vulgaris following vaccination with BCG

Figure 25.4: Lupus vulgaris. The buttocks are a common site
show varying degrees of hyperkeratosis that may be

severe enough to produce cutaneous horns. The lesion
is usually dry but may occasionally be accompanied by
a thin sero-purulent discharge and moist crusts due to
secondary infection. Lesions may reach enormous sizes
over the years and cause considerable damage and
mutilation. Squamous cell carcinoma has been described
to complicate long-standing lesions (39). The classical site
of lesion is the face but it is seen at least as commonly on
the buttocks [Figure 25.4] and lower limbs in Indian
patients. The lesion is usually single but less commonly,
multiple lesions may develop in one anatomic area or
may be scattered over the skin surface. Rarely,
symmetrical lesions may develop. Lupus vulgaris may Figure 25.6: Lupus vulgaris of the ear lobe. Note scars of
develop at the site of cutaneous extension of TB from an healed scrofuloderma on the neck
carefully from the least keratotic area and incised deep

enough to include the underlying indurated plaque, else,
only thickened stratum corneum will be seen. An
adequate biopsy reveals an enormously thickened
epidermis with small epithelioid granulomas amidst an
infiltrate of lymphocytes and plasma cells in the upper
and mid dermis. Necrosis is absent and AFB cannot
usually be demonstrated or grown from biopsy material.
Scrofuloderma
Scrofuloderma is the term applied to lesions that develop
in the skin from contiguous spread or extension of TB
infection from an underlying or adjacent structure. Most
Figure 25.7: Indurated plaque with a horny, keratotic surface often, the primary focus is in the lymph nodes
[Figure 25.10] but bones [Figure 25.11] and joints may
Figure 25.8: Tuberculosis verrucosa cutis. The sole is often affected

Figure 25.9: Tuberculosis verrucosa cutis. Very advanced disease
which is usually thickened and hyperkeratotic. The with the entire foot appearing to be encased in a keratotic boot
granulomas may show necrosis; AFB cannot, as a rule,
be demonstrated in the sections. Culture of the biopsy
material is not rewarding.
Tuberculosis Verrucosa Cutis

Tuberculosis verrucosa cutis, probably a variant of lupus
vulgaris is characterized by a striking degree of
hyperkeratosis in the lesions. The lesion usually develops
over the acral parts of the extremities as a gradually
progressive indurated plaque with a rough, horny
surface [Figures 25.7 and 25.8]. With time, the lesions
become progressively larger and hyperkeratotic and may
involve the entire foot [Figure 25.9]. Multiple lesions are
unusual and lymph nodes show changes similar to those
seen in lupus vulgaris. Constitutional signs are usually Figure 25.10: Scrofuloderma overlying tuberculosis
absent. The TST is positive. Skin biopsies must be taken of the cervical and axillary lymph nodes
388 Tuberculosis
Figure 25.11: Scrofuloderma secondary to tuberculosis of the bone. Figure 25.12: Esthiomene secondary to healed scrofuloderma of
Note the thickened metacarpals underlying the sinus on the dorsum the inguinal and external iliac lymph nodes. Note the scars in the
of the hand area of both inguinal ligaments
also be the source of infection. The cutaneous lesion is a Tuberculosis Gumma

sinus with 3 to 5 mm orifice discharging a thin,
Tuberculosis gumma refers to soft, subcutaneous
seropurulent material. The edge of the sinus usually
swellings which often break through the overlying skin
shows a purple discolouration, is thinned and may be
to produce ulcers [Figure 25.14]. The lesions resemble
eroded. The sinus is usually attached to the underlying
scrofuloderma on clinical, histopathological and
structure. Crusts are present and may be large. Some
microbiological grounds and can be considered as a
patients show episodic activity in lesions with the amount
variant produced by haematogenous seeding of sub-
of discharge showing periodic variations and even
cutaneous tissue with Mycobacterium tuberculosis.
drying up completely to recur after varying periods of
time extending up to several months. In long standing Tuberculosis Cutis Orificialis
lesions, there are usually broad atrophic scars that
represent spontaneously healed sinuses. Scarring and Tuberculosis cutis orificialis develops by the inoculation
fibrosis of lymph nodes may lead to lymphoedema and of Mycobacterium tuberculosis derived from visceral
elephantiasis [Figure 25.12]. In contrast to filariasis, the
skin of the lymphoedematous area often shows lesions
of cutaneous TB, usually lupus vulgaris [Figure 25.13].
The TST is positive. The AFB can be demonstrated in the
discharge from the lesions and Mycobacterium tuberculosis,
and rarely nontuberculous mycobacteria [NTM] such as
Mycobacterium avium complex, Mycobacterium scrofulaceum
can also be cultured. Fine needle aspiration cytology
[FNAC] of the underlying structure, usually lymph node,
confirms the diagnosis of TB. Biopsy from the edge of
the sinus reveals a mixed cell granuloma consisting of
epithelioid cells and histiocytes admixed with
neutrophils and eosinophils. There are areas of necrosis
and AFB may be identified in the biopsy. Culture of
biopsy material grows Mycobacterium tuberculosis or NTM Figure 25.13: Lymphoedema of the right lower
in some patients. limb with gummas on the skin
fulfilled to designate a condition as tuberculid: [i] the

skin lesion must show a tuberculoid histopathology;
[ii] Mycobacterium tuberculosis must not be demonstrable
in the lesion; [iii] the tuberculin test must be strongly
positive; and [iv] treatment of the underlying TB focus
must lead to resolution of the skin lesions. In some cases,
it is easy to document the focus while in others this may
not be possible. In clinical practice, physical examination
and simple imaging procedures are undertaken to look
for TB elsewhere. If these tests fail to reveal a focus and
clinical suspicion of a tuberculid is high, presumptive
treatment for TB can be attempted.
Since Mycobacterium tuberculosis cannot be demon-
Figure 25.14: Tuberculosis gummas which have strated in tuberculids, there has been considerable
broken down to form ulcers controversy over the existence of this entity. Historically,
the label was applied to all skin conditions that showed
infection into the skin around the draining orifices. a tuberculoid granuloma on histopathology that were
Usually, lesions develop around the perianal area [Figure
not neccessarily due to TB. It was hypothesized that such
25.15] or around the mouth in patients with abdominal
skin lesions represented a hypersensitivity response to a
or pulmonary TB. The lesion is a nodule that breaks down manifest or occult TB focus elsewhere in the body. This
to form an indolent, deep ulcer. The diagnosis is usually
led to the grouping together of a heterogenous group of
suspected when the ulcer does not heal in spite of
conditions that were subsequently shown to share no
antibiotic therapy. Biopsy from the edge of the ulcer aetiologic or pathogenetic similarity. Presently, three
reveals epithelioid granulomas. Acid-fast bacilli may
conditions are unequivocally accepted as tuberculids,
occasionally be demonstrated or grown from the lesion.
namely, lichen scrofulosorum, papulonecrotic tuber-
culids and erythema induratum. In addition, TB is an
Tuberculids
important cause of erythema nodosum in Indian patients.
Tuberculids are skin lesions that develop as a hyper- Recent studies employing the polymerase chain reaction
sensitivity response to the presence of a TB focus [PCR] have demonstrated the presence of mycobacterial
elsewhere in the body. The following criteria must be DNA in biopsies from patients with erythema induratum
(42,43) and papulonecrotic tuberculids (42,44) providing
further evidence of the association between these
conditions and TB.
Lichen Scrofulosorum
Lichen scrofulosorum typically presents as a crop of 2 to
5 mm erythematous papules that show a tendency to
grouping [Figure 25.16]. Many papules show crusting.
The eruption has a predeliction for the trunk but may
occur at other sites also. Individual papules tend to
resolve in about two weeks with hyperpigmentation but
crops of lesions may come and go over several months.
Uncommonly, the eruption may develop after initiation
of antituberculosis treatment; these lesions subsided on
continuing treatment (45). The TST is strongly positive
Figure 25.15: Orificial tuberculosis. Indolent, non-healing ulcer and may show ulceration. Biopsy reveals focal epithelioid
of the anus. The patient had abdominal tuberculosis cell granulomas within and around the hair follicle or
390 Tuberculosis
the epidermis and upper dermis with underlying epi-

thelioid granulomas. A focus of active TB can usually be
demonstrated in these patients.
Erythema Induratum
Erythema induratum presents as indolent, mildly tender,
dull red nodules ranging in size from 5 to 7.5 cm that
usually develop on the calves. The nodules soften and
break down to form deep persistent ulcers that gradually
heal over several weeks with scarring [Figure 25.18]. New
nodules may continue to develop while the old lesions
are resolving. The TST is positive. Skin biopsy reveals a
granulomatous panniculitis with vasculitis of the dermal
Figure 25.16: Lichen scrofulosorum. Grouped, minute vessels. A focus of TB is demonstrable in many patients.
erythematous papules However, a significant proportion of patients who show
the typical clinical and histopathological features of
the duct of the sweat gland. The underlying TB focus erythema induratum do not have TB. In these patients,
may be in the lymph nodes, lungs or at some other site. the reaction pattern has presumably been triggered by
some other cause.
Papulonecrotic Tuberculids
Erythema Nodosum
Papulonecrotic tuberculids present as an eruption of
multiple, papulonodular lesions ranging in size from 2 Erythema nodosum presents as erythematous, tender,
to 5 cm occurring over the trunk and extremities. The 2.5 to 5 cm nodules that usually develop on the shins
eruption may be preceded by fever and constitutional [Figure 25.19] but may also involve the thighs, buttocks
symptoms. Individual lesions show pustulation and and forearms in severe cases. Low grade fever and
crusting at the centre [Figure 25.17]. Removal of the crust swelling of the ankle joints accompany the skin lesions
reveals a deep ulcer. The lesions heal gradually over four in some patients. The lesions regress spontaneously
to six weeks with scarring. Crops of lesions recur at becoming dull red, violaceous, finally leaving behind
variable intervals. The TST is strongly positive and often macular hyperpigmentation. Ulceration and scarring are
ulcerates. Skin biopsy reveals wedge-shaped necrosis of not features of erythema nodosum. Recurrent crops of
Figure 25.17: Papulonecrotic tuberculid. Indurated Figure 25.18: Erythema induratum. Persistent ulcers with
papulo-nodules with a central necrotic crust underlying induration on the posterior aspect of the leg
Figure 25.20: Nodules papules and pustules on the buttock of a

Figure 25.19: Erythema nodosum. Tender, erythematous, patient with Cushing’s syndrome. Numerous acid-fast bacilli were
non-ulcerated nodules on the shins seen on biopsy
lesions may develop. Skin biopsy reveals a septal panni- to culture (47). Biopsy reveals a neutrophilic infiltrate
culitis with no evidence of vasculitis. Erythema nodosum which may be admixed with histiocytes. Epithelioid cells,
is a reaction pattern that may be provoked by a variety giant cells and well-formed granulomas are uncommon;
of triggers, infective and non-infective. However, in India AFB are usually seen in large numbers. Culture from the
TB is still an important cause of this condition justifying lesions usually grows Mycobacterium tuberculosis or NTM.
its inclusion as a tuberculid. Most patients appear to recover with antituberculosis
treatment but some may die inspite of appropriate
Others treatment.
Multiple episodes of Sweet’s syndrome were recently
reported during treatment of scrofuloderma and LABORATORY DIAGNOSIS
probably represent a hypersensitivity phenomenon
The laboratory diagnosis of cutaneous TB depends on
similar to the tuberculids (46).
the direct demonstration of Mycobacterium tuberculosis in
The reader is referred to the chapter “Musculoskeletal
smears or biopsy specimens, culture of the organism.
manifestations of tuberculosis” [Chapter 24] for more details.
Sometimes, in the absence of mycobacteriological confir-
mation, histopathology may provide a compatible
CUTANEOUS TUBERCULOSIS IN
diagnosis.
IMMUNOCOMPROMISED HOSTS
It is easy to obtain tissue specimens in patients with
The human immunodeficiency virus [HIV] epidemic has cutaneous TB; however, the diagnostic yield is uniformly
focussed attention on the manifestations of TB in patients poor. The Mycobacterium tuberculosis has been demons-
with acquired immunodeficiency syndrome [AIDS] trated in four to nine per cent of cases (32,33) and is hardly
(37,47-51). Similar features may, however, be seen in ever seen in lupus vulgaris and tuberculosis verrucosa
persons who are immunosuppressed due to other cutis. The AFB are found in about 35 per cent of cases
reasons as well (52,53). Clinically, the lesions do not fit (35,36). The results of culture of biopsy material are
into the above-described categories and usually present equally disappointing. Cultures were found to be positive
as papules, nodules, vesicles or induration. Ulceration in less than 10 per cent of cases (32,33,35,36). However,
and discharge from the surface of the lesions may be a much higher yield has been reported from other studies
feature [Figure 25.20]. The diagnosis is usually not ranging from 23.5% (31) to 56.9% (54). Availability of
suspected clinically and it has been suggested that all radiometric methods has decreased the time taken for
atypical cutaneous lesions developing in immuno- culture but is expensive and is unlikely to be of much
suppressed individuals should be biopsied and subjected use in cutaneous TB which is paucibacillary (55).
392 Tuberculosis
Histopathological examination reveals a granulomatous Table 25.2: Skin lesions due to BCG vaccination
dermatitis in 82 to 100 per cent of cases (32-36). However,
Local lesions
it is difficult to demonstrate Mycobacterium tuberculosis Keloid
in tissue sections. Abnormally large ulcer
The TST is positive in 73 to 100 per cent of patients Subcutaneous abscess
(32-36). Increasing the cut-off for a positive test increases Epithelial cyst
the specificity of the test but decreases the sensitivity Eczematous reaction
Granulomatous reaction
(56,57). In 1992, Victor et al (44) first described the use of
Lupus vulgaris
PCR in cutaneous TB. Several reports have since docu- Warty tuberculosis
mented the use of the test in lupus vulgaris, scrofulo-
Generalized lesions
derma and the tuberculids (43,58-69). Some workers
Erythema nodosum
(67,68) have demonstrated a high sensitivity of the Tuberculids
technique in cutaneous TB, though another group (69) Scrofuloderma
did not find it useful in paucibacillary forms. In a study Non-specific haemorrhagic eruptions
on 66 cases and 47 controls from India, a true positive BCG = bacille Calmette-Guérin
rate of 25.8 per cent and a false positive rate of 27.7 per Based on references 75 and 76
cent were reported with PCR (70). It appears that clinical
decisions about the diagnosis and treatment of patients Humans acquire Mycobacterium marinum disease from
with cutaneous TB should not be based on PCR results infected fish or water through breaches in the skin,
alone. usually of the upper and the lower limb (77,78). These
Finally, when all the diagnostic modalities are incon- infections have been termed ‘fish tank granuloma’ and
clusive, a therapeutic trial with antituberculosis ‘swimming pool granuloma’. A nodule, or less
treatment is frequently used to confirm the diagnosis in commonly, an ulcer, pustule or abscess develops at the
difficult cases (71-74). Evidence is available suggesting site of injury about two weeks following exposure. In
that when a therapeutic trial is undertaken in cutaneous one-third of the cases, lesions are arranged linearly along
TB, six weeks treatment with isoniazid, rifampicin, the lymphatics in a “sporotrichoid” pattern. The infection
pyrazinamide and ethambutol drugs appears adequate extends to the deeper tissues, usually the tenosynovium
to prove [or disprove] the diagnosis (71-74). in one-third of the patients; joints and bone may also be
If there is no improvement at all after six weeks, anti- involved. Systemic dissemination of infection is rare. Skin
tuberculosis therapy should be stopped and the diagnosis biopsy reveals a range of patterns from acute neutrophilic
should be revised. There is no benefit of continuing the inflammation to granulomas admixed with neutrophils.
trial for longer periods. The AFB are difficult to find in tissue sections (79). The
organism grows best at 30 to 33 oC on mycobacterial
BACILLE CALMETTE-GUÉRIN AND media. Several antibiotics have been found to be effective
CUTANEOUS LESIONS including rifampicin and ethambutol, doxycycline and
minocycline, clarithromycin and cotrimoxazole.
Skin complications due to BCG vaccination have been
Treatment is recommended for two months after clinical
classified into local and generalized forms (75,76). These
healing; deep infections require treatment for longer
details are shown in Table 25.2.
periods. Surgical debridement should be considered in
deep infections, immunocompromised patients or if
CUTANEOUS LESIONS DUE TO NONTUBER-
medical therapy fails.
CULOUS MYCOBACTERIA
Buruli ulcer disease is the third most common myco-
Skin involvement due to NTM such as Mycobacterium bacterial disease in immunocompetent people, after TB
marinum and Mycobacterium ulcerans are clearly defined and leprosy (80,81). It is caused by Mycobacterium ulcerans,
clinical entities and are considered first. This is followed a mycobacteria found in soil and vegetation in many
by a description of miscellaneous lesions caused by a parts of the world, especially in tropical rain forests. The
number of other NTM. organism enters the skin through abrasions and injuries
and is more common on the extremities. Children are reader is referred to the chapter “Treatment of tuberculosis”
affected more frequently though no age is exempt. Three [Chapter 52] for more details. Using these regimens, lupus
clinical stages are described: pre-ulcerative lesions may vulgaris and TB verrucosa cutis were found to heal
be papules, nodules or plaques. These progress to completely in four to five months. The skin lesions of
necrosis of the subcutaneous fat and undermined ulcers scrofuloderma healed in five to six months while the
of the overlying skin. Untreated, ulcers may extend and lymph nodes regressed in seven to nine months. There
attain large sizes. On skin biopsy, large numbers of AFB were no relapses in the patients who were followed up
can be detected in about 60 per cent of cases at this stage for three and half years (71,90). Drug resistance in
accompanied by necrosis of the dermis and subcutaneous cutaneous TB appears to be rare though recent reports
fat and minimal inflammation (82). The final stage of of culture-documented cases with drug resistant TB
scarring follows spontaneous healing of the ulcers. gummas and scrofuloderma are a worrisome develop-
Scarring can lead to contractures and ankylosis and is a ment (91-93). Under the Revised National Tuberculosis
major cause of disability. Surgery is the treatment of Control Programme [RNTCP] of the Government of
choice. Excision of pre-ulcerative and ulcerative lesions India, DOTS is available for patients with all forms of TB
is curative. The excision should remove all necrotic including cutaneous TB. Under the RNTCP, patients with
material and extend into healthy tissue to prevent cutaneous TB [limited disease] receive Category III
relapses. In vitro, Mycobacterium ulcerans is sensitive to treatment. When cutaneous involvement is a part of
some antimycobacterial agents but not in vivo; drug miliary or disseminated TB, Category I treatment is
therapy is thus of little value. administered. The reader is referred to the chapter
A large number of other NTM have been reported to “Revised National Tuberculosis Control Programme” [Chapter
cause cutaneous infections in immunocompetent and 63] for details on this topic.
immunocompromised hosts (83-89). Most of these
mycobacteria are present in the environment and gain REFERENCES
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Lymph Node Tuberculosis
26
Arvind Kumar
‘Tis called the evil: EPIDEMIOLOGY

A most miraculous work in this good king;
Myocobacterial lymphadenitis has shown marked
Which often since my here-remain in England
geographical variation. In the developing and under-
I have seen him do. How he solicits heaven,
developed countries, TB lymphadenitis continues to be
Himself best knows; but strangely visited people,
the most common and lymphadenitis due to NTM is
All swollen and ulcerous, pitiful to the eye,
seldom seen. In several studies from India Myco-
The mere despair of surgery, he cures,
bacterium tuberculosis has been the most common
Hanging a golden stamp about their necks,
pathogen isolated from patients with mycobacterial
Put on with holy prayers; and ‘tis spoken,
lymphadenitis accounting for almost all the cases (3-6).
To the succeeding royalty he leaves
One year data from July 1, 2000 to June 30, 2001 [i.e.,
The healing benediction
from Quarter 3, 2000 to Quarter 2, 2001] from 16 districts
William Shakespeare under the Revised National Tuberculosis Control
Macbeth, IV, iii, 146 Programme [RNTCP] of the Government of India,
lymph node TB constituted 1630 of the 2816 [58%] new
extra-pulmonary TB cases (7). In another community-
INTRODUCTION based house-to-house survey of a population of 23 229
in 35 neighbouring villages with 7900 children aged 0
Mycobacterial lymphadenitis has plagued humanity to 14 years in the rural area of Wardha district,
since ancient times. It has been called as “scrofula” [a Maharashtra State, Central India from May 1993 to May
term derived from the Latin for “glandular swelling” or 1994 and from March 1995 to February 1996, the
from the French “full necked sow”] and “King’s evil”. prevalence of lymph node TB was reported to be 4.43
Peripheral lymph node involvement is the commonest per 1000 children (8).
form of extra-pulmonary mycobacterial disease and the On the other hand, NTM are the most frequently
cervical region is the most frequently affected site (1-3). isolated pathogens from the lymphadenitis specimens
In the present era, Mycobacterium tuberculosis is the most in several reports from the developed world (9,10). In
common cause of mycobacterial lymphadenitis and Australia (11) and British Columbia (12), NTM have been
lymphadenitis due to nontuberculous mycobacteria detected 10 times more frequently than Mycobacterium
[NTM] is also being increasingly encountered. Peripheral tuberculosis. In studies reported from the USA, Mycobacte-
and mediastinal lymph node tuberculosis [TB] are com- rium tuberculosis accounted for 95 per cent of all mycobac-
monly seen in patients with human immunodeficiency terial lymphadenitis in adults, whereas in children, 92
virus infection [HIV] and the acquired immunodeficiency per cent of the mycobacterial lymphadenitis was due to
syndrome [AIDS]. NTM (13,14).
398 Tuberculosis
In addition to geographical variation, there has been disease. The reader is referred to the chapter “Nontuber-
a changing trend in the prevalence of these organisms culous mycobacterial infections” [Chapter 48] for more
over a period of time at some places. In England, there details.
has been a decline in TB lymphadenitis and a rise in NTM
lymphadenitis (15). A high frequency of disease has been CLINICAL PRESENTATION
reported in populations hailing from areas where TB is
highly endemic. In the study reported by Thompson Tuberculosis Lymphadenitis
et al (2), patients from the Indian subcontinent, who othe-
Clinical presentation of TB lymphadenitis is summarized
rwise constituted only 10 per cent of the population of
in Tables 26.1, 26.2 and 26.3 (2-4,23,24). Tuberculosis
that region, accounted for 81 per cent of 61 cases of
cervical lymphadenitis tends to occur more often in
mycobacterial lymphadenitis. Similar results have been
females and in young adults [Table 26.1]. Patients usu-
reported among Native Americans and in patients from
ally present with slowly enlarging lymph nodes and may
South-east Asia and Africa (16,17). A high frequency of
otherwise be asymptomatic. Cervical lymph nodes are
disease has also been reported among Asians and
most commonly affected, although axillary and inguinal
Hispanic patients in the San Francisco area by Lee et al
lymph nodes may also be involved. Associated
(17). Patients of Asian origin and African-Americans also
mediastinal lymphadenopathy may also be present
seem to have a high predilection for developing lymph-
sometimes. Some patients with lymph node TB may
adenitis due to Mycobacterium tuberculosis (18-21).
manifest systemic symptoms. These include fever, weight
loss, fatigue and occasionally night sweats [Table 26.1].
PATHOGENESIS
Cough may be a prominent symptom in patients with
Tuberculosis lymphadenitis is considered to be the local mediastinal lymphadenopathy.
manifestation of a systemic disease, whereas lymphade- Jones and Campbell (25) had classified peripheral TB
nopathy due to NTM is truly a localized disease. lymphadenopathy into five stages [Table 26.4]. Physical
Mycobacterium tuberculosis generally enters the body via examination findings depend upon the stage of the
the respiratory tract and undergoes haematogenous and disease. The enlarged lymph nodes may be of varying
lymphatic dissemination. Hilar and mediastinal lymph size, discrete or matted. The lymph nodes may be firm
nodes are the first lymphoid tissues encountered in the or cystic in consistency [Figure 26.1], if necrosis and
lymphatic spread from the lung parenchyma. This abscess formation has taken place. The lymph nodes are
involvement may occur at the time of primary infection usually not tender unless secondary bacterial infection
or may occur later in life due to reactivation of previous has occurred. Physical examination may be unremark-
infection. Tonsil is also an important portal of entry. The able but for palpable lymphadenopathy. Sometimes,
infection may then spread via the lymphatics to the lymph node abscess may burst leading to a chronic non-
nearest cervical lymph nodes. healing TB sinus and ulcer [Figure 26.2]. The typical TB
In the initial stages, the nodes may be discrete sinus has thin, bluish, undermined edges with scanty
clinically. Periadenitis results in matting and fixity of the watery discharge.
lymph nodes. The lymph nodes coalesce and break down Various complications have also been described due
to form caseous pus. This may perforate the deep fascia to TB mediastinal lymphadenitis. These include
and present as a fluctuant swelling on the surface [collar- dysphagia due to pressure on the oesophagus (26,27),
stud abscess]. Overlying skin becomes indurated, breaks oesophago-mediastinal fistula (28-30), tracheo-
down and leads to the formation of a sinus which if oesophageal fistula (31,32). Sometimes, TB tracheo-
untreated may remain unhealed for years. Healing may oesophageal fistula may mimick a malignant tracheo-
occur from each of the three stages with calcification and/ oesophageal fistula. Occasionally, upper abdominal and
or scarring. mediastinal lymph nodes may cause thoracic duct
In NTM lymphadenitis, the pathogens usually enter obstruction and present as chylothorax, chylous ascites
the lymph nodes directly via oropharyngeal mucosa, or chyluria (33). Rarely, jaundice occurs because of biliary
salivary glands, tonsils, gingiva or conjunctiva (14,22) obstruction due to enlarged lymph nodes (34). Cardiac
and lymph node involvement represents a localized tamponade (35) due to TB mediastinal lymphadenitis,
Lymph Node Tuberculosis 399
Table 26.1: Demographic characteristics and symptoms at presentation in adult patients with peripheral lymph node tuberculosis
Variable Studies from India Studies from other parts of the world
Dandapat Subrahmanyam Chen Thompson Fain

et al (3) (4) et al (23) et al (2) et al (24)
[n = 80] [n = 105] [n = 71] [n = 67] [n = 59]
Asian group* White group

[n = 54] [n = 13]
Place of study Berhampur Solapur Taipei Leicester Leicester Paris

Duration of study [years] 1 1.5 6 10 10 4
Mean age [years] † ‡ 42 41.8 46.9 37.6
Male:Female 1:12 1:1.3 1:1.5 1:1.5 1:2.3 1:1.5
History of contact with a case ND 5.7 ND 48 7.7 23.7
of TB or family history [%]
Symptoms [%]
Fever 40 45 9.9 13 7.7 30.5
Weight loss 85 78 9.9 13 23.1 47.5
Night sweats 37 35 ND 9.3 15.4 22
Cough 10 ND 8.5 14.8 0 0
Others ND ND § || || ¶
* Patients from the Indian subcontinent

† Mean age was not described. Age range = 1 to 65 years
‡ Mean age was not described. Age range = 1.5 to 68 years
§ Other symptoms included dysphagia [2.8%]; haemoptysis [2.8%]; vomiting [2.8%]
|| Anorexia occurred in 7.4% patients in the Indian subcontinent group and 15.4% patients in the White group
¶ Asthenia occurred in 47.5% cases
TB = tuberculosis; ND = Not described
Tuberculosis Lymphadenitis in Patients with

Human Immunodeficiency Virus Infection
Lymph node enlargement is a common feature in
patients with HIV infection and lymphadenopathy can
result from primary HIV-induced pathology and from
diseases, such as TB lymphadenitis, NTM lymph-
adenitis, nodal Kaposi’s sarcoma and nodal lymphoma
(37,38). In HIV-seronegative patients, TB lymphadenitis
often occurs as a focal cervical lymphadenopathy with
other groups of lymph nodes being occasionally
involved [Table 26.2]. The disease often presents as
multifocal lymphadenopathy in HIV-seropositive
patients. Comparison of clinical presentation of TB
lymphadenitis in HIV-seropositive and HIV-sero-
Figure 26.1: Right sided cervical lymphadenitis due to
tuberculosis negative patients is shown in Table 26.5 (37,38).
massive haemoptysis due to tracheo-pulmonary artery Nontuberculous Mycobacterial Lymphadenitis

fistula and pseudoaneurysm of the pulmonary artery (36) Very little is known regarding lymphadenitis due to
have also been reported. NTM from India. It often occurs in children. Constitu-
400 Tuberculosis
Table 26.2: Physical signs at presentation observed in adult patients with peripheral lymph node tuberculosis
Dandapat Subrahmanyam Chen et al Thompson Fain et al (24)

et al (3) (4) (23) et al (2) [n = 59]
[n = 80] [n = 105] [n = 71] [n = 67]
Asian group* White group

[n = 54] [n = 13]
Site of involvement [%]

Cervical 70 93.3 91.5 85 84.5 73.1
Axillary 6 3.8 12.7 11.1 7.7 15.4
Inguinal 9 2.9 7 3.7 7.7 9.6
Multiple sites 15 ND 14.0† ND ND 15.3‡
Physical findings [%]
Matting and fixity 55 68 ND ND ND ND
Discrete nodes 22.5 32 ND ND ND ND
Abscess formation 15 15.2 ND ND ND ND
Sinuses 13 10.5 ND ND ND ND
Ulcers ND 7.6 ND ND ND ND
* Patients from the Indian subcontinent

† Right elbow nodes were enlarged in 1.4% patients. Two sites were involved in 14%; three sites were involved in 7% and four sites
were involved in 4.4% patients
‡ Of the 59 patients studied, 69 different lymph node sites were noted; 46 patients [78%] had exclusive lymph node disease. A
superficial distribution was found in 52 cases [88.1%] and isolated superficial lymph node involvement was found in 32 patients
[54.2%]. Deep lymph node involvement [mediastinal and abdominal] was observed in 17 patients [32.7%] and isolated deep lymph
node involvement was found in 7 patients [11.9%]
ND = not described
Table 26.3: Evidence of associated pulmonary tuberculosis in adult patients with peripheral lymph node tuberculosis

et al (3) (4) et al (23) et al (2) et al (24)
[n = 80] [n = 105] [n = 71] [n = 59]* [n = 59]
Asian group† White group

[n = 11] [n = 48]
Associated pulmonary 5 16.2 42‡ 44 18 ND

TB [%]
* Chest radiographs were done in 59 of the 67 patients studied

† Patients from the Indian subcontinent
‡ Among those with cervical lymph node TB, 33% of those with upper-third cervical lymph node involvement and 58.7% of patients
with lower-third cervical lymph node involvement had radiological features of pulmonary TB
TB = tuberculosis; ND = not described
tional symptoms seldom occur and the disease generally rupture, sinus formation and heal with fibrosis and
remains localized to the upper cervical area [Table 26.6]. calcification (16,22,25). Appropriate laboratory tests must
If untreated, the nodes often progress to softening, be performed to differentiate lymphadenitis due to NTM
Table 26.4: Physical appearance of lymph node tuberculosis somewhere in the drainage area], the lymph node is
usually hard and may be fixed to the surrounding
Stage 1
Enlarged, firm, mobile, discrete nodes showing non-specific structures.
reactive hyperplasia
Stage 2
DIAGNOSIS
Larger rubbery nodes fixed to surrounding tissue owing to
periadenitis Apart from a focussed history and a detailed clinical
Stage 3
Central softening due to caseation necrosis and abscess
examination, several other studies are required for
formation confirming the diagnosis of lymph node TB.
Stage 4
Collar-stud abscess formation Tuberculin Skin Test
Stage 5
Sinus tract formation Tuberculin skin test [TST] is positive in about 75 per cent
Based on “Jones PG, Campbell PE. Tuberculous lymphadenitis patients with lymph node TB while it is often non-
in childhood; the significance of anonymous mycobacteria. Br J reactive in patients with NTM lymphadenitis (1,9,10).
Surg 1962;50:302-14 (reference 25)” However, a negative TST does not rule out the possibility
of TB. The reader is referred to the chapter “Tuberculin
skin test” [Chapter 11] for more details. More recently,
and Mycobacterium tuberculosis as response to antituber-
interferon-gamma release assays [IGRAs] have become
culosis drugs is not good in the former. The reader is
available and may be useful in the diagnosis of TB
referred to the chapter “Nontuberculous mycobacterial
infections” [Chapter 48] for more details. infection. The reader is referred to the chapter “Diagnosis
of latent tuberculosis infection: recent advances and future
DIFFERENTIAL DIAGNOSIS directions [Chapter 12]” for details on this topic.
There are numerous causes of peripheral lympha- Imaging

denopathy. This list includes reactive lymphadenitis
[secondary to viral and bacterial infections], TB In patients with TB lymphadenitis, abnormalities are
lymphoma, sarcoidosis, secondary carcinoma and often discernible on the chest radiograph [Table 26.3].
uncommon causes like fungal diseases, toxoplasmosis However, there is a wide variation in the reported
and diseases of the reticulo-endothelial system among incidence of chest radiographic abnormalities with
others (38). Multiplicity, matting and caseation are three the figure ranging from five to forty-four per cent
features which help in the diagnosis of TB lymphadenitis. [Table 26.3]. The reported incidence of paratracheal, hilar
In patients with lymphoma, the lymph nodes are rubbery and mediastinal lymphadenopathy [seen on the chest
in consistency and are not matted. In patients with radiograph] in patients with peripheral lymphadeno-
secondary deposits in the lymph node [from a primary pathy has varied widely from five to twelve per cent
Figure 26.2: Tuberculosis lymphadenitis. Clinical photograph showing chronic non-healing sinus and ulcers over right cervical region
and chest wall [A]; suprahyoid, bilateral cervical and axillary lymphadenitis with chronic non-healing ulcers [B]; and suprasternal and left
supraclavicular lymphadenitis with discharging sinuses [C]
402 Tuberculosis
Table 26.5: Comparison of clinical characteristics of lymph node tuberculosis in HIV-positive and HIV-negative patients
Variable Bem (37) Mohan et al (38)
HIV-positive HIV-negative HIV-positive HIV-negative

[n = 157] [n = 71] [n = 34] [n = 390]
Mean age [years] 30.6 30.6 28.4 27.8
Male:Female 1:0.9 1:1.2 1:1.3 1:1.3
Site of involvement [%]
Cervical 99* 96 96 90
Axillary 82 43 82 37
Inguinal 84 14 71 10
Multiple sites 90 39 89 33
Physical findings [%]
Firm and mobile 51 51 ND ND
Matted, irregular/hard and 49† 49 ND ND
additional local signs
Histopathlogical type
Epithelioid granulomas
with caseation necrosis ND ND 18 75
without caseation necrosis ND ND 21 23
Suppurative variety ND ND 29 01
Non-reactive ND ND 32 01
Chest radiograph findings [%] ND ND
Pulmonary infiltration 46‡ 60§ ND ND
Cavitation 3‡ 0§ ND ND
Pleural effusion 17‡ 13§ ND ND
Pericardial effusion 13‡ 0§ ND ND
* Among patients with lymph node TB, lymphadenopathy was confined to the neck in 10% HIV-positive patients compared to 57% HIV-
negative patients. Further, isolated unilateral TB cervical lymphadenitis was observed in only 1 of the 157 HIV-positive patients compared
to 32% in HIV-negative patients
† Among HIV-positive patients with lymph node TB, local signs included sinuses [n = 2]; cold abscess [n = 3]; tender nodes [n = 3];
inflammatory mass [n = 3]. Among HIV-negative patients with lymph node TB, local signs included sinuses [n = 2]; tender nodes [n = 1];
inflammatory mass [n = 1]. None of the patients with primary HIV lymphadenopathy demonstrated local signs
‡ Tested in 110 patients
§ Tested in 15 patients
(2,3,14,16). The other radiological investigations include with hypodense areas, sometimes central necrosis with
an ultrasound of the abdomen and a computed peripheral rim enhancement or calcification [Figures 13.5,
tomography [CT] of the chest, when indicated. Ultra- 13.6, and 26.3]. The reader is referred to the chapter
sonography and CT of the abdomen may be required to “Roentgenographic manifestations of pulmonary tuberculo-
assess the status of retroperitoneal, porta hepatis or sis” [Chapter 13] for more details. Magnetic resonance
mesenteric lymph nodes. It may reveal enlarged lymph imaging [MRI] also reveals lymph node enlargement
nodes or a confluent mass with central necrosis. with multiple hypodense areas (39).
Sometimes the nodes may show calcification. Computed Imaging modalities are also helpful in identifying
tomography of the chest is required for accurate deeply located abscesses in the cervical and axillary
evaluation of the thoracic lymph nodes if the chest regions and, therefore, facilitate radiologically-guided
radiograph shows any evidence of mediastinal or hilar anti-gravity aspiration or surgical drainage of the
lymphadenopathy. The lymph nodes show enlargement abscesses if the pus collection is substantial.
Table 26.6: Comparison between tuberculosis lymphadenitis and nontuberculous mycobacterial lymphadenitis
Variable Tuberculosis lymphadenitis NTM lymphadenitis
Age Any age group Children

Sex Female preponderance Equal between sexes
Constitutional symptoms Common Rare
Lymph node involvement Cervical lymph nodes are most commonly Localized disease often involving cervical
involved lymph nodes [jugulodigastric, submandibular,
Axillary and inguinal lymph nodes may also preauricular]. Unilateral involvement is common
be involved. Bilateral involvement is common
Chest radiographic evidence Common Rare
of pulmonary or pleural TB
Tuberculin skin test Often reactive Non-reactive
Response to antituberculosis Good Poor
treatment
NTM = nontuberculous mycobacteria; TB = tuberculosis
Cytopathology and Histopathology as the first diagnostic technique for the diagnosis of
peripheral lymphadenopathy. The characteristics
The definitive diagnosis of lymph node TB is established cytopathological changes include epithelioid cell
by visualizing mycobacteria on histopathology sections granulomas with or without multinucleate giant cells and
or on smears stained for acid-fast bacilli [AFB] or by caseation necrosis (43-46). Several authors have evaluated
mycobacterial culture. Traditionally, excision biopsy of the sensitivity and specificity of FNAC in the diagnosis
the lymph nodes has been done to diagnose lymph node of peripheral lymphadenopathy by comparing it with
TB [Figure 26.4]. In patients with mediastinal lymph- the gold standard [i.e., histopathological examination]
adenopathy, various techniques including ultrasound and found it to be a useful technique (45-50). Lau et al
or CT-guided percutaneous biopsy, cervical mediastino- (46) reported their experience with 108 patients whose
scopy, video-assisted thoracoscopic surgery, endoscopic FNAC samples showed granulomatous inflammation
transbronchial or transoesophageal biopsy (40-41) have suggestive of TB. Of these, 68 patients underwent surgical
been used to obtain lymph node material for tissue excision of the lymph nodes. The authors reported the
diagnosis. sensitivity and specificity of FNAC in the diagnosis of
As the mycobacteria are not documented in every lymph node TB to be 77 per cent and 93 per cent respec-
case, certain histopathological changes have been accep- tively. They also noticed that smears with necrosis had a
ted as suggestive of TB. These include granulomatous higher rate of AFB positivity [47%] compared to the
inflammation with caseation necrosis [Figure 26.4]. smears with no necrosis [15%]. Dandapat et al (3) reported
However, it must be clarified that, although highly a true positive diagnosis in 83 per cent, a false negative
suggestive, these changes are by no means specific and result in 14 per cent and equivocal results in three per
may sometimes be seen in other diseases also (42). cent. Other authors [Table 26.7] have reported similar
Moreover, the surgical procedure of excision biopsy is results. In another study (45) of 272 patients with FNAC
associated with certain morbidity. proven TB lymphadenitis, mycobacterial cultures were
Fine needle aspiration cytology [FNAC], a relatively positive in 49 per cent and AFB were present in 30 per
non-invasive, pain-free, out-patient procedure with no cent of direct and concentrated smears. Combining the
morbidity is available nearly for two decades. Over a smear and culture methods together, the microbiological
period of time, it has established itself as a safe, cheap diagnosis was possible in 57 per cent patients. This figure
and reliable procedure for the diagnosis of peripheral went up to 63 per cent in the sub-group of patients with
lymphadenopathy also (43-44). It has also been suggested caseation necrosis (4-5).
404 Tuberculosis
Figure 26.4: Tuberculosis lymphadenitis. Photomicrograph

showing epithelioid granulomas with caseation necrosis and peri-
pheral lymphocyte infiltration [upper panel, left; Haematoxylin and
eosin, x 100], well-defined epithelioid granulomas with lymphocytic
infiltration [upper panel, right; Haematoxylin and eosin x 200],
epithelioid granuloma, caseation, lymphocytic infiltration [lower
panel, left; Haematoxylin and eosin x 200] and multinucleated
Langhans’ giant cell and lymphocytic infiltration [lower panel, right;
Haematoxylin and eosin, × 400]
rate was only 16 per cent of the histopathology proved

cases (51). Others have reported positive culture in up to
65 to 68 per cent cases (3,52). For transportation of the
excised lymph node to the specialized centre for culture
of mycobacteria, selective Kirchner’s liquid medium has
been reported to be the best and specimens can be stored
in this medium in the refrigerator for up to 15 days
without any loss in culture positivity (52). Excision biopsy
of the lymph node remains the gold standard for the
diagnosis of lymph node TB.
Figure 26.3: CECT of the neck and chest showing bilateral Molecular and Other Methods
cervical [A] [asterisk]; right-sided axillary [asterisk] and
intrathoracic [arrow] lymphadenopathy [B], [C]. Peripheral rim Polymerase chain reaction [PCR] has been used on fine
enhancement with central attenuation can be seen. Fine needle needle aspirate specimens Papanicolaou-stained fine
aspiration cytology of the cervical lymph node confirmed the needle aspirated smears and formalin-fixed, paraffin-
diagnosis of tuberculosis embedded histopathological specimens have yielded
varying results in the diagnosis of lymph node TB
In a prospective study (51) comparing FNAC with (51,53-56). Presently available evidence suggests that
excision biopsy conducted at the All India Institute of PCR may be helpful in establishing the aetiological
Medical Sciences hospital, New Delhi, where coded diagnosis in some patients with granulomatous lymph-
samples were submitted to the laboratory and the adenitis in whom the conventional methods of FNAC,
laboratory personnel were not aware of the clinical histopathology and mycobacterial culture are inconclu-
diagnosis, the author observed that the culture positivity sive.
Table 26.7: Method of diagnosis in adult patients with peripheral lymph node tuberculosis

et al (3) (4) et al (23) et al (2)* et al (24)
[n = 80] [n = 105] [n = 71] [n = 67] [n = 59]
Fine needle aspiration 83† ND ND ND 38‡‡
cytology [n = 26]
Lymph node biopsy
Histopathology 100‡ 100 100|| 100** 100§§
[n = 64] [n = 60] [n = 39]
Microbiology 65 § 80¶ 100†† 36
[n = 10] [n = 7] [n = 39]

Numbers in square brackets indicate number tested
* Included 54 patients of Asian origin and 13 White patients
† False-negative results were observed in 14% and equivocal results were observed in 3% patients
‡ 80% patients had caseating granulomas; and 20% had non-caseating granulomas
§ Microbiological examination was not done in this study
|| A total of 64 specimens were obtained for histopathological exmamination [excision biopsy [n = 32]; total excision [n = 29]; neck
dissection [n = 3]. Acid-fast bacilli were found in 35 of the 64 specimens
¶ Only 10 of the 64 specimens were subjected to culture on Lowenstein-Jensen medium and eight yielded Mycobacterium tuberculosis.
**Histopathological examination was done in only 60 of the 67 patients. Biopsy specimens were not sent for microbiological examination
in 13 of these 60 patients. Histopathology was positive in all the 60 patients. In 13 of these 60 patients, both histopathological and
microbiological methods yielded the diagnosis
†† In 7 patients, histopathological exmination was not done and microbiological examination alone was done
‡‡ Of the 26 patients in whom fine needle aspiration was performed, bacteriological diagnosis was possible in 38% cases and acid-fast
bacilli were positive in 2 of them
§§ Of these 39 patients, histopathological examination revealed caseating granulomas in 82%, isolated granulomata in 13% and non-
specific inflammatory lesions which revealed Mycobacterium tuberculosis in 5%
TREATMENT initially and later to six months (6). In 1990, the group
from Tuberculosis Research Centre [TRC], Chennai (5)
Presently, it is generally agreed that antituberculosis reported results of their prospective trial evaluating a
treatment alone is sufficient in majority of the cases and supervized short-course [six months] intermittent
surgical intervention is required only in selected cases chemotherapy regimen consisting of streptomycin,
for specific situations. In India, majority of the patients rifampicin, isoniazid and pyrazinamide three times a
with lymph node TB receive DOTS under the RNTCP of week for two months followed by streptomycin and
the Government of India. The reader is referred to the isoniazid twice a week for four months on an out-patient
chapters “Treatment of tuberculosis”[Chapter 52] and basis in children with lymph node TB. Out of 168 patients
Evolution of chemotherapeutic regimens in the treatment of finally analysed, favourable clinical response was noted
tuberculosis and their scientific rationale” [Chapter 51] for in most patients at the end of the treatment. They
more details. concluded that in children, TB lymphadenitis can be
The number of drugs required and the ideal dura- successfully treated with a short-course chemotherapy
tion of treatment for lymph node TB have been an area regimen of six months. Thereafter, the BTS next trial
of intense research. Observations from a series of (57,58) compared the following regimens: rifampicin,
randomized clinical trials conducted by the British isoniazid, ethambutol for the initial two months,
Thoracic Society [BTS] resulted in the shortening of the followed by rifampicin and isoniazid for the subsequent
duration of treatment from 18 months to nine months seven months; rifampicin, isoniazid, pyrazinamide for
406 Tuberculosis
the initial two months, followed by rifampicin and invariably require longer duration of treatment and
isoniazid for the subsequent four months. The six-month sometimes require addition of second-line antituber-
regimen was found to be equally effective in terms of culosis drugs. While response to antituberculosis treat-
response with an advantage of increased convenience ment may be delayed in patients with TB lymphadenitis,
and reduced cost. There was no difference in the speed it is a common practice among physicians and surgeons
of resolution of nodes, in the percentage of patients with to label these patients with a diagnosis of MDR-TB
residual nodes at the end of the treatment or in the lymphadenitis. But it must be understood that MDR-TB
numbers developing fluctuation or sinuses. However, is a laboratory diagnosis and for establishing this, the
seven patients in the ethambutol group and only one in organisms must be grown in the laboratory and in vitro
the pyrazinamide group required aspiration of pus from resistance to rifampicin and isoniazid must be demons-
lymph nodes. This may be because pyrazinamide, being trated. Since lymphadenitis is a paucibacillary disease,
bactericidal kills bacteria which are intracellular, making it is not easy to grow Mycobacterium tuberculosis in cultures
glands less likely to become fluctuant on treatment. In a in most instances. Therefore, a label of MDR-TB lymph-
recent study (6), patients with biopsy confirmed adenitis should be used judiciously. Occasionally,
superficial lymph node TB were randomly allocated to treatment of TB lymphadenitis with Category II
receive two-drug regimens of either a daily self- antituberculosis drugs may be gratifying but this can be
administered six-month regimen [n = 136] of rifampicin tried on a case-to-case basis and cannot be recommended
and isoniazid, or a twice-weekly, directly observed, six- as a public health approach. In an occasional patient with
month regimen of rifampicin and isoniazid plus delayed response to conventional treatment, addition of
pyrazinamide for the first two-months, followed by a fluoroquinolone and streptomycin to the existing
rifampicin and isoniazid for the subsequent four months treatment regimen has been found to be helpful.
[n = 141]. Of the 277 enrolled patients, data were available However, these measures should be undertaken by a well
for analysis in 268 patients [n = 134 from each group]. At experienced clinician and the appropriate dosage
the end of the treatment, 87 per cent patients in each schedule and duration of treatment should be tailored
treatment group had a favourable clinical response; 14 to the needs of the individual patient. These issues merit
[11%]; and 17 [13%] patients had a doubtful response, further study. The results of various studies have shown
and four [3%]; and one [1%] patients had an unfavourable that lymph nodes may enlarge in size or, new nodes
response among those treated with the daily and twice- may appear during or after antituberculosis treatment
weekly regimen, respectively. The authors (6) suggested (5,6,60). These nodes may show histopathological
that these regimens may be considered as alternatives to features characteristic of TB but are sterile on culture.
the existing regimens. Experience at the Paediatric The development of new nodes while on treatment may
Tuberculosis Clinic at the AIIMS hospital, New Delhi (59) represent an immunological response. This phenomenon
[n = 459], indicated that pulmonary TB was the is usually transient and the nodes ultimately regress in
commonest followed by lymph node TB. Of the 16 child- size. Fluctuation may appear in some lymph nodes
ren with isolated lymph node TB who received category while on treatment and the pus should be aspirated
III treatment, 12 were cured with the primary regimen; under strict aseptic conditions. In case there is
three achieved cure with extended primary regimen; and secondary bacterial infection presenting as a classical
one was lost to follow-up. The authors (59) suggest that abscess, drainage and appropriate broad-spectrum
it is feasible to classify and treat lymph node TB in antibiotics may be required in addition to antituber-
children based on the World Health Organization’s culosis treatment.
guidelines for adult TB. While the term “immune reconstitution inflammatory
The overall opinion in the literature at present seems syndrome [IRIS]” is usually used in HIV-seropositive
to be in favour of a short-course chemotherapy with four patients who are receiving antiretroviral treatment
drugs [rifampicin, isoniazid, ethambutol, pyrazinamide] [ART], the term “paradoxical reaction” is generally used
given for the first two months with rifampicin and to describe a clinical worsening of TB disease in HIV-
isoniazid being given for the subsequent four to seven seropositive and HIV-seronegative patients after
months. However, in the author’s experience, patients initiation of antituberculosis treatment (61). In the past,
studies on TB-associated IRIS have used a variety of non- considered for patients with extensive Mycobacterium
standardized general case definitions. Recently, case avium intracellulare complex lymphadenitis or poor
definitions for paradoxical TB-associated IRIS, ART- response to surgical therapy (63). The reader is referred
associated TB [Figure 26.5] and unmasking TB-associated to the chapter “Nontuberculous mycobacterial infections
IRIS [provisional] have been described (62). These [Chapter 48]” for more details.
definitions can be used by clinicians and researchers in
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410 Tuberculosis
Tuberculosis in
Otorhinolaryngology
27
Subirendra Kumar, BC Roy, SC Sharma
INTRODUCTION The site of involvement in some of the recently published

series on head and neck TB is shown in Table 27.1 (1-3).
Granulomatous infections that involve head and neck
include a number of well-known diseases. Infections due
to mycobacteria are the most prominent amongst them. TUBERCULOSIS OF CERVICAL LYMPH NODES
Patients with granulomatous lesions including Cervical lymph node involvement is the most common
tuberculosis [TB] in the head and neck region usually form of lymph node TB and is also the most frequently
present with lymphadenopathy or chronic inflammation seen head and neck manifestation of TB [Figures 27.1,
that does not respond to antibacterial therapy (1-3). 27.2A, 27.2B, 27.3, and 27.4]. The chapter “Lymph node
In the pre-chemotherapeutic era, patients with active tuberculosis” [Chapter 26] covers this topic in detail.
pulmonary TB often developed laryngeal, otological,
nasal and paranasal sinus involvement and deteriorated
TUBERCULOSIS OF SPINE
progressively. Laryngeal involvement was a dreaded
consequence and was considered to be a harbinger of Patients with TB of cervical spine may occasionally
death. The classical description of TB involving head and present to the otorhinolaryngologist with torticollis,
neck emanated from that period. With the advent of effec- stiffness of neck due to spasm of the neck muscles and
tive antituberculosis treatment the incidence of otolaryn-
gological TB has come down significantly. The
resurgence of TB as a consequence of human immuno-
deficiency virus [HIV] infection and acquired immuno-
deficiency syndrome [AIDS] has brought otolaryngolo-
gical TB into focus once again.
TUBERCULOSIS IN HEAD AND NECK REGION

Although not as common as pulmonary TB, head and
neck involvement by TB occurs in a significant proportion
of cases. Head and neck TB develops due to: [i] spread
of the bacilli to the upper airway by contaminated
sputum from a pulmonary focus; [ii] haematogenous;
and [iii] lymphatic dissemination. Primary involvement
of the tonsil as the portal of entry with subsequent Figure 27.1: Tuberculosis lymph node abscess
involvement of the cervical lymph nodes is also known. in suprahyoid region
Tuberculosis in Otorhinolaryngology 411
Table 27.1: Site of involvement in some of the recently published series on head and neck TB
Variable Menon et al (1) Nalini and Vinayak (2) Prasad et al (3)

[n = 128] [n = 117] [n = 165]*
Place of study Bradford, UK Mumbai, India Mangalore, India
Male:Female 68:60 41:76 108:57
Site of involvement†
Cervical lymph nodes 111 [87] 111 [95] 121 [73.3]
Larynx 02 [1.6] 02 [1.7] 24 [14.5]
Cervical spine 0 01 03 [1.8]
Oropharynx 02 [1.6] 01 08 [5]
Nasopharynx 01 0 01
Ear 02 [1.6] 01 04 [2.4]
Eyes 02 [1.6] 0 0
Retropharyngeal abscess 01 01 0
Salivary glands 05 [3.9] 0 03 [1.8]
Thyroid 01 0 0
Temporomandibular joint 0 0 01
Skin 01 0 0
Associated pulmonary TB and 20 31 24.2
TB of other organs
* Of the 65 patients who were tested, 30% were found to have co-existing HIV infection
† Values in square brackets indicate percentage
UK = United Kingdom; HIV = human immunodeficiency virus
Figure 27.2A: Tuberculosis lymph node abscess Figure 27.2B: Ruptured tuberculosis lymph node abscess in the
same patient as in Figure 27.2A. Repeated aspirations did not
prevent rupture of the abscess
painful movement of the spine. Difficulty in swallowing muscles and manifests in the neck as an abscess. Epidural
and breathing, and a midline bulge in the posterior sepsis in the neck can be the cause of musculoskeletal
pharyngeal wall suggest a retropharyngeal or paraverte- symptoms [polyradiculopathy] which can go undiag-
bral abscess. Children with this condition may present nosed before it manifests with some more obvious
with stridor. Pus from the TB lesion of the spine may features (4). The reader is referred to the chapter “Skeletal
track downwards and laterally along the prevertebral tuberculosis” [Chapter 23] for more details.
412 Tuberculosis
Figure 27.3: Tuberculosis sinus from a cold abscess. Note the Figure 27.5: Tuberculosis of the tongue. Patient recovered
scarring adjacent to the sinus opening completely with antituberculosis treatment
single or multiple, painful or painless (5). Usually, the

lesions are well-circumscribed, but irregular ulcers may
also occur. These lesions sometimes begin as nodules,
fissures or plaques (6). Initial picture may resemble a
malignant process and histopathology confirms the diag-
nosis of TB (7). Other sites of involvement include: floor
of mouth, soft palate, anterior pillars and uvula (8).
Secondary involvement of the draining lymph nodes
may occur. Majority of these patients also have
pulmonary TB (5,7, 9-11).
TUBERCULOSIS OF LARYNX
Pathogenesis
Laryngeal TB classically develops due to direct spread
Figure 27.4: Preauricular sinus with tuberculosis infection
to the larynx from contaminated sputum [bronchogenic
spread]. This form of involvement, frequent in patients
TUBERCULOSIS OF ORAL CAVITY
with sputum smear-positive pulmonary TB, most
The oral cavity is an uncommon site of involvement by commonly involves the posterior glottis. It is thought to
TB. Infection in the oral cavity is usually acquired through develop due to the pooling of infected sputum when the
infected sputum coughed out by a patient with open patient is in the recumbent position (12). The broncho-
pulmonary TB. Infection may also be acquired by genic spread to the larynx results in localized oedema,
haematogenous spread. In general, the intact mucosa of granuloma or ulcerations (13). The laryngeal involve-
the oral cavity is relatively resistant to invasion and saliva ment may also occur due to lymphohaematogenous
has inhibitory effect on the growth of mycobacteria. A spread. Isolated laryngeal involvement may occur
breach in the mucosa due to any reason is one of the without any evidence of pulmonary TB. Recent evidence
important predisposing factors for the development of suggests that the occurrence of laryngeal TB with
TB of the oral cavity. Tongue is the most common site of oedematous, polypoid panlaryngitis as a consequence
involvement and accounts for nearly half the cases of lymphohaematogenous spread that is not easily
[Figure 27.5]. The lesions are usually found over the tip, distinguishable from chronic laryngitis is increasing
borders, dorsum and base of the tongue. They may be (14-18).
Epidemiology In their study of laryngeal TB, Soni and Chatterjee (20)

reported hoarseness in 98.6 per cent, dysphagia and
Before the availability of antituberculosis chemotherapy,
odynophagia or pain in throat in 35.8 per cent and
laryngeal involvement was considered a grave
referred otalgia in 28.6 per cent of patients. In 14.3 per
prognostic sign indicative of severe disease. It was seen
cent of their cases, the symptoms were not referred to
in nearly one-third of cases with pulmonary TB (19). With
larynx.
the availability of effective antituberculosis treatment,
The physical examination findings associated with
there has been a gradual decline in the burden of
laryngeal TB include oedema, hyperaemia, nodularity,
laryngeal TB. However, with the advent of the HIV
ulceration, exophytic mass, vocal cord thickening, and
infection and the AIDS, the incidence of laryngeal TB is
obliteration of anatomic landmarks. The ulcero-
increasing (14,16).
infiltrative lesions which predominantly affected the
In the present era, it has been observed that in
posterior larynx were observed frequently in the past and
countries where TB is highly endemic, almost all patients
are rare now. At the present time the macroscopic
with laryngeal TB have been found to have radiological
appearance corresponds to a diffuse oedema or to a
evidence of pulmonary TB and many of them may be
pseudotumoral image located in any zone. The laryngeal
sputum smear-positive (19-21). On the contrary, most of
TB should be suspected in a patient with non-specific
the patients with laryngeal TB in countries with a low
chronic laryngitis of poor evolution (18). The epiglottis
prevalence of TB seldom have any evidence of
may be markedly oedematous [turban epiglottis] and the
pulmonary TB (22,23). However, patients with a heavy
vocal cord oedema can resemble polypoid corditis.
bacillary load and strongly positive sputum specimens
Subglottic oedema or granulation in the true vocal cords
may not have laryngeal involvement. The incidence of
can result in stridor. Vocal cord paralysis secondary to
laryngeal involvement in patients with pulmonary TB
mediastinal lymphadenopathy can also cause stridor
has ranged from 1.5 to 50 per cent in recently published
(27). Any laryngeal structure can be affected by TB
studies (20,24-27).
[Figure 27.6] and the common sites include true vocal
cord, the epiglottis, the false vocal cord, the aryepiglottic
Pathology
fold, the arytenoids, the interarytenoid area and the
The tubercle bacilli induce low-grade inflammation with subglottis (17,28,29).
the formation of typical TB granulation tissue. Occasionally, patients may present with rapid onset
Coagulation necrosis occurs in large TB granulomas. of hoarseness of voice similar to that encountered in acute
Later, caseation may develop. Laryngeal lesions reveal viral laryngitis. Because of the acute onset, TB is rarely
oedema and hyperaemia, granulomas or ulceration. suspected as the cause. When these patients fail to
Vocal cord thickening and palsy can occur. Epiglottis may
show irregular margins and nibbled appearance. Myco-
bacterium tuberculosis may be found in the subepithelial
tissue. The process of destruction and the repair often
proceeds simultaneously. The submucosa of epiglottis
and aryepiglottic folds are likely to undergo fibrous infil-
tration resulting in pseudoedema. Described as turban
epiglottis, this lesion is not commonly seen in the present
era.
Clinical Features
Patients often present with hoarseness of voice and
laryngeal TB should be considered in the differential
diagnosis in any patient with unexplained hoarseness
of voice. Pain is also an important feature which may
radiate to one or both ears and may lead to odynophagia. Figure 27.6: Endoscopic view of the laryngeal tuberculosis
414 Tuberculosis
respond to conservative management, microlaryngo-

scopic examination, biopsy and histopathological
examination may confirm the diagnosis of vocal cord TB.
Co-existence of laryngeal TB and carcinoma is well-
known. Clinical features of these conditions may overlap
and the lesions may look similar (21,22). The incidence
of this co-existent TB and cancer of larynx has been
reported to be 1.4 per cent (30). Antituberculosis
treatment should be given for at least two to three weeks
period before the treatment of laryngeal carcinoma is
initiated. In a study of 201 patient with TB complicating
a neoplastic condition, 45 had head and neck cancers (31).
When TB develops after antineoplastic therapy, the
infection is more severe with a higher mortality
(21-23,30,31).
Figure 27.7A: Tuberculosis parotitis with facial nerve palsy
before antituberculosis treatment
TUBERCULOSIS OF THE SALIVARY GLANDS
Tuberculosis sialitis is usually secondary to TB of the oral
cavity or pulmonary TB. Primary TB of the salivary
glands is also known, but, is rare. Parotid is the most
common salivary gland involved [Figures 27.7A and
27.7B]. Tuberculosis of the submandibular gland is also
known (32). Clinical presentation can be acute or chronic.
Acute presentation may resemble acute non-TB sialitis
and clinical differentiation may be difficult. Occasionally,
the diagnosis of TB may be a surprise following surgery
performed for a suspected salivary gland tumour (33).
Unsuspected TB parotid abscess may be wrongly drained
mistaking it to be a pyogenic [non-TB] abscess. This may
lead to the formation of a persistent sinus. In one such
case (34), the diagnosis of TB was made when superficial
parotidectomy was performed as part of the treatment
Figure 27.7B: Following antituberculosis treatment, facial nerve
for fistula. In patients with suspected TB sialitis, chest
palsy recovered and parotid gland swelling subsided
radiograph and fine needle aspiration cytology are useful
in confirming the diagnosis.
full evolution; and [iv] chronic progressive TB in which
cancer develops (37). Lymphoreticular malignancy may
TUBERCULOSIS OF PHARYNX
be associated with TB abscess and sinus of the neck
Tuberculosis involvement of the tonsils and pharynx is [Figure 27.8]. Rarely, malignancy and TB may involve
uncommon at present. These cases may be confused two different organs (36).
with carcinoma at the time of presentation (35). The
presenting features include: [i] ulcer on the tonsil or TUBERCULOSIS OF THE EAR
oropharyngeal wall; [ii] granuloma of the nasopharynx;
and [iii] neck abscess. Co-existence of TB (36) and cancer While the association between pulmonary TB and TB
of pharynx could be: [i] a mere coincidence; [ii] meta- infection of the middle ear cleft is known since early
static carcinoma developing secondarily in a recent or nineteenth century, primary infection of ear is rare
old TB lesion; [iii] TB infection engrafted on cancer in (38-40).
Figure 27.9: Facial nerve palsy in a patient with tuberculosis of

middle ear and mastoid. Ear became dry with antituberculosis
Figure 27.8: Tuberculosis sinuses associated with
treatment. Facial nerve palsy did not recover as it was long-standing
lymphoma of cervical lymph nodes
Pathogenesis Physical examination may show adenoid hypertrophy

without any distinguishing features. In a study of 40
Ear can become infected with Mycobacterium tuberculosis
patients reported by Tse et al (46), young femlaes in the
by the bacilli invading the Eustachian tube while the
age range of 20 to 40 years were frequently affected by
infant is being fed, or, by haematogenous spread to the
nasopharyngeal TB. The most common clinical manifes-
mastoid process.
tation was cervical lymphadenopathy [53%], followed
by hearing loss [12%], tinnitus, otalgia, nasal obstruction
Clinical Manifestations
and postnasal drip [6% each]. Systemic symptoms such
Patients with aural TB present with painless otorrhoea as fever, weight loss and night sweats were evident in
and hearing loss. However, patients with TB mastoiditis 12 per cent patients. Direct endoscopic examination
may complain of otalgia. Pale granulation tissue may be showed nasopharyngeal mucosal irregularity or mass in
present in the middle ear with dilatation of vessels in the nasopharynx in a majority [70%] of the patients.
the anterior part of the tympanic membrane (41-44). Primary infection of nasopharynx by TB is very rare
Multiple perforations of tympanic membrane may occur (47). Nasal obstruction or middle ear effusion is the
as a result of caseation necrosis. These perforations may common presenting feature.
coalesce to form a large perforation which may involve
annulus as well. Pars flaccida is usually not involved by TUBERCULOSIS OF THE PARANASAL SINUSES
TB. Facial nerve palsy may occur in patients with TB of
Paranasal sinus TB is a rare entity and is nearly always
the ear with or without a sequestrum [Figure 27.9]. Persis-
secondary to pulmonary or extra-pulmonary TB (48-50).
tent non-healing granulations in a post-mastoidectomy
The sinuses most frequently affected are maxillary and
patient may occasionally be the result of TB infection.
ethmoid, though any sinus may be affected. The infection
Pre-auricular lymphadenopathy with post-auricular
reaches the sinus either via the blood stream or by a direct
fistula has been considered to be pathognomonic of TB
extension from TB of the skull base (51). In sinonasal TB,
otitis media (43).
infection may be limited to the submucosa only. Here,
Tuberculosis of the external ear is uncommon.
the sinus mucosa may be thickened or filled with a polyp,
However, lupus vulgaris of the external ear has been
which has a pale and boggy appearance with minimal
reported (45).
purulent discharge. This form is more common than the
second type, which is characterized by the bony involve-
TUBERCULOSIS OF THE NASOPHARYNX
ment [osteomyelitis] with a sequestrum and fistula
Tuberculosis of the nasopharynx is uncommon. The most formation. The latter form is more difficult to treat. Like
common complaint is nasal obstruction and rhinorrhoea. any other pyogenic infection, the sinonasal TB can also
416 Tuberculosis
spread to the brain or orbit resulting in brain abscess, smear microscopy, culture and the chest radiography
epiphora and deterioration of vision. Rarely, TB of the (14,45,53).
maxillary sinus may be associated with a carcinoma (52). A high index of suspicion is required to diagnose TB
Tuberculosis of the sphenoid sinus can present with of the ear. Tissue biopsy should be done to confirm the
blindness and features of cavernous sinus thrombosis diagnosis. However, due to the atypical nature of the
with gradual onset and slow progression (50). Computed clinical presentation, TB is not suspected initially and
tomography [CT] may show a heterogeneous soft tissue the patient may frequently undergo middle ear explora-
mass lesion in a sinus with bone erosion and extension tion. The diagnosis may become evident subsequently
to the surrounding tissue. Magnetic resonance imaging when histopathology reveals the classical changes.
[MRI] may delineate the soft tissue extension better. Diagnosis of TB otitis media is ascertained by smear
and mycobacterial culture examination of the ear
NASAL TUBERCULOSIS discharge and histopathologic study of the affected tissue.
Smear and culture examination of the nasal discharge,
Tuberculosis of nasal cavity usually manifests as nasal nasopharyngeal secretions collected by nasal endoscopy
obstruction and catarrh. Physical examination may reveal along with histopathological examination of biopsy
pallor of the nasal mucosa with minute apple-jelly material are useful in the diagnosis of TB of the nose,
nodules that do not blanch with nasal decongestants. paranasal sinuses and pharynx. Histopathological and
Other sites which can be involved include inferior microbiological examination of biopsy material is useful
turbinate, septal mucosa and the vestibular skin. These in confirming the diagnosis of TB of the tongue, oral
nodules may coalesce to form a granular lesion with cavity and salivary glands. Diagnosis of cervical lymph
subsequent perforation of the septal cartilage (14). node TB is covered in the chapter “Lymph node tuber-
Involvement of nasolacrimal duct can occur rarely. culosis” [Chapter 26].
Tuberculosis of the nose can cause complications, like Molecular methods of diagnosis, such as polymerase
septal perforation, atrophic rhinitis and scarring of nasal chain reaction [PCR] seem to be useful in the diagnosis
vestibule. of otolaryngological TB. Their usefulness needs to be
confirmed in large studies.
IMAGING IN HEAD AND NECK TUBERCULOSIS
Laryngeal TB must be differentiated from squamous cell
carcinoma and other granulomatous inflammatory Although CT and MRI scanning can accurately demon-
diseases, such as fungal infections, syphilis, leprosy, strate the site, pattern and extent of the disease, however,
Wegener’s granulomatosis, and sarcoidosis. Multiple both these modalities have limitations in the evaluation
biopsies may be required to confirm the diagnosis. of head and neck TB (47). The radiological features are
Tuberculosis of the nose and paranasal sinuses results variable and non-specific. However, CT and MRI have a
in ulceration, granuloma formation and pain in the nose definitive role in the diagnosis of TB of spine. Tubercu-
and the infected sinus cavity. Usually, other granulo- losis lymphadenitis is often characterized by areas of low
matous disorders of the paranasal sinuses are painless. attenuation or low signal intensity with peripheral rim
Tuberculosis of the oral cavity should be differentiated enhancement or calcification on the CT.
from primary syphilis, fungal infections, chronic The CT findings in laryngeal TB are also non-specific.
traumatic ulcers and squamous cell carcinoma. There may be a diffuse thickening of the epiglottis or
vocal cords. Deep submucosal infiltration to pre-
epiglottic or paraglottic space and cartilage destruction
DIAGNOSIS
is usually not seen unlike laryngeal carcinoma. Kim et al
Diagnosis of laryngeal TB involves demonstration of (54) described the CT findings in 12 patients with
Mycobacterium tuberculosis in sputum, laryngeal swab by laryngeal TB. Bilateral involvement was noted in nine
smear and culture methods and histopathological patients [75%], while unilateral involvement was seen
examination of the biopsy material (40). Co-existent in three [25%]. Diffuse thickening of free margin of the
pulmonary TB should be carefully looked for by sputum epiglottis was a characteristic and frequent finding in
TB [50%]. No deep submucosal infiltration of the pre- involvement and two of these patients were HIV-
epiglottic and paralaryngeal fat spaces was seen even positive. The most common symptoms were hoarseness,
when there was extensive involvement of the laryngeal odynophagia and shortness of breath. The majority of
mucosa. Cartilage destruction was not found in any case. the patients had white exophytic lesions involving any
By comparison, laryngeal carcinoma presented with area of the larynx and these lesions resembled carcinoma
unilateral involvement, infiltration of the pre-epiglottic or chronic laryngitis. Systemic symptoms, such as fever,
and paralaryngeal fat spaces by a submucosal mass, night sweats, and weight loss were very common in
cartilage destruction, and extra-laryngeal invasion. patients with AIDS and coupled with other illnesses
In patients with TB mastoiditis, the plain radiograph masked the possibility of laryngeal disease and resulted
or the CT may reveal the presence of a sequestrum. in a delay in the diagnosis.
Further, in patients with aural TB, the CT of temporal In another retrospective study (53), the characteristics
bone may demonstrate destruction of the osseous chain, of TB confined to the head and neck region in 38 patients
sclerosis of the mastoid cortex, and opacification of the infected with HIV were reported. These patients were
middle ear and mastoid air cells. The CT evidence of divided into two groups on the basis of the HIV status at
widespread bone destruction without clinical signs of presentation. Group 1 included 11 patients [29%] with
aggressive infection, should suggest TB mastoiditis (55). AIDS at presentation. Group 2 included 27 patients [71%]
The MRI may show thickened seventh and eighth nerve with HIV infection but without AIDS. The authors
complex in the internal auditory meatus. This finding is reported that the cervical lymphatics were the most
frequently seen in the post-contrast scans in patients with common site for isolated head and neck TB [89%], with
sensory neural hearing loss and facial nerve paralysis the supraclavicular lymph nodes most often involved
[Figure 27.10]. [53%]. Extra-lymphatic involvement was less common
[11%], but involved a variety of anatomic locations [skin,
IMPACT OF HUMAN IMMUNODEFICIENCY VIRUS spinal cord, larynx, parotid salivary gland]. The present-
INFECTION ing history and physical examination had a low
Sparse literature is available on otorhinolaryngological sensitivity for TB in patients with HIV infection, mainly
TB in patients with HIV infection and AIDS (53,56-58). because of the presence of multiple confounding factors.
Singh et al (58) reviewed the clinical presentation of Purified protein derivative testing was highly sensitive
laryngeal TB in HIV-positive patients. In this study, eight for TB in patients with HIV infection alone [61%];
of the 146 patients with head and neck TB had laryngeal however, its usefulness was diminished in patients with
AIDS [14%]. Fine needle aspiration biopsy was 94 per
cent sensitive for diagnosing TB and was not affected by
the status of HIV infection. Surgical biopsy was the gold
standard for diagnosing TB but was associated with
chronically draining fistulas in a significant number of
cases [14%]. These data suggest that TB should be
considered in the differential diagnosis of all head and
neck lesions in patients infected with HIV, even in the
absence of pulmonary involvement.
Six of the fourteen children with HIV-1 infection
described by Schaaf et al (57) presented with otorrhoea.
Ear swabs were the source of Mycobacterium tuberculosis
culture in three of them. Chest radiographs were
abnormal in all of them.
TREATMENT OF TUBERCULOSIS IN THE HEAD

AND NECK
Figure 27.10: Post-contrast MRI scan showing thickened seventh
and eighth nerve complex in the internal auditory meatus and Antituberculosis chemotherapy is the mainstay of
arachnoiditis [arrow] treatment for patients with TB of head and neck region.
418 Tuberculosis
The reader is referred to the chapter “Treatment of the tissue specimens to culture and sensitivity whenever
tuberculosis” [Chapter 52]. Patients should be treated for nontuberculous mycobacterial infection or DR-TB is
six months; however, prolongation of therapy should be suspected.
considered in a patient if response to treatment is
inadequate and slow (59). As the larynx heals, fibrosis of REFERENCES
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420 Tuberculosis
Ocular Tuberculosis
28
SP Garg, Rohan Chawla, Pradeep Venkatesh
INTRODUCTION The impact of acquired immunodeficiency syndrome

[AIDS] epidemic on various ocular manifestations of TB
Tuberculosis [TB] is a serious global public health
remains unclear and ocular TB is uncommon in patients
problem (1). The incidence of ocular TB in a population
with human immunodeficiency virus [HIV] infection and
is difficult to estimate (2). Estimates of incidence and
AIDS (11-17).
prevalence of ocular TB have usually been drawn from
reports of histopathologically proven ocular TB, studies
PRIMARY AND SECONDARY OCULAR
on experimental ocular TB and surveys of ocular disease
TUBERCULOSIS
in patients with proven systemic TB (3). In a report (4)
from a sanatorium in the USA, 1.4 per cent of 10 524 Two different definitions have been given to “primary”
patients were treated for ocular TB between 1940 and ocular TB. The term “primary ocular TB” has been used
1966. In a 10-year review of cases from Romania the when the TB lesions are confined to the eyes and no
incidence of ocular TB has also been reported as being systemic lesions are clinically evident. The term has also
one per cent of all the TB patients (5). The incidence of been used to describe the cases where the eye has been
TB uveitis in India has varied from two to thirty per cent the initial portal of entry (18,19). “Secondary” ocular TB
(6,7). The large variation in the incidence rates in different has been defined as ocular infection resulting from
reports possibly stems from differences in the diagnostic contiguous spread from adjacent structures or
criteria used. In the studies reporting higher incidence haematogeneous spread from the lungs (20).
rates, the diagnosis of TB uveitis was often based on a Well-documented cases of primary ocular TB have
positive tuberculin skin test [TST]. been rarely described in the literature (17,21-23). Primary
Ocular manifestations of TB are protean. While TB ocular infection rarely results in disseminated TB (24).
can affect all areas of the visual system, the choroid is Intraocular and orbital TB are considered to represent
probably the most commonly affected intraocular secondary infections (25,26).
structure. Choroidal tubercles constitute the most Studies to detect the ability of Mycobacterium tuber-
common intraocular manifestation of TB (8). Woods (9) culosis to penetrate intact conjunctival or corneal
estimated that the choroid is involved in about one per epithelium have revealed conflicting results. Finnoff (26)
cent of patients with pulmonary TB. Primary TB of the reported that a breach in the epithelium was necessary
eyelid, conjunctival sac and optic nerve is rare. Rarely, to initiate an infection. Therefore, epithelial injury to the
serious manifestations, such as panophthalmitis or cornea may lead to primary ocular TB (27,28). However,
endophthalmitis can also occur. Certain ocular mani- Bruckner (29), experimenting on guinea pigs observed
festations, such as vasculitis due to TB [e.g., Eale’s that Mycobacterium tuberculosis could be carried into the
disease] are presumably due to hypersensitivity to a subepithelial tissue by phagocytosis despite an intact
sequestered antigen rather than TB disease per se (10). epithelium in the presence of chronic conjunctivitis.
Ocular Tuberculosis 421
Besides Mycobacterium tuberculosis, nontuberculous Conjunctival tuberculomas start insidiously and three
mycobacteria [NTM] can also cause ocular TB. to four weeks later lead to regional lymphadenopathy.
The enlarged preauricular and rarely the submandibular
EYELID TUBERCULOSIS lymph nodes may suppurate resulting in sinus formation.
Tuberculosis affects the eyelids infrequently. The disease Thus, conjunctival TB is one of the causes of Parinaud’s
occurs as a result of spread of infection from the face oculoglandular syndrome of an infectious conjunctivitis
and lymph nodes or by the haematogenous route. Pri- accompanied by regional lymph node enlargement. Very
mary eyelid involvement is extremely rare. Tuberculosis rarely, the disease may start as an acute purulent or
eyelid abscess has been reported in the literature in mucopurulent conjunctivitis with symptoms of fever and
conjunction with lung infection or sinus disease (30-32). malaise.
Eyelid lesion begins as a red papule that becomes Several types of conjunctival granulomas have been
indurated. Eventually, it enlarges to form a nodule or described (36,37) and include ulcerative, nodular,
plaque that ulcerates. The ulcer is chronic and painless. polypoid or hyperplastic lesions. These lesions may be
In majority of the cases, regional lymphadenopathy also solitary or multiple. Solitary tuberculomas involving the
occurs. Rarely, the skin lesion is hyperkeratotic and bulbar conjunctiva are observed in two to thirty per cent
papular. of the cases (38). The nodular prototype may simulate a
Lupus vulgaris of the face may spread to involve the trachomatous lesion. It has a propensity to involve the
eyelid. The disease progresses slowly leading to the bulbar and upper forniceal conjunctiva (17). Associated
characteristic soft “apple-jelly” nodule appearance. This follicles and corneal infiltration may be present. The
feature is best appreciated on diascopy. Atrophic scars, nodule may enlarge to assume a cauliflower-like lesion
ectropion and destruction of the lid may develop. with central ulceration. The ulcerative form has a
Tuberculosis of the tarsal plate can simulate recurrent propensity to involve the inferior cul-de-sac. It can also
chalazion and finally causes its destruction (33). involve the bulbar conjunctiva and tarsus and may also
When lid involvement occurs by spread from the spread to involve the cornea, lid or sclera. Mycobacterium
underlying bone, lacrimal sac or lymph node, the initial tuberculosis can often be found in the ulcer crater (36,37).
manifestation is a red, fluctuant nodule with induration. The hyperplastic variety develops most commonly in the
This lesion ulcerates in several cases and a fistula fornix and rarely on the tarsus. This form is associated
surrounded by granulation tissue develops in the ulcer with severe conjunctival chemosis and lid oedema. It may
crater. Tuberculids of the eyelid present as small, multiple assume a pedunculated appearance like the polypoid
papular and chronic lesions. It is not clear whether they form.
are a non-specific form of granuloma or a hypersensi- Conjunctival tuberculids are a manifestation of
tivity reaction to tuberculoprotein. The reader is referred hypersensitivity reaction. They appear as small conjunc-
to the chapter “Cutaneous tuberculosis” [Chapter 25] for tival nodules. They could be evanescent or remain
more details. localized. They are associated with TB involvement of
the uveal tract, sclera, skin or other regions of the body.
CONJUNCTIVAL TUBERCULOSIS Tuberculosis of the bulbar conjunctiva is usually
Tuberculosis can involve the conjunctiva primarily or associated with an interstitial keratitis.
secondarily. Conjunctival TB and lupus vulgaris are Phlyctenulosis can involve the lid margin, cornea or
manifestations of primary infection while tuberculids conjunctiva. A phlycten [from the greek word for blister]
and phlyctenulosis are manifestations of secondary is a hypersensitivity reaction to tuberculoprotein. In the
conjunctival infection. Primary lesions present as conjunctiva, it can affect the bulbar, conjunctival or limbal
unilateral nodular or ulcerative conjuctivitis (34,35) region. However, the most common site is the limbal
associated with regional lymphadenopathy. Children are region. It usually appears as a small nodule with
most commonly affected (34). Secondary lesions due to surrounding hyperaemia. It gradually ulcerates and heals
spread from contiguous disease or haematogenous without scarring. This is in contrast to the corneal
dissemination are more common in older patients. The phlyctenulosis, which leaves a scar on healing. Limbal
disease may be bilateral and may cause regional lymph- phlyctenules leave a characteristic triangular scar because
adenopathy (34,35). the conjunctival portion, unlike the corneal portion heals
422 Tuberculosis
without scar formation. Tuberculosis phlcytenular presentation is also known (48,49). Physical examination
keratoconjunctivitis also occurs. Mycobacterium tubercu- may reveal preauricular and submandibular lymph-
losis has been demonstrated in only one-fourth of patients adenopathy. The scleritis develops due to direct scleral
with conjunctival TB (17). In the west, Staphylococcal infection or, by spread from the conjunctiva, uveal tract
infection has replaced TB as the leading cause of or by haematogenous route and produces a nodular
phlyctenular keratoconjunctivitis. Phlyctenular kerato- lesion [Figure 28.1]. Peripheral cornea is often secondarily
conjunctivitis due to TB usually occurs in malnourished affected and granulomatous uveitis may also develop.
older children and is more common in girls. Symptoms The scleral nodules may undergo caseous necrosis and
usually last for one to two weeks and consist of excessive ulceration. Subsequently, perforation may develop.
lacrimation, pain, photophobia and blepharospasm. The
severity of symptoms depends on the site of involvement.
Corneal involvement indicates a much more severe form
of the disease. Recurrence is frequent and may occur at a
different site.
CORNEAL TUBERCULOSIS
Manifestations of TB in the cornea include phlycte-
nulosis, interstitial keratitis, ulceration and infiltrations
(39-42). Rarely, these patients may also have active
pulmonary TB (43,44). Phlyctens of the cornea usually
arise from limbus. Corneal involvement is characterized
by intense photophobia, pain and blepharospasm.
Marginal, miliary and fasicular phlyctenular patterns
have been described. Corneal phlyctenules heal with a
variable degree of scarring and vascularization.
Interstitial keratitis is uncommon in TB. However, as
compared to syphilis, TB interstitial keratitis is associated Figure 28.1: Nodular scleritis in a patient with miliary
with more intense scarring and vascularization in the tuberculosis
deeper layers (45). Besides being usually unilateral, TB
often has selective propensity to involve the lower part TUBERCULOSIS OF LACRIMAL SYSTEM
of the cornea. Sclerosing keratitis may occur as sequelae
Tuberculosis involvement of the lacrimal gland, lacrimal
to TB involvement of the sclera. Clinically, sclerosing
canaliculi and lacrimal sac is unusual. Tuberculosis
keratitis appears as peripheral corneal scleralization. On
dacryoadenitis usually develops during haematogenous
resolution, it leaves behind a triangular or tongue-shaped
dissemination, occasionally due to spread from conjunc-
opacity with the base directed towards the limbus.
tival or corneal disease and still infrequently due to an
Corneal ulceration due to TB usually develops from
injury. It appears as a gradually enlarging painless
the contiguous spread of infection from the conjunctiva
swelling. When the eyelid is involved, lid oedema and
or uveal tract. These ulcers are indolent and refractory
pseudoproptosis are prominent features. If the orbit is
to treatment.
involved, proptosis and restriction of upward gaze are
SCLERAL TUBERCULOSIS evident. Abscess formation with a chronic draining
fistula in the upper lid can also occur. Regional lymph-
Although TB was reported as a frequent cause of scleritis
adenopathy is a prominent manifestation in patients with
earlier, it was considered rare by 1926 (46). Watson and
TB of the lacrimal system.
Hayreh (47) found TB of the sclera in only one of the 217
cases of episcleritis.
ORBITAL TUBERCULOSIS
Tuberculosis of the sclera is characterized by scleral
and conjunctival ulceration. Focal necrotising anterior Abadie in 1881 (50) was the first to describe orbital TB.
scleritis is the most common presentation, but a diffuse Since then, several cases of orbital TB have been reported.
Orbital TB can occur in several forms, notably, periostitis, TB usually results from haematogenous dissemination.
tuberculomas and myositis. A case of TB osteomyelitis However, their presence is not diagnostic of miliary TB
involving the orbit and masquerading as post-traumatic (60-63), although investigation for the same in a patient
haematoma has also been reported (51). may be rewarding. The finding of choroidal tubercles in
Orbital TB occurs by haematogenous spread or by TB meningitis is still rarer. In one study, 28 to 60 per cent
extension of infection from adjacent structures, such as of patients with miliary TB were reported to have choroi-
the paranasal sinuses. It is usually unilateral and typically dal tubercles on ophthalmoscopic examination (63).
occurs in the first two decades of life. It usually has a However, in the same study (63), only one of the
protracted course. Tuberculosis periostitis has an 18 patients [0.05%] with TB meningitis without miliary
insidious onset and presents as a chronic, painless disease had choroidal tubercles. Sharma et al (64) found
inflammation, most commonly of the malar bone. Over choroidal tubercles in only 4.5 per cent [4 of the 88
months, oedema and discolouration of the overlying skin patients] HIV-seronegative patients with miliary TB at
can progress to cold abscess, fistula formation, New Delhi. Massaro et al (62) found choroidal tubercles
cicatrization and regional lymphadenitis. Tuberculomas, in 30 per cent of patients with pulmonary TB. Patients
firm masses of chronic granulomatous inflammation, can with choroidal tubercles may be asymptomatic or the
occur anywhere in the orbit. These lesions can occur at only symptom may be blurring of vision. On clinical
any age. They cause gradual painless proptosis and examination, choroidal tubercles may be solitary [Figure
sclerosis and, thus, mimic benign and malignant 28.2] or multiple [Figure 28.3] and of varying dimensions
tumours, orbital pseudotumours and fungal infections. ranging from about a quarter of the disc diameter to
Occasionally, they involve extraocular muscles and are several disc diameters [Figures 28.4A and 28.4B]. They
bilateral in location. Tuberculomas may also start in the are most frequently situated in the posterior pole (62).
maxillary or ethmoid sinuses, erode into the orbit and Up to 60 choroidal tubercles have been described but,
form fistula in the skin. Overt signs of chronic sinusitis usually less than five are seen. They appear as yellowish-
accompany this presentation. Epiphora and epistaxis are grey elevated nodules with or without overlying
also common symptoms. inflammation in the vitreous during the active stage
[Figure 28.5]. The overlying and surrounding retina may
TUBERCULOSIS OF THE UVEAL TRACT be detached. Though suggestive of TB they are not
diagnostic and may occur in other conditions such as
Mycobacterium tuberculosis can involve the two principal
fungal infections, sarcoidosis, syphilis and metastatic
internal layers of the eye: the uveal and the retinal layers.
deposits in the choroid.
Rarely, it can cause a panophthalmitis (52-59). Tuber-
culosis involving the uvea may present as choroidal
tubercles or granulomas, disseminated choroiditis,
chronic or acute granulomatous iridocyclitis, pars
planitis, ciliary body granulomas or endophthalmitis. It
involves the choroid more frequently than the iris and
ciliary body. In a series of 40 patients with histo-
pathological evidence of Mycobacterium tuberculosis
infection affecting the internal layers of the eye (3), the
mean age at diagnosis was 32 years. Males and females
were equally affected and the disease was mostly
unilateral.
CHOROIDAL TUBERCULOSIS
Choroidal tubercles and tuberculomata [large, solitary
masses] are the most common ocular manifestations of
TB. Choroid is a highly vascular structure and choroidal Figure 28.2: Solitary tuberculoma in miliary tuberculosis
424 Tuberculosis
Figure 28.3: Multiple choroidal tubercles in miliary Figure 28.4B: Post-treatment photograph of the same patient
tuberculosis [arrows] showing significant resolution of the choroidal tuberculoma
Figure 28.4A: Pre-treatment photograph in a patient with a large Figure 28.5: Choroidal lesion in a patient with intestinal
solitary choroidal tuberculoma tuberculosis
There is no typical diagnostic pattern of these lesions followed by late hyperfluorescence (65) or hyper-
[small and large tuberculomas] on fluorescein angio- fluorescence from the early phases itself which increases
graphy or ultrasonography. Thus, these investigations in intensity with time (66). However, intense hyperfluore-
in cases of tuberculomas are more helpful in ruling out scence in the late phases of the angiogram is always seen
other causes, such as haemangioma or melanoma, which in large tuberculomas [Figure 28.7].
have a more characteristic presentation. On ultrasono- Most patients with miliary TB and choroidal tubercles
graphy most choroidal tuberculomas appear as dome- have no anterior segment involvement (67,68) perhaps
shaped choroidal masses with low to moderate internal because these patients are unable to mount an effective
reflectivity. In cases with extensive caseous necrosis immunologic response to infection. Rarely, however,
leading to formation of cold abscess, sonography may choroidal tubercles may co-exist with panuveitis (69,70).
show a loculated anechoic area within the mass [Figure Tuberculosis can affect the retina either by direct
28.6]. Fluorescein angiography of choroidal tubercles, infection or because of a hypersensitivity reaction.
tuberculomas may reveal early hypofluorescence Isolated involvement of the retina by direct infection is
Traditionally, mutton fat keratic precipitates, early

formation of dense synechiae and formation of iris
nodules of Koeppe or Bussaca were considered to be
characteristic of TB iridocyclitis. Such lesions must be
distinguished from sarcoid nodules which are larger and
more pink.
Tuberculosis Endophthalmitis and Panophthalmitis
Rarely, TB infection may lead to an endogeneous pan-

ophthalmitis [Figure 28.7] or endophthalmitis (52-59).
Most of these cases have been reported in debilitated and
immunocompromised individuals, drug abusers or
children. Certain features that might point to TB aetiology
Figure 28.6: Ultrasonography showing a choroidal tuberculoma include painless loss of vision despite significant
intraocular inflammation, presence of iris or scleral
nodules, spontaneous perforation of the ocular coats and
early development of neovascularization of the anterior
chamber starting from the angle and progressing
centrally. Pain may develop due to secondary glaucoma.
Endophthalmitis might begin as a posterior or an
anterior diffuse type [Figure 28.8]. In the anterior diffuse
type the primary involvement is restricted to the anterior
chamber and iris. The patient may present with
significant exudation, hypopyon with a silent posterior
segment.
Figure 28.7: Fluorescein angiogram in a patient with choroidal It is important to identify and treat such cases early
tuberculoma
to avoid enucleation. Also, a complete systemic work-
up to rule out any focus of systemic infection must be
extremely rare. Experimental and clinical studies have carried out.
revealed that Mycobacterium tuberculosis rarely affects the
retina directly (4,43,44,71). The retina is more commonly
affected secondarily from adjacent choroidal lesions.
Some workers have attributed retinal periphlebitis to
direct infection (72,73). In an atypical presentation, Saini
et al (74) found histopathological evidence of TB in an
eye that had been enucleated for presumed retino-
blastoma.
TUBERCULOSIS IRITIS AND IRIDOCYCLITIS

Gradenigo in 1869 (70) first reported histopathological
evidence of TB of the iris in a patient with miliary TB at
autopsy. Tuberculosis was considered an important
cause of granulomatous uveitis until the early 1960s.
However, there has been a dramatic decline in the
number of these cases probably due to identification of Figure 28.8: Anterior segment photograph in a patient with
other diseases, like sarcoidosis and toxoplasmosis. tuberculosis panophthalmitis
426 Tuberculosis
Presumed Intraocular Tuberculosis segment inflammation [Figures 28.9A, 28.9B, and 28.10].
These cases must be investigated thoroughly for any
There are certain ocular conditions which are presumed
evidence of TB. High positivity of PCR for Mycobacterium
to be due to TB, however, actual demonstration of
tuberculosis in the ocular fluids in these patients needs to
tubercle bacilli in such cases is lacking. The list includes
be investigated further.
Eale’s disease and serpigeneous choroiditis.
Another disease attributed recently to TB is serpigi-
Eale’s disease, an idiopathic, non-infective, inflam-
neous choroiditis. Gupta et al (83) have demonstrated
matory vasculitis of the retinal vasculature has been
Mycobacterium tuberculosis DNA in ocular fluids of cases
attributed to hypersensitivity to tuberculoprotein. This
with serpigineous choroiditis. These patients also had
disease is an important cause of visual morbidity in
systemic evidence of TB. However, classically described
healthy young adults, especially from the Indian
serpigineous choroiditis is idiopathic and responds to
subcontinent. It affects persons in their second and third
corticosteroid and immunosuppressive therapy. Further
decades of life (75). Males are more frequently affected
(76). In about 90 per cent of the patients, the disease
becomes bilateral within a few years. Most patients
present with painless, sudden visual loss in one eye due
to vitreous haemorrhage.
Eale’s disease is characterized by retinal periphlebitis
and capillary non-perfusion that result in hypoxia. This
leads to neovascularization either on the retinal surface
or on the optic nerve head. The new vessels being
extremely fragile have a propensity to bleed into the
vitreous. In some cases, this can lead to retinal detach-
ment and an irreversible visual loss.
The reasons for associating Eale’s disease with TB
include increased prevalence of tuberculoprotein hyper-
sensitivity (25,76-79); presence of concurrent active or
healed pulmonary TB (77,79); and response to antituber-
culosis treatment in some patients. Recently, Figure 28.9A: Pre-treatment photograph of a patient with
Mycobacterium tuberculosis deoxyribonucleic acid [DNA] tuberculosis anterior diffuse endophthalmitis
has been identified using polymerase chain reaction
[PCR] on vitreous and epiretinal membrane samples in
a significantly greater proportion of patients with Eale’s
disease as compared to controls (10,80). This, however,
is not an indicator of active TB infection. But it provides
support to the hypothesis that a sequestered TB antigen
might be involved in the cascade of events leading to a
hypersensitivity reaction. Histopathologically, no
features typical of TB inflammation have been described
in Eale’s disease (77,81,82). In most cases, a non-specific
perivascular cuff of lymphocytes has been described.
Thus, empirical antituberculosis therapy in patients
with Eale’s disease is not recommended presently.
However, it is important to identify a subset of patients
with Eale’s disease, who apart from the typical features
of vasculitis and neovascularization also show significant
perivascular exudation, vitritis, snowball vitreous Figure 28.9B: Post-treatment photograph of the same patient
opacities, pars plana exudation or extensive anterior showing considerable resolution of the lesion
PATHOLOGY
Histopathologically phlyctenules are characterized by a
dense accumulation of lymphocytes, histiocytes and
plasma cells. Neutrophils may be seen in the acute stage.
There is a notable absence of giant ells and eosinophils.
Mycobacterium tuberculosis is seldom seen. Choroidal
tubercles are similar to the tubercles found elsewhere in
the body. Granulomas may be caseating or non-caseating.
The characteristic giant cells may also be seen. In contrast
to the histopathology of choroidal tubercles, TB
endophthalmitis is characterized by marked caseation
necrosis and exudation. The reader is also referred to the
chapter “Pathology” [Chapter 5] for more details.
Figure 28.10: Fundus photographs of a case showing vasculitis DIAGNOSIS

due to tuberculosis
Definitive diagnosis of ocular TB can be made only by
demonstrating Mycobacterium tuberculosis in the ocular
studies are required to clarify as to which subset of tissues. However, obtaining ocular tissue for diagnostic
patients with serpigineous choroiditis might have TB purposes is not only difficult, but is also associated with
aetiology. Tuberculosis can rarely cause pars planitis (84). significant ocular morbidity. Hence, the diagnosis of TB
can rarely be definitely confirmed before enucleation.
OCULAR TUBERCULOSIS IN HUMAN Only 25 per cent of patients with ocular TB give past
IMMUNODEFICIENCY VIRUS INFECTED history of TB and 50 per cent have normal chest radio-
INDIVIDUALS graphs (9,86). Orbital radiographs may reveal bony
erosions.
Though there are some published case reports of ocular
A high degree of clinical suspicion is, therefore, the
TB in HIV-infected patients (13-15), ocular TB appears
key to early diagnosis. Easily accessible sites, such as
to be a rare manifestation in these patients. Shafer and
eyelid, conjunctiva (48), lacrimal gland and sclera (87),
associates (11) did not report a single case of ocular TB
should preferably be biopsied to demonstrate the charac-
in a study of 199 consecutive patients with HIV infection
teristic findings of caseating granulomas with Langhans’
and extra-pulmonary TB. Small et al (12) reviewed
giant cells and Mycobacterium tuberculosis. Despite all
132 patients with AIDS and TB. In this study (12), TB
investigations patients with clinically suspicious lesions
was entirely extra-pulmonary in 30 per cent and both
should receive empirical standard antituberculosis
pulmonary and extra-pulmonary in 32 per cent of
treatment and should be carefully followed-up for
patients and no ocular involvement was reported. In
therapeutic response.
another study (16), ocular TB was seen in 15 [2%] of the
766 consecutive patients with HIV infection and AIDS.
In a recent report (17) from New Delhi, ocular mani-
festations were present in six of the 135 [4.4%] HIV- A positive TST in a patient with granulomatous uveitis
seropositive patients studied; five patients had TB was considered to be a positive evidence of ocular TB. A
choroiditis [unilateral in 2, bilateral in 3 patients] and positive TST is, however, only indicative of infection with
one patient had optic atrophy due to TB meningitis. Mycobacterium tuberculosis and does not necessarily reflect
Paradoxical worsening of the ocular TB lesions in HIV- the disease activity (36,39,62,88-91). Rosenbaum and
seropositive patients receiving antiretroviral treatment Wernik (92,93) calculated that a patient with uveitis and
[ART] has also been described (85). a positive TST test has only one per cent probability of
428 Tuberculosis
having active TB. However, recent conversion of a Table 28.1: Suggested criteria for the diagnosis of intraocular
previous non-reactor favours the diagnosis of TB. Use of tuberculosis in patients presenting with a compatible clinical
systemic corticosteroids for severe ocular inflammation picture in whom there is no definite histopathological or
microbiological evidence of tuberculosis
can interfere with the TST results. Therefore, though a
routine TST has been advocated in patients with uveitis, Major criteria
it is rarely diagnostic (91,94-96). In countries where TB is Evidence of pulmonary or other systemic pathology consistent
with TB occurring concurrently with the ocular disease
highly endemic, a caution is advocated before
Response of ocular and systemic disease to antituberculosis
interpreting a positive TST result in isolation. A positive treatment [with or without steroids]
TST can be considered to be supporting evidence in a Exclusion of other aetiological causes, like sarcoidosis,
patient with a clinical picture highly suggestive of TB tumours, secondary metastases
such as choroidal tubercles or tuberculoma or when other Minor criteria
investigations such as a chest radiograph also have Positive IGRAs or TST
findings compatible with TB. On the other hand, a Positive PCR for Mycobacterium tuberculosis in ocular fluids
negative TST is considered by some as being more or biopsy
relevant as it rules out TB if the patient is immunocom- All major criteria fulfilled = highly probable intraocular TB; 2 major
petent. This, however, is also not always true as there and 1 minor criterion fulfilled = probable intraocular TB
are several causes of anergy (97). TST = tuberculin skin test; IGRAs = interferon-gamma release
assays; PCR = polymerase chain reaction; TB = tuberculosis
Serological and Molecular Methods
In patients with ocular TB, it is seldom possible to procure
TREATMENT
adequate tissue for diagnosis and the number of
organisms present may be too small to be detected by When patients with TB elsewhere in the body develop
conventional methods. The utility of serological tests in clinical features of ocular involvement, thorough
the diagnosis of ocular TB needs further evaluation in ophthalmologic evaluation is warranted. Similarly when
well-designed studies with a large sample size. patients are detected to have ocular involvement, a
Polymerase chain reaction appears to be a promising tool complete systemic evaluation must be done. Treatment
to establish the definitive diagnosis of ocular TB (98-101). of ocular TB is on the same lines as treatment of TB
Despite rapid advances in medicine, ocular TB still elsewhere in the body. The disease is said to respond
remains an important diagnostic challenge. The criteria well to standard antituberculosis treatment and there is
for the diagnosis of ocular TB differ greatly and very often no role for topical treatment. The reader is referred to
the diagnosis is based on a compatible clinical picture the chapter “Treatment of tuberculosis” [Chapter 52] for
and good therapeutic response to antituberculosis more details. However, as significant damage can occur
treatment rather than mycobacterial isolation. to ocular tissues from infection as well as inflammation,
Earlier, it has been suggested that clinical diagnosis it is prudent to add systemic corticosteroids as an
of ocular TB be based on the presence of at least three of adjuvant to the standard antituberculosis treatment. This
the following five features (102): [i] suggestive clinical must be done in consultation with a physician keeping
picture; [ii] exclusion of other aetiology; [iii] positive TST; in mind the general condition of the patient and the
[iv] therapeutic response to antituberculosis treatment; presence of associated co-morbidities. It is not clear how
and [v] present or past history of TB. soon after initiation of antituberculosis treatment one
In patients with a clinical picture suggestive of intra- should start corticosteroids in patients with ocular TB.
ocular TB [including all clinical manifestations descri- However, as in cases of TB meningitis starting steroids
bed above except those which come under presumed early may be beneficial.
intraocular TB] in whom there is no definite histopatho- Under the Revised National Tuberculosis Control
logical or microbiological evidence of TB, the criteria Programme [RNTCP] of the Government of India,
shown in Table 28.1 can be helpful. patients with giant TB granulomas in the choroid and
those with vision threatening disease, constitute serious including visual evoked responses [VER] are useful in
form of extra-pulmonary TB similar to meningeal and confirming the involvement of the optic nerve and retina
spinal TB and should receive Category I DOTS treat- in patients receiving ethambutol.
ment. The reader is referred to the chapter “Revised Ethambutol related ocular toxicity is strongly dose
National Tuberculosis Control Programme [RNTCP]” related (107-117). In a study reported by Carr and
[Chapter 63] for more details. Henkind in 1962 (107), 45 per cent of patients receiving
Anterior segment inflammation should be managed 60 to 100 mg/kg/day developed ocular toxicity. At that
with topical steroids and cycloplegics. Treatment of TB time the older racemic mixture of ethambutol was used
phlyctenulosis also involves topical corticosteroids and (116). Another report showed the incidence of ocular
cycloplegic agents in addition to standard antituber- toxicity to be 18.6 per cent in patients receiving more than
culosis treatment. Conjunctival lesions causing only mild 53 mg/kg/day of ethambutol (109). With 25 mg/kg/day,
symptoms may respond to local astringents. Muco- the reported incidence of ethambutol related optic
purulent discharge suggests secondary bacterial infection neuritis was 1.3 to 15 per cent (110). However, less than
and should be treated accordingly. Conjuctival lesions two per cent patients develop this complication with
heal without scarring, but corneal phlyctenules leave doses below 15 mg/kg/day (111-116). Most cases of
superficial scars of variable severity. ethambutol optic neuropathy occur six to eight weeks
Adjunctive therapy with topical antibiotics, such as after starting chemotherapy (118).
streptomycin, amikacin or isoniazid has also been tried As the incidence of ethambutol toxicity is low with
in the treatment of TB scleritis with varying results (87). the currently favoured dose of 15 to 20 mg/kg/day, and
also because it is reversible in most cases, sophisticated
Antituberculosis Treatment Induced Ocular Toxicity electrophysiological tests like electroretinography and
Several antituberculosis drugs can cause ocular adverse VER are not required in all cases. However, in all patients
effects, which if not recognized early can result in an receiving ethambutol, a baseline best corrected visual
irreversible loss of vision. Often patients are referred to acuity and colour vision record should be routinely
ophthalmologists for evaluation of ocular toxicity obtained. Thereafter, patients should be questioned
following prescription of drugs for TB elsewhere in the monthly about any changes in vision. Any significant
body. Sometimes patients themselves notice a diminution alteration in vision needs to be promptly investigated.
in vision while on antituberculosis treatment and get Isoniazid has also been reported to cause optic neuritis
evaluated by an ophthalmologist. Ocular toxicity due to (119-125). In these cases, the dose of isoniazid has ranged
ethambutol, isoniazid and streptomycin has been well from 200 to 900 mg/day and symptoms have been
documented. Of these, ethambutol has the greatest reported as early as the tenth day. Isoniazid has to be
potential to cause ocular toxicity. In general, adverse drug discontinued at the first sign of ocular toxicity and
reactions occur less frequently in patients receiving pyridoxine may probably be beneficial both in the
intermittent regimens as compared to daily regimens. treatment as well as prophylaxis (122,123). There have
Three types of optic neuritis have been described with been few reports of ocular toxicity due to streptomycin
ethambutol (103). These include the axial, the periaxial of which, only the report by Sykowski (124) has been
and the mixed type. Both eyes are usually involved and widely accepted.
the visual loss may vary from mild to severe. Colour The most common adverse effect of rifampicin in the
vision is also variably affected. In the axial form of optic eye is conjunctivitis. It can result in the production of
neuritis, on visual field recording pericentral or peri- tears that are orange coloured and this can stain contact
pheral scotoma may be evident. Quadrantic field defects lenses (125). Rifabutin has been associated with the
have also been commonly found. Although mild disc development of an endophthalmitis-like response (126).
hyperaemia and disc oedema have been reported, fundus Clofazimine has been associated with several ocular side
examination may be normal in the acute phase of etham- effects; these include: a brownish discolouration of the
butol toxicity (104). Peripapillary splinter haemorrhages, conjunctiva, brown swirls in the cornea (127,128) and
macular oedema and focal pigmentary changes have also bull’s eye maculopathy resulting in visual loss due to
been described (105,106). Electrophysiological studies macular degeneration (129,130).
430 Tuberculosis
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434 Tuberculosis
Breast Tuberculosis
29
Puneet Gupta, M. Tewari, HS Shukla
INTRODUCTION from the world literature.

In developing countries, the incidence of breast TB
Tuberculosis [TB] of the breast is extremely rare (1). It is
in surgically treated breast disease was found to be 3 to
uncommon even in those countries where the incidence
4.5 per cent (15). Although the first case of TB mastitis
of pulmonary and extra-pulmonary TB is high (2-8).
from India was reported by Chaudhary (16) in 1957, there
Because of non-specific clinical features, the condition
have been occasional reports on breast TB from India
remains undiagnosed and is often mistaken for
(2,17-19). The prevalence of breast TB in India has been
carcinoma or pyogenic breast abscess. It also presents as
reported by several authors to vary between 0.64 and
a diagnostic problem on radiological and microbiological
3.59 per cent (18,19). In an extensive review of benign
investigations.
breast disorders in India, Shukla and Kumar (20) found
a high prevalence of breast TB [5.2% of all breast
EPIDEMIOLOGY
disorders and 32% of all infective lesions].
Tuberculosis involves breast infrequently as compared Tuberculosis of the breast is rare in the western
with other organs of the body. This is due to the fact countries, with the prevalence being less than 0.1 per cent
that, like skeletal muscles and spleen, it provides infertile of breast lesions examined histologically (21,22). But with
environment for survival and multiplication of the dynamics of global spread of acquired immuno-
Mycobacterium tuberculosis (9). deficiency syndrome [AIDS], mammary TB may no
Sir Astley Cooper reported the first case of mammary longer be uncommon even in the developed world (23).
TB in 1829 and called it “scrofulous swelling of the
bosom” (10). Morgan reviewed literature in 1931 and MODE OF INFECTION
found 439 cases of TB mastitis and estimated the
incidence to be between 0.5 and 1.04 per cent (11). In According to Mckeown and Wilkinson (14), the breast
1944, Klossner (12) reported 50 cases of breast TB in TB could be primary when the breast lesion is the only
women, out of 75 000 with pulmonary involvement. manifestation of TB, or secondary when demonstrable
Haagensen (13) could detect only five cases of breast TB TB lesion is present elsewhere in the body. However, it
out of approximately 8000 breast specimens studied is now increasingly accepted that the breast TB is almost
between 1938 and 1967. Similarly, at the New York invariably secondary to a lesion elsewhere in the body
Hospital, only two cases of breast TB were encountered (17,18,24).
among 2 141 breast specimens studied between 1949 and The breast may become infected in several ways:
1954 (13). In 1952, Mckeown and Wilkinson (14) descri- [i] haematogenous spread; [ii] lymphatic route;
bed the primary and secondary forms of breast TB. Hamit [iii] spread from contiguous structures; [iv] direct
and Ragsdale (15) in 1985 could document only 500 cases inoculation; and [v] ductal infection. Of these, the most
Breast Tuberculosis 435
accepted view for spread of infection is centripetal prevalence of TB in the faucial tonsils of suckling infants
lymphatic spread from lungs to breast tissue via the with the higher incidence of breast TB in lactating
tracheobronchial, paratracheal, mediastinal lymph trunk women in India; thereby suggesting the spread of
and internal mammary nodes (2,14). infection orally from the suckling infant to the nipple,
The infection may also spread through retrograde and in turn, to the lactating breast via lacticiferous
lymphatic spread from the axillary lymph nodes. A ducts (28). Tuberculosis of the breast is rare in males
communication between the axillary glands and the (11,29).
breast emphasizes the Cooper’s theory of secondary
involvement of the breast by lymphatic extension (25). Clinical Presentation
The retrograde flow may also occur from cervical and
Tuberculosis of the breast usually presents as a unilateral
less commonly from paratracheal and internal mammary
disease and bilateral involvement is uncommon, being
lymph nodes (17,18). Direct extension from contiguous reported in less than three per cent of the cases (17).
structures such as infected rib, costochondral cartilage,
In patients with TB of the breast, the duration of
sternum, shoulder joint and even through the chest wall
symptoms varies from a few months to several years but,
from TB pleurisy or via abrasions in the skin has been is usually less than a year (19,30). The clinical findings in
described (24,26). In all cases the bacilli infect the ducts
TB of the breast are summarized in Table 29.1.
and spare the lobules.
A lump in the breast is the most common presentation
(9,31). It is commonly found in the central or upper outer
CLINICAL PRESENTATION quadrant of the breast (20) [Figure 29.1], due to frequent
Age and Sex extension of TB from axillary lymph nodes to the breast.
Presentation with multiple lumps is less frequent (18). A
Tuberculosis of the breast commonly affects young lump of TB mastitis is irregular, ill-defined and hard
women in their reproductive age group [21 to 30 years]
(20,27). It is relatively uncommon in older women and Table 29.1: Clinical findings in tuberculosis of the breast
in the prepubertal age (27). Pregnant and lactating
Lump[s] in the breast with and without axillary nodes
women are more susceptible to develop breast TB since Ulcer
the lactating breast is vascular with dilated ducts, Breast abscess with and without discharging sinuses
predisposed to trauma making it more susceptible to Peau d’orange
TB infection (17,27). Wilson and MacGregor (28) Purulent nipple discharge
proposed an interesting hypothesis by correlating the Persistent discharging sinus
Figure 29.1: Breast tuberculosis. Clinical photograph showing a lump, overlying ulceration [arrow] with undermined margins in the upper
outer quadrant of the right breast and nipple retraction [A], and clinical photograph of the same patient with the arm abducted showing the
lump with ulceration [arrow] [B]
436 Tuberculosis
similar to carcinoma. The lump may be painful, mobile is the dominating feature. It presents as a hard painless
or fixed to either skin or muscle or even chest wall (27). slow growing lump with nipple retraction. Suppuration
The breast remains mobile unless involvement is is rare. It may be misdiagnosed as a schirrotic carcinoma
secondary to TB of the underlying chest wall (17). (27). Often the entire breast becomes hard because of
An ulcer in the skin overlying the breast and breast dense fibrous tissue.
abscess can also occur (20). Nipple retraction and peau
d’orange are at times seen. Breast oedema is evident in Tuberculosis Mastitis Obliterans
patients with extensive axillary nodal TB.
Tuberculosis mastitis obliterans is characterized by duct
infection that produces proliferation of lining epithelium
CLASSIFICATION OF BREAST TUBERCULOSIS
and marked epithelial and periductal fibrosis. Cystic
The breast TB has been classified into different types as spaces are formed due to occlusion of ducts and the
described in Table 29.2 (14). condition resembles ‘cystic mastitis’.
Table 29.2: Classification of breast tuberculosis Acute Miliary Tuberculosis Mastitis

Older classification
Sometimes, breast involvement can occur as a part of
Nodular TB mastitis
Disseminated or confluent TB mastitis generalized miliary TB.
Sclerosing TB mastitis
TB mastitis obliterans
INVESTIGATIONS
Acute miliary TB mastitis
Recent classification Investigations are done with the aim to establish TB
Nodular TB mastitis infection of the breast, presence of active or dormant TB
Disseminated or confluent TB mastitis
focus elsewhere in the body and to rule out other lesions
Breast abscess
of the breast which closely resemble breast TB, especially
Source: reference 2 breast cancer.
TB = tuberculosis
Nodular Tuberculosis Mastitis
A positive tuberculin skin test [TST] indicates infection
Nodular TB mastitis is the most common form of breast
with Mycobacterium tuberculosis and is not a marker for
TB. It presents as a well-circumscribed, slowly growing
active disease. Therefore, it is of no diagnsotic value in
painless mass[es] that progress to involve the overlying patients with breast TB in areas where TB is highly
skin, may ulcerate, form sinuses and may become
endemic.
painful. In early stage it is difficult to differentiate from
a fibroadenoma, while in later stages it mimics a Chest Radiograph
carcinoma (32,33).
The chest radiograph may show evidence of active or
Disseminated or Confluent Tuberculosis Mastitis healed TB lesion[s] in the lungs in a few cases (19). It
Disseminated or confluent TB mastitis is a rare form of may also reveal clustered calcifications in the axilla
breast TB and is characterized by multiple foci suggesting the possibility of healed TB of the lymph
throughout the breast that later caseate leading to sinus nodes (34).
formation. The overlying skin is thickened and stretched
Mammography
with or without painful ulcers. The breast may be tense
and tender. The draining axillary lymph nodes are The mammographic findings in breast TB are non-
enlarged and matted (27). specific and may include mass, coarse calcification [but
absence of microcalcification], asymmetric density of
Sclerosing Tuberculosis Mastitis breast parenchyma with spiculated margin, skin
Sclerosing TB mastitis usually affects involuting breasts thickening, nipple retraction and axillary lymph node
of older females. Excessive fibrosis rather than caseation enlargement (35). A dense tract connecting an ill-defined
breast mass to a localized skin thickening and bulge [skin surrounding enchancing rim on contrast CT. A direct
bulge and sinus tract-sign] suggests the possibility of a fistulous connection with the pleura or a destroyed rib
TB abscess (36). Mammographically, nodular, dissemi- fragment in the abscess can also be seen (40). The CT
nated and sclerosing types of TB mastitis can be also shows area[s] of lung destruction beneath the
differentiated. The mammographic picture of nodular pleural disease (41,42). The TB breast abscess can also
breast TB is very similar to carcinoma except the size of be drained percutaneously under CT guidance (41). It
the lesion, which correlates with the clinical size (27). is a valuable tool in demonstrating extent of the disease,
Usually, a dense round area with indistinct margins is and is therefore, useful in planning for surgery and in
seen without the classic ‘halo sign’ found in fibro- assessing the response to treatment.
adenoma (37). The disseminated variety mimics
inflammatory carcinoma and the radiographs show Magnetic Resonance Imaging of the Breast
dense breast with thickened skin (37). Sclerosing TB
mastitis reveals a homogeneous dense mass with fibrous Only a few reports on magnetic resonance imaging [MRI]
septae and nipple retraction (17,27,36,38). However, the findings in breast TB are available (35,42,43). A breast
mammogram is of limited value in the diagnosis of breast abscess is identified by T2-weighted images as a smooth
TB as the findings are often indistinguishable from or irregular ring like bright signal intensity. However,
carcinoma of the breast. The age of the patient is consi- this finding in gadolinium diethylenetriaminepentaacetic
dered while evaluating the mammogram for suspected acid [Gd-DTPA] enhanced MRI scan is non-specific and
breast TB. is also seen in breast carcinoma and bacterial and fungal
abscesses. Despite these limitations, MRI is very useful
Ultrasonography of the Breast in demonstrating the extra-mammary extent of the lesion
(35,42,43).
No sonographic details of breast TB are available (37).
The ultrasonography is useful in characterizing the ill-
Fine Needle Aspiration Cytology
defined densities seen in mammogram and differentiat-
ing cystic from solid mass. It also reveals heterogeneous, Fine needle aspiration cytology [FNAC] from the breast
intermediate internal echoes in the breast parenchyma lump is useful in the diagnosis of breast TB (1,44). Up to
or retromammary region (35). In nodular form of the 73 per cent of breast TB can be confidently diagnosed
disease lesions are either hypoechoic with ill-defined when both epithelioid cell granulomas and necrosis are
margins or complex cystic masses (37). In diffuse breast present (1). Failure to demonstrate necrosis on FNAC
TB, ill-defined hypoechoic masses are seen whereas in does not exclude the diagnosis of TB in view of small
patients with sclerosing breast TB, increased echogene- quantity of the sample examined. Sometimes, acid-fast
city of the breast parenchyma often with no definite mass bacilli [AFB] can also be detected on FNAC examination
is seen (35,37). At times, a beak-like fistulous connection (45). In regions endemic for TB like India, the diagnosis
between retromammary abscess and thoracic wall is seen of granulomatous mastitis must be made with caution,
in the sonogram (36,39,40). Ultrasound-guided fine even in the absence of AFB. An alternative diagnosis
needle aspiration can be done for cytological and should be suspected if the patient fails to respond to
microbiological studies (38). adequate antituberculosis treatment (44).
In TB breast abscess, the FNAC picture may be
Computed Tomography of the Breast dominated by an acute inflammatory exudate. In this
Although basic imaging techniques used for the diag- situation presence of AFB or histopathological evidence
nosis of breast TB are mammography and ultrasono- of TB is mandatory for the diagnosis of breast TB (1). A
graphy, computed tomography [CT] may be helpful in breast abscess, which fails to heal despite adequate
defining the involvement of thoracic wall in patients drainage and antibiotic therapy and with persistent
presenting with deeply adherent breast lump (41). discharging sinuses should raise suspicion of under-
Tuberculosis abscesses are seen as smoothly margi- lying TB. Biopsy of the abscess wall will confirm the
nated, inhomogeneous, hypodense lesions with diagnosis of breast TB (1).
438 Tuberculosis
Open Biopsy Carcinoma and TB of the breast are occasionally

found coincidentally in the same patient. Similar findings
The FNAC examination may be inconclusive in several
in the axillary lymph nodes may also be seen (13,34). In
cases. Open biopsy [incision or excision] is the most
assessing diagnosis, it is therefore, important to
reliable examination in doubtful cases (27). Biopsy from
remember that recognition of the presence of breast TB
the wall of a suspected TB breast abscess cavity leads to
does not exclude concomitant breast cancer.
a definite diagnosis (1).
Histopathologically, TB mastitis [Figure 29.2] is a form
of granulomatous inflammation. There are a considerable TREATMENT
number of other conditions that are characterized The management of breast TB consists of antituberculosis
histologically by a tuberculoid type of tissue reaction. treatment and surgery with specific indications.
These conditions include sarcoidosis, various fungal
infections, and granulomatous reactions to altered fatty Antituberculosis Treatment
material. Sometimes the microscopic picture in these
Antituberculosis treatment is the mainstay of therapy
conditions is indistinguishable from that seen in breast
(46-49). All patients should be treated for at least six
TB (24).
months following surgery (27). Antituberculosis
treatment is administered as in pulmonary TB (28,47).
The reader is referred to the chapter “Treatment of
Surgical Treatment
Sir Astley Cooper was the first to suggest the role of
surgery in breast TB (10). Wilson and MacGregor (28)
advocated simple mastectomy for most cases of breast
TB and emphasized that the lesions tend to persist and
reappear with conservative management with antituber-
culosis treatment.
Currently, most investigators agree that breast TB is
eminently treatable without mutilating surgery (50,51).
Surgical management may include drainage of abscess,
Figure 29.2: Tuberculosis mastitis. Photomicrograph showing
biopsy from abscess wall, scraping of sinuses in the
breast parenchyma, Langhans’ giant cells and granulomas
[asterisk] [Haematoxylin and eosin × 100]
breast, excisional biopsy, segmentectomy and rarely
simple mastectomy (9,17,27). Generally, an excision
biopsy followed by a full course of antituberculosis
DIFFERENTIATION FROM CARCINOMA BREAST
treatment is suitable for small lesions (27). Residual lump
Clinical examination usually fails to differentiate following antituberculosis treatment may also be
carcinoma from TB of the breast. The features that removed. Only rarely, simple mastectomy with or with-
suggest breast TB include presence of pain, constitutional out axillary clearance is required for extensive disease
symptoms, lack of fixation of the lump to deeper comprising of large, painful ulcerated mass involving
structures, multiple sinuses and an intact nipple and the entire breast and draining axillary lymph nodes
areola (17). In addition, patients are young, married, rendering organ preservation impossible (27). Modified
multiparous or lactating (27). Nipple retraction, peau radical mastectomy is best avoided unless there is a co-
d’orange and involvement of axillary lymph nodes are existing malignancy.
more common in malignancy than in breast TB.
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Tuberculosis in Pregnancy
30
Sunesh Kumar
INTRODUCTION area in London, UK, the incidence of active TB disease

during pregnancy was reported to be 252/100 000
Since the days of Hippocrates, the initial presentation of
deliveries.
tuberculosis [TB] in temporal relation to pregnancy has
Reliable epidemiological data regarding TB in preg-
been a subject of concern and controversy. Tuberculosis
nancy are not available from India. In a prospective study
in a pregnant woman can present in several ways. Preg-
from Pune (9), 24 of the 715 human immunodeficiency
nant women may give a past history of TB. Occasionally,
virus [HIV] infected women who were followed-up for
the disease may be diagnosed in a pregnant woman when
480 postpartum person-years developed TB, yielding a
she develops symptoms and signs suggestive of TB.
TB incidence of 5 cases per 100 person-years. A baseline
Many a times, pregnant women may remain asympto-
CD4+ cell count less than 200 cells/mm3, an HIV load
matic and TB may be diagnosed either incidentally or
greater than 50 000 copies/ml and a positive tuberculin
by way of a screening programme. Atypical presentation
skin test [TST] result were found to be predictors for the
of TB in pregnant women poses difficulties in confir-
development of active postpartum TB disease in HIV-
mation of the diagnosis. Tuberculosis in pregnancy, thus,
seropositive women.
has important implications for the mother and child (1,2).
During pregnancy, pulmonary TB is the most common
lesion and extra-pulmonary TB occurs less commonly.
EPIDEMIOLOGY Miliary TB and TB of lymph nodes, bones and kidneys
are also encountered during pregnancy (10). Tuberculosis
During the year 1985, the Centers for Disease Control
meningitis (11,12), TB mastitits (13), TB peritonitis (14),
and Prevention [CDC], Atlanta, estimated that TB in
and perineal TB (15) have also been described.
association with pregnancy occurred at a rate of 49.6/
100 000 population among the Asians and the Pacific
CLINICAL PRESENTATION OF TUBERCULOSIS
Islanders compared to a figure of 5.7/100 000 in the
DURING PREGNANCY
American whites and 26.7/100 000 in the African-
Americans (3,4). In the series reported by Schaefer et al About one-half to two-thirds of pregnant women with
(5), between 1966 and 1972, 3.2 per cent of patients with TB remain asymptomatic (16). Some of the symptoms,
active TB at the New York Lying-in Hospital were first such as increased respiratory rate and fatigue may mimic
diagnosed during pregnancy. Bailey et al (6) estimated the physiological changes that occur in pregnancy and,
the incidence of TB during pregnancy to be 4.8 per cent thus, make the diagnosis difficult. In the series reported
at New Orleans. Margono et al (7) reported that, between by Schaefer et al (5), minimal symptoms were observed
1985-1990, 12.4 cases of active TB were identified per in 65 per cent pregnant women with TB. Good et al (17)
100 000 deliveries and during 1991-1992, this number found 19 per cent women to be asymptomatic among
increased to 94.8 per 100 000 deliveries. In another study 371 women admitted to the National Jewish Hospital,
(8) from a district general hospital in a high prevalence Colorado. Of these, 27 patients had reactivation of TB
442 Tuberculosis
during or within 12 months after pregnancy. They also therapeutic abortion was advocated for pregnant women
reported cough [74%], weight loss [41%], fever [30%], with pulmonary TB. During this period, a number of
malaise and fatigue [30%], and haemoptysis [19%] as the conflicting reports evaluating the impact of pregnancy
common presenting symptoms. Maurya and Sapre (18) on TB appeared (10).
screened 209 pregnant women for TB by tuberculin test, However, it is currently believed that pregnancy
direct sputum examination for acid-fast bacilli [AFB] and neither predisposes to the development of TB nor results
chest radiograph [done after 12 weeks of gestation with in the progression of the disease. Two large studies
abdominal shielding]. Of these 209 patients, 12 per cent (19,20), although somewhat old, clearly showed that
had active TB; 70.3 per cent were sputum smear-negative, pregnancy does not appear to result in the progression
but had chest radiographic evidence of TB and a raised of the disease. One study (19) described 250 pregnant
erythrocyte sedimentation rate [ESR], 14 per cent had a women; 189 with pulmonary and 61 with extra-pulmo-
past history of adequately treated TB but no evidence of nary TB. None of them were given antituberculosis
active disease; and 2.9 per cent had no evidence of TB treatment and the treatment largely consisted of
and were tuberculin negative. They found cough [75%], sanatorium therapy. It was found that TB improved in
weight loss [23%], fever [15%] and malaise [30%] to be 9.1 per cent women while the disease progressed in seven
the common symptoms in 100 symptomatic women. per cent and most of the women remained stable (19). In
Clinical presentation of TB in pregnancy as reported in
another study, de March (20) evaluated the influence of
some published studies is shown in Table 30.1.
pregnancy as a relapse factor for pulmonary TB in 215
patients who received adequate treatment and concluded
EFFECT OF PREGNANCY ON TUBERCULOSIS
that pregnancy, labour, puerperium, and lactation did
At the start of the twentieth century it was believed that not predispose to the risk of relapse of pulmonary TB
pregnancy had a deleterious effect on TB (10). In fact, when the disease was adequately treated.
Table 30.1: Clinical presentation of tuberculosis in pregnancy
Variable Good et al (17) Margono et al (7) Maurya and Sapre (18)
Study period 1965-1974 1985-1992 1989-1992

Place of study Denver New York Gwalior
No. of patients
Pulmonary TB 27* 10 172‡
Extra-pulmonary TB 0 6† 0
Total 27 16 17
HIV-seropositive [%] ND 64 [n = 11] ND
Tuberculin positive [%] 96 40 [n = 15] ND
Method of diagnosis
Microbiological [%] 100§ 100|| ¶
Histopathological [%] 0 19|| ¶
Numbers in parantheses indicate number of patients tested

* In 6 patients TB was diagnosed during pregnancy [first trimester n = 3; second trimester n = 1; third trimester n = 2]. In the remaining
11 patients, TB was diagnosed during the postpartum period [up to 12 months following delivery]
† Included 2 patients with TB meningitis and 1 each with mediastinal, renal, gastrointestinal and pleural TB
‡ Of the 209 patients studied, 6 patients had no evidence of TB and were tuberculin negative; 31 patients had past history of adequately
treated TB
§ 16 patients had drug-resistant TB
|| Patients with cultures of sputum, urine or cerebrospinal fluid positive for Mycobacterium tuberculosis whether or not smears were
positive were included. In patients with mediastinal, pleural and gastrointestinal TB [1 patient each], diagnosis of TB was confirmed by
histopathological examination
¶ Detailed break up not given
TB = tuberculosis; HIV = human immunodeficiency virus; ND = not described
Tuberculosis in Pregnancy 443
Schaefer et al (5) compared the course and outcome difference in mean gestational age, preterm births or
of TB in pregnant women during the pre-chemotherapy mean birth weight among live births.
and chemotherapy era; 88 per cent women in pre- Maurya and Sapre (18) reported two preterm
chemotherapy and 91 per cent in the chemotherapy era deliveries and one intrauterine foetal death in the sub-
remained stable during pregnancy. Eleven of the 27 cases group with active TB. Maternal mortality and foetal
of reactivation or relapse of pulmonary TB described by complications were more frequent in pregnant women
Good et al (17) occurred in the postpartum period. with drug-resistant TB compared to those with drug-
However, these and other studies highlight a small but sensitive disease in the study by Good et al (17).
definite risk of relapse and deterioration in the post- In the study reported by Jana et al (23), 33 patients
partum period (10). with extra-pulmonary TB [12 with TB lymphadenitis and
9 with intestinal, 7 with skeletal, 2 with renal, 2 with
EFFECT OF TUBERCULOSIS ON PREGNANCY meningeal, and 1 with endometrial TB] were followed
through their deliveries. Of the 33 patients, 29 received
Contrary to old reports, following the advent of effective
antituberculosis treatment during pregnancy. The ante-
antituberculosis treatment, current literature does not
natal complications, intrapartum events, and perinatal
suggest that TB has an adverse impact either on the
outcomes were compared with those among 132 healthy
course of pregnancy or labour (1,2).
pregnant women without TB who were matched for age,
parity and socio-economic status. It was observed that
Abortions
TB lymphadenitis did not affect the course of pregnancy
Selikoff and Dorfmann (21) reported seven early spon- or labour or the perinatal outcome. However, as com-
taneous abortions and nine antepartum or intrapartum pared with the control subjects, 21 women with involve-
foetal deaths in 616 pregnant women with TB, where ment of other extra-pulmonary sites had significantly
600 pregnancies resulted in the birth of 602 normal live higher rates of antenatal hospitalization [24% vs 2%],
infants. Maurya and Sapre (18) reported four sponta- infants with low Apgar scores [< 6] soon after birth [19%
neous abortions in the group previously treated for TB. vs 3%], and low birth-weight [less than 2.5 kg] infants
[33% vs 11%]. The authors concluded that extra-
Preterm Delivery pulmonary TB that is confined to the lymph-nodes has
Schaefer et al (5) did not find any evidence of increased no effect on obstetrical outcomes, but TB at other extra-
risk of prematurity in their series. Maurya and Sapre (18) pulmonary sites does adversely affect the outcome of
reported only two premature deliveries among 31 pregnancy (23).
pregnant women with a past history of TB. Outcome of pregnancy in patients with active pulmo-
Bjerkedal et al from Norway (22) described the course nary TB as reported in some of the published studies is
and outcome of pregnancy in 542 women with TB [study shown in Table 30.2.
group] and 112 530 women without TB [control subjects].
PLACENTAL TRANSMISSION OF TUBERCULOSIS
Study group had increased frequency of pregnancy
induced hypertension [7.4% vs 4.7%] and vaginal Placental transmission of TB infection has now been
bleeding [4.1% vs 2.2%]. Labour was induced more often conclusively proven by a number of case reports (24-26).
in the study group than among the control subjects [14.6% In the literature, cases where newborn babies were found
vs 9.1%]. Labour was also reported to be more often to have acquired TB from the diseased endometrium
complicated in the study group than in control subjects have been described. Nemir and O’Hare (24) described
[15.1% vs 9.6%] and interventions during labour were one female child carefully investigated and treated for
required more often in the study group [12.6% vs 7.7%]. congenital TB in neonatal period. This child had positive
Intrauterine foetal death rate between 16 and 28 weeks subumbilical lymph nodes indicating umbilical vein as
was nine-fold higher in the study group [20.1/1000 in the route of transmission.
cases versus 2.3/1000 control subjects]. However, no Myocbacterium tuberculosis has also been demons-
difference was found in the number of congenital trated in placental specimens and tissues from stillborn
anomalies or subsequent conception rate. There was no infants (27,28). Kalpan et al (29) reported two interesting
444 Tuberculosis
Table 30.2: Outcome of pregnancy in patients with active pulmonary tuberculosis
Variable Maurya and Sapre (18) Schaeffer et al (5)
Study period 1989-1992 1933-1951 1952-1972

[n = 172] [n = 506] [n = 1059]
Pregnancy outcome [%]
Normal delivery 87 61.6 64.5
Forceps delivery 0 27.6 28.7
Breech 0 4.5 2.7
Caesarean section 13 6.3 4.1
Elective 9 ND ND
Emergency 4 ND ND
n = number of subjects studied; ND = not described
cases. In the first case, a 25-year-old pregnant woman radiation exposure to foetus does not justify the policy
had been treated with multiple drugs for cavitary pulmo- of routine chest radiograph examination during
nary TB. She desired an elective abortion at six weeks of pregnancy [34 to 36 weeks]. However, if a chest radio-
gestation. Endometrial curettage smear revealed graph is indicated, pregnancy should not be considered
Mycobacterium tuberculosis. In the second case, a 24-year- as an absolute contraindication. A chest radiograph
old pregnant woman presented at 34 weeks of gestation should be taken with abdominal shielding, preferably
with premature rupture of membranes. An emergency after the first trimester of pregnancy.
caesarean section performed 24 hours later revealed Estimated radiation from a chest radiograph is
fibrinous exudates on peritoneal surface and a placenta approximately 50 mrad to the chest and 2.5 to 5 mrad to
densely adherent to the uterus. Both exudates and tissue the gonads (32,33-35). Prenatal radiation exposure has
from the endometrium grew Mycobacterium tuberculosis. been correlated with subsequent risk of malformations
These findings suggest that subclinical endometrial and cancer. Mole (36), in a detailed analysis estimated
infections can be an important source for transplacental such a risk to be zero to one case per 1000 patients if
transmission of disease in patients with congenital TB. irradiated by one rad in utero during the first four months
of pregnancy. Therefore, a chest radiograph carried out
CONGENITAL TUBERCULOSIS during pregnancy does not seem to carry a measurable
risk to the foetus since radiation exposure from a chest
The reader is referred to the chapters “Pathology” [Chapter
radiograph is much less (32-35).
5] and “Tuberculosis in children” [Chapter 41] for more
details.
Detection of Tuberculosis Infection
DIAGNOSIS The TST identifies persons infected by Mycobacterium

tuberculosis but does not define the activity or extent of
It is important to identify pregnant women suffering
disease. Generally, the TST becomes positive two to ten
from TB as it may help to prevent transmission of disease
weeks after initial exposure (37). In the past, a concern
to the newborn and close contacts.
had been expressed regarding the effect of pregnancy
on TST positivity (38). However, subsequent studies have
Chest Radiograph
not found pregnancy to affect the TST reactivity (39,40).
In the past, a routine chest radiograph was advocated Present and Comstock (40) evaluated 25 000 patients over
during pregnancy in order to detect active and inactive a one-year period and reported that pregnancy did not
TB (21,30,31). Bonebrake et al (32) advised against such a affect the TST results. There appears to be no risk either
policy as most patients with significant findings on chest to the pregnant woman or her foetus from the TST (41).
radiograph also had positive findings on physical Carter and Mates (42) while reviewing cases of TB
examination and a positive TST result. Concern about during pregnancy over a four-year span in Rhode Island
found that most patients with TB infection remain regimen has been shown to prevent seizures in neonates
asymptomatic. They concluded that the TST screening born to mothers treated with isoniazid during pregnancy
in pregnancy may prevent risk to the foetus, newborn (1). The reader is referred to the chapter “Antituberculosis
and the obstetric ward workers. treatment induced hepatotoxicity” [Chapter 54] for further
However, usefulness of such a policy in areas where details.
TB is highly endemic remains doubtful. The recently
available interferon-gamma release assays [IGRAs], offer Rifampicin
several advantages over the TST and are increasingly
Although increase in limb defects have been observed
being used for the diagnosis of latent TB infection. The in foetuses of mothers taking rifampicin (1). Snider et al
reader is referred to the chapters “Tuberculin skin test”
(44) failed to detect increased incidence of teratogenicity
[Chapter 11] and “Diagnosis of latent tuberculosis infection:
among mothers taking rifampicin during pregnancy.
recent advances and future directions” [Chapter 12] for more Presently, rifampicin is considered to be an essential
details.
component of antituberculous treatment during
pregnancy (1,47).
Microbiological Methods
Demonstration of Mycobacterium tuberculosis in sputum, Ethambutol
body fluids or material by Ziehl-Neelsen staining and
Although ethambutol is known to be teratogenic in
Lowenstein-Jensen culture confirms the diagnosis of TB
experimental animals, there are no reports of maldeve-
disease. However, low yield in these specimens remains lopment including ocular injury in human foetuses
a practical problem.
(48-50).
TREATMENT OF ACTIVE TUBERCULOSIS Streptomycin

DURING PREGNANCY
Use of streptomycin during pregnancy has been reported
Pregnant women with active TB should be immediately to be associated with vestibular and auditory impairment
started on antituberculosis treatment as untreated TB is in the newborns (51,52). Streptomycin induced
far more hazardous to a pregnant woman and her foetus ototoxicity has been reported irrespective of period of
than the adverse effects related to the treatment of the gestation. Therefore, streptomycin should not be used
disease (43). Though first-line drugs, such as isoniazid, during pregnancy.
rifampicin, streptomycin and ethambutol cross the
placenta, with exception of streptomycin induced Pyrazinamide
ototoxicity, none of these drugs appear to be teratogenic
Due to faster sputum conversion rate, this drug is
or toxic to the foetus (44).
commonly used in the short-course treatment regimens.
As recommended by the World Health Organization
Isoniazid
[WHO] and International Union Against Tuberculosis
Even though isoniazid crosses the placenta, no significant and Lung Disease [IUATLD], pyrazinamide can be safely
teratogenic effects have been noted even when used used in pregnancy (53). If pyrazinamide is not included
during the first four months of pregnancy (45). However, in the initial treatment regimen, the minimum duration
one report mentioned about two-fold increase in the risk of treatment is nine months. Benefits of the use of
of malformations when mothers were exposed to pyrazinamide in HIV-seropositive pregnant women
isoniazid (46). outweigh the undetermined potential risks to the foetus.
Hepatitis is a frequently observed side-effect of
isoniazid. Pregnant and postpartum women may be Principles of Treatment
particularly at higher risk for isoniazid induced hepatitis. Active disease discovered in antenatal period should be
An addition of pyridoxine in a dose of 50mg/day has promptly treated. Isoniazid, rifampicin, pyrazinamide
been recommended during pregnancy to prevent and ethambutol should be initially used. The reader is
neurotoxicity in the mother and the foetus (43). This referred to the chapter “Treatment of tuberculosis” [Chapter
446 Tuberculosis
52] for more details. Duration of antituberculosis Treatment should consist of combination of three or four
treatment need not be modified because of pregnancy. drugs with demonstrated efficacy against the infecting
Active TB disease discovered close to the time of delivery strain.
should also be actively treated. Neonate should be
carefully examined and kept under surveillance for TREATMENT OF LATENT TUBERCULOSIS
development of TB. Placenta should be examined for INFECTION
possible infection by Mycobacterium tuberculosis. If
The reader is referred to references 60 and 61 for details
patients receiving antituberculosis drugs conceive,
regarding treatment of latent TB infection in pregnancy.
pregnancy should be allowed to continue while the
Efficacy and safety of isoniazid chemoprophylaxis during
patient continues antitubercuolsis treatment. Appro-
pregnancy, in areas where TB is highly endemic, like
priate steps should be taken to prevent TB infection in
India, are unclear.
the newborn.
MANAGEMENT OF TUBERCULOSIS IN INFANTS
Second-Line Drugs
BORN TO MOTHERS WITH TUBERCULOSIS
Little is known about the teratogenic effects of the second-
If the mother had been receiving treatment for TB during
line antituberculosis drugs. Due to high incidence of side-
pregnancy, the newborn should be assessed for
effects, their usefulness is limited. Teratogenic effect has
symptoms and signs of congenital TB. Infant should
been attributed to ethionamide (54). Kanamycin and
undergo the TST at birth. Chest radiograph and smear
capreomycin theoretically share the potential for
and culture examination of the gastric aspirate should
producing ototoxicity with streptomycin. The potential
be performed. If active TB is ruled out, the child should
hazard of such treatment must be considered by the
be treated with isoniazid for two to three months, or till
parents and the treating physician.
such time the mother, known to be complying with
Treatment of Drug-resistant Tuberculosis During treatment, becomes smear and culture negative (10).
Pregnancy The child should be carefully followed up thereafter.
If active disease is detected, the child should receive a
Women who are being treated for drug-resistant TB full course of antituberculosis treatment with rifampicin,
should receive counselling concerning the risk to the isoniazid and pyrazinamide. Ethambutol should
foetus because of the known and unknown risks of preferably be avoided in neonates as it is difficult to
second-line antituberculosis drugs. There have been monitor the ocular toxicity.
occasional case reports and small case series in the
published literature regarding the management of Breast Feeding
multidrug-resistant TB [MDR-TB] during pregnancy
Breast feeding should not be discouraged in nursing
using second-line drugs (55-58). These data suggest that
mothers receiving antituberculosis treatment as the
treatment of MDR-TB during pregnancy is beneficial
concentrations of these drugs secreted in the breast milk
both to the mother and the child. However, studies
seldom attain toxic levels (10). However, drugs in breast
involving large sample size with a long-term follow up
milk should not be considered to serve as effective
are awaited.
treatment for the disease or as chemoprophylaxis in a
As the majority of teratogenic effects occur in the first
nursing infant (62,63). Pyridoxine supplementation
trimester, treatment should be delayed until the second
should be given to breast feeding women taking
trimester. The decision to postpone the treatment should
isoniazid.
be based on the analysis of the risks and benefits and
should be acceptable to both the doctor and patient.
ANTITUBERCULOSIS TREATMENT AND
Injectable agents, aminoglycosides and capreomycin
CONTRACEPTION
should be avoided during pregnancy and if possible
ethionamide should also be avoided (59). The decision Rifampicin induces the P-450 mixed function oxidase
should also take into consideration the severity of illness. system that metabolises oral contraceptives and other
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Rovinskey JJ, Gulmatcher AF, editors. Medical, surgical and
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Female Genital Tuberculosis
31
Sunesh Kumar
INTRODUCTION Genital Tuberculosis in Infertile Women
Female genital tuberculosis [TB], though known to have Schaefer (7) estimated the worldwide incidence of genital
existed for centuries, was first described by Morgagni in TB in infertile women to be five to ten per cent. Incidence
1744 during an autopsy on a 20-year-old girl known to of genital TB has been estimated to range from 1 to 26.7
have died of TB peritonitis (1). Infertility, menstrual per cent in various studies from India (8,11-15). Malkani
irregularities and chronic pelvic or lower abdominal pain and Rajani (13), based on endometrial biopsies from
are the most common manifestations of female genital infertile women, reported the incidence of genital TB to
TB (2-4). It is almost always secondary to a focus be 9.3 per cent. Deshmukh et al (8) reported a similar
elsewhere in the body. Fallopian tubes are the first and incidence at laparoscopy in 500 infertile women. Dam et
the most commonly affected genital organs, followed by al (14) from Kolkata, India reported that genital TB was
endometrium, ovary and cervix (5). Occasionally, other an important aetiological cause in patients [n = 81] with
sites may also be affected. A number of patients may unexplained infertility with apparently normal pelvic
remain asymptomatic and the disease may also be dis- and non-endometrial tubal factors and repeated in vitro
covered incidentally (6). The last century has witnessed fertilization [IVF] failure. In another recent study (15)
changing trends in incidence of female genital TB, from New Delhi, India, 26.7 per cent of the 150 women
initially due to improvement in economic standards in with infertility were found to have genital TB. In a study
developed countries and subsequently by the global (16) from Islamabad, Pakistan, 2.43 per cent of the 543
pandemic of the human immunodeficiency virus [HIV] women with infertility were found to have female genital
infection. TB. The incidence of female genital TB among patients
with infertility in the USA has been reported to be less
EPIDEMIOLOGY than one per cent in various series (5-7,17).
Genital tract TB has been reported in patients presenting

Genital Tuberculosis in Women with Abnormal
with infertility, chronic pelvic pain and menstrual irregu-
Uterine Bleeding
larities, in autopsy series, and recently in laparoscopy
series of infertility cases (5-8). Twentieth century Sutherland (18) described endometrial TB in 10 out of
witnessed dramatic reduction of female genital TB cases 1000 patients with abnormal uterine bleeding. Roy et al
in the developed world. However, a similar trend has (19) described a series of 246 patients with abnormal
not been observed in the developing countries. Incidence uterine bleeding between 15 and 60 years of age. Histo-
of genital TB varies greatly depending upon the pathological evidence of TB was found in 20 patients.
geographical location ranging from 10.3 per cent in India Further, mycobacterial cultures were reported to be
(9) to being less than one per cent in the USA (6) and positive in 21 specimens and guinea pig inoculation was
Sweden (10). positive in 18 specimens. Tripathy and Tripathy (20)
450 Tuberculosis
studied 62 women with sputum positive pulmonary TB TB is most common, extra-pulmonary organs such as
using laparoscopy, they observed various findings such kidneys, gastrointestinal tract, bone or joints may also
as bands of adhesion, tubercles and hyperaemia in 37, be the primary source of infection (10). In patients with
intestinal adhesions in 15, tubercles on fallopian tubes miliary TB, genital organs may be one of the many organs
in 14 and adhesions in pouch of Douglas in seven women. involved. Primary genital TB, though extremely rare, has
The incidence of female genital tract TB has been been described in the female partners of males affected
estimated to be four to twelve per cent in autopsy studies by active genitourinary TB. Lattimer et al (28) first
(21). Rarely, female genital TB can present with post- reported the presence of Mycobacterium tuberculosis in the
menopausal vaginal bleeding (22). semen of male partners of women with genital TB.
Sutherland et al (29) in a series of 128 women with proven
Age Distribution genital TB found five of their husbands to have active
Schaefer (7) reported that 80 to 90 per cent of his patients genitourinary TB. Female partners of three of these five
husbands had evidence of a focus of TB elsewhere in the
were between 20 and 40 years of age. A changing trend
body. In patients with primary genital TB, cervix or vulva
in the age at diagnosis has been highlighted by
Sutherland (2) in a large series of 704 patients with female may be the site of involvement.
Haematogenous or lymphatic route is the usual mode
genital TB seen between 1951 and 1980. The mean age
of spread. However, direct contiguous spread from other
was 28.2 years in the initial 10 years compared to 38.9
years observed in the last decade of the study (2). Reports intraperitoneal organs may occur in a minority of patients
(7,30). Simultaneous occurrence of peritoneal TB in
from Swedish hospitals showed that 46 per cent patients
patients with genital TB increases the possibility of
with female genital TB were older than 50 years in the
period between 1968 and 1972 and the figure increased ruptured caseous lymph nodes or involvement of genital
organs during the haematogenous spread.
to 62 per cent between 1972 to 1977 (10). A series from
Fallopian tube is usually the initial site of focus, being
Turkey reported 29.2 per cent cases of female genital TB
to be older than 40 years of age (23). In India, however, it affected in 90 to 100 per cent cases, with subsequent
spread to other genital organs. Other affected sites
is not uncommon to find TB endometritis at an younger
include endometrium in 50 to 60 per cent, ovaries in 20
age in patients undergoing investigations for amenor-
rhoea or infertility. In several series reported from India to 30 per cent, cervix in five to fifteen per cent and vagina
in one per cent of the cases (31).
(11,24-27), 68 to 89 per cent cases of genital TB were
between 20 and 30 years of age [Table 31.1]. Fallopian Tube Tuberculosis
Fallopian tubes are involved in almost all patients with
PATHOGENESIS
genital TB (5,7). Ampullary portion of the fallopian tube
Genital tract TB is almost always secondary to TB is the most common site of the disease. Isthmus is less
infection elsewhere in the body. Although pulmonary commonly involved and involvement of the interstitial
Table 31.1: Age distribution of patients with genital tuberculosis
Study (reference) No. of patients Age group [years]
<20 20-30 30-40 >40
Gupta (11) 47 13.0 68.0 19.0 0

Devi (24) 144 12.0 70.0 14.0 4.0
Hafeez and Tandon (25) 120 3.3 89.0 6.0 1.7
Chhabra (26) 58 1.7 74.2 8.6 15.5
Rattan et al (27) 50 0 76.0 24.0 0
Distribution of patients in various age groups is shown as percentage

All values are corrected to first decimal place
Female Genital Tuberculosis 451
portion is unusual. Generally, the disease tends to be Microscopically [Figure 31.1], diagnosis is based upon
bilateral. Disease may start on the peritoneal surface or the presence of chronic inflammatory cells with or
in the muscularis mucosa of the tube, however, involve- without caseation, granulomas with lymphocytes,
ment of the mucosal layer is almost universal. Gross Langhans’ giant cells and epithelioid cells. Such lesions
appearance of the fallopian tube may vary depending may be focal or generalized. Due to cyclical shedding of
upon the severity of disease and stage at which it is endometrium such lesions may be seen close to the
encountered. In early cases, congestion of tubes and other surface of endometrium. Granulomas may be better seen
pelvic organs with flimsy adhesions and fine miliary in premenstrual phase or within 12 hours after onset of
tubercles on the surface of the tube and other pelvic organs menstruation (35).
may be seen. In severe disease, dense plastic adhesions However, typical granulomas may not be seen in all
between the fallopian tubes and surrounding organs are cases (36). Bazaz-Malik et al (3) in a series of 1000 cases
seen. In old healed cases, hydrosalpinx or pyosalpinx may of TB endometritis noted discrete granulomas and
be present. Failure to visualize pelvic organs at laparo- caseation in 60 per cent cases only. They suggested
scopy or laparotomy may be due to dense adhesions in presence of dilated glands, destruction of epithelium,
patients with pelvic TB. In 25 to 50 per cent cases, the inflammatory exudates in the lumen as additional criteria
fallopian tubes remain patent with everted fimbriae for diagnosis of TB endometritis. Bourno and Williams
giving rise to so called “tobacco pouch appearance” (32). (37) suggest that focal collection of lymphocytes in the
Microscopically, presence of chronic inflammatory endometrium should be considered to be of TB origin
cells, with or without caseation, granulomas with unless proved otherwise.
Langhans’ giant cells may be evident. However, micro-
scopic appearance may be variable depending upon the Ovarian Tuberculosis
severity of the disease and whether the disease is in active Ovarian involvement occurs in 15 to 25 per cent cases
or healing phase. The tubal mucosa may be totally des- (5) and most often results from direct extension of the
troyed or may have hyperplastic or adenomatous
appearance which may be confused with adenocarci-
noma (33). Papillae in the endosalpinx are usually fused,
and may lead to implantation of embryo in the fallopian
tubes resulting in ectopic pregnancy.
Endometrial Tuberculosis
Endometrial involvement in genital TB is secondary to
tubal involvement (31,32). Schaefer (31) reported
endometrial involvement in 50 to 80 per cent cases of
genital TB. In a large series of 1436 cases of genital TB,
Norgales-Ortiz et al (32) reported endometrial involve-
ment in 79 per cent of cases. Oosthuizen et al (34) in a
study of 109 patients with infertility, found evidence of
genital TB in the form of positive culture in menstrual
blood in 16 and positive endometrial tissue for Figure 31.1: Endometrial tuberculosis. Photomicrograph showing
Mycobacterium tuberculosis in four patients. endometrial glands with clusters of epithelioid cells and lymphocytic
Gross appearance of endometrium is mostly infiltration [asterisk] [upper panel, left; Haematoxylin and eosin,
unremarkable. However, in advanced cases, ulcerative × 60], stroma of endometrium, epithelioid granulomas [asterisk],
or atrophic endometrium or an obliterated endometrial Langhans’ giant cell [arrow] and lymphocytic infiltration [upper panel,
right; Haematoxylin and eosin × 200]. Fallopian tube tuberculosis.
cavity due to extensive intrauterine adhesions may be
Photomicrograph showing congested tubal plicae with epithelioid
seen. Total destruction of endometrium by the disease clusters and lymphocytic infiltration [asterisk] [lower panel, left;
process with resultant secondary amenorrhoea has been Haematoxylin and eosin, × 60], epithelioid granulomas in the fallopian
reported in a few cases (32). tube [asterisk] [lower panel, right; Haematoxylin and eosin × 60]
452 Tuberculosis
disease from fallopian tubes (10). In such cases, ovary CLINICAL PRESENTATION
may be surrounded by adhesions or may be the site of
tubo-ovarian cyst formation or tubo-ovarian mass with Symptoms
adhesions surrounding them. In patients with haemato- The most frequent presenting symptoms in patients with
genous spread caseating granulomas may be seen in the female genital TB include infertility, pelvic pain,
parenchyma of ovary (7,32). menstrual disturbances, vaginal discharge and poor
general condition [Table 31.2]. However, none of these
Tuberculosis of Cervix are specific for female genital TB.
Tuberculosis of the cervix may be seen in five to fifteen
Infertility
per cent cases of genital TB (5). Cervix mostly gets
affected by downward spread of the disease from the Primary and secondary infertility are the most common
endometrium. However, rarely cervical disease may presenting symptoms in patients with female genital TB.
All reported series have identified this association
occur secondary to deposition of infected semen by the
[Table 31.2].
male partner (29). Mostly, cervical lesions tend to be
hypertrophic resembling cervical carcinoma (38) and less Chronic Lower Abdominal or Pelvic Pain
often an ulcerative lesion may be seen (32).
Chronic lower abdominal or pelvic pain is the second
Microscopic examination reveals granulomatous
most common symptoms in patients with female genital
inflammation. Inflammatory atypia with frequent hyper-
TB [Table 31.2]. Pain is non-characteristic and is usually
plastic mucosal changes may be seen along with
localized in the lower abdomen or pelvis. Pain tends to
caseation (1). The endocervical involvement is common
be chronic and is usually dull aching. Occasionally, acute
(32) and may explain increased mucus production.
pain may occur similar to that of acute pelvic inflam-
Cervical TB has been diagnosed cytologically by
matory disease or a twisted pelvic organ. Episodes of
various workers (39-41). Multinucleated giant cells, acute pain, as a result of superadded bacterial infection,
histiocytes, epithelioid cells arranged in clusters simulat- can occur and require administration of antibiotics. Acute
ing the appearance of granulomas are characteristic of episodes of pain may occur after diagnostic procedures,
the disease in Papanicolaou smear examination. Cyto- such as endometrial biopsy, dilatation and curettage or
logical diagnosis of genital TB in association with carci- hysterosalpingography [HSG]. Patients with chronic pain
noma in situ and Trichomonas vaginalis has been described are more likely to have abnormal findings on pelvic
(40,41). examination.
Tuberculosis of the Vagina, Vulva and Alterations in Menstrual Pattern

Bartholin Gland All types of menstrual irregularities, such as amenor-
Tuberculosis of the vulva and vagina occurs in one per rhoea, menorrhagia, oligomenorrhoea or even postmeno-
cent of cases (5). Tuberculosis of Bartholin gland and pausal bleeding can occur [Table 31.2].
vesicovaginal fistula due to genital TB has been described
Persistent and Abnormal Vaginal Discharge
(42,43). Involvement of the vagina or vulva is usually
secondary to the involvement of other parts of genital Occasionally, patients with persistent vaginal discharge
tract. However, transmission of the disease by a male may be found to have genital TB affecting cervix or
partner due to involvement of epididymis or seminal vagina (38-40). Such a symptom is more likely to occur
vesicles has been reported (28). in women with endocervical TB or in patients with TB
Lesions on vulva and vagina may present as hyper- of the cervix or vagina.
trophic lesions resembling malignancy, less often non-
healing ulcers in the vulva may be seen. Histopatho- Unusual Symptoms
logical examination of the lesion is useful in confirming Several unusual symptoms as presentation of female
the diagnosis. genital TB have been described from time to time. These
Table 31.2: Clinical presentation of patients with genital tuberculosis

Study (reference) No. of patients Infertility Amenorrhoea Menorrhagia or Postmenopausal Chronic
Oligomenorrhoea bleeding pelvic pain
Sutherland (18) 250 40 10 18 20 ND

Malkani and Rajani (13) 106 ND 43.4 43 ND ND
Mukherjee et al (44) 138 100 60 19.7 ND ND
Munjal et al (36) 140 37.1 42.8 41.4 1.4 ND
Klein et al (4) 20 70 20 ND ND 30
Falk et al (10) 187 12.8 41.2 ND ND ND
Bazaz-Malik et al (3) 1000 47 26 15 1.0 2.4
Bohate et al (12)* 337 58.6 26.4 ND ND ND
Chhabra (26) 58 29.3 18.9 15.5 3.4 43.1
Sfar et al (45) 118 81 ND ND ND ND
Saracoglu et al (23) 72 47 11 ND ND 32
Gupta et al (15) 40 40 10 40 ND 20

* These series included patients with tuberculosis endometritis only
ND = not described
include vulval lesions, Bartholin gland swelling (42), Presence of ascites or doughy feel of the abdomen
vesicovaginal fistula (43), pelvic masses (46), uterocuta- especially in young unmarried girls with low-grade fever
neous fistula (47), retention of urine due to pelvic masses and alteration in menstrual pattern should raise suspicion
of TB origin (48). Miranda et al (49) described a case where of genital TB. Enlargement of uterus due to pyometra
pelvic TB presented as an asymptomatic pelvic mass with especially in a postmenopausal patient may be due to
rising levels of serum cancer antigen-125 [CA-125]. pelvic TB (48,51). Tuberculosis of cervix, vagina and
vulva usually presents as hypertrophic or ulcerative
Physical Signs lesions. Biopsy helps to differentiate such a lesion from
No physical sign on abdominal or pelvic examination is malignancy.
characteristic of genital TB. A high index of suspicion is,
DIAGNOSIS
therefore, required to make an early diagnosis.
Minimal induration in adnexal areas on both sides is As genital TB is a pauci-bacillary disease, it is not possible
the most commonly noted physical finding during pelvic to demonstrate Mycobacterium tuberculosis in every case.
examination in these patients. However, it is not specific Therefore, one has to rely on imaging and histopathology.
for female genital TB. Bilateral tubo-ovarian masses, Endometrial biopsy for histopathological examination
especially in nullipara or unmarried girls in the absence and mycobacterial culture remain the most commonly
of fever should raise a strong suspicion of genital TB (5). used procedures for the diagnosis of female genital TB.
Sutherland (2), in a large series of patients over a 30-year Laparoscopy, HSG, ultrasonography of pelvic organs,
period, found a decreasing incidence of palpable adnexal computed tomography [CT] and magnetic resonance
masses. Falk et al (10), in a series of 187 patients from imaging [MRI] are other investigative procedures which
47 Swedish hospitals, found tubo-ovarian masses in are carried out if the endometrial biopsy is not conclusive.
46 patients. However, on exploration, five of these Recently, a number of newer investigations, such as
46 patients had adnexal malignancy and two had benign polymerase chain reaction [PCR] have been applied for
ovarian tumours. Lack of tenderness during palpation the diagnosis of genital TB [Table 31.3] with variable
may be an indication of TB mass (46). Physical results. However, diagnostic hysteroscopy and
examination may be entirely normal in 31.6 to 50 per laparoscopy have emerged as the most useful investi-
cent cases (24,50). gations. These investigations not only facilitate the visual
454 Tuberculosis
Table 31.3: Diagnostic modalities for female genital or by dilatation of the cervix and curettage of the endo-
tuberculosis metrium [D and C] is useful for the diagnosis of TB
Site Diagnostic procedures [Figure 31.1]. Best time to perform such a procedure is
shortly before the menstruation (5) as lesions are likely
Fallopian tube Laparoscopy, hysterosalpingography,
to be close to surface of endometrium during this phase
peritoneal fluid for Mycobacterium tuber-
of the menstrual cycle.
culosis smear and culture, tubal biopsy,
serological tests Histopathologically proven TB is present in 50 to 76
Endometrium Endometrial histology per cent patients with genital TB [Table 31.4]. In the
Endometrial smear and culture for absence of granulomas and caseation necrosis, other
Mycobacterium tuberculosis features such as dilatation of glands, destruction of
Hysteroscopy epithelium and presence of inflammatory cells are seen
Menstrual blood culture for Mycobacterium on histopathology (3). Malkani and Rajani (13) suggested
tuberculosis
that the focal collection of chronic inflammatory cells or
Cervix Biopsy
Exfoliative cytology
presence of proliferative endometrium in the premens-
Vagina and vulva Biopsy trual week in a patient with past history of TB in other
parts of the body or a family history of TB would favour
a diagnosis of female genital TB.
examination of the lesions and confirmation of the A negative endometrial biopsy does not rule out the
diagnosis, but also help in picking up unsuspected pelvic involvement since sampling errors are common
pathology such as endometriosis or malignancy in a and disease may have involved other pelvic organs
number of cases. without associated TB endometritis (1).
Endometrial Biopsy Mycobacterial Isolation

Endometrial tissue obtained by endometrial biopsy Endometrial biopsy specimen, menstrual blood, cervical
curette or by aspiration with a plastic disposable cannula and vaginal secretions, tubal biopsy material or
Table 31.4: Comparison of the mycobacterial culture and histopathological examination of endometrium in
the diagnosis of female genital tuberculosis
Study (reference) No. of patients Culture positive HPE positive Both culture and
HPE positive
Malkani and Rajani et al (13) 57 17.5 100.0 *

Halbrecht and Tiqva (52) 103 36.9 10.6 52.5
Klien et al (4) 20 37.5† 62.5† ND
Nogales-Ortiz et al (29) 1436 100.0‡ 76.1§ ND
Falk et al (10) 187 29.4 69.5 ND
Chhabra et al (53) 150 6.0 6.7 1.3
Sfar et al (45) 118 7.0 46.0 ND
Roy et al (19) 800 10.9 9.8 11.8
Gupta et al (15) 40 2.5 25 2.5
Positive yield is shown as percentage

All values have been corrected to first decimal place
* 57 endometrial biopsy proven patients were included in the study
† Culture and histopathology yield available for 16 patients
‡ Culture yield available for 30 patients
§ Histopathology yield available for 201 patients
ND = not described; HPE = histopathological examination
peritoneal fluid obtained during diagnostic laparoscopy

have been subjected to mycobacterial smear and culture
examination (4,10,13,54-56).
Endometrial Culture versus Histopathology

A number of studies have evaluated histopathology and
mycobacterial culture for the diagnosis of endometrial
TB [Table 31.4]. Most studies have found a higher
diagnostic yield with histopathological examination of
endometrium than culture of biopsy material (10).
Hysterosalpingography
The HSG visualization of uterine cavity and fallopian
Figure 31.3: Hysterosalpingogram showing ragged and jagged
tubes by injecting a radio-opaque contrast medium into contour of the tube. Only one tube could be visualized in this case.
the uterus through cervix is routinely performed for Terminal end of the tube presents leopard skin-like speckled appear-
investigation of infertility [Figure 31.2]. A number of ance
findings on HSG may suggest genital tract TB (57,58).
The HSG performed during the acute stage of the disease tubes, irregular tubal outline, calcification of the tubes
may, however, result in exacerbation of the disease and and ovary, filling defects in the line of tubal shadow and
is, therefore, contraindicated. Winifred (59) noted such fistulous tracts on HSG as suggestive of TB .
an event in four of the fourteen cases subjected to HSG. Rozin (63) has described several radiographic signs
Seigler (60) reported fever as the most common compli- that were presumptive of TB. These include: [i] golf club
cation following HSG. Serious pelvic infections have been appearance, when only isthmus and proximal ampulla
reported in 0.3 to 1.3 per cent cases (60). are visualized, isthmic segment has a rigid stove pipe
Magnusson (61) described two typical forms of the appearance [Figure 31.4]; [ii] a beaded appearance due to
disease based upon HSG findings: [i] ragged and jagged alternate areas of tube filled with and without radio-
tubal contour with small lumen defects [Figure 31.3]; and graphic contrast [Figure 31.5]; [iii] maltese cross
[ii] straight rigid contour of the lumen with stem pipe- appearance, completely filled tube with rigid, irregular
like configuration of the tube. Seigler (62) described rigid outline [Figure 31.6]; [iv] rosette appearance, where the
Figure 31.2: Hysterosalpingogram with normal findings. The uterine Figure 31.4: Hysterosalpingogram showing rigid stove pipe-like
cavity has a normal outline. Both the fallopian tubes are outlined appearance of the fallopian tubes. There is a small area of
with free peritoneal spill of radio-opaque contrast irregularity along the right uterine wall
456 Tuberculosis
distal end of tube is filled with dye [Figure 31.7]; [v]

numerous diverticula in isthmic area; and [vi] leopard skin-
like speckled appearance, of the ampulla due to tube being
partially filled with the contrast [Figure 31.3].
The presence of calcified tubes, ovary or pelvic lymph
nodes is considered as the most significant finding. In
addition, uterine cavity may be shrivelled and deformed
[Figure 31.8]. The tubes may be patent in 37 per cent of
cases with TB endometritis (64).
Figure 31.7: Hysterosalpingogram showing dilated portion of the

left fallopian tube without any spill of dye. Only proximal part of the
right fallopian tube is seen
Laparoscopy and Hysteroscopy

Laparoscopy and hysteroscopy are important procedures
in the diagnostic work-up of patients with infertility.
Laparoscopy provides direct visualization of the pelvic
organs and peritoneal surfaces. In addition, it helps in
confirming tubal patency. A number of observations may
be made during laparoscopy in these cases. These include
endometriosis, pelvic inflammatory disease or fibroids.
Figure 31.5: Hysterosalpingogram showing irregular uterine outline Despite normal physical examination, several abnormali-
and patchy filling of the dye in the right fallopian tube resulting in ties can be detected in about 60 per cent of the cases
beaded appearance
during laparoscopy (65) [Figures 31.9A, 31.9B, and
Figure 31.6: Hysterosalpingogram showing completely filled tube Figure 31.8: Hysterosalpingogram showing extensive extravasa-
on the right side with a rigid outline. Dilatation of the distal half of tion of radio-opaque contrast in pelvic vessels. Fallopian tubes are
the left tube with doubtful spill of the contrast is seen. A small filling not visualized indicating bilateral cornual occlusion
defect is also seen in the uterine cavity
31.9C]. Diagnostic yield of laparoscopy in patients with

infertility due to suspected female genital TB has been
documented in several studies [Table 31.5]. Based upon
various laparoscopic findings and guided biopsy, Palmer
and Olivera (67) have described a subacute and chronic
stages in the natural history of pelvic TB.
Subacute Stage
The subacute stage of female genital TB is characterized
by the presence of whitish-yellow and opaque miliary
granulations, surrounded by hyperaemic areas over the
fallopian tubes and uterus. The pelvic organs may be
congested, red and oedematous with adhesions. Multiple
fluid filled pockets may also be seen.
Figure 31.9C: Laparoscopic view of pelvis in a patient with pelvic
tuberculosis showing tubercles on the surface of uterus and fluid
in the Pouch of Douglas
Table 31.5: Incidence of genital tuberculosis at laparoscopy
Study (reference) No. of patients Incidence (%)

Krishna et al (9) 697 10.3
Deshmukh et al (8) 500 9.0
Merchant (66) 687 14.1
Gupta et al (15) 150 26.7
Chronic Stage
Figure 31.9A: Laparoscopy view in a patient with pelvic tuberculosis The chronic stage of female genital TB is recognized by
showing vascular adhesions on the posterior surface of uterus. the presence of the following findings.
The fallopian tube is congested and oedematous with tobacco
pouch appearance of the fimbrial end Nodular salpingitis A series of yellow coloured small
nodes may be seen on a normal looking tube.
Patchy salpingitis Short and swollen tubes with
agglutinated fimbriae may be seen.
Hydrosalpinx Fallopian tubes are distended at their
terminal end due to agglutination of fimbriae. These
tubes tend to be “retort shaped”. Bilateral involvement
of the tubes is almost always seen.
Caseosalpinx Ampulla of the tube is deformed by an
ovoid dilatation which is whitish-yellow with poor
vascularization. The tube is distended with caseous
material. This finding also tends to be bilateral.
Figure 31.9B: Laparoscopic view of pelvis in a patient with pelvic

Adhesions Bands of adhesions may be seen between
tuberculosis showing surface tubercles on pelvic organs. Distal loops of intestine and the omentum. Sometimes broad
end of the tube is dilated bands may mask the whole adnexae. Laminar adhesions
458 Tuberculosis
covering the tubes and ovary and fixing them, are has encountered a number of patients with infertility or
occasionally seen in the chronic phase of genital TB. chronic pelvic pain with adnexal masses and free fluid
Tripathy and Tripathy (20) performed laparoscopy in the pelvis on ultrasonography who were found to have
in 62 sputum smear-positive pulmonary TB patients. genital TB on subsequent investigations [Figure 31.10].
They found bands of adhesion, tubercles and hyperaemia
in 59.6 per cent cases and intestinal adhesions in 24.2 Computed Tomography
per cent patients. Tubercles were observed on the A number of findings have been described on CT as
fallopian tubes in 22.6 per cent cases and adhesions in suggestive of abdominal and pelvic TB. These include
the pouch of Douglas were evident in 11.3 per cent low density ascites, uncommon patterns of adenopathy,
patients. presence of multiple pelvic lesions, hepatic, adrenal and
Bhide et al (68), in a laparoscopy study of 71 patients splenic lesions. Though these lesions may mimic
with genital TB, reported pelvic adhesions in 48 per cent, malignancy, they should raise a suspicion of TB especially
tubercles in 33.8 per cent, unilateral adnexal mass in 11.3 if they encountered in young patients suffering from
per cent and bilateral adnexal masses in 21.1 per cent infertility (72).
patients. Further, encysted effusion [8.45%] and lesions
on the bowel and/or omentum [25.4%] were also Magnetic Resonance Imaging
observed. Marana et al (69), in a laparoscopy study of
254 patients with primary or secondary infertility from Magnetic resonance imaging is being increasingly used
Italy, found tubal factor to be responsible in 101 patients. for evaluating pelvic and other abdominal masses
[Figures 31.11A and 31.11B] and has been found to be
Of these, only two patients had histopathological and
useful in localizing soft tissue abnormalities in patients
culture-positive endometrial TB. In a third patient with
with female genital TB (73).
laparoscopic findings suggestive of TB, the organisms
were cultured from urine. In a recent study on female
Serodiagnosis
genital TB in infertile women from New Delhi [n = 40]
(15), laparoscopic examination revealed abnormally Due to a low positivity rate of demonstration of Myco-
dilated, tortuous, and blocked fallopian tubes [n = 13]; bacterium tuberculosis in smear and culture in
peritubal and periovarian adhesions [n = 18]; Fitz-Hugh- patients with female genital TB, there has been a search
Curtis syndrome [n = 15]; omental adhesions [n = 18];
and bowel adhesions [n = 15]. Hysteroscopy revealed
flimsy intrauterine adhesions [n = 7]. Hysteroscopic
observations also suggest that the female genital TB is
an important cause of Asherman’s syndrome in
India (70).
The frequent use of laparoscopy and hysteroscopy
has made it possible to diagnose a number of cases of
genital TB among women with infertility and chronic
pelvic pain.
Ultrasonography
Ultrasonography, being non-invasive with no radiation
hazard, has been increasingly used in evaluating pelvic
and other abdominal masses. Lee et al (71) described
Figure 31.10: Ultrasonography in pelvic tuberculosis. A longitudinal
sonographic features of TB endometritis in a 59-year-old
scan in a 33-year-old parous woman with a history of oligomenor-
female. Demonstration of bilateral, predominantly solid, rhoea. The scan shows fluid collection in the Pouch of Douglas
adnexal masses containing scattered small calcifications [asterisk]. Investigations confirmed the diagnosis of genital
is highly indicative of TB involvement (72). The author tuberculosis
Figure 31.11A: Magnetic resonance imaging in pelvic tuberculosis. Figure 31.11B: Magnetic resonance imaging T1-weighted coronal
Post-gadolinium T1-weighted coronal scan in a 26-year-old nullipara scan of the same patient one year after antituberculosis treatment.
with history of chronic pelvic pain unresponsive to usual treatment. Scan shows complete resolution of abscesses
Hypointense masses with rim enhancement [arrows] abutting the
left pelvic wall and tracking to subgluteal region suggestive of endometrial aspirate sample from an infertile patient
abscesses with normal laparoscopy was also positive. Multiple
sampling from different sites increased the diagnostic
for serological tests to diagnose the disease in these
yield by the PCR. The reader is referred to the chapter
patients. A number of reports on serological tests for
“Laboratory diagnosis” [Chapter 10] for more details.
diagnosis of TB have appeared in the literature. Early
promising results have repeatedly given way to a low
specificity. TREATMENT
Treatment of genital TB is similar to treatment of TB
Polymerase Chain Reaction
elsewhere in the body. Availability of effective
The PCR is a useful supporting test for the diagnosis of antituberculosis drugs has significantly decreased the
female genital TB (15,74,75). Used judiciously, the PCR requirement for surgical treatment in patients with female
can help in the diagnosis of TB in certain clinical genital TB. In India, patients with female genital TB receive
situations. In a double-blind study (75) from New Delhi, DOTS under the Revised National Tuberculosis Control
India, endometrial aspirates, endometrial biopsies, fluid Programme [RNTCP] of the Government of India. The
from the Pouch of Douglas were investigated for the reader is referred to the chapters “Treatment of tuberculo-
presence of the mpt64 gene of Mycobacterium tuberculosis sis” [Chapter 52], and Revised National Tuberculosis Control
by PCR in 25 women with infertility and the PCR results Programme” [Chapter 63] for more details.
were correlated with laparoscopic findings (71). The PCR Prior to the availability of effective drug therapy,
was positive in 14 out of 25 patients [56%], compared to surgery produced a significant degree of morbidity and
one smear with acid-fast bacilli [1.6 %] and two culture- complications. These included bowel fistula [14%] and
positive samples [3.2%]. All patients with laparoscopy an operative mortality rate of 2.2 per cent (76). These
findings suggestive of TB, 60 per cent of those with a complications are rarely seen now. Indications for
probable diagnosis and 33 per cent of those with surgical intervention in patients with female genital TB
incidental findings were positive by PCR. However, one are shown in Table 31.6.
460 Tuberculosis
Table 31.6: Indications for surgical intervention in genital Pregnancy Following Treatment of
tuberculosis Female Genital Tuberculosis
Persistence or increase of pelvic masses after a six-month course Full-term pregnancy is uncommon after treatment of
of antituberculosis treatment histopathologically proven genital TB (78). From time to
Recurrence of positive endometrial culture or histology after a time occasional case reports have appeared about
six-month course of antituberculosis treatment
successful term pregnancies in patients with genital TB
Persistence or recurrence of pain or bleeding after six-months of
who have undergone treatment (79,80).
antituberculosis treatment
Postmenopausal patient with a recurrent pyometra due to
If pregnancy takes place in a treated patient with
tuberculosis female genital TB, it is more likely to result in ectopic
pregnancy or abortion (81). Among 206 patients with
female genital TB treated by Sutherland (82), 45
pregnancies were reported in 26 women. Of these, 11
Minimal Genital Tuberculosis
were ectopic pregnancies and 11 pregnancies ended in
Minimal disease is usually asymptomatic, except for abortions. Fourteen women had 23 live births (82).
infertility and is diagnosed by finding TB endometritis Merchant (66) in a study of 101 patients with female
on curettage or biopsy or tubercle bacilli on culture of genital TB, diagnosed on laparoscopy, reported three
the curettings of menstrual blood. The patient is started ectopic pregnancies, 11 intrauterine pregnancies and
on standard antituberculosis treatment and is examined nine term pregnancies. In two patients abortion was
at monthly intervals. After six months, a procedure of induced for medical reasons. Jindal et al (79) reported
dilatation and curettage is done and the endometrial three pregnancies among 14 women with histopatho-
curettings are examined histologically and bacteriolo- logically proven endometrial TB. Falk et al (10) in a study
gically. of 187 patients from 47 Swedish hospitals reported four
Wherever feasible, the patient should be followed up ectopic pregnancies and no intrauterine pregnancy after
annually for an indefinite period of time as exacerbations antituberculosis treatment. Saracoglu et al (23), in a series
have been reported up to 10 years after apparent cure of 72 patients with pelvic TB from Turkey, reported one
before the advent of modern short-course treatment. This intrauterine pregnancy without any surgical or medical
is highly unlikely with current therapy.
treatment of pelvic TB.
Advanced Genital Tuberculosis
Tuboplasty
Advanced genital TB is diagnosed by the presence of
palpable tubo-ovarian masses and histopathologic or Since infertility is the most common symptom in patients
bacteriologic evidence of TB. The patient is started on with genital TB, reconstructive tubal surgery is often
standard antituberculosis treatment and is examined at performed after adequate medical treatment. Reactiva-
monthly intervals. tion of silent pelvic TB following tuboplasty procedure
Schaefer (5) has suggested that, if palpable adnexal has been reported by Ballon et al (83). Schaefer (5)
masses persist after six months of antituberculosis advocates against such procedures in patients with
treatment, total abdominal hysterectomy and bilateral female genital TB.
salpingo-oophorectomy are performed (5). However,
there is no consensus regarding this view (5) as a number In Vitro Fertilization
of these patients suffer from infertility and are also young.
With reports of successful pregnancies in patients with In the last few years a number of reports have appeared
female genital TB following in vitro fertilization and in the literature highlighting the role of in vitro fertili-
embryo transfer [IVF-ET] procedures (77), adequate zation in patients with treated female genital TB (77,84).
therapy with standard antituberculosis treatment However, the results of IVF-ET have been disappointing
regimens is desirable before surgical intervention is in patients with female genital TB as compared to the
undertaken. success rates observed in non-TB tubal factors.
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Genitourinary Tuberculosis 463
Genitourinary Tuberculosis
32
AK Hemal
INTRODUCTION Acquired immunodeficiency syndrome [AIDS] has

caused a worldwide resurgence of TB. Tuberculosis
Genitourinary tuberculosis [TB] is still a major problem
occurs in approximately 10 per cent of patients with AIDS
in developing countries. Nearly all patients can be cured
and involves at least one extra-pulmonary site in nearly
by effective antituberculosis treatment if the disease is
50 per cent of the cases (7), with kidney being the most
diagnosed early. However, more often than not, the
common genitourinary site of involvement (8). Therefore,
diagnosis is delayed, and a number of patients present
a proportional increase in urogenital TB can be expected
with non-functioning kidney, ureteric stricture and
after an appropriate latent period, especially if survival
shrunken urinary bladder. Early diagnosis and treatment
rates in patients with AIDS improve.
of genitourinary TB is important because undiagnosed
and untreated disease can result in renal failure and
PATHOGENESIS
death.
Mycobacterium tuberculosis is the usual cause of urinary
EPIDEMIOLOGY tract TB. Haematogenous dissemination from an active
site of infection [often pulmonary] leads to the formation
With the advent of modern chemotherapy and effective of metastatic lesions in the kidneys. The bacilli are initially
treatment of pulmonary TB, the incidence of genito- disseminated throughout the cortices of both kidneys and
urinary TB has shown a decline in the developed world. form microscopic granulomas (9).
However, genitourinary TB remains to be a major The intensity of infection depends upon the infecting
problem in the developing world. dose, virulence of the organism and the resistance of the
Urogenital TB complicates three to four per cent of host. Macroscopic progression of the disease is mostly
all cases of pulmonary TB and constitutes at least 30 per unilateral (10). Usually, these multiple tubercles heal
cent of all cases of extra-pulmonary disease (1-3). Medlar either spontaneously or as a result of antituberculosis
(4) found bilateral renal cortical lesions in patients with treatment administered to control the clinically active
pulmonary TB and suggested haematogenous spread primary focus. Nevertheless, one or more tubercles may
from the primary lesion in the lungs. Colabawalla (5) in enlarge after years of inactivity and rupture into the
a multicentric study from India reported the incidence nephrons producing bacilluria without a radiographic
of TB to be in 10 to 34 per cent in patients with various lesion (9). The bacilli descend along the nephrons and
urological diseases. In a study conducted by the Indian form more granulomas within the medulla and papilla.
Council of Medical Research in 2240 patients suspected These granulomas may coalesce and form cavities which
to have urinary tract TB, the incidence of microbiological may communicate with the pelvicalyceal system [PCS]
and/or histopathological proven diagnosis of TB was following rupture. They may also result in necrosis and
10.7 per cent (6). sloughing. Tuberculomas in the renal parenchyma can
464 Tuberculosis
result in displacement of the calyces without communi-

cating with the PCS. The appearance of a renal mass can
also be produced by localized hydrocalycosis due to
stricture of the infundibular or calyceal neck. The bacilli
when shed into urine infect the walls of the calyces
leading to ulceration, granuloma formation and
ultimately result in fibrosis with strictures. Early scarring
is reversible by adequate steroid treatment, but end-stage
fibrotic strictures are irreversible (8). These changes are
summarized in Table 32.1. Renal TB progresses slowly
and often silently. In addition to loss of renal parenchyma
by caseation, intrarenal scars and infundibular strictures
lead to obstruction and dilatation of segments of the PCS.
The intrarenal scars may also cause sharp kinking of the
Figure 32.1A: Plain X-ray of the kidney, ureter and bladder [KUB]
renal pelvis with resultant obstruction. showing calcified kidney [arrows] on the left side resulting in
Urinary obstruction from the strictures and caseation autonephrectomy
of the renal parenchyma results in destruction of the
kidney or its parts. Obstruction may predominate, in
which case, massive hydronephrosis or hydrocalyx may
be the final stage. If parenchymal caseation, necrosis and
calcification predominate, the kidney will be destroyed.
Usually, both the processes occur and may lead to a
malfunctioning, calcified kidney [Figures 32.1A and
32.1B]. This process is called “autonephrectomy”.
From the kidney, the disease passes to the perirenal
tissues. The fat is greatly thickened and becomes densely
adherent to the kidney. When the renal capsule bursts, a
Table 32.1: Changes that occur in renal tuberculosis

Early changes
Papillary necrosis or papillitis
Cavity formation
From sloughed off papilla
From rupture of abscess into the pelvi-calyceal system
Strictures
Cortical scars
Caliectasis
Biked up pelvis
Figure 32.1B: Intravenous urogram of same patient showing
Hydronephrosis
normally functioning kidney on the right side and calcified nonfunc-
Pelvi-ureteric junction stricture causing back pressure changes
tioning kidney [arrow] on the left side
Perinephric abscess
Rupture of tuberculosis abscess into the perinephric space
peri-nephritis occurs. Later, peri-ureteritis and
Pseudocalculi
Due to calcification in the lesions perinephric abscess may follow.
Caseous masses The cut surface of a TB kidney has the following
Caseous transformation of renal lobes characteristics: [i] the papillae are destroyed; [ii] the
Diffuse miliary involvement calyces are deeply ulcerated; [iii] yellowish, caseous,
Diffuse involvement of the kidney
tuberculous masses may be seen at the base of pyramids;
and [iv] numerous cavities of varying sizes with ragged urethral stricture and periurethral abscess or fistula
edges and containing creamy, sterile pus are seen in the formation (9).
cortex.
Renal calcification is a major sequelae of the renal TB CLINICAL PRESENTATION
(11). Its aetiology remains obscure. These calcific shadows
The clinical presentation of genitourinary TB is summa-
tend to be ill-defined and irregular in outline. They are
rized in Table 32.2. Active urogenital disease usually
neither as dense nor as well-defined as radio-opaque
occurs five to twenty years after primary pulmonary
renal calculi. These lie in the cortex and strongly suggest
infection. Therefore, renal involvement is rare before the
the presence of TB. It is an unfavourable prognostic sign
age of 20 years. The disease is usually encountered
when non-surgical treatment is used. In spite of anti-
between the second and fourth decades of life.
tuberculosis treatment, there is less likelihood of stable
Genitourinary TB is rare in children and in persons over
urinary conversion, and a greater propensity for deterio-
50 years of age (1-6,16). In a recently published retros-
ration of renal function. Radiographs should be repeated
pective series from the All India Institute of Medical
every six months to determine an increase in size of the
Sciences [AIIMS], New Delhi (17), 241 patients with
calcification in which case surgical intervention may be
genitourinary TB [mean age 34.6 years] were studied.
indicated.
Majority of them presented with irritative voiding
Ureteric involvement occurs due to the antegrade
symptoms. Azotaemia was seen in 54 [22.4%] cases. The
flow of urine from an infected kidney. Tuberculosis of
most commonly involved organ was the kidney in 130
the ureter produces mucosal and wall ulceration, fibrosis,
[53.94%] cases. Preoperative bacteriologic diagnosis was
stricture and calcification. The ragged, saw-tooth ureter
confirmed in 70 [29%] cases. In the author’s experience,
seen in ureteric TB develops due to multiple active ulcers
the duration of clinical history did not correlate with the
and spasm of the ureteric wall. The bacilli also descend
severity of the disease.
to the bladder, affecting the collecting system and ureter
and cause obstruction, reflux or both due to involvement Table 32.2: Clinical presentation of genitourinary
of ureteric orifices and intramural ureter (12). tuberculosis
Gradually, the bladder becomes small and contracted Common
and even a “thimble bladder” may develop. Stiffening Irritative voiding symptoms
or fibrosis of the bladder wall can result in compromise Haematuria
of the valve mechanism at the ureterovesical junction, Flank pain
Renal mass
leading to vesico-ureteric reflux or occasionally obstruc-
Sterile pyuria
tion. Recurrent urinary tract infection
Genital TB is almost always acquired by haemato- Chronic renal failure
genous dissemination from an extra-genital source Urinary calculi
(13,14). The most common primary site is the lung. Acute presentation mimicking pyelonephritis
Direct extension from an adjacent affected organ, such Rare
Non-healing wound, sinuses or fistula
as urinary tract, may occur. The primary focus of genital
Spontaneous vesico-vaginal fistula
TB in the female is the fallopian tube. Spread from the “Hour-glass” bladder
fallopian tube to the uterus can occur in up to 50 per cent Haemospermia
of patients with tubal infection (15). Tuberculosis of the Suprapubic fistula
fallopian tubes can rarely occur as a sexually transmitted Nephro-colo-cutaneous fistula
infection when a woman acquires the infection from a
Tuberculosis of the Kidney
man with epididymal TB (14).
In men, the prostate, seminal vesicles and epididy- Specific symptoms include dysuria, haematuria, fre-
mis may be involved, where caseating granulomas, quency and nocturia. These symptoms worsen as TB
abscesses and calcification may ensue (10). The bacilli cystitis develops. Backache, abdominal and flank pain
may also descend rarely to the urethra and may result in are common and may occasionally be due to a renal cold
466 Tuberculosis
abscess or perirenal abscess. These symptoms worsen becomes withdrawn, rigid and dilated assuming the
with fluid overload and pelvicalyceal obstruction. Non- “golf hole” appearance. The ureters become rigid in their
specific constitutional symptoms, such as fever, anorexia, lower third and give rise to ureteric reflux. With the use
weight loss and anaemia may occur. of modern chemotherapy, this is a rare occurrence now.
Occasionally, whole of the bladder is covered by angry-
Tuberculosis of the Ureter looking inflammed, velvety granulations with ulcera-
tions. Once the disease reaches this stage, it is unlikely
Tuberculosis ureteric stricture is a common complication
that even with modern chemotherapy, there will be
of the disease and may be present at the time of diagnosis
of renal TB. However, it often develops or progresses sufficient recovery of the bladder from the sequelae of
the disease. Gradually, the bladder becomes small and
during otherwise effective treatment with antitubercu-
contracted and even a “thimble bladder” may develop.
losis agents. The most common site for TB stricture is
ureterovesical junction followed by pelviureteric
Genital Tuberculosis
junction. Occasionally, the middle third of ureter is
affected and rarely the entire ureter can be affected Genital TB may present with painless haemospermia,
resulting in complete stenosis, fibrosis and even scrotal pain and swelling or nodularity of the epididymis,
calcification. vas deferens, seminal vesicle or prostate. Testicular
In the author’s experience (18), of 34 cases of ureteric involvement is rare. Chronic infection in any of these
stricture seen during a 10-year period, ureteric lesions sites can lead to sinus formation, such as nephro-
occurred on the right side in 18 patients, on the left side cutaneous fistula, nephro-colo-cutaneous fistula, perineal
in eight patients, while eight patients had bilateral fistula and vesico-vaginal fistula (19,20). In the female,
lesions. The most common site of involvement was the infection of the ovaries, fallopian tube, endometrium,
lower ureter [n = 18], followed by middle [n = 7] and vagina and urethra may cause infertility, vaginal
upper ureter [n = 4]. Five patients had extensive discharge, menstrual dysfunction, dyspareunia or pelvic
involvement including two patients with complete pain. Generalized abdominal tenderness can occur due
involvement of ureter. Of the eight patients with bila- to pelvic abscess. Other presentations include hyper-
teral disease, five had deranged renal functions. Six tension from total or partial ischaemia of the kidney and
patients had TB in the past and had received adequate chronic renal failure. Occasionally, calcification in the
antituberculosis treatment. One patient had discontinued renal area may be detected on an abdominal radiograph.
treatment after a month of therapy.
Tuberculosis of the Testis
Tuberculosis of the Urinary Bladder
Tuberculosis of the testis is always secondary to infec-
Bladder lesions are secondary to renal TB. The earliest tion of the epididymis, which in most cases is haemato-
form of infection starts around one or the other ureteric genous. Tuberculosis orchitis without epididymal
orifice which becomes red, inflammed and oedematous. involvement is very rare. If the orchitis is secondary to
Later, bullous granulations appear and completely epididymal TB, the testicular lesion rapidly responds to
obscure the ureteric orifice. Tuberculosis ulcers may be chemotherapy after the epididymis has been removed,
present, but they are rare and are a late finding. These provided the destruction of the testicular tissue is not
ulcers are irregular in outline. They are superficial with extensive.
a central inflammed area which is usually surrounded
by raised granulations. In the initial stage, they are close Tuberculosis of the Epididymis
to the ureteric orifices. However, as the disease prog- Foci of TB in the epididymis are caused by metastatic
resses, they can appear in any part of the bladder. If the spread of the organisms through the blood stream. The
disease progresses further, the inflammation spreads disease usually starts in the globus minor, because of its
deep and the muscle is eventually replaced by fibrous rich blood supply than the other parts of the epididymis.
tissue. The fibrosis starts around the ureteric orifice, Tuberculosis epididymitis may be the first and only
which contracts and can either produce a stricture or presenting symptom of genitourinary TB (21,22). The
disease usually develops in young, sexually active males can progress to cause a TB cavernositis with involvement
and in 70 per cent of patients there is a previous history of the urethra. The diagnosis is confirmed by biopsy.
of TB.
The usual presentation is a painful, inflammed scrotal Tuberculosis of the Urethra
swelling. The globus minor alone is affected in 40 per
Tuberculosis of the urethra is also rare (27). It is caused
cent of the cases. In extensive disease, there may be by spread from a focus in the genital tract. Its rarity is
generalized epididymal induration with beading of the
difficult to understand as there is almost constant
palpable vas deferens (21,22).
exposure of the urethra to infected urine. It may present
in either acute or chronic form. In the acute phase, there
Tuberculosis of the Prostate
will be urethral discharge with involvement of the
Tuberculosis of the prostate is rare. In many cases it is epididymis, prostate and other parts of the renal tract.
diagnosed by the pathologist or is found incidentally after The diagnosis is not difficult at this stage as the organism
a transurethral resection. Very rarely, the disease spreads is always isolated. In the chronic form, the diagnosis is
rapidly and cavitation may lead to a perineal sinus (23). difficult because the disease presents as urethral
Advanced lesions may cause a reduction in the volume obstruction or stricture. In such cases, urethral biopsy is
of semen, a sign that may help in the diagnosis. The route required for confirmation of the diagnosis.
of infection may be either haematogenous or descending.
On palpation most often the gland is nodular, non-tender DIAGNOSIS
and rarely enlarged, with soft areas being extremely
Undiagnosed and untreated urinary tract TB can cause
uncommon. Sometimes, the chronic granulomatous
renal failure and finally death. Diagnostic difficulties in
inflammation of the prostate leads to caseation necrosis
genitourinary TB are usually due to failure to consider
which heals by fibrosis or due to poor host defense results
the disease from the symptoms described. The diagnosis
in cavitation and sloughing. This has been termed
is considered as a path of four steps, each being slippery
“autoprostatectomy” by the author (24).
enough to trip even the most careful urologist. These are:
The transmission of genital TB from male to female
[i] clinical suspicion; [ii] bacteriological confirmation of
is rare. This is quite surprising because many men with
diagnosis; [iii] radiological localization; and [iv] endo-
genital TB have Mycobacterium tuberculosis in the semen.
urological evaluation and biopsy.
This form of the disease is unlikely to be seen in the
A full blood count, erythrocyte sedimentation rate
developed world, but it does appear in developing count-
[ESR], urea and electrolyte values should be obtained in
ries. A painful swollen inguinal gland in a woman, if it
every case. In addition, if calcification is present, a
is proven to be TB, should alert the clinician to a possible
complete biochemical assessment of calcium metabolism
diagnosis of genital TB in the male partner. The lesion
is performed. In cases with elevated ESR, measurement
responds well to antituberculosis treatment. Infertility
at monthly intervals may give some indication regarding
is also one of the presentations.
response to treatment. Tuberculin skin test is usually
positive in most patients with genitourinary TB.
Tuberculosis of the Penis
Tuberculosis of the penis is very rare. Earlier, it was seen Urine Examination
as a complication of ritual circumcision, when it was the Urine is examined for red blood cells and pus cells, the
usual practice for the operators, many of whom had open pH and concentration are noted. Urine culture and sensi-
pulmonary TB, to suck the penis (25). Primary TB of penis tivity tests are performed to isolate the non-specific
occurs after coital contact with organisms already present organisms. Secondary bacterial infection is found in
in the female genital tract or by contamination from about 20 per cent of patients with TB. The usual organism
infected clothing (26). Secondary penile TB occurs as a is Escherichia coli. Persistent sterile pyuria and haematuria
secondary manifestation of active pulmonary TB. The in the absence of recent antibiotic treatment is a common
lesion appears as a superficial ulcer of the glans penis. It finding and in such a context urological TB must always
is indistinguishable from malignant disease, although it be considered.
468 Tuberculosis
Microbiological Methods Plain Radiograph

Since urinary bacillary excretion is intermittent, at least Plain radiographs of the urinary tract may show
three, but preferably five, consecutive early morning calcification in the renal areas [Figures 32.2A and 32.2B]
specimens of urine should be cultured, each on two slopes: and in the lower genitourinary tract. Ureteric calcification
[i] Lowenstein-Jensen culture medium; and [ii] a pyruvate due to TB is very rare, unless there is extensive renal
egg medium containing penicillin to identify calcification. It must be distinguished from that seen in
Mycobacterium bovis, which is partially anaerobic and schistosomiasis. In ureteric TB, the calcification is
grows on the surface of the culture medium. If the cultures intraluminal and appears as a cast of ureter which is
are positive, sensitivity tests are always conducted, in
order to rule out drug-resistant TB. Smear and culture
examination of urine and secretions from a discharging
sinus or material procured by fine-needle aspiration are
helpful in confirming the diagnosis. However, urine
smears for Ziehl-Neelsen staining are often negative and
urine mycobacterial culture results are available only after
six to eight weeks.
Polymerase Chain Reaction

Polymerase chain reaction [PCR] has been applied for
the early diagnosis of genitourinary TB. In a study of 42
patients with clinical suspicion of genitourinary TB from
India (28), radiographic abnormalities suggestive of
genitourinary were found in 37 [88%]; Mycobacterium Figure 32.2A: Plain radiograph of the abdomen showing
tuberculosis TB was isolated from the urine in 13 [31%]; bilateral calyceal calcification [arrows]
histopathology of the urinary bladder was suggestive of
TB in 11 [46%]; and the urine PCR for Mycobacterium
tuberculosis was positive in 34 cases [81%]. Of 35 cases
with proven genitourinary TB, the urine PCR for
Mycobacterium tuberculosis was positive in 33 [94.3%]. In
another study from Egypt (29), urine specimens from
1000 patients with clinical suspicion of urinary TB were
examined using conventional methods of smear and
culture examination and two PCR protocols; the
Mycobacterium tuberculosis species-specific insertion
sequence, IS6110 and mycobacterium genus-specific
sequence encoding ribosomal ribonucleic acid [16S
rRNA] for nontuberculous mycobacteria. Compared
with mycobacterial culture, the sensitivity and specificity
of acid-fast bacilli staining were 52.1 per cent and 96.7
per cent respectively; the overall sensitivity and
specificity of the IS6110-PCR assay was 95.6 per cent and
98.1 per cent respectively. The corresponding results for
the 16S rRNA gene-PCR were 87.1 per cent and 98.9 per
cent. These results suggest that urine PCR is a useful test
for the rapid diagnosis of genitourinary TB in the appro- Figure 32.2B: Intravenous urogram showing lobar calcification of
priate clinical setting. The reader is referred to the chapter the inferior pole [white arrow] and dilated upper and middle calyces
“Laboratory diagnosis” [Chapter 10] for more details. in the left kidney [black arrow]
thickened and not dilated. In schistosomiasis, the

calcification is mural and the ureter is dilated and
tortuous. Plain radiographs of the chest and spine are
also performed to exclude pulmonary or spinal disease.
Intravenous Urography
Intravenous urography [IVU] is still the mainstay of
investigation for renal tract pathology (30). In patients
with genitourinary TB, it helps in localization of the
disease besides functional and anatomical delineation
[Figure 32.3]. The renal lesion may appear as distortion
of a calyx, a calyx that is fibrosed and completely
occluded [lost calyx], multiple small calyceal deformities,
or a severe calyceal and parenchymal destruction.
Urography may reveal a hydroureteronephrosis, a poorly
functioning or a non-functioning kidney. Irreversible TB
ureteritis is manifested by dilatation above a uretero-
vesical stricture, or if the disease is more advanced, by a
rigid fibrotic ureter with multiple strictures [Figure 32.4].
The cystographic phase of the urogram can give valuable Figure 32.4: Intravenous urogram showing stricture of the lower
information about the condition of the bladder, which end of the ureter in a solitary functioning kidney [arrow]
may be small and contracted or irregular with filling
defects and bladder asymmetry [Figure 32.5].
Figure 32.5: Intravenous urogram showing non-functioning kidney

Figure 32.3: Intravenous urogram showing no excretion of contrast on the right side, hydronephrosis [black arrow] on the left side and
on the right side and hydroureteronephrosis on the left side [arrows] thimble bladder [white arrows]
470 Tuberculosis
Magnetic Resonance Urography kidney can be assessed by measurement of creatinine

clearance by leaving percutaneous nephrostomy tube, if
Magnetic resonance urography imaging can also be done
desired. Nephrostogram [Figure 32.7] can be performed
in these cases to delineate the anatomy of the urinary
through the percutaneous nephrostomy tube.
tract without the need for contrast. However, it gives an
idea of anatomy alone. Hence, it needs to be supple-
Arteriography
mented by a functional study.
Arteriography is an invasive investigation and is of
Retrograde Pyelography limited value in the routine evaluation of a patient with
Presently, retrograde pyelography is sparingly done. genitourinary TB. It is useful when there is a suspicion
There are two indications for its use: [i] stricture at the of coincidental renal tumour.
lower end of the ureter where it is necessary to delineate
Voiding Cystourethrogram
the length of the stricture and the amount of obstruction
and dilatation above the stricture [Figure 32.6]; and Voiding cystourethrogram is a very useful investigation
[ii] to obtain urine samples for culture from each kidney. to delineate bladder pathology. The bladder outline may
be irregular due to localized deformity from cicatrization
Percutaneous Antegrade Pyelography or due to a hyperplastic inflammatory lesion (12).
Percutaneous antegrade pyelography is becoming more Tuberculosis in the vesical wall produces large, multiple
important as an alternative to retrograde ureterography lesions and may manifest radiologically as filling defects
in patients with large hydronephrotic obstructed kidneys. simulating carcinoma (9). In patients with TB cystitis,
It is useful in visualizing a non-functioning kidney or in chronic ulceration produces hypertrophy of the bladder
determining the condition of all excretory pathways wall and marked cicatricial contraction of the bladder.
above an obstruction. It can be used to aspirate the Fibrosis in the region of the trigone produces gaping
contents of the renal pelvis so that they can be sent for ureteric orifices, which may show vesico-ureteric reflux
diagnostic examination. An isolated function of ipsilateral on voiding cystourethrogram [Figure 32.8].
Figure 32.6: Retrograde ureteropyelogram showing reno-colo-

cutaneous fistula, narrow ureter [back arrow], colon, extravasation Figure 32.7: Right nephrostogram showing multiple
of the contrast through the sinus tract [white arrows] strictures in upper and lower ureter [arrows]
urography gives an accurate picture. Computed

tomography may help in case of a difficult intrarenal
lesion or if there is a possibility of a co-existing renal
carcinoma. Subtle ureteric changes are better appreciated
with a combination of a ureterogram and an image
intensifier. Computed tomography may be useful to deli-
neate granulomatous lesion, mass lesion [Figure 32.9] and
diseased seminal vesicles that were not originally thought
to be infected (31).
Figure 32.8: Voiding cystourethrogram showing no excretion of

contrast on the right side and hydroureteronephrosis on the left
side [arrows]
Retrograde Urethrography
Figure 32.9: CECT of the abdomen showing an irregular
Retrograde urethrography is performed to delineate the hypodense lesion in the right kidney [arrow]
urethral anatomy and to rule out narrowing or stricture
of urethra due to urogenital TB. Cystoscopy
Cystoscopy has important place in the evaluation of a
Ultrasonography
patient with suspected urinary tract TB, especially when
Ultrasonography as the initial investigation for genito- there is haematuria and persistent irritative voiding
urinary TB is of limited value. However, it is a non- symptoms [frequency, urgency and dysuria]. It helps to
invasive technique and can be used to monitor kidney evaluate the capacity of the bladder, any obvious bladder
lesions found by an intravenous urogram while the lesions and the nature of efflux from either ureter. Above
patient is receiving antituberculosis treatment. It can all, biopsy can be taken from a suspicious lesion for histo-
show whether a cavity is increasing or decreasing in size pathological diagnosis. Thus, urethroscopy, sampling of
and helps in avoiding repeated radiographic exami- urine from both the kidneys and bladder biopsy must be
nations. It can also be used to monitor the volume of a attempted in patients with suspected genitourinary TB.
contracted bladder during treatment and is of value in
assessing the need for bladder augmentation. Ultra- TREATMENT
sound-guided fine-needle aspiration and cytopathologi-
cal examination and biopsy of an abscess or a renal mass Antituberculosis Treatment
can be performed. Antituberculosis treatment is an essential component of
the treatment of genitourinary TB. Modern antituber-
Computed Tomography
culosis treatment is highly successful in the treatment of
Computed tomography [CT], as an early investigation genitourinary TB, although the optimum duration is not
of genitourinary TB, is of limited value as intravenous yet fully defined (8,32). The reader is referred to the
472 Tuberculosis
chapter “Treatment of tuberculosis” [Chapter 52] for more together with hypertension and ureteropelvic junction
details. [UPJ] obstruction; and [iii] co-existing renal carcinoma.
When kidney is destroyed completely or is not
Surgery functioning [as identified on renal scan], nephrectomy
may be the simplest answer. Laparoscopic [retroperito-
Surgery still has a vital role in the management of
neoscopic] nephrectomy and nephroureterectomy may
obstructive and advanced lesions in the urinary tract in
be performed safely and successfully for non-functioning
conjunction with antituberculosis treatment [Table 32.3].
kidneys (35). However, this procedure may be difficult
Advanced lesions are rare in the west, but are still
and complex when extensive perirenal fibrosis is present.
commonly encountered in the developing countries.
In such cases, segmental nephrectomy should be
Howsoever, normal the upper urinary tract may seem
considered.
at the first instance, a second IVU must be performed
Obstruction of the pelviureteric junction can be dealt
within three to four weeks as TB lesion contracts on
with endourological treatment [endopyelotomy
healing and may result in hydroureter and hydro-
antegrade and retrograde], or, with open pyeloplasty
nephrosis.
depending on the grade and severity. However, if an
Renal abscess not resolving within two weeks of the
area of the hilum is severely cicatrized, ureterocalyco-
treatment can be drained with ultrasound guidance
stomy may be required. In a kidney affected by TB, renal
[Figure 32.10]. Strictures may occur in any part of the
stone leading to pyeloduodenal fistula is rare. Surgical
urinary tract. In the kidney, these may be seen at the neck
treatment consists of nephrectomy and primary repair
of the calyx producing a hydrocalyx. Earlier these lesions
of duodenum [Figures 32.11A, 32.11B and 32.11C].
had to be unroofed and drained [cavernostomy]. Now,
hydrocalyx can be managed by ultrasound-guided Partial Nephrectomy
aspiration. A silent blocked-off calyx can be left to resolve
Partial nephrectomy is rarely carried out, because with
with antituberculosis treatment (33).
modern antituberculosis treatment, the response of a
Nephrectomy
Nephrectomy is indicated in the following situations (34):
[i] a non-functioning kidney with or without calcification;
[ii] extensive disease involving the whole kidney,
Figure 32.10: Ultrasonography showing an enlarged hypoechoic Figure 32.11A: Intravenous urogram showing functioning right
left kidney [thick arrow] with an anechoic cavity in the lower pole kidney with hydronephrosis [long arrow]. The left kidney is not
[asterisk] due to tuberculosis. A large psoas abscess [thin arrows] visualized. A radio-opaque shadow can be seen in the upper ureter
is also seen [small arrow]
Table 32.3: Surgical management of genitourinary tuberculosis
Renal tuberculosis
Nephrectomy or nephroureterectomy by conventional open surgery or by laparoscopic [retroperitoneoscopic] nephroureterectomy
Partial nephrectomy
Partial nephrectomy with fistulectomy
Nephrectomy with excision of fistula with primary repair of gut
Pyeloplasty
Ureterocalycostomy
Ureteric stricture
Lower part
Dilatation or balloon dilatation or endoureterotomy and stenting
Ureteroneocystostomy
Ureteroneocystostomy + psoas hitch or Boari’s flap
Middle part
Dilatation or balloon dilatation or endoureterotomy and stenting, or ureteroneocystostomy + psoas hitch or Boari’s flap according
to the nature and location of the stricture
Intubated ureterotomy
Interposition with appendix on the right side ileal replacement
Upper part
Dilatation or balloon dilatation or endoureterotomy and stenting
Percutaneous nephrostomy
Pyeloureteroplasty
Ureterocalycostomy
Pyeloplasty
Ileal replacement
Multiple strictures or total stricture of the urethra
Ileal replacement of the ureter
Diversion
Permanent ureterostomy
Ureterosigmoidostomy
Nephrostomy
Urinary bladder tuberculosis
Step I: Antituberculosis treatment
Step II: If cystitis is severe, bladder capacity is moderate, corticosteroids can be added to antituberculosis treatment
Step III: Bladder neck incision
Hydraulic dilatation
Step IV: Augmentation
Small capacity bladder [30 to 150 ml]
Ileal patch
Ileocystoplasty
Ileocaecoplasty
Sigmoidcolocystoplasty
Thimble bladder [10 to 30 ml]
Cystectomy + orthotopic neobladder
Tuberculosis of urethra
Endoscopic dilatation
Internal urethroplasty
Staged urethroplasty
Meatoplasty
Genital tuberculosis
Epididymectomy
Orchiectomy
Excision of fistula
Partial penectomy
474 Tuberculosis
Figure 32.11B: Intraoperative photograph of Figure 32.11C: Cut section of the kidney
the same patient showing pyeloduodenal fistula specimen removed during operation
local lesion in the kidney is rapid and effective. It is If there is stricture in upper ureter or at UPJ,
indicated in the following situations: [i] localized polar endoscopic stenting may first be attempted provided it
lesion containing calcification that has failed to respond is passable. The stent is left for six to twelve weeks. The
after six weeks of intensive chemotherapy; and [ii] an result is assessed after removal of the stent with an
area of calcification that is slowly increasing in size and intravenous urogram. In cases, where stenting is not
is threatening to gradually destroy the whole kidney. possible, percutaneous nephrostomy is indicated. After
Renal calcification is increasingly becoming a hazard adequate antituberculosis treatment for at least four
in renal TB. In one study, 28 per cent of all large areas of weeks, pyeloplasty is performed. Both Anderson-Hynes
calcification that were excised had viable Mycobacterium technique and the Culp technique give satisfactory
tuberculosis in the calcified matrix (33). Small lesions can results. Pyelostomy is an essential part of the technique
be kept under review on an annual basis. Larger areas of in cases in which a previous nephrostomy has not been
calcification should be excised and non-functioning performed. The pyelostomy tube is clamped the day after
kidneys with extensive calcification should be removed. the silicone stent is removed and is removed after urine
A reno-colo-cutaneous fistula due to TB is extremely is shown to be draining satisfactorily. However, if there
rare, and so far only six such cases have been documented is involvement of the upper ureter with a poorly
in the literature. Two such cases were managed by single- functioning kidney, nephroureterectomy is advisable. If
UPJ is totally obliterated and pyeloplasty is not feasible,
stage surgery [nephroureterectomy, fistulectomy and
then ureterocalycostomy may be performed.
primary repair of the colon] and antituberculosis
treatment (20).
Stricture of the Middle Third of the Ureter
Stricture of the Upper Third of the Ureter
Usually this part of ureter is involved with extensive
Stricture at UPJ is seen infrequently. Probably by the time stricture. Isolated stricture of the middle third of the
the stricture develops at the UPJ, the kidney may already ureter is rare. The management starts with an endouro-
have been destroyed. logical procedure if the stricture is passable, failing which,
one may resort to Davis’ intubated ureterostomy

technique over a silastic stent with the hope that ureteral
mucosa will regenerate around it. The silastic stent
should be left in place for at least six to eight weeks.
Possible complications include recurrent stricture or total
narrowing after stent removal. Occasionally, interposi-
tion of appendix has been attempted on the right side
for midureteric strictures.
Stricture of the Lower Third of the Ureter

Lower ureter is the commonest site of ureteric stricture
in genitourinary TB. Once obstruction is identified, it
necessitates careful follow-up and the patients are started
on antituberculosis treatment. Tailored IVU should be
done at the end of three weeks or earlier to assess the
progression or stabilization of the stricture. If it starts
worsening, then corticosteroids should be added to
antituberculosis treatment. Early stenting should be
considered in such cases. Endoscopic dilatation of the
ureteral stricture has been suggested by Murphy et al (36) Figure 32.12: Intravenous urogram showing stricture of the lower
who reported 64 per cent success. Ureteric dilatation can end of the ureter [black arrows] with spontaneous extravasation of
be performed with the help of simple ureteric catheters, the contrast in solitary functioning kidney [white arrow]
Brasch catheters or a ureteral balloon dilator. With the
recent availability of miniature ureteroscopes, uretero- Complete Ureteric Stricture
tomy can be performed with the help of cold knife,
In patients with complete ureteric stricture, ileal
diathermy or laser followed by stenting (37).
However, a stricture not yielding to endoscopic replacement of ureter [Figure 32.13], joining a tailored
or plicated ileum to the calyx of the kidney cranially, and
maneuvering should be dealt with ureteroneocysto-
to the urinary bladder caudally is a useful surgical
stomy. The ureteric stricture should be assessed with
retrograde ureterography and on cystoscopy the bladder technique.
is assessed. For strictures less than 5 cm, ureteroneo-
Surgery for Urinary Bladder Tuberculosis
cystostomy can be performed in a good capacity blad-
der. However, in long strictures, either a psoas hitch or a If urinary bladder is small in capacity [< 100 ml],
Boari’s flap may be required. When the ureteric stricture augmentation is warranted to take care of frequency on
is associated with small capacity bladder, then, bladder account of storage problem. Bladder augmentation can
is augmented and ureteroneocystostomy is performed. be done utilizing ileal segment, ileocaecal segment,
Similarly, in small capacity [thimble] bladder, simple sigmoid colon and even incorporating a segment of
cystectomy is done and ureteric reimplantation is stomach [Figures 32.14A and 32.14B] (38-41).
performed in the neobladder. Detubularization is not always essential, as low pressure
The author had encountered an unusual case with bladder achieved by this means may not have enough
stricture at the lower end of the ureter leading to sponta- contractile power to empty itself.
neous extravasation of contrast in a solitary non- Augmentation does not work in all cases in thimble
functioning kidney [Figure 32.12]. This patient was bladder [10 to 30 ml capacity] and can give rise to
treated with antituberculosis drugs, unilateral dilatation problems of diverticulation of augmented segment,
and stenting. Later, the patient was carefully followed- anastomotic site stricture and suprapubic pain. Therefore,
up and dilatation was regularly performed at six monthly the author’s technique of simple cystectomy and
intervals. orthotopic neobladder may be most useful in this
476 Tuberculosis
situation (40). The author has reported good long-term

results in four patients with thimble bladder employing
the orthotopic bladder replacement using the ileocaecal
segment in three patients and sigmoid colon in the fourth
[Figures 32.5, 32.15A and 32.15B] (40).
Surgery for Other Forms of Genitourinary Tuberculosis

Tuberculosis of the prostate can vary from infiltration of
stroma to an abscess cavity, bursting into perineum or
rectum. These lesions respond very well to antituber-
culosis treatment. The residual bladder neck obstruction,
if required can be dealt endoscopically.
The author had come across an unusual case of TB
vesico-vaginal fistula which was treated with antituber-
culosis treatment and surgical repair of the fistula with
omental interposition. The author also has experience of
managing vesico-sigmoid fistula with antituberculosis
treatment and surgical repair (18).
Involvement of seminal vesicles and vas deferens
Figure 32.13: Intravenous urogram showing ileal gives rise to infertility. While many patients may respond
replacement of ureter [arrows]
to antituberculosis treatment, some may require surgical
intervention. Direct involvement of epididymis may be
Figure 32.14A: Intravenous urogram showing small capacity

thimble bladder [arrows]. The kidney is not visualized on the right Figure 32.14B: Cystogram in the same patient following
side augmentation cystoplasty utilizing sigmoid colon [arrows]
Figure 32.15A: Reconstruction of orthotopic neobladder with Figure 32.15B: Post-void cystogram of the same patient
ileocaecal segment after simple cystectomy [arrows] demonstrating complete clearance [arrows]
difficult to differentiate from bacterial epididymis. Some- patients who undergo reconstructive procedures, a
times epididymectomy may be required for chronic rigorous and prolonged follow-up would be required.
fistula and orchalgia.
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Tuberculosis in Chronic Renal Failure 479
Tuberculosis in
Chronic Renal Failure
33
SK Agarwal
INTRODUCTION to improve leucocyte adhesion and chemotaxis (8,9). Use

of conventional cellulose membrane causes activation of
Tuberculosis [TB] is one of the major causes of morbidity
the alternate complement pathway leading to changes
and mortality throughout the world. Susceptibility to TB
in granulocyte cell adhesion molecules CD11b, CD18
has been attributed to host resistance, socioeconomic (1)
[MAC-1] and L-selectin. These changes correlate with
and environmental factors (2). Because of the immuno-
the development of leucopenia and its reversal (10).
suppressive effect of uraemia, use of corticosteroids and
Similarly, phagocytosis is impaired both before and
immunosuppressive drugs during renal transplantation
during haemodialysis. Impairment of phagocytosis
[RT], these patients are at a high risk of developing TB.
during haemodialysis is more often encountered with
Consequently, TB has been found to occur more
cuprophane membrane than with newer membranes
frequently in patients with chronic renal failure [CRF],
(11). Dialysis with cuprophane membrane also increases
during maintenance haemodialysis [MHD] and
production of reactive oxygen species, thus decreasing
following RT than in general population (3-7).
responsiveness to an infectious challenge (12).
Another major defect in lymphocyte function in
PATHOGENESIS
uraemia and in patients on haemodialysis is decreased
Uraemia is also an acquired immunodeficiency state interleukin-2 [IL-2] production by activated T-helper cells
leading to excessive morbidity and mortality related to (13). Whether the major defect is in the T-cells, antigen
infections. Functional abnormalities of neutrophils, T- presentation to the T-cell or is monocyte derived, is still
and B- lymphocytes, monocytes and natural killer [NK] controversial. Altered macrophage Fc-receptor function
cells have been described in these patients. These in vivo and in vitro has been demonstrated in persons
abnormalities are often exacerbated by chronic haemo- undergoing haemodialysis. This correlated very well
dialysis and following RT. Bio-incompatibility during with the incidence of severe infection during a two-year
haemodialysis frequently leads to immune activation and follow-up period. Defective antigen presentation by
subsequent leucocyte dysfunction, thus exacerbating the monocyte has also been demonstrated in patients on
underlying immune defect of uraemia. haemodialysis (14).
Granulocyte functions, like chemotaxis, adherence Following successful RT, infection remains the
and phagocytosis, are marginally defective in uraemia leading cause of morbidity and mortality. The inflam-
but patients on haemodialysis have pronounced defects matory response to microbial invasion in the transplant
in these functions. Leucocyte chemotaxis has been patients is attenuated by concomitant immunosup-
reported to be diminished in patients with end stage renal pressive therapy. The risk of infection in these patients
disease [ESRD] and MHD. In these patients, in vitro and is primarily determined by the interaction between
in vivo administration of 1,25[OH]2D3 has been shown exposure to mycobacteria and immune status of the
480 Tuberculosis
patient. Immunosuppression is a complex state deter- occurrence of TB, especially miliary TB has been observed
mined by the interaction of a number of factors, the most in RT patients receiving cyclosporine compared with
important of which are the dose, duration and temporal those who did not [unpublished observations]. There is
sequence of immunosuppressive drugs employed. a limited information on the occurrence of TB in RT
recipients on newer immunosuppressive medication like
MAGNITUDE OF THE PROBLEM tacrolimus, mycophenolate, among others. In a recent
study (34), a higher incidence of TB was found in patients
There is limited information on the magnitude of the
receiving these drugs as compared to cyclosporine and
problem of TB in patients with CRF. However, a recently
also TB developed earlier in these patients (34). However,
published study from China (15) reported 30 times higher
these results have not been confirmed by another
prevalence of TB in patients with CRF as compared to
study (35).
general population of same city (15). The study reported
Possible transmission of TB by renal allograft has been
inverse association between renal function and TB.
reported (26,36-38). The most definitive report (38) was
Problem of TB in patients already on MHD has been more
concerning a donor with culture proven TB meningitis,
commonly studied (3-6,16,17). All available studies are
whose kidneys were transplanted in two patients. Both
retrospective and the incidence of TB in such patients
of them developed definitive TB on days 35 and 39
has varied from 1 to 13.3 per cent (4-6,18-21). It has been
respectively. In other published studies, disseminated TB
estimated that patients undergoing dialysis have a 10-
developed in four of the six patients who acquired the
to 12-fold higher risk of developing TB compared to the
disease through renal allograft (36,37). Graham et al (39)
general population (5,6). The incidence of TB in Indian
have documented definite donor organ transmitted TB
patients receiving MHD has been reported to be 3.7 to
using hemi-nested inverse PCR of the IS6110 region both
13.3 per cent (16,17). Majority of these patients have
in the donor and recipient (39).
undergone haemodialysis for 12 to 24 months only. An
increasing trend of TB has been observed in patients
undergoing haemodialysis during the 1990s compared CLINICAL PRESENTATION
with the previous decade at author’s centre [personal
Clinical Presentation of Tuberculosis during
observation]. A recent report also indicates transmission
Maintenance Haemodialysis
of TB from a health care worker to 29 patients and 13
employees in a dialysis centre (22). Clinical presentation of TB in patients on MHD is
The incidence of TB in RT recipients has been more summarized in [Table 33.1]. The age distribution of
systematically studied as these patients are regularly patients on MHD who developed TB was similar to that
followed-up. Incidence of TB in RT patients has ranged observed in general population (4). Males were nearly
from one to four per cent in Northern Europe (23-26); twice as commonly affected as compared to females
0.5 to 1 per cent in North America (26,27) and nearly five (4,18). This probably reflects the sex difference observed
to ten per cent in several studies reported from India in patients with CRF. Regular MHD usually tends to
(28-33). Incidence of TB in RT patients has been found to improve the general immune status of the patients with
be more or less similar among those who received CRF. Therefore, a majority of these patients develop TB
cyclosporine and those who did not (18,30,31,33). prior to initiation or within a short period from the
However, few differences have been reported in these beginning of MHD, a time when effect of uraemia on
two groups. Higgins et al (7) reported that among RT immune status is still pronounced. Sasaki et al (4) and
patients who received cyclosporine based protocols, TB Andrew et al (5) have reported the development of TB
developed only in those patients who were clearly at risk within six months of MHD, however, this period was
of developing the disease due to previous exposure. much longer in another study (6). Prior exposure to TB
Similarly, John et al (33) suggested that TB developed in and diabetes mellitus were found as risk factors in nearly
the early post-RT period in patients on cyclosporine, as 50 per cent of the patients for the development of TB (6).
compared to those patients who did not receive cyclo- Constitutional symptoms attributable to TB have been
sporine. At another hospital in north India, early reported in 30 to 92 per cent patients in various series
Table 33.1: Clinical presentation of tuberculosis in patients on maintenance haemodialysis

Variable Sasaki et al (4) Andrew et al (5) Rutsky et al (6) Malhotra et al (17) Venkata et al (40)
[n = 367] [n = 172] [n = 885] [n = 150] [n = 900]
No. of TB patients [%] 12 [3.3] 10 [5.8] 9 [1] 20 [13.3] 36 [4]
Mean age [years] 45 49 48 20 52
Male:female 2:1 1.5:1 2:1 3:1 11:1
Time of diagnosis of TB in relation
to duration of HD [%] 42 40 ND 0 61.1*
Prior HD
Less than 6 months 42 50† ND 95‡ ND
Six months to 1 year 8 0 ND 5 ND
More than 1 year 8 0 ND 0 ND
Site of TB [%]§ ||
Pulmonary 8 60 33 10 36
Pleural 8 10 33 45 28
Lymph node 17 10 11 30¶ 14
Miliary or disseminated 50 0 11 0 11
Neurological 8 10 0 0 0
Colon 8 0 0 0 0
Peritoneal 0 10 11 5 0
Bone and joints 0 0 0 5 8
Renal 0 10 0 0 0
Hepatic 0 0 0 0 0
Clinical presentation [%]
Fever 92 ** †† ‡‡ 72
Appetite loss 100 ** †† ‡‡ 72
Weight loss 75 ** †† ‡‡ 25
Cough 25 ** †† ‡‡ ND
Neurological deficit 50 ** †† ‡‡ ND
Diagnosis [%]§§
Microbiology |||| 33 50 90¶¶ 20 16.6
Histopathology|||| 17 40 20 45 30.5
Autopsy 50 10 0 5*** ND
Mortality [%]
TB mortality 75 0 22 10 25
Overall mortality 75 20 44 60 ND
* 14 patients were on regular dialysis [13 on HD, 1 patient was on continuous ambulatory peritoneal dialysis], and 8 were on irregular dialysis.
Among patients on regular dialysis, TB was identified within 1 year of dialysis in 4, and in the remaining, TB was diagnosed between 1 and 9
years of dialysis
† In 1 patient [10%], the diagnosis of TB was made concurrent with the initiation of HD
‡ In 3 patients [15%], the diagnosis of TB was made concurrent with the initiation of HD
§ More than one site was involved in some patients
|| The site of TB was not clear in one patient. This patient responded well to antituberculosis treatment
¶ One patient had left hilar lymphadenopathy
** Details of clinical presentation were not described. The presenting symptoms were non-specfic and constitutional in nature. Fever, malaise,
anorexia and weight loss were most commonly encountered. Headache, chills, and shortness of breath were less common [< 30% of the
patients]
†† Of the 885 patients studied, a diagnosis of TB was made in 9 patients on HD and 8 patients who had CRF but did not require long-term
dialysis. The clinical symptoms were not separately described for these 2 groups of patients
‡‡ Consolidated break-up of clinical features was not provided. Of the 20 patients in whom TB was diagnosed, 75% presented with fever, 50%
with pleural effusion; 30% had lymphadenopathy, pulmonary abnormalities were found in 20% and ascites and hepatomegaly were observed
in 10% patients. Other features included marked anorexia [10%], abnormal weight loss [5%] and bony swelling [5%]
§§ More than 1 method was positive in some patients
|||| Cumulative yield from various tissue and fluid specimens
¶¶ NTM were isolated from 3 of the 9 patients
*** A patient who had shown TB peripheral lymphadenopathy during life revealed histopathological evidence of TB in hilar and tracheobronchial
lymph nodes on autopsy
TB = tuberculosis; HD = haemodialysis; ND = not described; CRF = chronic renal failure; NTM = nontuberculous mycobacteria
482 Tuberculosis
(4-6,16) and may include low- or high-grade fever. In a retrospective cohort study (46) of TB disease in
Malhotra et al (17) reported that 15 per cent of their 272 024 patients in the US Renal Data System initiated
patients on MHD who developed TB presented with on dialysis therapy between April 1995 and December
pyrexia of unknown origin [PUO]. In other studies (6,18- 1999, cumulative incidence of TB in patients undergoing
21,40), this presentation has been rarely observed. either peritoneal or haemodialysis was found to be 1.2
In majority of the studies (6,17-21,40), lung is the most per cent and 1.6 per cent, respectively. In this study (46),
common site of involvement in patients on MHD. In these advanced age, unemployment, availing health insurance
studies (6,17-21,40), incidence of pulmonary TB ranged [Medicaid], reduced body mass index, decreased serum
between 40 to 92 per cent. However, in some studies albumin, haemodialysis, both Asian and Native
(5,6,40), isolated extra-pulmonary TB has been found in American race, ischaemic heart disease, smoking, illicit
56 to 60 per cent cases. Malhotra et al (17) have reported drug use and anaemia were found to be risk factors for
that pleural effusion occurred more frequently than the development of TB in patients receiving peritoneal
pulmonary parenchymal lesions. However, this or haemodialysis. Furthermore, in patients receiving
observation has not been corroborated by other workers dialysis, TB was independently associated with
who have found parenchymal lesions to be more common increased mortality.
than pleural effusion (6,18-21). Lymph node involvement Clinical Presentation of Tuberculosis following
has been found to be the most common extra-pulmonary Renal Transplantation
site of TB in patients on MHD [15% to 30%] (4,6,17-
Tuberculosis can be encountered in RT patients in two
19,33,40). In the series reported by Malhotra et al (17),
settings. First, a patient with renal failure suffering from
lymph node TB occurred in 30 per cent of patients; in 25
TB in the pre-transplant phase may continue to suffer
per cent of the patients, this was the only presenting
from TB in the post-RT phase as well. On the other hand,
feature (17). Other sites of extra-pulmonary involvement
patients may develop TB for the first time following RT.
include abdomen (4-6), meninges (4), bone and joints
The present description is regarding patients in the latter
(19,33). Chuang et al (41) while describing extra-
category.
pulmonary TB in dialysis patients, have reported
Patients who develop TB following RT [Table 33.2]
involvement of peritoneum [35.3%] cervical lymph nodes
are usually younger. Males are more often affected. This
[17.6%], involvement of bone marrow, spine, knee joint,
could be because of the fact that young males undergo
brain, pericardium, cutaneous tissue and genitourinary RT more often in a country like India (30-32). Similar
system [5.7% each]. These observations suggest that, observations have been reported from the west as well
almost any organ can be affected by TB in these patients. as from other countries (47). Past history of TB has been
Disseminated TB miliary TB have also been observed reported in 5.6 to 8.9 per cent patients in studies reported
as the presenting feature in these patients. Nearly half of from India [Table 33.2]. When TB develops, constitutional
the patients studied by Sasaki et al (4) presented with symptoms are more often encountered in RT patients
disseminated or miliary TB. In most of the other series, than in patients on MHD (31-33). The lung is the most
the incidence of miliary TB ranged between 10 to 15 per common site of involvement in RT patients who develop
cent (6,19). None of the patients described by Malhotra et TB (29-33). Other sites of TB involvement in RT patients
al (17) had miliary TB. Two of the 100 patients with miliary include abdomen (7,33); pericardium (30,33); thalamus
TB reported by Sharma et al (42) had CRF as a predisposing (30); bone and joints (7,30). Miliary TB has also been
factor. reported in seven to thirty-six per cent of RT patients
Tuberculosis peritonitis has been described in patients (7,30-33,36-38). Thus, RT patients develop pulmonary TB
on continuous ambulatory peritoneal dialysis [CAPD] more often, and manifest constitutional symptoms more
(43-45). In these patients, the ascitic fluid may reveal commonly compared with patients on MHD.
predominance of polymorphonuclear leucocytes. In Comparison of presentation of TB during haemo-
addition to causing morbidity, it can also cause ultrafil- dialysis and after RT [n = 923] at the author’s centre is
tration failure of CAPD and require shifting to other shown in [Table 33.3] [unpublished data]. Pleuro-
modality of renal replacement therapy. pulmonary TB appears to be more common in both
Table 33.2: Clinical presentation of tuberculosis in renal transplant patients
Variable Hariharan Higgins John Sakhuja Agarwal

et al (32) et al (7) et al (33) et al (31) et al (30)*
[n = 550] [n = 633] [n = 808] [n = 305] [n = 461]
No. of patients with TB [%] 46 [8.4] 11 [1.7] 41 [5.1] 36 [11.8] 67 [14.5]

Mean age [years] 32.5 43.9 † 33.9 14
Male:Female 4.1:1 1.8:1 4.9:1 6.2:1 3.5:1
Mean time interval between 20 26.4 ‡ 20.7 24
renal transplantation and
detection of TB [months]
Past history of TB ND ND ND 5.6 8.9
Immunosuppression D D/T D/T D/T D/T
Site of TB [%] §
Pulmonary 39 18 49 31 37
Pleural 13 9 0 14 22
Lymph node 17 0 2 3 8
Disseminated or miliary TB 7 36 27 25 8
Neurological 4 0 0 0 5
Abdominal 4 18 7 3 5
Genitourinary 0 9 5 3 0
Skin, soft tissue 0 0 7 3 0
Pericarditis 0 0 0 0 0
Bone and joints 0 0 2 0 1.5
Diagnosis [%]ll
Microbiology¶ 52 55** 98†† 14 3
Histopathology¶ 26 27 10 33 12
Autopsy 4 0 0 3 11
Mortality [%]
TB related mortality 4 9 12 6 0
Overall mortality 9 9 46 19.4 0
Percentage values are corrected to the nearest round figures

* Figures from 1992 have been revised and updated till 1997
† Mean age of patients receiving cyclosporine immunosuppression and conventional immunosuppression was 39.9 and 37.3 years
respectively
‡ Median time [months] of diagnosis of myobacterial infection after transplantation in patients receiving cyclosporine immunosuppression
and conventional immunosuppression was 5.5 and 2.4 months respectively
§ Some patients had involvement of more than 1 site
ll More than 1 method was positive in some patients
¶ Cumulative yield from various tissue fluids and specimens
** 1 patient had infection with Mycobacterium kansasii
†† 2 patients had nontuberculous mycobacterial infection
TB = tuberculosis; ND = not described; D = double immunosuppression; T = triple immunosuppression
484 Tuberculosis
Table 33.3: Comparison of site of tuberculosis involvement culosis treatment in a country like India where TB is
in patients with chronic renal failure [n = 923] pre- and post- endemic.
renal transplantation Diagnosis of TB in patients with uraemia is difficult.
Site of tuberculosis Pre-RT Post-RT Patients with uraemia can have a high erythrocyte
No. [%] No. [%] sedimentation rate [ESR] due to anaemia and various
Number of cases 152 156 other reasons and, therefore, ESR is not of much use in
Pleural* 50 [32.9] 17 [10.9] these patients. The tuberculin skin test [TST] is often
Pulmonary 44 [28.9] 45 [28.8] negative in patients on MHD and following RT (21,48,49).
Abdominal* 16 [10.5] 4 [2.6] The newer diagnostic methods for detecting latent TB
Nodal 14 [9.2] 13 [8.3]
infection such as interferon-gamma release assays
Pericardial* 11 [7.2] 0
Presentation as PUO* 10 [6.6] 46 [29.5] [IGRAs] appear to have a potential role in the diagnosis
Genitourinary 3 [1.9] 0 of TB infection in these patients (50). Radiological
Bone and joints 2 [1.3] 2 [1.3] findings in immunocompromised patients with
Miliary* 1 [0.6] 14 [8.9] pulmonary TB are often atypical. In these patients
Neurological* 1 [0.6] 9 [5.8]
cavitary lesions are seldom seen and lower lung field
Miscellaneous 0 6 [3.9]
Laryngeal 0 2
and multiple lobar involvement are often seen. Patients
Orchitis 0 1 on MHD can develop pleural effusion due to heart
Skin 0 1 failure, uraemic pleuritis or hypoproteinaemia. Similarly,
Psoas abscess 0 1 pericarditis and/or pericardial effusion and ascites in
Gluteal abscess 0 1 these patients are often due to dialysis associated
* Statistically significant difference pericarditis and/or ascites (51). Pleural fluid in uraemic
RT = renal transplant; PUO = pyrexia of unknown origin pleuritis can also be exudative and haemorrhagic with
high protein and lactate dehydrogenase levels with a
settings. In RT recipients, presentation with PUO and predominance of lymphocytes (52,53). These findings are
miliary TB is significantly more common as compared often encountered in TB pleural effusion and are
to patients on MHD. Furthermore, abdominal TB was therefore, unreliable. Diagnostic value of adenosine
significantly more common during dialysis while deaminase activity in pleural fluid even in RT patients is
neurological TB was more common after transplantation. also unreliable (54). The acid-fast bacilli [AFB] can seldom
Overall, patients with renal failure while on MHD be seen and mycobacteria are rarely cultured from the
manifest extra-pulmonary TB more frequently [60%] as pleural fluid. Usefulness of modern diagnostic tests, such
compared to pulmonary TB [40%] [Table 33.1]. By as polymerase chain reaction [PCR], has not been
contrast, site of involvement in RT-recipients resembles systematically explored in the diagnosis of TB in patients
that observed in immunocompetent individuals; pulmo- with renal disease. Studies with a large sample size are
nary TB is more frequent [60%] [Table 33.2], probably required to establish the usefulness of these investi-
due to improvement in their immune status. gations.
DIAGNOSIS MANAGEMENT
Definitive diagnosis of TB requires demonstration or Principles of antituberculosis treatment during dialysis
isolation of Mycobacterium tuberculosis. In majority of the and following RT remain similar to that in other patients
studies published from the west, diagnosis of TB was with TB. The choice of safe and effective antituberculosis
based on demonstration of the organism in the body treatment for these patients depends upon the pharma-
fluids and/or tissues or on the basis of histopathological cology of drugs in the setting of renal failure and during
findings (5-7). In contrast, 8.6 to 68 per cent of the patients MHD and their interaction with immunosuppressive
in various Indian studies have been diagnosed to have drugs used in patients with RT. Pharmacological
TB only on clinical grounds (30-32). This is probably due properties of antituberculosis drugs that determine how
to the low threshold for therapeutic trial with antituber- the levels of these drugs are likely to be influenced by
renal impairment have been extensively reviewed by as the individual dosage is increased from 300 to 900 mg,
several workers (55-58). probably as a result of biliary excretion route becoming
Renal insufficiency complicates the management of saturated. Daily treatment with rifampicin for a period
TB because some antituberculosis medications are cleared of one week or more, results in the induction of hepatic
by the kidneys. Management may be further complicated enzymes, which deacetylate the drug. Such induction
by the removal of some antituberculosis drugs via significantly reduces half-life of rifampicin and probably
haemodialysis. Thus, some alteration in the dosage of reduces urinary excretion of the unchanged drug. About
antituberculosis medications is commonly necessary in 14 per cent of the dose is recovered in urine whether or
patients with renal failure and ESRD receiving haemo- not liver enzymes have been induced. It is thought that
dialysis. Decreasing the dose of selected antituberculosis effect of renal impairment on rifampicin excretion is
drugs may not be the best method of treating TB because, negligible at a dose of 450 mg, modest at 600 mg and
although toxicity may be avoided, the peak serum substantial at 900 mg (56). Therefore, rifampicin up to a
concentrations may be too low. Therefore, increasing the dose of 600 mg/day does not require reduction at any
dosing interval instead of decreasing the dosage of the degree of renal failure (56).
antituberculosis drugs is recommended (59).
Pyrazinamide
Isoniazid
As little as three to four per cent of ingested pyrazina-
Ninety-six per cent of the administered dose of isoniazid
mide is excreted unchanged in the urine. Its half-life is
is recoverable in the urine as unchanged drug together
six to ten hours and very little change is expected even
with its metabolites (60). All metabolites of isoniazid are
in patients with severe renal failure (67,68). However,
devoid of antituberculosis activity. They are less toxic
Fabre et al (68), suggested to avoid its use in severe renal
than isoniazid and are more rapidly excreted through
failure, while Anderson et al (69), and Andrew et al (5),
the kidneys (61). In anuric patients, half-life of isoniazid
suggested reduction in the dose to 12 to 20 mg/kg/day.
varies with acetylator status. Half-life is essentially
However, such a dosage schedule will cause suboptimal
unaltered in rapid acetylators while in those who are
slow acetylators, it has been observed to increase by 40 therapeutic levels (70). Controlled clinical trials have
per cent. It is, therefore, recommended that normal daily shown that thrice weekly treatment is therapeutically
dosage of isoniazid [300 mg or 5 mg/kg body weight] more effective than daily administration (71). It is, there-
should be given in patients with severe renal impairment fore, recommended that patients with renal impairment
including anuric patients. In slow acetylators with severe should be treated either thrice or twice weekly with 40
renal impairment and who are not on dialysis, 5 to 6 to 60 mg/kg pyrazinamide. However, in most of the
mg/kg body weight isoniazid will be equivalent to daily published studies, patients had received daily dose of
dose of 7 to 9 mg/kg body weight in normal subjects. It pyrazinamide (67,68).
has been shown that isoniazid is well tolerated at this
dose in these patients (62). Therefore, previous recom- Streptomycin
mendation to reduce the daily dose of isoniazid to
Nearly 80 per cent of the dose of streptomycin, like other
150 mg in patients with severe CRF is unjustified (63,64).
aminoglycosides, is excreted unchanged in the urine.
Also, there is convincing evidence that isoniazid at a
Aminoglycosides are excreted by glomerular filtration
dosage less than 200 mg/day significantly decreases
and not by active secretion (72,73). Line et al (72) demons-
therapeutic response (65). Some suggestions regarding
trated significant correlation between degree of renal
administering isoniazid eight hourly are unwarranted
failure and serum levels of streptomycin. Therefore, if
(66) and there is no justification for estimation of
streptomycin is to be used in the treatment of TB in
isoniazid levels in these patients (60).
presence of renal failure, its dosage must be decreased.
It is preferable to give streptomycin twice or thrice weekly
Rifampicin
without decreasing the usual dose. If possible, drug
Serum half-life of rifampicin and the proportion of the trough level should be measured and should not exceed
unchanged drug excreted in the urine increase steadily 4 mg/l.
486 Tuberculosis
Ethambutol any of the injectable agents to minimize dose-related

toxicity, while providing effective doses. Currently,
About 80 per cent of the dose of ethambutol is excreted
enough data are not available on antituberculosis drug
unchanged in urine and major reduction in daily
dosage modification in patients receiving peritoneal
ethambutol doses are recommended in patients with
dialysis and the drug removal mechanisms differ
renal failure. Recommended dosage in presence of renal
between haemodialysis and peritoneal dialysis.
failure varies from 5 to 10 mg/kg/day by various
Therefore, such patients may require close follow-up and
workers (6,74,75). Ethambutol can result in blindness. If
therapeutic drug monitoring.
treatment of TB in renal failure requires administration
of a fourth drug, in addition to rifampicin, isoniazid and
pyrazinamide, streptomycin seems to be a better choice Treatment of Tuberculosis in Patients on Dialysis
as compared to ethambutol. As the measurement of
Treatment of TB is imperative as soon as the diagnosis is
streptomycin levels is much easier compared to measur-
confirmed or strongly suspected. Isoniazid and
ing ethambutol levels, better therapeutic drug monitor-
rifampicin have been used in majority of the studies
ing is possible with the use of streptomycin. There is
(4-6,16,21). Streptomycin is not so commonly used now
report of irreversible blindness in a patient of ESRD
a days in patients with renal failure. Isoniazid at a dosage
treated with ethambutol for TB and, thus, periodic
of 200 to 300 mg/day does not cause significant toxicity
ophthalmic examination should be done in these
in adult patients with renal failure. However, vitamin
patients (76).
B6 in a dose of 10 to 20 mg should be administered
prophylactically in all these patients. Dosage modifica-
Second Line Antituberculosis Drugs
tion is not required for rifampicin but it should be
Dosages of kanamycin, amikacin, and capreomycin must administered cautiously in patients with CRF who are
be adjusted in patients with renal failure because of renal not on haemodialysis as it can result in acute renal failure
excretion of these drugs. Administration of these drugs or deterioration in the renal functions (80). Dosing
just prior to haemodialysis, removes approximately 40 recommendations for adult patients with reduced renal
per cent of the dosage (77). Dosing interval of these drugs function [creatinine clearance < 30 ml/min] and for
should be increased. Ethionamide is not cleared by the adult patients receiving haemodialysis are presented in
kidneys, nor is the drug removed with haemodialysis, Table 33.4 (59). The antituberculosis drugs should be
so no dose adjustment is necessary (78). Para-amino administered after haemodialysis to avoid any loss of
salicylic acid [PAS] is moderately cleared by haemodialy- the drugs during the procedure, and to facilitate direct
sis [6.3%] but its metabolite, acetyl-PAS, is substantially observation of the treatment (59). The possibility of
removed by haemodialysis; twice daily dosing [4 g] impaired absorption of antituberculosis drugs because
should be adequate (78). Cycloserine is excreted of co-morbid clinical conditions, such as diabetes mellitus
primarily by the kidney, and is cleared by haemodialysis with gastroparesis that are frequently present in these
[56%]. Thus, an increase in the dosing interval is patients should also be kept in mind.
necessary to avoid accumulation between haemodialysis Under the Revised National Tuberculosis Control
sessions, and the drug should be given after hemodialysis Programme [RNTCP] of the Government of India,
to avoid underdosing (78). The fluoroquinolones under- patients receive DOTS. Under the programme, standard
go some degree of renal clearance that varies from drug intermittent antituberculosis treatment has been
to drug. For example, levofloxacin undergoes greater advocated for all patients including those with renal
renal clearance than moxifloxacin (79). It should be noted failure on conservative management, MHD or following
that the fluoroquinolone dosing recommendations for RT. Monitoring of renal or hepatic function is not done
ESRD provided by the manufacturers were developed under programme conditions. As of now, there are no
for treating pyogenic bacterial infections. These recom- published data on the efficacy and safety of these
mendations may not be applicable to the treatment of regimens in patients with CRF on conservative
TB in patients with ESRD. It is important to monitor management or MHD. There is no consensus for the
serum drug concentrations in persons with renal duration of antituberculosis treatment in these patients.
insufficiency who are taking cycloserine, ethambutol, or These issues merit further studies.
Table 33.4: Dosing recommendations for adult patients with reduced renal function* and
for adult patients receiving haemodialysis
Drug Change in Dosage schedule

frequency of
administration
First-line drugs
Isoniazid No change 5 mg/kg [maximum 300 mg] once daily, or 15 mg/kg [maximum 900 mg]
per dose, three times per week
Rifampicin No change 10 mg/kg [maximum 600 mg] once daily, or 10 mg/kg [maximum 600 mg]
per dose, three times per week
Pyrazinamide Yes 25 to 35 mg/kg per dose three times per week [not daily]
Ethambutol Yes 15 to 25 mg/kg per dose three times per week [not daily]
Streptomycin Yes 12 to 15 mg/kg per dose two or three times per week [not daily]
Second-line drugs
Cycloserine Yes 250 mg once daily, or 500 mg per dose three times per week†
Ethionamide No change 15 to 20 mg/kg/day [maximum 1 g; usually 500 to 750 mg] in a single daily
dose or two divided doses‡
Para-aminosalicylic acid No change 8 to 12 g/day, in two or three doses
Capreomycin Yes 12 to 15 mg/kg per dose two or three times per week [not daily]
Kanamycin Yes 12 to 15 mg/kg per dose two or three times per week [not daily]
Amikacin Yes 12 to 15 mg/kg per dose two or three times per week [not daily]
Levofloxacin Yes 750 to 1000 mg per dose three times per week [not daily]
* Creatinine clearance less than 30 ml/min

† The appropriateness of 250 mg daily doses has not been established
‡ The single daily dose can be given at bed time or with the main meal. No data to support intermittent administration
The medications should be given after haemodialysis on the day of haemodialysis
Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption without excessive accumulation,
and to assist in avoiding toxicity
Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended
for patients receiving haemodialysis and verify adequacy of dosing, using monitoring of serum concentration
Rifampicin is an inducer of hepatic enzymes and is However, these findings require validation in future
known to alter the metabolism of many drugs. In this studies. There are no published data on the efficacy and
regard, rifampicin use becomes an important issue in safety of the standard intermittent regimens used in the
patients before and following RT. Majority of these DOTS strategy used in the RNTCP of Government of
patients also receive antihypertensive drugs, and with India in RT recipients. Controlled trials with large sample
the use of rifampicin, an adequate blood pressure control size are required to establish the efficacy, safety, and
may not be achieved and the dose modification may be optimum duration of the standard treatment regimens
required for the antihypertensive drugs. Rifampicin also used in the RNTCP in patients with CRF.
decreases the efficacy of other drugs such as cortico-
steroids, cyclosporine and tacrolimus. Therefore, dosages Treatment of Latent Tuberculosis Infection in
of these drugs also need to be modified. This has lead to Patients with Chronic Renal Failure on Dialysis
use of non-rifampicin based protocols for treatment of Treatment
TB in RT recipients with an aim of decreasing the cost of The ATS guidelines (83) mention the relative risk of
therapy as well as avoiding frequent monitoring (81,82). developing TB in patients with CRF and those on MHD
488 Tuberculosis
to be 10 to 25.3 and targeted tuberculin testing and rapamycin [sirolimus], mycophenolate mofetil, misori-
treatment of latent TB infection is a well-accepted strategy bin have been used in some western countries. There
in developed countries with low transmisison of TB such have been no recommendations to decrease the dosage
as the USA (59,83). However, this approach does not of immunosuppressive medication if patients develop
seem to have much relevance in highly endemic areas. TB after RT.
Published data suggest that TST is not a reliable test for During rifampicin therapy, daily dosage of cortico-
diagnosis of latent TB in patients with CRF (84-86). The steroids should be increased or maintained to nearly one
potential role of IGRAs in this setting merits further and a half times the baseline dosage, as rifampicin is
study. The reader is referred to the chapter “Diagnosis of known to be an inducer of the enzymes involved in the
latent tuberculosis infection: recent advances and future hepatic metabolism of corticosteroids (89). Azathioprine
directions” [Chapter 12] for more details. sometimes causes hepatotoxicity, which has to be
In a randomized, double-blind, placebo-controlled, differentiated from hepatotoxicity due to antituberculosis
prospective trial of isoniazid prophylaxis in patients on drugs. The major interaction of antituberculosis drugs is
haemodialysis from India (87), some degree of protection with cyclosporine A. Rifampicin produces lowering of
was shown. This protection appeared to be insignificant blood levels of cyclosporine A by producing an increase
when the number of cases who dropped out due to in its hepatic metabolism (90). Ideally, cyclosporine A
various reasons and significant number of patients blood levels should be monitored and its dose adjusted
developing TB in the treatment group were also taken if the patient is also receiving rifampicin. Fluoroquino-
into consideration. Another recently published trial on lones decrease the metabolism of cyclosporine A and
isoniazid prophylaxis in patients due to undergo RT who replace it from the bound form, thus, increasing its
were receiving MHD (88) documented that TB developed toxicity. Optimum duration of antituberculosis treatment
in 16.7 per cent patients in the isoniazid group compared in RT recipients is again controversial. Patients who
with 32.7 per cent patients in the control group, suggest- receive DOTS under the RNTCP of Government of India
ing that there was a significant reduction in the incidence are treated for six months with standard intermittent
of TB if isoniazid was started early. These issues need treatment regimens. In individual cases, treatment
further clarification. duration may be prolonged by another three [e.g., extra-
Another issue, which is not clear, is the optimum pulmonary TB] to six [e.g., TB meningitis] months.
duration of antituberculosis treatment before a patient However, in some studies most patients have received
with CRF can be safely taken up for RT. Controlled trials treatment for 12 months or more (29-32,91). The efficacy
have not been conducted to answer this question and of short-course chemotherapy has not been studied in
there is no consensus. Possibly, four to six weeks treat- detail in these patients.
ment with an adequate antituberculosis drug regimen
should be enough before the surgery especially if the Treatment of Latent Tuberculosis Infection in
patient is showing a good clinical response to treatment. Renal Transplant Recipients
The relative risk of a RT patient developing TB has been
Treatment of Tuberculosis in Recipients of Renal
estimated to be 37 (83). Therefore, the recent American
Transplantation
Thoracic Society [ATS] guidelines recommend treatment
Management of TB after RT is similar to management of of latent TB infection in RT recipients (83). However, it
TB in patients on MHD with few differences. First, is possible for a person to develop TB inspite of chemo-
following successful RT, renal function become normal prophylaxis (92). In a recent study published from India
and dosage modification done during MHD is no longer (93), isoniazid prophylaxis started at the time of RT
required. Secondly, antituberculosis drug interaction offered some protection from the development of TB (93).
with immunosuppressive drugs is an important issue in In this study, 11.1 per cent patients receiving isoniazid
these patients. Three most commonly used immunosup- prophylaxis developed TB as compared to 25.8 per cent
pressive drugs in these patients are prednisolone, cyclo- in the control group [relative risk 0.36]. However, these
sporine and azathioprine. Sometimes, cyclophosphamide differences were not statistically significant. With the
is also used. Recently, newer drugs like tacrolimus, advent of IGRAs as more reliable indicators of detecting
latent TB infection as compared with TST, more infor- 2. Comstock GW. Frost revisited: the modern epidemiology of
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85. Poduval RD, Hammes MD. Tuberculosis screening in dialysis
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Disseminated and Miliary
Tuberculosis
34
SK Sharma, Alladi Mohan
The whole surface, in front and behind, as well as within deficiency virus [HIV] infection, acquired immuno-
the interstitium of the major lobes, was covered with firm deficiency syndrome [AIDS], disseminated and miliary
small white corpuscles, of the size of millet seeds…. TB are particularly common (1,3,10,11).
— John Jacob Manget
EPIDEMIOLOGY
INTRODUCTION
The epidemiology of miliary TB as documented in several
Disseminated tuberculosis TB refers to concurrent published studies is depicted in Table 34.1 (12-36).
involvement of at least two non-contiguous organ sites Miliary TB accounts for less than two per cent of all cases
of the body, or, involvement of the blood or bone marrow of TB and up to 20 per cent of all extra-pulmonary TB
by tuberculosis [TB] process (1-3). One form of dissemina- cases in various clinical studies in immunocompetent
ted TB, miliary TB, results from a massive haemato- individuals; the corresponding figures in autopsy studies
genous dissemination of tubercle bacilli which results in have been higher [Table 34.1]. Caution must be exercised
tiny discrete foci usually the size of millet seeds [1 to 2 while comparing these epidemiological data as these
mm] more or less uniformly distributed in the lungs and studies are hospital based or autopsy studies.
the other viscera (4-9). Miliary pattern on the chest The emergence of the HIV/AIDS pandemic and
radiograph is the hallmark of miliary TB. widespread use of immunosuppressive drugs have
Miliary and disseminated TB continue to be a changed the epidemiology of miliary TB. Since its first
diagnostic problem even in areas endemic to TB, where description by John Jacob Manget, the clinical presen-
clinical suspicion is very high. Mortality from miliary tation of miliary TB has changed dramatically. Especially,
TB disease has remained high despite effective therapy its occurrence as a complication of childhood infection
being available. In patients with human immuno- is diminishing and the “cryptic form” [vide infra] in a
Table 34.1: Epidemiology of miliary tuberculosis
Study (reference) Frequency of miliary TB
Overall [%] Among extra-pulmonary TB [%]
Adults, autopsy studies (12-18) 0.3-13.3 11.9-40.5

Adults, clinical studies (19-22) 1.3-2.0 0.64-20
Children, clinical studies (23-26) 0.7-41.3 1.3-3.2
All age groups, epidemiological studies, — 0.4-10.7
public health data (27-36)
TB = tuberculosis
494 Tuberculosis
much older group is emerging (37-39). The modulating to caseation of an extra-pulmonary site, discharge of
effect of bacille Calmette-Guerin [BCG] vaccination caseous material into the portal circulation and initial
resulting in substantial reduction in miliary TB and TB hepatic involvement with the classical pulmonary
meningitis among young vaccinees, increasing use of involvement occurring late (4-9). The reader is referred to
computed tomography [CT], and wider application of the chapter “Immunology of tuberculosis” [Chapter 7] for
invasive diagnostic methods could also have contributed more details regarding the molecular mechanisms under-
to the demographic shift (4). lying the pathogenesis of disseminated and miliary TB.
Miliary TB is a common manifestation of congenital
Age and Gender Distribution TB in neonates. Acquisition of infection during the
In patients with miliary TB, presently two additional perinatal period through aspiration and ingestion of
peaks are evident–one involving adolescents and young infected maternal genital tissues and fluid and
adults and another later in life among elderly people subsequent haematogenous dissemination may rarely
(4-9). Sparse published data are available on dissemi- lead to the development of MTB in neonates. The reader
nated TB. In a recently published series from northern is referred to the chapter “Pathology” [Chapter 5] for more
Taiwan (2), patients with HIV/AIDS who had dissemi- details regarding congenital TB.
nated TB [n = 23] were younger [mean age 37.1 years], CLINICAL PRESENTATION
compared with HIV-seronegative disseminated TB
Most of the patients with disseminated and miliary TB
patients with [n = 64; mean age 61.4 years] and without
often have non-specific predisposing or associated
other co-morbid conditions [n = 77; mean age 58.9 years].
conditions [Table 34.2]. Their pathogenetic role is unclear.
Males seem to be more frequently affected by miliary
TB in children as well as adults (4-9). Similarly, 119 of Table 34.2: Conditions predisposing to or associated with
the 164 patients [73%] with disseminated TB reported disseminated and miliary tuberculosis
by Wang et al (2) were men. However, a few recent adult Childhood infections
series on miliary TB (16,20,40,41) describe a female Malnutrition
preponderance. This shift probably reflects increased HIV infection and AIDS
awareness and use of health services by women. Further Alcoholism
Diabetes mellitus
work is required to understand the influence of other Chronic renal failure, haemodialysis
factors such as socio-economic and nutritional status, co- Post-surgery [e.g., gastrectomy*]
morbid illnesses, and host genetic factors other than Organ transplantation
ethnic variations in the causation of disseminated and Drugs
Corticosteroids
miliary TB.
Immunosuppressive and cytotoxic drugs
Immunomodulator drugs [e.g., infliximab, etanercept]
PATHOGENESIS Connective tissue disorders
Miliary TB develops due to a massive lymphohaemato- Pregnancy, postpartum
Underlying malignancy
genous dissemination of Mycobacterium tuberculosis from
Silicosis
a pulmonary or extra-pulmonary focus and embolization Iatrogenic causes
to the vascular beds of various organs [Figure 34.1] (4). Ureteral catheterization*
Less commonly, simultaneous reactivation of multiple foci Extracorporeal shockwave lithotripsy†
in various organs can result in miliary TB. This reactivation Laser lithotripsy†
Cardiac valve homograft replacement‡
can occur either at the time of primary infection or later
Intravesical BCG therapy for urinary bladder carcinoma
during reactivation of dormant foci. When miliary TB
develops during primary disease [early generalization], * Predisposes to TB in general
† Patient had undiagnosed genitourinary TB
the disease has an acute onset and is rapidly progressive.
‡ Contamination of homografts, probably occurred at the time of
Late generalization during post-primary TB can be rapidly harvest from cadavers
progressive [resulting in acute miliary TB], episodic, or HIV = human immunodeficiency virus; AIDS = acquired immuno-
protracted, leading to chronic miliary TB. Re-infection also deficiency syndrome; BCG = bacille Calmette-Guerin; TB = tuber-
has an important role, especially in areas where TB is culosis
highly endemic. Rarely, miliary TB can also develop due Adapted from reference 4
Disseminated and Miliary Tuberculosis 495
Figure 34.1: Gross pathology of miliary tuberculosis. Multiple lesions of miliary tuberculosis in both lung fields with areas of haemorrhage
[A]; liver slice showing multiple confluent as well as discrete tubercles [B]; spleen showing multiple grey-white varying sized lesions [C];
cut-section of spleen showing miliary seeding [D]; omentum showing multiple tubercles, caseation is evident in larger lesions [E]; kidney
with tubercles seen over the surface [F]
496 Tuberculosis
Common presenting symptoms and signs noted at Organomegaly is also a frequent physical finding.
presentation in patients with disseminated and miliary Choroidal tubercles are bilateral, pale, greyish-white
TB are listed in Table 34.3 (40-56). Although disseminated and oblong patches which occur less commonly in adult
and miliary TB involves almost all organs, most often patients with miliary TB than children (4). If present,
the involvement is asymptomatic. Clinical manifestations choroidal tubercles are pathognomonic of miliary TB and
of disseminated and miliary TB are protean and can be offer a valuable clue to the diagnosis [Figure 28.3].
obscure till late in the disease. Fever and inanition are Therefore, systematic ophthalmoscopic examination after
relatively common. Cough and dyspnoea are often mydriatic administration must be done in every
present. Chills and rigors, usually seen in patients with suspected patient with miliary TB. Skin involvement in
malaria, or, sepsis and bacteraemia, have often been the form of erythematous macules and papules have also
described in adult patients with miliary TB (2,17-23). been described (4-9). Signs of hepatic involvement may
Table 34.3: Presenting symptoms in miliary and disseminated tuberculosis

Variable Miliary TB Disseminated
TB‡
Adults [%]* Children [%]†
Symptoms
Fever 35-100 61-98 48
Chills 15-28 ND ND
Anorexia 24-100 04-81 06
Weight loss 20-100 04-60 07-46
Night sweats 08-100 08-75 03
Weakness/fatigue 25-100 14-54 10-75
Cough/sputum 27-82 17-90 23-33
Chest pain 03-49 01-03 ND
Dyspnoea 08-100 07-25 11-17
Haemoptysis 03-15 01 ND
Headache 02-18 02-08 02
Altered sensorium 05-26 02-08 09
Seizures ND 07-30 ND
Nausea 01-19 ND ND
Abdominal pain 05-19 03-15 06
Diarrhoea 02-03 ND ND
Urinary symptoms 02-06 ND 04
Signs
Fever 35-100 39-75 48
Pallor 36-59 31 ND
Cyanosis 01-02 ND 06
Icterus 05-09 03 07-46
Lymphadenopathy 02-30 05 03
Chest signs 29-84 34-72 10-75
Hepatomegaly 14-62 39-82 23-33
Splenomegaly 02-32 24-54 ND
Ascites 04-38 06-09 11-17
Choroidal tubercles 02-12 02-05 ND
Neurological signs 03-26 19-35 02
All values are expressed as percentages corrected to the nearest round figure
* Data from references 13,20,40-54
† Data from references 21,23,26,55,56
‡ Data from reference 2. In this series, 23 of the 164 patients were HIV seropositive
TB = tuberculosis; HIV = human immunodeficiency virus; ND = not described
be evident in the form of icterus and hepatomegaly. Table 34.4: Atypical clinical manifestations in miliary
Neurological involvement in the form of meningitis or tuberculosis
tuberculomas is common. Tuberculosis meningitis has Cryptic miliary tuberculosis
been described in 10 to 30 per cent of adult patients with Pyrexia of unknown origin
miliary TB (14,20,40-53). Conversely, about one-third of Acute respiratory distress syndrome
patients presenting with TB meningitis have underlying “Air-leak” syndrome [pneumothorax, pneumomediastinum]
miliary TB (57). Clinically significant cardiac or renal Myelophthisic anaemia , myelofibrosis, pancytopenia, immune
involvement is uncommon in patients with miliary TB haemolytic anaemia
(4-9). Overt adrenal insufficiency at presentation, or Acute empyema
during treatment has also been described in miliary TB Septic shock, multiple organ dysfunction syndrome
(58). In some studies, headache and abdominal pain Thyrotoxicosis
when present are supposed to have specific implications Renal failure due to granulomatous destruction of the interstitium
in miliary TB, headache signifying the presence of Immune complex glomerulonephritis
meningitis and abdominal pain signifying abdominal Sudden cardiac death
involvement (4-9). Mycotic aneurysm of aorta
Clinical presentation of miliary TB in children is Native valve and prosthetic valve endocarditis
similar to that observed in adults, but with important Myocarditis, congestive heart failure, intracardiac masses
differences [Table 34.3]. In children with miliary TB, Cholestatic jaundice
chills, night sweats, haemoptysis, and productive cough Presentation as focal extra-pulmonary tuberculosis
have been reported less frequently, while peripheral Incidental diagnosis
lymphadenopathy and hepatosplenomegaly are more Syndrome of inappropriate antidiuretic hormone secretion
common, compared with adults. Likewise, a higher Deep vein thrombosis
proportion of children with miliary TB have TB
Data from references 37,39-53, 58-75
meningitis compared with adults.
immunosuppression in advanced HIV infection
Rare Manifestations
[CD4+ cell counts < 200/μl], disseminated and miliary
Table 34.4 shows various atypical manifestations in TB are seen more frequently (54,76,77). Cutaneous
patients with miliary TB. Atypical presentations can involvement is unusual in MTB but is more commonly
delay the diagnosis and disseminated and miliary TB is seen in HIV-seropositive patients with CD4+ cell counts
often a missed diagnosis. Patients with occult dissemi- below 100/μl (78). The cutaneous lesions that have been
nated and miliary TB can present with “pyrexia of described include tiny papules or vesiculopapules
unknown origin” without any localizing clue. Clinical variously described as ‘tuberculosis cutis miliaris
presentation such as absence of fever, and progressive disseminata’, ‘tuberculosis cutis acuta generalisita’, and
wasting strongly mimicking a metastatic carcinoma can disseminated TB of the skin (79). Rarely, macular,
occur, especially in the elderly. Proudfoot et al (37) sug- pustular, or purpuric lesions, indurated ulcerating
gested the term “cryptic miliary TB” for this presentation. plaques, and subcutaneous abscesses have also been
Table 34.5 (37-39) highlights the important differences reported (79). In HIV/AIDS patients with disseminated
between classical and cryptic forms of miliary TB. The and miliary TB, intrathoracic lymphadenopathy and
reader is referred to the chapter “Tuberculosis and acute tuberculin anergy are more common; sputum smears are
lung injury” [Chapter 36] for details regarding TB and seldom positive and blood culture may grow Mycobac-
acute respiratory distress syndrome [ARDS]. terium tuberculosis, especially in patients with profound
immunosuppression (1,2,4-9,54).
Disseminated and Miliary Tuberculosis in the Immune reconstitution inflammatory syndrome
Immunosuppressed Patients [IRIS] has been implicated as the cause of paradoxical
The clinical presentation of TB in early HIV infection worsening of lesions in patients with TB. Consequently,
[CD4+ cell counts > 500/μl] is similar to that observed HIV-seropositive patients with miliary TB may develop
in immunocompetent individuals. With progression of acute renal failure (80) or ARDS (81). The reader is
498 Tuberculosis
Table 34.5: Comparison of classical and cryptic miliary tuberculosis
Variable Classical miliary TB Cryptic miliary TB
Age at diagnosis Majority < 40 years Majority > 60 years

Fever Present in > 90% Rarely present, few
localizing signs evident
Weight loss Present in 60%-80% Dominant clinical feature
Meningitis Seen in 20%-30% adults 30%-40% children Rare unless terminal
Lymphadenopathy Present in 20% Rarely present
Chest radiograph Classical miliary pattern common Normal
HRCT of the chest Required only when classical miliary pattern is Required for diagnosis
not evident. May also reveal additional findings
Tuberculin skin test Positive in 60% Rarely positive
Confirmation of diagnosis Invasive procedures Usually made at autopsy*
* Diagnosis can be made with computed tomography at present during life time
TB = tuberculosis; HRCT = high resolution computed tomography
Adapted from references 37-39
referred to the chapter “Tuberculosis and human immuno- Table 34.6: Laboratory abnormalities in disseminated and
deficiency virus infection” [Chapter 40] for more details. miliary tuberculosis
Haematological
LABORATORY FINDINGS Anaemia
Leucocytosis
Haematology and Serum Biochemistry Neutrophilia
Lymphocytosis
A number of haematological and biochemical abnorma- Monocytosis
lities are known to occur in disseminated and miliary Thrombocytosis
TB but their significance is controversial [Table 34.6]. Leucopenia
Anaemia of chronic disease, leucocytosis, leucopenia, Lymphopenia
leukaemoid reactions, thrombocytopenia and dissemi- Thrombocytopenia
Leukaemoid reaction
nated intravascular coagulation are all known to occur.
Elevated ESR, CRP levels
Erythrocyte sedimentation rate is usually elevated in Biochemical
patients with disseminated and miliary TB (4-9). The Hyponatraemia
reader is referred to the chapter “Haematological manifes- Hypoalbuminaemia
tations of tuberculosis” [Chapter 37] for more details. Hyperbilirubinaemia
Hyponatraemia in miliary TB was first described in Elevated tranaminases
Elevated serum alkaline phosphatase
1938 by Winkler and Crankshaw (82). Shalhoub and Hypercalcaemia
Antoniou (83) postulated an acquired disturbance of
neurohypophyseal function resulting in unregulated ESR = erythrocyte sedimentation rate; CRP = C-reactive protein
antidiuretic hormone [ADH] release as the underlying
mechanism. Vorherr et al (84) demonstrated an antidiure- has been documented in miliary TB but is uncommon
tic principle in the lung tissue affected by TB and (4-9).
suggested that it may either produce ADH or absorb an
inappropriately released hormone from the posterior
pituitary. Hyponatraemia in miliary TB has also been Majority of patients with disseminated and miliary TB
attributed to meningeal involvement (43). Presence of are tuberculin skin test [TST] positive [Table 34.7]. The
hyponatraemia in patients with miliary TB is thought to reader is referred to the chapter “Tuberculin skin test”
be of prognostic significance [vide infra]. Hypercalcaemia [Chapter 11] for more details.
Table 34.7: Results of tuberculin skin test in miliary have patterns that are indistinguishable from interstitial
tuberculosis** pneumonia (4,52). Some of the patients may manifest
Study No. studied No. tested Negative coalescent opacities [Figures 34.2A, 34.2B, and 34.3].
(reference) TST [%] When patients with miliary TB develop ARDS, the chest
radiograph may be identical to that seen in ARDS due to
Paediatric series
other causes (4,59). Majority of the patients [88%] in the
Kim et al (23) 84 84 51
study reported by Sharma et al (52) had chest radiographs
Aderele (55) 44 26 35
consistent with miliary TB and in some, these classical
Rahajoe (56) 80 80 54
radiological changes evolved over the course of the
Hussey et al (21) 94 94 62
disease. The diagnosis of miliary TB is easier when
Gurkan et al (26) 23 23 74
patient presents with classical miliary shadowing on
Adult series
chest radiograph in an appropriate setting. However, the
Biehl (42) 68 26 39
diagnosis may be difficult in those situations where chest
Munt (43) 69 57 48
radiograph does not show classical miliary shadows. This
Campbell (44) 48 30 20
fact is highlighted by 12 patients in the series reported
Gelb et al (45) 109 72 44
by Sharma et al (52) who had atypical chest radiographs
Grieco et al (46) 28 21 52
and the case of a patient with fever of unknown origin
Onadeko (47) 41 23 65
who presented with a very subtle suggestion of miliary
Prout et al (49) 62 21 62
mottling on the chest radiograph. This chest radiograph
Kim et al (50) 38 38 68
was passed off as normal in a busy outpatient department
Maartens (51) 109 47 57
[Figure 34.4]. High resolution CT [HRCT] [vide infra]
Mert et al (40) 38 38 62
Sharma SK 134 107 70
[unpublished
observations]
* Varying strengths and methods were employed for TST in

different studies
TST = tuberculin skin test
Interferon-gamma Release Assays

Newer in-vitro T-cell based interferon-gamma release
assays [IGRAs] appear to be promising in detecting TB
infection as compared to the TST and may be useful in
patients with disseminated and miliary TB. The reader
is referred to the chapter “Diagnosis of latent tuberculosis
infection: recent advances and future directions” [Chapter 12]
for further details on this topic.
Imaging
Chest Radiograph
The radiographic hallmark of miliary TB is the miliary Figure 34.2A: Chest radiograph [postero-anterior view] showing
pattern on chest radiograph [Figure 13.3]. The term confluent shadows instead of miliary mottling in a patient with miliary
tuberculosis
miliary refers to the “millet seed” size of the nodules
Reproduced with permission from “Sharma SK, Mohan A, Prasad
[< 2 mm] seen on classical chest radiographs (4). Some KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory
patients with miliary TB, however, may have normal characteristics and outcome in miliary tuberculosis. QJM
chest radiographs when they seek medical care and some 1995;88:29-37 (reference 52)”
500 Tuberculosis

subtle miliary shadows
Figure 34.2B: HRCT of the chest of the same patient in Figure KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory
34.2A, showing miliary pattern characteristics and outcome in miliary tuberculosis. QJM
Reproduced with permission from “Sharma SK, Mohan A, Prasad 1995;88:29-37 (reference 52)”
KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory
characteristics and outcome in miliary tuberculosis. QJM
1995;88:29-37 (reference 52)”
Figure 34.5: CT of the chest of the same patient in Figure 34.4

showing extensive miliary shadows
KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory
characteristics and outcome in miliary tuberculosis. QJM
1995;88:29-37 (reference 52)”
diagnosis in this patient [Figure 34.6]. This re-emphasizes

the fact that though the clinical and laboratory para-
miliary mottling and a cavity in the left upper lobe meters are indicative of the disease, they are not sensitive
enough to allow an accurate provisional diagnosis. Thus,
suggested a miliary pattern [Figure 34.5] and excision if there is a high index of suspicion of miliary TB and
biopsy of the supraclavicular lymph node which the chest radiograph is atypical, it is suggested that HRCT
developed over the course of the disease confirmed the be done to support the diagnosis.
extra-pulmonary sites, an exercise that was earlier

possible only at post-mortem examination. Abdominal
CECT is useful in identifying lesions in the liver and
spleen, intra-abdominal lymphadenopathy, and cold
abscesses (3,4,85). Miliary lesions in the liver and spleen
may appear as confluent or discrete hypodense lesions,
sometimes with peripheral rim enhancement on the
CECT of the abdomen (3,4,85).
Ultrasonography, CECT, and MRI may help in identi-
fying adnexal masses, ascites in women, and epididy-
mitis and seminal vesicle lesions in men with genital tract
involvement. The CECT or MRI of the brain and spine
are useful in the evaluation of patients with concomitant
Figure 34.6: Lymph node biopsy showing confluent, caseating
TB meningitis [Figure 34.7] or spinal TB. Interventional
epithelioid cell granulomas with giant cells suggestive of radiological procedures such as fine needle aspiration
tuberculosis [Haematoxylin and eosin × 80] cytology and biopsy under CT or MRI guidance are
Reproduced with permission from “Sharma SK, Mohan A, Prasad useful for procuring tissue fluid for confirmation of
KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory diagnosis.
characteristics and outcome in miliary tuberculosis. QJM 1995;88:
29-37 (reference 52)”
Imaging findings which are commonly encountered
in patients with disseminated TB are shown in Figures
Ultrasonography 34.8A, 34.8B, 34.9A, 34.9B, 34.10A, 34.10B, 34.11, and
34.12] .
In patients with disseminated and miliary TB, ultra-
Sharma et al (86) assessed the CT appearances of
sonography is useful in the detection of associated
miliary TB [Figures 34.13, 34.14, 34.15, 34.16A, 34.16B,
lesions, such as loculated ascites, focal hepatic and
and 34.17] and the CT findings were correlated with
splenic lesions, adnexal masses [in women] and cold
pulmonary functions and gas exchange. The effect of
abscess. Diagnostic thoracic or abdominal paracentesis
antituberculosis treatment on various observed findings
under ultrasound guidance is useful to procure fluid
was also studied. It was found that the HRCT was
for diagnostic testing, especially when it is loculated.
superior to the conventional CT in defining the paren-
Computed Tomography and Magnetic chymal details. A significant positive correlation was
Resonance Imaging observed between the visual chest radiograph and CT
High resolution computed tomography has considerably scores (86). Further, CT of the chest also revealed lymph
improved the antemortem diagnosis of disseminated and nodal enlargement, calcification and pleural lesions in
miliary TB. The interlobular septal thickening or intra- more patients than plain films. Curiously, Sharma et al
lobular fine network that is evident on HRCT in miliary (86) also described air trapping on CT both at
TB seems to be caused by the presence of tubercles in the presentation and during follow-up period and attributed
interlobular septa and alveolar walls. Centrilobular this to TB bronchiolitis [Figures 34.15, 34.16A, 34.16B,
nodules and branching linear structures producing a tree- and 34.17]. The clinical significance of these findings is
in-bud appearance–a pattern seen in active post-primary unclear at present.
pulmonary TB–may sometimes be evident in miliary TB. Pipavath et al (87) in a recent report [n = 16] docu-
Contrast enhanced CT [CECT] is better for detecting mented the following changes on HRCT in patients with
intrathoracic lymphadenopathy, calcification, and miliary TB: miliary pattern [n = 16]; intrathoracic
pleural lesions (3,4). lymphadenopathy [n = 8]; alveolar lesions such as
Magnetic resonance imaging [MRI] and CECT are ground glass attenuation and/or consolidation [n = 5];
also useful in demonstrating miliary lesions at occult pleural and pericardial effusions [2 patients each]; and
502 Tuberculosis
Figure 34.8A: CECT of the chest of a patient with disseminated

tuberculosis showing bilateral parenchymal lesions
Figure 34.8B: CECT of the abdomen of the same patient

showing multiple, low attenuation lesions in the liver and spleen
peribronchovascular interstitial thickening and

emphysema [1 patient each].
Figure 34.7: MRI of the brain [T1-weighted image, axial view] in
a patient with miliary tuberculosis showing multiple hyperintense
disk-like lesions [tubercles] [A] that are enhanced after the
Pulmonary Functions, Gas Exchange Abnormalities
administration of contrast medium [arrows] [B]. Contrast Miliary TB is associated with abnormalities of pulmonary
enhanced MRI of the brain [T1-weighted image, axial section]
functions typical of diffuse interstitial disease of the lungs
showing multiple hyperintense enhancing disk-like lesions of
varying sizes scattered within the brain [C,D, and E]. Some of (4). The impairment of diffusion has been the most
them have coalesced to produce a hyperintense enhancing frequent and severe abnormality encountered (4).
irregularly shaped lesions [arrows] [F]. Sharma et al (88) studied the pulmonary functions
Figure 34.9A: CECT of the abdomen of a patient with disseminated

tuberculosis showing a large, low attenuation lesion in the spleen
Figure 34.10A: CECT of the abdomen of a patient with dissemina-
[arrow]
ted tuberculosis showing multiple, low attenuation lesions in the
spleen
Figure 34.10B: CECT of the abdomen of the same patient

showing ascites with loculations [arrows]
Figure 34.9B: CECT of the abdomen of the same patient showing With antituberculosis treatment, mean arterial
psoas abscess [asterisk] on the right side. Erosion of the vertebral oxygen tension [PaO2] showed a significant increase from
body [arrow] can also be seen the pre-treatment values [Figure 34.18]. The mean post-
treatment values of forced vital capacity [FVC], forced
[n = 31] and gas exchange abnormalities on arterial blood expiratory volume in the first second [FEV1], peak expira-
gas analysis [n = 13] in patients with miliary TB. They tory flow rate [PEFR], maximal mid expiratory flow rate
found a mild restrictive ventilatory defect, impairment FEF 25-75, forced expiratory flow at 50 per cent vital
•
of diffusing capacity and hypoxaemia due to widening capacity [V50] and forced expiratory flow at 25 per cent
•
of alveolar-arterial oxygen gradient. A mild reduction vital capacity [V25] did not show a significant increase at
in the flow rates suggestive of peripheral airways the end of treatment (88). The functional residual capacity
involvement was also observed. [FRC] and residual volume [RV]/total lung capacity
504 Tuberculosis
Figure 34.11: CECT of the chest of a young woman who presented with low-grade fever for 3 months, cough and dysphagia showing
subcarinal [A] and right hilar [B] lymph nodes. Arrows point to hypodensities which indicate necrosis in the lymph nodes. CECT of the
abdomen of the same patient showing bilateral psoas abscesses [C] [arrows]. Coronal reconstruction of the CECT of the abdomen of the
same patient showing bilateral psoas abscesses [D] [arrows]. CT guided fine needle aspirate from the psoas abscess revealed numerous
acid-fast bacilli
Reproduced with permission from “Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53 (reference
3)”
[TLC] [%] also did not decrease significantly at the end system and the pulmonary functions in 16 patients with
of treatment. Antituberculosis treatment resulted in miliary TB. They observed a significant correlation
improvement in gas exchange [Figure 34.18]. between the disease extent score and the FVC, FEV1, TLC,
Pipavath et al (87) assessed the correlation between arterial oxygen saturation [SaO2], and diffusion capacity
the disease extent score as evaluated by a visual scoring of the lung for carbon monoxide [DLCO].
Figure 34.12: Tuberculosisof the spleen. CECT of the abdomen [A] showing multiple hypodense lesions in the spleen [A]. CECT of
the abdomen [B] showing multiple hypodense lesions in the spleen [black arrows] and liver [white arrows]
Figure 34.13: HRCT of the chest at intermediate bronchus level

showing non-uniform distribution of nodular lesions in both the lungs Figure 34.14: CT of the chest through upper lobes showing
with areas of conglomeration extensive, fine nodules in both the lungs with relative peripheral
Reproduced with permission from “Sharma SK, Mukhopadhyay S, sparing
Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography Reproduced with permission from “Sharma SK, Mukhopadhyay S,
in miliary tuberculosis: comparison with plain films, bronchoalveolar Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography
lavage, pulmonary functions and gas exchange. Australasian Radiol in miliary tuberculosis: comparison with plain films, bronchoalveolar
1996;40:113-8 (reference 86)” lavage, pulmonary functions and gas exchange. Australasian Radiol
1996;40:113-8 (reference 86)”
Cardiopulmonary Exercise Testing exercise. Following successful treatment, most patients

reveal reversal of abnormalities. However, some of these
Patients with miliary TB have abnormal cardiopulmo-
abnormalities may persist following treatment (89,90).
nary exercise performance with lower maximum oxygen
consumption, maximal work rate, anaerobic threshold,
Immunologic Abnormalities and
peak minute ventilation, breathing reserve, and low
Bronchoalveolar Lavage
maximal heart rate (89,90). Other abnormalities include
higher respiratory frequency, peak minute ventilation Sharma et al (88) reported that patients with miliary TB
at submaximal work, and high physiological dead space/ had a significantly higher total cell count and increased
tidal volume ratio. Some of these patients manifest a proportion of lymphocytes, CD3+, and CD4+ T-lym-
demonstrable fall in oxygen saturation [4% or more] with phocytes in the bronchoalveolar lavage [BAL] fluid
506 Tuberculosis
Figure 34.16B: Follow-up CT of the same patient after 7 months

of antituberculosis therapy. The nodules have disappeared and air
trapping has increased significantly
Figure 34.15: HRCT of the chest at carina showing extensive Reproduced with permission from “Sharma SK, Mukhopadhyay S,
nodular lesions with confluence mainly in the right lung and focal Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography
area of bronchiectasis or a thin walled cavity in the left lung along in miliary tuberculosis: comparison with plain films, bronchoalveolar
with scattered areas of air trapping lavage, pulmonary functions and gas exchange. Australasian Radiol
Reproduced with permission from “Sharma SK, Mukhopadhyay S, 1996;40:113-8 (reference 86)”
Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography
in miliary tuberculosis: comparison with plain films, bronchoalveolar
lavage, pulmonary functions and gas exchange. Australasian Radiol
1996;40:113-8 (reference 86)”
Figure 34.17: Follow-up CT of a patient at the end of antituber-

Figure 34.16A: CT through upper lobes showing non-uniform culosis therapy. The nodules have disappeared but air trapping
distribution of nodules with areas of air trapping in both the lungs has increased
Reproduced with permission from “Sharma SK, Mukhopadhyay S, Reproduced with permission from “Sharma SK, Mukhopadhyay S,
Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography
in miliary tuberculosis: comparison with plain films, bronchoalveolar in miliary tuberculosis: comparison with plain films, bronchoalveolar
lavage, pulmonary functions and gas exchange. Australasian Radiol lavage, pulmonary functions and gas exchange. Australasian Radiol
1996;40:113-8 (reference 86)” 1996;40:113-8 (reference 86)”
[Figures 34.19, 34.20 and 34.21]. In patients with miliary inflammation. With antituberculosis treatment, total cell
TB, BAL showed lymphocytic alveolitis (88,91). The count in BAL fluid decreased but continued to be higher
finding of increased CD4+ lymphocytes in the BAL fluid than that in normal control subjects. The proportion of
and their depletion in the peripheral blood suggested lymphocytes did not change significantly [Figure 34.22
compartmentalization of lymphocytes at the site of upper panel].
Figure 34.18: Effect of antituberculosis treatment on lung volumes and maximal expiratory flow rates [upper panel (A)] and gas exchange,
Raw and SGaw [lower panel (B)]. Single asterisk indicates p < 0.05; double asterisk indicates p < 0.01; solid bars = pre-treatment;
hatched bars = post-treatment
Reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and
immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)”
FVC = forced vital capacity; FEV1 = forced expiratory volume in the first second; PEFR = peak expiratory flow rate; FEF25-75 = maximal
• •
mid expiratory flow rate; forced expiratory flow at 50 per cent vital capacity = V50 ; V25 = forced expiratory flow at 25 per cent vital capacity;
FRC = functional residual capacity; RV = residual volume; TLC = total lung capacity; Raw = airway resistance; SGaw = airway conductance
Figure 34.19: Absolute number of pre-treatment T- and B-lymphocytes in the peripheral blood of patients with miliary tuberculosis [MTB]
and normal control subjects [N]
508 Tuberculosis
Figure 34.21: CD4+/CD8+ ratio in the peripheral blood and BAL fluid
Figure 34.20: Lymphocyte subsets in bronchoalveolar [BAL] fluid in normal controls [N] and patients with miliary tuberculosis [MTB]
in normal controls [N] and patients with miliary tuberculosis [MTB] NS = not significant
NS = not significant Reproduced with permission from “Sharma SK, Pande JN, Singh
YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir
Dis 1992;145:1167-71 (reference 88)”
Sharma et al (88) also observed that the immuno- were thought to be due to persistent mycobacterial
globulins [Ig] G, IgA, IgM were increased in the periphe- antigenic stimulus. Increased BAL fluid fibronectin
ral blood and BAL fluid in 18 patients [Tables 34.8 and (88,92) and serum complement [C3] (88) have also been
34.9]; suggesting polyclonal hypergammaglobulinaemia. described in patients with miliary TB [Table 34.9]. The
With antituberculosis treatment, serum immuno- increase in serum C3 has been thought to be the result of
globulins, IgG and IgA showed an insignificant increase. “acute phase response” to ongoing inflammation and
The decrease in serum IgM value was not statistically elevated BAL fluid fibronectin compared with peripheral
significant. The mean BAL fluid IgG, IgA values showed blood suggested local synthesis in the lung.
a decline following antituberculosis treatment, but the
difference did not attain statistical significance. Although DIAGNOSIS
BAL fluid IgM did not show a significant fall with
antituberculosis treatment, the mean post-treatment Even in an endemic area, the diagnosis of disseminated
value in MTB patients was quite close to the mean in and miliary TB can be difficult as the clinical symptoms
normal control subjects [Figure 34.22, lower panel]. have been non-specific, the chest radiographs do not
Sharma et al (88) postulated that elevation of IgM always reveal the classical miliary changes and atypical
occurred in the acute and active phase of the infection presentations such as ARDS, and shadows larger than
only, whereas, IgG and IgA continued to be raised even miliary on chest radiograph commonly occur. In patients
after apparent cure of infection. These increased levels with suspected disseminated and miliary TB, attempts
Figure 34.22: Effect of antituberculosis treatment on bronchoalveolar lavage [BAL] fluid findings in patients with miliary tuberculosis
FR = fluid recovery, AM = alveolar macrophages, LYM = lymphocytes, TC = total cells, POLY = polymorphs, FN = fibronectin, Ig =
immunoglobulin;
Single asterisk indicates p < 0.05; solid bars = pre-treatment; hatched bars = post-treatment
Table 34.8: Pre-treatment serum immunoglobulins and complement [C3] in patients with
miliary tuberculosis and normal control subjects*
Measurement Miliary TB Normal control
subjects
BMI < 18 BMI > 18 Total patients
IgG [mg/dl] 1868 [1.161] 1969 [505] 1913 [906]† 1063 [371]
[n = 10] [n = 8] [n = 8] [n = 70]
IgA [mg/dl] 321 [86.5] 350 [155] 333.8 [118.4]† 139 [65]
[n = 10] [n = 8] [n = 8] [n = 70]
IgM [mg/dl] 240 [130] 193.5 [65.4] 218 [104]† 94.32 [26.3]
[n = 9] [n = 8] [n = 17] [n = 70]
Complement C3 234 [129] 299 [104] 262 [121]† 124.7 [31.9]
[mg/dl] [n = 13] [n = 10] [n = 23] [n = 10]
* All values are expressed as mean [SD]

† p < 0.001, miliary TB versus normal control subjects
Modified and reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary
function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)”
BMI = body mass index [kg/m2]; TB = tuberculosis
510 Tuberculosis
Table 34.9: Pre-treatment bronchoalveolar lavage findings in patients with miliary

tuberculosis and normal control subjects*
Measurement Normal control subjects Miliary TB Total patients

[n = 17]
BMI < 18 BMI > 18
Fluid recovery [%] 44.35 [11.32] 53.4 [11.9] 54.8 [17.5] 54.10 [14.65]‡
[n = 16] [n = 15] [n = 31]
Total cell count 0.76 [0.36] 2.22 [1.47] 4.39 [3.86] 4.39 [3.86]
[106 cells/ml] [n = 13] [n = 14] [n = 27]
Alveolar macrophages 86 [12.3] 39 [12.8] 39.2 [21.7] 39.11 [17.29]‡
[%] [n = 14] [n = 13] [n = 27]
Lymphocytes [%] 10.58 [10.25] 53.4 [12.5] 54.9 [20.8] 54.15 [16.7]‡
[n = 14] [n = 13] [n = 27]
Neutrophils [%] 5 [12.23] 7.57 [6.58] 5.69 [4.89] 6.67 [5.80]
[n = 14] [n = 13] [n = 27]
Fibronectin 6.69 [1.44] 34.6 [19.7]§ 19.8 [8.88] 27.89 [17.15]‡
[μg/mg albumin] [n = 12] [n = 10] [n = 22]
IgG [μg/mg albumin] 254 [90.2] 1973 [671] 1634 [916] 1794 [804]‡
[n = 8] [n = 9] [n = 17]
IgA [μg/mg albumin] 155 [22.4] 799 [473] 719 [571] 757 [514]‡
[n = 9] [n = 10] [n = 19]
IgM [μg/mg albumin] 3.33 [3.13] 7.57 [3.86] 5.78 [3.49] 6.67 [3.68]||
[n = 9] [n = 9] [n = 18]
* All values are expressed as mean [SD]

† Cell count for four patients not included because of the presence of epithelioid cell granulomas in the BAL fluid
‡ p<0.001, normal subjects versus total miliary TB patients
§ p<0.01, normal subjects versus total miliary TB patients
|| p<0.03, BMI < 18 versus >18, miliary TB group
BMI = body mass index [kg/m2]; BAL = bronchoalveolar lavage; TB = tuberculosis
Modified and reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary
function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)”
must be made to confirm histopathological microbio- methods, such as polymerase chain reaction in the field
logical diagnosis. Sputum, pleural fluid, cerebrospinal setting needs to be established. Although a positive
fluid, urine, bronchoscopic secretions, blood and tissue serodiagnostic or molecular method can support the
biopsy specimens have all been employed to confirm the diagnosis in the appropriate clinical setting, a negative
diagnosis of disseminated and miliary TB with varying test cannot rule out disseminated and miliary TB and
results [Tables 34.10A, 34.10B, and 34.10C]. treatment should not be withheld just because of negative
test[s] (3).
Serodiagnostic and Molecular Methods In geographical areas where the prevalence of TB is
high, when a patient presents with a compatible clinical
Enzyme linked immunosorbent assay for detecting picture and a chest radiograph suggestive of classical
mycobacterial antigens, antibodies, and immune miliary pattern, it is a common practice to start the
complexes in the blood and body fluids have been used antituberculosis treatment straight-away keeping in
for the diagnosis of disseminated and miliary TB. The mind the potential lethality of the condition. Measures
usefulness of serodiagnostic tests and molecular to confirm the diagnosis are initiated simultaneously.
Table 34.10A: Body fluids and tissues commonly tested for The following criteria (1) have been suggested for the
diagnostic confirmation in disseminated and miliary diagnosis of disseminated TB: [i] clinical features
tuberculosis suggestive of TB; [ii] concurrent involvement of at least
Fluids two non-contiguous organ sites; or demonstration of
Sputum [spontaneously expectorated, induced with Mycobacterium tuberculosis in the blood, or, bone marrow;
hypertonic: 3% or 5% saline] [iii] microbiological and/or histopathological evidence
Bronchoscopic specimens
Aspirate
of TB; and [iv] marked improvement on antituberculosis
Washings therapy.
Brush smear
Bronchoalveolar lavage fluid Differential Diagnosis
Transbronchial lung biopsy
Cerebrospinal fluid Many conditions that can present with a miliary pattern
Pleural fluid on the chest radiograph are shown in Table 34.11.
Pericardial fluid
Peritoneal fluid
TREATMENT
Gastric lavage*
Pus from cold abscess Untreated, disseminated and miliary TB is uniformly
Tissues
fatal within one year (1-9). Delay in confirmation of the
Lymph node
Peripheral† diagnosis often leads to late institution of specific anti-
Intrathoracic‡§ tuberculosis treatment and significantly contributes to
Intraabdominal‡|| the mortality. A high index of clinical suspicion and
Peritoneum, omentum|| efforts towards confirming the diagnosis by demonstrat-
Liver
ing Mycobacterium tuberculosis early in the disease are
Bone marrow aspiration and trephine biopsy
Skin lesions imperative.
Lung§ There is no consensus regarding the optimum
Operative specimens duration of treatment in patients with disseminated and
Peripheral blood¶ miliary TB [Table 34.12]. According to the World Health
* Often used in children Organization [WHO] guidelines (94,95), MTB is
† FNAC/excision biopsy included under treatment Category I and patients
‡ Radiologically guided FNAC/biopsy receive six months of treatment. In the absence of
§ Mediastinoscopic/video-assisted thoracoscopic surgery, biopsy
associated meningeal involvement, the American
|| Laparoscopic biopsy
¶ Useful in advanced HIV infection Academy of Pediatrics [AAP] (96) advocates nine
FNAC = fine needle aspiration cytology; HIV = human immuno- months of treatment. However, the American Thoracic
deficiency virus Society [ATS], the Centers for Disease Control and
Prevention [CDC], the Infectious Disease Society of
America [IDSA] (97), and the National Institute of for
Sharma et al (52) suggest the following criteria for the Health and Clinical Excellence [NICE] TB guidelines
diagnosis of miliary TB: [i] clinical presentation consis- (98) guidelines state that six months of treatment is
tent with a diagnosis of TB, such as pyrexia with evening adequate for disseminated and miliary TB. The NICE
rise of temperature, weight loss, anorexia, tachycardia TB guidelines suggest that all patients with
and night sweats of greater than six weeks duration disseminated [including miliary] TB should be tested
responding to antituberculosis treatment; [ii] classical for central nervous system [CNS] involvement by CT
miliary pattern on chest radiograph; [iii] bilateral diffuse or MRI of the brain and/or lumbar puncture for those
reticulonodular lung lesions on a background of miliary with CNS symptoms and lumbar puncture for those
shadows demonstrable either on plain radiograph or without CNS symptoms and signs. In the presence of
HRCT; and [iv] microbiological or histopathological associated TB meningitis, treatment needs to be given
evidence of TB. for at least 12 months (96-98). The NICE TB guidelines
512 Tuberculosis
Table 34.10B: Method of confirmation of diagnosis in adults with miliary tuberculosis*

Variable Biehl (42) Prout and Kim et al Wilcox Maartens Sharma Al-Jahadali Cumulative
Benatar (49) (50) et al (93) et al (51) et al (52) et al (53) yield [%]
Sputum † 13/26 31/39 25/33 ND 29/75 10/88 6/22 41.4

Bronchoscopy‡† ND 3/3 12/19 34/41 38/95 2/37 7/10 46.8
Gastric lavage † 20/35 ND 6/8 ND 7/11 ND ND 61.1
CSF† 15/45 1/31 0/26 ND 14/44 ND ND 21.2
Urine† 7/29 3/17 18/27 ND 5/28 ND ND 32.7
Bone marrow§† ND 20/21 9/22 ND 18/22 3/11 8/11 66.7
Liver biopsy ND 12/13 11/12 ND 11/11 6/9 ND 88.9
Lymph node biopsy 3/3 ND ND ND 9/9 16/19 2/2 90.9
* Data are shown as number positive/number tested. Criteria for subjecting the patients to these tests not clearly defined in any of the
studies. Often, more than one test has been performed for confirming the diagnosis. For histopathological diagnosis, presence of
granulomas, caseation and demonstration of acid-fast bacilli have been used to define a positive test
† Yield from smear and culture
‡ Yield from bronchoscopic aspirate, washings, brushings, bronchoalveolar lavage and transbronchial lung biopsy
§ Yield from aspiration and/or trephine biopsy
CSF = cerebrospinal fluid; ND = not described
Table 34.10C: Characteristic body fluid findings in disseminated and miliary tuberculosis
Variable Pleural fluid Ascitic fluid Pericardial fluid Cerebrospinal fluid
Appearance Straw coloured Straw coloured Straw coloured or Clear early;Turbid

serosanguineous with chronicity cob-
web formation
Cell count 1000-5000 150-4000 Not well described 100-500
Total count [/mm3] Leucocyte count is Rarely > 1000
usually increased
Differential count 50%-90% lymphocytes, Predominantly PMN preponderant PMN preponderant
eosinophils < 5% lymphocytes early. Later early. Later, up to
mononuclear cells 95% mononuclear
predominate cells
Protein Usually high [> 2.5 g/dl] Usually high [> 2.5 g/dl] Usually high Usually high
Serum–ascitic fluid [100-500 mg/dl]
albumin gradient Can be very high with
< 1.1 blockage or chronicity
Glucose Usually less than Low Low Usually 40-50 mg/dl
simultaneously collected [about 50% of blood
peripheral blood value glucose]
Smear microscopy [%] < 10 <3 <1 5-37
Mycobacterial culture [%] 12-70 < 20 25-60 40-80
PMN = polymorphonuclear leucocytes

(98) recommend to start antituberculosis treatment even patients’ liver function deteriorates significantly on
if initial liver functions are abnormal. Liver function antituberculosis treatment.
tests should be monitored carefully during follow-up. There are no published data from controlled trials
Drug treatment should be appropriately modified if the assessing the efficacy of the standard WHO treatment
Table 34.11: Common causes of fever with a miliary pattern The reader is referred to the chapter “Treatment of
on chest radiograph tuberculosis” [Chapter 52], for more details.
Infections
Mycobacteria Corticosteroids
Tuberculosis Sparse published data are available regarding the useful-
Fungal infections
ness of adjunct corticosteroid therapy in patients with
Histoplasmosis
Blastomycosis
miliary TB with conflicting results. A beneficial response
Coccidioidomycosis was observed in one study (99) although such benefit
Cryptococcosis could not be documented in another study (100).
Bacteria Presence of associated adrenal insufficiency is an absolute
Legionellosis indication for their administration. Adjunctive cortico-
Staphylococcus aureus bacteraemia
steroid treatment may be beneficial in miliary TB with
Mycoplasma pneumonia
Nocardiosis TB meningitis, large pericardial effusion, dyspnoea and/
Melioidosis or disabling chest pain, IRIS, ARDS, immune complex
Tularaemia nephritis, and histiocyticphagocytosis syndrome (4).
Psittacosis
Brucellosis Antiretroviral Drugs
Parasites
Toxoplasmosis The reader is referred to the chapter “Tuberculosis and
Strongyloides stercoralis hyperinfection human immunodeficiency virus infection” [Chapter 40] for
Schistosomiasis more details.
Immunoinflammatory disorders
Sarcoidosis
Pneumoconiosis COMPLICATIONS
Malignant
Bronchoalveolar carcinoma Complications are often self-limited and improve with
Carcinoma lung with lymphangitis carcinomatosa antituberculosis treatment alone. However, at times they
Bronchial carcinoid can be life-threatening, necessitating prompt recognition
Metastatic carcinoma
and treatment. Important complications in patients with
Lymphoproliferative disorders
Lymphoma
miliary TB include airleak syndromes [e.g., pneumo-
Lymphomatoid granulomatosis thorax, pneumopericardium], ARDS, antituberculosis
drug induced hepatotoxicity, and fulminant hepatic
failure. Rarely, cardiovascular complications such as
regimens (94,95) that are widely used in national TB myocarditis, congestive heart failure, infective endo-
control programmes worldwide. Furthermore, there are carditis, pericarditis, intracardiac mass, mycotic aneu-
sparse data regarding the efficacy of standard treatment rysm, and sudden cardiac death have been described in
regimens in the treatment of disseminated and miliary miliary TB and should be carefully examined for (4).
TB in HIV co-infected patients.
Under the Revised National Tuberculosis Control PROGNOSIS
Programme [RNTCP] of Government of India, patients
with disseminated and miliary TB get treated with The mortality related to miliary TB [Figures 34.23A and
Category I DOTS for six months. Though this duration 34.23B] is about 15 to 20 per cent in children (21,23,26,55,
of treatment is adequate in a majority of the patients, 56) and is slightly higher in adults [25% to 30%] (14,20,
each patient needs to be assessed individually, and 40-53). Delay in diagnosis and initiation of specific
wherever indicated, treatment duration may have to be antituberculosis treatment appears to be the most
extended. important factor responsible for mortality.
514 Tuberculosis
Table 34.12: Antituberculosis drug regimens used in the treatment of disseminated and
miliary tuberculosis in various clinical series
Study (reference) Year of Age group Number Drug regimen(s) used* Adjunct
publication studied corticosteroid
[No.]
Disseminated TB
Wang (2) 2007 Adults 164 2EHRZ/4HRE [7HRE if ND
skeletal involvement is present]
Miliary TB
Kim et al (23) 1969 Children 84 1HSP/3HS2P 44
Hussey et al (21 ) 1991 Children 94 EHRZ [n = 68]; HREth [n = 23] 43
Gurkan et al (26) 1998 Children 23 2HRZ/10HR 7
Munt et al (43) 1972 Adults 69 2HSP/16HP/6H 21
Gelb et al (45) 1973 Adults 109 HSP [n = 89]; HESCy† [n = 20] 20
Onadeko et al (47) 1975 Adults 41 HPS [n = 36] 10
Prout (49) 1980 Adults 62 H [n = 46]; S [n = 31]; R [n = 23] ND
Kim et al (50) 1990 Adults 38‡ HER [n = 11]; HR [n = 11]; ND
EHS [n = 5]; EH [n = 5];
ERCyK [n = 1]; HRS [n = 1];
ERS [n = 1]
Sharma et al (52) 1995 Adults 100 2EHRZ or 2SHRZ/7HR 11
Mert et al (40) 2001 Adults 38 EHRZ or SHRZ [n = 23]; 4
HRS [n = 7]
Hussain et al (41) 2004 Adults 110§ 4 drugs [n = 87]; 5 drugs [n = 14]; 34
6 drugs [n = 2]||
Swaminathan et al (54) 2007 Adults¶ 31 2E3H3R3Z3/4R3H3 ND
[intermittent thrice weekly]
* Numbers preceding alphabets represent the duration in months; numbers given in subscript represent frequency of administration per
week [daily if not specified]
† Cycloserine was added if meningitis was present
‡ Two patients did not receive any treatment
§ Only 103 patients received treatment
|| Pattern of drug usage was as follows: E [90%], H [92%], R [90%], Z [93%] and S [13%]; second-line antituberculosis drugs were used
in 9%
¶ HIV-seropositive patients
TB = tuberculosis; E = ethambutol; H = isoniazid; R = rifampicin; Z = pyrazinamide; S = streptomycin; P = para-aminosalicylic acid;
Eth = ethionamide; Cy = cycloserine; K = kanamycin; HIV = human immunodeficiency virus; ND = not described
Several studies have attempted to identify prognostic in Table 34.13. They may be helpful in guiding the
markers for predicting outcome in patients with clinicians caring for patients with disseminated and
disseminated and miliary TB. These details are shown miliary TB.
Figure 34.23: Mortality in children with miliary tuberculosis [A]. Data derived from Kim et al (23), Aderele (55), Rahajoe (56), Hussey et
al (21), Gurkan et al (26). Mortality in adults with miliary tuberculosis [B]. Data derived from Biehl (42), Munt (43), Gelb et al (45), Grieco
and Chmel (46), Onadeko et al (47), Prout and Benatar (49), Kim et al (50), Maartens et al (51), Sharma et al (52), Long et al (20), Al-
Jahdali et al (53), Hussain et al (41)
Table 34.13: Predictors of poor outcome in patients with disseminated and miliary tuberculosis
Study (reference) Year of publication Predictors of poor outcome
Gelb et al (45)* 1973 Stupor, meningismus, increasing age, cirrhosis of liver, leucopenia,
leucocytosis
Grieco and Chmel (46) 1974 Increasing age, presence of underlying disease, history of cough, night
sweats
Kim et al (50) 1990 Female sex, altered mental status
Maartens et al (51) 1990 Age > 60 years, lymphopenia, thrombocytopenia, hypoalbuminaemia,
elevated transaminase levels, delay in starting antituberculosis treatment
Sharma et al (52) 1995 Dyspnoea, chills, temperature > 39.3 oC, icterus, hepatomegaly,
hypoalbuminaemia, hyponatraemia, elevated serum alkaline
phosphatase
Long et al (20) 1997 Presence of one or more risk factors†
Mert et al (40) 2001 Male sex, presence of atypical chest radiographic pattern, delay in
starting antituberculosis treatment
Hussain et al (41) 2004 Presence of altered mental status, lung crackles, leucocytosis,
thrombocytopenia, need for ventilation
Wang et al (2)‡ 2007 Hypoalbuminaemia, hyperbilirubinemia, renal insufficiency, and delay
in starting antituberculosis treatment
* No statistical analysis was performed

† Listed in Table 34.2
‡ Disseminated TB
TB = disseminated tuberculosis
Modified and adapted from reference 4
REFERENCES 2. Wang JY, Hsueh PR, Wang SK, Jan IS, Lee LN, Liaw YS, et al.
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Complications of
35
D Behera
INTRODUCTION 35.1 and 35.2]. Important causes of haemoptysis in

patients with pulmonary TB are listed in Table 35.2.
Complications of pulmonary tuberculosis [TB] signifi-
Walls of a TB cavity may be affected by inflammation
cantly contribute to morbidity and mortality of patients
and necrosis and may become atrophic. Increased
and are listed in Table 35.1.
pressure can lead to weakening of the walls, dilatation of
blood vessels and formation of Rasmussen’s aneurysms
HAEMOPTYSIS (5,6) [Figure 35.3]. Further, these blood vessels rupture
Haemoptysis is a common and potentially serious
complication of pulmonary TB (1-4). The incidence of
haemoptysis in patients with pulmonary TB is reported
to range from 30 to 35 per cent (1-3). Occurrence of
haemoptysis does not imply that the TB is active.
Haemoptysis may occur as the initial manifestation of
active TB, during the course of treatment, or, even after
the disease is apparently cured. Haemoptysis can be
streaky or massive and life-threatening. Massive
haemoptysis may be associated with atelectasis [Figures
Table 35.1: Complications of pulmonary tuberculosis

Local
Haemoptysis
Post-tuberculosis bronchiectasis
Fungal ball [aspergilloma]
Tuberculosis endobronchitis and tracheitis
Spontaneous pneumothorax
Scar carcinoma
Disseminated calcification of the lungs
Pulmonary function changes, obstructive airways disease
Figure 35.1: Chest radiograph [postero-anterior view] of a patient
Secondary pyogenic infections
who presented with massive haemoptysis showing collapse of the
Systemic
left lung
Secondary amyloidosis
Reproduced with permission from “Sharma SK, Mohan A.
Chronic respiratory failure
Pulmonary tuberculosis: typical and atypical cases. Case track
Chronic cor-pulmonale
series 1. Mumbai: Merind; 1997 (reference 3)”
520 Tuberculosis
Figure 35.2: Chest radiograph [postero-anterior view] of the same

patient following vigorous chest physiotherapy and suction showing
bilateral infiltration of both the lung fields. Sputum smear revealed
Mycobacterium tuberculosis
Reproduced with permission from “Sharma SK, Mohan A.
Pulmonary tuberculosis: typical and atypical cases. Case track
series 1. Mumbai: Merind; 1997 (reference 3)”
Table 35.2: Causes of haemoptysis in pulmonary

tuberculosis
Bleeding from cavity wall

Rupture of Rasmussen’s aneurysm Figure 35.3: Rasmussen’s aneurysm. Dynamic and three-
Direct erosion of capillaries or arteries by granulomatous dimensional views of the pulmonary and bronchial vasculature on
inflammation computed tomography obtained after the injection of contrast
Tuberculosis endobronchitis material demonstrated a large pulmonary aneurysm [panels A and
Post-tuberculosis bronchiectasis B, arrows] obtained from a 54-year-old man who presented with a
Aspergilloma 3-month history of haemoptysis. The patient underwent successful
Broncholith, cavernolith embolization of the pulmonary artery aneurysm and its feeding
Scar carcinoma vessel. However, the haemoptysis resolved only after subsequent
embolization of the bronchial artery
Reproduced with permission from “van den Heuvel MM, van
due to increased pressure during strenuous exercise or
Rensburg JJ. Images in clinical medicine. Rasmussen’s aneurysm.
coughing and can result in haemoptysis. The vessel walls N Engl J Med 2006;355:e17 (reference 5)” Copyright [2006]
can also be eroded directly either because of endarteritis, Massachusetts Medical Society. All rights reserved
or, vasculitis secondary to TB. Sometimes intense allergic
response to antigen[s] of Mycobacterium tuberculosis the bronchial blood vessels which are under systemic
damages the vessel wall and gives rise to haemoptysis. pressure can be the source of bleeding. All these factors
Bleeding from TB granulomas in the bronchi can result should be taken into consideration while managing
in haemoptysis. Blood vessels with aneurysmal dilatation haemoptysis in patients with TB.
and accentuated bronchopulmonary communications are In most instances bed rest, sedation, and resuscitative
present surrounding these granulomas. In this setting, measures aimed at restoring fluid balance and
Complications of Pulmonary Tuberculosis 521
haemodynamic status control the bleeding. Broad ASPERGILLOMA [MYCETOMA; “FUNGUS BALL”]
spectrum antibiotics are administered to treat super-
Mycetoma is a mass of fungal hyphal material that grows
added bacterial infection. Antituberculosis treatment is
in a lung cavity. Although other fungi like Zygomycetes
indicated in patients with active TB. However, if the
[mucor] and Fusarium may cause the formation of a
bleeding is massive, and repetitive, fibreoptic broncho-
fungal ball, Aspergillus species, particularly, Aspergillus
scopy [to localize the site of bleeding] and high resolution
fumigatus, are by far the most common aetiological agents.
computed tomography [HRCT] are performed.
The overall incidence of aspergilloma in general
Angiography along with bronchial artery embolization
population has been estimated to be between 0.01 per
is done in patients with massive haemoptysis [Figures
cent in Great Britain to 0.017 per cent in the USA (11,12).
35.4A and 35.4B] (7,8). Rarely, resection of the site of
In a large multicentric study by the British Tuberculosis
bleeding may be indicated (9,10).
Association (11), which surveyed 544 patients with
healed TB cavities on chest films, measuring 2.5 cm or
greater in diameter, 25 per cent had precipitins to
Aspergillus in serum and 11 per cent had radiologic
evidence of aspergilloma. Aspergilloma occurred as
frequently in patients with recently healed TB as in those
with inactive disease for long periods (11). A follow-up
study (12) of this group, three years after the first survey,
revealed an increase in incidence of aspergilloma to 17
per cent. The new aspergilloma cases were generally
patients who had only serum precipitins during the first
survey (11,12). Aspergillomas have been identified in
cavities associated with tuberculosis, histoplasmosis,
sarcoidosis, bronchial cysts, bullae, neoplasms, pulmo-
nary infarctions, asbestosis, ankylosing spondylitis,
bronchiectasis, and malignant diseases (13,14). Of these,
TB is the most frequently associated condition (15).
Occasionally, they are described in cavities due to other
fungal infections (16,17).
The natural history of an aspergilloma is highly
variable and it may remain stable, increase in size or
spontaneously resolve. In the early phase of its develop-
ment, the fungus ball grows inside a lung cavity
consisting of both living and dead fungus. The future
course depends upon the predominance of these living
or dead fungi. If local conditions favour death, the fungus
ball liquifies and the secretions are expectorated out.
Calcification occurs less frequently.
Figure 35.4: Intra-arterial digital subtraction angiograpy [IA-DSA]
Clinical Features
in a patient with right upper lobe pulmonary tuberculosis showing
a hypertrophied intercosto-bronchial trunck producing contrast The fungus ball may be present for long periods without
extravasation and pulmonary artery filling in the region of
any clinical symptoms and may be an incidental finding
fibrocavitary lesion [A]. The IA-DSA after embolization with polyvinyl
alcohol particles showing obliteration of the angiographic in majority of cases and the lesion remains stable. In
abnormality with patent parent artery [B] approximately 10 per cent of cases, it may increase in
Kind courtesy: Dr Sanjiv Sharma, Department of Cardioradiology, size or resolve spontaneously without treatment (18).
All India Institute of Medical Sciences, New Delhi Rarely, the aspergilloma increases in size (11). But
522 Tuberculosis
eventually, most of them will manifest with some The initial suspicion of a fungus ball is raised from
symptoms. The most common presentation in such cases the chest radiograph. Sputum culture may confirm the
is haemoptysis and the estimated frequency varies from presence of fungus, but may be negative in about 50 per
five to ninety per cent. The amount may be very minimal cent of cases (27). The serum precipitins [IgG antibodies]
to severe particularly in patients with associated TB (19). to Aspergillus are positive in almost 100 per cent of cases
Bleeding usually occurs from the bronchial blood vessels. except in cases of aspergilloma due to other Aspergillus
The exact cause of haemoptysis associated with asper- species or if the patient is on corticosteroid therapy (28).
gilloma is not certain, but has been variously ascribed to Skin tests are less helpful and may be positive only in a
mechanical friction of mycetoma, an endotoxin with minority of patients (27). In some cases bronchoscopy
haemolytic properties, an anticoagulant factor derived may be helpful in identifying the site of bleeding and
from Aspergillus, local vasculitis, and direct vascular sometimes one may see the fungus ball in direct
invasion in cavity wall vessels (20-23). The mortality rate continuity with the bronchial lumen. Bronchial washings,
varies between two and fourteen per cent. Other features brushings and forceps biopsy may be carried out to
include chronic cough, weight loss, and rarely fever and isolate Aspergillus.
dyspnoea (20-23).
Risk factors associated with poor prognosis of Treatment
aspergilloma include severe underlying disease, increas-
ing size or number of lesions as seen on chest radiograph, The treatment of aspergilloma is controversial because
immunocompromised state including corticosteroid of variability in its natural history. No therapy is warran-
therapy, increasing Aspergillus-specific immunoglobulin ted in asymptomatic cases. Systemic antifungal therapy
G [IgG] titres, recurrent large volume haemoptysis, and is ineffective in treating these lesions. The anti-fungal
underlying sarcoidosis or human immunodeficiency drugs cannot penetrate into the intracavitary fungi (29).
virus [HIV] infection (24). Attempts are made to instill local intrabronchial intra-
cavitary or inhalational antifungal agents [amphotericin
Diagnosis B, nystatin, sodium iodide] with varying success (30-32).
Systemic antifungal therapy using intravenous
Aspergilloma usually comes to clinical attention as an
Amphotericin B has no effect (33). Itraconazole therapy
incidental finding on a routine chest radiographic
has been tried with varying success (34). Bronchial artery
examination or during an evaluation of haemoptysis. The
embolization rarely controls haemoptysis because of
typical radiographic appearance of aspergilloma is
described as a bell-like image, with the fungus ball extensive collateral blood vessels. This procedure may,
appearing as a clapper inside a bell. A semicircular however, be used as a temporary measure to control
crescentic air shadow appears around the radio-opaque massive, life-threatening haemoptysis (35).
fungus ball located in an upper lobe lung cavity (25). Some advocate routine surgery because of the fear of
The fungus ball is mobile and changes its position as the haemoptysis in future. However, the clinical approach
patient moves, which is best seen on fluoroscopy or by should be individualized. In some cases the severity of
taking chest radiographs or computed tomography [CT] the underlying lung disease will not allow surgical
[Figure 35.5] at different positions. A change in position resection, even in the presence of life-threatening haemo-
of the aspergilloma with the change in position of the ptysis. The surgical treatment of aspergilloma is asso-
patient is an interesting but a variable sign (26). ciated with a relatively high mortality rate that ranges
Occasionally, it may be difficult to recognize the mass between seven and twenty-three per cent (36,37). The
on a routine chest radiograph, and tomography or chest most common causes of death following surgery are
CT may be necessary to visualize the aspergilloma. The severe underlying lung disease, pneumonia, acute
adjacent pleura may be thickened. The radiographic myocardial infarction, and invasive pulmonary
differential diagnosis includes organized haematoma or aspergillosis. In addition, there is a significant post-
pus inside a cavity, neoplasm, abscess, Wegener’s operative morbidity, including bleeding, residual pleural
granulomatosis and a ruptured hydatid cyst. An space, bronchopleural fistula, empyema, and respiratory
aspergilloma may co-exist with any of these conditions failure. In younger patients with adequate lung reserve
also. the morbidity and mortality are lower (38,39).
Figure 35.5: CT of the chest [lung window, supine position] showing a cavity in the left upper lobe [A and
B] containing a radio-opaque shadow with a semi-circular air crescent around it [arrow] suggestive of a
fungal ball [asterisk]. When the CT is repeated with the patient in the prone position [C and D], the fungal
ball can be seen to have changed its position
The best approach seems to wait and watch and appears to be a relatively rare manifestation in HIV-
surgery is indicated only when there is repeated and seropositive patients with pulmonary mycetoma. In a
severe haemoptysis. Patients with mild infrequent study (21) comparing the clinical presentation, disease
haemoptysis or without symptoms may be observed progression, treatment, and outcome of pulmonary
carefully. Surgical approach needs to be considered in mycetoma in patients with [n = 10], and without [n = 15]
patients with massive haemoptysis and adequate HIV infection, the following observations were
pulmonary reserve (36-40). documented. Although TB and sarcoidosis were the most
prevalent predisposing diseases, a history of Pneumocystis
Mycetoma and Human Immunodeficiency jirovecii pneumonia and the consequent cavitation was
Virus Infection found to be a risk factor for pulmonary aspergilloma in
Pulmonary mycetomas have also been documented in HIV infected individuals. In HIV-positive patients with
human immunodeficiency virus [HIV] seropositive a CD4+ count of less than or equal to 100 cells/μl, the
individuals (21,41-43). Although life-threatening disease progressed disease despite treatment. Compared
haemoptysis has occasionally been documented (41), it with HIV-positive patients, significant haemoptysis
524 Tuberculosis
requiring intervention was more likely in HIV-negative “sicca” type of bronchiectasis because of the effective
individuals. drainage of the upper lobes by gravity. The usual
In another study (43), Pneumocystis jirovecii presentation is with haemoptysis or repeated episodes
pneumonia was found to be a risk factor for pulmonary of secondary bacterial infection.
mycetoma in the HIV infected individuals. These wor- Although the chest radiograph is important in the
kers (43) also reported that though the disease progressed evaluation of a patient with suspected post-TB
rapidly, life-threatening haemoptysis rarely occurred in bronchiectasis, the findings are often non-specific.
HIV-infected patients with mycetoma. A combination of Bronchography performed with a radio-opaque,
anti-fungal and anti-retroviral therapy may improve the iodinated lipid dye, provides an excellent visualization
clinical outcome in HIV-infected patients with pulmo- of the dilated airways [Figure 35.6]. However, in the
nary mycetoma. recent years, it has been replaced by HRCT. As compared
to the bronchography, the CT is a relatively non-invasive
POST-TUBERCULOSIS BRONCHIECTASIS investigation.
The pathogenesis of bronchiectasis in TB is multifactorial
TUBERCULOSIS ENDOBRONCHITIS
(44). Caseation necrosis and granulomatous inflamma-
AND TRACHEITIS
tion in the wall of the dilated and destroyed bronchi
suggest that this may represent an extension of the TB Tuberculosis endobronchitis and tracheitis are observed
process. Scarring that follows TB inflammation produces in about one-third of the patients with pulmonary TB
bronchial stenosis. This, when followed by mixed (45). These structures can be infected by direct implanta-
bacterial infection and retention of purulent bacterial tion of Mycobacterium tuberculosis, through submucosal
secretions, leads to destruction and dilatation of the bron- lymphatics, haematogenous spread or from the lymph
chi as is the case with other types of bronchiectasis. nodes. Clinical manifestations include cough, haemop-
The ongoing pathological changes may be perpe- tysis, breathlessness and soreness or constriction in the
tuated by products of inflammation. Compression of the sub-sternal region. Healing can lead to bronchostenosis.
bronchial lumen by enlarged lymph nodes produces
consequences similar to those of an intraluminal obstruc-
tion. This is more so in the case of young children and
adolescents in whom TB hilar lymphadenitis is more
common. In both these situations, inflammatory
destruction of the bronchial wall is by and large the
sequelae of secondary bacterial infection rather than the
direct effect of Mycobacterium tuberculosis. Another rare,
but important cause of bronchial obstruction is
penetration of the airway by a calcified TB lymph node
and the formation of broncholith. Some or all of the
bronchiectatic cavities may represent healing or healed
TB cavities that have been re-lined with ciliated columnar
epithelium. Bronchiectasis structurally resembles small/
large cavities in the bronchial wall. Recently, it has
been reported that, Mycobacterium avium-intracellulare
infection of the lungs is associated with bronchiectasis
in apparently healthy individuals, or, in persons with
emphysema. It seems that such an association may either
be due to a primary infection or colonization. Post-TB
bronchiectasis is commonly seen in the upper lobes, since Figure 35.6: Bronchography showing right upper lobe post-
the disease is more common at this site. It is a “dry” or tuberculosis bronchiectasis
The reader is referred to the chapter “Endobronchial may also give history of coughing out calcified stones in
tuberculosis” [Chapter 16] for more details. the sputum [broncholiths or pneumoliths]. Extensive
calcification, may result in respiratory failure or chronic
SPONTANEOUS PNEUMOTHORAX cor-pulmonale.
Spontaneous pneumothorax has been reported in five to TUBERCULOSIS LARYNGITIS

fifteen per cent of patients with pulmonary TB (46,47).
Involvement of larynx during the course of pulmonary
In countries where TB is a common problem, it is an
TB occurs in about four to forty per cent of cases (49).
important cause of pneumothorax [Figure 35.7].
The incidence increases with extensive involvement of
Spontaneous pneumothorax may result from rupture of
lungs and presence of cavitary disease. The usual mode
a subpleural TB cavity into the pleural space. Infection
of infection is by direct implantation or through lympha-
of pleural cavity results in pyopneumothorax. Other
tics and blood vessels. The symptoms include soreness
causes of pneumothorax include rupture of an open
or pain in the throat, dry, hacking cough and hoarseness
healed cavity or rupture of a bleb or bulla [Figure 35.8]
of voice. Laryngoscopy may reveal an ulcer, granuloma,
secondary to fibrosis and destruction of the lung (48).
paresis or paralysis, destruction of cords, or stenosis of
the vocal cords. The vocal cords, arytenoids and the inter-
arytenoid space are most commonly affected. The
sputum is usually positive for Mycobacterium tuberculosis.
The reader is referred to the Chapter “Tuberculosis in
otorhinolaryngology” [Chapter 27] for details.
TUBERCULOSIS ENTERITIS
Tuberculosis enteritis seldom occurs as a complication
of pulmonary TB in the present era. The reader is referred
to the chapter “Abdominal tuberculosis” [Chapter 19] for
further details.
“OPEN-NEGATIVE” SYNDROME
Patients with “open-negative syndrome” have thin
Figure 35.7: Chest radiograph [postero-anterior view]
walled cavities with epithelialization extending from
showing hydropneumothorax on the right side bronchioles down to the inner lining of the cavity (50-
52). These are observed more frequently following the
advent of chemotherapy. Although they are known as
CALCIFICATION
“isoniazid cavities”, they can also occur due to other
Tuberculosis lung lesions heal by calcification. In fact, antituberculosis drugs. Complete epithelialization
localized or extensive calcification of the lungs is a feature prevents these cavities to collapse and fibrose but renders
of healed primary TB (47). Calcification can either be them innocuous. From a clinical point of view, they are
microscopic or macroscopic. Most often these calcifica- regarded as inactive cavities. However, histopathological
tions are innocuous and present as discrete radio-opaque examination of such cavities may reveal incomplete
shadows in patients with parenchymal disease epithelialization and necrotic foci showing Mycobacterium
[Figure 35.9] and sheet-like calcification in patients with tuberculosis. These present radiologically as “ring
pleural disease [Figure 35.10]. Occasionally, however, shadows” with thin walls.
these calcified concretions may get detached from the Although the cavities themselves will not produce
lung tissue and erode through a bronchial wall or blood any symptoms, they are associated with certain
vessel and result in massive haemoptysis. The patient hazards like secondary infection, colonization with fungi
526 Tuberculosis
Figure 35.8: Chest radiograph [poster-anterior view] [A], CT of the chest [coronal reconstruction, B], [C], and [D] of a patient who
presented with breathlessness showing bilateral bullous lung disease [arrows]. This patient had sputum smear-positive pulmonary
tuberculosis a decade ago and had received adequate antituberculosis treatment
Figure 35.9: Chest radiograph [postero-anterior view] showing Figure 35.10: Chest radiograph [postero-anterior view]
parenchymal calcification on the left side showing sheet-like pleural calcification on the right side
producing fungal balls, scar carcinoma, spontaneous

pneumothorax, and loss of effective volume of the lungs.
SCAR CARCINOMA
Development of lung cancer in association with old scars
[scar carcinoma] is common in conditions, such as
progressive systemic sclerosis with lung involvement.
The relationship between the scars of pulmonary TB and
lung cancer has been a matter of debate for a long time.
In the series reported by Auerbach et al (53), scar cancer
was observed in 82 of the 1186 autopsied cases [1%]; 23.2
per cent of these had originated from TB scars. A similar
association between scars of TB and lung cancer has been
documented in several other reports (54,55). However,
other reports indicate that the association between TB
and lung cancer was merely coincidental (56,57).
Impaired lung ventilation and concomitant increase Figure 35.11: Chest radiograph [postero-anterior view] of a patient
in pulmonary carbon dioxide levels, which in turn causes with old, healed pulmonary tuberculosis showing extensive
pronounced hyperplasia of pulmonary neuroendocrine parenchymal destruction, bronchiectatic changes and pleural
thickening on the left side. On the right side, compensatory
cells have been postulated as the possible mechanisms emphysema and pseudobulla formation can be seen
underlying the genesis of lung cancer in patients with
chronic lung diseases. A receptor with sensitivity for
oxygen and carbon dioxide which produce a number of
autocrine growth factors is considered to be crucial in
the malignant transformation (58-60). These issues merit
further study.
PULMONARY FUNCTION CHANGES

Thirty to sixty per cent of cases with pulmonary TB suffer
from diffuse airways obstruction (61,62), which is distinct
from chronic bronchitis. Further, because of diffuse
parenchymal fibrosis, pleural effusion and thickening,
and fibrothorax, a restrictive type of pulmonary function
defect is also possible. Thus, in a patient with pulmonary
TB an obstructive, restrictive, or a mixed type of lung
function abnormality is possible depending upon the
type and extent of involvement or residual damage (63).
CHRONIC RESPIRATORY FAILURE Figure 33.12: Chest radiograph [postero-anterior view] of a patient
with pulmonary tuberculosis showing extensive parenchymal
Chronic respiratory failure may complicate pulmonary destruction, bronchiectatic changes and pleural thickening on the
TB, especially if the disease had been extensive and the left side. On the right side, compensatory emphysema can be seen
patient survived because of adequate treatment.
Respiratory failure develops due to extensive destruction Associated pleural thickening and fibrothorax result in
of pulmonary parenchyma [Figures 35.11 and 35.12] and thoracic wall malfunction and further add to the
• •
the resultant ventilation-perfusion [V/Q ]mismatch. mechanical disadvantage of the lung, thus contributing
528 Tuberculosis
to the pump failure (64-66). Atrophy or disuse of the non-perfused at rest, but can be recruited when needed
respiratory muscles can also contribute to chronic to expand the pulmonary vascular bed causing a decrease
respiratory failure. Tachypnoea, hypoxia and hyper- in pulmonary vascular resistance. There is no humoral
capnia develop ultimately and the patient may die from counterpart of the renin-angiotensin system that is
these abnormalities. capable of evoking sustained pulmonary artery hyper-
tension.
PULMONARY ARTERY HYPERTENSION AND Normal mean pulmonary artery pressure is 13 to 14
CHRONIC COR-PULMONALE mm Hg in a young adult and is less than 18 mm Hg in
80 per cent of subjects of all ages. Pulmonary artery
Cor-pulmonale is defined as enlargement [dilatation pressure of greater than 20 mm Hg signifies pulmonary
and/or hypertrophy] of the right ventricle due to increa-
artery hypertension. Blood flow through the pulmonary
sed right ventricular afterload from intrinsic pulmonary
capillaries is achieved by a pressure drop of only 5 to
diseases including those of pulmonary circulation,
9 mm Hg [pulmonary artery to left atrial pressure]
inadequate function of the chest bellows or inadequate
compared to 90 mm Hg for the systemic circuit. Accor-
ventilatory drive from the respiratory centres; when right
dingly, the normal pulmonary vascular resistance is 10
heart abnormalities secondary to left heart failure or
to 20 times less than systemic vascular resistance.
congenital heart disease are excluded. Right heart failure
It is generally agreed that the decrease in extent of
need not be present, although this is a clinical manifes-
the pulmonary vascular bed is insufficient to play a
tation of the overloaded right ventricle that precedes the
predominant role in the pathogenesis of pulmonary
clinically unrecognizable cor-pulmonale. Except in rare
hypertension unless the reduction is extreme. The effec-
instances when the disease is complicated by massive
tive cross-sectional area of the pulmonary vascular bed
pulmonary thromboembolism, cor-pulmonale is usually
must be reduced by more than 50 per cent before any
chronic.
change in pulmonary artery pressure can be detected at
The possible causes of chronic cor-pulmonale in
rest, although exercise will increase the pressure at lower
pulmonary TB include abnormalities of the pulmonary
levels of increased blood flow. Experiments in dogs have
parenchyma or thoracic wall. The underlying basic
shown that more than two-thirds of the lungs had to be
pathophysiology of chronic cor-pulmonale is an increase
ablated before pulmonary artery pressures approach
in the pulmonary artery vascular resistance and
hypertensive levels (67,68). Obliterative vascular diseases
pulmonary hypertension. Mechanisms causing these
increase pulmonary vascular resistance by vascular
changes include occlusion or destruction of vascular bed
occlusion, while diffuse interstitial and parenchymal
due to lung parenchymal destruction, vasculitis, and
diseases act primarily by compressing and obliterating
endarteritis with diminished cross-sectional area of the
small vessels.
pulmonary circulation (67,68). Other less important
The diagnosis of chronic cor-pulmonale is often not
causes include hypoxia, acidosis with hypercapnia, and
made until significant right ventricular hypertrophy or
increased blood viscosity due to polycythaemia. The
latter may not be important in developing nations overt right ventricular failure is present. Heart failure
because of a high prevalence of malnutrition and occurs insidiously, causing further impairment of lung
anaemia. These causes also happen to be important in function and is frequently misinterpreted as worsening
the causation of chronic cor-pulmonale in patients with of the underlying lung disease. Episodes of leg oedema,
chronic obstructive pulmonary disease. atypical chest pain, exertional dyspnoea, exercise-
Normally, pulmonary circulation is a highly dis- induced cyanosis in the periphery, prior respiratory
tensible, low pressure and low-resistance circulation that failure, and excessive daytime sleepiness are non-specific
transmits the entire cardiac output without much change but important historical clues suggesting the possibility
in pressure because the pulmonary arteries are thin- of cor-pulmonale.
walled with little resting muscular tone. In adults, there General physical examination reveals distended neck
is a negligible response in terms of capacity, distensibility, veins, peripheral oedema, and cyanosis. Oedema in
or resistance to flow following autonomic nervous system chronic cor-pulmonale may not be necessarily due to
stimulation. Many small arterioles and capillaries are overt heart failure. Signs and symptoms suggestive of
heart failure like dyspnoea, orthopnoea, oedema, hepato- waves in the right precordial leads in combination with
megaly, and raised jugular venous pressure [JVP] can “suggestive” criteria, are more definite indices. Non-
also occur due to chronic obstructive airways disease invasive investigations such as Doppler and 2-D trans-
without right heart failure. However, the raised JVP thoracic echocardiography may be used periodically to
is present in both phases of respiration in right heart monitor pulmonary artery pressure and right ventricular
failure. function.
The apical impulse and the right ventricular lift are
often not palpable. The second heart sound may be AMYLOIDOSIS
palpable in the pulmonary area. The earliest sign of
pulmonary hypertension is an accentuated pulmonic Secondary amyloidosis is known to occur in a wide
component of the second heart sound. A right ventricular variety of clinical situations and is characterized by the
S3 gallop is heard in the epigastrium along the sternum. deposition of an extracellular eosinophilic substance in
With advanced pulmonary artery hypertension, charac- various organs. Although the name suggests carbohy-
teristic diastolic murmur of pulmonary regurgitation and drate deposition, in fact, the substance is predominantly,
pansystolic murmur of tricuspid regurgitation which if not exclusively, protein in origin (72). Several cytokines
accentuates during inspiration can be heard along with including interleukin-1 [IL-1], interleukin-6 [IL-6] and
a systolic ejection sound. Right ventricular failure is tumour necrosis factor-α [TNF]-α stimulate hepatic
usually precipitated by some acute episode like pneumo- synthesis of serum amyloid A precursor during TB
nia. Associated clinical features of the underlying basic inflammation. The incidence of renal amyloidosis in TB
disease will be present. has been reported to range from eight to thirty-three per
Cor-pulmonale due to restricted vascular bed is cent (73-77). Differences in the method used to detect
manifested by a strikingly high pulmonary arterial pres- amyloidosis could also have contributed to this wide
sure associated with a low cardiac output. Hypoxaemia variation. The incidence of amyloidosis was 1.01 per cent
is often mild. Tachypnoea which persists even during of 6431 postmortems and 8.4 per cent of 1980 renal biop-
sleep is the rule, particularly with multiple pulmonary sies at the Postgraduate Institute of Medical Education
emboli. Chest pain is common. Enlargement of right and Research, Chandigarh (76). While 87.1 per cent had
ventricle in its pure form is manifested in these disorders. secondary amyloidosis, 3.5 per cent had primary
Prominent “a” and “v” waves appear in the jugular veins. amyloidosis and the remaining had multiple myeloma.
The classic radiographic evidence of right ventricular Tuberculosis of various organs was the most common
enlargement [crossing the right vertebral border] will be predisposing cause accounting for 59.1 per cent of
present. This is manifested by enlargement of the outflow secondary amyloidosis, followed by chronic suppurative
tract of the right ventricle, the main pulmonary arteries, lung diseases (76). Pulmonary TB was the leading cause
and their central branches, in association with attenuated in 81.6 per cent of cases followed by glandular and
peripheral branches of the pulmonary arterial tree. abdominal TB. The interval between the onset of the
Enlargement of the pulmonary artery is considered to predisposing disease and the first evidence of secondary
exist when the diameter of the right descending pulmo- renal amyloidosis varied from one to thirty years with a
nary artery is greater than 16 mm and the left descending mean of 6.9 years in this study. The interval was greater
pulmonary artery is greater than 18 mm, although the than five years in 67 per cent of patients. However, other
true sensitivity and specificity of these measurements are reports suggest that this interval varies widely and may
not known. be as short as six months or as long as 43 years (77).
The “suggestive” indices of pulmonary hypertension Secondary amyloidosis is now rare as a complication of
[right ventricular enlargement] in the electrocardiogram pulmonary TB because of the availability of effective
include: p pulmonale in leads II, III, aVF, S1Q3, or S1-S2- antituberculosis treatment. Nonetheless, TB is still the
S3 patterns, right axis deviation, R:S ratio in V6 of 1.0, commonest cause of secondary amyloidosis in Indian
rSR pattern in the right precordial leads, and partial or patients (76). Abdominal fat pad, rectal, mucosal, liver,
complete right bundle branch block (69-71). Dominant or kidney biopsy specimens are useful in confirming the
R or R’ in lead V1 or V3R in association with inverted T diagnosis of secondary amyloidosis.
530 Tuberculosis
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532 Tuberculosis
Tuberculosis and
Acute Lung Injury
36
DR Karnad, KK Guntupalli
INTRODUCTION of arterial oxygen tension [PaO2] to fraction of oxygen in

inspired air [FIO2] is normally close to 450. A value of
Acute lung injury [ALI] is a disorder characterized by
200 or less, in the presence of the above-mentioned three
inflammatory damage to the alveolar capillary memb-
criteria, is diagnostic of ARDS and a value between 201
rane producing severe derangement of gas exchange,
and 300 is diagnostic of ALI. Thus, ALI represents a
which could result from a variety of insults, ultimately
milder form of the pulmonary abnormalities that
resulting in severe hypoxaemia, non-cardiogenic
characterize ARDS (1,6).
pulmonary oedema, and the acute respiratory distress
syndrome [ARDS] (1). In general, abnormalities of gas PATHOGENESIS
exchange are uncommon in pulmonary tuberculosis [TB]
Acute lung injury and ARDS occur in approximately 40
because concomitant involvement of ventilation and
per cent of patients with sepsis and the systemic
perfusion results in maintenance of the normal
inflammatory response syndrome (6). Initially, there is
ventilation-perfusion relationship (2). However, severe
an inflammatory damage to the pulmonary endothelial
hypoxic respiratory failure due to ALI can sometimes
cell barrier, resulting in increased pulmonary capillary
complicate severe forms of pulmonary including miliary
permeability. This produces leakage of protein-rich
TB (3-5). This complication is associated with a very high
pulmonary oedema at normal pulmonary artery wedge
mortality despite treatment. Hence, early recognition and
pressure. A series of inflammatory events then damages
appropriate management of this uncommon compli-
the alveolar epithelial cells [Figures 36.1 and 36.2].
cation is of utmost importance.
Damage to the Type I cells further worsens alveolar
flooding and gas-exchange. Type II cuboidal cells, which
DEFINITION
produce surfactant, too are damaged in later stages of
The term ALI has been loosely used until the 1994 the disease resulting in collapse of the more severely
American-European Consensus Conference laid down affected alveoli during end-expiration. Pro-inflammatory
a specific definition for this condition in order to ensure cytokines interleukin-1 [IL-1], interleukin-6 [IL-6], inter-
uniformity in research, diagnosis and management (1,6). leukin-8 [IL-8], and tumour necrosis factor-α [TNF-α]
It is essentially used to identify an earlier stage of the attract and activate inflammatory cells like neutrophils,
ARDS. Both ALI and ARDS require the following com- macrophages. These cells release other inflammatory
mon diagnostic features (6): [i] acute onset; [ii] bilateral substances like elastases, other proteases, oxygen free
infiltrates on chest radiograph; and [iii] pulmonary artery radicals, leukotrienes and platelet activating factor.
wedge pressure of less than or equal to 18 mm Hg or Endogenous anti-inflammatory substances like soluble
absence of clinical evidence of left atrial hypertension. IL-1 receptor antagonist [sIL-1RA], soluble tumour
The fourth criterion, which defines the oxygenation necrosis factor receptor [sTNF-R] and anti-inflammatory
defect, is used to differentiate ALI from ARDS. The ratio cytokines, interleukin-10 [IL-10] and interleukin-11
Tuberculosis and Acute Lung Injury 533
Figure 36.1: The normal alveolus [left-hand side] and the injured alveolus in the acute phase of acute lung injury and the acute respiratory
distress syndrome [right-hand side]. In the acute phase of the syndrome [right-hand side], there is sloughing of both the bronchial and
alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are
shown adhering to the injured capillary endothelium and marginating through the interstitium into the air space, which is filled with
protein-rich oedema fluid. In the air space, an alveloar macrophage is secreting cytokines, interleukin-1, 6, 8, and 10, [IL-1, 6, 8, and 10]
and tumour necrosis factor-α [TNF-α], which act locally to stimulate chemotaxis and activate neutrophils. Macrophages also secrete
other cytokines, including interleukin-1, 6, and 10. Interleukin-1 can also stimulate the production of extracellular matrix by fibroblasts.
Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor [PAF].
A number of anti-inflammatory mediators are also present in the alveolar milieu, including interleukin-1-receptor antagonist, soluble
tumour necrosis factor receptor, autoantibodies against interleukin-8, and cytokines such as interleukin-10 and 11 [not shown]. The influx
of protein rich oedema fluid into the alveolus has led to the inactivation of surfactant. MIF denotes macrophage inhibitory factor
Reproduced with permission from “Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49
(reference 6)” Copyright [2000] Massachusetts Medical Society. All rights reserved
[IL-11] too are present in the alveoli, but their role in the pulmonary circulation (9,10). This classical situation is
pathogenesis of ALI is not clear (6). present in severe miliary TB where widespread distri-
The inflammatory process is not limited to the lung bution of the bacterial load may result in diffuse lung
(7,8). Activation of coagulation is common and frank injury and ARDS (11). Mycobacterial cell wall compo-
disseminated intravascular coagulation may develop in nent lipoarabinomannan [LAM] and mycobacterial
some patients. Inflammatory mediators arising from the cytosolic heat-shock protein-65kD [HSP-65] have been
lung may also play a role in the development of the multi- shown to induce release of inflammatory cytokines (12).
ple organ dysfunction syndrome in these patients (7). Lipoarabinomannan binds to CD14 receptors on human
In patients with TB, ALI is believed to result from mononuclear macrophages and induces the production
the release of mycobacteria or their products into the and release of cytokines including interleukin-1β [IL-
534 Tuberculosis
Figure 36.2: Mechanisms important in the resolution of acute lung injury and the acute respiratory distress syndrome. On the left side of
the alveolus, the alveolar epithelium is being repopulated by the proliferation and differentiation of alveolar type II cells. Resorption of
alveolar oedema fluid is shown at the base of the alveolus, with sodium and chloride being transported through the apical membrane of
type II cells. Sodium is taken up by the epithelial sodium channel [ENaC] and through the basolateral membrane of type II cells by the
sodium pump [Na+/K+–ATPase]. The relevant pathways for chloride transport are unclear. Water is shown moving through water channels,
the aquaporins, located primarily on type I cells. Some water may also cross by a paracellular route. Soluble protein is probably cleared
primarily by paracellular diffusion and secondarily by endocytosis by alveolar epithelial cells. Macrophages remove insoluble protein and
apoptotic neutrophils by phagocytosis. On the right side of the alveolus, the gradual remodelling and resolution of intra-alveolar and
interstitial granulation tissue and fibrosis are shown
Reproduced with permission from “Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49”
1β], TNF-α, interleukin-1α [IL-1α], IL-6, IL-8, IL-10, and probably similar to those seen in gram-negative
granulocyte macrophage colony-stimulating factor bacterial sepsis (9,10,12).
[GM-CSF]. Heat-shock protein-65kD too induces the Some authors have also suggested that ALI may be
release of cytokines, but to a lesser extent than LAM, partly due to a cell-mediated immune response to myco-
and by a mechanism that does not involve the CD14 bacterial antigens (13). This could result either from an
receptor (12). Mycobacteria also induce expression of enhancement of the delayed hypersensitivity response
the intercellular adhesion molecule-1 [ICAM-1] on or from a decrease in suppressor mechanisms (13,14).
endothelial cells, which facilitates adhesion of activated This may probably play an important role in ALI that
neutrophils to capillary walls (12). Another compound, develops in some patients after institution of antituber-
muramyl dipeptide, stimulates chemotaxis, and culosis treatment and in patients with human immuno-
enhances phagocytosis and release of inflammatory deficiency virus [HIV] infection receiving antiretroviral
mediators (13). The subsequent series of events are drugs (11-15).
INCIDENCE or disseminated TB, n = 7; and TB pneumonia, n = 6]

were identified with TB as a primary cause requiring
Even though ALI and ARDS are well recognized compli-
mechanical ventilation. Eight of these patients developed
cations in patients with pulmonary and miliary TB,
ARDS. In contrast, ARDS occurred in only five per cent
sparse epidemiological data are available on this entity.
of 100 Indian patients with miliary TB studied by Sharma
Varying denominators have been used in the published
et al (3), and in seven per cent of 109 South African
studies because of which meaningful comparison of these
patients studied by Maartens et al (20). It can occur in
data is not possible. In a study from Korea, Choi et al (16)
patients at all ages and the youngest patient reported is
found that 1.7 per cent of 1010 patients with pulmonary
a seven-month-old child (24).
TB had acute respiratory failure. The incidence is as high
Fever, non-productive cough, chest discomfort and
as 20 per cent in patients with miliary TB and 0.8 per
dyspnoea are the common symptoms and the average
cent in TB pneumonia (1). The incidence increases with
interval between onset of symptoms and diagnosis is 14
any delay in diagnosis and institution of appropriate
therapy for miliary TB (17). In a study from Mumbai, days (20,21). In more than 50 per cent of patients, the
ALI due to TB accounted for 1.7 per cent of admissions diagnosis of TB is not known at the time of admission
to the medical intensive care unit [ICU] (18). In a report with respiratory failure (11). In these patients, radiologi-
from Chandigarh (19), nine of the 187 patients [4.8%] cal features of ARDS usually mask the typical miliary
admitted to a respiratory ICU had TB-ARDS. In a large mottling (9). The interval between admission and
study from India, Sharma et al (5) reported that of 2733 diagnosis in a large series was one to twenty days (11).
TB patients treated during 1980-2003, 29 [1.06%; 1.21 In up to 10 per cent of patients with ALI, the miliary TB
patients per year] developed ARDS. may be cryptic with systemic dissemination and a normal
chest radiograph (17,21,25). A large proportion of these
PREDISPOSING FACTORS patients may harbour HIV infection (17). Other clinical
findings include hepatosplenomegaly, mild hepatic
Acute lung injury invariably occurs in patients with dysfunction and pancytopenia (21). In a patient with
severe TB such as miliary TB, or TB bronchopneumonia unexplained ARDS, a history of fever of more than 15
(9,10). A number of predisposing factors have been days duration and elevation of serum alkaline phos-
described. Malnutrition is the commonest predisposing phatase should arouse the suspicion of disseminated TB
factor seen in patients with pulmonary TB developing as the underlying cause (21).
acute respiratory failure (11,20,21). Other factors include In less than half the number of cases, ALI develops
alcoholism, diabetes mellitus, immunosuppressive
in diagnosed patients with miliary TB after antituber-
therapy with corticosteroids or other drugs, HIV infec-
culosis treatment is initiated (11). In patients with miliary
tion, drug addiction, chronic liver disease and pregnancy
TB, auscultation of the chest is generally normal.
(2,11,13,21,22). In the study reported by Sharma et al (5),
Tachypnoea and presence of diffuse rales while on drug
presence of miliary TB, duration of illness beyond 30 days
therapy are ominous signs of early ALI.
at presentation, absolute lymphocyte count less than
Mortality in patients with ARDS due to miliary TB is
1625/mm3 and serum alanine aminotransferase [ALT]
between 40 to 80 per cent, despite use of mechanical
greater than 100 IU/l were independent predictors of
ventilation and corticosteroids (9,11,23,26). At autopsy,
ARDS development.
alveoli may show intense perifocal inflammation,
interstitial granulomas and obliterative endarteritis,
CLINICAL SYNDROMES characteristic of miliary TB (27). In addition, changes of
ALI may be present [Figures 36.3 and 36.4], in the form
Acute Lung Injury in Miliary Tuberculosis
of increased vascularity, presence of dense exudates in
Kim et al (23) reported that 8 of the 34 South Korean the alveoli, and hyaline membrane formation (27,28).
patients [24%] with miliary TB seen during the period
1990 to 1999 [0.9 patients per year] developed ARDS. Acute Lung Injury in Tuberculosis Pneumonia
Penner et al (11) reported that, over a 10-year period in Nodular lesions resulting from air-space consolidation
the province of Manitoba, Canada, 13 patients [miliary due to endobronchial spread to lobar or multilobar
536 Tuberculosis
45 days. Seven of the 29 patients in the series reported

by Sharma et al (5) had pulmonary TB. Chest radiographs
show nodular lesions, with mixed consolidation and
ground glass opacities [Figures 36.5 and 36.6] (3,11). High
resolution computed tomography [HRCT] shows
Figure 36.3: Tuberculosis pneumonia presenting as acute respi-

ratory distress syndrome. Epithelioid cells are identified within the
alveoli [Haematoxylin and eosin x 100]
Figure 36.5: Chest radiograph [done bedside, with a portable

machine] showing consolidation with air-bronchogram
Reproduced with permission from “Sharma SK, Mohan A, Pande
JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory
characteristics and outcome in miliary tuberculosis. QJM 1995;
88:29-37 (reference 3)”
Figure 36.4: Acute respiratory distress syndrome in tuberculosis.

There is an inflammatory exudate in the alveolus and fibrin deposi-
tion [arrows] along the alveoli [Haematoxylin and eosin x 400]
locations is termed TB pneumonia (11). The development

of ALI due to TB pneumonia was first reported in 1977
by Agarwal et al (2). They reported 16 patients with acute
respiratory failure, 10 of whom required mechanical
ventilation. Alcholism and chronic liver disease were the
predisposing factors in almost all cases. In a ten-year
review of patients with TB requiring mechanical Figure 36.6: Chest radiograph [postero-anterior view] of the same
ventilation for ARDS, Penner et al (11) found that 50 per patient in Figure 36.5 showing classical miliary shadows evolving
cent of his cases had TB pneumonia. These patients after a few days
Reproduced with permission from “Sharma SK, Mohan A, Pande
formed 0.8 per cent of patients with non-miliary TB that JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory
were seen during the study period. The mean interval characteristics and outcome in miliary tuberculosis. QJM
between the onset of symptoms of TB and treatment was 1995;88:29-37 (reference 3)”
bronchogenic dissemination with ground glass attenua- and a TST [1 TU of PPD] reading of 7 mm. His condition
tion (9). The classical tree-in-bud appearance is seen on deteriorated eight days after starting treatment; ESR
computed tomography [CT] in less than 50 per cent of increased to 100 mm at the end of first hour and there
cases (16). was an increase in all the parameters of immune function.
He required mechanical ventilation for ARDS, and
Acute Lung Injury in Cavitary Pulmonary Tuberculosis methylprednisolone was administered to reduce
In a retrospective analysis of patients with TB and acute pulmonary inflammation. This patient died 13 days after
respiratory failure, Zahar et al (17) found that 11 per cent starting treatment.
of patients had an isolated apical cavity on chest The authors (13) mention that both patients had in
radiograph preceding the onset of ALI. Choi et al (16) vivo and in vitro anergy and depression of lymphocyte
found cavities in HRCT of 45 per cent of patients with function, probably due to poor nutritional status, excess
ALI. Extensive endobronchial spread of TB following alcohol consumption and the severe infection itself. On
rupture of a cavity into the bronchus is thought to initiate treatment, there was a progressive reversal of the
ALI (29). The initial symptoms of TB in these patients immune deficiency and the ALI may have been due to
are fever and cough, which are followed after two weeks an exaggerated delayed hypersensitivity reaction to
to two months by acute onset of dyspnoea and severe mycobacterial antigens released by the dying organisms.
hypoxaemia (29). The chest radiograph shows diffuse Tuberculoprotein and muramyl dipeptide have been
bilateral alveolar infiltrates as in ARDS, but unlike in implicated as possible immunogenic cell-wall compo-
miliary TB complicated by ARDS, these patients tend to nents (13). Cell-mediated damage to the pulmonary
have unilateral preponderance of the infiltrates and alveolar-capillary membrane is believed to cause ARDS
physical signs (29). They may have systemic manifesta- in these patients (13).
tions like disseminated intravascular coagulation [DIC] Akira and Sakatani (14) have reported the radiological
and hypotension. Mycobacteria are easily demonstrable features in five patients who developed ALI due to
in tracheal aspirates in almost all cases. paradoxical worsening after treatment of TB. All five
patients had unilateral cavitary TB restricted to one lobe.
Acute Lung Injury After Initiation of After treatment, chest radiographs revealed progression
Antituberculosis Treatment of the original lesion, and appearance of new lesions in
the other lung and other regions in the same lung. The
In 1986, Onwubalili et al (13) described two alcoholic, HRCT revealed that in addition to the segmental or lobar
malnourished patients with bilateral extensive sputum cavitation in the original locations, extensive areas of
smear-positive pulmonary TB, who developed paradoxi- ground glass opacities were present bilaterally in all the
cal worsening of the disease resulting in ARDS during cases. However, a predominantly dependent distribu-
the second week of antituberculosis treatment. One of tion, which is characteristic of ARDS due to sepsis, was
them had TB bronchopneumonia. Baseline tests of not seen. Transbronchial lung biopsy [TBLB] showed the
immune function revealed a negative tuberculin skin test presence of intra-alveolar and interstitial pulmonary
[TST] with 10 tuberculin units [TU] of purified protein oedema. Two of these five patients died.
derivative [PPD], lymphopenia, failure of peripheral Transient radiological worsening of pulmonary
blood mononuclear cells to respond to stimulation with lesions has been reported in three to fourteen per cent of
PPD and severely depressed natural killer cell activity. patients receiving antituberculosis treatment (30).
This patient experienced severe breathlessness, However, the patients may remain asymptomatic in this
worsening of radiological lesions and hypoxaemia setting. In 0.6 per cent of cases, the process may be severe
11 days after starting antituberculosis treatment. At this enough to cause respiratory failure due to ALI (14).
time, the erythrocyte sedimentation rate [ESR] had Paradoxical worsening is more frequent and also more
increased to 110 mm at the end of first hour, TST [1 TU severe in patients with HIV infection, especially those
of PPD] revealed an induration of 8 mm, and there was also receiving antiretroviral drugs due to the immune
considerable improvement in the tests of immune reconstitution inflammatory syndrome (15,31). However,
function. The second patient had fibrocavitary disease Wendel et al (31) showed that 11 per cent of patients with
538 Tuberculosis
HIV infection receiving antiretroviral drugs along with European Consensus Conference diagnostic criteria
antituberculosis treatment developed clinically relevant mentioned earlier (1). Recently ARDS Network has
paradoxical worsening compared to seven per cent proposed pulse oximetric saturation [SpO2] to FIO2 ratio
receiving antituberculosis treatment alone; the difference [S/F ratio] as a surrogate to diagnose ALI and ARDS
was not statistically significant. when PaO2/FIO2 ratio is not available (35). An S/F ratio
Increase in severity of fever and a rising ESR may of 235 corresponded with a PaO2/FIO2 ratio of 200 while
help identify patients who are likely to develop severe an S/F ratio of 315 corresponded with a PaO2/ FIO2 ratio
paradoxical worsening (13,14). Injectable methylpredni- of 300. The non-invasive measurements can be used to
solone or oral prednisolone in a dose of 1 to 2 mg per kg facilitate an early diagnosis of ARDS even in resource-
body weight, daily for one to two weeks which is limited settings.
gradually tapered is recommended in patients with para- The diagnosis of TB in patients presenting with ARDS
doxical worsening, although there are no randomized is difficult, and needs a high index of suspicion. Early
controlled trials to prove their benefit (15). diagnosis is important as delay in treatment may worsen
the respiratory failure and increase mortality.
Other Manifestations Radiographic changes of ARDS may mask underlying
TB and alveolar infiltrates that are more organized or
As in severe systemic sepsis, dysfunction of other organs appear more nodular than usual should arouse suspicion
is seen in 35 per cent of patients with ALI due to TB even (28). Choi et al (16) systematically reviewed the chest
in the absence of other bacterial infections (17,22,32). radiographic and HRCT findings in 17 patients with ALI
These manifestations are encountered more often in due to TB [Table 36.1]. During resolution, HRCT may
miliary TB than in TB pneumonia (11). Mycobacterial reveal bilateral extensive thin-walled cystic lesions.
infection itself can cause septic shock, with increased Whether these represent parenchymal damage due to
cardiac index, and low systemic vascular resistance (33). TB or ventilator-induced lung injury is not clear. These
Non-mycobacterial sepsis due to secondary infection cysts resolve completely over several months (16).
may supervene in approximately 40 per cent of patients The TST is invariably negative (9,21). Detection of
receiving mechanical ventilation (11). A significant immunoglobulin G [IgG] or immunoglobulin M [IgM]
number of patients also have co-existing DIC (20). antibodies to Mycobacterium tuberculosis antigens in
Mortality in these patients is close to 100 per cent (34). serum by enzyme linked immunosorbent assay is of little
Up to 10 per cent of patients may also have acute renal value in endemic areas since up to 50 of normal healthy
failure (17). Pancytopenia has been frequently reported adults have a positive test (9). The yield of acid-fast bacilli
in ARDS due to miliary TB (20,21). Mechanisms include in the tracheal secretions depends on the type of
bone marrow infiltration by TB granulomas and underlying pulmonary TB lesion. In fibrocavitary
cytokine-induced bone marrow suppression. Pancyto- disease, TB pneumonia and endobronchial spread
penia responds well to antituberculosis treatment, but leading to bronchopneumonia, endotracheal aspirate will
these patients have poor survival rates (21). be positive for Mycobacterium tuberculosis in over 60 to
100 per cent of cases (5,17). In miliary TB, the yield is
DIAGNOSIS much lower at approximately 33 per cent (20). Fiberoptic
bronchoscopy with TBLB or bronchoalveolar lavage may
Acute lung injury is suspected in patients with severe increase the yield to 88 per cent (20). In many cases,
hypoxaemia, bilateral extensive rales on auscultation, especially those with cryptic miliary TB who do not have
presence of bilateral confluent alveolar opacities on chest miliary mottling on chest radiograph, the diagnosis is
radiograph in patients with proven pulmonary TB or invariably established by demonstration of TB
prolonged fever (9,10,32). Arterial blood gas analysis will granulomas in the liver biopsy specimen (21,25).
reveal a widened alveolar-arterial oxygen gradient and
the PaO2/FIO2 ratio would help to differentiate between
MANAGEMENT
ALI and ARDS. Type I respiratory failure with normal
or low arterial carbon dioxide tension [PaCO2] is usually The basic principles of management of ALI in TB are the
seen (7,10,27,32). The diagnosis is made by the American- same as for ALI due to other causes: treatment of basic
Table 36.1: Radiological findings in patients with acute respiratory failure

due to pulmonary tuberculosis
Plain radiograph High resolution computed tomography
Findings % Findings %
Small [ < 10 mm] nodular lesions 96 Nodular lesions 100

Air space consolidation 76 Ground glass opacities 91
Ground glass opacities 70 Air space consolidation 73
Reticular lesions 24 Septal thickening 73
Cavitary lesions 24 Tree-in-bud appearance 45
Cavities 45
Mediastinal lymphadenopathy 27
Pleural effusion 27
Pericardial effusion 27
Spontaneous pneumothorax 9
cause, maintenance of optimum oxygen delivery, vres and prone positioning of the patient may sometimes
provision of adequate nutrition [preferably by the enteral help. The possibility of barotrauma and ventilator-
route] and prevention of complications like nosocomial induced lung injury should be kept in mind while
infections, upper gastrointestinal haemorrhage and deep changing ventilator settings (6). The risk of developing
vein thrombosis (6). pneumothorax due to barotrauma is particularly high in
patients with TB as a cause of ARDS.
Oxygen Therapy
Antituberculosis Drugs
Initial treatment of hypocapnoeic acute respiratory
Antituberculosis treatment should be instituted as early
failure consists of oxygen administration. The aim of
therapy is to maintain arterial PaO2 above 60 mm Hg as possible. Administration of parenteral drugs is not
superior to enteral therapy. Enteral therapy may not be
and arterial oxygen saturation [SaO2] above 90 per cent.
possible in all patients. In these cases, parenteral therapy
Using an oxygen mask can increase FIO2 to 50 to 60 per
cent. Pulse oximetry helps in rapidly adjusting the FIO2 with aminoglycoside and isoniazid should be initiated.
Injectable rifampicin may be added where available.
to provide adequate oxygenation. If the desired SaO2
cannot be achieved, oxygen administered by a non-
Corticosteroids
rebreathing mask with a reservoir bag may help. If these
measures fail, or respiratory distress is severe, or patient Corticosteroids have been used in TB causing ALI in
appears fatigued, tracheal intubation and mechanical various dosages (9,13,15,20,26,36). In addition to their
ventilation may be needed (3,6,10,32). immunosuppressive effects, corticosteroids also inhibit
synthesis of several mediators of inflammation including
Mechanical Ventilation cytokines like IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α and
The initial ventilatory strategy in patients with ALI or GM-CSF (36). They also prevent induction of the
ARDS is to deliver tidal volume of 6 ml/kg of ideal body inducible forms of nitric oxide synthase and cyclo-
weight, using 100 per cent FIO2 with positive end-expira- oxygenase-2 (36). In a recent update on the use of
tory pressure (6). After PaO2/FIO2 ratio reaches the corticosteroids in pulmonary disease, Jantiz and Sahn
desired levels, the FIO2 can be reduced gradually to less (36) have reviewed the evidence for the use of cortico-
than 60 per cent, provided SaO2 remains above 90 per steroids in pulmonary TB. There is only one controlled
cent. Most patients will require sedation and neuro- trial (36) in which 28 patients with miliary TB were
muscular blockade to prevent discomfort (6). In patients treated with isoniazid, streptomycin, and para-
with refractory hypoxaemia, lung recruitment manoeu- aminosalicylic acid alone, and 27 patients also received
540 Tuberculosis
prednisone in addition to these drugs. The dose of 5. Sharma SK, Mohan A, Banga A, Saha PK, Guntupalli KK.
prednisone was 10 mg four times a day for one week, Predictors of development and outcome in patients with acute
respiratory distress syndrome due to tuberculosis. Int J
followed by 20 mg daily for six weeks (36). It was then
gradually tapered and the total course lasted for three to 6. Ware LB, Matthay MA. The acute respiratory distress
five months. Mortality was seven per cent in the syndrome. N Engl J Med 2000;342:1334-49.
corticosteroid group compared with 18 per cent in the 7. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM,
control group (36). Most workers recommend that Brienza A, et al. Effect of mechanical ventilation on
inflammatory mediators in patients with acute respiratory
corticosteroids be given to all patients with ALI due to distress syndrome: a randomized controlled trial. JAMA
TB along with antituberculosis drugs, especially since 1999;282:54-61.
up to 10 per cent of these patients also have adrenal TB 8. Ranieri VM, Giunta F, Suter PM, Slutsky AS. Mechanical
leading to adrenal insufficiency (15,20,37). The increased ventilation as a mediator of multisystem organ failure in acute
risk of upper gastrointestinal bleeding and secondary respiratory distress syndrome. JAMA 2000;284:43-4.
9. Jindal SK, Aggarwal AN, Gupta D. Adult respiratory distress
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corticosteroid therapy (37). 10. Chandana I. Tuberculosis and acute lung injury. In: Sharma
SK, Mohan A, editors. Tuberculosis. First edition. New Delhi:
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PROGNOSIS
11. Penner C, Roberts D, Kunimoto D, Manfreda J, Long R.
Tuberculosis as a primary cause of respiratory failure requir-
Overall mortality in ALI due to TB is between 40 to 80
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per cent. Non-survivors of ARDS, regardless of the cause, 12. Zhang Y, Doerfler M, Lee TC, Guillemin B, Rom WN.
die of respiratory failure in less than 20 per cent of cases Mechanisms of stimulation of interleukin-1 beta and tumour
(38). Most deaths are primarily related to the underlying necrosis factor alpha by Mycobacterium tuberculosis
disease, the severity of the acute illness, and the degree components. J Clin Invest 1993;91:2076-83.
13. Onwubalili JK, Scott GM, Smith H. Acute respiratory distress
of dysfunction of other organs (38). In the study reported
related to chemotherapy of advanced pulmonary
by Sharma et al (5), acute physiology and chronic health tuberculosis: a study of two cases and a review of literature.
evaluation II [APACHE II] score greater than 18; QJM 1986;230:599-610.
APACHE II score less than 18 in the presence of hypo- 14. Akira M, Sakatani M. Clinical and high-resolution computed
natraemia and PaO2/FIO2 ratio less than 108.5 were tomographic findings in five patients with pulmonary
tuberculosis who developed respiratory failure following
predictors of death in patients with TB-ARDS. Zahar
chemotherapy. Clin Radiol 2001;56:550-5.
et al (17) have shown that patients receiving treatment 15. American Thoracic Society, Centers for Disease Control and
more than one month after onset of symptoms have a Prevention, Infectious Diseases Society of America. Treatment
3.5 times higher risk of death than those in whom of tuberculosis. Am J Respir Crit Care Med 2003;167:606-62.
treatment is started early. 16. Choi D, Lee KS, Suh GY, Kim TS, Kwon OJ, Rhee CH, et al.
Pulmonary tuberculosis presenting as acute respiratory
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542 Tuberculosis
Haematological Manifestations
of Tuberculosis
37
Shaji Kumar
INTRODUCTION be significantly different compared to a matched group

of children without TB. In general, the reported haemato-
The interactions between the mycobacteria and the
logical changes in TB appear to be more frequent and
haematopoietic system have been a major focus of
profound among patients with disseminated TB
interest for haematologists and mycobacteriologists alike
compared to localized disease.
for several decades. Patients with mycobacterial infec-
tions can present with myriad different, often puzzling,
ANAEMIA
haematological abnormalities (1,2) [Table 37.1] and
different mycobacterial infections often afflict patients Anaemia is the most common haematological manifesta-
with haematological disorders. Though haematological tion of TB, and is seen in 16 to 94 per cent of patients
abnormalities associated with tuberculosis [TB] have with pulmonary or extra-pulmonary TB. The prevalence
been well recognised, few studies have carefully of anaemia is likely to be higher in the developing
evaluated their prevalence and relationship with disease nations, given the high rates of nutritional deficiencies
severity. Haematological changes have been observed as well as other causes of iron deficiency anaemia, such
with focal as well as disseminated TB and are usually as worm infestations. Morris et al (4) observed anaemia
reversible with antituberculosis treatment. Haematologi- in 60 per cent of patients with pulmonary TB, males being
cal manifestations of TB can be due to direct effect of the more frequently affected than females. In this study (4)
infectious process itself or may be a consequence of anti- there was a correlation between the degree of anaemia
tuberculosis treatment. While haematological changes and the presence of acid-fast bacilli [AFB] in the sputum
are also commonly seen in children with TB, a study (3) and failure to correct anaemia was associated with
from a developing nation suggested that they may not persistence of AFB in the sputum. The anaemia observed
with TB is multifactorial in aetiology [Table 37.2] and
Table 37.1: Haematological changes in tuberculosis tends to be mostly normocytic, normochromic and less
often microcytic anaemia. The peripheral blood picture
Anaemia
and the haematological indices usually indicate an
Leucocyte changes
Leucopenia or leucocytosis
anaemia of chronic disease. The inflammatory response
Lymphocytopenia seen in TB leads to increased secretion of cytokines such
Neutropenia or neutrophilia as tumour necrosis factor-α [TNF-α] from the monocytes,
Monocytopenia or monocytosis which result in a blunted response to erythropoietin and
Thrombocytopenia or thrombocytosis decreased ability to utilize the marrow iron stores. Morris
Pancytopenia et al (4) found that 81 per cent of patients with pulmonary
Deep vein thrombosis TB had increased iron stores, suggesting decreased
Disseminated intravascular coagulation release of marrow iron stores and suppression of
Haematological Manifestations of Tuberculosis 543
Table 37.2: Aetiological factors for anaemia in tuberculosis member 1 gene [SLC11A1], previously known as natural
resistance-associated macrophage protein 1 [NRAMP1],
Anaemia of chronic disease
including INT4, D543N and 3’UTR was examined for a
Iron deficiency
possible association with susceptibility to TB. The authors
Nutritional deficiency
(10) studied 378 patients with active pulmonary TB and
Secondary to chronic blood loss
436 healthy control subjects from the same neighbour-
Folate deficiency
hood with the same socio-economic status. Anaemia was
Vitamin B12 deficiency
present in 63.2 per cent of the patients with active
Myelophthisic anaemia
pulmonary TB compared with 6.8 per cent of the control
Haemolytic anaemia
subjects. Anaemia was more pronounced in female
Hypoplastic or aplastic anaemia
patients and those with extensive disease as assessed by
Pure red cell aplasia
the chest radiograph. Patients with active pulmonary TB
Sideroblastic anaemia
and anaemia had lower plasma iron levels, iron binding
Drug-induced anaemia [includes marrow aplasia and
haemolysis]
capacity and higher ferritin levels. Even without iron
Primary haematological disorder with tuberculosis disease
supplementation, antituberculosis treatment resulted in
normalization of the plasma iron, iron binding capacity
and ferritin levels. However, NRAMP1 gene polymor-
erythropoiesis by inflammatory response mediators.
phisms were not associated with TB susceptibility, TB
However, the bone marrow iron was found to be
decreased in another study (5). Similarly, serum iron and severity or anaemia. The authors (10) concluded that
total iron binding capacity have been observed to be anaemia in patients with active pulmonary TB was
decreased in patients with pulmonary TB and anaemia probably due to inflammation and not to iron deficiency.
compared to those without anaemia. In addition, Macrocytic anaemia is less frequently associated with
erythropoietin level itself has been noted to be low in TB and is usually unrelated to folate or vitamin B12 defi-
patients with TB (6). Ebrahim et al (6) using an in vitro ciency (4,11). In a study of 138 patients with megaloblastic
system of hepatocellular carcinoma cell lines demonstra- haematopoiesis, who were also life-long vegetarians, 17
ted suppression of erythropoietin secretion by monocyte patients were found to have TB (11). However, Morris et al
supernatants from patients with pulmonary TB. The (4) found that the serum vitamin B12 levels were elevated
levels of TNF-α were higher in these sera and addition in over half of the patients with pulmonary TB, while serum
of neutralizing antibodies to TNF-α reversed some of and red cell folate levels were normal in most of them. The
these effects. Serum ferritin levels have been found to be vitamin B12 levels were higher in patients with leucocytosis
an unreliable marker for iron deficiency in patients with possibly because of the elevated levels of R-binders which
TB (4,7). The inflammatory process in TB results in lead to increased concentration of vitamin B12. In a study
increased ferritin synthesis and high levels of ferritin in (12) of Nigerian patients with TB, the cobalamin status did
spite of decrease in iron stores. Ferritin acts as an acute not appear to influence the severity of anaemia seen in
phase reactant and the levels correlate with C-reactive pulmonary or disseminated TB. Administration of vitamin
protein concentration. In patients with TB, raising the B12 does not correct the anaemia in these patients. Low
cut-off values of serum ferritin to 30 μg/l or less, correctly serum folate levels have been observed in a study (5), while
diagnosed 88 per cent patients with iron deficiency no relationship between folate levels and megaloblastic
compared with a figure of 61 per cent when a cut-off haematopoiesis was found in another study (4). Auto-
value of 10 μg/l or less was used (8). A higher red blood immune haemolytic anaemia has been reported in
cell volume distribution width [RDW] similar to that association with both pulmonary and disseminated TB
observed in iron deficiency anaemia has been reported and may disappear with treatment (13-15). Pure red cell
in untreated anaemic patients with TB. The RDW values aplasia [PRCA] has been seen in association with TB in
tended to become normal with antituberculosis treat- children (16,17). Sideroblastic changes have been reported
ment (9). in the marrow of patients with localized or disseminated
In a study (10) from Indonesia, the distribution of TB and the anaemia has been reported to respond to
three polymorphisms in the solute carrier family 11 pyridoxine administration (18).
544 Tuberculosis
There are only limited studies on the haematological in disseminated and miliary TB (38,39). Lymphopenia
changes in patients with disseminated and miliary TB appear to be more common than lymphocytosis in
(19-24). In a study (21) comparing patients with dissemi- patients with pulmonary TB (31,39,40). The decreased
nated and miliary TB and those with pulmonary TB, count usually returns to the normal level following
normocytic, normochromic anaemia was the most effective therapy (41). While the reasons behind the
common abnormality observed in both the groups. lymphopenia in TB are not entirely clear, it may reflect
Moderate degree of anaemia has been observed in 52 to continued recruitment of CD4+ T-lymphocytes to the
72 per cent of the patients in most series (22,23,25). The sites of granuloma formation (41). In a study (42) of
anaemia is predominantly normocytic and normochro- lymphocyte populations in peripheral blood, pleural
mic (26). Autoimmune haemolytic anaemia [AIHA] and fluid, and ascites during TB infection, recent infection
PRCA have been reported in association with dissemi- was associated with peripheral blood lymphocytosis
nated TB (27-29). Anaemia can be a prominent finding involving both CD4+ and CD8+ cells compared to no
in patients with gastrointestinal TB, where blood loss can changes in previously diagnosed patients. No changes
complicate the anaemia of chronic disease (30). were found in the numbers of B-lymphocytes or natural
killer cells in either recently infected or previously
LEUCOCYTE CHANGES diagnosed patients. The pleural effusion and ascitic fluid
samples contained T-lymphocytes, the majority of which
Mild leucocytosis and a left shift with increased
were CD4+ cells. These lymphocytes also showed an
myelocytes and metamyelocytes, in the peripheral blood
inverted CD45RA-to-CD45RO ratio, and had high-level
is the most common finding in most of the studies and
expression of the interleukin-2 receptor [CD25] in some
has been seen in six to twenty-two per cent of patients
patients.
(31). Patients with pulmonary TB more frequently have
Both monocytosis and monocytopenia have been
leucocytosis whereas leucopenia is rare. Tuberculosis can
documented in patients with TB (4). Monocytopenia has
result in increased myelopoiesis and the bone marrow
been reported in as many as 50 per cent of the patients
and peripheral blood may show a leukaemoid reaction
and may correlate with the disease severity (43). Baso-
(32-34). Patients with advanced TB often have higher
philia has been reported in patients with disseminated
counts than those with minimal disease. Mild leucopenia
TB (32). Hypereosinophilic syndrome with organ
with counts less than 4 x 109/l has been documented in
damage (44) as well as isolated eosinophilia (45,46) have
1.5 to 4 per cent of patients (4). Prevalence of leucopenia
also been reported in association with TB.
in most studies is either equal to or higher than
leucocytosis (31). Leucopenia and neutropenia were
PLATELET ABNORMALITIES
significantly higher in patients with disseminated TB.
Neutrophilia has been observed in 20 to 60 per cent of Patients with pulmonary or disseminated TB usually
patients while leucopenia has been documented in 10 to have mild thrombocytosis, probably due to increased
30 per cent patients with miliary TB (19,20,35). Neutro- thrombopoiesis reflecting an acute phase reaction (31,47).
penia has been observed in patients with disseminated The increased thrombopoiesis may be in part be driven
TB (31). The mechanisms of neutropenia may include by inflammatory cytokines, such as interleukin-6 [IL-6].
hypersplenism, increased neutrophil demand, or The IL-6 is known to increase the megakaryocytes in vitro
excessive margination of neutrophils. Cell-mediated (48). In a study comparing patients with pulmonary TB
autoimmune mechanisms may be responsible for with healthy volunteers, the median IL-6 concentrations
neutropenia in some of the patients (36). Presence of were higher among those patients with thrombocytosis
Pelger-Huet anomaly [two symmetric, usually rounded compared to those with normal platelet counts (49). The
nuclear lobes joined by a thin-strand formed by hyper- IL-6 concentrations were significantly correlated with
condensation of nuclear chromatin that creates a AFB positivity. Hence, it appears that IL-6 might play a
spectacle-like appearance] has been described in TB (37). contributory part in reactive thrombocytosis and acute
Decrease in the peripheral blood CD4+ subset of phase response in TB.
T-lymphocytes has also been documented and may be Thrombocytopenia is more common in patients with
seen in up to 15 per cent of patients and is more common disseminated TB, whereas, thrombocytosis is more
common in pulmonary TB. However, isolated thrombo- including pancytopenia often reverse with effective
cytopenia has occasionally been described in pulmonary therapy (61).
TB and its pathogenesis is believed to be immune
mediated (31,50,51). Anti-platelet antibodies and platelet COAGULATION ABNORMALITIES
associated immunoglobulin G [IgG] have been demons-
Various coagulation abnormalities have been described
trated in some patients. Boots et al (50) reported a case of
in patients with pulmonary as well as disseminated TB.
immune thrombocytopenia with pulmonary TB, where
Disseminated intravascular coagulation [DIC] has been
additional studies showed presence of platelet bound IgG
documented in disseminated as well as pulmonary TB
antibodies without any circulating anti-platelet anti-
and often is accompanied by a high mortality rate (59,
bodies. In contrast to antibodies in patients with idio-
65-70). In these patients activated partial thromboplastin
pathic thrombocytopenic purpura, the antibodies in this
time and thrombin time are increased and the
patient did not react with normal donor platelets and
antithrombin-III [AT-III] activity is often reduced. In a
the thrombocytopenia resolved with intravenous
retrospective study of 833 culture-proven TB patients
immunoglobulin therapy (50,51). There is an inverse
with DIC were evaluated before starting antituberculosis
correlation between platelet count and the mean platelet
treatment (71). Nearly 3.2 per cent of them had TB
volume, and increased numbers of small platelets have
induced DIC with a mortality rate of 63 per cent. Seven
been described in these patients which have a shortened
of the 27 patients with DIC [25.9%] had disseminated
survival (52). Thrombocytopenia is more common in
TB. An early institution of antituberculosis treatment
patients with disseminated TB and has been reported in
significantly improved survival in this study. Acquired
23 to43 per cent of patients (20,53,54). Majority of these
Factor V deficiency with variable bleeding manifestations
patients, however, does not have any significant
has been described in patients with pulmonary TB. This
bleeding. Thrombotic thombocytopenic purpura has
abnormality disappears with antituberculosis treatment
been seen with lymph node as well as pulmonary TB
(72). Sarode et al (71) reported the presence of platelet
and has been hypothesized to be due to an increased pro-
hyperaggregation in 88 per cent patients with intestinal
coagulant activity of interleukin-1 [IL-1] on endothelial
TB. Serum and plasma from 15 of these patients, when
cells (55,56).
incubated with normal platelets caused hyperaggrega-
tion as well (71). This abnormality may be related to
PANCYTOPENIA
increased levels of C-reactive protein in these patients.
Pancytopenia is infrequent and has been observed in only Transient thrombasthenia has been reported in patients
three to twelve per cent of cases (57). Pancytopenia is with TB (73). Transient protein S deficiency has been
rare in patients with pulmonary TB and may occcur reported in association with TB and deep vein thrombosis
occasionally as a result of drug toxicity in these patients [DVT]; however, a direct pathological relationship could
(53,57-61). It is mostly associated with an underlying not be established.
haematological disease although cases associated with Deep vein thrombosis confirmed by venography has
severe miliary TB alone have been described. Patients been observed in three to four per cent of patients with
with disseminated TB may have splenomegaly as a result pulmonary TB (74). In a group of patients with active
of the disease process, underlying haematological disease pulmonary TB, thrombocytosis, elevations in plasma
or both. Splenomegaly may contribute to the haematolo- fibrinogen, fibrin degradation products [FDP], tissue
gical abnormalities including pancytopenia in some of plasminogen activator [t-PA] and inhibitor [PAI-1] with
these patients (62). The pancytopenia may resolve after depressed AT-III levels were seen (75). In another study
splenectomy in some of these patients, suggesting that (76) comparing 45 patients of active pulmonary TB with
hypersplenism may be one of the mechanisms of pan- healthy volunteers, elevated levels of plasma fibrinogen,
cytopenia in these patients. Pancytopenia in dissemi- Factor VIII, PAI-1 and depressed AT-III and protein C
nated TB has also been attributed to haemophagocytosis, levels were observed. Following treatment, fibrinogen
even though hypocellularity of the marrow has also been and Factor VIII, protein C and AT-III levels normalized.
reported (62-64). All these haematological abnormalities, There was no evidence of activated protein C resistance.
546 Tuberculosis
Platelet aggregation studies demonstrated increased

platelet activation. Age, sex and disease matched indivi-
duals with venographically proven DVT had higher FDP,
t-PA, and functional PAI-1 activity. Fibrinogen levels in
all patients rose during the first two weeks of therapy
and, together with related disturbances, corrected within
12 weeks. Bone marrow emboli have been reported in
patients with miliary TB (77). Budd Chiari syndrome has
been reported in a child with hepatic TB (78). Portal vein
thrombosis has been reported in association with
abdominal TB (79).
BONE MARROW CHANGES IN TUBERCULOSIS

Figure 37.1: Bone biopsy showing a well-defined tuberculosis
Both localized and disseminated TB, can lead to a spec- granuloma composed of epithelioid cells and Langhans’ giant cells
trum of histopathological changes in the bone marrow [arrow] [Haematoxylin and eosin × 100]
[Table 37.3]. These changes include typical caseating
granuloma formation, non-caseating granulomas,
marrow hypoplasia, red cell aplasia, megaloblastosis,
haemophagocytosis, and necrosis of the marrow (24,80).
In majority of the patients, the bone marrow shows
normal to increased cellularity and myeloid hyperplasia
(66). In most patients with pulmonary TB, the marrow
shows “reactive changes” with increased granulocytic
hyperplasia with mild to moderate plasmacytosis (4).
Bone marrow plasmacytosis is seen less frequently in
miliary TB and can be a helpful differentiating feature
(4,24,81).
Bone marrow granulomas [Figures 37.1 and 37.2] are
present in 50 to 100 per cent of patients with miliary TB Figure 37.2: Bone biopsy showing a tuberculosis granuloma
and are usually absent in pulmonary TB (82). In a study composed of epithelioid cells [asterisk] and Langhans’ giant cells
(83) of 6 988 bone marrow biopsies, six per cent of patients [arrows] [Haematoxylin and eosin × 400]
in whom granulomas were present in the bone marrow
had TB as the inciting cause. Patients with peripheral usually show the presence of Langhans’ giant cells and
blood abnormalities are more likely to have granulomas caseation necrosis in 60 to 70 per cent of cases (20,24).
in the bone marrow (35). Tuberculosis granulomas Caseation necrosis and the presence of AFB in the
granulomas is diagnostic of TB. It has been observed that
Table 37.3: Bone marrow changes in tuberculosis near these granulomas the marrow cellularity is often
Myeloid hyperplasia greater or lower, and there may be an increase in reticulin
Plasmacytosis fibres and in severe cases myelofibrosis may occur (84).
Megaloblastoid maturation Reticuloendothelial cells in the bone marrow may show
Hypoplasia or aplasia
phagocytosis of erythrocytes, leucocytes and platelets,
commonly referred to as haemophagocytosis. It is more
Haemophagocytosis
often seen in disseminated TB and disappears with
Caseating and non-caseating granulomas
treatment (85,86). Haemophagocytic syndrome has been
Bone marrow necrosis
reported with localized extra-pulmonary TB as well (87).
Myelofibrosis
Rarely, life-threatening haemophagocytic syndrome
related to Mycobacterium tuberculosis can occur (88). Bone lesions and clusters of epithelioid cells and lymphocytes
marrow necrosis has been described in patients with (92). Unlike the granulomas associated with TB, necrosis
disseminated TB (89,90). The bone marrow in patients is not commonly seen in these granulomas. Usually, few
with untreated TB may show megaloblastic changes in bacteria are demonstrable in the bone marrow biopsy in
as many as 60 per cent of patients with disseminated TB, patients with TB, whereas numerous AFB can be seen in
but this does not reflect vitamin B12 or folate deficiency patients with disease due to Mycobacterium avium
in these patients (24). Bone marrow aspirate iron stores intracellulare complex [MAIC]. Farhi et al (92) found
are usually increased reflecting poor iron usage, though granulomas in the bone marrow in 12 of 24 patients with
they may be decreased in some patients. Patients with disseminated MAIC infection (92).
poor nutritional status may have decreased iron status
on bone marrow examination (27). DRUG-INDUCED HAEMATOLOGICAL CHANGES
Bone marrow examination is often a helpful diagnos-
Many of the abnormalities seen with TB can also be
tic tool in TB. The AFB may be demonstrated in the bone
induced by the antituberculosis drugs and often makes
marrow morphologically within the granulomas or by
the diagnosis difficult in a patient initiated on therapy
mycobacterial culture. In a study of patients with
[Table 37.4]. Drug-induced AIHA can be precipitated by
pulmonary TB (91), AFB were detected in 55 per cent
isoniazid, rifampicin, streptomycin as well as para-
cases in the buffy coat, and in 48.3 per cent cases in the
aminosalicyclic acid [PAS] (94-96). In patients receiving
bone marrow. In 38.3 per cent cases, the AFB could be
rifampicin, a flu-like prodrome may precede the onset
demonstrated both in the buffy coat as well as the bone
of the intravascular haemolysis. In many of these
marrow. It is possible to use polymerase chain reaction
patients, direct Coomb’s test will become positive.
[PCR] to detect Mycobacterium tuberculosis in bone
Sideroblastic anaemia is a well-documented adverse
marrow aspirate material and this technique may be
more sensitive than the conventional culture methods. Table 37.4: Haematological changes due to
The PCR technique has the added advantage of being a antituberculosis treatment
rapid test compared to cultures. Lombard et al (46)
Autoimmune haemolytic anaemia
reported that the overall sensitivity for the detection of Rifampicin
Mycobacterium tuberculosis in the bone marrow aspirate Para-aminosalicylic acid
improved to 58 per cent by using both conventional Isoniazid
culture and PCR techniques. Megaloblastic anaemia
Para-aminosalicylic acid
NONTUBERCULOUS MYCOBACTERIAL INFECTION Sideroblastic anaemia
Isoniazid
Haematological abnormalities are commonly observed Cycloserine
in patients with localized or disseminated infection Pyrazinamide
caused by nontuberculous mycobacteria [NTM], but a Pure red cell aplasia
causal relationship is often difficult to confirm given the Isoniazid
usual immunocompromised status of the typical host Agranulocytosis
and other predisposing illnesses. Nontuberculous Streptomycin
Thioacetazone
mycobacterial infections are on the rise globally, espe-
Para-aminosalicylic acid
cially due to the ongoing acquired immunodeficiency
Autoimmune thrombocytopenia
syndrome [AIDS] epidemic. Anaemia can be seen in Rifampicin
almost all patients with NTM (92). Leucopenia, thrombo- Para-aminosalicylic acid
cytopenia and pancytopenia have been observed in Isoniazid
nearly half of the patients (93). Plasmacytosis and Aplastic anaemia
granulocytic hyperplasia are common findings in the Streptomycin
bone marrow (92). Granulomas can be found in approxi- Para-aminosalicylic acid
mately half of the patients and range from small and Disseminated intravascular coagulation
Isoniazid
lymphohistiocytic aggregates to larger lymphohistiocytic
548 Tuberculosis
effect of isoniazid therapy and usually occurs after or one of its substrates and antigenically modifies the
several weeks of therapy (97,98). The bone marrow protein resulting in autoantibody production. Para-
usually shows normoblastic hyperplasia with ring aminosalicylic acid can produce hypothrombinemia (4).
sideroblasts and the indices of iron metabolism are Increased incidence of DVT has been reported among
usually within normal range. The anaemia reverses on patients with TB receiving rifampicin (4). This may be
withdrawal of the drug and administration of pyrid- related to the induction of enzyme cytochrome P-450
oxine. Sideroblastic anaemia has also been occasionally system by rifampicin which alters the balance between
reported with pyrazinamide (99). Isoniazid may also anticoagulant and coagulant proteins resulting in a state
produce an immune-mediated PRCA which reverses on of hypercoagulability. A relationship between adminis-
withdrawal of the drug (100). Aplastic anaemia has been tration of isoniazid alone or in combination with rifam-
documented with disseminated bacille Calmette-Guerin picin and fibrinogen as well as AT-III blood levels has
[BCG] infection (101). Treatment with PAS may cause been seen in one study (123). These observations indicate
malabsorption and result in vitamin B 12 deficient a protective effect of the synchronous administration of
megaloblastic anaemia (102). rifampicin in the preservation of fibrinogen blood levels
Leucopenia, agranulocytosis and aplastic anaemia by enzyme induction mechanisms.
have been observed following isoniazid, rifampicin and
PAS administration (77,103-107). Antituberculosis ACQUIRED IMMUNODEFICIENCY SYNDROME
treatment induced leucopenia appears to be more
commonly seen in elderly patients (108). Leucopenia is Various haematological abnormalities have been
rare with ethambutol use (104). Para-aminosalicylic acid described in patients with human immunodeficiency
can produce atypical lymphocytosis simulating virus [HIV] infection and AIDS (124-127). In patients with
infectious mononucleosis. Eosinophilia can occur with AIDS, isolated thrombocytopenia has been observed
rifampicin therapy (109) and also has been reported with during early part of the disease (128); severe degree of
ethambutol (110). anaemia, leucopenia and pancytopenia are more often
The use of rifampicin may produce immune- observed in advanced disease (129,130). Leucocytosis is
mediated thrombocytopenia and the antibodies may be more often observed in patients with extra-pulmonary
directed against the glycoprotein Ib/IX complex (111- TB without HIV infection than in patients with AIDS
114). Antibodies of IgG and immunoglobulin M [IgM] (131). Hill et al (132) have observed absolute lymphocyte
type have been demonstrated in many of these patients. count of less 1 x 109/l in 80 per cent of HIV-seropositive
Thrombocytopenia has been more frequently observed patients and in only 40 per cent of HIV-seronegative
when twice weekly regimen of 900 mg rifampicin was patients.
used and it resolves with reduction of dose to 150 to 300 Approximately 60 per cent of these patients have
mg/day. Isoniazid, pyrazinamide (115), streptomycin, granulomas in the bone marrow (131,132). Non-
ethambutol (116,117), and PAS (118) may also produce granulomatous reaction occurs in the presence of severe
thrombocytopenia. Thrombotic thrombocytopenic overwhelming infection. The granulomas may have areas
purpura has been reported in association with rifampi- of necrosis with many AFB. The surrounding inflamma-
cin (119). tion when present consists mainly of polymorphonuclear
Coagulation abnormalities are rare with antituber- cells and macrophages in contrast to usual cellular
culosis drugs. Rarely, DIC following isoniazid and components of a granuloma seen in HIV-seronegative
rifampicin therapy has been documented (120). Acquired patients with TB (131). In a study from India (133), AFB
Factor XIII deficiency due to inhibitors has been reported could be demonstrated in 12.9 per cent of the 140 bone
with isoniazid therapy (121). In most cases, the inhibitors marrow aspirates obtained from HIV-seropositive
have been shown to be IgG antibodies and these patients patients suggesting that in countries with a high
may present with severe subcutaneous and retroperito- prevalence of TB, AFB staining of the bone marrow
neal bleeding. The pathogenesis of isoniazid associated aspirate is useful in establishing the diagnosis of TB. In a
Factor XIII inhibitor is not fully understood. Lorand et al study from sub-Saharan Africa (134), low selenium
(122) have proposed that isoniazid binds to Factor XIII concentrations, high viral load, and high IL-6
concentrations were associated with anaemia in HIV- 14. Siribaddana SH, Wijesundera A. Autoimmune haemolytic
seropositive adults with active pulmonary TB. anaemia responding to anti-tuberculous treatment. Trop Doct
1997;27:243-4.
These manifestations could be partly secondary to 15. Kuo PH, Yang PC, Kuo SS, Luh KT. Severe immune hemolytic
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in Tuberculosis
38
GA Prasad, SK Sharma, N Kochupillai
INTRODUCTION disease’ is now used to refer to all forms of chronic primary

adrenocortical insufficiency (8). Seventy five years ago,
Overt clinical features of adrenal insufficiency appear
Guttman (9) reviewed 403 autopsy reports of patients with
only after the destruction of more than 80 to 90 per cent
adrenal insufficiency and reported that adrenal TB was
of both the adrenal glands (1). However, subclinical
present in 70% patients, while idiopathic atrophy occurred
adrenal insufficiency which may exist without any
in 20 per cent of the patients. In 1956, Sanford and Favour
evidence may be important in stressful situations such
(10) reported that TB was the aetiological cause of adrenal
as acute and chronic infections, which require increased
insufficiency in 25 per cent of the cases. Dunlop (11)
release of adrenocortical hormones to meet heightened
reported that 79 per cent of the cases had TB as the cause
metabolic demands. The rich vascularity, and the high
of Addison’s disease in an autopsy series of 24 patients
local levels of corticosteroids which suppress cell-
during 1928 to 1938. However, subsequent studies have
mediated immune response, make the adrenal glands
generally reported a declining proportion of TB. Nerup
an ideal nidus for organisms, such as mycobacteria,
(12) reported that the majority [66%] had the idiopathic
Histoplasma species and involvement of the adrenal gland
type of Addison’s disease while only seven per cent of
frequently occurs following haematogenous dissemina-
patients had a TB aetiology.
tion in tuberculosis [TB] and histoplasmosis.
Ethnic variations have been described in the aetiology
Acute infections are usually associated with increased
of hypoadrenalism (13). Tuberculosis as a cause of
release of adrenal steroids (2). However, adrenal reserve
hypoadrenalism was seen in only four per cent of
in chronic infections, especially in TB has been a subject
Caucasians [92% due to autoimmune disease] while in
of great controversy (3,4). Estimation of adrenal reserve
Polynesians, who have a 10-fold higher incidence of TB
assumes greater importance in view of the appearance of
than Caucasians, hypoadrenalism due to TB was detected
reports of clinical deterioration and sudden death in
in 63 per cent of cases (13). In a study from South Africa
patients with TB on commencement of antituberculosis
(14), it has been reported that the probable aetiology of
therapy, especially rifampicin (5). Rifampicin, a potent
Addison’s disease was idiopathic in 42 per cent, related
inducer of hepatic microsomal enzymes, is known to
to active TB in 18 per cent, old TB in 16 per cent and
reduce the half-life and tissue availability of corticosteroids
autoimmune in 12 per cent. In another recent autopsy
(6). Hence, it may unmask subclinical adrenal insufficiency
study (15), adrenal TB was seen in six per cent of the
which may lead to clinical Addisonian crisis.
patients with active TB and in 25 per cent of them the
adrenal gland was the only organ involved by TB. Thus,
TUBERCULOSIS ADDISON’S DISEASE
autoimmune adrenalitis is the most common cause of
In 1855, Thomas Addison first described the chronic type adrenal insufficiency in developed countries, TB is still a
of hypoadrenalism (7). Presently, the term ‘Addison’s common cause in the developing world (1,16).
554 Tuberculosis
Activated hypothalamo-pituitary-adrenal axis in TB Various methods to estimate adrenal reserve using

causes increased cortisol secretion which results in a shift cosyntropin have been advocated. Intramuscular
in the Th1/Th2 balance towards Th2 T-cell dysfunction injection of cosyntropin with estimation of serum
due to high cortisol and low dehydroepiandrosterone cortisol before, 20 and 60 minutes has been used (23).
levels. This may be responsible for immunologically- The need to measure serum cortisol early i.e., within 60
mediated tissue damage in TB (1). minutes of injection of 250 μg of cosyntropin intramus-
cularly was emphasized in a study done by Danowski
Clinical Manifestations et al (24).
Patients with acute adrenal insufficiency present with Some workers (25-27) felt that 250 μg of synthetic
severe hypotension or hypovolaemic shock, acute ACTH provides a very high blood ACTH concentration
abdominal pain, vomiting, and fever. Patients with resulting in a ‘supraphysiological’ dose. Therefore, it has
chronic adrenal insufficiency complain of fatigue, lack been postulated that this dosage may induce false-
of stamina and energy, reduced muscle strength, and positive cortisol responses and may result in under-
increased irritability. Weight loss, nausea, and anorexia diagnosis of adrenal insufficiency. Therefore, 1 μg of
or failure to thrive [in children], and arthralgias are also ACTH has been considered to be an adequate dose to
present (1,7,8). The combined measurement of early provide ‘physiological’ adrenocortical stimulation and
morning serum cortisol and plasma adrenocorticotrophic has been used in some studies (25-27).
hormone [ACTH] separates patients with primary
adrenal insufficiency from healthy individuals and those Effect of Rifampicin on Corticosteroids
with secondary disease (17). Rifampicin, a well-known inducer of hepatic microsomal
enzymes, causes serious reduction in the plasma concen-
Imaging Appearances
tration of concomitantly administered drugs metabolized
In patients with Addison’s disease due to TB with recent in the liver. These drugs include corticosteroids, oral
or active infection, the adrenal glands may appear contraceptives, oral hypoglycaemic agents and digitalis
enlarged (1,18). Non-homogeneous appearance and (6). Hence, it may unmask subclinical adrenal insuffi-
presence of non-enhancing areas may indicate foci of ciency which may lead to clinical Addisonian crisis.
caseous necrosis (19). In patients with remote infection, McAllister et al (28) studied the pharmacokinetics of
the gland may be atrophied or calcified (18). On the prednisolone to quantify the effect of rifampicin on
contrary, adrenocortical functions may be normal despite prednisolone and found that the clearance of predni-
adrenal involvement by TB (1,18,19). solone increased by 45 per cent and the tissue availability
reduced by 66 per cent. Therefore, they recommended
ESTIMATION OF ADRENOCORTICAL RESERVE doubling of prednisolone dosage when given in combi-
Before the advent of synthetic analogues, corticotrophin nation with rifampicin.
derived from the bovine or porcine pituitary gland was This observation was supported by Edwards et al (29)
used for the stimulation and estimation of adrenal gland who cite the case of a patient with Addison’s disease who
reserve. However, its use often led to allergic reactions. required a three-fold higher dose of corticosteroids when
Cosyntropin, a synthetic polypeptide, contains the first put on rifampicin. Instances of acute adrenal insuffi-
24 of the 39 amino acids of ACTH responsible for the ciency being precipitated following introduction of
biological activity of ACTH (9). antituberculosis treatment [including rifampicin] have
The advantages of using the cosyntropin test to assess also been reported in the literature (5,30). The diagnosis
adrenal function include a reduced incidence of hyper- of acute adrenal insufficiency was confirmed by Wilkins
sensitivity reactions (20,21), ease of performance of the et al (5) by a short cosyntropin test. The altered pharmaco-
test, [as only three intravenous punctures are required] kinetics of corticosteroids was also reported by
and reliability of the method in excluding or confirming Buffington et al (31) in their study on recipients of renal
adrenal insufficiency (22). allografts.
Adrenocortical Reserve in Tuberculosis 555
Effect of Malnutrition of Adrenal Function may yield fallacious information. The extent of compro-
mise of adrenal reserve reported in these studies [Table
Adrenal function in malnutrition has also been a subject
38.1] ranged from normal (36) to a very significant extent
of controversy as views expressed range from hypofunc-
(3,37). Chan et al (36) reported that about 41 per cent of
tion to hyperfunction. Bajaj et al (32) induced protein
patients were negative responders to the cosyntropin
malnutrition in rhesus monkeys to study their adrenal
stimulation test. However, about 75 per cent of these
function and observed hypoproteinaemia, fasting
patients had basal cortisol in the supranormal range.
hypoglycaemia and a rise of basal serum cortisol with
Hence, this lack of rise following cosyntropin
loss of diurnal variation. They proposed that the hyper-
administration was attributed to the basal hyperstimula-
cortisolism observed could be due to: [i] the metabolic
tion of the gland. Matah and co-workers (38) reported that
stress induced by protein malnutrition; [ii] the fasting
five per cent of patients showed a subnormal response,
hypoglycaemia; and [iii] reduction in the clearance of
while 12.5 per cent of patients did not respond at all to
cortisol. The adrenal reserve was found to be normal
cosyntropin administration. However, criteria used for
despite increased adrenal activity. Loss of diurnal
defining the response were not mentioned in the study.
variation was interpreted to be due to the sustained
Reversibility of changes in adrenal reserve following
ACTH release because of hypoglycaemia. Enwonwu
the administration of antituberculosis therapy has also
et al (33) also made similar observations in their study
been investigated. Ellis and Tayoub (3) repeated the ACTH
on malnourished non-human primates. Mean plasma
stimulation test two weeks after starting treatment. They
11-hydroxy-corticosteroid levels were found to be higher
found that the proportion of negative responders drop-
in malnourished children by Alleyne and Young (34).
ped to 30 per cent from the figure of 55 per cent observed
They did not observe any evidence of reduced adrenal
before treatment. Interestingly, all 12 patients who
reserve in these patients either.
remained negative responders after two weeks of therapy
were on rifampicin containing regimens. The authors
Overview of Past Experience
concluded that though therapy does improve adrenal
Table 38.1 briefly summarizes the previously published reserve, rifampicin possibly prevented a similar improve-
studies on this subject (3,4,35-43). Basal cortisol was ment when given as part of the antituberculosis treatment.
reported to be either normal or increased [Table 38.1], Barnes et al (4) re-assessed adrenal function three to four
except in one study (41), where the mean basal serum weeks after starting antituberculosis treatment and
cortisol level was low. The most common explanation concluded that therapy significantly improves adrenal
advanced for raised levels of basal cortisol was function, as only one out of seven patients had a negative
hyperfunctioning of the adrenal glands in response to response to cosyntropin stimulation. However, unlike the
the stress caused by infection (35). Chan et al (36) observations reported by Ellis and Tayoub (3), rifampicin
demonstrated a direct correlation between elevated did not appear to have any adverse effect on adrenal
serum cortisol at presentation and subsequent mortality function in this study (4) or in the study reported by
during treatment. They also demonstrated in their Francois Venter et al (44). Chan and co-workers (36) also
autopsy series that the only patient with demonstrable measured both basal and post-ACTH cortisol levels two
granulomas in the adrenals had the highest basal cortisol months after antituberculosis treatment in 22 of their 39
concentration. Srivastava and colleagues (35) found that patients. They found that basal cortisol concentrations
the duration of symptoms was inversely proportional to were normal in all the cases studied. The incremental
basal cortisol levels, while a direct correlation existed response to cosyntropin in these patients was significantly
with parameters like sputum positivity for Mycobacterium higher than the response at presentation. Analysis of three
tuberculosis, extent of disease, fever, and raised erythro- patients, who had developed hypotension after
cyte sedimentation rate. antituberculosis was started, revealed that serum cortisol
Measurement of serum cortisol after stimulation of the was extremely high in all three patients [> 1000 nmol/l].
adrenals by ACTH or synthetic analogues of ACTH is a Post-mortem examination revealed normal adrenal glands
very reliable method of estimating adrenal reserves, as in one patient and granulomas in the adrenal glands in
compared to measurement of basal cortisol alone, which two other patients.
556 Tuberculosis
Table 38.1: Summary of studies on adrenocortical reserve in tuberculosis

Study No. of Parameters studied Results Comments
(reference) subjects,
Type of TB Basal Post- Diurnal Others Basal Post-ACTH Diurnal
cortisol ACTH variation cortisol cortisol variation
cortisol
Srivastava 84, PTB Y NS NS – Elevated in – – Cortisol levels reduced

et al (35) all patients with increasing duration
of symptoms.
SS+ patients had higher
serum cortisol
Ellis and 41, PTB NS Y NS – – 55% patients – –
Tayoub (3) had negative
cosyntropin test
Barnes 30, PTB Y Y NS – Normal 61% 8% patients – –
et al (4) 30, MTB Elevated 39% had negative
30, EPTB cosyntropin test
Chan 39, PTB Y Y NS – Normal 82% 41% patients – Basal cortisol
et al (36) Elevated 18% had negative significantly higher in
cosyntropin patients who died.
test 11 of 16 patients with
abnormal response had
elevated basal cortisol
Sarma 39, PTB NS Y Y DST – 50% patients Lost in DST positive hence
et al (37) had negative patients normal pituitary activity;
cosyntropin with PTB primary adrenal
test insufficiency
Matah 40, PTB Y Y NS Serum Elevated in 17.5% patients – Hyponatraemia due to
et al (38) sodium all patients had negative adrenal insufficiency or
cosyntropin test due to SIADH
York 37, PTB Y NS Y – Normal – Lost in patient –
et al (39) with active disease
Keven 21, PTB Y Y NS DST Normal in 7 – – Insufficient suppression
et al (40) 1, Pleural TB [32%], elevated of plasma cortisol levels
in 14 [64%] and in 9 [41%] patients
low in one patient before treatment
Prasad 30, PTB Y Y NS – Low in patients Compromised – –
et al (41) 33, DTB/MTB in 49.5% of
34, DR-TB patients
Kaplan 18, HIV+, PTB Y Y NS T3, T4, Higher in – – Mean cortisol after sti-
et al (42) 22, HIV–PTB TSH patients mulation with 1 µg did
32, Control Serum not differ either in HIV+
subjects sodium and HIV–patients or the
Plasma control. Primary hypo-
osmolality adrenalism was present
in a single patient
Zargar 28, PTB Y Y Y - Comparable 14 [35%] ACTH stimu- Adrenocortical reserve
et al (43) 12, EPTB between the patients lation revealed was inversely related to
10, Control patients and exhibited significant the radiological severity
subjects controls sub-optimal cortisol rise in and chronicity of PTB
subjects cortisol patients with
response active TB at 4
and 8 hours only,
whereas in healthy
controls, the cortisol
rise was more pro-
longed and conti-
nued up to 24 hours
ACTH = adrenocorticotrophic hormone; PTB = pulmonary tuberculosis; MTB = miliary tuberculosis; EPTB = extra-pulmonary tuberculosis;
DTB = disseminated tuberculosis; DR-TB = drug-resistant tuberculosis; TB = tuberculosis; HIV+ = human immunodeficiency virus-seropositive; HIV– = human
immunodeficiency virus-seronegative; SS+ = sputum smear-positive; DST = dexamethasone suppression test; T3 = serum tri-iodothyronine;
T4 = serum thyroxine; TSH = serum thyroid stimulating hormone; SIADH = syndrome of inappropriate antidiuretic hormone secretion; NS = not studied; Y = studied
Sharma et al (45) prospectively studied the adrenal logy due to its high spatial and density resolution which
reserve and morphology in 105 human immunodefi- allows precise demonstration of normal [Figure 38.1] and
ciency virus [HIV] negative patients with various forms abnormal [Figures 38.2, 38.3, 38.4A and 38.4B] glands.
of TB [pulmonary TB in 72 and extra-pulmonary TB in Calcification of the adrenal glands can also be identified
33] and 27 normal control subjects. Baseline standard- much earlier on CT. Appearance of radiological
dose ACTH stimulation test was done on all the subjects, abnormalities of the adrenal gland depends on the
before starting the treatment and all of them received duration of TB. Initial involvement often leads to gland
standard antituberculosis treatment, depending on the enlargement and as the disease progresses the gland size
type of disease and were followed up for a period of 30 decreases and finally atrophy may occur (13,48).
months. Adrenocorticotrophic hormone stimulation test Kelestimur et al (49) on comparing the adrenal gland size
was performed at follow-up, every six months. Before measured on CT, have found a similar correlation
antituberculosis treatment was started, ACTH between gland size and duration of the disease. A study
stimulation test revealed that 52 of 105 patients [49.5%] from India (41) revealed that 14 of the 86 patients [16.3%]
were found to have compromised adrenal reserve. At had adrenal gland enlargement on CT. Further, patients
six months, the percentage of responders had increased with enlarged glands had a longer duration of disease
to 71 per cent with a gradual increasing trend noted
thereafter. At 24 months, 31 of the 32 patients [97%]
who were followed up demonstrated a normal response
to ACTH stimulation. The percentage of responders was
comparable in both pulmonary [21 of 22 patients; 95%]
and extra-pulmonary TB [10 of 10 patients; 100%] groups
at follow-up. The authors (45) suggested that nearly half
of the patients with active TB have a subclinical adrenal
insufficiency indicated by an impaired response to ACTH
stimulation test. It is important to recognize this fact as
this has clinical relevance in the acute stressful setting.
However, with antituberculosis treatment, the adrenal
insufficiency seems to reverse completely in a majority
of the patients.
Serum cortisol estimations over 24 hours reveal a
normal diurnal variation with maximal values attained
Figure 38.1: CECT of the abdomen showing normal
in the mornings and a normal nadir in the evenings (46). suprarenal glands [arrows]
However, Sarma et al (37) and York et al (39), reported
loss of this normal diurnal variation in all their patients
with TB. No definite reason was advanced by these
workers to explain this loss of diurnal rhythm. A possible
explanation could be the basal hyperstimulation of the
adrenal gland due to the stress of infection. But, basal
cortisol was not elevated in any of these studies. An
interesting observation made by Matah et al (38) was the
presence of significant hyponatraemia in 27.5 per cent
of the patients with pulmonary TB. The possible reasons
could be, firstly due to adrenocortical insufficiency itself;
and secondly, due to dilutional hyponatraemia occurring
secondary to the syndrome of inappropriate secretion of
antidiuretic hormone (47).
Computed tomography [CT] can be used as an Figure 38.2: CECT of the abdomen showing bilateral and diffuse
imaging modality to assess the adrenal gland morpho- enlargement of suprarenal glands [arrows]
558 Tuberculosis
as compared to those with normal glands. Majority of

the patients with enlarged glands in this study had drug-
resistant TB. These patients remain sputum-positive for
a long time thereby leading to a greater bacteriologic load
providing greater opportunity for dissemination of
disease. It was observed that patients with enlarged
glands had lower basal, 30 and 60 minutes cortisol values
than those with normal glands. These facts and the
observation that 13 of the 14 patients [92.8%] had
unilateral enlargement of the gland supports the
hypothesis that gland enlargement is due to involvement
of the gland by the TB process rather than due to stress
induced hyperplasia.
Figure 38.3: CECT of the abdomen showing unilateral focal left
adrenal gland enlargement [arrow] Adrenocortical Reserve in Patients Co-infected with
Human Immunodeficiency Virus and Tuberculosis
Sparse literature is available regarding adrenocortical
reserve in patients co-infected with HIV and TB. In a
report from Kenya [n = 174] (50), 90 HIV-positive and 84
HIV-seronegative patients with active TB were assessed
for adrenocortical insufficiency using the 30 minutes
synacthen stimulation test. Overall, a sub-normal cortisol
response was observed in 51 per cent patients with
pulmonary TB and 56 per cent patients with extra-
pulmonary TB. There was no statistically significant
difference in the prevalence of compromised adreno-
cortical reserve in HIV-seropositive and negative patients
with active TB. In another study from Uganda (51), 21 of
Figure 38.4A: CECT of the abdomen showing enlargement of
the 113 [19%] critically ill HIV-infected adults not
left suprarenal gland before treatment [arrow] receiving corticosteroids were found to have functional
adrenal insufficiency [defined as morning total serum
cortisol level of < 25 μg/dl]. Of the 46 patients with
clinical suspicion of TB disease, eight [17%] had
functional adrenal insufficiency. Five patients [24%] with
functional adrenal insufficiency [n = 21] were being
treated with rifampicin compared to four [4%] of those
with normal adrenal function [n = 92] indicating that
rifampicin use was associated with the occurrence of
functional adrenal insufficiency. The authors (51)
postulated Mycobacterium tuberculosis infection of the
adrenal gland or induction of the cytochrome enzyme
system which enhances the metabolism of cortisol as the
likely explanations for this phenomenon.
In conclusion, it is evident from the above studies that
Figure 38.4B: CECT of the abdomen showing regression of the exact status of adrenal reserve in patients with TB is
suprarenal gland enlargement after one year of antituberculosis far from clear. This difference in opinion in these studies
treatment [arrow] is in part, due to the different patient groups selected,
the differences in methodology, and different standards 17. Oelkers W, Diederich S, Bahr V. Diagnosis and therapy
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Dis 1998;2:419-24. Juma ES, et al. No increased prevalence of adrenocortical
41. Prasad GA, Sharma SK, Mohan A, Gupta N, Bajaj S, Saha insufficiency in human immunodeficiency virus-associated
PK, et al. Adrenocortical reserve and morphology in tuberculosis. Tuber Lung Dis 1996;77:444-8.
tuberculosis. Indian J Chest Dis Allied Sci 2000;42:83-93. 51. Meya DB, Katabira E, Otim M, Ronald A, Colebunders R,
42. Kaplan FJ, Levitt NS, Soule SG. Primary hypoadrenalism Njama D, et al. Functional adrenal insufficiency among
assessed by the 1 microg ACTH test in hospitalized patients critically ill patients with human immunodeficiency virus in
with active pulmonary tuberculosis. QJM 2000;93:603-9. a resource-limited setting. Afr Health Sci 2007;7:101-7.
Endocrine Implications
of Tuberculosis
39
R Goswami, S Mishra, N Kochupillai
INTRODUCTION ing complaint is headache followed by visual changes

(12). These lesions may also lead to erosion of the sella (2).
Being a systemic disease with a capacity for widespread
It is difficult to differentiate them from pituitary
dissemination, it is obvious that tuberculosis [TB] can
adenomas, but radiological findings like leptomeningeal
affect various endocrine glands in the body. Moreover,
enhancement, parenchymatous brain tuberculomas,
antituberculosis drugs are known to induce cytochrome
intense enhancement of a lesion or a thickened pituitary
P-450 oxidase enzymes, thereby enhancing the
stalk on contrast magnetic resonance imaging [MRI],
catabolism of endogenous cortisol in the liver. In active
suggest the diagnosis of a sellar tuberculoma (12-14).
pulmonary TB, endocrine abnormalities including sick
Though hypothalamic-pituitary dysfunction is common
euthyroid syndrome, hypogonadotropic hypogonadism
in patients with a history of TB who also have radiological
and hypoadrenalism are common (1). In a similar
abnormalities in hypothalamic region, endocrine
manner, due to a variety of factors other endocrine glands
dysfunction can occur even when there are no gross
may also be the target organs for lodgement and tissue
anatomical changes (9). Recently, MRI in these patients
invasion by Mycobacterium tuberculosis.
has revealed areas of abnormal enhancement in the
The present chapter deals with the endocrine impli-
suprasellar region possibly related to the granulomatous
cations of TB. The reader is also referred to the chapter
tissue at these sites (9). The long time interval between
“Adrenocortical reserve in tuberculosis” [Chapter 38] for
the occurrence of TB meningitis and the development of
more details.
endocrine dysfunction suggests a chronic process of
necrosis and scarring possibly due to devascularization
TUBERCULOSIS AND HYPOTHALAMUS-
of the hypothalamus or pituitary (8).
PITUITARY INVOLVEMENT
Endocrine dysfunction related to pituitary or
Hypothalamus-pituitary involvement in TB may arise hypothalamic involvement can occur secondary to
either from haematogenous spread or due to extension of intracranial TB in several ways, the most common being
the local lesions (2). Generally, TB of the adenohypophysis growth hormone and gonadotrophin deficiency (5,15-
is observed in patients with a past history of TB menin- 17). In a review of 13 adult cases of sellar tuberculoma,
gitis (3). It may manifest as a space occupying lesion 86 per cent had suprasellar extension and 78.6 per cent
[tuberculoma] or as sellar or suprasellar calcification had anterior pituitary dysfunction. Only a few cases of
(4-9). Intrasellar tuberculoma may also present as apop- suprasellar tuberculoma have been reported in children
lexy (10). The reported frequency of sellar tuberculomas and usual presentation includes both anterior and
is between 0.25 per cent and 4 per cent in western countries posterior pituitary involvement or compressive features
(11). Sellar tuberculomas usually present at younger age (18). Though pituitary is the usual site of abnormality,
with female preponderance. The most common present- hypothalamus may be the primary site in some. In the
562 Tuberculosis
latter subset of patients, growth hormone response studied by Sims and associates (29) and they found that
through insulin induced hypoglycaemia [acting through primary renal or adrenal abnormality did not explain
hypothalamus] is abnormal but response following hyponatraemia in patients with pulmonary TB. Schwartz
growth hormone releasing hormone infusion is normal et al (30) defined the syndrome of inappropriate anti-
(15). diuretic hormone secretion [SIADH] as incomplete
Clinically, these abnormalities manifest as short suppression of peripheral arginine vasopressin [AVP]
stature or hypogonadism. The adverse effect of growth secretion in the presence of subnormal plasma osmolality
hormone deficiency on adult height is observed in with no volume depletion. Weiss and Katz (31) first sug-
patients who suffer from TB meningitis before comple- gested that hyponatraemia of pulmonary TB fulfilled
tion of the growth spurt (17). It is important for the these criteria. The syndrome is usually accompanied by
clinicians caring for children with TB meningitis to be hyponatraemia, elevated urine osmolality and urinary
aware of this preventable cause of short stature. The sodium concentration. Since then several cases of
diagnosis of hypopituitarism due to TB should be consi- hyponatraemia associated with pulmonary TB have been
dered in patients with sellar or suprasellar calcification. described (32,33). This syndrome is also observed in
However, sellar and suprasellar calcification following patients with extra-pulmonary TB, such as TB meningitis
meningitis may not be accompanied by endocrine (34-36), TB epididymoorchitis (37) and miliary TB (38).
disturbances (19). Suprasellar calcification in a young The source of increased vasopressin hormone and
male with diabetes insipidus and anterior pituitary defects in vasopressin action in these patients are not
hormone deficiency may also be seen in craniopharyn- clear. Vorherr et al (39) could isolate bioassayable hor-
gioma and should be considered in the differential diag- mone from lung tissue of a patient with fatal pulmonary
nosis of TB hypopituitarism (20). Less common endocrine TB. He concluded that increased AVP in the lung tissue
abnormalities seen with TB are deficiency of the cortico- was due to adsorption of the hormone produced from
trophic and thyrotrophin hormones manifesting as the posterior pituitary (39). There is only one study where
secondary adrenocortical insufficiency and hypo- AVP has been measured by radioimmunoassay and the
thyroidism (5,15). Posterior pituitary deficiency can also nature of diluting defect systematically studied by water
occur and manifest as diabetes insipidus (5,21-23). load test (32). Hill et al (32) studied 28 patients with
Though hypopituitarism is the most common pulmonary TB and hyponatraemia, [mean serum sodium
abnormality with hypothalamic-pituitary involvement level 126 ± 3 mmol/l] and reported measurable levels of
due to TB, patients may also present with hormonal AVP at a time when it should have been undetectable
overactivity presenting as central precocious puberty by virtue of reduced plasma tonicity. They postulated
(24-26) or hyperprolactinaemia (5,15). In fact, Desai et al that hyponatraemia of TB may be regarded as a form of
(26) reported preceding history of TB meningitis in as SIADH (32). Since vasopressin was partially suppressed
many as 31 per cent of girls and 27 per cent of boys with by a further decrement in tonicity [following water load
centrally mediated precocious puberty in India (26). test], the source of inappropriate AVP was likely to be
Hyperprolactinaemia occurs as a result of stalk compres- the hypothalamic neurohypophyseal osmoregulatory
sion due to tuberculoma and release of anterior pituitary centre. This study excluded release of hormone from
from the inhibiting effect of dopamine (5,15). ectopic sites because AVP hormone could be suppres-
sed by water load test (39,40). A variable water load
ALTERED WATER AND ELECTROLYTE response has also been observed in these hyponatrae-
METABOLISM IN TUBERCULOSIS mic patients (32,41). Majority of these hyponatraemic
patients demonstrate impaired water excretion.
The syndrome of hyponatraemia and renal loss of sodium However, a subset of them also showed normal response
in patients with advanced pulmonary TB was first to water load and can be considered to have ‘reset osmo-
recognized by Winkler and Crankshaw in 1930 (27). stat’ (32,41). Thus, a disturbed or downset osmoregula-
Subsequently, Westwater et al (28) detected hyponatrae- tory mechanism occurring as a remote effect of active
mia in 48 per cent of patients with pulmonary TB. The TB is the mechanism for hyponatraemia and water
possible mechanism responsible for this syndrome was excretion abnormalities observed in patients with TB. The
Endocrine Implications of Tuberculosis 563
stimulus for abnormally increased AVP levels is not can also occur via congenital transmission (56,57). The
precisely known but could be the circulating mediators newborns of mothers with untreated TB have been
of the acute phase reaction, fever or inflammatory cyto- reported to have thyroid TB at birth (56,57).
kines acting on posterior pituitary (32,42,43). The reader Miliary involvement of the thyroid gland is more
is referred to the chapter “Disseminated and miliary tuber- common (58). Less commonly, focal TB of the thyroid
culosis” [Chapter 34] for more details regarding the signi- may occur, presenting as a localized swelling (58), cold
ficance of hyponatraemia in patients with miliary TB. abscess appearing superficially (59), acute abscess (60)
The hyponatraemia of TB is generally mild, asympto- or as diffuse thyroid enlargement (44,47). Fibrosis and
matic and self-limiting. Water restriction, the conven- adherence to adjacent structures may occasionally give
tional therapy for SIADH, has been effective in reversing rise to pressure symptoms (61) with dyspnoea or
the hyponatraemia in these patients (30,32,44) but is recurrent laryngeal nerve palsy (62). Presence of cervical
usually reserved for patients with symptomatic and/or lymphadenopathy and pressure symptoms have often
severe hyponatraemia [serum sodium < 120 to 125 resulted in erroneous diagnosis of malignancy in patients
mmol/l]. Occurrence of this syndrome in patients with with TB goitre (59). Chronic fibrosis of the thyroid has
TB meningitis carries a poor prognosis (34) and herein been described in association with TB (58). However, the
lies the importance of its prompt recognition and aetiological relationship of TB with sclerosing thyroiditis
management. remains doubtful. Clinically patients with thyroid TB
may present with features of hyperthyroidism and acute
TUBERCULOSIS AND THE THYROID GLAND thyroiditis (50,63-65).
Diagnosis of thyroid TB is not difficult to make if the
In 1862, Lebert (45) first described a case of TB of the possibility is considered. Seed (66) in 1939 proposed three
thyroid gland in a patient with disseminated TB (46). In prerequisites for making this diagnosis. These include:
1878, Chiari (47) described seven cases of microscopic [i] demonstration of Mycobacterium tuberculosis within the
involvement of thyroid in 1000 autopsies in patients who thyroid gland; [ii] a necrotic gland or TB abscess having
died from disseminated TB. Bruns (48) in 1893, first epithelioid cell granulomas with peripheral lymphocyte
described a case of TB of the thyroid gland even when cuffing, Langhans’ giant cells and central caseation
there was no clinical evidence of pulmonary TB. With necrosis; and [iii] demonstration of a definite focus of
increasing prevalence of HIV, concomitant infection of TB outside thyroid. Presently, it is believed that histologi-
thyroid TB is being reported (49). The true incidence of cal and bacteriological confirmation is adequate to make
TB thyroiditis, however, is difficult to determine because a diagnosis and fulfillment of the third criterion is not
clinical suspicion is rarely made by the physician. On essential (55). Fine needle aspiration cytology demons-
the other hand, the TB involvement of the thyroid is not trates abundance of lymphocytes and is a cost effective
uncommon [2% to 7%] in autopsy studies (50,51). Preva- approach for the diagnosis of thyroid TB. However, the
lence of the disease was first recognized when Coller and stained smear may be negative for acid-fast bacilli [AFB],
Huggins (52) in 1926 found evidence of TB in 5 of 1 200 and in such situations, detection of Mycobacterium
histopathological specimens of goitre operated between tuberculosis by polymerase chain reaction may be helpful
1921 to 1926. Rankin and Graham (53) studied a large (67,68). Microscopic features of the disease resemble
series of 20 758 partial thyroidectomy specimens from sarcoidosis and subacute [giant cell] thyroiditis. The
the Mayo Clinic between 1920 and 1931 and diagnosed granulomatous inflammation in subacute thyroiditis is
TB in 21 cases (53). A similar incidence was reported by characterized by scattered disorganized follicles lined
Levitt (54) who found only two cases of TB among 2 114 with necrotic epithelium and infiltration by neutrophils,
consecutive thyroidectomy specimens (54). In a study macrophages and multinucleate cells. However, unlike
from India, Das et al (55) reported the prevalence of TB TB, subacute thyroiditis is not associated with caseation
to be 0.6 per cent among 1 283 thyroid lesions subjected necrosis (69). Mycobacterium tuberculosis does not grow
to aspiration cytology. The mode of spread of TB infection in the centre of caseating lesions because of its high
to the thyroid gland is not known. Besides disseminated oxygen requirement. However, thyroid gland is an
TB and cervical lymphadenopathy, thyroid involvement exception because of its rich vascularity (69). Computed
564 Tuberculosis
tomography of the thyroid may reveal peripheral raised level has also been observed in those with normal
enhancing low density abscess and ultrasound demons- serum calcium (85). The presence of hypercalcaemia has
trates heterogeneous hypoechoic mass with regional been observed even in anephric patients with TB (87).
lymphadenopathy (70). The finding of increased concentration of 1,25[OH]2D3
The treatment of TB with para-aminosalicylic acid in patients with end-stage renal failure and TB is in
and ethionamide may produce goitre (71). Both drugs marked contrast to that observed in other patients with
have actions similar to propylthiouracil and complete end-stage renal failure with no TB (87). Lung is the
resolution of the goitre occurs when these drugs are extrarenal site of 1,25[OH]2D3 synthesis as is supported
withdrawn (72). by detection of high concentration of this hormone in
A few patients with thyroid TB also have dysfunction the pleural fluid of patients with TB pleuritis (88). In vitro
of the thyroid gland. Mosiman (73) observed nine such studies have shown that alveolar macrophages and
patients with seven of them having thyrotoxicosis on lymphocytes are important source of 1,25[OH] 2 D 3
clinical examination. Kapoor et al (74) described a patient production in patients with TB (89-91). The hormone
of hyperthyroidism [high 131I uptake with uniform tracer production does not seem to be regulated by the factors
distribution] with histopathological specimen of the that normally modulate renal 1-α-hydroxylase activity
thyroid showing evidence of TB. However, such as there is hypercalcaemia and increased circulating
occurrence of thyrotoxicosis does not prove the cause and 1,25[OH]2D3 despite suppressed serum parathyroid
effect relationship. Hypothyroidism as a result of prog- hormone and high normal serum phosphate (77,92).
ressive thyroid destruction is expected and has been more Decline in serum parathyroid hormone and increase in
commonly observed (55). serum calcium and phosphorus concentrations are the
Alterations in circulating thyroid hormones levels are physiologic factors that reduce vitamin D synthesis in
also frequent in chronic non-thyroid illnesses (75,76). healthy subjects. Studies on culture of alveolar macropha-
Serum thyroid hormones levels in patients with TB may ges recovered from patients with sarcoidosis have
show low or normal serum total T4, low serum total T3, suggested that some lymphokines produced locally or
normal thyroid stimulating hormone [TSH] and increase systemically may be the main factors regulating 1-α-
in reverse T3, a profile consistent with sick euthyroid hydroxylase activity in granulomatous tissue (93). The
syndrome. Chow et al (75) reported 63 per cent prevalence production of 1,25[OH]2D3 by the granulomatous tissue
of this syndrome in pulmonary TB. They also observed may also play an important role in the regulation of the
that patients with severe illness had lower free T3 values antituberculosis immune response (94,95). Indeed it has
and higher mortality. been shown in patients with active pulmonary TB that
CD4+ T-lymphocytes recovered from bronchoalveolar
HYPERCALCAEMIA AND TUBERCULOSIS lavage fluid express 1,25[OH]2D3 (96,97). Production of
ectopic 1,25[OH]2D3 within granulomatous tissue could
Hypercalcaemia has been described in up to 50 per cent be regulated by antimycobacterial products, independent
of adult patients with TB (77-80). Differences in the of parathyroid hormone and 25[OH]2D 3. Increased
dietary intake of calcium and vitamin D account for the 1,25[OH]2D3 can exert its effect locally and enhance
wide variation in the prevalence of this disorder (77,78). antimycobacterial activity of human monocytes and
In a hospital-based study from Hong Kong, Shek et al macrophages. Further experiments on cultured macro-
(80) observed that TB constituted six per cent of all cases phage (97) and supplementation studies on TB patients
of hypercalcaemia and was the second most common have shown that the efficacy of pyrazinamide is
cause of hypercalcaemia after malignancy. Hyper- enhanced by vitamin D and its active metabolites. Thus,
calcaemia has also been reported among children with hypercalcaemia observed in TB and other granulomatous
TB though exact prevalence is not known (81-83). disorders may be the result of an antigen driven host
Abnormal vitamin D metabolism has been implicated defense. Asymptomatic hypercalcaemia may be present
in the pathogenesis of hypercalcaemia in TB. A higher in up to one-third of newly diagnosed patients with TB.
mean serum 1,25[OH]2D3 has been reported in patients Presence of hypercalcaemia has also been reported in
with TB compared with control subjects (83-86) and the extra-pulmonary TB as, e.g., abdominal and hepatic
(98-100). Infection with nontuberculous mycobacteria 1,25[OH]2D3 (91-98) and serum levels of parathyroid
such as Mycobacterium avium-intracellulare complex in hormone may rise by 36 per cent in response to hypocal-
acquired immunodeficiency syndrome [AIDS] is also caemia induced by isoniazid therapy (111). Addition of
associated with hypercalcaemia (101,102). rifampicin increases stress on calcium metabolism and
However, hypercalcaemia may be masked at the time parathyroid hormone levels may further rise by 57 per
of initial presentation because of low serum albumin cent (112). Mechanism by which these drugs produce
levels and manifests only when serum albumin levels their effects are different. Rifampicin acts through hepatic
become normal with antituberculosis treatment (79). enzyme induction and conversion of 25[OH]D3 to an
Besides hypercalcaemia, hypercalciuria has also been inactive metabolite (111). Isoniazid induces inhibition of
observed in some patients with TB. Calcium absorption 1-α-hydroxylation and decreases calcitriol synthesis
studies have shown that this hypercalciuria is of (111). In developing countries antituberculosis treatment
absorptive nature, possibly related to increased serum may trigger osteomalacia (98). This may be related to pre-
calcitriol levels (103-105). existing vitamin D deficiency in these patients because
Patients with TB [and sarcoidosis] may be abnormally it is not observed in places like Hong Kong where vitamin
sensitive to vitamin D supplementation (79). If TB occurs D status is normal (119).
in a patient with renal failure, serum calcium levels may
increase and vitamin D supplementation may have to VITAMIN D DEFICIENCY AND TUBERCULOSIS
be withdrawn (87). Despite the apparent similarity with
the pathogenesis of hypercalcaemia and hypercalciuria A role of vitamin D in TB has been speculated for a long
in sarcoidosis, there are important differences in the time. Cod liver oil was first advocated for the treatment
presentation, clinical course and prognosis of abnormal of TB in 1770 and was widely used till the nineteenth
calcium metabolism in these two disorders. In sarcoi- century (120-122). Many workers tried calciferol in the late
dosis, hypercalcaemia frequently occurs during the 1940s and rationalized this treatment by suggesting its role
summer months following exposure to sunlight and in the calcification of TB lesions. It was believed to be
patients are often hypercalcaemic at the time of presen- effective in the treatment of skin TB (121,122). It was also
tation. Further, the hypercalcaemia and hypercalciuria claimed that in both guinea pigs (123) and humans (124),
are often protracted and may lead to lithiasis, nephrocal- severe late disease would be fatal if treated with
cinosis, urinary tract infection, chronic renal failure and tuberculostatic drugs alone and could be cured if calciferol
even death. In contrast, hypercalcaemia associated with was also added to the treatment. With the advent of
TB is usually mild and asymptomatic (105), occurs after effective antituberculosis drugs in the mid 1950s,
several months of antituberculosis treatment (106) and enthusiasm for treating TB with vitamin D subsided.
generally carries a good prognosis (107). In both the However, it formed the basis of subsequent investigations
diseases, hypercalcaemia is corrected by the administra- linking vitamin D deficiency in Asian Indians to their
tion of glucocorticoids (108). Ketoconazole administra- susceptibility to develop pulmonary TB (84,114,125-129).
tion inhibits cytochrome P-450 dependent 1-α-hydroxy- Davies et al (114) compared 25[OH]D3 levels in untreated
lase and reduces serum 1,25[OH]2D3 in healthy subjects TB patients with healthy control subjects and found
(109). Administration of this drug for hypercalcaemia in significantly lowered levels in patients with TB. In a similar
patients with TB resulted in normalization of serum study, Grange et al (129) showed that patients with higher
calcium levels and decline of 1,25[OH]2D3 levels within 25[OH]D3 levels had less extensive radiographic disease.
48 hours (110). In an another retrospective study, foreign-born persons
The problem of hypercalcaemia in TB and its exacer- in London with TB were found to have significantly lower
bation with antituberculosis drugs may not be common level of 25[OH]2D3 (130).
in India because of the wide prevalence of vitamin D Recently, vitamin D deficiency and single nucleotide
deficiency in India (111). Antituberculosis drugs are polymorphisms in the vitamin D receptor [VDR] gene
known to affect calcium and phosphorus metabolism have been shown to be associated with post-primary
(112-118). Both rifampicin and isoniazid have been pulmonary TB in Asian Gujarati community living in
shown to decrease serum levels of 25[OH]D 3 and London (131). There was high prevalence of 25[OH]D3
566 Tuberculosis
deficiency among this community with lowest serum DIABETES MELLITUS AND TUBERCULOSIS
concentration found in patients with active disease.
Several retrospective (139,140) and prospective (141,142)
Undetectable 25[OH]2D3 levels were associated with a
studies have highlighted that patients with diabetes
10-fold increased risk of TB. This study (131) further
mellitus are at higher risk for the development of TB. In
revealed the synergistic association between the presence
a retrospective study involving 1529 patients with
of T-allele related to TaqI single nucleotide polymorphism
diabetes mellitus, the risk of acquiring TB was found to
[SNP] of the VDR gene and 25[OH]D3 deficiency. The
be 4.8 per cent compared to 0.8 per cent for the general
presence of f-allele related to FokI SNP of the VDR gene
population (139). The risk was highest [24%] in patients
was also observed to be frequent in patients with extra-
with Type I diabetes mellitus [38 times more compared
pulmonary disease (131). There are variable reports
to the general population under 40 years of age] (139).
related to VDR expression and SNP of common VDR
Lester (141) found TB to be the most common complicat-
polymorphisms, i.e., FokI, BsmI and TaqI (132,133). In a
ing illness [16.5%] in Ethiopian patients with Type I
case-control study, Babb et al (134) did not find an
diabetes mellitus. In India, Patel (140) found TB to be
association between VDR genotype and TB, however,
most common complicating illness [5.9%] in a large
the time taken to convert to sputum negativity while on
cohort of 8 793 patients with diabetes mellitus. Similar
antituberculosis treatment was independently predicted
findings have been reported by Swai et al (142) who
by the VDR genotype (134). Till date no study has prospectively followed 1250 African patients with
assessed expression of VDR in pulmonary macrophages diabetes mellitus for seven years. Seventy of them [5.4%]
and its association with pulmonary TB. Therefore, the developed pulmonary TB and 0.2 per cent developed
exact mechanism linking the SNPs of VDR with TB, is spinal TB. In 25.7 per cent, TB was diagnosed prior to
not known. It has, therefore, been postulated that vitamin the onset of diabetes mellitus and in 45.7 per cent
D plays a protective role in TB by reducing the incidence diagnosis was made subsequently (142). In 20.6 per cent,
of infection developing into overt disease and later by TB and diabetes mellitus were diagnosed simultaneously.
retarding its progression. The prevalence of TB was greater in the young, in those
Douglas et al (135) have provided further evidence with a low body mass index [BMI], in insulin dependent
in support of vitamin D deficiency and susceptibility to diabetes mellitus patients compared to those with non-
TB. They reported a striking seasonal variation of TB insulin dependent diabetes mellitus [9% vs 2.7%] and in
incidence, with peak after the summer and nadir in the those with poorly controlled diabetes mellitus (142).
spring; unlike that observed in other respiratory diseases. Mortality rate in these 70 patients was 24.3 per cent. In
They suggested seasonal changes in vitamin D levels as another study (143) in 702 patients with diabetes mellitus,
the cause for the paradoxical reversed seasonality of TB the morbidity due to pulmonary TB was found to be 9.4
(135). In the post-winter period, low levels of vitamin D times higher as compared to the general population.
may result in reactivation of dormant mycobacteria Recently, diabetes mellitus has been found to be
(136,137). Cellular basis for vitamin D deficiency and associated with a progressive shift of male predominance
susceptibility to TB has been explained by an effect of in pulmonary TB (144). Pulmonary TB has been reported
vitamin D deficiency on cell-mediated immunity to be a common complication among diabetic patients
(136-137). Monocytes have been shown to have receptors from Africa (145). Diabetes mellitus is the most common
for 1,25[OH] 2D 3. Rook et al (136) have shown that co-morbidity in pulmonary TB followed by malignancy
incubation of macrophages with physiological and is associated with a higher probability of cavitary
concentration [10 –9 M] of 1,25[OH] 2 D 3 results in nodules (146).
inhibition of intracellular growth of Mycobacterium Though the relative risk for developing pulmonary
tuberculosis which is in addition to the effect of inter- TB disease is 3.5 times higher in patients with diabetes
feron-γ. Mycobacterial killing is enhanced by mellitus than in the matched control subjects (147), rate
1,25[OH]2D3 by an increased nitric oxide production of infection with Mycobacterium tuberculosis is not
(138). Mice deficient in nitric oxide synthase 2 and different. Similar prevalence of tuberculin skin test
vitamin D had more severe form of pulmonary lesion reactivity has been observed in patients with diabetes
(138). mellitus and normal subjects (148). The sputum positivity
rate in patients with diabetes mellitus and co-existent diabetes mellitus as well as TB patients (155). Tsukaguchi
TB has been variable in comparison to subjects without et al (156) have reported significantly lowered production
diabetes mellitus with pulmonary TB. Sputum AFB of interleukin-1β [IL-1β] and tumour necrosis factor-α
positivity has been variably reported to be relatively [TNF-α] by the peripheral blood monocytes in patients
higher (148) to less than usual (149) in subjects with with TB and co-existent diabetes mellitus compared to
diabetes mellitus. Recently, the impact of diabetes patients with TB who do not suffer from diabetes
mellitus as a risk factor for incident pulmonary TB cases mellitus. The production of IL-1β and TNF-α was
was estimated using India as an example (150). Diabetes significantly lower in patients with poor glycaemic
mellitus accounted for 14.8 per cent of pulmonary TB control (156). An increased susceptibility to TB could also
and 20.2 per cent sputum smear-positive TB cases. The be due to thickened alveolar epithelium and pulmonary
incidence of smear-positive cases was about 15 per cent basal lamina, reduced pulmonary diffusion capacity,
higher in urban as compared to rural areas (150). These lung volumes and elastic recoil in patients with diabetes
observations suggest that diabetes mellitus significantly mellitus. Pathogenesis of these changes is currently
contributes to the burden of incident TB cases in India thought to be due to non-enzymatic glycosylation of
and the association is particularly strong for the infectious tissue proteins inducing an alteration in connective tissue
form of TB. These findings are important for planning in diabetes mellitus (157). Further, diabetic autonomic
TB control activities as future projections indicate that neuropathy also leads to abnormal basal airway tone due
the burden of diabetes mellitus in India is likely to to an alteration in vagal pathways and, thus, causes a
increase in coming years (150). reduced bronchial reactivity and bronchodilation (157).
Clinical symptoms and presentation of pulmonary The side-effects of modern antituberculosis treatment
TB are similar in patients with and without diabetes do not differ in patients with and without diabetes
mellitus (151). Pulmonary TB occurs predominantly in mellitus (158) except peripheral neuropathy which is
lung apices. It has been suggested that in patients with much more common in patients with diabetes mellitus
diabetes mellitus, TB occurs predominantly in the lower (128). Insulin requirements may also occasionally
lobes with frequent cavitary lesions (151). Lower lung increase in patients with diabetes mellitus receiving
field TB was found to be significantly associated with rifampicin (159).
female gender and, in patients older than 40 years of age Bacteriological conversion rates have been found to
(152). However, in a recent case-control study, be similar for TB patients with and without diabetes
distribution of lesions including cavitary disease was mellitus (160). The degree of control of diabetes mellitus
found to be similar in chest radiographs of TB patients does not influence this conversion rate. Relapse rates after
with or without diabetes mellitus (153). The reader is short-course antituberculosis treatment have been found
referred to the chapter “Lower lung field tuberculosis” to be similar for TB patients [10%] with and without
[Chapter 15] for more details. diabetes mellitus and relapse occurred at a similar time
The cause of an increased susceptibility of diabetic interval [6 to 30 months] in both the groups (160).
patients to develop TB is not known. In a recent study However, most of the TB patients without diabetes
analysing the association between human leucocyte mellitus relapsed with sensitive strains and a good
antigen-[HLA-] DRB[1], DQB[1] gene and pulmonary TB response was observed on re-treatment while patients
complicated with diabetes mellitus, the presence of with diabetes mellitus relapsed more often with resistant
DRB[1]*09 allele was found to increase the susceptibility strains (160). Bashar et al (161) found significant increase
towards pulmonary TB, while DQB[1]*05 was observed in multidrug-resistant TB in patients with diabetes
to be protective for TB in patients with diabetes mellitus mellitus [36% vs. 10%] compared to individuals without
(154). diabetes mellitus.
An increased susceptibility of patients with diabetes Kameda et al (160) found no relationship between
mellitus to develop TB could be due to neutrophilic degree of glycaemic control and relapse rate. However,
dysfunction and impaired cytokines production (155). a significant negative correlation was observed between
Interferon-α [IFN-α] production capacity of white blood the glycaemic control and the relapse rate by Kado et al
cell culture has been found to be reduced in patients with (162). Thus, TB patients with diabetes mellitus seem to
568 Tuberculosis
have a response rate and long-term relapse rate similar in the pathogenesis of diabetes mellitus (174-176).
to those without diabetes mellitus. However, they have Roychowdhury and Sen (169) have suggested TB of the
a poor prognosis once the relapse occurs. pancreas to be a possible cause of glucose intolerance.
However, pancreatic involvement is rare in TB. Another
TUBERCULOSIS AND DIABETES MELLITUS suggested possibility is stress induced diabetes mellitus
which can occur in major illnesses like TB (171).
Though the evidence that diabetic patients are at
The evidence that mycobacteria are linked to diabetes
increased risk of developing TB is well-known, the
mellitus has been increasing rapidly. The pancreatic islet
converse relationship, i.e., the patients with TB have a
amyloid deposits have been observed in patients with
higher prevalence of diabetes was not known till 1950s
systemic TB and undergo resolution following rifampicin
(163,164). When oral glucose tolerance test was used for
treatment. Transitory changes in carbohydrate metabo-
diagnosis, as in the study reported by Nichols in 1957
lism in patients with TB may lead to insulin deficiency
(163), a high prevalence of diabetes was observed in
with persistent hyperglycaemia (177).
patients with TB. Since then, several studies have shown
Abnormalities of glucose tolerance in TB improve
high prevalence of impaired glucose tolerance test in
following commencement of antituberculosis treatment.
patients with TB (165-169) with rates varying from 1.9 to
However, some patients with rifampicin induced early
41 per cent. Comparison between these studies is difficult
phase hyperglycaemia have been reported (159).
due to different criteria used for the diagnosis of diabetes
Augmented intestinal absorption of glucose has been
mellitus. In 1985, the World Health Organization
postulated to be the cause of this abnormality as the
proposed criteria for the diagnosis of diabetes mellitus
intravenous glucose tolerance is normal in these patients
and glucose tolerance test which gained wide acceptance
(159).
(170). Adopting these criteria, Mugusi et al (171) investi-
The widespread involvement of endocrine glands in
gated the prevalence of glucose tolerance abnormalities
clinical TB is an important consideration to be kept in
in 506 Tanzanian patients with active TB. He reported a
mind by the physicians managing TB. Further studies
crude prevalence rate of four per cent for diabetes
are required to conclusively explore the reported
mellitus in these patients, which is four times higher
predisposition of certain endocrine disorders, such as
compared to that for the general population [0.9%].
vitamin D deficiency to TB and causes of increased
Impaired glucose tolerance was observed in additional
prevalence of diabetes mellitus in TB.
16.2 per cent of patients, a prevalence which was twice
the rate observed in general population [8.8%]. In another
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574 Tuberculosis
Tuberculosis and
Human Immunodeficiency
Virus Infection 40
Srikanth Tripathy, Myo Paing, Jai P Narain
INTRODUCTION deaths, including 230 000 infected with HIV (7). These
deaths comprise 25 per cent of all avoidable deaths in
Tuberculosis [TB], an ancient disease, continues to remain
developing countries. Ninety-five per cent of TB cases
even today a major public health problem in much of
and 98 per cent of TB deaths occur in developing count-
the developing world (1). The problem is now further
ries. Three-fourths of TB cases in developing countries
complicated by relentless spread of the human
occur among the economically productive age group i.e.,
immunodeficiency virus [HIV], which causes acquired
15 to 40 years.
immunodeficiency syndrome [AIDS] pandemic (2,3). The
The situation is further complicated by the rapidly
rapid growth of HIV epidemic in many countries of the
spreading HIV pandemic (8). According to the recent
world resulted in an equally dramatic rise in the
World Health Organization [WHO] and the Joint United
estimated number of new TB cases. Human immuno-
Nations Programme on HIV/AIDS [UNAIDS] update
deficiency virus related TB continues to increase even in
on AIDS epidemic, the revised global estimate of people
the countries with well-organized national TB control
living with HIV/AIDS [PLHIV] has been calculated to
programmes that are successfully implementing the
be 33.2 million [range 30.6 to 36.1 million], a reduction
DOTS, the internationally recommended strategy for TB
of 16 per cent compared with the estimate of 39.5 million
control (4). Infection with HIV results in progressive
in 2006 (9,10). The major contribution to this new estimate
immunodeficiency and renders the infected person
has been from the revised figures for India. According
increasingly vulnerable to a wide range of pathogens. In
to the new estimates, 2.5 million people [range 2 to 3.1
many parts of the world, TB is the most common
million]; or about 0.4 per cent of adult population in India
opportunistic infection [OI] in HIV infected persons (5,6).
are HIV-seropositive and these estimates are less than
The immune defects produced by HIV influence the
half the earlier reported figures of 5.7 million [range 3.4
natural history of TB infection. Thus, the HIV pandemic
to 9.4 million] people (11). In light of these data, it is likely
has altered both the epidemiology of TB and the measures
that the estimates related to HIV-TB co-infection will be
for approaches to its control. In populations where the
revised in near future.
risk of TB and HIV infection is high, the incidence of TB
The HIV epidemic has reached a generalized stage at
is expected to increase particularly in a number of
the national level in three countries of Asia: Cambodia,
developing countries in Africa and Asia.
Myanmar and Thailand (12-14). In 2003, in Cambodia
the prevalence of HIV infection among those aged 15 to
EPIDEMIOLOGY
49 years was estimated to be 2.6 per cent, in Myanmar
Mycobacterium tuberculosis infects a third of the world’s the prevalence was 0.7 per cent and in Thailand the preva-
population. Globally, in 2006, there were about 9.2 lence was 1.4 per cent. The HIV epidemic is generalized
million new cases of TB of which nearly 700 000 were in five states of India, namely, Andhra Pradesh,
infected with HIV (6). In 2006, there were 1.7 million TB Karnataka, Maharashtra, Manipur, and Nagaland (13).
Tuberculosis and Human Immunodeficiency Virus Infection 575
As per WHO/UNAIDS estimates [2004] (12), up to 50 Table 40.1: Estimated prevalence of human immuno-
per cent of people with HIV or AIDS develop TB. At least deficiency virus in new tuberculosis cases and estimated
11 per cent of AIDS deaths and possibly 50 per cent are incidence of tuberculosis in human immunodeficiency virus-
positive adults aged 15-49 years*
caused by TB. Of the 3.6 million adults with HIV infection
in the South-East Asia Region, nearly half are likely to be Prevalence of HIV Incident cases of
infected with TB. Tuberculosis is the most important life- in new adult TB [all forms] in HIV+
TB cases [%]† adults [thousands]‡
threatening associated with HIV infection. In Thailand
60 per cent of AIDS patients have had pulmonary TB. Cambodia 13.0 6.5
This was 80 per cent in Myanmar, 56 per cent in India and China 0.7 5.8
75 per cent in Nepal (6). Myanmar 6.8 5.5
Figure 40.1 (7) and Table 40.1 (15,16) show geog-
Nepal 2.9 0.9
raphical distribution of HIV-TB cases and incidence of
India 5.2 54.4
TB among HIV-positive adults respectively, in countries
with a high TB/HIV burden in Asia (6,7,15,16). The three- Indonesia 0.5 2.3
fold higher proportion in South-East Asia could be Thailand 8.7 5.3
attributed primarily to the high burden in India (8). Vietnam 2.8 1.7
Table 40.2 shows the proportion of estimated TB
deaths [numbers and rates] among those infected with *Detailed methodology as per reference 15
HIV for some countries in the two regions. In the South- † Source: reference 6
East Asia Region, 0.7 per cent of prevalent TB cases are ‡ Year 2002 estimates. Source: reference 16
TB = tuberculosis, HIV = human immunodeficiency virus;
co-infected with HIV and four per cent of TB deaths [11% + = positive
in Thailand] occurred among HIV infected cases (6,7).
Figure 40.1: Geographical distribution of HIV-positive TB cases in 2006. For each country or region, the number of incident TB cases
arising in people with HIV is shown as a percentage of the global total of such cases
AFR* is all countries in the WHO African Region except those shown separately; AMR* excludes Brazil; EUR* excludes the Russian
Federation; SEAR* excludes India
HIV = human immunodeficiency virus; TB = tuberculosis; WHO = World Health Organization; AFR = African region; AMR = American
region; EMR = Eastern Mediterranean region; EUR = European region; WPR = Western Pacific region; SEAR = South-East Asian region
Reproduced with permission from “WHO Report 2008. Global Tuberculosis Control: surveillance, planning, financing. Geneva: World
Health Organization;2008. WHO/HTM/TB/2008.393 (reference 7)”
The World Health Organization updates these data annually. The reader can access theupdated information from the WHO report of the
current year available at the URL: http:/www.who.int/topics/tuberculosis/en/
576 Tuberculosis
Table 40.2: Deaths due to tuberculosis in human immuno- The HIV sentinel surveillance carried out among TB
deficiency virus positive patients in countries with high patients in many countries of the world shows that HIV
tuberculosis and human immunodeficiency virus burden prevalence rates are increasing quite rapidly. The HIV
Numbers Rate [per 100 000 seroprevalence among TB patients in different regions
[thousands] population] of India varies [Table 40.3] (17-34). These differences
India 22.2 2.1 could be due to selection bias, but a trend could be noted
Myanmar 1.4 2.9
for the individual site.
Clinical and surveillance data show that TB is now
Thailand 1.3 2.1
the most important life-threatening OI associated with the
South-East Asia 26.0
HIV in Asia. For example, in Thailand, 60 per cent of AIDS
Cambodia 2.4 17.6
patients seen in a Bangkok hospital between 1985 and 1993
China 2.2 0.2
had pulmonary TB. Similar data have been reported from
Malaysia 0.1 0.3 Myanmar [80%], India [56%] and Nepal [75%] (12,13). The
Papua New Guinea 0.1 2.2 HIV is clearly the most potent risk factor for the
Philippines 0.2 0.3 development of clinical TB in many individuals.
Vietnam 0.4 0.5
Western Pacific 5.5 PATHOGENESIS
Total 31.5
The reader is referred to the chapters “Pathology” [Chapter
Source: reference 6 5] and “Reactivation and reinfection tuberculosis” [Chapter
47] for more details regarding the natural history and
pathogenesis of TB including HIV-TB.
Given the annual risk of clinical TB, which varies from
five to eight per cent, among individuals dually infected CLINICAL PRESENTATION
with HIV and TB, further increases in TB incidence seem
Unlike other OI which occur at CD4+ counts below 200/
inevitable. Rapid increase in TB is attributed primarily
mm3, active TB occurs throughout the course of HIV
to HIV in countries of sub-Saharan Africa, such as
disease (3). The clinical presentation of TB in HIV infected
Tanzania, Zambia, Malawi and Burundi (6,7).
patients varies depending on the severity of
The HIV epidemic is already having a profound and
immunosuppression. In patients with earlier stages of
prolonged impact on TB in Asia and the Pacific. In the
HIV disease, clinical presentation of TB tends to be similar
Chiang Rai province in Northern Thailand a case control
to that observed in persons without immunodeficiency.
study between 1990 and 1998 has shown that the Pulmonary disease is the most common, often with focal
proportion of TB cases attributable to HIV rose to 72 per infiltrates and cavities. In patients with more marked
cent in male patients and 66 per cent in female patients. immunodeficiency, with CD4+ counts of less than
This continuing increase in TB cases attributable to HIV 200/mm3, the features of TB are often atypical, with a
has occurred even when there is marked reduction in much greater frequency of extra-pulmonary involve-
HIV prevalence in the area (12-14). ment, especially of the lymph nodes. Diffuse pulmonary
The incidence of TB in HIV infected patients is about disease without cavitation often involving the lower lobes
a 100-fold greater than that in the general population. and prominent mediastinal or paratracheal adenopathy
Even more dramatic is the effect seen when persons who are often seen in patients with advanced HIV disease.
are already infected with HIV become newly infected The radiological shadows in the lungs may change
with Mycobacterium tuberculosis. In two outbreaks, in rapidly. Patients with advanced HIV disease more often
which HIV infected persons were exposed to infectious have miliary TB and involvement of the lymphatic
TB cases, 40 per cent of the infected persons developed system, central nervous system [parenchymal and
active TB within a few months (8). In HIV infected meningeal], soft tissue, bone marrow, liver and other
persons, active TB seems to develop soon after infection viscera. Mycobacterium tuberculosis may be isolated from
and progress rapidly, often resulting in death (8,12,13). the blood or faeces in some cases (3).
Table 40.3: Human immunodeficiency virus seroprevalence in tuberculosis patients as reported

in various studies published from India
Author (reference) Place of Period of No. of TB HIV-positive

study study patients cases No. [%]
Sharma et al (17) Delhi 1994-99 500 2 [0.4]

Sharma et al (18) Delhi 2000-02 555 52 [9.4]
Piramanayagam et al (19) Delhi 2003-05 374 31 [8.3]
Ramachandran et al (20) Chennai 1997-98 2361 111 [4.7]
Ahmad et al (21) Aligarh 1996-97 1006 8 [0.8]
1997-98 1215 11 [0.9)
1998-99 1126 14 [1.2]
1999-00 1330 24 [1.8]
2000-01 1204 34 [2.8]
1996-2001 5881 91 [1.6]
Shahab et al (22) Aligarh* 1999-2000 250 5 [2.0]
Prasad et al (23) Lucknow 1995-96 400 † [1.3]
1996-97 225 † [1.8]
1997-98 350 † [4.3]
1995-98 975 24 [3.1]
Purohit et al (24) Ajmer 1993-95 2448 18 [0.7]
Mohanty and Basheer (25) Mumbai 1988-89 468 12 [2.6]
1989-90 707 19 [2.7]
1990-91 641 25 [3.9]
1991-92 678 65 [9.6]
1992-93 596 59 [9.9]
1993-94 788 90 [10.2]
1989-94 3878 260 [6.7]
Paranjape et al (26) Pune 1991 344 11 [3.2]
1992 187 11 [5.9]
1993 395 20 [5.0]
1994 1046 105 [10.0]
1995 1189 184 [15.5]
1996 1457 293 [20.1]
1991-96 4618 694 [15.0]
Tripathy et al (27) Pune 1995 1256 152 [12.1]
Solomon et al (28) Chennai 1991 392 3 [0.8]
1992 680 9 [1.3]
1993 358 12 [3.4]
1991-93 1430 24 [1.7]
Samuel et al (29) Chennai 1996 112 19 [17.0]
WHO/IUATLD Project (30) Delhi 1995 11657 * [1.0]
Banavaliker et al (31) Delhi 1994-95 1002 5 [0.5]
Gupta et al (32) Udaipur 1995-96 520 40 [7.7]
Talib et al (33) Aurangabad 1995-96 340 16 [4.7]
Vasudeviah (34) Pondicherry 1994 500 20 [4.0]
1995 550 19 [3.5]
1996 500 27 [4.9]
1994-96 1600 66 [4.1]
* Paediatric series
† Exact number of HIV-seropositive patients not mentioned
TB = tuberculosis; HIV = human immunodeficiency virus; WHO = World Health Organization; IUATLD = International Union Against
Tuberculosis and Lung Disease
578 Tuberculosis
In a patient with HIV infection, large lymph node kept in mind that these HIV-positive children may have
size [> 4 cm], rapidly growing lymph nodes, asym- other OI apart from TB.
metrical lymphadenopathy, tender, painful lymph nodes Clinical signs suggesting HIV infection in children
not associated with local infection, matted or fluctuant are weight loss or abnormally slow growth, chronic
lymph nodes, presence of constitutional features [fever, diarrhoea, more prolonged fever lasting more than a
night sweats, weight loss] and hilar or mediastinal month, generalized lymphadenopathy, oropharyngeal
lymphadenopathy on chest radiograph warrant further candidiasis, recurrent common infections [ear infections,
investigation. In HIV infected persons with TB and severe pharyngitis], persistent cough, generalized rash, neurolo-
immunosuppression, TB lymphadenopathy may be gical problems, delay in development, bilateral parotid
acute and resembles acute pyogenic lymphadenitis. gland enlargement, hepatosplenomegaly, recurrent
Tuberculosis serositis, especially pleural effusion is abscesses, meningitis and recurrent herpes simplex.
more common in HIV-seropositive individuals. Tuber- In India, provision is available under the Revised
culosis may occur at unusual sites. Tuberculomas of the National Tuberculosis Control Programme [RNTCP] and
brain, abscesses of the chest wall, testes or elsewhere can the National AIDS Control Programme to evaluate
occur. In the presence of marked immunosuppression patients with TB for HIV infection and vice versa to
sputum smears may be negative for acid-fast bacilli [AFB] maximize the case detection rates (36).
even in the presence of extensive radiological changes
and the tuberculin skin test [TST] may be negative. In a
DIAGNOSIS
patient with TB, presence of generalized lymphadeno-
pathy, oral candidiasis, chronic diarrhoea not responding Given the fact that most cases with HIV-TB have extra-
to standard anti-diarrhoeal treatment for more than a pulmonary TB and smear-negative or paucibacillary
month, herpes zoster, recurrent pneumonia, bacteraemia pulmonary TB, there is an urgent need for development
[especially caused by Salmonella typhimurium], oral hairy of newer diagnostic tools to facilitate an early diagnosis.
leukoplakia, persistent painful genital ulceration or These tests should be cheaper, user friendly and should
Kaposi’s sarcoma suggest the possibility of associated have wider application in field settings. This becomes
HIV infection. The presence of symptoms such as weight more important in areas where HIV is highly prevalent
loss more than 10 kg or more than 20 per cent of the in order to interrupt disease transmission and prevent
original body weight, pain on swallowing [due to oral morbidity and mortality.
candidiasis] and burning sensation of the feet [peripheral Published evidence suggests that sputum smears
sensory neuropathy] should also alert the clinician to the reveal AFB less frequently in HIV-seropositve patients
possibility of associated HIV infection in a patient with with pulmonary TB, especially in late HIV disease
TB. According to the revised WHO clinical staging of (37-40). However, in one study the yield of sputum smear
HIV/AIDS for adults and adolescents [2005] (35), a and culture was similar in pulmonary TB patients with
patient with pulmonary TB diagnosed in last two years and without HIV infection (41). Clinicians should also
is staged as having clinical stage 3 disease, whereas a subject all bronchoscopy and biopsy specimens from an
patient with extra-pulmonary TB is staged as having HIV infected patient to mycobacterial smear and culture
clinical stage 4 disease. examination (42). Diagnosis of extra-pulmonary, dissemi-
nated and miliary TB may require mycobacterial culture
Paediatric Tuberculosis
of bone marrow, lymph node, pleural or ascitic fluid,
The natural history of TB in a HIV infected child depends brain tissue, cerebrospinal fluid, urine, stool or blood.
on the stage of the HIV disease. As in the case of adults, In HIV-seropositive patients with mild degree of
clinical presentation of TB in HIV infected children with immunosuppression, the histopathological appearance
early HIV disease is similar to that observed in immuno- of TB lymph nodes shows caseating lesions with few or
competent children without HIV infection. However, TB no AFB. In HIV infected individuals with a severe degree
bacilli are more likely to disseminate to other parts of of immunosuppression, the lymph node histopatholo-
the body in a child who has HIV infection. Tuberculosis gical appearance presents as little cellular reaction with
meningitis, miliary TB, and generalized enlargement of many AFB. The reader is referred to the chapter
lymph nodes are more likely to occur. It must also be “Pathology” [Chapter 5] for more details.
The TST is commonly used to detect latent tuber- prophylaxis against some bacterial causes of pneumonia
culosis infection [LTBI]. More recently, interferon-gamma and diarrhoea and their complications (46-48). The
release assays [IGRAs] are increasingly being used to UNAIDS and WHO have recommended the use of
detect LTBI and have several advantages. The reader is cotrimoxazole preventive treatment [CPT] in HIV infec-
referred to the chapters and “Diagnosis of latent tuberculosis ted individuals as part of a minimum package of
infection: recent advances and future directions” [Chapter 10] care (49,50). Cotrimoxazole preventive treatment is the
“Tuberculin skin test” [Chapter 11] for more details. gold standard in industrialized countries for HIV infected
individuals with CD4+ T-lymphocyte count less than
MANAGEMENT OF TUBERCULOSIS AND HUMAN 200/mm 3 regardless of TB (51). The Thai Clinical
IMMUNODEFICIENCY VIRUS CO-INFECTION Management Guidelines recommend the use of co-
trimoxazole following clinical eligibility criteria for those
Experiences from several countries have demonstrated
who can not afford to have CD4+ counts done (52,53).
that a continuum of care from hospital to home is the
Further studies are necessary to evaluate the best models
optimum to provide care and support to those affected
for the use of co-trimoxazole in HIV infected TB patients
with HIV. Patients co-infected with HIV-TB should
in South-East Asia. For example in Thailand PLHIV
benefit from HIV/AIDS care and support based on this
groups and non-government organizations have
approach. Community-and home-based care is one of
launched an initiative to provide access to treatment for
the key activities to strengthen the continuum of care
prevention of OIs for PLHIV (52).
with referral linkages to TB services and vice versa.
Comprehensive care should link the formal [hospitals
Highly Active Antiretroviral Therapy
and health services] and the informal [family and
community care] sections of the health system in a Rapid progress in developing antiretroviral therapy
cohesive network of services. The success of a compre- [ART] led in 1996 to the introduction of highly active
hensive care model depends on the cooperation and antiretroviral therapy [HAART]. This includes a combi-
collaboration of health care workers at all levels [primary, nation of at least three antiretroviral [ARV] drugs. This
secondary and tertiary] and the active involvement of revolutionized the treatment of HIV infection. As with
communities at risk, PLHIV and their families and care antituberculosis treatment, a combination of ARV drugs
givers. If comprehensive care across the continuum provides efficacy and decreases the risk of drug
operates successfully then it will facilitate reduction in resistance. Antiretroviral therapy is the global standard
the impact of illness, an improvement in the quality of of care in the treatment of HIV infection. Although not a
life of PLHIV, and a reduction in the level of stigma and cure for HIV infection, ART usually results in near-
discrimination in clinical and community care settings. complete suppression of HIV replication. It is a lifelong
Providing comprehensive HIV/AIDS care includes (43); treatment. The prime objectives of ART are to delay the
clinical and nursing care, in particular, the prevention onset of HIV disease progression; improve the quality of
and treatment of common OIs including TB, psychosocial life of the infected individual; reduce the transmission
support, financial support, housing and legal assistance, of HIV infection and maintain the “health of the public”.
care and support of orphans and widows and These objectives are achieved by initiation of ART in
information and training of care givers. patients at risk of disease progression and can be
The common HIV-related infections, e.g., Pneu- achieved only by using drug combinations of at least
mocystis jiroveci, pneumonia and bacterial infections, three antiretroviral agents. These drug combinations
cause considerable morbidity during treatment of HIV- result in impairment of viral replication with restoration
TB co-infection. Pneumonia due to Pneumocystis jiroveci, of immune function and reduced rates of clinical
is commonly reported OI in Thailand and India (44,45). progression.
Preventive treatment against these intercurrent infections The ART results in dramatic reductions in morbidity
represents a possible way to decrease morbidity and and mortality in HIV infected people. There are several
mortality in HIV infected TB patients. Studies in PLHIV requirements for successful use of ART. These include
in Cote d’Ivoire showed the benefit of cotrimoxazole considerable efforts to maintain adherence to lifelong
580 Tuberculosis
treatment and to monitor response to treatment, drug Zidovudine and Stavudine

toxicities and drug-drug interactions. Although the
Zidovudine [ZDV] and stavudine [d4T] are thymidine
benefits of ART are considerable, administration is not
NRTI inhibitors. They must not be co-administered due
easy. Many HIV infected persons cannot tolerate the toxic
to competition for intracellular phosphorylation. The
effects of the drugs. Adherence is difficult because of
choice between d4T or ZDV should be made at the
often large numbers of pills and complicated treatment
country level but both agents should be available. Use of
regimens. Poor adherence to treatment leads to the
ZDV essentially requires haemoglobin monitoring before
emergence of drug-resistant viral strains which are very
and during therapy. The WHO haemoglobin colour scale
difficult to treat.
can be used when laboratory-based haemoglobinometry
Access to ART is limited to very few HIV infected
methods are unavailable. While d4T is generally better
people where the burden of HIV is greatest [in sub-
tolerated, concerns exist about the development of
Saharan Africa and Asia]. The WHO estimated that in
lipoatrophy and other metabolic complications.
2002 there were six million people in developing
countries in need of ART (54,55). Of these, only 230 000
Nevirapine
had access to ART [and half of those were in one country,
Brazil]. There were increasing international efforts to Nevirapine [NVP] is a non-nucleoside reverse transcrip-
improve access to ART in resource-limited settings in tase inhibitor [NNRTI]. It is administered on a twice daily
recent years. The ART has become increasingly available basis. Significant side effects include rash [which may
in resource-poor countries since late 2003. The WHO/ evolve into Stevens-Johnson syndrome] and hepatitis.
UNAIDS estimated that in June 2005, the number of Nevirapine should be avoided in patients receiving
people receiving combination ART for HIV/AIDS in rifampicin-based antituberculosis treatment. Further
developing countries has increased significantly – more studies on the concomitant use of NVP and anti-
than doubling from 400 000 in December 2003 to tuberculosis treatment are required.
approximately one million in June 2005 (54,55).
National standardized approaches should be Efavirenz
developed when deciding on first-line ART combinations Efavirenz [EFV], an NNRTI, is administered on a once
in resource limited settings. The WHO recommends that daily basis. This drug should be used with caution because
antiretroviral treatment programmes choose few potent of its teratogenic potential. The WHO recommends that
first-line ART regimen to start treatment in the majority it should not be used in women of child-bearing potential
of patients (56). Clinical trials of different triple drug unless adequate contraception is used. This drug may be
regimens have generally revealed comparable antiviral used in patients on antituberculosis treatment.
potencies. Therefore, the choice among these regimens The antiretroviral drug dosages and commonly
generally relies on other considerations including: side- encountered adverse drug reactions are listed in Tables
effect profiles, safety in pregnancy, potential drug-drug 40.4 and 40.5. While there are many potential first-line
interactions [especially with medications used to treat ART combinations, the WHO currently suggests only four
TB], co-morbidities [e.g., TB, hepatitis], maintenance of combinations consisting of five drugs. Using the
alternative options in the setting of treatment failure, “5-drug, formulary approach” outlined above [{d4T or
drug availability, cost, likely HIV [sub]-types and ‘cold ZDV} + 3TC + {NVP or EFV}], results in four possible first-
chain’ requirements (56). line regimens: [i] d4T/3TC/NVP; [ii] d4T/3TC/EFV;
[iii] ZDV/3TC/NVP; and [iv] ZDV/3TC/EFV (48,52,54).
Lamivudine
Lamivudine [3TC] is a cytidine nucleoside reverse
transcriptase inhibitor [NRTI]. It is well tolerated and Due to the high prevalence of TB among HIV infected
can be administered either in a once or twice daily individuals living in the South-East Asia Region, many
schedule. It has activity against hepatitis B virus as well patients who are candidates for ART will have active TB
as HIV. Resistance develops quickly to this drug if used (57). In addition, patients already receiving ART may
as part of a sub-optimal combination. develop clinical TB. Effective treatment and control of
Table 40.4: Nucleoside reverse transcriptase inhibitors agents produce unacceptable drug interactions with
antituberculosis agents and can increase toxicity of TB
Name Dose Comments and common
side-effects
treatment (59-67). The DOTS strategy should be initiated
promptly in HIV-seropositive patients diagnosed to have
Lamivudine 150 mg twice Generally well tolerated TB. The two major issues in the clinical management of
[3TC] daily Active against HBV
patients with HIV and TB are when to start ART and
Stavudine 30 mg twice daily Peripheral neuropathy
which regimen to use. The optimum time at which to
[d4T] [1% to 4% in early studies;
24% in expanded access commence ART in a patient with HIV-TB co-infection is
patients with CD4+ counts unknown. An early initiation of ART is recommended
< 50/mm3] for TB patients at very high risk for HIV disease
Zidovudine 300 mg twice Initial nausea, headache, progression and mortality. For patients with a CD4+
[ZDV] daily fatigue, anaemia, count less than 200 cells/mm3, ART is recommended as
neutropenia, neuropathy, soon as the antituberculosis treatment is tolerated,
myopathy
usually between two weeks and two months [Table 40.6,
HBV = hepatitis B virus Figure 40.2]. For patients who develop TB with CD4+
counts in the 200 to 350 cells/mm3 range, ART should
be started after the first two months of antituberculosis
Table 40.5: Non-nucleoside reverse transcriptase
inhibitors
Table 40.6: Antiretroviral therapy for individuals co-infected
Name Dose Comments and common with human immunodeficiency virus and tuberculosis
side effects
Situation Recommendations
Nevirapine 200 mg daily for Rash, hepatitis
[NVP] two weeks, then CD4+ count Start TB treatment. Start one of these
200 mg twice daily < 200 cells/mm3 regimens as soon as TB treatment is
Efavirenz 600 mg daily Rash, hepatitis, tolerated [between 2 weeks and 2 months]:
[EFV] [evening] neuropsychiatric Recommended regimen:
manifestations ZDV/3TC/EFV
Alternatives:
ZDV/3TC/SQV/r
TB is a central priority when developing treatment ZDV/3TC/ABC*
strategies for HIV co-infected patients (58). The aims of d4T/3TC/ABC or SQ/r
antituberculosis treatment are to cure patients with TB, [for ZDV intolerance]
to prevent death from active TB or its late effects, to CD4+ count Start TB treatment. Start one of these regimens
prevent relapse and to decrease TB transmission to 200 to 350 after 2 months of TB treatment:
others. The WHO recommends the same treatment cells/mm3 Recommended regimen:
ZDV/3TC/EFV
regimen for TB patients with and without HIV co-infec-
Alternatives:
tion. In India, the Revised National Tuberculosis Control ZDV/3TC/SQV/r
Programme [RNTCP] uses intermittent thrice weekly ZDV/3TC/ABC
DOTS both in the initial intensive phase as well as in the CD4+ count Treat TB. Monitor CD4+ counts if available.
continuation phase of chemotherapy. While new patients > 350 cells/mm3 Defer ART
are treated with Category I treatment, retreatment cases
* Although this regimen does not require modification of dosages
are treated with Category II treatment. For HIV-TB when co-administered with rifampicin, it is inferior for HIV/AIDS
treatment, there is no Category III treatment. The reader treatment
is referred to the chapters “Treatment of tuberculosis” TB = tuberculosis; ZDV = zidovudine; 3TC = lamivudine; EFV =
[Chapter 52], and “Revised national tuberculosis control efavirenz; SQV/r = saquinavir/ritonavir; ABC = abacavir; d4T =
stavudine; ART = antiretroviral treatment; HIV = human
program in India” [Chapter 63] for more details.
immunodeficiency virus; AIDS = acquired immunodeficiency
Thioacetazone should not be used in HIV-seroposi- syndrome
tive patients. The management of HIV and TB co-
Source: references 50 and 56
infection is complicated because some antiretroviral
582 Tuberculosis
While protease inhibitors [PIs] should not be used

concomitantly with rifampicin because rifampicin
induces hepatic enzymes that reduce the PIs to sub-
therapeutic levels, however, saquinavir/ritonavir [SQV/
r] [1000/100 mg twice a day or 400/400 mg twice a day]
and lopinavir/ritonavir [400/400 mg twice a day] can
be co-administered with rifampicin (66,67).
Highly Active Antiretroviral Treatment and

Rifabutin-based Antituberculosis Treatment
While rifabutin [RBT] is costly, it provides a better option
for concomitant use with PIs. Two NRTIs/NtRTIs in
combination with any of the available PIs and NNRTI
can be co-administered with RBT-based except for
saquinavir, ritonavir or delavirdine (66,67). The dose of
nelfinavir [750 mg to 1000 mg three times a day] and
indinavir [800 mg to 1000 mg three times a day] should
Figure 40.2: World Health Organization guidelines on timing of be increased. The dose of rifabutin [300 mg three times a
antiretroviral treatment in patients with HIV-TB co-infection
week, when used with nelfinavir, indinavir, amprenavir
HIV = human immunodeficiency virus; TB = tuberculosis; HAART
= highly active antiretroviral therapy; OI = opportunistic infection and fosamprenavir and 150 mg three times a week when
Reproduced with permission from “Sharma SK, Mohan A, concurrently used with atazanavir or ritonvir-boosted
Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and PI regimens] should be decreased. The dose of rifabutin
management. Indian J Med Res 2005;121:550-67 (reference 3)” should be increased to 600 mg three times a day when
co-administered with EFV (66,67).
therapy, because the toxicity of TB treatment is greatest
during this period. In patients with CD4+ count greater When patients already receiving ART develop TB,
the ART regimen should be adjusted to be compatible
than 350 cells/mm3, the ART should be deferred and
with antituberculosis treatment. Following completion
the patient is monitored closely.
of antituberculosis treatment, the ART regimen can be
Highly Active Antiretroviral Treatment and continued or changed depending upon the clinical and
Rifampicin-based Antituberculosis Treatment immunologic status of the patient.
Details of HAART and antituberculosis treatment are When rifampicin is being used, ART regimens
provided in Table 40.7. Co-administration of triple drug containing EFV and ABC are preferred for use in older
regimen of NRTI or nucleotide reverse transcriptase and younger children respectively. However, in many
inhibitor [NtRTIs] with rifampicin does not require dose countries in South-East Asia, ABC is not available in
modification of antiretroviral drugs, as there are no drug- liquid formulation and the tablet form is expensive. If
drug-interactions. However, the drug regimen is of lower ABC and PIs are not available, NVP is an acceptable alter-
potency for HIV/AIDS treatment. Non-nucleoside native. Serum NVP level is lowered by approximately
reverse transcriptase inhibitor-based regimen consists of 30 per cent when concurrently used with rifampicin.
two NRTI/NtRTIs in combination with a NNRTI [EFV Therefore, it is reasonable to increase the dose of NVP
or NVP] and rifampicin-based antituberculosis treat- by around 20 per cent when rifampicin is being co-
ment. The standard dose of NVP [200 mg twice a day] administered. When used along with rifampicin, the dose
can be used concomitantly with rifampicin (68,69). While of EFV should be increased by 20 to 30 per cent.
both dosages of EFV [600 and 800 mg per day] have been
Treatment and Response to Therapy
used (70), CDC guidelines recommend daily dose of 800
mg of EFV when administered concomitantly with While majority of the HIV seropositive patients with
rifampicin (66,67) pulmonary TB will respond to the standard antituber-
Table 40.7: Co-administration of highly active antiretroviral therapy and antituberculosis treatment
Rifampicin-based antituberculosis drug regimen
Dose NRTI/NtRTI backbone
NNRTI
EFV 600 or 800 mg qd 2NRTI/NtRTIs
NVP 200 mg bid 2NRTI/NtRTIs
PI
Saquinavir/ritonavir 1000/100 mg bid or 400/400 mg bid 2NRTI/NtRTIs
Lopinavir/ritonavir 400/400 mg bid 2NRTI/NtRTIs
Rifabutin-based antituberculosis drug regimen

Dose Nucleoside backbone Rifabutin dose
NNRTI
EFV 600 mg qd 2NRTI/NtRTIs 600 mg qd or 600 mg qod
NVP 200 mg bid 2NRTI/NtRTIs 300 mg qd or 300 mg three times a week
PI
Indinavir 1000 mg tid 2NRTI/NtRTIs 300 mg three times a week
Nelfinavir 1000 mg tid 2NRTI/NtRTIs 300 mg three times a week
Amprenavir 1200 mg bid 2NRTI/NtRTIs 300 mg three times a week
Fosamprenavir 1400 mg bid 2NRTI/NtRTIs 300 mg three times a week
Atazanavir 400 mg qd 2NRTI/NtRTIs 150 mg three times a week
Lopinavir/ritonavir 400/100 mg bid 2NRTI/NtRTIs 150 mg three times a week
Ritonavir combined with
amprenavir, indinavir,
fosamprenavir or saquinavir 400/100 mg bid 2NRTI/NtRTIs 150 mg three times a week
NRTIs do not have drug-drug interaction with PIs

Co-administration of three NRTIs is an inferior regimen
NRTI = nucleoside reverse transcriptase inhibitor; NtRTI = nucleotide reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse
transcriptase inhibitor; EFV = efavirenz; NVP = nevirapine; qd = once daily; bid = twice daily; qod = every other day; tid = thrice daily; PI
= protease inhibitor
culosis treatment. Some evidence is available suggesting IMMUNE RECONSTITUTION SYNDROME IN

that the chances of relapse of TB in HIV-seropositive HUMAN IMMUNODEFICIENCY VIRUS–
individuals are also higher than in HIV-seronegative TUBERCULOSIS CO-INFECTED PATIENTS
individuals. Hence, it may be useful to prolong the With increased co-prevalence of TB and HIV and
continuation phase of treatment to reduce the chances increasing access to ART in the developing world,
of relapse. In intravenous drug users and in other cases clinicians in these countries should be able to identify
where compliance is likely to be poor, a fully supervised immune reconstitution inflammatory syndrome [IRIS]
regimen is recommended. The safety of streptomycin and relieve symptoms without compromising clinical
injections in areas with high prevalence of HIV infection care (3,72,73). The HAART for HIV infection suppresses
must be taken into consideration, if the standards of viral replication, allowing the partial restoration of the
sterilization are suspect. One should ensure high immune system. This immune reconstitution, however,
standards of sterilization. If at all possible, one should can result in an inflammatory response against infectious
use disposable syringes and needles and make sure that and non-infectious antigens and apparent clinical
they are destroyed after use (71). deterioration of the patient. This phenomenon has been
584 Tuberculosis
described as IRIS. The IRIS can occur with many con- Drug-Resistant Tuberculosis
comitant infections including Mycobacterium tuberculosis,
In early 1990, several institutional outbreaks of multidrug-
nontuberculous mycobacteria [NTM], leishmania, fungal
resistant TB [MDR-TB] among HIV infected patients drew
and viral infections. Other diseases, such as sarcoidosis, attention to the problem (70). However, HIV infection per
Grave’s disease and lymphomas, can also occur as a part se does not appear to be a predisposing factor for the
of the IRIS. Though IRIS is a widely recognized development of MDR-TB. Recent studies have found that
phenomenon, various non-standardized general case drug-resistant TB including MDR-TB is no more common
definitions have been used to describe in the published among people infected with HIV (74,75).
literature. The case definitions for paradoxical TB- Several factors can contribute to outbreaks of MDR-
associated IRIS, ART-associated TB and unmasking TB- TB. Increasing incidence of TB in some areas will bring
associated IRIS [provisional] have been recently more persons with active, infectious TB into institutional
described (73). These definitions can be used in resource- settings such as health care and correctional facilities,
limited settings also and their use is expected to facilitate many of which serve populations in which there is also
standardization and comparability of data. a high proportion of HIV infected persons. This will
Several risk factors for development of paradoxical create practices for controlling the transmission of
IRIS include: [i] a low baseline CD4+ cell count; [ii] a airborne disease. In addition, recognition of drug-
higher baseline viral load; [iii] a shorter interval between resistant TB is often delayed because current methods
commencing antituberculosis treatment and HAART; for diagnosing TB and performing drug susceptibility
[iv] disseminated TB; [v] a greater increase in CD4+ cell tests require weeks to months, especially in resource
count; and [vi] a greater reduction in viral load after limited settings. Furthermore, the selection of drugs
starting HAART. The manifestations of IRIS include available for treating TB is limited, which makes the
hectic fever, increase in size or development of lymph- treatment of drug-resistant cases particularly difficult.
adenopathy, appearance of new lesions or worsening of Recent findings suggest that once or twice weekly
existing pulmonary infiltrates, and development of therapy including isoniazid and a rifamycin increases
respiratory failure. Other manifestations include the risk of acquired rifamycin resistance among TB
occurrence or worsening of pleuritis, pericarditis, or patients with advanced HIV disease with very low CD4+
ascites, intracranial tuberculomas, meningitis, dissemi- cell count [< 60/mm 3 ] (76,77). It has, thus, been
nated skin lesions, epididymitis, hepatosplenomegaly, recommended that persons with HIV-TB and CD4+ cell
counts less than or eual to 100/mm3 should not be treated
soft tissue abscesses (3,72,73). The IRIS is a diagnostic
with highly intermittent [i.e., once or twice weekly]
challenge and remains a diagnosis of exclusion. Drug-
regimens. These patients should receive daily therapy
resistant TB and alternative diagnoses [other OIs] must
during the intensive phase and daily or three doses a
be ruled out. Conversion of TST from negative to positive
week during the continuation phase, preferably under
is a common finding during IRIS. Paradoxical reactions
directly observed therapy (76,77). These issues merit
have a median duration of about eight weeks but may
further study.
last longer especially those associated with lympha-
Treatment of MDR-TB is usually more problematic
denopathy. Most of these cases are self-limiting. Usually, since both isoniazid and rifampicin become less effective.
treatment with non-steroidal anti-inflammatory drugs Commonly, regimens that include five or six drugs are
[NSAIDs] is sufficient. Antituberculosis drugs and necessary. Initial drugs must be chosen depending on
HAART treatment should be continued in patients with the local pattern of drug susceptibility. Modifications may
IRIS. However, corticosteroids may be indicated for very be required based on the results of susceptibility testing
severe IRIS and HAART may be temporarily withheld of the organisms isolated from the patient. The use of
in patients with very severe and life-threatening IRIS. second-line antituberculosis drugs is frequently
Surgical intervention may be required for indications associated with toxicity and intolerance. Patients may
such as organ rupture and drainage of abscesses etc. need admission to hospital at the beginning of treatment.
The reader is referred to the chapter “Drug resistant Table 40.8: World Health Organization recommended policy
tuberculosis” [Chapter 49] for more details topic. on bacille Calmette-Guerin in human immounodeficiency
virus infection
Extensively Drug-resistant Tuberculosis [XDR-TB] Country TB WHO recommended policy
prevalence
Following an earlier description of a lethal outbreak in
HIV infected patients in South Africa (78), extensively High BCG for all children [according to standard
drug-resistant TB [XDR-TB] has been described programme] except children with symptoms
of HIV disease/AIDS
worldwide (79-82). Extensively drug-resistant TB is
Low Do not give BCG immunization to HIV
defined as MDR-TB that includes resistance to any infected children
fluoroquinolones and one of the second-line antituber-
culosis injectable agents, kanamycin, amikacin, or WHO = World Health Organization; TB = tuberculosis;
BCG = bacille Calmette-Guerin; HIV = human immunodeficiency
capreomycin, is potentially untreatable. The reader is
virus; AIDS = acquired immunodeficiency syndrome
referred to the chapter “Drug-resistant tuberculosis”
[Chapter 49] for more details topic.
vast majority of cases, BCG immunization is considered
CONTROLLING TUBERCULOSIS TRANSMISSION to be safe. The WHO recommended policy depends on
IN SETTINGS WITH HUMAN IMMUNODEFICIENCY the TB prevalence in a country, as shown in Table 40.8.
VIRUS INFECTED PERSONS In a country with high TB prevalence, the possible
benefits of BCG immunization outweigh the possible
Inexpensive infection control measures can be disadvantages.
implemented to help reduce transmission of TB in health
care facilities at the district or referral level hospitals. This PREVENTION
will reduce exposure of Mycobacterium tuberculosis
including drug-resistant strains to immunocompromised Preventing HIV-associated TB as public health action
persons as well as health care workers. The reader is goes beyond the full implementation of DOTS. It includes
referred to the chapter “Tuberculosis in health care workers” preventing HIV infection in the first place, as well as
[Chapter 45] for more details topic. preventing progression of latent TB infection [LTBI] to
active disease and the provision of HIV/AIDS care and
treatment. In 2002, WHO Regional Office for South-East
ROLE OF BACILLE CALMETTE-GUERIN
Asia developed a HIV/TB regional strategic plan
VACCINATION IN PREVENTING TUBERCULOSIS
following discussions held among the Joint National
IN HUMAN IMMUNODEFICIENCY VIRUS INFECTED
AIDS and TB Programme Managers and Global TB/HIV
INDIVIDUALS
Working Group Meetings. The plan has adapted to the
The benefit of bacille Calmette-Guerin [BCG] is in epidemiology and the ongoing national responses to HIV
protecting young children against disseminated and and TB in the region and it is also consistent with Global
severe TB, such as TB meningitis and miliary TB. The TB/HIV Strategic Framework (83,84). The goal of the
BCG vaccine has little or no effect in reducing the number strategy is to reduce HIV/TB-associated morbidity and
of adult cases with pulmonary TB. It is not known if HIV mortality. To achieve the above goal the plan has
infection reduces the protection conferred by BCG against proposed four strategies including preventing HIV trans-
TB in children. There is some evidence that conversion mission and progression of LTBI to active TB among
to a positive TST after BCG is less frequent in HIV infected HIV infected individuals.
children. The significance of this finding for protection Interventions related to preventing increase in
against TB is not clear. There have been a few case reports number of HIV-TB co-infection call for control of both
of local complications and disseminated BCG disease epidemics as well as intensified efforts that require
following BCG immunization in HIV infected children. collaboration between two programmes. Since HIV fuels
However, prospective studies comparing BCG immuni- the TB epidemic, interventions to prevent HIV transmis-
zation in HIV infected and uninfected infants showed sion should contribute to decreasing the TB burden.
no difference in risk of complications. Therefore, in the Reduction in the number of sexual partners, expanding
586 Tuberculosis
access to condoms, syndromic management of sexually symptomatic for investigation and treatment of active
transmitted infections [STIs], harm reduction for injecting TB. Screening should occur both in the ICT setting and
drug users [IDUs] and integrated counselling and testing also in the HIV care setting on a regular basis.
[ICT], [earlier called voluntary counselling and testing, The HIV is the most potent known risk factor for
VCT] have all been shown to be effective in preventing progression to active TB both in people with recently
HIV infection. acquired infection and those with latent Mycobacterium
The most efficient way to prevent the spread of HIV tuberculosis infection. The annual risk of developing TB
is to target populations with high HIV case reproduction in HIV infected individuals co-infected with Mycobacte-
number, e.g., those with the most sexual partners and rium tuberculosis ranges from five to ten per cent. Up to
IDUs who share needles and syringes. Among the range 60 per cent of TST positive people with HIV/AIDS
of measures with immediate impact in decreasing develop active TB during their lifetime compared to
HIV transmission are 100 per cent condom use about 10 per cent of purified protein derivative [PPD]
programme, management of STIs and needle-syringe positive HIV-seronegative individuals [Figure 40.3]. The
exchange programmes. Thailand has shown the effective- HIV increases the rate of recurrent TB, either due to
ness of the “100 per cent condom programme” targeting endogenous reactivation or exogenous re-infection. An
commercial sex workers and their clients in brothels on increase in the number of TB cases in PLHIV augments
a national scale. It is well known that the HIV epidemic the risk of TB transmission to the general community.
started in IDU population in several Asian countries and Treatment of LTBI is thought to decrease the risk of a
then spread to other risk groups and the general first or recurrent episode of TB. The WHO and UNAIDS
population. Harm reduction through provision of sterile recommend treatment of LTBI for six months for TST-
injecting equipment, peer education and continuing drug positive, HIV infected individuals who do not have TB
treatment are proven to be effective in preventing HIV disease. A six-month course of treatment with daily
transmission among IDUs. isoniazid [5 mg/kg] is effective in preventing progres-
Majority of TB patients do not know their HIV status sion of Mycobacterium tuberculosis infection to disease.
and several HIV infected TB patients receive antituber- Among PLHIV, treatment of LTBI is likely to provide
culosis treatment regardless of their HIV status. Such protection against the risk of developing TB through two
patients, therefore, do not have access to prevention and mechanisms. First one is by decreasing the risk of prog-
treatment of HIV associated OIs and ART. Similarly, ression of recent infection, and secondly, by decreasing
many of the HIV-seropositive individuals may be har- the risk of reactivation of latent Mycobacterium tuberculosis
bouring TB which may be undetected unless specifically infection. In populations with high TB prevalence, the
looked for. duration of benefit following completion of a six-month
The ICT services can serve these purposes. The course of isoniazid treatment is limited [up to 2.5 years].
recommended intervention to obtain an HIV test result This is probably due to continued exposure to Mycobacte-
is voluntary and confidential process by which the client rium tuberculosis. The duration of protection depends on
chooses to be tested. This process includes pre-test the duration of preventive treatment.
counselling, HIV testing, and post-test counselling for
both HIV-seropositive and HIV-seronegative persons.
Post-test counselling for HIV-seropositive individuals
should always include information about the symptoms
of common HIV-related illnesses in particular TB. The
ICT can also be an effective entry point to HIV/TB
activities directed towards preventing progression of
LTBI to active disease and reducing HIV-related
morbidity among TB patients.
Intensified TB case finding is meant for screening
HIV-seropositive people for TB symptoms. Intensified Figure 40.3: Lifetime risk of active TB
case finding has two-fold purpose – to consider those TB = tuberculosis; TST = tuberculin skin test; HIV = human
with LTBI for treatment and to refer those who are immunodeficiency virus; + = positive; – = negative
Table 40.9: Potential disadvantages and necessary precautions of treatment of latent tuberculosis infection
Potential disadvantage Necessary precaution
Risk of drug toxicity [especially liver damage] Do not give to people with chronic disease or who
regularly drink excessive amounts of alcohol
Emergence of drug resistance [if the patient has In all cases exclude TB disease by sputum microscopy and
undetected TB disease and not just Mycobacterium chest radiograph
tuberculosis infection]
Diversion of resources from NTP activities Funding must be from sources other than NTP [e.g.,
AIDS control programme, voluntary sector] or extra
funding sources for the NTP must be found. Treatment
of latent TB infection could be integrated into HIV care
package under responsibility of AIDS unit
TB = tuberculosis; NTP = National Tuberculosis Programme; HIV = human immunodeficiency virus; AIDS = acquired
immunodeficiency syndrome
Data from the former Zaire [now the Democratic in the community in different studies done in India, a
Republic of Congo], and in Haiti showed a higher rate of combination of drugs may be required to prevent onset
recurrent TB in HIV infected individuals than in non- of TB in HIV-seropositive individuals. However, it is
HIV-infected individuals treated with a six-month worth to note that some studies indicate that short-course
regimen containing rifampicin (85,86). In Zaire and Haiti, multi-drug regimens, compared to isoniazid mono-
post-treatment prophylaxis [isoniazid and rifampicin in therapy, were much more likely to require disconti-
the study in Zaire and isoniazid in the study in Haiti] nuation of treatment due to adverse effects.
decreased the risk of TB recurrence in HIV-infected The choice of regimen will depend on factors, such
individuals, but did not prolong survival. Further studies as costs, adverse effects, adherence and drug resistance.
are needed to confirm the benefit, establish the optimum Appropriate policy on treatment of LTBI needs to be set
regimen [drugs and duration] and assess operational up based on above scientific findings and feasible
feasibility, before widely recommending treatment strategies should be identified where pertinent.
aimed at decreasing risk of TB recurrence.
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Tuberculosis in Children
41
SK Kabra, Rakesh Lodha
INTRODUCTION contribution to the spread of TB. In several estimates,

childhood TB is estimated to constitute 10 per cent of the
Tuberculosis [TB] is one of the major infections affecting
TB burden (4). However, available data linking the
children worldwide. It causes a significant morbidity and
incidence of TB to the TB caseload represented by child-
mortality, especially in infants and young children as TB
ren suggest an exponential increase in the proportion of
infection can progress rapidly to disease, particularly in
childhood TB. With the rise in the incidence of TB,
this group. Tuberculosis in children reflects the
children may constitute nearly 40 per cent of the caseload
prevalence of the disease in adults as well as current
in certain high incidence communities (5).
transmission rates in the community. Children born to
Tuberculosis infection and disease among children
human immunodeficiency virus [HIV] infected parents,
are much more prevalent in developing countries, where
whether infected or not, are at high risk of developing
resources for TB control are scarce (6). It is estimated that
TB because of the increased risk of exposure to the disease
in developing countries the annual risk of TB infection
(1,2). Tuberculosis is more common among the dis-
in children is two to five per cent and in India it is 1.5 per
advantaged and vulnerable groups in each society and
cent (7). The estimated lifetime risk of developing TB
the impact of overcrowding, undernutrition and poverty
disease for a young child infected with Mycobacterium
is particularly severe on children. Mycobacterium
tuberculosis as indicated by positive tuberculin skin test
tuberculosis infects millions of children worldwide every
[TST] is about 10 per cent (8). About five per cent of those
year, yet accurate information on the extent and
infected are likely to develop disease in the first two years
distribution of disease in children is not available for most
after infection and another five per cent in rest of their
of the world. Recent studies have documented an
lifetime. These rates increase in HIV infected individuals.
increase in the occurrence of TB in children, both in
Nearly eight to twenty per cent of the deaths caused by
developed and developing countries. Mortality rates
TB occur in children (9). The age of the child at acquisition
from TB are also highest in early childhood, mainly due
of TB infection has a great effect on the occurrence of TB
to disseminated forms such as meningeal and miliary
disease. Approximately 40 per cent of infected children
TB (3).
less than one year of age, if left untreated, develop
radiologically significant lymphadenopathy or
EPIDEMIOLOGY
segmental lesions; the comparative figures for children
Since most children acquire the organism from adults in in the age groups one to ten years and 11 to 15 years are
their surroundings, the epidemiology of childhood TB 24 per cent and 16 per cent, respectively (10).
follows that in adults. Global burden of childhood TB is
unclear. This is because of the difficulty of confirming TRANSMISSION
the diagnosis of childhood TB. The other important Transmission of Mycobacterium tuberculosis occurs from
reason is that children do not make a significant person-to-person via the inhalation route. Several factors
592 Tuberculosis
are associated with the risk of acquiring Mycobacterium Outcome of Bronchial Obstruction
tuberculosis infection (11). The risk of acquiring infection
Bronchial obstruction may resolve in several ways
has been associated consistently with the extent of contact
including: [i] complete expansion and resolution of the
with the index case, bacillary burden in the sputum, and chest radiograph findings; [ii] disappearance of the
the frequency of cough in the index case. Patients with segmental lesions; and [iii] scarring and progressive
sputum smear-positive pulmonary TB are more likely to compression of the lobe or segment leading to bronchiec-
transmit infection. Markers of close contact such as tasis. A caseous lymph node may erode through the wall
residence in urban locality, overcrowding, and lower of the bronchus, leading to TB bronchitis or endobron-
socio-economic status all are correlated with the acquisi- chial TB. Fibrosis and bronchiectatic changes may
tion of infection. An increased risk-developing infection supervene. Discharge of Mycobacterium tuberculosis into
has been demonstrated in multiple institutional settings, the lumen may lead to bronchial dissemination of
including nursing homes, correctional institutions, and infection.
homeless shelters. The risk of acquiring infection Haematogenous dissemination of Mycobacterium
increases with age from infancy to early adulthood, likely tuberculosis occurs early in the course of the disease when
attributable to increasing contact with other persons. the bacilli find their way into the blood stream through
lymph nodes. This may result in foci of infection in
NATURAL HISTORY various organs. If the host immune system is good, then
these foci are contained and disease does not develop.
The natural history of TB infection is covered in detail in
Seeding of apex of the lung leads to development of
the chapter “Pulmonary tuberculosis” [Chapter 14].
Simon’s focus. Lowering of host immunity may lead to
Progressive primary disease is a serious complication of
activation of these metastatic foci and development of
the pulmonary primary complex [PPC] in which the PPC,
disease especially seen in young infants, severely
instead of resolving and calcifying, enlarges steadily and
malnourished children, and children with immuno-
develops into a large caseous centre. The latter then
deficiency including HIV infection. Massive seeding of
liquefies and may empty into an adjacent bronchus
blood stream with Mycobacterium tuberculosis leads to
leading to formation of a cavity. This is associated with
miliary TB, where all lesions are of similar size. This
a large number of bacilli (12). During this stage, the bacilli
usually occurs within three to six months after initial
may spread to other parts of the lobe or the entire lung.
infection.
This may lead to consolidation of an area of the lung or Pulmonary TB resulting from endogenous reactivation
the development of bronchopneumonia. The cavitary of foci of infection is uncommon in children; but may be
disease is uncommon in children. It may be difficult to seen in adolescents. The commonest site for this type of
differentiate progressive primary disease from a simple disease is the apex of the lung [Puhl’s lesion], because the
TB focus with superimposed acute bacterial pneumonia. blood flow is sluggish at apex. Regional lymph nodes are
On the chest radiograph, the segmental lesion appears usually not involved in this type of TB (19).
as a fan-shaped opacity representing mainly atelectasis
and almost always involves that very segment occupied
CLINICAL FEATURES
by the primary pulmonary focus (13,14).
Some of the manifestations are also the consequence Childhood TB can be broadly classified as intra-thoracic
of intrathoracic lymphadenopathy. The enlarged lymph and extra-thoracic TB. Most children develop pulmonary
nodes may compress the neighbouring airway (15,16). TB. Nonetheless, the recognition of extra-thoracic TB is
Ball-valve effect due to an incomplete obstruction may equally important because of its great potential for
lead to distal air-trapping or focal emphysema (17,18). causing morbidity.
Enlarged paratracheal nodes may cause stridor and
Intrathoracic Tuberculosis
respiratory distress. The subcarinal nodes may impinge
on the oesophagus and cause dysphagia. Atelectasis The onset of symptoms is generally insidious, but may
occurs due to complete bronchial obstruction. be relatively acute in miliary TB. Primary infection
Tuberculosis in Children 593
usually passes off unrecognized. Asymptomatic the involved organs. The child may present with high-
infection is defined as infection evident only as a grade fever. Sometimes, dyspnoea may be a prominent
positive TST, but without any clinical or radiographic symptom. The physical examination may be unremark-
manifestations. Children with primary complex able and occasionally, cyanosis, fine crepitations and
predominantly manifest constitutional symptoms in the rhonchi may be present. These findings may be confused
form of mild fever, anorexia, weight loss, and decreased with other acute respiratory infections of childhood. The
physical activity. Cough is an inconsistent symptom and illness may be severe, with the child having a high fever
may be absent even in advanced disease. Irritating dry with rigors and altered sensorium. In addition, these
cough can be a symptom of bronchial and tracheal children may have lymphadenopathy and hepatospleno-
compression due to enlarged lymph nodes. In some megaly. Sometimes, miliary TB may present with insi-
children, the lymph nodes continue to enlarge even after dious onset, with fever and loss of weight. Choroid tuber-
resolution of parenchymal infiltrates (20,21). This may cles may be seen in about 50 per cent children. Meningitis
lead to compression of neighbouring regional bronchus. may occur in 20 to 30 per cent of cases (21-24).
The PPC is the most commonly encountered presenta- The rupture of a subpleural focus into the pleural
tion in the out-patient setting. In a community setting, cavity may result in pleural effusion. The pleura may
primary infection may not be associated with significant also be involved by haematogenous spread from the
constitutional symptoms to warrant medical advice. The primary focus. The effusion usually occurs due to
PPC may be picked up accidentally during evaluation hypersensitivity to tuberculoprotein[s]. Minor pleural
of intercurrent infections (22). effusions associated with the rupture of primary foci are
Children with progressive primary disease may usually not detected. Tuberculosis pleural effusion is
present with high-grade fever and cough. Expectoration uncommon in children younger than five years of age, is
of sputum and haemoptysis are usually associated with more common in boys, and is rarely associated with
advanced disease and development of cavity or ulcera- segmental lesion and miliary TB (19). The onset may be
tion of the bronchus. Physical findings of consolidation insidious or acute with fever, cough, dyspnoea and
or cavitation depend on the extent of the disease. Abnor- pleuritic chest pain on the affected side. There is usually
mal chest signs consist mainly of dullness, decreased air no expectoration. The pleuritic pain may disappear once
entry, and crepitations. Cavitary pulmonary TB is the fluid separates the inflammed pleural surfaces and a
uncommon in children. However, this may not always vague discomfort may then be felt. An increase in the
be true as is evident from the study by Maniar (23) who pleural effusion may make breathing shallow and
reported a series of 75 children, less than two years of difficult. The clinical findings depend on the amount of
age presenting with primary cavitary pulmonary TB. fluid in the pleural sac. In early stages, a pleural rub may
Children with endobronchial TB may present with be present. Other early signs include decreased chest wall
fever, troublesome cough with or without expectoration. movement, impairment of percussion note and
Dyspnoea, wheezing and cyanosis may be present. diminished air entry on the affected side. As the fluid
Occasionally, the child may be misdiagnosed to have collection increases, the signs of pleural effusion become
bronchial asthma. In a wheezing child less than two years more definite.
of age, the possibility of endobronchial TB should always Sometimes, acute secondary bacterial infection may
be considered, especially if there is a poor response to also occur and the child may, present with a high-grade
asthma medications. Partial compression of the airway fever, cough and crepitations. The symptoms and signs
can lead to emphysema. Features of collapse may be respond partially to the conventional antibiotics, but the
present if a large airway is completely compressed (21,22). chest radiographic findings due to underlying TB persist.
Miliary TB is an illness characterized by heavy Calcification of the primary complex occurs more
haematogenous spread and progressive development of commonly in children.
innumerable small foci throughout the body. The disease
is most common in infants and young children. The onset Extra-thoracic Tuberculosis
of illness is often sudden. The clinical manifestations A complete description of extra-thoracic TB is beyond
depend on the numbers of disseminated organisms and the scope of this chapter, but clinicians must consider
594 Tuberculosis
this possibility when evaluating children with a history of Mycobacterium tuberculosis or one of its components;
of persistent fever. The most common forms of extra- and [ii] demonstration of host’s response to exposure
thoracic disease in children include TB of the peripheral to Mycobacterium tuberculosis. The reader is referred to
lymph nodes and the central nervous system. Other rare the chapter “Diagnosis of childhood tuberculosis: recent
forms of extra-thoracic disease in children include advances and applicability of new tools” [Chapter 42] for
osteoarticular, abdominal, gastrointestinal, genito- more details.
urinary, cutaneous, and congenital TB.
Tuberculosis of the peripheral lymph nodes can rarely Radiology
be associated with drinking unpasteurized cow’s milk
On the chest radiograph, the PPC manifests as an area
or can be caused by extension of primary lesions located
of airspace consolidation of varying size, usually unifocal,
at the upper lung fields or abdomen leading to involve-
ment of the supraclavicular, anterior cervical, tonsillar, and homogeneous [Figure 41.1]. Enlarged lymph nodes
and submandibular nodes. Although lymph nodes may may be seen in the hilar, or right paratracheal region.
become fixed to surrounding tissues, a low-grade fever Sometimes, lymphadenopathy alone may be present in
may be the only systemic symptom. A primary focus is children with primary TB.
visible on the chest radiograph only in 30 to 70 per cent Consolidation in progressive primary disease is
of children. The TST is usually reactive. Although sponta- usually heterogeneous, poorly marginated with predilec-
neous resolution may occur, in patients with untreated tion of involvement of apical or posterior segments of the
lymphadenitis caseation necrosis, capsular rupture, and upper lobe or superior segment of the lower lobe
spread to adjacent nodes and overlying skin, resulting [Figure 41.2]. Features of collapse may as well be present
in a draining sinus tract develop (25). [Figure 41.3]. Bronchiectasis may occur in a progressive
Central nervous system disease is the most serious primary disease because of: [i] destruction and fibrosis of
complication of TB in children and arises from a caseous lung parenchyma resulting in retraction and irreversible
lesion in the cerebral cortex or meninges that resulted bronchial dilatation; and [ii] cicatricial bronchostenosis
from an early occult lymphohaematogenous spread. secondary to localized endobronchial infection resulting
Infants and young children are more likely to experience in obstructive pneumonitis and distal bronchiectasis. In
a rapid progression to hydrocephalus, seizures, and children, cavitary disease is uncommon [Figure 41.4].
cerebral oedema. In older children, signs and symptoms Pleural effusion may occur with or without lung lesions
progress over several weeks, beginning non-specifically [Figure 41.5]. In miliary TB, the lesions are less than 2
with fever, headache, irritability, and drowsiness. Disease mm in diameter [Figure 41.6].
abruptly advances with symptoms of lethargy, vomiting,
nuchal rigidity, seizures, hypertonia, and focal neuro-
logic signs. The final stage of disease is marked by coma,
hypertension, decerebrate and decorticate postures, and
eventually death. Rapid confirmation of TB meningitis
can be extremely difficult because of the wide variability
in cerebrospinal characteristics, non-reactive TST results
in 40 per cent, and normal chest radiographs in 50 per
cent of the cases. Because an improved outcome is
associated with early treatment, an empirical antituber-
culosis treatment should be considered for any child with
basilar meningitis and hydrocephalus or cranial nerve
involvement that has no other apparent cause (26).
DIAGNOSIS
Laboratory Tests
Figure 41.1: Chest radiograph [postero-anterior view] in a child
The diagnostic tests for pulmonary TB can be broadly with progressive primary complex showing left-sided hilar
divided into two categories: [i] demonstration/isolation adenopathy and an ill-defined parenchymal lesion
Figure 41.2: Chest radiograph [postero-anterior view] in a child

with progressive primary disease showing consolidation in the right Figure 41.4: Chest radiograph [postero-anterior view]
mid-zone showing a cavity [arrow] in the right mid-zone

collapse consolidation of the right upper lobe Figure 41.5: Chest radiograph [postero-anterior view]
showing massive pleural effusion on the left side
Occasionally, the chest radiograph may be normal
and lymphadenopathy may be evident only on compu- HRCT is more sensitive than chest radiograph for the
ted tomography [CT]. In addition, CT features such as detection of miliary TB and shows randomly distributed
low attenuation of lymph nodes with peripheral multiple, small [< 2 mm diameter] nodules (29). The
enhancement, calcification, branching centrilobular nodules may be so numerous that they coalesce to form
nodules and miliary nodules are helpful in suggesting larger nodules greater than 2 mm in diameter and at
the diagnosis in cases where the radiograph is normal times areas of consolidation with air bronchograms may
or equivocal. Other features such as segmental or lobar be seen. Thickening of the interlobular septa may also
consolidation and atelectasis are non-specific (27). In a be a feature. Mediastinal and hilar lymphadenopathy
study by Kim et al (28), CT including high-resolution may also be present. Cavitation is reported to be rare
CT [HRCT] revealed lymphadenopathy, and paren- on the chest radiograph in children with TB. However,
chymal lesions that were not evident in 21 per cent and children co-infected with HIV and TB may manifest
35 per cent of the chest radiographs, respectively. The atypical radiographic features (30,31). In children co-
596 Tuberculosis
Scoring Systems for Predicting

Childhood Tuberculosis
Though demonstration of mycobacterium in various
clinical specimens remains gold standard, for diagnosis,
this is often not possible in children due to the pauci-
bacillary nature of the illness. Clinical features may be
non-specific and the chest radiograph and TST results
are difficult to interpret. In addition, these do not give
conclusive evidence for the disease. To overcome these
problems, a combination of clinical features, history of
exposure to adult patients with TB, results of TST and
radiological finding, have been evaluated by various
workers (35,36). Various scoring systems have been
developed after giving different weightage to these
variables [Table 41.1] (35,36). In these scoring systems,
more weightage is given to microbiological and histo-
Figure 41.6: Chest radiograph [postero-anterior view] showing pathological evidence, suggestive radiographic picture
miliary mottling and right-sided paratracheal adenopathy and a reactive TST result [> 10 mm induration]. These
scoring systems need to be validated in individual
infected with HIV and TB, CT may show areas of cavita- countries before use. Table 41.2 depicts the proposed
tion that are not apparent on the chest radiograph criteria by Migliori et al (37) for diagnosis of pulmonary
(30,31). The HRCT and colour doppler ultrasonography TB in children in countries where mycobacterial culture
have been found to be useful in the diagnosis of cervical facilities are not available.
lymphadenopathy (32).
Tuberculosis of the spine is the most common site DIAGNOSTIC ALGORITHM FOR PULMONARY
of skeletal involvement. The utility of magnetic TUBERCULOSIS
resonance imaging [MRI] has been documented in The suggested algorithm for diagnosis of pulmonary TB
children with TB spondylitis (33,34). In a retrospective in children is given in Figure 41.7.
study (33), MRI of 53 children under the age of 13 years
were interpreted by three readers using a consensus DRUG-RESISTANT TUBERCULOSIS
method. The salient observations included contiguous Pattern of drug resistance among children with TB tends
involvement of two or more vertebral bodies [85%]; an to reflect that found among adults in the same population.
intraspinal or paraspinal soft tissue mass or abscess
Table 41.1: Scoring systems for diagnosis of childhood
[98%]; and subligamentous extension [64%]. Rim
tuberculosis
enhancement of the soft tissue mass was seen in 65 per
cent patients following gadolinium administration (33). Parameters Stengen Nair and
et al (35) Philip (36)
Contrast enhanced MRI is emerging as a very useful
technique for diagnosing neurological TB, as it demons- Demonstration of acid-fast bacilli +3 +5
trates the localized lesions, meningeal enhancement and Histopathological evidence in biopsy +3 +5
specimens
the brain stem lesions (34).
Tuberculin skin test > 10 mm +3 +3
Suggestive radiology +2 +3
Compatible physical examination +1 +3
Tuberculin skin test is most widely available and Contact with TB family +2 +2
commonly used for establishing the diagnosis of TB Scores 1-2 = TB unlikely; 3-4 = TB possible; 5-6 = TB probable;
infection in children. The reader is referred to the chapter > 7 = TB unequivocal
“Tuberculin skin test” [Chapter 11] for more details. TB = tuberculosis
Table 41.2: Diagnostic criteria for pulmonary tuberculosis in [RFLP] analysis. Six adult-child pairs with cultures positive
children in countries where mycobacterial culture facilities for Mycobacterium tuberculosis were identified. Drug
are not available susceptibility pattern and RFLP analysis were identical
Gastric washings positive for AFB for five adult-child pairs. The strain isolated from a child,
or in whom a source case was not evident, was different from
Two or more of the following criteria that isolated from the source cases. However, the strain
History of contact with a TB adult
isolated from this child was prevalent in the community
Symptoms suggestive of pulmonary TB [cough for more than
2 weeks] in which he resided. This study (38) supports the view
2 TU PPD reaction positive that majority of the childhood contacts of adults with
> 10 mm in unvaccinated BCG patients MDR-TB are likely to be infected by these source cases.
> 15 mm in vaccinated BCG patients Childhood contacts of adults with MDR-TB should,
Radiological findings compatible with pulmonary TB
therefore, be treated according to the drug susceptibility
Response to treatment [body weight increase > 10% after
2 months of treatment, plus clinical improvement]
patterns of Mycobacterium tuberculosis strains of the likely
source cases unless the susceptibility pattern of the strain
TB = tuberculosis; TU = tuberculin units; PPD = purified protein isolated from the child indicates otherwise. In a report from
derivative; BCG = bacille Calmette-Guerin; AFB = acid-fast bacilli
South Africa (39), of the 306 mycobacterial culture and
sensitivity results available from 338 children [under 13
years of age], the prevalence of isoniazid resistance and
multidrug-resistance [defined as isolates resistant to
isoniazid and rifampicin with or without resistance to
other antituberculosis drugs] were 6.9 per cent and 2.3
per cent, respectively (39). Clinical features were similar
in children with drug-susceptible and drug-resistant TB
(39). Only two of the children with culture proven drug-
resistant TB [n = 338] had received antituberculosis
treatment in the past; of these, one isolate was mono-
resistant to isoniazid and the other was multidrug-
resistant. However, this study was conducted concurrently
with a study of childhood contacts [under five years of
age], of adults with multidrug-resistant pulmonary TB at
the same hospital. Four of seven children identified with
MDR-TB were part of the latter study.
TREATMENT
The principles of treatment in children with TB are
similar to that followed in adults (40). During the last
few years, dramatic changes have occurred in the
therapeutic approach to childhood TB. Short-course
Figure 41.7: Diagnostic algorithm for paediatric TB
chemotherapy, with the treatment duration as short as
TB = tuberculosis; CXR = chest X-ray; TST = tuberculin skin test
six months, has become the standard of care. Intermittent
A four-year prospective study (38) in the Western Cape regimens have been documented to be as effective as
province of South Africa evaluated 149 childhood contacts daily regimen in the paediatric population (41-45). The
of 80 adult multidrug-resistant tuberculosis [MDR-TB] DOTS has been success-fully used in adults but there are
cases. Culture for Mycobacterium tuberculosis was obtained sparse data regarding the utility of this approach in
from both the adult source cases as well as the child children. An observational trial (46) evaluated directly
contacts. Isolates were compared by drug susceptibility observed six-month regimen for pulmonary, pleural and
pattern and restriction fragment length polymorphism lymph node TB in children using two weeks of daily
598 Tuberculosis
isoniazid, rifampicin and pyrazinamide therapy; and in some children with pulmonary TB. These are
followed by six weeks of twice weekly isoniazid, mainly useful in settings where the host inflammatory
rifampicin and pyrazinamide therapy; and 16 weeks of reaction contributes significantly to tissue damage. Short-
twice weekly isoniazid and rifampicin (46). Of the 175 courses of corticosteroids are indicated in children with
children evaluated [159 with pulmonary and intra- endobronchial TB that causes localized emphysema,
thoracic lymph node TB, 4 with pleural, and 12 with segmental pulmonary lesions or respiratory distress.
cervical lymph node TB], 81 per cent completed treatment Some children with severe miliary TB may show
in six months. Of the 33 patients who received extended dramatic improvement with corticosteroids, if alveolo-
treatment, three did so because of physician’s choice, 17 capillary block is present.
had an inadequate response to initial therapy, and two
had significant adverse reactions to drugs, and 16 had Management of an Infant Born to a Mother with
poor adherence to the direct observation of treatment. Tuberculosis
Only 37 per cent of patients had complete resolution of
disease at the end of treatment, but all continued to Congenital TB is rare. The diagnosis is frequently missed.
improve after therapy was stopped. Only one patient The foetus may be infected either haematogenously
relapsed after four years. through umbilical vessels or through ingestion of the
The major problem in inclusion of children in infected amniotic fluid. In the former situation there will
programmatic treatment is difficulty in demonstration be primary focus in liver and in the latter it will be in the
of AFB and classification of different clinical lungs. It is difficult to find the route of transmission in a
manifestations according to categories described for newborn with multiple foci of infection. It is difficult to
adults. There have been efforts to develop classification differentiate between congenital and postnatally
of different types of childhood TB into three categories acquired TB. According to the criteria proposed by
similar to those for adults. A classification was developed Cantwell et al (50) in 1994, congenital TB is diagnosed if
and evaluated in the TB clinic of a tertiary care hospital the infant has proven TB lesion[s] and at least one of the
(47). In this study (47), of the 459 children with TB, 365 following criteria: [i] appearance of lesions in the first
[80%] completed the treatment. Of these, 302 [82.7%] week of life; [ii] a primary hepatic complex or caseating
were cured with the primary regimen assigned to them hepatic granulomas; [iii] TB infection of the placenta or
in the beginning, 54 [14.8%] required extension of the maternal genital tract; and [iv] exclusion of the
treatment for three months and nine [2.5%] patients possibility of postnatal transmission by a thorough
required change in the treatment regimen. The authors investigation of contacts including the infant’s hospital
(47) concluded that it is feasible to classify and manage attendants or birth attendant.
various types of TB in children in different categories All infants born to mothers with active TB should be
similar to World Health Organization [WHO] guidelines screened for evidence of disease by doing a good physical
for adult TB. Recently, a consensus statement jointly examination, TST and chest radiograph. If physical
prepared by the Indian Academy of Pediatrics and examination and investigations are negative for TB
Revised National Tuberculosis Control Programme disease, the infant should be started on isoniazid
[RNTCP] of Government of India has also proposed a prophylaxis [5 mg/kg/day] for six months. After three
classification of different types of TB in children into three months, the child should be examined for evidence of
categories (48). The categorization and standardized
TB and a repeat TST is done. If TST result is negative, the
treatment regimens for use in children under the RNTCP
infant can be immunized with bacille Calmette-Guerin
of Government of India are described in Tables 63.5A
[BCG] vaccine and isoniazid can be stopped. If TST is
and 63.5B (49).
positive but the infant is totally asymptomatic, isoniazid
prophylaxis is continued for another three months.
Corticosteroids
Infants with congenital TB should be treated with four
Corticosteroids, in addition to antituberculosis drugs, are drugs [isoniazid, rifampicin, pyrazinamide, streptomy-
useful in the treatment of children with neurological TB cin] in the intensive phase followed by two drugs
[isoniazid, rifampicin] during maintenance phase for the initiation of highly active antiretroviral therapy (53,54).
subsequent four months. Rarely, paradoxical reactions have been described in
HIV-seronegative patients as well. These can be brief or
Management of a Child in Contact with an Adult prolonged with multiple recurrences. Paradoxical
with Tuberculosis reactions pose a diagnostic challenge and have to be
distinguished from TB treatment failure, drug resistance
In a recent study (51), nearly one-third of children
and other opportunistic infections that are common
[aged < 5 years] in contact with adults with active TB
among HIV-infected patients (53,54).
disease had evidence of TB infection. The infection
was more commonly associated with younger age, Radiological Criteria
severe malnutrition, absence of BCG vaccination,
contact with an adult who was sputum smear- Clinical improvement precedes radiological clearance of
positive, and exposure to environmental tobacco lesion on the chest radiograph. The optimal frequency
smoke (51). It is suggested that children below six of radiological monitoring in children with pulmonary
years of age in contact with adult patients with TB is unclear. One protocol suggests obtaining chest
sputum smear-positive TB should receive six months radiographs after four to eight weeks of treatment. If it
of isoniazid prophylaxis. It is mandatory to screen shows improvement in combination with clinical
all children for evidence of TB in the household of an response, no further radiographic evaluation is required.
adult patient with sputum smear-positive TB. In the authors’ opinion, the first follow-up chest radio-
graph during treatment should be done after eight weeks
Monitoring of Therapy i.e., at the end of intensive phase. In patients who show
increase or little change in radiological features coupled
Response to treatment can be judged by using the
with delayed clinical response, prolongation of intensive
following criteria: clinical, radiological, bacteriological,
phase by a month is suggested. Further films are taken
and laboratory test results.
after four weeks and the child, if better, should be shifted
Clinical Criteria to continuation phase; else, the child is investigated for
failure of treatment and drug resistance. The degree of
Clinical improvement in a child on antituberculosis
radiological clearance can be graded as: [i] complete
therapy is the mainstay of judging response to treatment.
clearance; [ii] moderate to significant clearance [half to
The child should be seen once in every two to four weeks
two-thirds clearance]; [iii] mild clearance [one-third or
initially, and once in four to eight weeks thereafter. On
less decrease in size]; or [iv] no clearance or appearance
each visit, improvement in fever, cough, appetite and
of new lesion[s]. Treatment should not be continued till
subjective well-being is assessed. The child is examined
complete radiological clearance as improvement in the
for weight gain and improvement in findings on
chest radiograph may continue even after discontinua-
physical examination. Compliance is assessed by talking
tion of treatment (55).
to parents, checking medications on each visit. Majority
of children show improvement in symptoms within a Microbiological Criteria
few weeks.
In the presence of poor response or worsening of Most of the childhood pulmonary TB is paucibacillary.
symptoms or signs, the initial basis of diagnosis is In children, where isolation of Mycobacterium tuberculosis
reviewed, especially, if treatment compliance has been was possible at the time of diagnosis, every effort should
regular and the child should be assessed for the be made to document disappearance of bacilli during
possibility of drug-resistant TB. After the treatment is treatment.
over, follow-up every three to six months for next two
Other Measures
years is desirable (48,52).
Immune reconstitution inflammatory syndrome Although an elevated erythrocyte sedimentation rate
[IRIS] has been described in 32 to 36 per cent of patients [ESR] may be expected in children with TB, a recent study
with HIV-TB, usually within days to weeks after the found that one-third of children with TB had a normal
600 Tuberculosis
ESR at the time of diagnosis, suggesting little value in children. Second edition. New Delhi: Jaypee Brothers;
using ESR as a diagnostic and monitoring test for 2000.p.85-98.
20. Seth V, Singhal PK, Semwal OP, Kabra SK, Jain Y. Childhood
childhood TB (56).
tuberculosis in a referral center: clinical profile and risk
factors. Indian Pediatr 1993;30:479-85.
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602 Tuberculosis
Diagnosis of Childhood
Tuberculosis: Recent Advances
and Applicability of New Tools 42
Ben J Marais, Madhukar Pai
INTRODUCTION in Malawi reported a mortality rate of 17 per cent in

children diagnosed with TB (13). An autopsy study from
It is often stated that children with tuberculosis [TB]
Zambia showed that TB rivals acute pneumonia as a
rarely have sputum smear-positive disease and contri-
major cause of death from respiratory disease in children
bute little to disease transmission within the community.
from endemic areas, irrespective of the child’s HIV status
For this reason the diagnosis and management of TB in
(11). The complete spectrum of disease reported in
children is not considered a priority by TB control
children from a highly endemic area demonstrates the
programmes. However, children carry a huge disease
frequency with which severe TB disease manifestations
burden (1,2) and adolescent children in particular do
do occur (14). Standard antituberculosis treatment is
contribute to disease transmission within the community
extremely effective, but unfortunately treatment is rarely
(3,4). Of the estimated 8.3 million new TB cases reported
available to diseased children in endemic areas. This is
to the World Health Organization [WHO] in the year
demonstrated by the fact that the Global Drug Facility,
2000, 884 019 [11%] were children (2). The severity of the
at present, provides no child friendly treatment option
childhood TB disease burden has been recognised in
to countries with limited resources. In addition, TB
many developing countries (5-8). For example, a recent
control programmes largely focus on the treatment of
survey from South Africa reported that children under
adults with sputum smear-positive TB and establishing
13 years of age contribute 13.7 per cent of the TB disease
an accurate diagnosis of childhood TB is considered to
burden with a calculated incidence rate in excess of 400
be very difficult, especially in resource-limited settings.
per 100 000 per year (8).
The global epidemic of TB is closely linked to the
CHILDHOOD TUBERCULOSIS: A DIAGNOSTIC
spread and intensity of the human immunodeficiency
DILEMMA
virus [HIV] epidemic in many endemic areas, particularly
in sub-Saharan Africa (9). Although HIV infected The diagnosis of childhood TB is complicated by the
children are highly susceptible to develop TB following absence of a practical gold standard, as bacteriologic
infection, the majority of child TB cases are HIV- confirmation is rarely achieved (15,16). Sputum smear
uninfected (10), even in sub-Saharan Africa (11), where microscopy, often the only diagnostic test available in
TB/HIV co-infection is highly prevalent in adults. endemic areas, is positive in less than 10 to 15 per cent of
Another common misconception is that children usually children with probable TB (17,18), and culture yields are
develop mild forms of TB and that severe disease also low [< 30% to 40%] (17,18). For this reason,
manifestations are the exception. In reality, children can alternative strategies have been developed to diagnose
and do develop severe forms of TB. It has been reported childhood TB in non-endemic areas, the triad of
that TB accounts for 15 per cent of all paediatric deaths [i] known contact with an adult index case [e.g., house-
in some Indian hospitals (12), while a survey conducted hold contact]; [ii] a positive tuberculin skin test [TST] as
Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools 603
evidence of Mycobacterium tuberculosis infection; and [iii] highest risk. Disease progression occurs primarily within
suggestive signs on the chest radiograph provides an the first 12 months following primary infection (27), and
accurate diagnosis. Although it has not been formally therefore, it seems prudent to include all immune
validated, this approach is widely applied in non- competent children less than three years of age in the
endemic areas and it has been incorporated into the high-risk group. Children infected with HIV and/or
International Standards for Tuberculosis Care (19). However, those with other forms of immune deficiency experience
the diagnostic accuracy of the triad is greatly reduced in a similar high risk and they should be included in the
endemic areas where the majority of the population high-risk group irrespective of age (26,29). Due to the
acquire infection during childhood, and where transmis- frequency and rapidity with which disease progression
sion is not restricted to household contact with a known may occur in these high-risk children, an important
index case (20,21). Consequently, in endemic settings diagnostic challenge is to find a sensitive marker of
where the discriminatory value of known Mycobacterium Mycobacterium tuberculosis infection that will identify
tuberculosis exposure and/or infection is drastically those who may benefit from preventive treatment.
reduced, the diagnosis of childhood TB depends mainly Current diagnostic approaches, together with recent
on clinical features and the subjective interpretation of advances that may be applicable to diagnosis of
the chest radiograph (22,23). childhood TB in the near future, are summarized in
The WHO guidelines (24) categorize children as Table 42.1 (30).
suspect, probable and confirmed cases. The application
of these guidelines are limited by the frequency with ADVANCES IN SYMPTOM-BASED DIAGNOSIS
which children are infected in endemic areas, reducing
the diagnostic value of a positive TST, as well as the Screening for Disease
unavailability of radiology in most resource-limited The WHO guidelines regard the TST and chest
settings and the subjectivity of chest radiograph findings. radiograph as prerequisite tests for adequate screening
Hilar adenopathy is often regarded as the hallmark of of household contacts (31). However, this limits access
primary TB (25). However, the natural history of disease to preventive therapy in resource-limited settings where
demonstrates that asymptomatic hilar adenopathy is a these test are rarely available and where children are
transient phenomenon in the majority [50% to 60%] of frequently exposed to TB at a young and vulnerable age.
children following recent primary infection. Despite the A recent study evaluated the value of symptom-based
absence of antituberculosis treatment, very few children screening compared with TST and chest radiograph-
with asymptomatic hilar adenopathy develop progres- based screening in children exposed to Mycobacterium
sive disease, indicating that hilar adenopathy is more tuberculosis (32). The findings suggest that simple
indicative of recent primary infection than active disease symptom-based screening could have considerable value
in the absence of suspicious symptoms (26,27). The in resource-limited settings given the fact that more than
interpretation of radiologic signs is highly subjective and 90 per cent of children diagnosed with TB on chest
it should be interpreted with extreme caution in the radiograph reported symptoms, and in those that
absence of clinical data. However, chest radiograph reported no symptoms only isolated hilar adenopathy
remains the most widely used diagnostic test in clinical was observed, probably reflecting recent primary infec-
practice (23,28), and, when interpreted by an experienced tion and not disease. These findings require confirmation,
clinician, it does provide a fairly accurate diagnosis in but the use of a simple symptom-based screening test
the presence of suspicious symptoms. would facilitate the provision of preventive chemo-
The natural history of disease also demonstrates the therapy to asymptomatic, high-risk household contacts;
importance of risk stratification. In immune competent only symptomatic children would then be selected for
children, age is the most important variable that further investigation to exclude active TB.
determines the risk of disease progression following
primary Mycobacterium tuberculosis infection (26). Child- Diagnosing Disease
ren who become infected at a very young age [< 2 years], Due to the diagnostic limitations discussed and the
before immune maturation is complete, experience the difficulty in obtaining chest radiographs in many
604 Tuberculosis
Table 42.1: Summary of various diagnostic approaches, their potential application and perceived problems and benefits
Diagnostic approach Potential application Potential problems and benefits Validation
Current approaches
TB culture using solid or Bacteriologic confir- Slow turn around time, too expensive Accepted gold standard
liquid broth media mation of active TB for most poor countries
Poor sensitivity in children
Chest radiography Diagnosis of probable Rarely available in endemic areas with Marked inter- and intra-observer
active TB limited resources variability
Accurate disease classification essential Reliable in expert hands and in
Isolated hilar adenopthy may indicate presence of suspicious symptoms
recent primary infection and not disease
Current clinical diagnostic Diagnosis of probable Poor symptom definition Not well validated
approaches active TB
Tuberculin skin test Diagnosis of Mycobac- Rarely available in endemic areas with Various cut-offs advised in
terium tuberculosis limited resources different settings
infection Does not differentiate LTBI from active
disease
Not specific for Mycobacterium
tuberculosis infection
Particularly insensitive in immune
compromised children
Simple to use and less expensive than
blood-based LTBI tests
Recent advances
Symptom-based Screening child contacts Simple, limited resources required Not well validated
approaches of adult TB cases Should improve access to preventive
Symptom-based chemotherapy for asymptomatic high-risk
screening contacts
Refined symptom-based Diagnosis of probable Simple, limited resources required Additional validation required
diagnosis active TB Should improve access to chemotherapy
in resource-limited setting
Poor performance in HIV-infected children
Immune-based Diagnosis of probable Simple, point of care testing Additional validation required
approaches active TB Variable accuracy and difficulty in disting-
Antibody-based uishing between latent and active TB
immune assays
Antigen-based immune Diagnosis of probable Simple, point of care testing Not well validated
assay [e.g., LAM active TB Limited clinical data on accuracy
detection assay]
MPB 64 skin patch test Diagnosis of probable Simple and easy to use Not well validated
active TB Limited clinical data on accuracy, but
initial data suggests it distinguishes
latent infection from active TB
Interferon-gamma Diagnosis of LTBI; Limited data in children Not well validated in children
release assay potentially a “rule-out” Inability to differentiate LTBI from active TB
test for active TB Particular relevance in high-risk children,
disease where LTBI treatment is warranted
Expensive, not easily applicable in
resource limited settings
-Contd-
Table 42.1 -Contd-
Diagnostic approach Potential application Potential problems and benefits Validation
Bacteriology and mole- Bacteriologic confirma- Simple and feasible, but limited data in Not well validated
cular based approaches tion of active TB children
Colorimetric culture Potential for contamination in field
systems [e.g., TK-Medium] conditions
Phage-based tests Diagnosis of probable Limited data in children Not well validated
[e.g., FASTPlaque-TB] active TB, and detection Requires laboratory infrastructure
of rifampicin resistance Performs relatively poorly when used
on clinical specimens
Microscopic observation Diagnosis of probable Simple and feasible, but limited data in Not well validated
drug susceptibility assay active TB, and detection children
of drug resistance
Nucleic acid amplification Diagnosis of probable Rarely available in endemic areas with Extensively validated, but
tests active TB, and detection limited resources evidence not in favour of
of rifampicin resistance Sensitivity tends to be poor in smear- widespread use
negative and paucibacillary TB
Specificity a concern in endemic areas,
where LTBI is common
Requires adequate quality control systems
TB = tuberculosis; LTBI = latent TB infection; HIV = human immunodeficiency virus; LAM = lipoarabinomannan
Adapted from “Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 2007;92:446-52
(reference 30)”
endemic areas, a variety of clinical scoring systems have sensitivity [82.3%], specificity [90.2%], positive predictive
been developed. A critical review of scoring systems value [82.3%]. Clinical follow-up served as a valuable
concluded that they are severely limited by the absence additional diagnostic tool to differentiate active TB from
of standard symptom definitions and a lack of adequate other common diseases in those low-risk children who
validation (33). Accurate symptom definition is impor- did not meet the diagnostic criteria at presentation. This
tant to differentiate TB from other common conditions. approach also performed reasonably well in HIV
A recent community survey demonstrated that poorly uninfected children under three years of age, but more
defined symptoms [such as, a cough of > 3 weeks caution is required in this high-risk group due to the
duration] are frequently reported in a random selection rapidity with which disease progression may occur.
of healthy children and have poor discriminatory power However, the approach performed poorly in HIV
(34). However, a follow-up study demonstrated that the infected children, due to the presence of chronic symp-
use of well-defined symptoms with a persistent, non- toms caused by other opportunistic infections and/or
remitting character significantly improves the diagnostic HIV-related conditions, re-emphasizing the need for the
accuracy (35), although the diagnostic value of this provision of preventive chemotherapy following
approach required more extensive validation. exposure and/or documented infection in these children.
This was partially achieved in a recently completed The most common extra-thoracic manifestation of TB
prospective, community-based study that enrolled 1024 in children is cervical adenopathy. A simple clinical
children with suspicious symptoms over a three-year algorithm that identified children with persistent
period in Cape Town, South Africa (36). Combining three [> 4 weeks] cervical adenopathy, without a visible local
variables at presentation: [i] persistent non-remitting cause or response to first-line antibiotics, and a cervical
cough of greater than two weeks duration; [ii] documen- mass of greater than or equal to 2 × 2 cm showed excellent
ted failure to thrive during the preceding three months diagnostic accuracy in a recent study from a TB endemic
and [iii] fatigue, performed well in low-risk immune area (37). Regular clinical follow-up remains essential so
competent children three years or older, with good that children who do not respond to standard antituber-
606 Tuberculosis
culosis treatment are referred as soon as possible to antigen that may not be recognized by the host immune
establish a definitive diagnosis. In non-endemic areas, system during all stages of disease. The development of
where the pre-test probability of TB is low and where Mycobacterium tuberculosis specific antigen cocktails
the prevalence of latent TB infection [LTBI] is low, the partially addresses this problem. It has been suggested
addition of a positive TST result or the presence of other that each TB state is characterized by a specific “bacterial
immune markers of Mycobacterium tuberculosis infection, antigen signature”, and therefore, it seems important to
such as a positive T-cell assay, may offer significant study both negative as well as positive responses to a
additional value. For the definitive diagnosis of TB panel of antigens (44,45). A pattern of positive and
cervical adenopathy in children, fine needle aspiration negative responses [analogous to a bar code] may then
cytology has proven to be a robust and simple technique be used to distinguish between various disease stages,
that provides a rapid result and excellent bacteriologic but whether this approach will have clinical applicability
yields (37-40); the use of a small 23-gauge needle has been remains to be seen.
associated with minimal side-effects (37). Because of the limitations of existing serological assays,
efforts are underway to develop assays that focus on
ADVANCES IN IMMUNE-BASED DIAGNOSIS antigen rather than antibody detection. For example,
antigen-capture enzyme linked immunosorbent assay
Serological Tests [ELISA] for the detection of lipoarabinomannan in sputum
and urine samples has shown good promise in early trials
Serological tests for the detection of antibodies have been
(46), but further work is necessary to determine their utility
attempted for many years, and their performance has
in clinical practice. Another innovative immune-based
been extensively reviewed (41-43). Despite their long method uses transdermal application of MPB64 antigen
history and repeated attempts at improving these tests, as a patch test. The MPB64 is an immunogenic antigen
no assay is currently accurate enough to replace micro- specific to Mycobacterium tuberculosis complex. In studies
scopy and culture. However, commercial kits for conducted in Japan and the Philippines (47,48), the MPB64
antibody detection are widely available and they are skin patch test was able to distinguish active TB from LTBI
primarily marketed in endemic countries where regula- with 88 to 98 per cent sensitivity and 100 per cent
tory approval systems are weak. Several authors have specificity. Although the exact biological mechanism
analysed the reasons for the apparent failure of sero- behind the skin response remains unclear, the skin patch
logical tests (41-43). A major challenge with immunologi- test is currently being developed into a commercial test
cal diagnosis is the wide clinical spectrum of TB, ranging by Sequella Inc., Rockville, MD, USA. Its ability to detect
from LTBI to various degrees of active disease. Several active TB in children has not been evaluated.
other factors may also affect the performance of antibody-
based tests, including bacille Calmette-Guérin [BCG] Interferon-gamma Release Assays
vaccination, exposure to nontuberculous mycobacteria Due to advances in molecular biology and genomics, an
[NTM] and HIV co-infection; all of which are particularly alternative to the traditional TST has emerged in the form
prevalent in endemic areas. of blood-based assays that measure interferon-γ [IFN-γ]
Early versions of serological assays used crude, non- released by sensitized T-cells after stimulation by
specific antigenic mixtures. This led to loss of specificity, Mycobacterium tuberculosis antigens. The IFN-gamma
and the inability to distinguish active TB from LTBI and release assays [IGRAs] use antigens that are more specific
infection with NTM. The development of well-defined, to Mycobacterium tuberculosis than purified protein
purified recombinant proteins specific to Mycobacterium derivative [PPD]. These antigens include early secreted
tuberculosis partially overcame this problem, but antigen antigenic target 6 [ESAT-6], culture filtrate protein 10
recognition remains highly variable and varies across the [CFP-10], and TB7.7 [Rv2654]. The ESAT-6 and CFP-10
infection/disease spectrum, as Mycobacterium tuberculosis are encoded by genes located within the region of
expresses different genes and proteins during different difference 1 segment of the Mycobacterium tuberculosis
stages of the disease. Therefore, any immune-based test genome; they are more specific than PPD because they
should include antigens that are expressed during all the are not shared with any of the BCG strains and several
various stages of disease progression and not a single NTM species.
Two IGRAs are currently available as commercial kits; Various studies have documented the experience with
the T-SPOT.TB® test [Oxford Immunotec, Oxford, UK], the enzyme linked immunospot [ELISPOT] assay in
and the QuantiFERON®-TB Gold® [QFT-G] [Cellestis children. Compared to TST, the ELISPOT assay
Ltd, Carnegie, Australia] assay. The QFT-G assay is demonstrated improved sensitivity in children, as
approved by the US Food and Drug Administration reflected by better correlation with the degree of exposure
[FDA]. The QFT-G In Tube, a simplified, improved following a school TB outbreak in the UK (61). It also
version has been evaluated in field studies (49-51), and demonstrated higher sensitivity than TST in HIV-infected
is currently FDA approved. The T-SPOT.TB is licensed children with active TB, and was less affected by
for use in Europe, Canada, and other countries. malnutrition (62). In a study from South Africa, ELISPOT
Available evidence on IGRAs, reviewed extensively responses to ESAT-6 and CFP-10 were detectable in two-
elsewhere (52-56), suggests that these assays have higher thirds of children with a clinical diagnosis of TB; however,
specificity than the TST and better correlation with surro- the assay was more frequently positive [83%] in children
gate measures of exposure to Mycobacterium tuberculosis with culture-proven disease (63).
in low incidence settings. However, given the lack of a Overall, IGRAs appears to be a promising tool to
gold standard for LTBI, the sensitivity and specificity for diagnose LTBI and they may aid the diagnosis of active
LTBI cannot be directly estimated, and there is some TB in children, but available evidence is inadequate to
concern that the sensitivity for LTBI might be less than make any clinical recommendations at this time. It is
that of the TST, especially in vulnerable populations (55). important to emphasize that in the absence of symptoms
The US Centers for Disease Control and Prevention or radiologic signs, IGRAs, like the TST, fail to make the
recently recommended that the QFT-G assay can be crucial distinction between LTBI and active disease. The
used in place of the TST for all indications, including main application of these assays in non-endemic areas
screening of children (55), despite a lack of published may be to assess LTBI in contact and/or immigrant
paediatric data. screening. In endemic areas, its presumed superior ability
There are limited data on the performance of QFT-G to detect Mycobacterium tuberculosis infection in HIV-
assay in children. A study from Australia compared the infected individuals (62), compared to the TST that
performance of the TST and the QFT-G assay in 101 performs poorly in this group (64), may be of particular
children considered to be at risk for LTBI; 17 per cent of value, as the diagnosis of Mycobacterium tuberculosis
the QFT-G assays yielded indeterminate results (57). In infection is highly relevant in these high-risk children.
addition, the concordance between QFT-G and the TST A sensitive test for Mycobacterium tuberculosis infection
was poor [kappa 0.30] with 26 [70%] of the 37 children may also provide important supportive evidence to
defined as LTBI by TST having a negative QFT-G result establish or refute a diagnosis of active TB, particularly
(57). In contrast, a recent study among hospitalized in HIV-infected children where the value of symptom-
children in rural India showed high agreement between based diagnostic approaches is reduced by chronic HIV-
TST and QFT-G In Tube, but data were inadequate to related symptomatology and chest radiograph
estimate sensitivity among bacteriologically proven cases interpretation is complicated by HIV-related lung disease
of TB (58). In a study from Japan, five children diagnosed (65). Further research is needed to document the role of
to have TB who had typical chest radiograph findings, IGRAs as “rule out” tests for active TB in children.
such as cavitation, lymphadenopathy, and nodular hilar
shadows, were positive by the QFT-G assay (56). Of three ADVANCES IN BACTERIOLOGY-BASED AND
asymptomatic cases without radiologic abnormalities but MOLECULAR DIAGNOSIS
with a positive QuantiFERON®-TB Gold® 2G [QFT-2G]
Traditional Methods
response, one developed TB during follow-up. Among
12 QFT-2G negative children, no TB cases occurred Although the bacteriologic yield in children is said to be
during the follow-up period (59). Lastly, a recent case low, it must be emphasized that adolescent children
report suggested that the QFT-G assay may be useful in frequently develop sputum smear-positive adult-type
the diagnosis of perinatal TB, especially as the TST is not disease and sputum microscopy has definite diagnostic
a reliable test in this population (60). value in these older children (4). In addition, a recent
608 Tuberculosis
study demonstrated that the bacteriologic yield in children yield in this study remained poor [15% with 1 and 20%
with TB depends on the specific intra-thoracic manifesta- with 3 induced sputum specimens], the technique has
tion of the disease (66). A yield of 77 per cent was reported not been used outside the hospital setting and induced
in children with advanced disease, while the yield in those coughing may pose a transmission risk to health care
with uncomplicated hilar adenopathy was only 35 per workers, and also to other children if the procedure is
cent, using the liquid broth mycobacteria growth indicator not performed in a separate, well-ventilated room and/
tube [MGIT®] system [Beckton Dickinson, MD, USA]. or equipment is not adequately sterilized. Additional
Liquid broth systems as such, MGIT® and BACTEC® offer studies are awaited to confirm the feasibility, safety and
slightly superior sensitivity, reduced turn around time diagnostic value of collecting induced sputum specimens
compared to the conventional Lowenstein-Jensen [L-J] in primary health care settings. The various methods that
solid media (67). However, their excessive cost and have been used to collect a bacteriologic specimen are
requirement for laboratory infrastructure remains a major summarized in Table 42.2 (71).
limitation. This observation may explain the poor yield The string test is another novel approach that has
observed in developed countries, where active contact recently been evaluated for its ability to retrieve
tracing programmes are well established and children are Mycobacterium tuberculosis from sputum smear-negative
usually diagnosed at a very early stage of the disease. It HIV infected adults with TB symptoms (72). This test
also demonstrates the potential value of traditional, as well demonstrated superior sensitivity compared to induced
as more advanced bacteriology-based diagnostic sputum in this study population and was generally well
approaches, particularly in endemic areas where children tolerated. A recent study (73) also showed that the string
frequently present with advanced disease. test is well tolerated and achievable for most childhood
In addition to poor bacteriologic yield, the collection TB suspects as young as four years. Assessment of the
of bacteriologic specimens is often problematic. Two to bacteriologic yield and clinical utility of this test in
three fasting gastric aspirates collected on consecutive children is eagerly awaited.
days and usually requiring hospital admission are
routinely advised in young children who cannot cough
Novel Culture Systems and Detection Methods
up sputum. A retrospective study from California com-
pared the bacteriologic yield achieved in gastric aspirates The biggest limitations of traditional culture methods are
collected from hospitalized and non-hospitalized sub-optimal sensitivity, slow turn around time and
children (68). Although the yield in hospitalized children excessive cost. TK-Medium® [Salubris Inc., Cambridge,
was higher [percentage of positive cultures 48% vs 37%], MA, USA] is a novel colorimetric system that indicates
this difference was not statistically significant (68), which growth of mycobacteria and allows for early positive
suggests that hospitalization may not be a prerequisite identification, before bacterial colonies appear (74). The
for the collection of a good gastric aspirate specimen. TK-Medium also permits susceptibility testing for drug
Bronchoalveolar lavage, using flexible fiberoptic resistance, and can allow for differentiation between
bronschoscopy, has additive value when used in combi- Mycobacterium tuberculosis and NTM. Although TK-
nation with gastric lavage, but this technique is highly Medium promises to be a practical, low-cost, simple test,
specialized and is unavailable in most endemic areas (69). published evidence on this test is limited and the test is
In a study from Peru, mid-morning nasopharyngeal currently not US FDA approved (43). No data exist on its
aspiration was compared with early morning gastric value in childhood TB diagnosis. Field studies are ongoing
aspiration; gastric aspiration provided a slightly better and they should help to define the accuracy and robustness
yield than nasopharyngeal aspiration [38% vs 30%], but of this new rapid culture system under field conditions.
the results were comparable (70). Nasopharyngeal Mycobacteriophage-based tests use bacteriophages to
aspiration is minimally invasive, does not require infect live Mycobacterium tuberculosis and detect the
hospitalization or fasting, and can be performed any time presence of mycobacteria using either phage amplifica-
of the day. A study from South Africa demonstrated that tion on a bed of Mycobacterium smegmatis or the detection
a single specimen, using hypertonic-saline induced of light (75,76). In general, phage assays have a turn
sputum collection, may provide the same yield as three around time of two to three days, and require a laboratory
gastric aspirate specimens (18). However, the overall infrastructure similar to that required for performing
Table 42.2: Summary of various bacteriologic sample collection methods and perceived problems and/or benefits
Sample collection Potential problems and benefits Potential application
method
Sputum Not feasible in very young children Routine sample to be collected in children > 7 years of
Assistance and supervision may improve the age [all children who can produce a good quality
quality of the specimen specimen]
Induced sputum Increased yield compared to gastric aspirate To be considered in the hospital setting on an in- or out-
No age restriction; patient basis
Specialized technique, which requires
nebulization and suction facilities
Use outside hospital setting not studied
Potential transmission risk
Gastric aspirate Difficult and invasive procedure Routine sample to be collected in hospitalized patients
Not easily performed on an out-patient basis who cannot produce a good quality sputum specimen
Requires prolonged fasting
Sample collection advised on 3 consecutive days
Nasopharyngeal Less invasive than gastric aspirate To be considered in primary health care clinics or on an
aspiration No fasting required out-patient basis
Comparable yield to gastric aspirate
String test Less invasive than gastric aspirate Potential to become the routine sample collected in
Tolerated well in children > 4 years of age children who can swallow the capsule, but cannot
Bacteriologic yield and feasibility requires further produce a good quality sputum specimen
investigation
Bronchoalveolar Extremely invasive Only for use in patients who are intubated or who
lavage require diagnostic bronchoscopy
Urine, stool Not invasive To be considered with novel sensitive bacteriologic or
Excretion of Mycobacterium tuberculosis well antigen-based tests
documented
Blood, bone marrow Good sample sources to consider in the case of To be considered for the confirmation of probable
probable disseminated TB disseminated TB in hospitalized patients
Adapted from: “Marais BJ, Pai M. Specimen collection methods in the diagnosis of childhood tuberculosis. Indian J Med Microbiol
2006; 24:249-51 (reference 71)”
cultures. Phage amplification assays are available as Mycobacterium tuberculosis as “strings and tangles” of
commercial kits; the FASTPlaque-TB® [Biotec Laborato- bacterial cells in the broth medium with or without
ries Ltd, Ipswich, Suffolk, UK] assay can be used directly antimicrobial drugs [for drug susceptibility testing]. In a
on sputum specimens for diagnosis, and a variant, the recent, large study from Peru (77), MODS detected 94
FASTPlaque-TB Response® kit is designed to detect rifam- per cent of 1908 positive sputum cultures, whereas the
picin resistance in sputum specimens. The FASTPlaque- conventional L-J culture detected only 87 per cent. The
TB® kits are currently not US FDA approved, but are CE MODS also had a shorter time to culture positivity
marked for use in Europe. No information exists on its [average of 8 days] compared to L-J culture. Although
utility in the diagnosis of childhood TB. In adults, these MODS is a promising and inexpensive tool, no informa-
assays are fairly accurate for rifampicin resistance, tion exists on its utility in the diagnosis of childhood TB
especially when used on culture isolates (76). or detection of drug resistance in children.
Microscopic observation drug susceptibility assay
[MODS] is a novel assay that uses an inverted light Nucleic Acid Amplification Tests
microscope and Middlebrook 7H9 broth culture to Nucleic acid amplification [NAA] tests amplify nucleic
rapidly detect mycobacterial growth. The MODS uses acid regions specific to the Mycobacterium tuberculosis
inverted light microscopy to detect early growth of complex. These tests can be directly used on clinical
610 Tuberculosis
specimens [such as, sputum] and are available as either comment on the ability of this test to differentiate LTBI
commercial kits or in-house assays. Commercial kits from active TB, which is a particular concern in endemic
include the Amplified Mycobacterium tuberculosis Direct areas where LTBI is extremely common.
Test® [MTD] [Gen-Probe Inc., San Diego, CA, USA], the In summary, available NAA tests have not lived up
Amplicor® MTB tests [Roche Diagnostic Systems, to their early promise. In addition to concerns about
Branchburg, NJ, USA], and the BD ProbeTec ET assay accuracy and reliability, their high costs and requirement
[Becton Dickinson Biosciences, Sparks, MD, USA]. The for laboratory infrastructure reduce their applicability in
Amplicor® and MTD® tests are currently US FDA resource-limited settings. Therefore, efforts are underway
approved. to simplify testing protocols and increase their accuracy
The literature on NAA tests has been extensively (43,87). Many promising advances have been made in
reviewed (78-81). They have shown highly variable results the development of novel tools to diagnose TB in adults
and limited utility in children (82-85). Several recent meta- (43,52,87), but none of these tests are currently in position
analyses (78,80,81,85) have shown that sensitivity to replace sputum smear microscopy or culture. Very few
estimates are low in paucibacillary forms of TB [extra- of these novel approaches have been tested in children,
pulmonary TB, and smear-negative pulmonary TB], which the group in whom the current diagnostic dilemma is
represents the vast majority of childhood TB cases. A most pronounced. At present, the uses of simple
negative test, therefore, does not rule out the diagnosis of symptom-based diagnostic approaches with or without
TB. The same limitations apply to the use of NAA tests on the use of TST or IGRAs and improved access to chest
cerebrospinal fluid samples for the diagnosis of TB radiography seem to offer the most immediate benefit to
meningitis (81). Good results have been reported with the children (88). A flow diagram has been included to guide
use of a hemi-nested polymerase chain reaction [PCR] the diagnosis and appropriate management of children
technique in Peru (85), but the study used uninfected with suspected TB exposure or disease [Figure 42.1].
children as the control group and could therefore, not Improving the provision of preventive chemotherapy to
Figure 42.1: Algorithm for diagnosis and management of children with suspected tuberculosis exposure and/or disease based on
answering five simple questions. Question 5 refers to special circumstances such as human immunodeficiency virus infection, retreatment,
or exposure to a drug-resistant source case
Reproduced with permission from “Marais BJ, Gie RP, Schaaf HS, Beyers N, Donald PR, Starke JR. Childhood pulmonary tuberculosis:
old wisdom and new challenges. Am J Respir Crit Care Med 2006;173:1078-90 (reference 88)”
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Surgical Aspects of Childhood Tuberculosis 615
Surgical Aspects of
Childhood Tuberculosis
43
M Bajpai, V Jain, Arun K Gupta
INTRODUCTION Table 43.1: Clinical features of genitourinary tuberculosis
Diagnosis of tuberculosis [TB] in children poses a major Symptoms

problem and a high degree of suspicion is warranted to Progressive, diurnal urinary frequency
Dysuria
make an early diagnosis even in endemic regions. In this
Macroscopic haematuria with back and flank pain
chapter, the surgical aspects of TB in children will be Renal colic
discussed laying emphasis on the clinical, diagnostic and Systemic symptoms [fever, anorexia, night sweats, weight loss]
surgical principles involved. Hypertension
Chronic epididymitis
GENITOURINARY TUBERCULOSIS Other symptoms
Polyuria, hyponatraemia [with adrenal tuberculosis]
As there is a time lag of about four to twenty years Chronic renal insufficiency
between the initial infection and occurrence of genito-
urinary involvement, paediatric genitourinary TB
presents usually in the adolescent period. The time lag
epididymis with a thickened, beaded vas; a chronic,
noted is more than five years in two-thirds of the patients
draining scrotal sinus in the setting of history of TB
and is greater than 15 years in a quarter of the cases (1).
elsewhere in the body or definite history of contact
further support the diagnosis of genitourinary TB.
Clinical Presentation
Urinary frequency is the earliest symptom which is
Tuberculosis of the genital tract is uncommon before diurnal and progressive in nature (2). Frequency is
puberty. Majority of the young children with genito- secondary to vesical irritation, decreased bladder
urinary TB are asymptomatic. Symptoms are seen in the capacity and rarely as a result of polyuria with tubular
more advanced stages and usually after vesical dysfunction. The urine may be opalescent. Occasionally,
involvement. Symptoms and signs commonly observed patients may present with pyuria. The child may initially
in children with genitourinary TB are listed in Table 43.1. complain of suprapubic pain with a moderately full
Tuberculosis of the genitourinary tract must be bladder which gradually progresses to dysuria and
suspected if a child presents with chronic or recurrent strangury. Renal pain is usually absent but some patients
urinary tract infection [cystitis] not responding to may have a dull flankache. Painless haematuria may
adequate standard antibiotic therapy for recommended result because of ulcers at the renal papilla in five per
duration. The clinical suspicion is enhanced when pus cent cases (1,2). Renal and ureteric colic may occur due
cells are found without bacteria in an acidic urine or on to passage of a blood clot, secondary calculi or debris.
methylene blue staining of the urine sediment. Gross or There is usually no renal enlargement or tenderness.
microscopic haematuria; an enlarged, non-tender Rarely, the contralateral kidney may show compensatory
616 Tuberculosis
enlargement. Symptomatic chronic renal failure occurs manifestation of sexual abuse and there are reports of
rarely but subclinical impairment of renal functions may urethral involvement and penile lesions following ritual
be seen more oftenly. Five to ten per cent of patients with circumcision.
renal TB may have hypertension (1-3). Ocon et al (3) have In girls, lower abdominal pain and amenorrhoea may
shown that in most patients the hypertension is not be presenting symptoms of genital TB. Constitutional
mediated by the renin-angiotensin system and is symptoms are rare. Free peritoneal fluid and lower
therefore, not cured by nephrectomy. Genitourinary TB abdominal mass may be evident.
may present with other complications, such as peri-
nephric abscess, renal calculi, secondary amyloidosis and Role of Surgery
adenocarcinoma of the renal pelvis. Surgery is reserved for the management of local
Tuberculosis of the genital tract most often manifests complications, such as ureteral strictures, perinephric
as epididymitis in boys. Fever is seldom present. abscesses and non-functioning kidneys. Algorithm for
Enlarged epididymis may be felt as a hard, nodular the surgical management of children with genitourinary
swelling. A chronic draining scrotal sinus should suggest TB is shown in Figure 43.1. Surgery should be preceded
TB aetiology unless proved otherwise. A secondary by at least three weeks and preferably four months of
hydrocoele may accompany epididymitis. The testis may antituberculosis treatment with constant clinical and
be fixed by an extension of an epididymal abscess. The radiological monitoring. The principles of surgery for
prostate may be nodular or indurated and the seminal urogenital TB in children are same as those for adults.
vesicle is similarly involved. In the presence of prostatitis, The reader is referred to the chapter “Genitourinary
TB may spread via the semen. Genital TB may be a tuberculosis” [Chapter 32] for more details.
Figure 43.1: Algorithm for the surgical management children with genitourinary tuberculosis
IVP = intravenous pyelography
Adapted and reproduced with permission from reference 8
ABDOMINAL TUBERCULOSIS
The clinical manifestations of abdominal TB are protean
[Figures 43.2, 43.3, 43.4, 43.5 and 43.6]. All age groups
are at risk, and children between six and fourteen years
of age are often affected (4,5). Clinical presentation of
abdominal TB in children can be acute, sub-acute or with
other manifestations. The reader is referred to the
chapters “Tuberculosis in children” [Chapter 41A] and
“Abdominal tuberculosis” [Chapter 19] for more details
Figure 43.2: CECT of the abdomen showing calcified

retroperitoneal and mesenteric lymph nodes. A large psoas abscess
can also be seen on the left side [arrow]
Figure 43.4: Ultrasonography of the abdomen showing ascites [A]

and multiple hypoechoic masses in the prevertebral location [B]
suggestive of lymphadenopathy
regarding the clinical presentation, diagnosis and

medical management of this condition.
Role of Surgery
Antituberculosis treatment is the mainstay of manage-
ment (4-9). Surgical intervention is helpful in procuring
tissue for confirmation of aetiological diagnosis in
children with peritoneal and mesenteric lymph node
TB. An algorithm for assessment of suspected
abdominal TB is shown in Figure 43.7 (10). Surgery is
also helpful in the management of complications of
intestinal TB, such as perforation of intestinal ulcer and
intestinal obstruction. The possible role of surgical
Figure 43.3: Barium meal follow through examination showing intervention in children with abdominal TB is shown
ileocaecal tuberculosis [stricture marked by arrows] in Figures 43.8A and 43.8B.
618 Tuberculosis
Stricturoplasty is preferred to multiple resection anasto-

moses in multiple strictures as it conserves the bowel
and obviates the occurrence of blind loop syndromes.
Emergency surgery for intestinal obstruction is best
avoided as it is associated with a high mortality (12).
PERIPHERAL LYMPH NODE TUBERCULOSIS

Tuberculosis accounts for a high proportion of lymph-
adenopathy in children. Classically, the cervical nodes
are involved in 67 to 90 per cent of cases (13,14). The
exact incidence may vary in childhood but has been
reported in up to 55 per cent in a cohort of 223 children
under six years of age (15). Painless enlargement,
matting, fluctuant neck mass or a discharging sinus may
be evident. Multifocal [> 3 sites] or generalized lymph-
Figure 43.5: Plain radiograph of the lumbosacral region [antero- adenopathy is uncommon without co-existent dissemi-
posterior view] showing multiple calcified lymph nodes nated or miliary TB. Associated extralymphatic TB has
been described in five to fifteen per cent cases. These
figures increase when human immunodeficiency virus
[HIV] infection co-exists (13-16). Isolated TB lymph-
adenitis at sites other than cervical region has been
reported rarely.
Selective preauricular and intraparotid lymph nodal
TB with or without parotid parenchymal involvement
may sometimes be seen (17). The lower pole is usually
involved presenting as a swelling antero-inferior to the
ear and in front of the mastoid attachment of the
sternocleidomastoid muscle. The dense parotid fascia
limits the spread of infection and the resultant swelling
may mimic a tumour on physical examination.
Nontuberculous Mycobacterial Lymphadenitis in

Children
In lymphadenitis caused by nontuberculous mycobac-
Figure 43.6: Barium meal follow through examination showing short teria [NTM], females are mostly affected and lymph node
segment tuberculosis stricture [arrow] in the small bowel with involvement is unilateral (13). High cervical lymph nodes
proximal dilatation near the mandible are characteristically involved and the
enlarged lymph nodes are firm, rubbery and non-tender.
Surgery for abdominal TB must be cautious and They may not manifest the signs of inflammation and
minimal as the risk of inadvertent bowel injury with matting is exceedingly rare. Systemic symptoms are
subsequent entero-cutaneous fistulae is high. Procedures uncommon and history of exposure to TB is rarely
commonly adopted include closure of perforation, obtained.
exteriorization of bowel, adhesiolysis and resection- The reader is referred to the chapter “Lymph node
anastomosis of the bowel. The choice of surgery is tuberculosis” [Chapter 26] for more details on the clinical
dependent on several factors. Tuberculosis perforations presentation, diagnosis and management of lymph node
carry a high mortality [30% to 40%] despite surgery (11). TB.
Figure 43.7: Algorithm for assessment of suspected abdominal TB.

*Confirmatory investigations: 1. culture for Mycobacterium tuberculosis from accessible source; 2. peripheral lymph node
biopsy for histopathology and culture; 3. adenosine deaminase levels in ascitic fluid; and 4. CT of the abdomen if
ultrasonography is inconclusive
TB = tuberculosis; AFB = acid-fast bacilli; TST = tuberculin skin test
620 Tuberculosis
Table 43.2: Indications for lymph node sampling
Difficulty in clinical diagnosis and/or non-diagnostic fine needle

aspiration cytology
Abscess formation
History of rapid increase in size
Further significant increase in size on treatment
Supraclavicular lymph nodes
Hard or matted lymph nodes
Fixation to surrounding structures
Development of new signs and symptoms [fever, weight loss,
Figure 43.8A: Surgical intervention in patients with peritoneal TB night sweats]
TB = tuberculosis
Significant lymph node [> 2 cm] not responding to antibiotic
therapy in 4 to 6 weeks
Non-resolution of the lymphadenopathy in 8 weeks
by the enlarged intrathoracic lymph nodes can result in

atelectasis, obstructive emphysema, pulmonary infection
and even asphyxia (19-21). The enlarged mediastinal
lymph nodes can also cause perforation of the tracheo-
bronchial tree. The aim of effective surgical treatment in
childhood pulmonary TB includes restoring lung
function to normal and managing complications. The
indications for surgery are listed in Table 43.3 (19-23).
Role of Surgery
Figure 43.8B: Surgical intervention in patients with intestinal TB Major Airways Obstruction
TB = tuberculosis
Adapted from reference 9 When there is an obstruction of the major airways and
acute respiratory distress, administration of prednisolone
Role of Surgery [2 mg/kg/day] along with antituberculosis treatment
and nebulized bronchodilator therapy is indicated. Lack
Antituberculosis treatment is the mainstay in manage-
of improvement within 48 to 72 hours is an indication
ment of lymph node TB. The surgeon aids in obtaining
tissue for the confirmation of diagnosis [e.g., in Table 43.3: Indications of surgery in childhood
performing excision biopsy of the lymph node]. The pulmonary tuberculosis
indications for the lymph node sampling are listed in
Major airway obstruction by extraluminal lymph node compression
Table 43.2. or intraluminal tissue
Nontuberculous mycobacterial lymphadenitis is Post-TB pulmonary destruction
treated primarily by surgical excision (13). Parotid lymph
TB pleural disease
nodal TB may mandate superficial extirpation of an
Other indications
encapsulated mass with a 1 cm margin (17,18). Aspiration
Drainage of active TB lung abscess
of fluctuant lesions may also be required in some patients.
Repair of broncho-oesophageal and bronchopleural fistula
using vascularized muscle flaps
PULMONARY TUBERCULOSIS
Resection of persistently discharging chest wall sinuses
In children with primary pulmonary TB disease, comp-
ression of the relatively narrow and compliant airways TB = tuberculosis
for operative intervention. Following a pre-operative Post-tuberculosis Pulmonary Destruction

bronchoscopic assessment of the airway, usually a right Patients with post-TB pulmonary destruction present
thoracotomy is performed. An attempt to resect the entire with definite evidence of extensive pulmonary damage
nodal mass is hazardous and can lead to damage of the and are usually symptomatic. Decision making regarding
airway wall. Most of the nodes can be evacuated by pulmonary resection is primarily based on symptomato-
incising the capsule and removing the caseous material logy rather than the radiological findings. The risk to the
or by removing the calcified contents piece-meal. remaining pulmonary tissue should be kept in mind
When there is chronic compromise, these patients while planning for surgery. Intensive pre-operative
may be asymptomatic. Superinfection by pyogenic orga- preparation involving physiotherapy and use of broad-
nisms can result in an acute presentation. Also, the distal spectrum antibiotic treatment is mandatory. This
atelectatic or collapsed lung can undergo progressive regimen is continued till the sputum production is
damage despite effective medical therapy [Figure 43.9]. reduced to a minimum. One lung ventilation and prone
Recent evidence suggests that the early surgical decomp- position with head end lowered is recommended during
ression prevents irreversible pulmonary parenchymal surgery to avoid contamination of the normal lung.
damage. The risk of airway damage during evacuation
of lymph nodes is higher in this group. Nodal incision
Tuberculosis Pleural Disease
and curettage of the mass is recommended.
When the obstruction is due to intraluminal tissue Late pleural fibrosis after a TB empyema requires
[endobronchial TB], the collapsed lung is at high risk of decortication [Figure 43.10]. Patients with minimal or no
being permanently damaged by infection. Bronchoscopic respiratory symptoms despite radiographic evidence of
suction and removal of granulomatous tissue with biopsy pleural fibrosis do not require decortication unless there
forceps results in re-inflation of the lobe or lung in more is a significant postural problem [scoliosis]. Patients with
than 50 per cent of the cases. This usually requires minimal symptoms cope well with pleural fibrosis which
multiple attempts which are repeated every five to seven tends to regress with age and activity. It is also important
days. Haemorrhage during removal of the granulation to ensure that the underlying lung is not bronchiectatic
tissue is a possible complication. This procedure decrea- and unsalvageable before undertaking decortication.
ses the incidence of pulmonary resection and salvages Video-assisted thoracoscopic surgery [VATS] is also
lungs or lobes which are collapsed secondary to finding increasing use in the treatment of pleuro-
obstruction but are otherwise normal. pulmonary TB (24,25). Video-assisted thoracoscopic
Figure 43.9: Chest radiograph [postero-anterior view] showing Figure 43.10: CECT of the chest showing loculated encysted
collapse of left lower lobe which can be seen as a triangular empyema in right hemithorax with enhancing walls. Thickening of
radiodensity [arrow] in the left retrocardiac region extrapleural soft tissues can also be seen
622 Tuberculosis
surgery is a safe approach and avoids the morbidity

associated with conventional thoracotomy. The current
role of VATS in the management of pleuropulmonary
TB is unclear but VATS has been found to be useful in
the following situations (25): [i] VATS is safe and effective
in achieving the diagnosis of TB through pleural biopsies
or wedge lung resection of indeterminate pulmonary
nodules; it is particularly useful for those patients who
are debilitated, thus making them poor candidates for
conventional open surgery; and [ii] in patients with
trapped lung or TB empyema, VATS could achieve full
lung re-expansion with minimal morbidity. However,
therapeutic lung resection using VATS in patients with
TB is technically demanding and potentially hazardous.
Its role is, at present, limited. The reader is also referred
to the chapter “Surgery for pleuropulmonary tuberculosis”
NEUROLOGICAL TUBERCULOSIS
Neurological TB constitutes almost half the cases of
childhood TB. Tuberculosis meningitis [TBM] is the most
common type of central nervous system TB. The reader
is referred to the chapter “Neurological tuberculosis”
[Chapter 21] and “Tuberculosis in children” [Chapter 41] for
more details.
Surgical Therapy
Figure 43.11: NCCT of the head showing obscured suprasellar
Intrathecal hyaluronidase has been used in children with cisterns [A] which manifest intense enhancement with intravenous
contrast. Communicating hydrocephalus with periventricular ooze
thick basal exudates. Besides clearing up meningeal
[arrow] is also seen [B]
adhesions hyaluronidase helps in better diffusion of
drugs and reverses or reduces vasculitis. A weekly dose hydrocephalus. Rarely, an intraluminal subependymal
of 1000 to 1500 units for five to ten weeks has been tuberculoma or a plug of ependymal exudate may block
recommended as treatment (26). the acqueduct.
In 50 per cent or more cases, there is established In patients with hydrocephalus due to TBM, surgical
hydrocephalus [Figures 43.11A and B] requiring treat- management is indicated if the signs and symptoms
ment. Meningeal exudates not only obstruct cerebro- suggestive of raised intracranial pressure persist despite
spinal fluid [CSF] pathways but can occlude large vessels adequate medical therapy. Increasing ventriculomegaly
in the circle of Willis, the middle cerebral artery in the with periventricular ooze, recent onset papilloedema and
Sylvian fissure and the lenticulostriate vessels causing signs and symptoms of raised intracranial pressure like
infarction. The aetiopathogenesis of hydrocephalus in vomiting, hypertonia, gaze palsies and bradycardia are
TBM involves blockage of the basal cisterns by the TB indications for shunt surgery (27,28). Ventriculoperito-
exudates in the acute stage and adhesive leptomeningitis neal shunts are preferred over ventriculoatrial shunts
in the chronic stage resulting in communicating unless the peritoneal cavity is involved in the disease.
hydrocephalus. The aqueduct of Sylvius may be blocked Various shunt systems are available and all of them
by circumferential compression of the brainstem by the involve a one-way pressure regulated valve. Cerebro-
meningeal exudates leading to non-communicating spinal fluid examination is mandatory before shunt
5. Aston NO. Abdominal tuberculosis. World J Surg 1997;21:

492-9.
6. al-Fadel Saleh M, al-Quorain A, Larbi E, al-Fawaz I, Taha O,
Satti MB. Tuberculous peritonitis in children: report of two
cases and literature review. J Pediatr Gastroenterol Nutr
1997;24:222-5.
7. Sharma AK, Agarwal LD, Sharma CS, Sarin YK. Abdominal
tuberculosis in children. Experience over a decade. Indian
Pediatr 1993;30:1149-52.
8. Bajpai M, Dave S. Genitourinary tuberculosis. In: Seth V,
editor. Essentials of tuberculosis in children. New Delhi:
Jaypee Brothers Medical Publishers; 1997.p.203.
9. Gupta DK, Bajpai M. Abdominal tuberculosis. In: Seth V,
editor. Essentials of tuberculosis in children. New Delhi:
Jaypee Brothers Medical Publishers; 1997.p.140.
10. Saczek KB, Schaaf HS, Voss M, Cotton MF, Moore SW.
Diagnostic dilemmas in abdominal tuberculosis in children.
Figure 43.12: CECT of the head showing contrast enhancing granu- Pediatr Surg Int 2001;17:111-5.
loma with lobulated outline and surrounding oedema. Tuberculoma 11. Bahari HM. Perforation of tuberculous enteritis: report of a
is difficult to differentiate reliably from other inflammatory case. Med J Malays 1978;32:282-4.
granulomas on the basis of CT alone 12. Bhansali SK. The challenge of abdominal tuberculosis in 310
cases. Indian J Surg 1978;40:65-77.
placement. The presence of persistent infection in the CSF 13. Venkatesh V, Everson NW, Johnstone MS. Atypical myco-
can lead to a low-grade peritoneal inflammation and bacterial lymphadenopathy in children- is it underdiagnosed?
pseudocyst formation. Further, the high protein content J R Coll Surg Edinb 1994;39:301-3.
of the CSF has been implicated in the higher incidence 14. Harris BH, Webb HW, Wilkinson AH Jr, Santdices AA.
Mycobacterial lymphadenitis. J Pediatr Surg 1982;17:589-90.
of shunt blockage seen in this setting. Intraventricular
15. Herzog LW. Prevalence of lymphadenopathy of the head and
septae and ependymal adhesions complicate the picture neck in infants and children. Clin Pediatr 1983;22:485-7
and cause incomplete decompression of ventricles. 16. Dandapat MC, Mishra BM, Dash SP, Kar PK. Peripheral
Ventriculoscopy and adhesiolysis may be required to lymph node tuberculosis: a review of 80 cases. Br J Surg
break the loculations and allow free CSF drainage. It must 1990;77:911-2.
be remembered that CSF shunting has definite serious 17. Zheng JW, Zhang QH. Tuberculosis of the parotid gland: a
report of 12 cases. J Oral Maxillofac Surg 1995;53:849-51.
complications and, therefore, the decision to place a shunt
18. Lindeboom JA, Kuijper EJ, Bruijnesteijn van Coppenraet ES,
must be individualized and based on definite indications. Lindeboom R, Prins JM. Surgical excision versus antibiotic
If the tuberculoma is large or is located in the pathway treatment for nontuberculous mycobacterial cervicofacial
of CSF circulation, surgical removal is essential [Figure lymphadenitis in children: a multicenter, randomized,
43.12]. However, in majority of the patients, controlled trial. Clin Infect Dis 2007;44:1057-64. Epub 2007
tuberculomas respond well to antituberculosis treatment Mar 2.
19. Goussard P, Gie R. Airway involvement in pulmonary
and corticosteroids.
tuberculosis. Paediatr Respir Rev 2007;8:118-23. Epub 2007
Jun 7.
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cases. Medicine 1974;53:377-92. childhood mediastinal tuberculous lymphadenitis. Ann
2. Wechsler H, Westfall M, Lattimer KK. The earliest signs and Thorac Surg 1995;59:644-6.
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J Urol 1960;83:801-3. Surgical management of airway obstruction in primary
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Izquierdo F, et al. Renal tuberculosis and hypertension: value 22. Rotman PE, Jones JC, Peterson HG. Endoscopic and surgical
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4. Millar AJW, Rode H, Cywes S. Abdominal tuberculosis in Child 1960;99:315-9.
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Pediatr Surg Int 1990;5:392-6. tuberculosis. Semin Thorac Cardiovasc Surg 1995;7:108-11.
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24. Yim AP, Low JM, Ng SK, Ho JK, Liu KK. Video-assisted 27. Bajpai M. Management of hydrocephalus. Indian J Pediatr
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Pediatr 1985;52:171-4.
Tuberculosis in Elderly
44
M van Cleeff, PCFM Gondrie, J Veen
INTRODUCTION EPIDEMIOLOGY
Population ageing was in the twentieth and still is in the The epidemiological pattern of tuberculosis [TB] in high
twenty-first century, one of the most distinctive incidence and low incidence countries shows a remark-
demographic events [Table 44.1] (1). Initially experienced able difference. In high incidence countries the peak of
by the more developed countries, in the near future the epidemic is among young adults and low in older age.
virtually all countries will face population ageing. In In low incidence countries there is an increase in the
absolute terms, the number of older persons has tripled burden of TB with growing age. In England and Wales,
over the last 50 years and will more than triple again from the year 1987 to 1989, while the increase in the
over the next 50 years. In relative terms, the percentage incidence of TB was six per cent for all ages combined, it
of older persons is projected to more than double was 13 per cent in females and 16 per cent in males over
worldwide over the next half century. the age of 75 years. The proportion of deaths due to extra-
Although the highest proportions of older persons pulmonary TB in the age group 75 and above increased
are found in the more developed regions, this age group by 3.2 per cent per annum from the year 1972 to 1992,
is growing considerably more rapidly in the less while in the other age groups, the mortality rates declined
developed regions. As a result, the older population will (5). It has also been reported that adverse drug reactions
be increasingly concentrated in the less developed to antituberculosis drugs occur more frequently in the
regions (2). The elderly population in India increased elderly persons (6). A similar trend was also observed in
from 20 million [5.5% of total population] in 1950 to 55 Canada. During the year 1981, persons aged 65 years or
million [6.5% of total population] in 1991 and almost 77 more constituted only 9.7 per cent of the total population,
million [7.6% of total population] in the year 2000 (3,4). but accounted for 28 per cent of all TB cases which occurred
These figures emphasize the extent and the importance in that year (7). In the United States of America [USA],
of this group of population in future. the incidence of TB in persons aged more than 65 years
Table 44.1: Number and proportion of population aged 60 years and older [1950 to 2050]
Region 1950* 2000* 2050*
World 205 475 [8] 605 785 [10] 1 963 767 [21]
More developed regions 95 473 [12] 231 442 [19] 395 106 [34]
Less developed regions 110 003 [6] 374 343 [8] 1 568 660 [19]
Least developed regions 10 733 [5] 32 167 [5] 173 222 [10]
* Data expressed as thousands [%]

Source: reference 1
626 Tuberculosis
has been estimated to be as high as 150 to 200 per 100 000 promised, and these changes have serious implications
in 1992 (8). In the USA, during the period 1986 to 1988, for the elderly to control infection (21,22). Several risk
elderly subjects [more than 65 years of age] constituted 12 factors contribute to this decline in immunity (23):
per cent of the population and accounted for about 28 per [i] underweight and/or malnutrition; [ii] concomitant
cent of the reported cases of TB. In the USA the incidence diseases, like cancer or diabetes mellitus; [iii] gastro-
of TB is found to be higher in the elderly residing in nursing intestinal surgery [gastrectomy, jejunoileal bypass];
homes [old age homes] as compared to the elder [iv] immunosuppressive treatment like corticosteroids;
ly in the community (9-11). This is attributed to clustering [v] heavy tobacco smoking; and [vi] human immuno-
of elderly population in nursing homes. However, some deficiency virus [HIV] infection. Recent data suggest that
studies (12,13) have found no significant difference in tumour necrosis factor-α blocking drugs [e.g., infliximab]
the incidence of TB in the institutionalized and non- have an unexpected influence on the T-cell balance and
institutionalized elderly. As per the Revised National contributes to reactivation of latent TB infection [LTBI]
Tuberculosis Control Programme [RNTCP] of Govern- (24).
ment of India data 2006 [n = 563 778] (14), persons aged The higher age specific incidence of TB in elderly age
65 years or above constituted eight per cent of the sputum group is attributed to enduring viability of Mycobacterium
smear-positive patients. tuberculosis and to the steadily diminishing T-lymphocyte
It seems that the diagnosis of TB is often missed in activity [immuno-senescence] (25,26). It has been
the elderly subjects and is being misdiagnosed as bron- demonstrated that high incidence of TB in elderly results
chitis, bronchiecstasis or pneumonia, and while in many from higher rate of infection experienced in early life
countries the population is ageing, TB in elderly becomes (26,27). In developed countries, the prevalence of TB
more important. Therefore, it is evident that TB can be a infection is higher in elderly as they have lived in highly
major health problem in some elderly populations. As endemic areas in their younger life and experienced high
an epilogue to Dubos’ book ‘The White Plague’ (15), the rates of infection. The reader is also referred to the chapter
prevalence of TB among elderly citizens may well be “Reactivation and reinfection tuberculosis” [Chapter 47] for
titled ‘The Grey Plague’ (16). more details.
REACTIVATION AND REINFECTION LATENT TUBERCULOSIS INFECTION IN ELDERLY

Tuberculosis in old people can be either due to exogenous Infection with Mycobacterium tuberculosis generally
infection or reinfection or endogenous reactivation. produces a positive tuberculin skin test [TST] indicated
Exogenous infection [or reinfection] is acquired from an by greater than 10 mm induration with an intradermal
outside source, usually a sputum smear-positive case, injection of five tuberculin units [TU] of purified protein
whereas endogenous reactivation arises from quiescent derivative [PPD]. Very often, the value of this test is
lesions in the lung or elsewhere in the body. It is difficult questioned in elderly subjects. In a large study (27) where
to be certain in individual cases, but there are theoretical 45 000 residents in 227 nursing homes were tested with
reasons for believing that in old people endogenous 5 TU of PPD, 20 to 30 per cent of those who were 60
reactivation is the predominant mechanism (17). When years old were found to be TST positive. This figure
transmission in the community is low, increased dropped to 10 per cent at the age of 90 years. In this study,
incidence in older age in over 90 per cent represents reacti- all the non-reactors had a booster effect on re-testing (28).
vation of latent infection (18). However, when transmis- American Thoracic Society [ATS] and Centers for Disease
sion in endemic environments is high, exogenous reinfec- Control and Prevention [CDC] have recommended a
tion does occur, as has been shown by Canetti et al (19). In two-stage TST (29,30). The TST positivity can be taken
developed countries with a relatively large influx from as a risk factor for developing active TB. Negative TST
refugees and asylum seekers, ongoing transmission in result, often found in elderly, is mainly due to failing
the elderly might even delay the elimination of TB (20). immune response to the PPD that can be restored by
During the natural ageing process the immune repeated administration of this antigen. Care should be
system undergoes many alterations. In particular, both taken in not misinterpreting booster effect as the TST
the CD4+ and CD8+ T-cell compartments become com- conversion.
Tuberculosis in Elderly 627
Although TST reactors have an increased risk of develop- Table 44.2: Comparison of clinical presentation of
ing active TB, they live longer as this is an indicator of tuberculosis in the young and the elderly patients
their immunocompetence. Among the non-reactors some Variable Young Elderly
are immunocompromised and die early in life due to
Constitutional symptoms
some infection while the immunocompetent subjects are
Fever + –
either not infected or have outlived the TB bacilli and, Night sweats + –
thus, have lost sensitivity to tuberculin (8). In fact, among Non-specific symptoms* + –
elderly patients with active TB, tuberculin anergy has Respiratory symptoms
been reported in 20 to 30 per cent of those without Cough + –
Haemoptysis + –
acquired immunodeficiency syndrome [AIDS] and in up
Dyspnoea – +
to 60 per cent in those with AIDS (30). Most patients with Co-morbid conditions † – +
active TB without AIDS who are TST negative in the Hypoalbuminaemia – +
beginning become positive after recovery with therapy TST positivity + –
for TB. The reader is also referred to the chapter “Tuber- Adverse drug reactions – +
culin skin test” [Chapter 11] for more details. * dizziness, mental dullness
There is a promising evidence suggesting that the † chronic obstructive pulmonary disease, diabetes mellitus,
interferon-gamma release assays [IGRAs] have a bronchiectasis, stroke
potential to perform better than the TST in the elderly + = more frequent; – = less frequent; TST = tuberculin skin test
population in detecting LTBI. The reader is referred to
the chapter “Diagnosis of latent tuberculosis infection: recent clinical presentation of TB in the elderly may be atypical,
advances and future directions” [Chapter 12] for more especially if it is due to new infection (37,38).
details.
CLINICAL FEATURES
Pulmonary TB is defined as TB affecting the tracheo-
Elderly subjects with TB may present with the systemic bronchopulmonary tree. This excludes the mediastinum
manifestations of TB such as fever, anorexia, weight loss, and the pleura. In the past the term ‘respiratory TB’ was
and symptoms attributable to the organ system involve- used, which included TB of all intra-thoracic pulmonary
ment but with important differences (31,32). Some of the structures. In some countries, especially in the former
difficulties apply to diagnosis in old people in general. Soviet Republics, this terminology is still used. Compari-
Elderly people may not give an accurate account of their son of the clinical presentation and diagnosis of
symptoms, due to contributing factors such as poor pulmonary TB in elderly persons in some published
memory or dementia, or loss of communicative skills due studies (39-42) is shown in Table 44.3.
to deafness or impairment of speech. Other diseases like Since primary infection at old age is rare, most clinical
cancer may mask the symptoms of TB and confuse the presentations of pulmonary TB is based on reactivation
clinical picture, both for the patient and the doctor. It is, of old lesions. Typical sites are the apical segments of
therefore, not uncommon that the diagnosis of TB is only both upper and lower lobes and the posterior segments
made at autopsy (33). Sometimes, apyrexial presentation of the upper lobes. The disease may develop as pneumo-
with progressive wasting strongly mimicking a metasta- nia with caseation, liquefaction and cavity formation.
tic carcinoma has been described in elderly patients with In the pre-chemotherapy era complications like
miliary TB and has been described as cryptic miliary TB exudative pleuritis, or pneumothorax were common.
(34-36). The reader is referred to the chapter “Dissemi- Though these are encountered less frequently in the
nated and miliary tuberculosis” [Chapter 34] for further elderly in areas of low TB transmission, they are
details on this topic. commonly seen in areas where TB is highly endemic (39-
Table 44.2 provides a comparison of clinical presen- 46). Tuberculosis should be included in the differential
tation of TB in young adults and elderly subjects. A diagnosis of any illness in an elderly patient, which
paucity of respiratory symptoms is frequently observed consists of ill-defined pleuropulmonary symptoms or
in the elderly (31,32). As compared to young adults, signs and pulmonary infiltrates of unknown cause.
628 Tuberculosis
Table 44.3: Comparison of the clinical presentation, and diagnosis of pulmonary tuberculosis in elderly patients
Variable Umeki (39) Gupta et al (40) Lee et al (41) Das et al (42)
No. of patients 35 50 119 30

Place of study Japan India Korea India
Mean age [years] 73.5 63.1 74.8 70.6
Predisposing/co-morbid conditions*
Alcoholism 11 ND ND ND
COPD 23 02 10.1 40
Hypertension or cardiovascular disease 34 06 15.1 ND
Diabetes mellitus 09 16 25.2 17
Cancer ND ND 0.8 ND
Malnutrition ND ND ND 13
Symptoms*
Fever 49 74 32.8 63
Cough 60 74 67.2 90
Sputum 69 68 67.2 87.5
Haemoptysis 03 14 14.3 17
Chest pain 09 38 04.2 ND
Dyspnoea 06 46 38.7 93
Fatigue 34 ND 50.4 ND
Anorexia 29 90 31.4 90
Weight loss 43 80 30.1 87
Night sweats 09 50 03.4 07
No symptoms 14 ND 01.7 ND
Signs*
Chest signs 49 60 ND ND
Hepatomegaly 14 ND ND ND
Altered consciousness 11 ND 13.4 ND
Chest radiograph*
Upper lobe involvement 69 ND 77.3 30
Bilateral disease 23 ND ND 40
Cavitation 40 32 ND 53.3
Pleural effusion 09 18 ND 03.3
Positive TST*† 20 [n = 12] ND ND ND
Diagnosis*†
Sputum smear-positive 43 70.7 [n = 41] 57.1 47
* All values shown as percentages

† Numbers in square brackets indicate number of patients tested
n = no. of patients studied; COPD = chronic obstructive pulmonary disease; TST = tuberculin skin test; ND = not described
Elderly subjects with reactivation or reinfection symptoms and cough, the chest radiographic abnor-
pulmonary TB present with fever, cough with expectora- malities are often seen in mid and lower zones (11). Due
tion, and haemoptysis. Chest radiographs may reveal to this atypical presentation, the diagnosis may be missed
fibronodular lesions in the upper zones with or without unless a high index of suspicion is maintained and
cavitation. Hilar and perihilar lesions may also be present sputum or bronchial aspirate is subjected to smear and
and these need to be differentiated from other opportu- culture examination. Further, delay in the diagnosis
nistic infections, bronchogenic carcinoma and results in transmission of infection to the fellow inmates,
lymphoma. especially if they are living in a crowded nursing home.
On the other hand, the clinical picture of primary TB The reader is also referred to the chapter “Pulmonary
infection in the elderly is different. Besides constitutional tuberculosis” [Chapter 14] for more details.
Extra-pulmonary Tuberculosis Tuberculosis meningitis is also more commonly seen

in elderly patients. These patients may present with non-
Extra-pulmonary TB is the result of reactivation of lesions
specific symptoms of headache, dizziness, confusion and
that were the result of haematogenous spread of bacilli
the classical signs of meningitis in the form of neck
in the primary phase of infection. Extra-pulmonary TB
rigidity and Kernig’s sign may be absent. Fever may or
becomes relatively more frequent than pulmonary TB
may not be present. Severe hyponatraemia due to synd-
with increasing age.
rome of inappropriate antidiuretic hormone secretion
Among 15 352 patients registered between 1993 and
may produce a confusional state in these patients. Thus,
2002 in the Netherlands the ratio of extra-pulmonary to
a high index of suspicion is necessary to diagnose this
pulmonary TB increased from 37 per cent in patients
condition. Computed tomography [CT] of the head and
under 14 years of age to 64 per cent in persons aged
lumbar puncture and cerebrospinal fluid [CSF]
55 to 64 years. The most common sites affected in people
examination should be performed. Usually, treatment is
over 65 years of age were bones and joints [24.3%],
based on limited clinical features and non-specific
urogenital [17.6%], abdominal [6.3%] and meningeal
laboratory findings, such as elevated proteins, low sugar
[3.6%]. There was, however, a large proportion [48.2%]
and lymphocytosis in the CSF.
of ‘other’ i.e., undefined sites (45). They may often present
with disseminated TB with involvement of two or more
non-contiguous organs. Generalized Tuberculosis
In elderly patients, TB lymphadenitis usually presents Miliary TB is increasingly being seen in the elderly as
as slowly enlarging lymphadenopathy. Cervical lymph compared to young adults (8,36). Miliary TB can be
nodes are most commonly affected. Fever and other difficult to recognize. The symptoms are often non-
systemic symptoms may not be evident and the patients specific, e.g. fever, weakness, weight loss, with no further
may otherwise be asymptomatic. Rarely, axillary and information from physical examination, TST or chest
inguinal lymphadenopathy may also be present. radiograph (11). A needle biopsy of liver or bone marrow
Physical examination may be unremarkable but for may be needed to establish the diagnosis.
palpable peripheral lymphadenopathy. Cold abscess, But also a slowly, progressive wasting syndrome with
chronic non-healing TB sinus and ulcer may rarely be low grade or absent fever, without localizing symptoms
seen. or signs and without a miliary pattern on the chest
Elderly patients with TB pleural effusion present with radiograph can be found (36,47). Computed tomography,
an insidious onset of symptoms. Pleuritic pain and non- especially high resolution CT, may reveal abnormalities
productive cough are the usual presenting symptoms. in these patients (36,48). An elderly patient with dissemi-
Fever and other systemic symptoms may also be evident. nated TB may have palpable peripheral lymphadeno-
However, many elderly patients with TB pleural effusion pathy and hepatosplenomegaly as the only positive
may remain asymptomatic and this may result in a finding on clinical examination.
delayed diagnosis. One variety of TB in elderly people has been called
Tuberculosis of bones and joints tends to affect such ‘areactive’ or ‘sepsis tuberculosa acutissima’ (49).
weight bearing joints as the vertebrae, hip or knee, Usually, the disease is of the miliary type with distinctive
causing a combination of osteomyelitis and arthritis. The pathological features. Contrary to the classical tubercle
clinical presentation is not distinctive and should be with a central core of caseous material surrounded by
suspected in any elderly patient with unexplained inflammatory cells, in areactive TB the tubercles consist
unifocal inflammation or destruction of bone or joint. of caseous and necrotic material containing large
Genitourinary TB often is a complication of reacti- numbers of tubercle bacilli but with a notable absence of
vation of dormant haematogenous foci in the kidneys. inflammatory cells (49). This characteristic is similar to
The most common symptoms are dysuria and that seen in HIV infected individuals and is the result of
urinary frequency caused by secondary TB cystitis. The a declining cell-mediated immunity. The reader is
disease should be suspected in any patient with sterile referred to the chapter “Disseminated and miliary tuber-
pyuria. culosis” [Chapter 34] for more details.
630 Tuberculosis
Tuberculosis and Human Immunodeficiency have insufficient strength to expectorate and may not be
Virus Co-infection in the Elderly able to provide an adequate sputum sample for testing.
If the clinical suspicion is high and the sputum smear is
Sparse published data are available on HIV-TB co-
negative, more invasive methods such as laryngeal swab,
infection in the elderly. The diagnosis of HIV infection is
fibreoptic bronchoscopy and examination of various
often missed in elderly patients, as it is not suspected in
bronchoscopic secretions and gastric aspirate can be
them (50-53). Furthermore, atypical clinical presentation
undertaken. Sputum examination is more likely to give
of TB in geriatric patients frequently results in a delayed
positive results in elderly with reactivation TB as com-
diagnosis.
pared to primary TB. In progressive primary disease,
where the number of bacilli is usually small, their
DIAGNOSIS demonstration is usually difficult (9).
From the afore-mentioned description it is evident that Mycobacterial culture results take six to eight weeks
a high index of suspicion is essential to make a diagnosis to become known. The reader is referred to the chapter
of various forms of TB in elderly subjects. All efforts “Laboratory diagnosis” [Chapter 10] for details on the
should be made to obtain a microbiological and/or various conventional and modern diagnostic methods.
histopathological diagnosis. Occasionally, patients are The value of the TST for the diagnosis of active TB in
treated empirically based on a strong clinical suspicion elderly is limited. In a patient suspected to have TB, a
and suggestive chest radiographic and CT findings in strongly positive TST increases the likelihood of
the absence of microbiological or histopathological diagnosis. However, a negative TST does not rule out
diagnosis. the diagnosis of TB.
Sometimes, elderly patients with pulmonary TB may In patients with extra-pulmonary TB, all efforts
remain asymptomatic [Table 44.3] (39-42). Furthermore, should be made to obtain appropriate specimens for
physical examination may be unremarkable in most microbiological and/or histopathological diagnosis and
situations. Co-morbid conditions such as chronic obstruc- these include fine needle aspiration cytology material
tive pulmonary disease frequently co-exist and because from lymph nodes, cold abscess, and other body fluids
of the associated long-standing cough, active pulmonary and secretions depending upon the clinical situation.
TB may not be suspected in these patients and the sputum
smear examination may be delayed (54). In the elderly, TREATMENT
congestive heart failure may mimic TB pleural effusion.
Haematological parameters have been observed to The principles of treatment of TB in elderly patients are
be similar in young and elderly patients with TB (39-42). broadly the same as in young adults. However, there are
Serum biochemistry has also been similar except for a a few problems in the treatment of elderly which require
mild elevation of alkaline phosphatase and liver enzymes emphasis. Old people notoriously are unreliable about
which has been attributed to asymptomatic involvement taking tablets regularly, at the right time, or in the right
of liver by TB (39-42). However, significant hypoalbumi- dose, especially if several drugs have to be taken together.
naemia may be present in elderly patients with TB (39- Again poor eyesight and memory or mental confusion
42,55). are contributing factors. But additionally, old people
The chest radiograph usually raises the suspicion of become apathetic and lack the determination to complete
TB in elderly persons. But since it is only a two-dimen- a treatment that has to last six months or longer. There-
sional shadow, it cannot be considered as a confirmation fore, it is important to make a reliable person responsible
of the diagnosis. This holds also true for CT. All elderly for their drug intake, who could be a family member, a
patients with pneumonia who do not respond to antibio- home help, or a nursing staff if the elderly is residing in
tics, should be investigated for TB (46). Spontaneously the old age home.
produced or induced sputum gives the best information Drug interactions are common with antituberculosis
about infectivity [Table 44.3] (39-42). Microscopy of a medications, especially with isoniazid and rifampicin.
smear prepared by the Ziehl-Neelsen method or For example, rifampicin increases the metabolic degrada-
fluorescence staining and detecting the acid-fast bacilli, tion of drugs, such as corticosteroids, digoxin, oral anti-
facilitates immediate diagnosis. However, elderly people coagulants and hypoglycaemic agents. Hence, the
dosages of these drugs need to be adjusted according to “Antituberculosis treatment induced hepatotoxicity” [Chapter
blood levels. Ideally, antituberculosis drugs should be 54] for more details. Ethambutol cannot be avoided, but
administered according to body weight and pyridoxine it may cause retrobulbar neuritis, which may be difficult
[25 to 50 mg] should be considered with each dose of to detect early in elderly patients with some impairment
isoniazid. In the elderly, streptomycin is preferably of vision or with cataracts. Streptomycin is preferably
avoided (56,57). avoided in elderly patients as it causes eighth nerve
In India, elderly patients receive DOTS under the damage particularly affecting the vestibular component
RNTCP of the Government of India. The direct observa- (18).
tion of treatment facilitates and aids regular drug intake.
The reader is referred to the chapters “Treatment of Treatment of Tuberculosis and Human Immuno-
tuberculosis” [Chapter 52], and “Revised National Tuber- deficiency Virus Co-infection in the Elderly
culosis Control Programme” [Chapter 63] for more details.
In addition to the usual concerns related to the treatment
It is thought that the problem of drug resistance is
of HIV-TB co-infection, polypharmacy and the conse-
less common in the elderly subjects as most of these
quent drug interactions are a concern in elderly patients
patients are thought to have reactivation of infection
with HIV-TB (50-53). Careful consideration should be
which was acquired many decades ago. Whenever drug
given to the medications being administered for co-
resistance is suspected, it should be treated according to
morbid conditions and the elderly patient with HIV-TB
the results of culture and sensitivity. If the sputum smears
co-infection should be carefully monitored for adverse
remain positive despite DOTS for a period of five months,
drug reactions.
antituberculosis drug resistance should be suspected. The
reader is referred to the chapter “Drug-resistant tuberculo-
Treatment of Latent Tuberculosis Infection
sis” [Chapter 49] for more details regarding the evaluation
of such patients. The administration of isoniazid aims at curing an
established infection with a small bacterial load.
Treatment Ex-juvantibus or ‘Trial Treatment’ Although theoretically other bactericidal drugs may also
be used for chemoprophylaxis, most experience has been
If no other cause for disease can be found and TB is
with isoniazid. The most important indication of giving
suspected, but cannot be proven with the available
isoniazid prophylaxis is recent conversion of the TST
armamentarium of investigations, a trial with a full
since these subjects have greater chances of developing
course of antituberculosis drugs is justified as the
active TB.
beneficial effects of treatment far outweigh the risk of
Data from countries with a low burden of TB where
relentless progression of untreated active TB which can
targeted testing using the TST is practised suggest that
be uniformly fatal. Subsequent clinical improvement
isoniazid treatment of LTBI definitely leads to low
lends support to the diagnosis and the course of standard
incidence of TB disease in the elderly (59). However, there
chemotherapy should be completed.
is a small but definite risk of hepatotoxicity. The overall
gain in survival may be very small, especially in elderly
Adverse Effects of First-line
aged more than 80 years and those with co-existing
Antituberculosis Drugs
diseases like chronic obstructive pulmonary disease and
Similar to other medications, the adverse reactions to congestive heart failure (60,61). Therefore, treatment
antituberculosis drugs are much more common in the of LTBI in elderly should be individualized and appears
elderly (46-52). The elderly patients usually suffer from to be of no benefit in elderly subjects over the age of
more than one disease and take medications for more 80 years. In areas where the prevalence of TB is low,
than one ailment at a time. Usually, antituberculosis however, elderly patients who are TST positive, have
regimens are well-tolerated. Advancing age is an impor- negative sputum cultures and fibrotic pulmonary lesions
tant risk factor for the development of antituberculosis compatible with old TB, or those that have certain risk
drug-induced hepatotoxicity (58) and should be carefully factors [e.g., patients with diabetes mellitus, those
watched for. The reader is referred to the chapter receiving corticosteroid or other immunosuppressive
632 Tuberculosis
agents] merit treatment of LTBI. In areas where TB is 14. Central TB Division. Directorate General of Health Service,
highly endemic, routine treatment of LTBI in elderly Ministry of Health and Family Welfare, Government of India.
TB India 2007. RNTCP Status report. New Delhi: Central TB
subjects, who are TST positive, is not recommended. The
Division. Directorate General of Health Service, Ministry of
reader is referred to the chapter “Tuberculin skin test” Health and Family Welfare, Government of India; 2007.
[Chapter 11] for a detailed discussion on this subject. 15. Dubos R, Dubos J. The White Plague. Tuberculosis, man and
society. Boston: Little, Brown and Company;1952.
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634 Tuberculosis
Tuberculosis in
Health Care Workers
45
SK Jindal
INTRODUCTION Most of the reports published in the recent past

support a higher risk of occurrence of both TB infection
There is a worldwide concern on the risk of acquiring and disease among HCWs (9). There is a paucity of data
tuberculosis [TB] by health care workers [HCWs] looking on this subject in spite of the fact that India accounts for
after patients suffering from an active infectious disease. about one-fifth of the total global TB burden and that
This is particularly so since the infection is air-borne and most disease related indices are alarmingly high (11). A
the presentation of the disease after acquisition of study from a teaching hosptial at Chandigarh (12)
infection is generally delayed. The contagious nature of revealed that, among resident doctors, the overall risk
TB was recognized long before the bacteriological aetio- of developing TB was calculated to be 11.2 cases per 1
logy was identified (1). Historically, there are innumer- 000 person-years of exposure and the overall incidence
able examples of relatives and close contacts of patients of TB was found to be 17.3 per 1000. But the findings
with TB themselves developing the disease and often available from other places around the world can be
dying from the same. The occurrence of TB in HCWs considered as an indicator of the enormity of the problem
especially the medical personnel, is a matter of concern in this country as well.
for lay persons and is frequently talked about in the lay
press (2). It seems quite appropriate to consider TB as an RECOGNITION OF TRANSMISSION OF
occupational disease as suggested in the recent medical TUBERCULOSIS
literature (3). Diagnosis of clinical TB is made on the basis of clinical
picture and microbiological positivity of sputum or other
TUBERCULOSIS CARE AS AN OCCUPATIONAL biological specimens. The presence of infection, however,
HAZARD is established long before the onset of disease symptoms.
Based on the circumstantial evidence, it is somewhat easy
There is a large body of data to suggest that looking after to attribute the occurrence of new clinical symptoms and
patients with TB constitutes an occupational hazard. This aetiology in a HCW to their exposure to TB. This,
belief was traced to the 1950s in an elegant historical however, cannot be definitely said unless the mycobacte-
review of the medical literature of the past 100 years (4). rial transmission can be traced to the specific source in a
There was a great hesitation initially in accepting the risk health care setting. This can be done with the help of
to the hospital employees for the fear of frightening sophisticated molecular techniques, such as the
people to adopt a health care career. It was perhaps in deoxyribonucleic acid fingerprinting.
1938 when a high incidence of TB among nurses was
demonstrated for the first time (5). Several other reports Tuberculin Skin Test
have appeared since then (6-9). Quite aptly, it has been A positive tuberculin skin test [TST] result is the most
recently termed as “the battle of a century” (10). frequently used marker of TB infection. There are several
Tuberculosis in Health Care Workers 635
difficulties in interpreting TST results and estimating TST and 1994 (8-10,18-30). This was up to a hundred times
conversion rates. This is generally attributed to factors higher than the estimated ARI in the general population
such as the prior bacille Calmette Guerin [BCG] of the Western Europe and the United States during the
vaccination and/or previous exposure to environmental period 1973 to 1992 (31). The calculated risk for the home
mycobacteria. The reader is referred to the chapter staff and the pulmonary fellows vis-a-vis general
“Tuberculin skin test” [Chapter 11] for more details. population was probably highest. Similarly, the annual
It is, therefore, difficult to attribute the presence of incidence of TB disease was considerably more in the
TB infection in HCWs to occupational exposure merely HCWs. The same observations are corroborated by the
from the presence of TST positivity unless a prospective findings of later studies which have appeared since 1994.
study on TST conversion rate is undertaken. The author Both the TB infection and the disease are reported to be
found a cut-off value of 10 mm useful in supporting the significantly higher in most studies among HCWs. The
diagnosis in patients with strong clinical suspicion of TB; criteria used for assessment of TB risk are diverse in
in other patients a 15 mm cut-off was more suitable (13). different studies. In the Western European countries,
From retrospective analyses, it is perhaps more pertinent USA, Canada and Australia where the TB prevalence is
to compare the number of TB patients among HCWs rather low, the positive TST and/or TST conversion are
versus general population in these areas, provided the most frequently employed tests to detect the presence
reliable data are available. Such comparisons are of infection. In a large study (32) involving 4070 HCWs
available from some of the developing countries (14-16). and 4 298 non-HCWs, a positive TST was observed in
Besides TST, a few other markers of exposure to 19.3 per cent HCW compared with 13.7 per cent in non-
Mycobacteria have also been utilized. A Western blot anti- HCWs; the significant differences were not explained by
Mycobacterium bovis A60 complex antibody was the employees characteristics, such as age, country of
evaluated on 127 exposed and 28 non-exposed HCWs birth and the past BCG status (32).
from a hospital in Italy and 140 non-exposed BCG- High TST positivity has been recorded among
vaccinated control subjects; and positivity of the test was physicians [45.9%] than in the general Canadian
found to be significantly higher in the exposed HCWs population (33). Similarly, physicians in USA had a high
and therefore, this was suggested as a more sensitive
rate of tuberculin reactivity [7%] although the TST
biological marker than the TST (17).
conversion rate was low (34).
Interferon-gamma Release Assays Higher infection rates among almost all categories
of HCWs including nurses and other ancilliary staff have
The advent of interferon-gamma release assays [IGRAs] been shown in several other studies (35-38). A TST
in the recent years has heralded a new era in the field of
coversion rate of 1.7 per cent over a 12-month period
TB diagnostics. The IGRAs, are emerging as the gold
was also seen in dental HCWs (39). In another report
standard for the diagnosis of latent TB infection. Recent
(40), nosocomial transmission was also reported to occur
guidelines (14-16) are also available for the judicious use
even from an extra-pulmonary site; 12 [13%] of 95 HCWs
of these newer diagnostic modalities for detecting TB
who were initially non-reactive to tuberculin developed
infection. In the near future, it is expected that IGRAs
a positive TST after exposure to an index patient with
may replace TST as the investigation of choice to detect
TB prostatic abscess who had undergone abscess
TB infection in HCWs. The reader is referred to the
drainage and bilateral orchiectomy and had expired
chapter. “Diagnosis of latent tuberculosis infection: recent
after 27 days of hospitalization. In a study from Turkey
advances and future directions” [Chapter 12] for more details.
(3), TB was seen three-fold more frequently among the
HCW at four urban hospitals than the general
RISK OF INFECTION
population and the workers of chest diseases were found
The annual risk of TB infection assessed using TST in to have a higher risk than those of other departments
HCWs varied from 0.09 to 10 per cent in different (3). Similar high risk of TB infection was reported in
populations in various studies published between 1975 several other studies (41-47).
636 Tuberculosis
FACTORS INFLUENCING NOSOCOMIAL and excreta affect the disease transmission. The TST
TRANSMISSION OF TUBERCULOSIS conversion rate has been shown to be strongly associated
with inadequate ventilation of the general patient rooms
Although most investigators have reported an increased
(52). Some of these factors are of particular importance
transmission of TB among HCWs, the rates have been
in this country where the wards are rather overcrowded
significantly variable. Furthermore, no increased risk of
and the ventilation is not adequate.
transmission has been shown in other studies (48-50).
These differences can be attributed to methodological or
Immune Status and Comorbidities
sampling variations and other factors affecting the
disease transmission. Some of these factors are listed in The presence of diseases, which predispose to TB and
Table 45.1. the status of immunity are important factors that
determine the prevalence of TB in HCWs. Prevalence of
Table 45.1: Factors influencing nosocomial transmission diseases such as diabetes mellitus, as well as many other
of tuberculosis among health care workers conditions requiring use of corticosteroids or other
Related to the health care facility immunosuppressive drugs, among HCWs is at least
Level of exposure similar to their prevalence in the community. Their
High vs low exposure areas presence in HCWs is likely to augment their predisposi-
Inadequate isolation of infected patients
tion to TB.
Environmental
Inadequate sanitation
Intrinsic immune status of an individual HCW is a
Inappropriate disposal of excreta particular point of interest. Immunodeficiency is an
Overcrowding in the wards independent risk factor for TB. In a study on the occupa-
Poor ventilation tional transmission in a haemodialysis unit, the TB
Host factors related to HCWs isolates from different sources showed the strains to be
Immune status of an individual
unrelated when tested with restriction fragment length
Co-morbid illnesses
BCG vaccination status polymorphism [RFLP] (53). Similarly, nosocomial
General clinical factors transmission of TB in human immunodeficiency virus
Delayed suspicion and diagnosis [HIV] infected patients is also known (54-56). The impact
Delayed initiation of treatment of HIV infection on increase in number of TB patients
Self administration of drug
was demonstrated in a South African district hospital
HCWs = health care workers; BCG = bacille Calmette-Guérin where the incidence rate of TB among HCWs and
ancillary staff was not significantly different than the age
specific rate in the community. But there was a five-fold
Level of Exposure increase in annualized incidence rate from 1991 to 1992
The HCWs directly involved in looking after patients and 1993 to 1996 which was directly attributable to HIV
with TB are more likely to get infected than others. Data infection (49). In another study (57), strains of tubercle
from several studies indicate that medical and nursing bacilli infecting eight [89%] of nine HCWs with HIV
personnel [especially chest physicians and HCWs in chest seropositivity had a clustered RFLP pattern, implying a
diseases wards] have higher risk ratios of TST conversion common source, i.e., an unrecognized occupational
and development of active TB disease (3,34,41,43,51). A transmission. The HIV infected HCWs who developed
strong association has also been shown with type and TB following a hospital outbreak of multidrug-resistant
duration of work; for example people working in respi- TB [MDR-TB] had more severe disease and died (58).
ratory therapy, physiotherapy and house-keeping have
greater risks (10). Bacille Calmette-Guérin Vaccination
The protective efficacy of BCG vaccination has remained
Environmental Factors
debatable. Nonetheless, it continues to be administered
Environment of hospital wards and the methods at birth or in early childhood as a general vaccination
employed for sanitation and disposal of waste materials policy in countries with high TB prevalence. The reader
is referred to the chapter “Tuberculin skin test” [Chapter ventilation. A similar curve was drawn for TB outbreak
11] for more details on the clinical implications of BCG from a brief but intense exposure during bronchoscopy
vaccination on TST results. (63). It can be, therefore, concluded that TB transmission
can be quantitatively assessed fairly well from the
Clinical Factors amount of room ventilation (64).
Besides factors related to the host, i.e., HCWs and the
environment in which they work, factors related to CONTROLLING OCCUPATIONAL TUBERCULOSIS
awareness of occupational transmission, preventive steps An increased occurrence of TB in HCWs has more serious
being used, the clinical suspicion and diagnosis of an early ramifications than a mere addition to the total pool of
disease are important in influencing disease occurrence. TB patients. There is the fear of spreading a serious
There was an inadequacy of knowledge on TB transmis- disease including that of MDR-TB, causing panic among
sion and infection control measures among HCWs in the the employees and the community and also scaring away
USA in a questionnaire-based survey (59). The situation people from hospital jobs. It is, therefore, an issue of great
is likely to be worse in most hospitals of the developing public and social importance. It has also the potential of
world, including India. Many HCWs are likely to be more forcing a return to the medieval practices of segregating
negligent in adopting routine measures while working patients to isolation chambers and wards. It is, thus
in the hospitals and tend to ignore precautionary practices important to adopt strategies to prevent and control TB
generally recommended for attendants and care in HCWs. Implementation of protection guidelines has
providers of patients. This is somewhat akin to attitudinal been shown to effectively reduce the risk in HCWs
desensitization in following guidelines, which might (65,66).
occur among workers with a callous attitude. There are two important strategies to control
occupational TB among HCWs: [i] early diagnosis and
RISK ASSESSMENT treatment; and [ii] prevention of infection and disease.
It is known that untreated patient with active TB trans-
Early Diagnosis and Treatment
mits acid-fast bacilli [AFB] and infects other individuals.
This risk is likely to be significant in the hospital It is important to make diagnosis and institute antituber-
surroundings with a larger number of patients staying culosis treatment at the earliest. Hospital employees have
in a closed door environment. More than the close the advantage of an easy availability of medical advice
personal contact; it is the inhalational route which is and investigations. It is, simpler to make an early
important in spreading TB. This was amply shown diagnosis in a symptomatic individual. In fact better
following a sharp outbreak of TB abroad the naval vessel detection and notification of cases of TB among HCWs
“Richard E Byrd” (60). Of the 66 men who shared a have been also considered as factors accounting for some
compartment with an index patient with TB, 80 per cent of the apparent increased risk among them (47).
had demonstrated TST conversion. Interestingly, 54 per While HCWs are better placed to seek early interven-
cent of 81 men in another compartment had also tions, they tend to ignore early symptoms more than
developed TST conversion. Although there was no direct people in the community. It is a common observation
patient contact in the second compartment, about three that hospital personnel including doctors and nurses
quarters of the ventilation came through interconnecting greatly rely on self-administered symptomatic treatment
ducts from the first compartment. It was, therefore, before seeking appropriate medical advice. This is
concluded that the rate of infection was proportional to particularly so in developing countries where medicines
the amount of contaminated air (61). are relatively easily accessible and available to medical,
The mathematical model for quantitative assessment nursing and paramedical personnel. These factors are
of air, borne infection vis-a-vis room ventilation likely to delay the diagnosis. Therefore, a careful
developed for measles epidemic has also been used for approach to diagnosis among symptomatic individuals
TB (61,62). The probability curve of TB infection clearly and routine screening programmes among HCWs are
showed the diminishing effectiveness of high level of important for success.
638 Tuberculosis
Considering the hospital work as a risk factor and tutional symptoms of even one week’s duration unless
the fact that more specialized expertise and care is explained by a definite alternative aetiology should be
available in a hospital setting one would tend to suggest considered as a TB suspect and investigated with the help
a more aggressive approach for early diagnosis of TB of both sputum microscopy for AFB and a chest radio-
disease among HCWs. A simplified algorithm [Figure graph examination. In case sputum smear is positive
45.1] for diagnosis and treatment of TB, may be useful in for AFB, treatment is given accordingly. In case sputum
the evaluation of HCWs who are TB suspects. It is smear is negative for AFB, and the chest radiograph
worthwhile introducing a standardized questionnaire of findings suggest TB, treatment for AFB-negative TB
symptoms as an instrument for active case finding for should be instituted and an attempt should be made to
screening of all HCWs on a regular basis. Any individual demonstrate AFB in the bronchoalveolar lavage [BAL]
who reports with respiratory and/or general consti- fluid and/or other appropriate investigations. In case the
Figure 45.1: Suggested algorithm for early detection of tuberculosis in HCWs in resource-limited
settings
HCWs = health care workers; TB = tuberculosis; AFB = acid-fast bacilli; BCG = bacille Calmette-
Guerin; TST = tuberculin skin test; IGRAs = interferon-gamma release assays; BAL = bronchoalveolar
lavage
chest radiograph is clearly normal or negative for TB, setting” has been chosen over the term “facility,” used
other diagnoses should be considered and appropriate in the previous guidelines. The term “health care setting”
investigations done. Treatment regimens in HCWs do includes not only the hospital related scenario [e.g., in-
not differ than those recommended for TB in other patient, outpatient settings, TB clinics], but also settings
groups. in correctional facilities in which health care is delivered,
settings in which home-based health care and emergency
Preventive Strategies medical services are provided, and laboratories handling
Different strategies are employed in different countries clinical specimens that might contain Mycobacterium
to prevent infection and mycobacterial transmission. The tuberculosis. Important changes in the current guidelines
difference in approach in India is related more to the (16) over the previously published one (68) are shown in
enormous disease burden and the existing health care Table 45.3. The reader is referred to reference (16) for a
infrastructure. Nonetheless, the infection control mea- detailed account of these guidelines.
sures which are recommended anywhere are generally In November 2007, The National Task Force [NTF]
similar [Table 45.2]. The efficacy of preventive program- for the involvement of Medical Colleges in the Revised
mes has been clearly shown in several studies National Tuberculosis Control Programme [RNTCP],
(36,37,66,67). The TST conversion rates were shown to Government of India, constituted Expert Working Group
significantly decrease following full implementation of to develop guidelines for Airborne Infection Control and
expanded infection control measures in US medical build the capacity at the national and state level for
school graduates (36). Similar observations were made advocating and ensuring implementation of airborne
at several other centres following infection control infection control measures in hospital settings (69). A
practices (37,66,67). coneptual framework for the control of TB in health care
The Centers for Disease Control and Prevention settings that conveys the key concepts outlined in the
[CDC], published the “Guidelines for Preventing the published guidelines is described below.
Transmission of Mycobacterium tuberculosis in Health Care
Facilities” in 1994 (68). These guidelines were Infection Control Measures
subsequently revised in 2005 by the CDC (16). According The most important source of mycobacteria in the
to the current guidelines (16) that have been expanded environment is an open patient with pulmonary TB who
to address a broader concept, the term “health care is excreting bacilli in the sputum. Bacteria are released
Table 45.2: Measures used for control of tuberculosis during coughing, laughing and talking and transmitted
transmission in health care workers to others through air-borne droplets. Infection control
measures are, therefore, designed to focus on reduction
General infection control measures
Reduction of environmental load by reducing the release of of environmental load of mycobacteria by one or more
mycobacteria of the following steps in transmission of infection.
Use of masks for patients
Isolation rooms Reducing the release of mycobacteria and preventing
Preventing environmental spread environmental distribution The most efficient method
Negative pressure rooms to prevent dispersion of infectious particles from a patient
Use of HEPA filters in a hospital room is to trap the particles at the patient’s
Use of ultraviolet radiation
mouth. This can be achieved by the masks covering the
Individual protection measures
Inhalational prevention strategies mouth and nose. In resource limited settings, simple
Use of simple masks gauze masks or a piece of cloth are commonly used for
Use of respirators: HEPA filters/PAPR this purpose. The respiratory droplets released on cough-
BCG vaccination ing are impinged on the mask.
Chemoprophylaxis
A mask is fairly effective but is not convenient for
Early detection and treatment
constant use. It gets wet very soon and cumbersome for
HEPA = high-efficiency particulate air; PAPR = powered air use in a patient with constant cough and sputum produc-
purifying respirator tion. Their use is, therefore, restricted to specific situations
640 Tuberculosis
Table 45.3: Salient changes in the Centers for Disease Control 2005 guidelines for preventing the transmission of
Mycobacterium tuberculosis in health care settings * over the 1994 guidelines†
The risk assessment process includes the assessment of additional aspects of infection control
These recommendations usually apply to an “entire health care setting” rather than “areas within a setting”
The term TST is used instead of purified protein derivative
The whole-blood interferon gamma release assay QuantiFERON®TB Gold test [Cellestis Limited, Carnegie, Victoria, Australia] might
be used instead of TST in TB screening programmes for HCWs
The frequency of TB screening for HCWs has been decreased in various settings, and the criteria for determination of screening
frequency have been redefined
The scope of settings in which the guidelines apply has been broadened to include laboratories and additional outpatient and non-
traditional facility based settings
Criteria for serial testing for Mycobacterium tuberculosis infection of HCWs are more clearly defined
New terms, airborne infection precautions [airborne precautions] and airborne infection isolation room [aII rooms], are introduced.
Recommendations for annual respirator training, initial respirator fit testing, and periodic respirator fit testing have been added
The evidence of the need for respirator fit testing is summarized
Information on ultraviolet germicidal irradiation and room-air recirculation units has been expanded
Additional information regarding MDR-TB and HIV infection has been included
* reference 16
† reference 68
TST = tuberculin skin test; TB = tuberculosis; HCWs = health care workers; MDR-TB = multidrug-resistant tuberculosis;
HIV = human immunodeficiency virus
for limited time periods. Adequate ventilation is useful Complete isolation of a TB patient is not feasible. As
to dilute the environmental concentration of mycobacte- per current practice and recommendations in India, a
ria. While the indoor load within a hospital is reduced, sputum smear-positive patient need not be admitted in
the method may prove to be counter productive by the hospital. If the medical indication for admission is
spreading the infectious airborne droplets in the strong, separate areas should be earmarked for such
surrounding areas. This would pose the risk of infection patients. The use of high-efficiency particulate air [HEPA]
to a larger number of employees and other people in the filter is useful to prevent dispersal. Separate cubicles and
building. Such incidents of spread of infection in the booths should be made available in the wards and
entire building have been reported in the literature. These laboratories for performance of procedures requiring
include the example of TB outbreak through ventilation coughing, such as induced sputum induction. Similarly,
in two adjoining compartments, in the naval vessel bronchoscopic examination in suspected TB patients
“Richard E. Byrd” (60) and another outbreak, where one should be performed in well equipped areas fitted with
worker with undiagnosed TB infected 27 of 67 colleagues HEPA filters.
over a four-week period (70). Similarly, it was shown
that the exposure in the hospital building treating HIV Air filtration and disinfection The HEPA filters,
patients with TB infection was universal and a sojourn permanently fixed for room ventilation remove droplet
of 40 or more hours per week was enough to get infection nuclei carrying tubercle bacilli from the air. They are
(71). This was attributable to recirculation of air from capable of removing almost 100 per cent of the particles
the infected source to the entire building. It is, therefore, of over 0.3 μm in diameter (72). The filter units are fitted
more useful to contain the infection within, rather than with blowers to recirculate air. The filtered air from the
ventilating it out. Internal containment includes the room or the booth can also be recirculated through a duct
prevention of dissemination of infectious droplets in the to create a negative pressure within. This type of HEPA
air by entrapment procedures as well as the air filtered self-contained booths for some specified purposes
disinfection. as listed earlier are already available commercially.
Air disinfection by ultra-violet [UV] radiation has also More effective than a simple mask is a respirator
been effectively used to kill or inactivate organisms in which removes the infectious particles through
several field trials for infectious diseases, such as measles impaction by filtration and/or electrostatic attraction. If
and influenza (73,74). Almost complete protection properly worn, a respirator can prevent up to 80 per cent
against TB was seen in medical and nursing students of exposure. But it is cumbersome to wear respirators
since none of them showed TST conversion while continuously in all situations. These are generally recom-
working in a TB ward in Milwaukee when UV air mended for personnel attending upon sputum smear-
disinfection was employed over a 12-year period (75). positive patients and during cough induction and
The UV radiation can also be combined with filtration bronchoscopic procedures (68). Leakage of droplet nuclei
units. It is doubtful if there is any additional advantage from a filter depends upon the filtration efficiency and
of the combined system. facial seal. Some of the important factors which deter-
The UV radiation has some advantages over HEPA mine the efficiency include the filter characteristics of
air disinfection. The resistance to airflow is much less mask size, distribution of particles and linear velocity
than with a HEPA filter. Therefore, the blowers used through the material (30,68,79-82). Loading of particles
are smaller and quieter. But the main disadvantage is
and electrostatic charge on the filter as well as the ability
the possibility of causing excessive exposure to the
of unfiltered air to penetrate a respirator between the
germicidal UV causing painful superficial irritation of
respirator’s edge and the wearer’s face are also important.
skin and eyes, although there are no serious long-term
The CDC (16,68) recommends that a respirator should
effects (76). There is no evidence of systemic immunosup-
meet the following criteria: [i] it should be able to filter
pression from UV germicidal irradiation employed for
particles of 1 mm in size with 95 per cent efficiency; [ii] it
room disinfection (77). To prevent personal exposure, the
should have a face seal leakage of 10 per cent or less; [iii]
germicidal UV is directed at the air in the upper part of
the room. The mixing of lower air with upper air permits it should have the ability to fit the different facial sizes
disinfection of all indoor air. This mixing is promoted and characteristics of health personnel; and [iv] it should
by convection and forced air movement by supplemental be checked for face piece fit by a HCW each time it is
fans. But when the ceilings are low, the upper air UV used.
radiation gets deflected downwards posing a greater risk Different types of filters which include HEPA and
to the occupants. The UV radiation can also be used in powered air purifying respirator [PAPR] masks have
the ventilating ducts to make the re-circulated air germ been employed (16,68). The high cost of these gadgets is
free. Generally, the upper air disinfection in each room a deterrent for their use in resource-limited settings.
is more effective than central duct irradiation but it
Bacille Calmette-Guerin vaccination Unfortunately, the
requires a more elaborate setting.
role of BCG vaccination in preventive TB has remained
Individual Protection doubtful and debatable (83). The available evidence
supports a good level of protection in children (84). As
Inhalational prevention strategies Protective measures
per current practices in India, BCG is administered at
which can be employed by an individual working in a
health care facility include the use of devices to prevent birth. Presumably, most adults including the HCWs
inhalation of infectious droplet nuclei. Unfortunately, should have received BCG vaccination in childhood.
most of these methods have their fallacies and failures. There is no recommendation at present to adopt the
Fortunately, the risk of infection in HCWs is minimal policy of revaccinating HCWs. The practice of prophylac-
from paediatric patients with primary TB (78). tic BCG vaccination in risk groups, such as HCWs, did
Historically, surgical face-masks have been employed exist in several countries in the past. The practice was
by visitors and HCWs attending upon TB patients. It is discontinued in view of an unproven efficacy and the
difficult to comment upon the usefulness of this method possibility of adverse reaction of BCG vaccination.
in the absence of any efficacy-study on their use. But there Regular screening is considered a more effective strategy.
is a complete lack of standardization, besides the The issue of BCG vaccination among HCWs, especially
difficulties involved in wearing of a well-fitted face-mask those who are tuberculin negative, remains to be re-
all the time. examined (85).
642 Tuberculosis
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646 Tuberculosis
Nutrition and Tuberculosis

46
Jason Andrews, Ramnath Subbaraman
INTRODUCTION the yearly incidence of the disease seems to only have

reached a steady state with a possible mild downward
Research has established clear connections between
curve at best (4). While the growing HIV epidemic is cited
malnutrition and impairment of immune defense,
as one reason for the lack of decline in TB (4,5), the
including decreased cell-mediated protection, abnormal
widespread prevalence of chronic malnutrition, the scale
phagocytic function, and reduced immunoglobulin
of which far exceeds HIV in India, is probably even more
production (1-3). Among infectious diseases, tuberculosis
significant in fuelling the smouldering fire of the TB
[TB] has a particularly powerful historical association
epidemic. While definitive data on the relative risk of TB
with malnutrition; its name has been linked to its wasting
among malnourished individuals are relatively scarce
effect on the body since at least the time of Hippocrates
due to the ubiquity of confounding risk factors, the best
in the fifth century BC.
available data suggest that the relative risk is six- to- ten
While many studies (1-3) have reinforced this
fold after controlling for other factors (6). Like HIV,
millennia-old association between malnutrition and TB,
malnutrition can cause profound immunosuppression,
remarkably few clarify the tangled relationship between
rendering the body unable to control mycobacterial
the two. The probable bi-directional influence of one on
infection. The mechanisms of immunological dysfunc-
the other [in which malnutrition predisposes to TB
tion have been elucidated mostly in animal models
infection even as TB causes wasting], the co-occurrence
(7-16), while the impact of malnutrition on the risk of TB
of malnutrition with many other poverty-associated risk
activation at the population level has been demonstrated
factors for TB [such as poor housing and sanitation], and
in clinical studies (17-35).
the increasing incidence of TB patients co-infected with
human immunodeficiency virus [HIV] [which itself Evidence from Animal Models
causes a wasting syndrome] are just a few of the issues
Recent animal studies have better characterized the
that confound the understanding of the relationship
physiological connection between malnutrition,
between malnutrition and TB. From a clinical perspec-
immunosuppression, and risk of active TB infection.
tive, literature on the impact of nutrition on the natural
Deficiency of protein, rather than of micronutrients,
history of TB as well as evidence-based guidelines for
appears to play a larger role in blunting the immune
nutritional management of such patients are also sparse.
response to TB. One common hypothesized mechanism
of zinc and protein deficiencies is thymic atrophy, which
IMPACT OF NUTRITION ON THE RISK OF ACTIVE
impairs the generation of mature T-lymphocytes (7). A
TUBERCULOSIS INFECTION AND ITS NATURAL
guinea pig model has yielded equivocal results on the
HISTORY
question of vitamin D and zinc deficiency as the risk
Despite India’s aggressive Revised National Tuberculosis factors for susceptibility to TB (8,9). However, the same
Control Programme [RNTCP] and scaling up of DOTS, model shows, that protein deficiency markedly impairs
Nutrition and Tuberculosis 647
T-cell function in response to bacille Calmette-Guérin Red Cross, adding 1300 daily calories to their diet and
[BCG] vaccination as demonstrated by a decreased nearly doubling their protein intake. The Russians, by
purified protein derivative response measured by the contrast, underwent a process of slow starvation on the
tuberculin skin test [TST] and decreased cytokine German rations, exhibiting much lower plasma protein
production, specifically interleukin-2 and interferon-γ levels and higher rates of anaemia.
(10,11). These malnourished animals also exhibit absolute The Russians had an active pulmonary TB prevalence
and relative T-lymphocyte deficiencies of many types, of 19 per cent while the relatively well-fed British soldiers
including CD2+, CD4+, and CD8+ cells (12-14). had a prevalence of 1.2 per cent, a 16-fold greater relative
In another set of experiments, lymphocytes trans- risk attributable to undernourishment. Moreover, the
ferred from protein deficient guinea pigs to syngeneic character of the disease was different in the two popula-
fully nourished animals did not protect the recipient tions. The Russians had rapidly progressive, highly fatal
guinea pigs from TB infection while the opposite was infection with massive tissue breakdown but little
true (15), leading the authors to conclude that protein granuloma formation, while infection in British soldiers
status has a direct influence on the potency of the followed a normal chronic course with good granuloma
lymphocytic response to TB. Similar observations in the formation. Furthermore, TB had the strongest association
mouse model described by Chan et al (16) make these with malnutrition; the prevalence of malaria, dysentery,
guinea pig data more persuasive. Most importantly, both and other infections was similar between the two groups.
the guinea pig and the mouse models exhibited recovery The second classic study (25) was carried out in
of resistance to active TB with reversal of the protein Norway in the 1940s, where the high rate of TB among
malnourished state, an encouraging finding for public naval recruits was initially believed to result from the
health specialists if also true in humans. young men’s overcrowded and unhygienic living condi-
tions. However, improvements in hygiene and housing
Clinical Evidence failed to reduce TB rates. Authorities then supplemented
This plethora of animal model data contrasts with the the recruits’ diets with milk, margarine, wheat bread,
paucity of basic clinical studies clarifying the connection fruits, vegetables, and cod liver oil, after which TB rates
between malnutrition and TB risk in humans. Many quickly declined. While this does not, of course, disprove
studies describe multiple macro- and micro-nutrient the prevailing wisdom of urban crowding and poor
deficiencies in TB patients (17-23). None of these studies living conditions as major risk factors for the spread of
can conclude, however, whether this malnourishment TB, it does highlight the equal relevance of nutrition at a
is primarily from TB preferentially activating in those population level for TB control.
with poor nutrition, or from the wasting induced by the More recent studies (26-28) attempt to identify
infection itself. High population density, poor sanitation, specific diets and micro-nutrient deficiencies that may
social crises, and other poverty-associated risk factors increase TB risk. Two studies (26,27) examining Hindu
also confound these analyses. vegetarian versus Muslim omnivore South Asian
Two classic studies (24,25) persuasively isolate the immigrants in Britain found vegetarianism correlated
role of malnutrition in predisposing individuals to active with a three- to four-fold increase in the relative risk of
TB. The first study (24), performed while the author active TB. Moreover, the latter study by Strachan et al
himself was a prisoner-of-war, “controls” for other major (27) showed a dose response relationship; decreasing
factors in the external environment by observing two levels of fish and meat consumption correlated with an
groups of soldiers [Russian versus British] held in the increased risk of TB. The studies speculate that B12 or
same living conditions in German prisoner-of-war vitamin D deficiency may be more specifically respon-
camps. The Germans provided both groups the same sible for the increased TB risk in vegetarians, but neither
meager rations vividly described by the author as meat examined these micro-nutrient levels in vivo. Another
“with high percentage of bone,” potatoes “largely frost- study (28) found that increased fruit, vegetable, and
bitten and inedible,” and a stew “full of small particles berry intake decreases the risk of active TB.
of grit and often containing large stones.” The British A non-randomized trial of vitamin and mineral
soldiers alone also received extra food rations from the supplements by Downes (29) in New York City in the
648 Tuberculosis
1940s suggested that micro-nutrients might indepen- In TB, weight loss is one of the most obvious
dently protect against TB. The trial of supplementation manifestations of nutritional wasting, though probably
versus no intervention was tested for five years in two not the most clinically relevant in terms of impact on
groups of families with similar prevalence and incidence health and survival. The bulk of weight loss in patients
of TB as well as similar food and living indices. The group with TB is fat mass, though the fat free component, which
without micro-nutrient supplementation had a three- is also lost in significant amounts, certainly has more of
times greater relative risk of active TB and the high rate an effect on the physical functioning of the patient.
of non-adherence in the experimental group suggests that Protein deficiency has been well described in the context
protective effects of micronutrients may be even greater. of TB, and albumin and prealbumin have been found to
Despite this evidence regarding micro-nutrients in be useful markers both for the diagnosis of deficiency as
general, the search for one single micro-nutrient that well as the monitoring of its reversal (21,37,40,41). The
confers a high degree of protection against TB has not predominant biochemical source of wasting is believed
been fruitful. One cohort study (30) found that low levels to be an increase in tumour necrosis factor-α [TNF-α],
of vitamins A and C increase TB risk, while another study which causes a net catabolic state (42). While some (43)
(28) found vitamin C to be unassociated. Two other have further described an “anabolic block”, or decrease
studies suggest that the active form of vitamin D may in protein synthesis, in the context of TB, other workers
help mediate the actions of macrophages in killing have failed to demonstrate this abnormal metabolism
mycobacteria (31,32). While multiple case-control studies (44). Leptin, a well-known cytokine involved in energy
show that TB patients have lower levels of vitamin D as metabolism, appears not to be involved in the wasting
compared to control subjects, it remains unclear whether process in TB (45). Finally, while the little research that
this is from nutritional wasting secondary to TB or from has been done comparing weight changes in pulmonary
vitamin D deficiency increasing risk of TB activation versus extra-pulmonary TB suggests that–at least as a
(22,33-35). subjective complaint–the loss is similar, the difference
While the data suggesting malnutrition predisposes in nutrient deficiencies in these manifestations of TB are
to active TB infection are persuasive, little of this research not well understood.
has been translated into public health interventions aimed Several vitamin deficiencies have been found to be
at curbing the epidemic. Correcting protein-energy common in TB patients and may be a result of TB wasting;
malnutrition, the deficiency most powerfully connected however, most of these studies are cross-sectional.
with TB, may require larger public policy changes; Furthermore, the risk of active TB has also been ascribed
however, mass multivitamin and mineral supplemen- to vitamin deficiency. Therefore, it can be difficult to
tation through public health programmes could also have distinguish vitamin deficiency that resulted from the
an impact on TB rates (29). Finally, by encouraging disease from vitamin deficiency that predisposed to the
increased protein intake and general micro-nutrient development of the disease. Vitamin A deficiency is
supplementation, as well as aggressively treating intestinal perhaps the best studied micro-nutrient deficiency in TB,
parasites and anemia, physicians can address malnutrition with several studies demonstrating greatly decreased
in all their patients as a method of TB prevention. serum levels in TB patients (20,21,39,46-48). In a study
(37) from India, serum vitamin A levels in TB patients
THE IMPACT OF TUBERCULOSIS ON NUTRITION were found to be half than that in household contacts,
Tuberculosis has been understood as a disease of wasting who presumably had a similar diet, suggesting that the
since its earliest descriptions, and we now know that it deficiency resulted from the disease.
causes significant deficiencies in nearly every nutritional Because of the relatively recent surge in HIV, which
marker. Body-mass index [kg/m2], skinfold thickness, is fuelling the TB epidemic worldwide, the impact of
mid-upper arm circumference, grip strength, body fat HIV-TB co-infection on nutrition merits special mention.
percentage, calorie stores, muscle mass, serum albumin, Like TB, HIV often leads to nutritional deficiencies and
blood haemoglobin, plasma retinol, plasma zinc, clinical wasting, particularly in its later stages (49,50).
selenium, iron, and vitamins A,C,D and E have all been “Acquired immunodeficiency syndrome [AIDS]
found to be depressed in TB patients (17-20,23,36-39). cachexia” and “HIV wasting” are well-characterized
phenomena, with the latter carrying precise clinical Malnutrition and the bacille Calmette-Guerin Vaccine
definitions. While HIV disease is itself, like TB, a net
catabolic state, evidence has suggested that, in regions Existing evidence suggests that malnutrition drastically
in which it is endemic, TB is the predominant cause of compromises the efficacy of the BCG vaccine in two
severe wasting in patients with HIV (51). different ways. First, maintenance of good nutrition is
The combination of these two diseases produces a critical for continuing vaccine-induced immune
profound cachexia, rapidly obliterating a patient’s protection. Deteriorating nutritional status between serial
nutritional stores in a fashion more damaging to TSTs after BCG vaccination resulted in a marked decrease
nutritional status than either HIV or TB alone (51-55). in the size of induration (57). Children with even mild
Given that malnutrition predicts survival in patients with levels of malnutrition in this study also had fewer positive
HIV independent of the CD4+ count, such co-infection TSTs after vaccination. These results suggest that vaccine-
is particularly concerning. Furthermore, co-infection may induced immune protection is a function of nutritional
blunt the normal improvements in nutrition that result status at any given time. Similar findings in animal
from TB chemotherapy. A study (56) conducted in models support these data (14,15,58).
Tanzania found that HIV-TB co-infected patients had Secondly, severe malnutrition at the time of BCG
lower vitamin A levels than HIV-seronegative TB control. administration can permanently affect vaccine-induced
Interestingly, treating TB in HIV-seronegative patients immune protection. Children who had kwashiorkor at
significantly increased vitamin A levels while these levels the time of BCG administration had very high rates of
did not increase at all in the HIV-seropositive patients negative TSTs, despite much better nutrition between the
on TB chemotherapy, suggesting that HIV blunted the time of vaccine administration and TST (59). This implies
nutritional recuperation. severe protein malnutrition prevented the vaccine from
Several studies have described nutritional deficien- “registering” with the immune system in the first place.
cies in the setting of TB; however, the causality and implica- Severely protein malnourished children may therefore
tions of these deficiencies have not been well characterized. derive greater benefit from being vaccinated with the
While it is difficult to sort out the predisposing nutrient BCG after improvement in their nutritional status, if such
deficiencies from those caused by TB, it is probably best to delay is feasible.
understand them as a spiraling force, with nutritional
deficiencies causing immune compromise which enables Diagnosis
TB to strengthen its hold in the body, and the proliferation
of TB as leading to further nutritional deficiencies. The Weight loss has long been identified as one of the most
challenge for clinicians is to interrupt that cycle, perhaps common presenting complaints of patients with TB
through the augmentation of chemotherapy with (60,61). In a population-based survey of TB symptoms
nutritional adjuvant support, as will be discussed below. carried out in the United States, weight loss was found
to be a presenting complaint in 43 per cent of patients
CLINICAL IMPLICATIONS AND INTERVENTIONS with pulmonary TB and 50 per cent of patients with extra-
Nutritional status has implications for both the diagnosis pulmonary TB [in developing countries, where delays
and management of TB; however, there is a paucity of in seeking or obtaining medical care are often greater,
clinical studies assessing the impact of nutritional these figures are likely higher]. Notably, there was not
interventions on outcomes in TB patients. The following much difference in pulmonary versus extra-pulmonary
section will review the nexus of TB and nutrition from a TB in this aspect of the presentation. Nevertheless,
clinical perspective, specifically considering the effects evidence suggests that severely malnourished patients
of malnutrition on the diagnosis of TB, the challenges are more likely to have an atypical presentation of
that malnutrition poses in the prevention of TB, nutri- pulmonary TB, including dyspnoea and diarrhoea, and
tional interventions in patients with active TB disease, a less frequent presentation of haemoptysis and cavita-
the relatively recent advent of immunotherapy as adjunct tion (24,62). This finding is similar to the presentation of
treatment for TB, and the monitoring of nutritional TB in patients with HIV, and immunodeficiency may be
markers in the clinical care of the TB patient. a common pathway for these manifestations.
650 Tuberculosis
Finally, there appears to be a relationship between stocking distribution, though it can also present as ataxia
the sensitivity of TST and the nutritional status of the or muscle weakness. Central nervous symptoms such as
patient. Studies have found a positive correlation seizures and confusion are less frequent presentations
between the size of a reaction and protein nutrition as of B6 deficiency from isoniazid.
reflected in serum albumin, leading to false negatives in Studies at the Tuberculosis Chemotherapy Centre,
those with low serum albumin levels (47,63). Similarly, Madras [now called Tuberculosis Research Centre,
evidence in animal studies shows an association between Chennai] (70), in India in the 1960s first identified the
specific micro-nutrient deficiencies, such as vitamin D role of low-dose pyridoxine supplementation [6 mg/day]
and zinc, and reduced TST reaction, perhaps as a result in protecting against isoniazid-induced peripheral
of fewer and less functional circulating T-cells. Again, neuropathy. Current guidelines for pyridoxine supple-
these findings parallel TST studies in HIV patients, mentation are based on the patient’s risk for isoniazid
suggesting clinicians should err on the side of liberally toxicity. Malnourished individuals, the elderly, pregnant
interpreting borderline TST reaction in undernourished women, cancer patients, chronic alcoholics, chronic liver
patients. disease patients, and children [especially adolescent
females] are at higher risk for pre-existing pyridoxine
Natural History of Tuberculosis in Malnourished deficiency even before TB treatment. In addition,
Patients isoniazid peripheral neuropathy occurs more frequently
Malnutrition is independently associated with mortality in those already at risk for neuropathy from other causes,
such as diabetes mellitus, renal failure, and HIV disease
in patients hospitalised for TB (64). In one study (65),
(68,71). Patients co-infected with HIV and TB on
nearly twice the number of moderate to severely
malnourished hospitalized TB patients died within one antiretroviral regimens containing stavudine or
didanosine are at especially high risk, as these drugs can
month as compared to those with mild malnutrition,
also cause peripheral neuropathy (72).
adjusting for all other risk factors. In another study, the
initial body weight of a TB patient on presentation was Current guidelines (71) recommend 6 to 10 mg daily
supplementation of pyridoxine for patients not at high
found to be a better predictor of survival than the
risk for isoniazid toxicity. Patients with one or more risk
commonly used inpatient outcome instrument acute
physiology and chronic health evaluation II [APACHE factor-require dosages of 25 to 50 mg daily. For patients
presenting with active isoniazids induced peripheral
II] score (41). The same group (66) has also suggested
neuropathy, seizures, or mental status changes, 100
that part of the adverse effect of poor nutrition on
mortality may be through diminishing plasma drug to 200 mg daily of pyridoxine is recommended for
treatment (71).
concentrations during treatment. This hypothesis is
Finally, data are also available indicating increased
supported by data showing that patients at less than 10
per cent of their ideal body weight had higher rates of rates of toxicity in patients with low baseline serum
albumin levels (73,74), suggesting that malnutrition may
treatment failure and relapse (67).
predispose patients to higher rates of drug-induced
Isoniazid and Vitamin B Deficiency hepatotoxicity from antituberculosis therapy treatment.
Isoniazid-induced peripheral neuropathy is a well-

Nutritional Interventions in Patients with Active
recognized adverse effect of TB treatment mediated by
Tuberculosis
nutritional deficiency of pyridoxine, or vitamin B6 (68).
Antituberculosis treatment has been shown to cause In light of the strong data demonstrating the impact of
significant reductions in plasma pyridoxine levels malnutrition on survival in TB patients, it would seem
within one week of therapy (69), and isoniazid may also intuitive that nutritional support would decrease
compete with pyridoxine in its role as a cofactor for morbidity and mortality. This idea, traditional wisdom
synthesis of neurotransmitters, such as gamma-amino- in the early days of TB therapy, has since come under
butyric acid. The result is a dose-dependent toxicity of question. In a classic study conducted by Ramakrishnan
numbness and tingling in the extremities in a glove and and colleagues (75) at Chennai in the late 1950s, 193
patients were randomized to treatment at home or in a and found that 62 per cent were deficient in plasma
TB sanatorium . The TB sanatorium provided nutritional vitamin A. Lower plasma levels were also associated
supplementation such that sanatorium patients had with more extensive or severe disease, including higher
significantly increased caloric, protein, carbohydrate, and rates of extra-pulmonary disease. However, high-dose
micro-nutrient intake as compared to patients treated at vitamin A therapy in this population was found to
home. Patients were followed for six months, after which have no effect on disease outcome, including physical
response to therapy was assessed using time to culture and biochemical markers compared to placebo (21).
negative sputum and improvement in chest radiograph. Furthermore, at six weeks, respiratory complaints had
It was found that in spite of a markedly poorer diet and resolved in more patients in the group receiving placebo
substantially less weight gain in the patients who [49%] than in those who received vitamin A [24%].
received treatment at home, the overall response to In contrast, a study (46) carried out in Indonesia found
therapy was similar in the two groups. In a multivariate that patients receiving vitamin A and zinc supplemen-
analysis, none of the dietary factors studied [calories, tation had earlier conversion to culture-negative sputum
carbohydrates, proteins, fats, minerals, and vitamins] and a greater improvement on chest radiograph at two
were found to influence the time to attainment of quie- months. Because the intervention group received both
scent disease. Another study (17) from Tanzania further zinc and vitamin A, it is possible that the benefit was
questioned the utility of aggressive nutritional support only from zinc and did not thereby contradict the afore-
for reducing mortality. Weight gain was found to be a mentioned South African study (21).
poor predictor of clinical outcomes; however, the authors Finally, iron supplementation has been successful in
did suggest that there may be a positive influence on improving haemoglobin levels in patients with pulmo-
quality of life and reduction in some morbidities (17). nary TB and mild to moderate anaemia by accelerating
In contrast, a recent randomized study (76) found that the normal resumption of haematopoiesis (77).
patients being treated for TB who were counselled to The absence of a well-demonstrated reduction in TB-
increase their intake through diet and high-energy associated morbidity and mortality from nutritional
supplements for six weeks after beginning therapy had interventions does not imply that nutritional support is
significantly greater increase in body weight, total lean inconsequential in the care of patients with TB. Rather,
mass, and grip strength compared with patients who two important points should be kept in mind. The first
received standard nutritional counselling. While clinical is that further research is needed in this area, especially
outcomes including morbidity, mortality, and TB cure focussing on greater levels of protein and high-energy
were not assessed, this study did find an overall improve- supplementation which may be necessary to overcome
ment in physical well being and quality of life in those the “anabolic block” that may occur with TB. The other
who received early nutritional support. critical lesson is that nutritional support can contribute
In addition to increased caloric intake, micro-nutrient greatly in the restoration of physical function, which is
supplementation has been studied as a potential adjuvant critical in contexts where individuals are dependent upon
for improving outcomes in TB patients. Some of the early their health to earn income for survival.
efforts at micro-nutrient supplementation involved the
use of vitamin D, the deficiency of which has been well Adjuvant Immunotherapy for Improving
associated with immune dysfunction [particularly Nutritional Status in Tuberculosis
impaired lymphocyte proliferation] and risk of active TB; With the understanding that TB wasting is a consequence
however, the utility of supplementation has not been of endogenous immune response, particularly involving
demonstrated by clinical trials and the potential side TNF-α, immune modulation has been proposed as an
effects of excessive vitamin D intake need further adjuvant therapy for improving nutritional status in
examination. patients with TB, HIV, and TB/HIV co-infection. Simple
Equally controversial, perhaps, is the use of corticosteroids have been used in several trials; however,
vitamin A supplementation as adjuvant therapy in in a review of these studies, Dooley et al (78) concluded
patients with active TB. Hanekom et al (21) looked at a that corticosteroids only contributed to short-term
cohort of South African children with pulmonary TB weight gains and had minimal long-term benefits or
652 Tuberculosis
improvement in outcomes. Thalidomide has also been TB wasting. Serum albumin may be a more accurate
used in hopes of reversing wasting by suppressing indicator than weight of improving nutritional status
TNF-α. Small controlled trials have found enhancement [especially with regard to crucial fat-free mass] in patients
in weight gain compared with placebo in patients with being treated for TB, as was demonstrated in a review of
TB and HIV-TB co-infection (79,80). However, the gains cases in Nigeria (41).
appear to be largely fat weight, rather than fat free mass,
which is clinically a more important component. Thalido- CONFRONTING THE VICIOUS CYCLE OF HUNGER
mide is not yet standard practice, and larger trials,
AND DISEASE
looking at a wider range of clinical outcomes, are needed.
Table 46.1 summarizes the critical nutritional consi-
Monitoring Nutritional Status in Tuberculosis Patients derations in the prevention and management of TB. This
Despite the contribution of wasting towards morbidity chapter illuminates the synergistic interaction between
and mortality from TB, the weight gains accompanying TB and malnutrition, which induces a vicious downward
antituberculosis treatment have not been demonstrated spiral of hunger and ill health. Malnutrition compromises
to improve or predict survival. This may be a result of the immune system, allowing TB infection to take
the type of mass that is gained. In one study, patients advantage of a fragile host environment. The myco-
being treated for pulmonary TB had a 10 per cent gain in bacteria then cause further wasting, confounding
body weight during treatment; however, they had a 44 nutritional repletion and disease treatment. The ultimate
per cent gain in fat mass, with very little increase in fat- result is lower quality of life for patients, poor clinical
free mass, including protein mass and bone minerals. outcomes, and, often, death. Is it any surprise, then, that
This is of great consequence, given that fat-free mass has India, the country with the largest burden of chronic
been more closely correlated with improvements in undernourishment in the world, also has the highest
quality of life and physical functioning. Thus, while number of TB cases? Is it not unsurprising that the
protein is one of the major components lost during an epidemic trend has been refractory to purely medical
episode of TB, it is not significantly regained during the attempts to confront it?
course of treatment, making overall weight gain an Dreze and Sen (82) have argued that hunger in the
inadequate clinical marker for following the reversal of modern world is a crisis of both food security and health
Table 46.1: Critical nutritional considerations in the prevention and management of tuberculosis
Prevention
Reduction of protein-energy malnutrition is critical to controlling and reducing rates of TB
Data supports wide scale daily multivitamin, mineral supplementation as an intervention to reduce TB rates
BCG vaccine efficacy is severely compromised in malnourished recipients
Protein repletion prior to BCG vaccine administration should be considered, if possible, in severely protein malnourished children
Diagnosis
Borderline PPDs in malnourished patients should be interpreted liberally, erring on the side of a positive read
Severe malnutrition is associated with atypical presentations of TB, parallelling patterns in AIDS patients
Treatment
While comprehensive nutritional support of TB patients may not decrease mortality, studies show that it is probably crucial in
improving quality of life
Repletion of tissue mass in TB patients requires greater than normal levels of nutritional intake, including protein and high energy
supplementation
Iron supplementation is recommended for anaemia due to pulmonary TB
Vitamin A and D supplementation for TB patients remains controversial
Weight gain alone can be a deceptive measure of clinical improvement and should be augmented by serum albumin monitoring for
a more accurate reflection of nutritional status
Improvements of serum albumin may be the earliest sign of improving nutritional status in patients being treated for TB
TB = tuberculosis; BCG = bacille Calmette-Guérin; PPD = purified protein derivative; AIDS = acquired immunodeficiency syndrome
care. Clinicians treating TB are in an ideal position to 12. Bartow RA, McMurray DN. Erythrocyte receptor [CD2]-
confront this combined entity of hunger and disease. bearing T lymphocytes are affected by diet in experimental
pulmonary tuberculosis. Infect Immun 1990;58:1843-7.
They can do this not only by optimizing nutritional status
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656 Tuberculosis
Reactivation and Reinfection

Tuberculosis
47
Sujatha Narayanan, JS Guleria
INTRODUCTION phylaxis in people who have recently been exposed to

infectious TB may be prudent, regardless of whether they
Exposure to Mycobacterium tuberculosis results in an
have evidence of prior infection. Furthermore, if exoge-
asymptomatic period of incubation or latency which may
nous reinfection is common, then new regimens that
progress to active disease. However, unlike most other
effectively eliminate infection or treat disease will be
infectious diseases, tuberculosis [TB] involves a delay
unfairly judged in clinical trials. The development of
between infection and disease that is extremely variable,
improved vaccines against TB will be especially challeng-
ranging from a few weeks to a lifetime. Thus, the develop-
ing if natural infection does not confer protective
ment of active TB in someone known to have been
immunity (2).
previously infected raises the question whether this
represents a recrudescence of the initial infection
NATURAL HISTORY OF TUBERCULOSIS
[endogenous reactivation] or infection by a new strain
INFECTION
[exogenous reinfection] (1-5). Some workers believe that
post-primary TB occurs primarily as a result of endo- Natural history of TB infection is shown in Figure 47.1
genous reactivation pathway [the unitary concept of TB] (1). Recurrence of TB in a person who completes a full
(3,5). According to this theory, primary infection [which course of treatment and is cured could be due to reinfec-
is usually acquired in the childhood in areas where TB is tion by a different strain or reactivation of the original
highly endemic] lies dormant for unknown reasons. infecting strain (6). Retrospective analysis of mycobac-
Under certain circumstances, the dormant infection gets terial culture and sensitivity data of several randomized
reactivated and results in post-primary TB. Others believe clinical trials conducted at the Tuberculosis Research
that exogenous reinfection pathway leads to the Centre [TRC], Chennai (7) indicates that active TB recurs
development of post-primary TB. These two pathways in two to seven per cent of patients infected with drug
are thought to be mutually exclusive (2,3,5). susceptible isolates who were treated with contemporary
Distinction between endogenous reactivation and short-course treatment. The earlier conventional methods
exogenous reinfection has important implications in the like phage typing and antibiotic susceptibility could not
planning of clinical trials and national TB control discriminate between reactivation and reinfection. Only
programmes. It would be catastrophic to assume that the after the advent and widespread application of molecular
elderly patients with TB have disease caused by infection biological techniques to genetically dissect the genome
that they acquired before the widespread emergence of of Mycobacterium tuberculosis, has it been possible to
drug-resistant organisms (2). If exogenous reinfection, understand whether the recurrence is due to relapse of
which may be clinically indistinguishable from relapse, the original infecting strain or due to exogenous
is common then the use of antituberculosis chemopro- reinfection.
Reactivation and Reinfection Tuberculosis 657
Figure 47.1: Natural history of Mycobacterium tuberculosis infection in immunocompetent and human immunodeficiency virus-infected
individuals
LTBI = latent tuberculosis infection; TB = tuberculosis; PTB = pulmonary TB; EPTB = extra-pulmonary TB; SS = sputum smear-positive;
TST = tuberculin skin test; SS– = sputum smear-negative
Adapted and reproduced with permission from “Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and
management. Indian J Med Res 2005;121:550-67 (reference 1)”
CLINICAL PRESENTATION primary disease can be encountered in older age groups.

In areas where TB is highly endemic, primary TB is While the primary lesion heals by calcification, the post-
commonly encountered in childhood, whereas, the post- primary lesion heals by fibrosis and scar formation.
primary form of the disease is often seen in adults. In the Important differences exist in the location of the
developed world, where the prevalence of TB is low, lesions in primary and post-primary TB [Table 47.1 and
658 Tuberculosis
Table 47.1: Comparison of clinical presentation of primary and exogenous reinfection pathways of pathogenesis of
and post-primary pulmonary tuberculosis in immunocompe- TB. The authors (3) propose that the interaction between
tent persons virulence of the organism, prior immunological
Variable Primary Post-primary experience and the risk of infection were responsible to
tuberculosis tuberculosis determine the route by which the apical implant is estab-
lished, thereby determining whether the endogenous
Location Any part of the lung Apical region
reactivation pathway or the exogenous reinfection
Size of the lesion Small Large
pathway or both ensue. They (3) suggest that while the
Cavitation Uncommon Frequent
primary implant can occur anywhere in the lungs, the
Local spread Uncommon Frequent
bacilli must gain access into the “vulnerable” regions in
Infectivity Uncommon Frequent
the apex of the lungs for the progression of infection to
Lymphatic involve- Common Minimal
disease. In areas of the world where there is a low risk of
ment
infection with Mycobacterium tuberculosis, low incidence
Tuberculin skin test May be negative Often positive
initially of vaccination or sensitization to environmental
mycobacteria, or high incidence of high virulent isolates,
Figure 47.2]. While the primary lesion can occur the virulent tubercle bacilli reach the vulnerable region
anywhere in the lung and follows a random chance via a bacillaemia during the first infection. In areas of
distribution; cavities, which are characteristic of post- the world where there is a high risk of infection with
primary TB, are almost always located in the apical region Mycobacterium tuberculosis, high incidence of vaccination,
of the lungs (3). or sensitization to environmental mycobacteria, or a high
incidence of low virulent isolates, the organisms reach
PATHOGENESIS the vulnerable region via the airway which requires
repeated episodes of infection, as the probability of the
Several factors, such as the dose of the infecting organism,
first implant occurring in the vulnerable region is low.
immune status of the host among others, have been
Implantation having occurred in the apical area by either
implicated in the pathogenesis of TB. Balasubramanian
of the mechanisms, the primary complex eventually gets
et al (3), critically reviewing the available evidence on
sterilized. Immunosuppressive events trigger the
this subject and their findings in a guinea-pig model of multiplication of the tubercle bacilli in the vulnerable
experimental TB (8), have postulated the “integrated apical area and the effect of cell-mediated immunity leads
model” which integrates the endogenous reactivation to caseation necrosis and cavity formation.
Vynnycky and Fine (9) estimated the age-dependent
risks of developing TB using the age-structured
deterministic model of the dynamics of TB infection and
disease in England and Wales since 1900. The best
estimates of the risks of developing ‘primary’ disease
[within 5 years of initial infection] for individuals infected
at ages under 10 years, 15 years and over 20 years were
found to be four per cent, nine per cent, and 14 per cent,
respectively. A previous infection appeared to impart
little protection against [further] reinfection, but, provi-
ded a 16 to 41 per cent protection against the develop-
ment of active disease subsequent to reinfection for
adolescents and adults. The authors (9) concluded that
Figure 47.2: Clinical presentation of primary and post-primary “risk of infection” is the single most important factor
tuberculosis in immunocompetent individuals. Primary disease is affecting the magnitude of TB morbidity in a popula-
usually characterized by a single lesion in the middle or lower right
tion, as it determines both the age pattern of initial
lobe with enlargement of the draining lymph nodes. Post-primary
disease is often accompanied by a single [cavitary] lesion in the infection [and hence the risk of developing the disease]
apical region and the risk of reinfection.
MOLECULAR EPIDEMIOLOGY culosis” [Chapter 49] for more details regarding these
The issue of reactivation or reinfection TB has been techniques.
studied employing DNA fingerprinting using restriction An alternative method of detecting exogenous
fragment length polymorphism [RFLP] (10,11). In reinfection or ongoing transmission has also been widely
patients with recurrent TB, if the DNA fingerprinting used. In this method, if two or more patients share the
results of the initial isolates are available, subsequent same RFLP pattern, they are categorized as belonging to
DNA fingerprinting can help in determining whether a “cluster”. A given cluster denotes exogenous reinfection
the second episode is due to reactivation or reinfection. or ongoing transmission and unique RFLP pattern is
The reader is referred to the chapter “Drug-resistant tuber- suggestive of endogenous reactivation [Figure 47.3] (12).
Figure 47.3: Restriction fragment length polymorphism can distinguish two isolates of Mycobacterium tuberculosis. The chromosomal
DNA from two clinical isolates of Mycobacterium tuberculosis was digested with restriction enzyme Pvu II. The resulting DNA fragments
were run on agarose gel electrophoresis along with molecular weight marker. The DNA fragments were transferred from the agarose gel
to nylon membrane by southern blotting and hybridized with non-radioactively labelled IS6110 repeat element
Adapted and reproduced with permission from “Narayanan S. Molecular epidemiology of tuberculosis. Indian J Med Res 2004;120:233-
47 (reference 12)”
660 Tuberculosis
The insertion sequence IS6110 has been most widely There have been a very few studies addressing the
used for RFLP studies. However, in certain regions of question of whether recurrences was due to relapse
the world, i.e., India and other South-East Asian count- [endogenous reaction] or exogenous reinfection. The
ries, several clinical isolates of Mycobacterium tuberculosis proportion of recurrent cases caused by reinfection in
harbour few or no copies of IS6110. In a multicentric these studies has varied widely. Factors influencing the
study from India (13), 56 per cent of the isolates showed rate of recurrence are the rate of exposure to new strains
high copy number of IS6110 [6 to 19], 13 per cent showed [the prevalence of active TB in the community] and the
intermediate copy number [3 to 5], 20 per cent showed presence of conditions that increase the likelihood of
low copy number [1 to 2], whereas 11 per cent isolates progression to active disease after exposure to new
lacked IS6110 element. Such variations should be kept strains, the most common predisposing factor being
in mind while attempting to study the molecular advanced HIV disease.
epidemiology of TB and more number of genetic probes The HIV has a profound effect on the pathogenesis
would have to be used. of TB. In patients with the acquired immunodeficiency
Use of convention epidemiological data in combi- syndrome [AIDS], TB infection progresses very rapidly
nation with the DNA techniques is helpful in answering to active disease, and the risk of a person co-infected with
important questions about the epidemiology of TB in HIV and TB developing active disease over two years
larger populations by helping us trace the source of exceeds the lifetime risk in HIV-seronegative individuals.
infection (14-21). These include RFLP using the insertion Patients with AIDS do not maintain protective immunity
sequence IS6110, direct repeat sequence, polymerase following infection, and thus, remain susceptible to
chain reaction [PCR] based typing methods such as exogenous reinfection.
spacer oligonucleotide typing [spoligotyping] based on van Rie et al (25) used DNA fingerprinting to examine
polymorphisms in the direct repeat locus and finger- isolates of Mycobacterium tuberculosis obtained over a
printing based on the variable number of tandem DNA period of almost six years from 698 patients from a
repeats [VNTRs]. Patients whose isolates have identical metropolitan area in South Africa that has one of the
patterns [i.e., cluster] are likely to have been infected highest rates of TB in the world. They (25) identified 16
recently and can be targeted for epidemiological patients with recurrent TB after curative therapy for
investigation to identify a chain of transmission, whereas which complete data were available (25). Of these, 15
patients whose isolates demonstrate unique patterns are were HIV-seronegative. After comparing the DNA
likely to have a latent infection (22). fingerprints of bacilli isolated during the initial episode
In geographical areas with a low incidence of TB, with those of bacilli isolated during the subsequent
recurrent TB is generally due to reactivation of the episode, the authors concluded that 12 patients has been
disease. But this is not a universal finding. In several low exogenously reinfected with a different strain. However,
incidence countries exogenous reinfection is more their analysis included only 16 of the 698 patients and
predominant. Although it was previously thought that their results must, therefore, be interpreted cautiously
90 per cent of TB cases in the developed world occurred as patients with exogenous reinfection may be over-
due to endogenous reactivation of latent infection, represented in the analysis. The low overall rate of
population-based RFLP studies conducted in the United contamination [3.4%] in this study strongly supports their
States and western Europe, areas with relatively low contention that laboratory error did not contribute to
incidence of TB, show that recent infection accounts for their result.
up to half of the cases among both human immuno- A cohort study (26), where it was possible to
deficiency virus [HIV]-seropositive and HIV-seronega- distinguish relapse and reinfection, revealed an increased
tive patients in urban areas (14-21). There have also been rate of recurrent TB among HIV-infected gold miners.
instances where, in high incidence countries like India, Furthermore, the data from this study (26) suggested that
the endogenous reactivation is more predominant among recurrent TB was predominantly due to reinfection. In
HIV-seronegative TB patients (23). In Africa, where TB HIV-seropositive patients, 62 per cent recurrences were
is endemic, it has generally been considered that most due to reinfection with a new organism, while in HIV-
cases of TB in patients with and without HIV infection seronegative patients, 94 per cent of the recurrences were
result from reactivation of a latent infection (24). due to relapse with the same organism. Overall, in
patients with and without HIV infection, 93 per cent of obtained from patients with pulmonary TB who were
recurrences within the first six months were due to recruited into controlled clinical trials. The isolates
relapse while 52 per cent of later recurrences were due originated from 52 patients who received short-course
to reinfection (26). Further studies are required to confirm chemotherapy for six to eight months. The initial isolate
these findings. was obtained before starting treatment and the subse-
quent isolate was obtained after stopping treatment.
DISTINGUISHING TREATMENT FAILURE AND Patients with quiescent disease were followed as long as
EXOGENOUS REINFECTION 60 months by monthly sputum examination for up to 24
months from the start of treatment and at three-monthly
Kruuner et al (27) from Estonia, studied patients with intervals thereafter, in order to determine the stability of
active pulmonary TB who were categorized as “treatment bacteriological relapse [true relapse], if two or more
failure”. These patients had at least three isolates tested positive cultures were obtained within the six-month
for drug susceptibility and were initially diagnosed to period. Coded samples of 44 pairs of clinical isolates were
have been infected with drug-susceptible Mycobacterium analysed by RFLP with direct repeat [DR] probe. On
tuberculosis. Eleven patients from whom 35 sequential analysis, 30 different patterns were observed and the
isolates of Mycobacterium tuberculosis had been obtained number of bands ranged from two to seven. On the basis
were recruited into the study. Their clinical data and of the number and molecular sizes of the bands similar
treatment charts were analysed and correlated with drug RLFP patterns were grouped. This laboratory based
susceptibility patterns and IS6110 RFLP profiles. Six of study, (29) showed that the patterns of 69 per cent of the
the eleven isolates were found to harbour isogenic drug- isolates from patients with relapses matched those with
susceptible Mycobacterium tuberculosis stains whereas in pre-treatment isolates, indicating that the rate of relapse
the other five patients, the isolated strain shifted from a caused by reactivation exceeded the rate of relapse
susceptible to resistant phenotype. In all the cases, this caused by reinfection (29) [Figure 47.4].
shift correlated with a shift in the RFLP pattern, which Data are also available from a population based
points out to reinfection with a new strain. Exogenous study (31) where molecular epidemiologic techniques
reinfection with drug-resistant Mycobacterium tuberculosis were used to investigate mechanisms and risk factors
may be misinterpreted as the emergence of drug resis- for TB transmission in a high prevalence rural area in
tance, if molecular testing techniques are not used (27). south India. The study was carried out at Tiruvallur
The detection of superinfection with a new strain of district, Tamil Nadu with a population of 580 000 and
Mycobacterium tuberculosis during the treatment of an incidence of sputum smear-positive TB of 76 per
episode of active TB is also possible only through the 100 000 population (32). The study subjects were all TB
use of molecular epidemiology tools. The results obtained patients undergoing treatment according to the
by the use of these tools make it clear that those patients guidelines of the Revised National Tuberculosis Control
who are treated in more than one hospital setting can Programme [RNTCP] of the Government of India. Of
become infected with a new or more virulent strain of 437 culture-positive patients, 378 isolates were available
Mycobacterium tuberculosis, if infectious patient are not for RFLP analysis. The combined RFLP analysis with
isolated. Molecular epidemiological studies in patients IS6110 and DR probes identified 236 [62%] patients with
with recurrent TB also facilitate the identification of distinct patterns, and 142 [38%] patients were in one of
antituberculosis treatment regimens with low recurrence the 35 clusters. More than two patients with identical
rates. The data from sub-Saharan Africa (28) suggest that RFLP patterns by IS6110 and DR probe were considered
the use of rifampicin both during the initial and to be in a given cluster. Though not statistically
continuation phase lowers the possibility of recurrent TB. significant, age above 45 years was associated with
India has the highest number of incident TB cases in clustering suggestive of ongoing transmission [reinfec-
the world. The limited numbers of molecular epidemio- tion]. Furthermore, a majority of the patients who had
logic studies conducted in India were laboratory based a relapse and were in a cluster, harboured a strain with
and comprised of small number of patients (29,30). In a only a single copy of IS6110. Risk factors, such as
report from the TRC, Chennai (29), the pretreatment and multidrug-resistance, alcoholism, literacy status and
relapse isolates of Mycobacterium tuberculosis were family size, were not associated with clustering.
662 Tuberculosis
Figure 47.4: Direct repeat restriction fragment length polymorphism patterns of the pre- and
post-treatment isolates. Lanes 1 and 2 represent the pre- and post-treatment isolate of a patient
and lanes 3 and 4 represent the pre- and post-treatment isolates of the second patient and so on
The findings of this study suggest that a majority of years to come. These observations also suggest that the
the TB cases in south India occur predominantly due to DOTS implementation should be sustained to control and
reactivation. These observations also have implications eventually attempt to cure TB.
for the RNTCP of the Government of India. With the The scenario has been different in patients co-infected
nation-wide coverage of DOTS, the transmission of with HIV and TB [Figure 47.5]. Follow-up data are
infection appears to have been reduced due to the higher available from the TRC, Chennai from patients co-
cure and lower relapse rates. However, reactivation of infected with HIV and TB after completion of treatment.
latent infection seems to contribute to the new cases for The positive mycobacterial cultures before treatment and
Figure 47.5: The direct repeat restriction fragment length polymorphism patterns before and after
treatment in patients co-infected with human immunodeficiency virus and tuberculosis
DR = direct-repeat
after recurrent infection have been analysed by RFLP 12. Narayanan S. Molecular epidemiology of tuberculosis. Indian
using more than two probes. In contrast to HIV- J Med Res 2004;120:233-47.
13. Chauhan DS, Sharma VD, Parashar D, Chauhan A, Singh D,
seronegative patients co-infected with TB, preliminary
Singh HB, et al. Molecular typing of Mycobacterium
results [unpublished observations] indicate that the tuberculosis isolates from different parts of India based on
recurrent TB is more frequently due to exogenous IS6110 element polymorphism using RFLP analysis. Indian J
reinfection among patients co-infected with HIV and TB. Med Res 2007;125:577-81.
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Nontuberculous Mycobacterial Infections 665
Nontuberculous
Mycobacterial Infections
48
VM Katoch, T Mohan Kumar
INTRODUCTION disease in man (12,13). The important NTM species are

listed in Tables 48.1A and 48.1B. Most of these NTM
Mycobacteria other than Mycobacterium tuberculosis
reveal in vitro resistance to many drugs that are used
complex [MOTT] mainly exist in the environment as
for the treatment of Mycobacterium tuberculosis. Some
saprophytes. First such mycobacterium was recognized
species like Mycobacterium celatum Mycobacterium
as a cause of human disease in 1908 (1). These organisms
genavense and Mycobacterium conspicuum were reported
in the past have been called atypical mycobacteria, the
for the first time in AIDS patients. Mycobacterium
term first coined by Pinner (2). Diseases caused by these
paratuberculosis also appears to be the likely causative
organisms are uncommon compared with tuberculosis
organism for Crohn’s disease. Besides being known as
[TB], but there has been a significant increase in
atypicals, these mycobacterial species have been given
pulmonary and non-pulmonary infections due to these
various names like ‘anonymous’, ‘nontuberculous’,
mycobacteria during the last two to three decades (3-8).
‘environmental’, ‘opportunistic’ mycobacteria and
This increase is in part explained by the increase in the
MOTT. None of these terms have become universally
number of susceptible and immunocompromised indivi-
acceptable and the name NTM seems to have better
duals but can also be attributed to the availability of better
consensus and is also endorsed by the American Thoracic
technology. While the infections caused by Mycobacterium
Society [ATS] and the Infectious Diseases Society of
tuberculosis, Mycobacterium bovis, Mycobacterium leprae are
America [IDSA] statement (11,14).
definite clinical entities, the diseases caused by other
mycobacteria have varied manifestations, are not usually
DISTRIBUTION IN THE ENVIRONMENT
transmitted from man to man and have been broadly
grouped as “other mycobacteriosis”. Even though these Most of the NTM are ubiquitous in distribution and have
mycobacteria were always there, the emergence of been isolated from stagnant water, mud, soil and food
human immunodeficiency virus [HIV] infection and items (15). Mycobacterium avium complex [MAC] have
acquired immunodeficiency syndrome [AIDS] has been isolated from natural waters; Mycobacterium kansasii
significantly increased the risk of TB and disease due to from tap water; and rapidly growing mycobacteria are
MOTT (9-11). In these individuals the infections due to found in soil and natural waters as well as in tap water,
nontuberculous mycobacteria [NTM] have been water used for dialysis or even in surgical solution (3).
observed to be major causes of morbidity and mortality Man-made changes in the environment may also have
in western countries (11). The NTM cause pulmonary altered the risks of these infections. For example, hot
and generalized infections in immunocompromised water systems are growth nidus for some of these
individuals and cervical lymphadenitis in children mycobacteria, such as Mycobacterium xenopi, in the
(3-8,11). Of the 121 known species of mycobacteria so hospital environment and use of showers may create
far, 45 species have been found to be associated with droplet inhalation of the mycobacteria.
666 Tuberculosis
Table 48.1A: Nontuberculous mycobacterial species

Mycobacterium avium intracellulare complex
Mycobacterium avium Mycobacterium wolinskyi
Mycobacterium intracellulare Mycobacterium goodii
Mycobacterium kansasii Mycobacterium thermoresistible
Mycobacterium paratuberculosis Mycobacterium neoaurum
Mycobacterium scrofulaceum Mycobacterium vaccae
Mycobacterium simiae Mycobacterium palustre
Mycobacterium habana Mycobacterium elephantis
Mycobacterium interjectum Mycobacterium bohemicum
Mycobacterium xenopi Mycobacterium septicum
Mycobacterium heckeshornense Mycobacterium bolletti
Mycobacterium szulgai Mycobacterium phocaicum and Mycobacterium aubaganense
Mycobacterium fortuitum-Mycobacterium chelonae complex Mycobacterium arupense
Mycobacterium fortuitum Mycobacterium parmense
Mycobacterium chelonae Mycobacterium canariasense [closely related
Mycobacterium immunogenum to Mycobacterium diernhoferi]
Mycobacterium marinum Mycobacterium fortuitum third biovariant complex
Mycobacterium genavense Mycobacterium boenickei
Mycobacterium haemophilum Mycobacterium houstonense
Mycobacterium celatum Mycobacterium neworleansese
Mycobacterium conspicuum Mycobacterium brisbanense
Mycobacterium haemophilum Mycobacterium porcinum
Mycobacterium celatum Mycobacterium parascrofulaceum
Mycobacterium conspicuum Mycobacterium gordonae
Mycobacterium malmoense Mycobacterium mucogeniceum
Mycobacterium ulcerans Mycobacterium nonchromogenicm
Mycobacterium smegmatis Mycobacterium shottsi
Mycobacterium terrae complex Mycobacterium pseudoshotti
Table 48.1B: Species of nontuberculous mycobacteria causing infections in humans
Mycobacterium arupense Mycobacterium haemophilum Mycobacterium phocaicum

Mycobacterium aubaganense Mycobacterium heckeshornense Mycobacterium porcinum
Mycobacterium avium Mycobacterium houstonense Mycobacterium pseudoshottsi
Mycobacterium boenickei Mycobacterium immunogenum Mycobacterium scrofulaceum
Mycobacterium bohemicum Mycobacterium interjectum Mycobacterium septicum
Mycobacterium bolletti Mycobacterium intracellulare Mycobacterium shottsi
Mycobacterium brisbanense Mycobacterium kansasii Mycobacterium simiae
Mycobacterium canariasnse Mycobacterium malmoense Mycobacterium smegmatis
Mycobacterium celatum Mycobacterium marinum Mycobacterium szulgai
Mycobacterium chelonae Mycobacterium neourum Mycobacterium thermoresistible
Mycobacterium conspicuum Mycobacterium neworleanense Mycobacterium terrae
Mycobacterium diernhoferi Mycobacterium nonchromogenicum Mycobacterium triviale
Mycobacterium elephantis Mycobacterium palustre Mycobacterium ulcerans
Mycobacterium fortuitum Mycobacterium parascrofulaceum Mycobacterium vaccae
Mycobacterium genavense Mycobacterium paratuberculosis Mycobacterium woliniskyi
Mycobacterium goodii Mycobacterium parmense Mycobacterium xenopi
The distribution of NTM and the incidence of disease injections, break in skin surface due to wounds and
caused by them are difficult to determine since systems generalized immune deficiency states, like AIDS and
of notification vary from country to country. In USA there use of immunosuppressive agents in transplant patients
have been attempts to understand the trends in myco- (11). The pathogenesis of NTM is not very clear and has
bacteriosis due to NTM (16). In 1980, NTM comprised of not been adequately investigated. The lipid rich outer
33 per cent of total mycobacterial isolates in US labora- envelope of the organisms may be important as the first
tories and most of the isolates were Mycobacterium avium, defence of these organisms but specific moeities on the
Mycobacterium kansasii, Mycobacterium fortuitum (16). The surface may also be important factors. Some NTM
picture did not significantly change during the next species, such as Mycobacterium avium and Mycobacterium
decade (17), however, the HIV/AIDS epidemic has simiae have been reported in patients with AIDS in
changed the scenario. There have been some reports of India (33). Very low CD4+ counts in patients with AIDS
NTM infection from Japan (18), UK (19) and India and defective cytokine response[s] have been linked to
(20-27). In Indian studies (24-30). Mycobacterium development of severe infections due to Mycobacterium
tuberculosis has always been found as the major cause of avium from the common sources, such as potable water
mycobacterial infections and the proportion of NTM has (37). Chronic obstructive pulmonary diseases, emphy-
varied from less than one to twenty-eight per cent. sema, pneumoconiosis, bronchiectasis, cystic fibrosis,
Species like Mycobacterium fortuitum, Mycobacterium thoracic scoliosis, aspiration due to oesophageal disease,
avium, etc., have been isolated in different studies (24- previous gastrectomy and chronic alcoholism are some
30). Mycobacterium fortuitum and Mycobacterium chelonae of the conditions which have been linked to disease due
are among the frequently isolated from clinical specimens to NTM.
in hospitals from India (25,26,29). As the culture with
strict criteria is still not routinely performed in most CLINICALLY IMPORTANT MYCOBACTERIA
parts of the country, and there is a tendency to ignore
Among the known 121 species of NTM, only one-third
such isolates and in the absence of clear-cut guidelines
have been associated with human disease.
it is difficult to comment on the exact magnitude of the
problem. Mycobacterium tuberculosis has been observed Mycobacterium avium intracellulare Complex
to be the most common cause of TB in Indian patients
with HIV/AIDS (31). Members of Mycobacterium avium intracellulare complex
Environmental exposure to NTM is common. This group have gained a major prominence in the west,
results in sensitization which can be detected by tuber- especially after an increased frequency of infections
culin test to NTM antigens and differential tuberculin produced by these organisms in patients with AIDS
testing with antigens prepared from other mycobacteria, (38-42). However, in western countries these organisms
e.g. purified protein derivative [PPD]-A [Mycobacterium were also a major cause of pulmonary and other infections
avium] or PPD-Y [Mycobacterium kansasii] has been in the pre-AIDS era (11,16,17). Mycobacterium avium has
considered as a satisfactory method of distinguishing been isolated from environment as well as clinical
sensitization due to NTM from Mycobacterium tuber- specimens including sputum from India (23,30). Certain
culosis. The reader is referred to the chapter “Tuberculin specific serotypes of Mycobacterium avium (11,35), plasmid
skin test” [Chapter 11] for more details. containing Mycobacterium avium (41) and in some
European and African countries certain restriction
fragment length polymorphism types of Mycobacterium
PREDISPOSING FACTORS
avium have been found to be more commonly isolated
It is well known that these environmental mycobacteria from patients with AIDS (35,42). As compared to Myco-
cause disease in individuals who offer some opportunity bacterium intracellulare, Mycobacterium avium appears to
due to altered local or systemic immunity (3,4,11,32-36). have a greater predilection for causing disease in patients
While the reasons may be less clear in children with with AIDS (35). Further, these organisms may cause mixed
cervical lymphadenitis such factors may be quite obvious infections along with other NTM, such as Mycobacterium
in patients with bronchiectasis, surgical procedures, kansasii (39) and Mycobacterium simiae (40), among others.
668 Tuberculosis
Infections caused by Mycobacterium avium intra- Mycobacterium paratuberculosis

cellulare complex were commonly observed in chronic
Mycobacterium paratuberculosis species is closely related
bronchitis, bronchiectasis and chronic obstructive air-
to Mycobacterium avium and has characteristic property
ways disease in the pre-AIDS era in geriatric patients. In
of dependence on mycobactin J. Members of this species
non-HIV patients Mycobacterium avium has been have been reported to be causative organisms of enteritis
associated with pulmonary disease, lymphadenitis and [Johne’s disease] in cattle, goats and sheep and can be
joint involvement (11). Unlike Mycobacterium tuberculosis, characterised rapidly with molecular techniques (47,48).
the Mycobacterium avium intracellulare complex strains With the help of gene probes, strains belonging to this
have a low virulence and despite being commonly found species have been linked to aetiology of Crohn’s disease
in the environment rarely cause disease (15,37). These in man (48). Demonstration of specific sequences in
usually produce clinical disease only when the CD4+ tissue sections by in situ hybridisation has provided a
count is very low [< 50 cells/μl] towards the end of definitive evidence of an aetiological relationship of this
natural history of disease, seen in four to five per cent organism with Crohn’s disease (49).
of HIV/AIDS patients (34). Mycobacterium avium complex
strains isolated from patients with AIDS in Africa have Mycobacterium scrofulaceum
been shown to be different as compared with western
The distribution of these pigmented organisms in nature
strains (35). In AIDS patients, the portal of entry is
is similar to that of Mycobacterium avium and Mycobac-
thought to be mainly through the gut (37) and the most
terium intracellulare complex (50). The most common
common presenting features include persistent high-
disease caused by these organisms is cervical
grade fever, night sweats, anaemia and weight loss in
lymphadenitis in children as well as chronic ulcerative
addition to non-specific symptoms of malaise, anorexia,
and nodular lesions (11). It may cause adult pulmonary
diarrhoea, myalgia and occasional painful adenopathy.
disease and disseminated infections in patients with
On examination, there may be hepatomegaly and chest AIDS (11,50).
radiograph as well as computed tomography of the chest
and abdomen may show a widespread intra-thoracic and Mycobacterium interjectum
intra-abdominal lymphadenopathy. The diagnosis is
generally not difficult as clinical specimens yield Mycobacterium interjectum is a new species found to be
numerous acid-fast bacilli [AFB] which can be cultured associated with chronic lymphadenitis (51).
and identified. Mycobacterium xenopi
Mycobacterium kansasii Mycobacterium xenopi is an unusual bacterium with

optimal growth temperature at 45 oC. It has been encoun-
These organisms are found in water and consequently tered as a pathogen in patients with other underlying
in some sputum samples as non- significant commensals. lung diseases (52-54). It has been isolated from hot water
Nevertheless, when repeatedly isolated from sputum reservoirs of hospitals and has been found to be asso-
they could be associated with pulmonary disease (11). ciated with clinical problems (11,52,53). Clinical mani-
Since long time Mycobacterium kansasii has been festations are similar to Mycobacterium avium complex
considered an important cause of pulmonary disease in patients with advanced AIDS. An instance of an
(3,11) and has become even more important in AIDS era outbreak of pulmonary disease due to this organism from
(39,43-46). Although in vitro susceptibility tests suggest hot water supply of a hospital has been reported (11).
that members of these species are more resistant to
antimicrobial agents than Mycobacterium tuberculosis, Mycobacterium simiae
infections with Mycobacterium kansasii frequently respond Mycobacterium simiae organism was initially isolated from
well to multiple drug therapy (6,45,46). New biotypes of a monkey and later recognised as an agent of human
Mycobacterium kansasii have been isolated from patients pulmonary disease in AIDS as well as non-AIDS cases
with AIDS (44). As with MAC infections, these patients (3,4,11,33,40). Another closely related organism with
may present with advanced AIDS with very low CD4+ similar pulmonary disease spectrum has been isolated
count [< 50 cells/μl]. in Cuba and named as Mycobacterium habana (8).
Mycobacterium szulgai Mycobacterium genavense

Mycobacterium szulgai species has been isolated on several These organisms were isolated for the first time from
occasions from patients with pulmonary disease. It is patients with AIDS. These organisms are grown with
confused often with some of the scotochromogenic myco- difficulty and need enrichment with mycobactin J. It
bacteria. This organism is also been associated with grows in liquid media, often after prolonged incubation
disseminated disease and also involves skin, joint and periods and has now been isolated from several countries
lymph nodes (55). These mycobacteria have been isolated (63-65). Patients are usually in advanced stage of AIDS
from India also (26,27). and present with weight loss, fever, abdominal pain and
diarrhoea. This organism has been found to be sensitive
Mycobacterium fortuitum-Mycobacterium chelonae to clarithromycin.
complex
Mycobacterium haemophilum
Mycobacterium fortuitum-Mycobacterium chelonae complex
are rapidly growing organisms that are commonly found This is a new emerging mycobacterial pathogen (66-70).
in the soil and are now being reported with increasing This slow growing organism has been recognized as a
frequency from human disease (4-8,11,25,27,29,30,56-58). cause of life-threatening infections in immunocom-
These are widely distributed in the Indian environment promised individuals, like AIDS, bone marrow trans-
and could emerge as important pathogens (25-30). plant recipients. The organism has been isolated from
Mycobacterium fortuitum causes pulmonary disease and the skin lesions, lymph nodes, synovial fluid, vitreous
also pyogenic lesions in the soft tissue, joints, bursae and fluid, bronchoalveolar lavage fluid [BAL], bone marrow
injection abscesses (3,4,11). Besides their common aspirate and blood. Recovery of this organism requires
causative association with soft tissue infections, cultivation in enriched chocolate agar or haemin or ferric
Mycobacterium fortuitum and Mycobacterium chelonae can ammonium citrate supplement and incubation at 30 oC
cause generalized disease in immunocompromised hosts up to eight weeks. Information about its environmental
and present as subcutaneous nodules, similar picture reservoirs and spread is limited. Despite aggressive
may be shared by other NTM, like Mycobacterium kansasii therapy with multiple antituberculosis drugs the
(11,56). Mycobacterium immunogenum, closely related to recurrence is common.
Mycobacterium abscessus has been reported as a cause of
human infections (59). EMERGING NEW MYCOBACTERIAL PATHOGENS
Mycobacterium marinum Several species of NTM have been isolated from AIDS
patients (71-74). Besides Mycobacterium genavense, other
This mycobacterial species has been recognized as a
species isolated for the first time from AIDS patients
causative organism of “swimming pool granuloma” or
include: Mycobacterium celatum (71) and Mycobacterium
fish tank granuloma. It causes papular lesions in the
conspicuum (72). Mycobacterium malmoense (73,74) has
extremities and may be confused with sporotrichosis
emerged as another pathogen which has not been isola-
(3,4,60-62). This has also been reported as a cause of
ted from the environment (15). Mycobacterium ulcerans
infections of hands and wrist (61) and bones, joints and
has been established as an important skin pathogen for
tendon sheaths, especially in patients with AIDS (62).
a long time (3,4,75). Other mycobacteria rarely associated
with disease are: Mycobacterium smegmatis (76), Mycobac-
Mycobacterium terrae Complex
terium thermoresistible (77), Mycobacterium neoaurum (78)
This complex consists of three species, Mycobacterium and Mycobacterium vaccae (79).
terrae, Mycobacterium nonchromogenicum and Mycobacte- Due to wider use of gene sequencing [16S rRNA,
rium triviale. They appear to be harmless saprophytes rpoB] these days several new species have been identified
but occasionally may be associated with disease which were earlier missed as variants of known species.
(3,11,29). These include several species from human clinical
670 Tuberculosis
specimens (80-92) and also marine animals (93,94). CLINICAL MANIFESTATIONS

Important examples are: Mycobacterium heckeshornense
Nontuberculous mycobacteria have been reported to be
(80), Mycobacterium bohemicum (81), Mycobacterium
associated with varied clinical manifestations (3,4-8,11).
woliniskyi and Mycobacterium goodii, both closely related
In non-HIV patients, NTM has been established to be
to Mycobacterium smegmatis (82), Mycobacterium palustre
responsible for pulmonary disease usually with some
(83), Mycobacterium elephantis (84), Mycobacterium septicum
local predisposing conditions, lymphadenitis, soft tissue
(85), Mycobacterium bolletti, Mycobacterium phocaicum and
infections, infections of joints and bones, bursae, skin
Mycobacterium aubaganense (87), Mycobacterium arupense
ulcers and generalized disease in individuals like
(88), Mycobacterium parmense (89), Mycobacterium
leukaemia, transplant patients etc., (3,4,11,95). In patients
canariasense closely related to Mycobacterium diernhoferi
with AIDS their spectrum may depend upon the degree
(90), members of Mycobacterium fortuitum, third
of immune deficiency and the manifestations may range
biovariant complex-Mycobacterium boenickei, Myco-
from localized pulmonary to intestinal and disseminated
bacterium houstonense, Mycobacterium neworleansese,
disease (11,96-98). Most of the NTM can be associated
Mycobacterium brisbanense and Mycobacterium porcinum
with both the localized as well as generalized disease
(91) and Mycobacterium parascrofulaceum (92).
depending upon degree of immune deficiency or local
Mycobacterium shottsi (93) and Mycobacterium pseudoshottsi
favourable conditions for their establishment and growth
(94) have been isolated from lesions from fish and bass.
[Tables 48.2 and 48.3].
These newly identified pathogens have been isolated
from a variety of conditions such as cutaneous, soft tissue
Diagnosis
and wound infections (82,85,86,91), from patients with
pulmonary disease (80,91,92), lymphadenitis (81,89), Diagnosis of the disease due to NTM depends upon the
bacteraemia (85,91), febrile conditions (90) and degree of suspicion and strict laboratory practices. Due
disseminated disease. The exact importance of these to ubiquitous presence of these organisms in the
potential pathogens in the causation of diseases will be environment, it is extremely important to rule out conta-
better known with routine use of modern techniques for mination. At present most of the experience is based on
molecular characterization. published findings from western countries and there is
Table 48.2: Localised clinical disease due to nontuberculous mycobacteria
Type of lesion Species
Pulmonary disease Common: Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium kansasii,
Mycobacterium malmoense, Mycobacterium xenopi
Uncommon: Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium
haemophilum, Mycobacterium celatum, Mycobacterium asiaticum, Mycobacterium
scrofulaceum
Lymphadenopathy Common: Mycobacterium avium complex, Mycobacterium scrofulaceum, Mycobacterium
malmoense
Uncommon: Mycobacterium genavense, Mycobacterium haemophilum, Mycobacterium
chelonae, Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium kansasii,
Mycobacterium szulgai
Skin, soft tissue, wound infections, Common: Mycobacterium marinum, Mycobacterium ulcerans, Mycobacterium chelonae,
bone disease Mycobacterium fortuitum, Mycobacterium abscessus
Uncommon: Mycobacterium avium complex, Mycobacterium haemophilum, Mycobacterium
mucogenicum, Mycobacterium nonchromogenicum, Mycobacterium kansasii, Mycobacterium
malmoense, Mycobacterium smegmatis, Mycobacterium szulgai, Mycobacterium terrae
complex
Crohn’s disease Mycobacterium paratuberculosis
Specimen contaminants: Mycobacterium gordonae, Mycobacterium haemophilum, Mycobacterium mucogenicum, Mycobacterium

nonchromogenicum and Mycobacterium terrae complex
Table 48.3: Disseminated disease due to nontuberculous mycobacteria

Condition Species
Without AIDS [usually transplant Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium chelonae,
patients, leukaemia etc., Mycobacterium scrofulaceum, Mycobacterium fortuitum including members of
Mycobacterium fortuitum, third biovariant complex-Mycobacterium boenickei, Mycobacterium
houstonense, Mycobacterium neworleansese, Mycobacterium brisbanense, and Mycobacterium
porcinum and Mycobacterium parascrofulaceum, Mycobacterium septicum, Mycobacterium
canariasense closely related to Mycobacterium diernhoferi, Mycobacterium haemophilum
With AIDS Mycobacterium avium complex, Mycobacterium haemophilum, Mycobacterium simiae,
Mycobacterium xenopi, Mycobacterium kansasii, Mycobacterium fortuitum-chelonae complex,
Mycobacterium genavense, Mycobacterium malmoense, Mycobacterium celatum,
Mycobacterium conspicuum
AIDS = acquired immunodeficiency syndrome
a general tendency of discarding these isolates as conta- histopathology. The gold standard for NTM disease
minants. These issues have been extensively debated and compared to colonization is a tissue biopsy showing
some broad guidelines have emerged. granulomatous inflammation, which may or may not
contain AFB and a positive culture, even if the sample is
Pulmonary Disease smear-negative.
Clinical presentation of the disease due to NTM may be
Other Clinical Forms
like TB and pulmonary infections may present as chronic
cough and infiltrates in the radiographs. Infection due Most of other manifestations should be considered in the
to NTM should be suspected especially in patients in differential diagnosis of any chronic infection, pyrexia
whom initial antituberculosis treatment has not of unknown origin and localized clinical disease [abscess,
produced clinical, radiographic and microbiological ulcers, nodules, infiltrates, etc.,] not responding to
response. Sputum should always be sent for smear and antibiotics. Attempts should be made to demonstrate and
culture examination and if the cough is non-productive isolate the NTM from such lesions using most stringent
it is better to do a bronchoscopy, BAL and or biopsy. criteria and precautions.
Infection with NTM may be asymptomatic and may As most of the NTM are not sensitive to routine
present with subacute or chronic illness. Symptoms antituberculosis treatment, it is imperative to correctly
include cough, sputum production, weight loss, haemo- identify the causative mycobacteria and if required
ptysis, shortness of breath, malaise, pleuritic chest pain, determine their sensitivity profile.
low-grade fever and night sweats. Radiological
appearances are similar to TB with cavities and infiltrates, Specimens
though the upper lobes are more involved and the distri- Because NTM are widely distributed in the environment
bution is more variable than TB. Thin-walled cavities and may be merely present as colonizing agents on the
with lesser parenchymal infiltrates have been described skin and mucous membranes, proper sample collection
as a suggestive feature (11). The changes may be is very important. The specimen should be obtained
unilateral or bilateral and more than one lobes may be directly from the lesion or organ concerned (11). For such
involved. In high resolution computed tomography, purposes biopsies and procedures, like BAL have
clusters of small nodules associated with areas of advantages. It is recommended to attempt repeated
bronchiectasis in the lower and middle zones are isolation in significant numbers to firmly link the isolate
common. Asymptomatic solitary nodules due to MAC with the aetiology. Further, the decontamination has to
have been documented. Pleural thickening and effusion be gentler than Mycobacterium tuberculosis. In case of the
are not common. Bronchoscopy is very useful to obtain disseminated infections such as in patients with AIDS
BAL samples for culture and biopsy samples for blood cultures have been shown to yield positive
672 Tuberculosis
cultures. Diagnosis of Mycobacterium avium complex is colony pigmentation. Since the days of Runyon it is
generally done by growing the mycobacteria from the conventional to initially classify the organisms as rapid
peripheral blood or bone marrow sample (99,100). and slow growers (106).
Histopathology Biochemical Tests

Histopathological examination of bone marrow, liver or After classifying the mycobacteria on the basis of growth
lymph nodes [aspirates or biopsy] showing granuloma and pigmentation most of the mycobacteria can be
may be helpful in the diagnosis, the greatest advantage identified by biochemical tests (106). A few simple
of this approach over the culture being the speed (38). It biochemical and culture tests can usually identify a strain
may be advisable to include some in situ methods to clinical satisfaction. These common tests are: niacin
[antigen detection and gene probes] to confirm the production, nitrate reduction, tween-80 hydrolysis,
histological diagnosis straightaway. arylsulphatase, urease, and catalase [qualitative and
quantitative] production, tellurite reduction, thiophene-
Cultivation 2-carboxylic acid hydrazide sensitivity, growth on
There has been a considerable progress in developing MaConkey agar, sodium chloride tolerance, among
and testing methods for isolation of NTM from others (106).
environment as well as clinical specimens (101-110). As
these mycobacteria may be susceptible to decontaminat- Lipid Patterns
ing procedures like NaOH treatment (101), approaches Mycobacteria can be characterized at group, species and
like paraffin bating such as paraffin coated slides become subspecies levels by analysis of their lipids by thin layer
attractive option (102,103). Most of these mycobacteria chromatography, high performance liquid chromato-
are easy to cultivate and these can be grown on ordinary graphy. These techniques are simple and have been
media for mycobacteria like Lowenstein-Jensen, Middle- developed along with easy software programmes for
brook and Dubos Broth and Agar (11,104,106). rapid analysis (107,108) by which isolates from liquid
Organisms like Mycobacterium haemophilum may have and solid media can be rapidly identified.
special requirements like hemin for which blood
containing media-chocolate agar or supplement of ferric Identification Techniques for Established,
ammonium citrate may be required. Various radiometric Reference Laboratories
systems, like BACTEC (104,105,108); non-radiometric Alternative methods for identification of mycobacteria
methods like mycobacteria growth inhibitor tube [MGIT] which would require special laboratories and expertise
and MB/Bac T (109,110) or liquid media like 13A or are described below:
BACTEC 12B broth medium (33) as well as agar-based
Serotyping These methods have been well developed
isolation systems have been described to be highly
for the members of Mycobacterium avium intracellulare
sensitive [up to 96%-98%] for MAC and other NTM
complex (99,111). Based on serotype specific sera, these
(3,4,11,17,99,100,104-110). Pyruvate containing medium
strains can be correctly identified and assigned to
may be necessary for growth of Mycobacterium bovis or
serotypes. Some serotypes (11,99) of Mycobacterium avium
bacille Calmette-Guerin [BCG] (107). Mycobacterium
have been shown to be preferentially associated with
genavense, Mycobacterium paratuberculosis will require
disease in patients with AIDS.
supplementation with mycobactin J. Different incubation
temperatures such as 30 oC for Mycobacterium ulcerans Isoenzyme and protein electrophoregrams Simple
and Mycobacterium marinum, 37 oC for most pathogens, electrophoretic techniques and schemes based on
45 oC for Mycobacterium xenopi etc will have to be selected electrophoretic mobilities of proteins and isoenzymes for
depending upon the suspected organisms. the characterization of strains of Mycobacterium tuber-
culosis and NTM have been developed which can be used
Identification of Isolates to confirm identity of the isolate rapidly (112-114). These
The first scheme for identification and grouping of patterns may be used both for rapid identification and
cultivable mycobacteria was based on growth rates and characterization of these mycobacteria (114).
Measurements of immunological relatedness Based on followed by capture plate hybridization has been
divergences in the structure of certain enzymes such as reported to be useful for Mycobacterium ulcerans (125)
catalase (115) and superoxide dismutases (116), various and Mycobacterium avium, Mycobacterium chelonae, Myco-
clinically relevant mycobacterial species can be identi- bacterium scrofulaceum (126). A reverse hybridization line
fied. This approach may also be evaluated in future probe assay [LipA][e.g., INNO-LiPA, Innogenetics,
studies. Ghent, Belgium] has been described to be quite useful
for rapid identification of mycobacteria (127).
New Molecular Methods for Identification and Polymerase chain reaction targeting certain regions on
Characterisation rRNA has been observed to be useful for quick identi-
fication of various NTM (130). These PCR methods can
Recent years have witnessed many advances in the
be used for rapid identification of clinical isolates
molecular genetics of various organisms including
mycobacteria. As these are based on the complementarity (121,122,124,125,129,130,133) as well direct detection of
pathogens from the clinical specimens (123,128).
of gene sequences, these techniques can achieve maxi-
Keeping in view the diversity of these organisms
mum sensitivity and specificity. By hybridization of
isolated ribonucleic acid [RNA], deoxyribonucleic acid present in different geographical locations, it would be
important to evaluate the usefulness of these techniques.
[DNA] from growth or tissue with specific probes,
Further, contamination from the environment will have
identity of isolates is rapidly established. Based on new
knowledge about the gene sequences many gene probes to be carefully ruled out.
for the identification of isolates as well as amplification DNA fingerprinting techniques Due to almost universal
of specific gene fragments from the lesions and mycobac- presence of these organisms in the environment, there
terial culture isolates have been developed and are has been interest in identifying the strains which would
described below. be more commonly associated with disease. Further, such
Gene probes During the last 20 years, a number of gene identification would be important to investigate hospital
probes for the identification of important NTM have been infections as well other sources of such infections
developed and some are also being commercially (134-145). The DNA fingerprinting techniques using
marketed (105,117-119). With the help of these probes, procedures such as pulsed-field gel electrophoresis
growth from solid slants and even liquid cultures [e.g., (134,143), random amplified polymorphic DNA [RAPD]-
BACTEC] can be identified and these have been found arbitrary PCR (135), rRNA probes (136-138) and different
to be fairly reliable and rapid. insertion and repeat elements have been described for
characterization of NTM (69,139,141,142). Insertion
Gene amplification methods Advances in gene
elements have been described to be useful for characteri-
amplification methods especially polymerase chain
sation of Mycobacterium haemophilum (69), Mycobacterium
reaction [PCR] technology have influenced almost every
avium (139,140,144,145), Mycobacterium scrofulaceum
discipline of medicine. Several PCR techniques for rapid
(142,144) as well as Mycobacterium kansasii (141). Using
detection and identification of various clinically relevant
these probes and fingerprinting systems, the aetiology
mycobacteria have been developed (120-133). These
of Crohn’s disease due to Mycobacterium paratuberculosis
include different types of PCR assays for detection of
has been established to a large extent (47,49). Further,
Mycobacterium avium, Mycobacterium intracellulare
some specific RFLP types of Mycobacterium avium have
(120,123,124) and Mycobacterium paratuberculosis (47)
been shown to be closely linked with disease in Europe
from the clinical specimens. The PCR assays using
and Africa (35,42). The IS1245 based RFLP analysis of
genus and group specific amplification followed by
Indian isolates of Mycobacterium avium suggested birds
restriction analysis have been developed for regions like
as origin of most of human isolates (140).
65 kD for Mycobacterium tuberculosis, Mycobacterium
avium, etc., (121), rRNA gene region for Mycobacterium Determination of sensitivity profiles The NTM tend to
avium, Mycobacterium chelonae, Mycobacterium xenopi, be generally resistant to low concentrations of various
etc., (129-133). A new PCR technique appears to be anti-tuberculosis drugs (11). However, at high concen-
potentially useful for characterizing various pathogenic trations [within the therapeutic limits], these organisms
NTM (133). Another PCR strategy using amplification may be sensitive. The media usually recommended for
674 Tuberculosis
Table 48.4: Recommended techniques to diagnose nontuberculous mycobacterial disease
Low resource settings Good Institute with moderate resources Reference laboratories
Repeated isolation on Repeated isolation on conventional Repeated isolation on conventional media and
conventional media and media and identification by selected identification by selected biochemical tests
identification by selected biochemical tests
biochemical tests
Growth in any liquid medium Growth in any standard liquid medium Growth in any liquid medium, like BACTEC, MGIT, MG/
and identification by lipid system, like BACTEC, MGIT, MB/Bac T, Bac T and identification by probe hybridization and lipid
patterns identification by probe hybridization and patterns by TLC or HPLC
lipid patterns by TLC or HPLC
Histopathology Histopathology; plus immunohisto- Histopathology; plus immunohistochemistry and in-situ
chemistry and in-situ hybridisation etc., hybridization, in-situ PCR etc.,
PCR-RFLP [if PCR available] PCR-RFLP PCR-RFLP
Drug susceptibility testing Drug susceptibility testing
16S rRNA/rpoB sequencing
DNA fingerprinting
Fluorochrome staining technique is preferred for NTM

Routine drug susceptibility testing of Mycobacterium avium complex isolates is recommended for clarithromycin only
Routine drug susceptibility testing of Mycobacterium kansasii is recommended for rifampicin only
Routine drug susceptibility testing of rapid growing mycobacteria [Mycobacterium fortuitum, Mycobacterium chelonae and Mycobacterium
abscessus] should be with clarithromycin, cefoxitin, doxycycline, fluorinated quinolones, amikacin, a sulphonamide
or trimethoprim-sulphamethoxazole, linezolid, imipenem [Mycobacterium fortuitum only] and tobramycin [Mycobacterium chelonae
only]
PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism; DNA = deoxyribonucleic acid; MGIT = mycobacteria
growth inhibitor tube; TLC = thin layer chromatography; HPLC = high performance liquid chromatography
sensitivity screening of Mycobacterium tuberculosis are also Laboratories with different levels of infrastructure
used for NTM. However, due to differences in the levels and financial commitment can follow different strategies
of sensitivity in broth (11), a caution is required. Other to deal with diagnosis and characterisation of NTM for
media, like chocolate agar supplemented with ferric management [Table 48.4].
ammonium salts and mycobactins etc., will be required
for sensitivity screening of other fastidious species. While Table 48.5: Prevention of nontuberculous mycobacteria
disease
newer techniques like BACTEC, MGIT and MB/Bac T
(109,110) have been quite promising in early detection Health care-associated NTM disease
of growth of NTM from clinical specimens, only BACTEC Avoid exposure of injection sites, intravenous catheters and
surgical wounds to tap water and tap water derived fluids
and E-test have been found to be useful for sensitivity
Avoid cleaning of endoscopes with tap water
determination of rapid as well as slow growing NTM
Avoid contamination of clinical specimens with tap water and
(146-148). Expert group of ATS (14) has suggested that
ice
there is no use of testing of sensitivity for rifampicin and
isoniazid for rapid growers as they are usually resistant Disseminated MAIC disease
Patients with AIDS [CD4+ T-lymphocyte count < 50 cells/µl]
to these drugs and other drugs such as sulphones, clari-
Azithromycin 1200 mg/week
thromycin, cefoxitin, amikacin etc., should be considered or
for the treatment of NTM disease. Likewise, higher cut- Clarithromycin 1000 mg/day
off values for determination of sensitivity should be or
considered for organisms, like Mycobacterium avium. Rifabutin 300 mg/day [less well tolerated]
Recombinant strain of Mycobacterium avium expressing AIDS = acquired immunodeficiency syndrome; MAIC = Mycobac-
beta galactosidase have been reported to be useful for terium avium intracellulare complex; NTM = nontuberculous
screening of activity of anti-mycobacterial compounds mycobacteria
(149). Adapted from reference 14
Table 48.6: Treatment of nontuberculous mycobacterial disease
Disease Drugs Dose Frequency Duration
Pulmonary MAC Disease

Nodular/bronchiectatic A regimen consisting of
disease clarithromycin or 1000 mg 3 times a week After achieving culture-
azithromycin 500-600 mg 3 times a week negative status, the same
and rifampicin 600 mg 3 times a week should be maintained while
and ethambutol 25 mg/kg 3 times a week on treatment for a further
period of 1 year
Fibrocavitary MAC lung A regimen consisting of
disease or severe nodular/ clarithromycin or 500*-1000 mg Daily Treat until culture-negative
bronchiectatic disease azithromycin 250 mg Daily on treatment for 1 year
and rifampicin 10 mg/kg Daily [maximum
600 mg]
or rifabutin 150 - 300 mg Daily
and ethambutol 15 mg/kg Daily
amikacin or streptomycin†
Disseminated MAC disease A regimen consisting of

clarithromycin or 1000 mg Daily Patient should be treated
azithromycin 500 mg Daily until resolution of symptoms
and ethambutol ± 15 mg/kg Daily and reconstitution of cell-
rifabutin 300 mg Daily mediated function
Mycobacterium kansasii A regimen consisting of

pulmonary disease isoniazid 300 mg Daily After achieving culture-
rifampicin and 600 mg Daily negative status, the same
ethambutol 15 mg/kg Daily should be maintained while
on treatment for a further
period of 1 year
Mycobacterium abscessus No drug regimen of proven

pulmonary disease efficacy available
Surgical resection of
localized disease with May produce symptomatic
multidrug regimens that improvement and disease
include clarithromycin 1000 mg Daily regression
NTM cervical lymphadenitis‡ Surgical excision is the

treatment of choice
Patient with extensive MAC Macrolide-based multidrug regimen such as that used for pulmonary disease
lymphadenitis or poor response
to surgical treatment
Non-pulmonary disease due to The drug regimen is based on in vitro drug susceptibilities. Surgical debridement is an essential
rapid growing NTM component of treatment. A macrolide-based drug regimen is frequently used for Mycobacterium
abscessus
* Lower dose for body weight < 50 kg

† The doses of streptomycin or amikacin will depend on the patient’s age, weight, and renal function and may range from 8 to 10 mg/
kg two to three times weekly [with a maximum dose of 500 mg for patients older than 50 years] to 25 mg/kg three times weekly
‡ The disease is due to MAC in majority of the cases
NTM = nontuberculous mycobacteria ; MAC = Mycobacterium avium complex
676 Tuberculosis
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682 Tuberculosis
Drug-Resistant
Tuberculosis
49
Sharmistha Banerjee, N Siddiqi, Seyed E Hasnain
INTRODUCTION unknown till the last decade. Even today, TB, a curable
disease, continues to be a major threat worldwide.
At the end of nineteenth century, Dr. Robert Koch
isolated the dreaded organism that was the aetiological
EPIDEMIOLOGY
agent of tuberculosis [TB] (1-3). Since then, there had been
desultory experiments with a variety of medical The epidemiology of drug-resistant TB including MDR-
applications in the management of pulmonary TB. The TB is extensively covered in the chapter “Antituberculosis
first success, marking the antibiotic era, came in the year drug resistance surveillance” [Chapter 50].
1944, with the introduction of streptomycin for TB
treatment. With the availability of isoniazid, and para- Molecular Epidemiology of Multiple
aminosalicylic acid [PAS], in the mid 1940s, predictable, Drug-Resistant Strains
curative treatment for TB became a reality. With the
Tools for Studying Molecular Epidemiology
introduction of rifampicin, pyrazinamide and
ethambutol in the subsequent years, short-course Several methods are used for antituberculosis drug
treatment became possible. Initial euphoria of ability to susceptibility testing, and are described in detail in the
cure TB led to indiscriminate use of antituberculosis chapter “Laboratory diagnosis” [Chapter 10]. A new tool
drugs and the laxity in monitoring of tedious drug that has been applied to TB epidemiology is the restriction
regimens led to the emergence of multidrug-resistant fragment length polymorphism [RFLP] analysis-based
strains of Mycobacterium tuberculosis. Multidrug-resistant deoxyribonucleic acid [DNA] fingerprinting that
-TB [MDR-TB] caused by isolates of Mycobacterium identifies specific strain of a microorganism. This
tuberculosis resistant to isoniazid and rifampicin with or technique has found widespread use in Mycobacterium
without resistance to other antituberculosis drugs, is a tuberculosis characterization by virtue of repetitive DNA
worrisome disease and is prevalent worldwide (4-10). sequences that are present in the genome in variable
Resistance to rifampicin and isoniazid, two frontline numbers and locations. These include the insertion
drugs that form the backbone of the short-course sequences [IS], direct repeats [DR], polymorphic GC-rich
treatment, would necessitate using drugs that are more sequences [PGRS], major polymorphic tandem repeats
toxic, costly and are administered for a long period. The [MPTR] and enterobacterial repetitive intergenic
MDR-TB patients that fail treatment have a higher risk consensus sequences [ERIC]. The greater polymorphism
of death (5-7) . shown by these repetitive sequences offers better
After the initial discovery of five or six antituber- identification power over the earlier typing techniques,
culosis drugs, no newer drugs have been discovered such as pulse field gel electrophoresis. Another
against Mycobacterium tuberculosis. The mechanism of advantage of these techniques is their standardization,
resistance to most antituberculosis drugs remained which offers greater intra- and inter-laboratory
Drug-Resistant Tuberculosis 683
comparisons of fingerprints. Few years back a new of spoligotyping compared to IS6110 fingerprinting is
method spacer oligonucleotide typing [spoligotyping] less, and consequently, its use for epidemiological studies
was introduced for diagnosis and epidemiology of of Mycobacterium tuberculosis is limited. The fluorescent
Mycobacterium tuberculosis [Figures 49.1A and amplified fragment length polymorphism [FAFLP]
49.1B] (11). It is based on the detection of various non- is a relatively new whole-genome DNA typing method
repetitive spacer sequences located between the direct (13-16).
repeats in the DR locus. It is a polymerase chain reaction Newer methods such as heteroduplex and mismatch
[PCR] based method hence the results can be obtained analyses, DNA sequencing, real-time PCR [RT-PCR],
in a shorter time (12). However, the discriminative power molecular beacons, and line probe assays have all been
Figure 49.1A: Chromosome of Mycobacterium tuberculosis hypothetical strain X and genotyping of Mycobacterium bovis bacille Calmette-
Guérin [BCG], the Mycobacterium tuberculosis laboratory strain H37Rv, and strain X on the basis of IS6110 insertion sequences and
mycobacterial interspersed repetitive units [MIRUs]. The top left-hand panel shows the chromosome of hypothetical strain X, as shown
by the arrows. The top right-hand panel shows the results of IS6110-based genotyping. Mycobacterial DNA is digested with the restriction
enzyme PvuII. The IS6110 probe hybridizes to IS6110 DNA to the right of the PvuII site in IS6110. The size of each hybridising fragment
depends on the distance from this site to the next PvuII site in adjacent DNA [fragments, a through f], as reflected by gel electrophoresis
of the DNA fragments of BCG, H37Rv, and X. The horizontal lines to the right of the electrophoretic strip indicate the extent of the
distribution of fragments in the gel, including PvuII fragments that contain no IS6110. The three bottom panels show the results of MIRU-
based genotyping. The MIRUs contain repeat units, and MIRU analysis involves the use of polymerase chain reaction [PCR] amplification
and gel electrophoresis to categorize the number and size of repeats in 12 independent loci, each of which has a unique repeated
sequence. The sizes of molecular-weight markers [M] and PCR products for the loci A, B, C, and D in BCG, H37Rv, and X are shown. The
specific sizes of the various MIRUs in each strain result in a distinctive fingerprint for the strain
Reproduced with permission from “Barnes PF, Cave MD. Molecular epidemiology of tuberculosis. N Engl J Med 2003;349:1149-56
684 Tuberculosis
Figure 49.1B: Spoligotyping. The direct-repeat [DR] locus is a chromosomal region that contains 10 to 50 copies of a 36-bp direct
repeat, separated by spacer DNA with various sequences, each of which is 37 to 41 bp. A copy of IS6110 is inserted within a 36-bp direct
repeat in the middle of the DR locus in most strains. Mycobacterium tuberculosis strains have the same overall arrangement of spacers
but differ in terms of the presence or absence of specific spacers. Spacer oligonucleotide typing [spoligotyping] involves polymerase-
chain reaction [PCR] amplification of the DR locus, followed by hybridization of the labeled PCR products to a membrane that contains
covalently-bound oligonucleotides corresponding to each of 43 spacers. Individual strains have positive or negative signals for each
spacer. The top section shows the 43 direct repeats [rectangles] and spacers [horizontal lines] used in spoligotyping. The middle section
shows the products of PCR amplification of spacers 1 through 6 of Mycobacterium bovis bacille Calmette-Guérin [BCG], Mycobacterium
tuberculosis strain H37Rv, and Mycobacterium tuberculosis hypothetical strain X, with the use of primers [white and black arrowheads]
at each end of the DR locus. The bottom section shows the spoligotypes of the three strains
Reproduced with permission from “Barnes PF, Cave MD. Molecular epidemiology of tuberculosis. N Engl J Med 2003;349:1149-56
used to screen for mutations that are responsible for the FAFLPs. Analysis of data revealed distinct geographic
development of antituberculosis drug resistance. partitioning of Mycobacterium tuberculosis strains across
Multiplex PCR, followed by hybridization on an these countries correlating genomic diversity with a
oligonucleotide microarray (17) or low-density DNA possible geographic evolution. They (19) hypothesized
oligonucleotide array [macroarray] (18) have also been that this might have occurred due to specific genomic
used to detect the DNA of Mycobacterium tuberculosis deletions and substitutions selected rigorously against
complex and to identify mutations associated with host defenses and environmental stresses on an evolu-
isoniazid and rifampicin resistance (6). tionary time-scale (19). Further, it suggests that the
Ahmed et al (19) described the population structure pathogen diversity may be a reflection of the host
and dynamics of Mycobacterium tuberculosis strains for population diversity.
more than hundred independent isolates from 11 W-Beijing genotype is well-known for its rapidity of
different countries by a chromosome-wide scan using spread and tenacity, and notably for its strong association
with multidrug-resistance (20,21). It is highly prevalent MECHANISMS OF DRUG RESISTANCE

in some regions of Asia and Eastern Europe, such as
Tuberculosis cavity usually contains 107 to 109 bacilli.
Estonia, Azerbaijan, and Russia. Outbreaks of drug-
Mutations causing resistance to isoniazid occur in about
resistant TB caused by W-Beijing strain have been
1 in 106 replications, and the mutations causing resistance
described from South Africa as well (22-24). The strains
to rifampicin occur in about 1 in 108 replications, and the
belonging to the W-Beijing family have been shown to
overall the probability of spontaneous mutations causing
exhibit a constant spoligotype and high degrees of
resistance to both isoniazid and rifampicin would be
similarity among IS6110 RFLP, PGRS, RFLP, and variable
106 × 108 which is equal to 1 in 1014 replications (6,7).
numbers of tandem repeats profiles. However, caution
Since this number of bacilli cannot be found even in
must be exercised while interpreting these data as these
patients with extensive cavitary pulmonary TB, the
observations need to be confirmed before definitely
chance of the development of spontaneous dual
linking the clone to the given host population (25).
resistance to rifampicin and isoniazid is very uncommon
Most of our understanding of TB dynamics in popula-
(5-7) and this forms the basis for administration of
tions has been derived indirectly by inference from
multiple drugs for the treatment of TB.
descriptive epidemiological data, as well as from clinical
trials conducted to test the efficacy of antituberculosis
drugs and vaccine immunization programmes. Usually MOLECULAR BASIS OF MULTIPLE
a small number of infected individuals end up with the DRUG-RESISTANCE
disease, also the long incubation period between infection
Predominantly, the molecular basis of drug resistance
and disease makes it difficult to identify source of infection
could be traced to mutations in genes coding for drug
and site of transmission. The diagnosis of TB can be
target proteins (29). However, as an efficient pathogen,
established definitively, only by isolation of Mycobacte-
Mycoobacterium tuberculosis is equipped with several
rium tuberculosis by culture from the individual suspected
defence strategies, including a complex cell wall, drug
of carrying the disease. Microscopic examination of
efflux pumps and multi-functional proteins (29-36).
sputum can detect organisms only when large numbers
Another mechanism for acquiring resistance that has
are present, thus it has sensitivity of no more than 50 to
been documented in other systems, but not yet in
70 per cent compared to culture. Because of high
Mycobacterium tuberculosis, is ‘drug alteration’ (29).
prevalence of TB and widespread use of bacille Calmette-
Guérin [BCG] vaccine, a positive tuberculin skin test [TST]
Rifampicin
does not identify the source or duration of the infection.
The ability to determine transmission links is, thus, limited Resistance to rifampicin is a relatively rare event (37) and
by technology. The integration of molecular methods of leads to selection of mutants that are already resistant to
strain identification with conventional epidemiology can other components of short-course treatment. Therefore,
be used to establish transmission links and to identify rifampicin resistance is often regarded as an excellent
individual and environmental risk factors. With the surrogate marker for MDR-TB (38). The association of
discovery of polymorphic DNA in Mycobacterium the ribonucleic acid [RNA] polymerase β subunit gene
tuberculosis, strain differentiation has become an [rpoB] with resistance to rifampicin has been documented
important tool in the study of epidemiology of TB (26). previously and subsequent reports from various groups
While understanding the molecular basis of drug have confirmed this association in clinical isolates of
resistance is important for development of new drug Mycobacterium tuberculosis (39-41).
targets, it is equally important to understand the relative Introduced in the early 1970s, rifampicin is a lipophilic
virulence and dynamics of multidrug-resistant strains of ansamycin and its efficacy as an antituberculosis drug
Mycobacterium tuberculosis. Multidrug-resistant strains lies in its ability to diffuse across the hydrophobic cell
have to pay a price to attain resistance to drugs for their envelope (39). The ‘ansa’ designation connotes an
survival that comes in terms of highly reduced virulence aromatic centre that is bridged on both the ends by an
and propagation (27). However, Ordway’s study (28) aliphatic chain. The conformational relationship between
reveals no such relationship between virulence and drug the aromatic nucleus and the aliphatic chains is very
resistance. important for microbiologic activity, probably because
686 Tuberculosis
of the interaction of the drug with its target. It is a potent promoter recognition for initiation of transcription. The
inhibitor of DNA dependent RNA polymerase. The RNA subunits α,β,β’ and σ are coded by the rpoA, rpoB, rpoC
polymerase is a multisubunit protein consisting of a core and rpoD genes, respectively (42). Rifampicin binds to
enzyme having four polypeptide chains [α2ββ’]. The the β subunit involved in the initiation and elongation
holoenzyme has an additional subunit ‘σ’ that allows of transcription [Figure 49.2].
Figure 49.2: Schematic representation of development of rifampicin resistance. Mutations in the rpoB leads to conformation change of
the β subunit which fails to bind to rifampicin resulting in rifampicin resistance
RIF = rifampicin; α,β,β’ and σ = subunits of RNA polymerase; rpoB = RNA polymerase gene subunit B; DNA = deoxyribonucleic acid;
mRNA = messenger ribonucleic acid
Rifampicin Resistance novel mutations that have been added to the list of
mutations in the rpoB gene in rifampicin-resistant strains.
The molecular mechanism of rifampicin resistance has
A study from Japan (51) established for the first time a
been thoroughly studied in Escherichia coli and supple-
relationship of these mutations to the level of resistance
mented with genetic studies in early 1980s (43-47).
demonstrated by the strains. Isolates with mutations in
Mutations occurring in a discrete region of rpoB gene
codons 513, 526 and 531 had high levels of drug resistance
were identified and correlated with rifampicin resistance
indicated by minimum inhibitory concentration [MIC]
by several investigators (46-48). This agnate region of
levels of greater than or equal to 50 μg/ml. In contrast,
Mycobacterium tuberculosis rpoB was first cloned and amino acid substitutions located at position 514, 521
sequenced by Telenti et al (49) on the basis of sequence or 533 resulted in low-level resistance [MIC < to
information available from rpoB gene of Mycobacterium 12.5 μg/ml]. These results have been confirmed by other
leprae (49,50). They identified a total of 15 distinct studies (52-54). It is important to mention here that in
mutations clustered in a 23-amino acid stretch [69 bases]. some of the rifampicin-resistant strains studied earlier,
Of the 15 mutations, eight were in the conserved amino no mutation either in the rpoB hotspot or its flanking
acid residues. Essentially, all mutations were missense region were found, suggesting that there must be
with major abundance of amino acid substitution in supplementary molecular mechanisms associated with
either residue 526 or 531 of the rpoB gene. Kapur et al the rifampicin-resistance.
(40) sequenced 121 rifampicin-resistant strains and Systematic studies on rifampicin-resistant strains
concluded that 90 per cent of the rifampicin-resistant related to its epidemiological relevance in India are
strains had sequence alteration in the 69 base pair [bp] urgently required as it has become apparent that there
hotspot that was present within the 350 bp region exists a distinct geographic variation in distribution of
showing considerable polymorphism amongst the mutations in rpoB gene. Siddiqi et al (55) sequenced about
rifampicin-resistant strains. These earlier efforts led to a 93 rifampicin-resistant isolates from various parts of
surprising discovery that certain mutations were India, majority of the samples being from North India.
relatively more abundant in one set of population than Amongst Indian isolates certain novel mutations were
the other, and pointed to geographic partitioning and identified along with the already reported ones. Most
strain divergence amongst the rifampicin-resistant rifampicin-resistant isolates had mutations at codon 531
strains. Subsequent work has documented several other [Figure 49.3]. Of the 93 rifampicin-resistant strains,
Figure 49.3: Summary of mutations at codons 508 to 532 in the rpoB gene. The wild type sequence and amino acids are shown in the
middle frame. Nucleotide changes are marked with arrows in the top frame and the corresponding amino acid changes are denoted in
the bottom frame. The amino acids are subscripted with numbers indicating the number of isolates harbouring the change. Amino acid
changes in squares indicate novel mutations; those in circles are silent mutations
688 Tuberculosis
28 had the missense mutation Ser531Leu and eight had spectrum of action. However, the high frequency of
the substitution Ser531Trp. The next most common spontaneous development of resistance to this drug in
mutations were the amino acid substitutions Asp516Val/ Mycobacterium tuberculosis precludes its use as a single-
Gly [20 isolates] and His526Tyr/Leu/Arg [19 isolates]. agent to treat TB.
Novel mutations included Ser509Arg, Leu511Val,
Asn518Thr, Ser522Gln, Lys527Asn, Arg528Pro and Isoniazid Resistance
Arg528His. Silent mutations included Leu511 and Isoniazid is a pro-drug and is converted into active yet
Leu521. Interestingly, this mutation at position 511 never an unstable electrophilic intermediate that inhibits the
occurred alone and was only present in isolates having biosynthesis of cell wall mycolic acids [long-chain α-
more than one mutation at the rpoB locus in this branched β-hydroxylated fatty acids], thereby making
study (55). An important outcome of the study by Siddiqi the mycobacteria susceptible to reactive oxygen radicals,
et al (55) is the direct correlation of certain mutations in nitric oxide [NO] and other hostile environmental factors
Indian isolates to high MIC values. Mutations in codons presented by the host. The mode of action of isoniazid is
516 and 521 conferred low-level resistance [MIC < 40 μg/ schematically represented in Figure 49.4. The formation
ml] to rifampicin, whereas mutations in codons 510, 526, of active intermediate requires the enzyme catalase-
527, 528 and 531 were seen to confer high levels of peroxidase, coded by the gene katG and an electron sink
resistance [MIC > 64 μg/ml]. The amino acids 526 to [hydrogen peroxide] (60). Therefore, it is apparent that
531 appear to be very important in drug-target mutation in katG gene would lead to isoniazid resistance
interactions, and mutations in them result in MIC levels in Mycobacterium tuberculosis.
in the range of 64 μg/ml and above. In a few cases double Experimental evidence to the mode of action of
mutations were found to have an additive effect on the isoniazid was provided by Middlebrook (61) and Zhang
degree of resistance (55). et al (62,63). These investigators (61-63) directly correlated
the involvement of catalase-peroxidase by restoring
Rifabutin Resistance
isoniazid susceptibility in isoniazid-resistant Mycobacte-
Rifabutin, a derivative of rifamycin S, while most useful rium smegmatis and Mycobacterium tuberculosis by
in the treatment of human immunodeficiency virus [HIV] providing the wild type katG (62). It was observed that
and TB co-infection, can be used in some patients with complete deletion of katG led to the development of high-
rifampicin-resistant TB (56,57). The observation that level resistance [MIC > 50 μg/ml] (63). Furthermore, it
rifabutin was effective only in some patients with was found that a subset of isoniazid-resistant strains of
rifampicin-resistant TB indicated that susceptibility to Mycobacterium tuberculosis had intact katG. Therefore,
rifabutin may depend upon the position and type of major deletions or insertions alone could not be the
mutation in rpoB gene. Bodmer et al (54) quantitatively proper explanation of resistance to isoniazid due to
tested rifampicin, rifabutin and some other antimyco- mutations in katG (64). Later several workers (65-67)
bacterial drugs. They could establish a direct correlation using PCR, single-strand conformation polymorphism
between specific mutations in rpoB and susceptibility to [SSCP] and sequencing, reported the presence of several
rifabutin. They found the strains with Leu-511 → Pro, missense mutations in the gene, the most common being
Asp-516 → Tyr, Asp-516 → Val or Ser-522 → Leu were CGG → CTG [Arg → Leu] at amino acid position 463.
either susceptible [MIC < 0.5 μg/ml] or had low resis- Additional missense mutations identified by them
tance to rifampicin. However, these investigations do included GTG → GCG [fMet → Ala at position 1], GAC
indicate that certain group of patients with rifampicin- → GCC [Thr-275Pro], AGC → ACC [Ser-315Thr] and
resistant TB could possibly be treated with rifabutin CTG → ATG [Leu-587Met], occurring singly or more
(58,59). than one. In a report from India (55), 24 isoniazid-
resistant isolates were analysed for insertions, deletions
Isoniazid and substitution mutations in the katG locus. The
Isonicotinic acid hydrazide [isoniazid], one of the key mutations in the 5' region [nt 3-239] and the mid-region
drugs for the treatment of TB is considered to be an ideal [nt 1187-1600] of the katG gene, corresponding to amino
antimicrobial agent because of its low cost, excellent acid positions 2-77 and 395-533, respectively were
intracellular penetration, bioavailability, and a narrow studied. Figure 49.5 summarizes the mutations observed,
Figure 49.4: Schematic representation of the mode of action of isoniazid

orf1 = open reading frame1; inhA = enoyl acyl-carrier protein reductase; H2O2 = hydrogen peroxide; ahpC = alkyl hydroperoxide reductase;
NADH = reduced nicotinic acid dinucleotide; katG = catalase-peroxidase; acpM = acyl-carrier protein; kasA = β-ketocyl acyl-carrier
protein synthase; ROs = reactive oxyen species
including some of the novel mutations. Apart from previously that this polymorphism in the katG locus
mutations, partial deletion of this locus was also observed might be more important as a marker for evolution than
in six isolates. Mutation Arg-463Leu [CGG → CTG] was resistance (68). However, to the pathogen, loss of
most common, but represented polymorphism amongst catalase-peroxidase activity means susceptibility to
isolates rather than drug resistance. It has been argued organic peroxides and redox stress as catalase-peroxidase
690 Tuberculosis
Figure 49.5: Summary of mutations in the katG gene. Deletions are indicated by a red arrow with minus sign. Insertions are depicted as
blue arrows with a plus sign. Substitutions are shown as black arrows
is the only peroxide-inducible protein of Mycobacterium second position of growing fatty acid chain linked to
tuberculosis (69). Overexpression of alkyl hydroperoxide ACP. This is a common enzyme reaction in long chain
reductase [ahpC] protein that can detoxify organic fatty acid biosynthesis, including mycolic acid biosynthe-
peroxides compensates for this loss. Sherman et al (70) sis in Mycobacterium tuberculosis. The activated
demonstrated that all katG mutant Mycobacterium electrophilic form of isoniazid, isonicotinic acyl anion and
tuberculosis strains overexpressed ahpC protein at isonicotinic acyl radicle, bind with NADH to form
significantly higher levels than isoniazid-sensitive isonicotinic acyl-NADH (73). This modified NADH
strains. Position 39 to 81 bp upstream from the ahpC start cannot participate in NADH-dependent reduction step
codon of each ahpC-upregulated and katG mutant isolate of long chain fatty acid biosynthesis. Resistance to
contained mutations that could increase the promoter isoniazid has been linked to mutations in inhA within or
activity (70). Hence, it was hypothesized that near the NADH binding site, resulting in decreased
compensatory mutations in the ahpC promoters were affinity of inhA for iso-NADH (74,75). Therefore,
selected naturally for survival of katG mutant isoniazid-dependent inhibition of mycolic acid biosyn-
Mycobacterium tuberculosis strains to withstand oxidative thesis in mutated inhA would require very high
stress. There was, however, an apparent inconsistency concentrations of NADH compared to wild type (74,75).
in upregulation of ahpC in katG, such as, ahpC upregula- Thus, there exists a correlation between the ability of the
tion was not observed among Mycobacterium tuberculosis enzyme to bind NADH and to become inhibited by
isolates with katG 315 codon mutations, even though it activated isoniazid. Furthermore, ACP substrates can
resulted in more than a 20-fold decrease in katG activity prevent isoniazid-dependent inhibition of inhA,
and conferred high MIC (66,71). This suggests that there suggesting that activated isoniazid also interacts with the
is more complexity to acquiring isoniazid resistance than substrate binding region of inhA (72,76-78). A ‘T>G’
a simple downregulation of katG and upregulation of transversion, observed in few of the resistant strains, at
ahpC. This also underlined the search for new position 280 [94ser → 94ala] or ‘ATC>ACC’ [Ile-16 →
mechanisms and additional genes involved in isoniazid thr16] in the inhA gene, this alters the binding affinity of
resistance. Banerjee et al (72) identified a locus containing inhA to iso-NAD[H], and ultimately results in isoniazid
two contiguous open reading frames [ORF], orf1 and resistance (66,79). Alternately, hyperexpression of inhA
inhA, that may participate in both resistance to isoniazid could result in weak isoniazid resistance owing to
and ethionamide. titrating out the drug. It has also been observed that, three
The probable role of ORFs, orf 1 and inhA in the causa- isoniazid-resistant isolates carried mutations in the
tion of isoniazid resistance has been schematically ribosomal binding site [RBS] upstream of the inhA gene
explained in Figure 49.4. In detail, two enzyme systems [Figure 49.6]. These mutations, probably, confer
intervene in mycolic acid biosynthesis. One involves resistance by a drug titration effect (55). However, further
reduced form of nicotinamide adenine dinucleotide experiments with mutants along with clinical evidence
[NADH] dependent enoyl acyl-carrier protein [ACP] dismissed the probability of inhA being the primary
reductase [inhA] and other involves 3-oxyacyl ACP- target for the activated form of isoniazid (80).
synthase [kasA]. Enoyl-ACP reductase [inhA] catalyses The activated form of isoniazid binds to the complex
the NADH-dependent reduction of the double bond at of kasA and an ACP called ACP-M. This prevents it from
Figure 49.6: A schematic representation of the mutations identified in the putative ribosomal binding site of the inhA gene. The inhA locus
is composed of two contiguous open reading frames [designated mabA and inhA] which are separated by a 21 bp non-coding sequence
mabA = mycolic acid biosynthesis A [reductase]; inhA = enoylacyl carrier protein reductase; RBS = ribosomal binding site; A = adenine;
G = guanine; T = thymine; C = cytosine
participating in mycolic acid biosynthesis. Mutation in ribosomal protein S12. The latter is involved in the
kasA also leads to isoniazid resistance. It is reported that translation machinery indirectly where it stabilizes the
kasA inhibition is detrimental to Mycobacterium tuberculosis quaternary ‘pseudoknot’ structure of 16S rRNA [Figure
growth, making it an important drug target (81). 49.7] (88,89). Therefore, any mutation in S12 can result
Comprehensively, resistance to isoniazid arises due in altered structure of 16S rRNA preventing binding of
to mutations in the katG (40,82,83) inhA (72,84), ahpC streptomycin, thus, conferring resistance (92).
(85,86), oxidative stress regulator [oxyR] (85,86) and kasA Polymorphism in 16S rRNA due to point mutations
gene loci (81). Broadly, katG and inhA mutations account has been mapped into two discrete regions, the 530 loop
for 70 to 80 per cent of isoniazid-resistant Mycobacterium and the 915 region in Mycobacterium tuberculosis. The A→G
tuberculosis isolates. transition found at 904 along with a missense mutation in
codon 88 of rpsL AAG→CAG [Lys→Gln] had been cor-
Streptomycin related with high resistance to streptomycin [greater than
The antibiotics aminoglycosides, macrolides and 60 μg/ml] (93). It has been shown in a clinical set-up that
tetracyclines target protein translation machinery of the disruption of the 530 loop as a result of either base pairing
pathogen. Streptomycin is an aminocyclitol glycoside between residue 524-526 or loss of adjacent bulge owing
that binds to 16S ribosomal RNA [rRNA] interfering with to base pairing between residue 504-507 results in
proof-reading step in protein translation (87-89). Most streptomycin resistance (94,95). Mutations in the riboso-
of the eubacteria have multiple copies of rRNA operons mal protein subunit 12 [rpsL] gene accounted for more
including 16S rRNA, and therefore, mutations in one than two-third of streptomycin resistant cases (96,97).
copy can be compensated by the active products of other Fourteen isolates resistant to streptomycin were
copies. But slow growing mycobacteria like Mycobacte- checked for mutations in the rpsL and 16S rRNA [rrs]
rium tuberculosis or Mycobacterium leprae have a single loci in one study (55). A novel silent mutation in eight
copy of 16S rRNA, implying that any mutation in these strains at amino acid position 121 in the rpsL locus where
genes would confer resistance to streptomycin (90,91). the codon AAA [Lys] was changed to AAG [Lys], but no
It is important to point out here that streptomycin mutations in the rrs genes were observed [Figure 49.8].
resistance in Mycobacterium tuberculosis arises due to The reported mutations at the rpsL locus are generally
alteration of the target than drug itself. Mutations in two Leu43Arg, Leu43Thr or Lys88Arg. It is still not clear that
target genes are associated with streptomycin resistance how this mutation leads to the development of
in Mycobacterium tuberculosis, the 16S rRNA and streptomycin resistance (55).
692 Tuberculosis
Overall, only two-third of the resistant isolates Ethambutol

sequenced had demonstrable mutations in the above two
loci. This indicates that there are more mechanisms Resistance to ethambutol is a typical case of drug
conferring streptomycin resistance that are yet to be resistance due to over-expression of the target gene. Exact
discovered. mechanism of action of ethambutol is still not known,
Figure 49.7: The secondary structure of the 16S rRNA of Mycobacterium tuberculosis. The mutations in the 530 loop and 904 regions
are marked by arrowheads, and these lead to streptomycin resistance
Figure 49.8: Schematic representation of mutations located in the rpsL gene encoding the S12 protein,
associated with streptomycin resistance in Mycobacterium tuberculosis
although several hypotheses have been put forward susceptible isolates (110). When, epidemiologically
which indicate more than one target for the drug. unassociated organisms alone are considered, 69 per cent
Inhibition of RNA metabolism (98), spermidine synthesis of ethambutol-resistant bacteria had an amino acid
(99), phospholipid biosynthesis (100,101), biosynthesis change in the region of embB studied, and most replace-
of arabinogalactan and transfer of arabinogalactan into ments [89%] occurred at position 306. Structural and
the cell wall of the pathogen are some of the proposed functional association with mutation at position 306 can
mechanisms for ethambutol action. The ethambutol be a promising area to further modify the drug to kill
susceptibility, however, is mainly due to alteration in the ethambutol-resistant Mycobacterium tuberculosis (110).
mycobacterial cell wall structure (102-106) that makes it
susceptible to host generated stress factors. Accumulation Pyrazinamide
of trehalose mono- and di-mycolates in the medium led
Though antimycobacterial properties of pyrazinamide
to hypothesis that ethambutol inhibits transfer of were known since 1952, its utility was realized only
arabinogalactan to cell wall, which could also justify the
during 1980s when it became a crucial part of short-
accumulation of mycolic acid and subsequent change in
course therapy and contributed to the shortening of the
morphology and declumping of mycobacteria after treatment duration from 12 to six months. A structural
ethambutol treatment (100,105). Belanger et al (107)
analog of nicotinamide, pyrazinamide is transported as
identified an operon of three genes in Mycobacterium
a neutral molecule to the cell where the pro-drug form is
avium designated as embC, embA, and embB. The converted into its active form pyrizinoic acid by an
corresponding genes in Mycobaterium tuberculosis are
enzyme pyrazinamidase. Evidence suggesting that
genes embC, embA, and embB (107,108). The embA, and
intrinsic resistance of Mycobacterium bovis to
embB genes encode for arabinosyl transferase III which pyrazinamide was due to absence of the enzyme
is responsible for the polymerization of arabinose into
pyrazinamidase led to the discovery of Mycobacterium
the arabinan of arabinogalactan, the primary cellular
tuberculosis pyrazinamidase [pncA] that had both
target for ethambutol (109). The ubiquity of the pyrazinamidase and nicotinamidase activities (111).
ethambutol-resistance region was investigated by
Sequence polymorphism because of mutations in pncA
Southern blot analysis with genomic DNA from
results in inactive pyrazinamidase and confers resistance
Mycobacterium avium, Mycobacterium smegmatis, to pyrazinamide. The mutations mapped onto
Mycobacterium tuberculosis, and Mycobacterium leprae.
Mycobacterium tuberculosis pncA from clinical isolates
Transposon insertion, however, narrowed down to the
included missense alterations, termination mutations,
fact that the ethambutol resistant phenotype requires nucleotide insertions and deletions [Figure 49.9].
only embA and embB and further, their copy numbers
However, some clinical isolates resistant to pyrazinamide
determined the resistance levels. Mapping of embA and
were found to carry no detectable mutations and were
embB in Mycobacterium tuberculosis showed the presence also checked positive for pyrazinamidase activity (112-
of a secondary stem loop structure between the embA
115). This indicated that polymorphism in pncA could
and the embB genes indicates that the embB gene in
be exploited for screening pyrazinamide-resistant strains,
Mycobacterium tuberculosis could be differentially but could not be considered to be the molecular
regulated (110). The most significant mutation found
mechanism underlining pyrazinamide resistance in all
among ethambutol-resistant isolates was the missense
clinical isolates. Cellular target of pyrazinamide is still
substitution in the conserved embB codon 306 that coded obscure and needs to be further explored.
for methionine (110). Their role in conferring resistance
to ethambutol was confirmed by gene transfer assays
Fluoroquinolones
(110). Mycobacterium tuberculosis strains with Met306Leu
and Met306Val substitutions demonstrated a higher MIC Fluoroquinolones are synthetic derivatives of nalidixic
for ethambutol [40 μg/ml] than those for organisms with acid, a family of antibiotics that inhibit replication of
Met306Ile substitutions [20 μg/ml]. Considerable DNA in permeable cell system (116). Fluoroquinolones
polymorphism was detected in the 1.892 kb of 5’ segment target the bacterial DNA gyrase, an ATP-dependent type
of embB among ethambutol-resistant and ethambutol- II DNA topoisomerase that catalyses the negative
694 Tuberculosis
Figure 49.9: Schematic representation of mutations in pncA associated with pyrazinamide resistance in Mycobacterium tuberculosis
supercoiling of DNA. This enzyme is made up of four

units [α2β2] that are encoded by the gyrA and gyrB genes,
respectively. Fluoroquinolones bind to the gyrase and
inhibit the supercoiling of DNA (117).
The eukaryotic homologue of gyrase, topoiso-
merase II, is less sensitive than gyrase to the quinolones;
making the quinolones clinically useful antibacterials
(118). The gyrA and gyrB genes of Mycobacterium
tuberculosis have been cloned and mutations in the Figure 49.10: A schematic representation of the reported mutations
quinolone binding site have been mapped (119,120). In in gyrA of fluoroquinolone resistant strains of Mycobacterium
subsequent studies the hot spot region for mutations in tuberculosis. The codons 87 to 96 form the hot spot region for
mutations at this locus. The middle panel has the wild type
the gyrA gene was identified. This extends from codon
sequence. The top panel shows the nucleotide mutations and the
81 to 95 and polymorphism at codons’ 87, 90, 91, 94 and bottom panel depicts the corresponding amino acid changes. The
95 are common (121). Figure 49.10 schematically underlined mutations are the novel mutations found in the authors’
represents the reported mutations in gyrA locus. study
Siddiqi et al (55), reported that mutations in gyrA
FAFLP. It revealed unique markers, especially the
could be correlated with high levels of ofloxacin
resistance, while gyrB mutations associated with low characteristic absence of the 383/384 base pair marker
[corresponding to pst C2 gene] in all 52 clinical isolates
levels of resistance in 68 ofloxacin-resistant isolates. It
with a documented ofloxacin resistance pattern in vitro
has been argued that the S95T mutation does not correlate
with drug resistance (68). It, therefore, appears that the [Figure 49.11] (33).
isolates have acquired resistance to ofloxacin via other
Other Anti-mycobacterial Agents
mechanisms (55).
In another study (33), all the 52 ofloxacin-resistant Several other drugs are used to treat drug-resistant TB
isolates mapped for their mutations in gyrA were also and nontuberculous mycobacteria [NTM]. These include
subjected to whole genome microrestriction analysis by ethionamide, kanamycin, capreomycin, viomycin
Figure 49.11: Fluorescent amplified fragment length polymorphism [FAFLP] analysis results comparing ICC154, an ofloxacin-resistant
isolate that also over-expresses a TAP-like efflux pump under drug pressure, to H37Rv. The FAFLP pattern was generated using primers
EcoRI+G/MseI+0 [upper panel], EcoRI+A/MseI+0 [middle panel] and EcoRI+T/MseI+0 [lower panel]. Horizontal scale represents marker
sizes in base pairs while vertical scale shows relative peak heights signifying quantitative variation in PCR products
macrolides [clarithromycin, azithromycin, and roxithro- Mycobacterium fortuitum (133) and Mycobacterium
mycin]. Little is known about the mechanisms of antituberculosis (120,134,135). The genome of Mycobacterium
tuberculosis drug resistance in these agents (121-129). tuberculosis [H37Rv] revealed presence of 20 such
Monotherapy with macrolides had resulted in emergence putative efflux proteins. However, negligible evidence
of resistance, mainly due to point mutations in exists related to their involvement of any of these proteins
domain V of 23S rRNA (128,129). to drug resistance in Mycobacterium tuberculosis. The fact
that many researchers have been unable to relate the level
Drug Efflux Pumps of resistance in multidrug-resistant strains to the
The drug efflux pumps are major contributors to drug mutations in the target genes indicate that like other
resistance in human pathogens and cancer cells. Reports bacteria, Mycobacterium tuberculosis also may have more
on presence of such pumps are available in bacterial than one drug efflux pumps.
pathogens to human cancers. Mycobacterial species are Most bacterial drug-resistant pumps are from the
no exception and there are few reports on the presence major facilitator family of efflux pumps (136). These are
of such pumps in Mycobacterium smegmatis (130-132), membrane translocases and use a proton motive force
696 Tuberculosis
as a source of energy. Few examples of this family include Table 49.1: Molecular mechanisms underlying
TetA, B and C proteins which mediate tetracycline export antituberculosis drug resistance
in Gram-negative bacteria, NorA, a quinolone resistance Drug Genes involved in resistance
protein of Staphylococcus aureus and the multidrug
Group 1 First-line oral
resistance protein [Bmr] from Bacillus subtilis. Another
antituberculosis agents
family of transporters involved in drug efflux is the Isoniazid Enoyl acyl carrier protein [acp]
adenosine triphosphate binding cassette [ABC] trans- reductase [inhA]
porters. These transporters contribute to resistance in Catalase-peroxidase [katG]
eukaryotes and an interesting example of this family is Alkyl hydroperoxide reductase [ahpC]
Oxidative stress regulator [oxyR]
P-glycoprotein (136).
β-Ketocyl acyl carrier protein synthase
Few of the efflux protein genes of Mycobacterium tuber- [kasA]
culosis that have been characterized are ABC-transporter Rifampicin RNA polymerase subunit B [rpoB]
drrABC, efpA and resistance to ethidium bromide [emrE] Pyrazinamide Pyrazinamidase [pncA]
genes. Recently, it was shown that Rv1258c gene of Ethambutol Arabinosyl transferase [emb A, emb B,
Mycobacterium tuberculosis encodes an efflux protein that and emb C]
is similar to Tap protein in Mycobacterium fortuitum and
Group 2 Injectable
confers weak resistance to tetracycline (133). Siddiqi antituberculosis agents
et al (33) have reported a novel and definite association Streptomycin Ribosomal protein subunit 12 [rpsL]
between drug resistance and transcription levels of 16s ribosomal RNA [rrs]
Rv1258c in a multidrug-resistant clinical isolate of Aminoglycoside phosphotransferase
Mycobacterium tuberculosis [ICC154] which possesses a gene [strA]
unique genotypic signature. In another study (126), the Capreomycin Haemolysin [tlyA]*
Mycobacterium bovis P55 gene, located downstream from Group 3 Fluoro- DNA gyrase [gyr A and gyr B]
the gene that encodes the immunogenic lipoprotein P27, quinolones
was characterized (135). The gene was identical to the * The tlyA gene in Mycobacterium tuberculosis encodes a 268-
open reading frame of the Rv1410c gene in the genome amino acid polypeptide, which shows striking similarity to a
of Mycobacterium tuberculosis H37Rv, annotated as a haemolysin/cytotoxin, tlyA, from the spirochete Serpulina
hyodysenteriae
probable drug efflux protein. The presence of specific
markers has implications in rapid identification of
multidrug-resistant clinical isolates and consequent
Table 49.2: Factors implicated in the causation of
disease management
multidrug-resistant tuberculosis
Molecular mechanisms of antituberculosis drug
resistance are summarized in Table 49.1. Factors related to previous treatment
Incomplete and inadequate treatment
Errors in management
POTENTIAL CAUSES OF DRUG RESISTANCE Use of a single drug
Addition of a single drug to a failing regimen
Several factors have been implicated in the causation of
Failure to identify pre-existing resistance
MDR-TB [Table 49.2] and have been discussed in detail Initiation of an inadequate primary regimen
in a recent review (6). The various causes of inadequate Failure to identify and address non-adherence to treatment
treatment are listed in Table 49.3 (138). Inappropriate isoniazid treatment of latent tuberculosis
infection
MULTIDRUG-RESISTANT TUBERCULOSIS Variations in the bioavailability of antituberculosis drugs
Logistic issues
IN THE IMMUNOCOMPROMISED
Lack of good reliable laboratory services
While reports from the early 1990s documented several Virulence of the organism
Host genetic factors
institutional outbreaks of MDR-TB among HIV infected
HLA-DRB1*1, DRB1*14
patients (5-7), it is presently believed that HIV infection HLA-DRB1*0803
per se does not appear to be a predisposing factor for the
development of MDR-TB. However, some studies Source: references 5-9,137
Table 49.3: Causes of inadequate treatment Table 49.4: Predisposing factors for development of
multidrug-resistant tuberculosis in persons with human
Causes Description
immunodeficiency virus infection/acquired immuno-
Lack of political commitment deficiency syndrome
Providers/programmes: Noncompliance with available
Increased susceptibility to TB
inadequate regimens guidelines
Increased opportunity to acquire TB
Absence of guidelines
Overcrowding
Poor training
Exposure to patients with MDR-TB due to increased hospital
Unsupervised treatment
visits
Poorly organized or funded
Malabsorption of antituberculosis drugs
tuberculosis
Inadequate antituberculosis treatment
control programmes
Administration of poor quality drugs
Drugs: inadequate Poor quality Frequent interruption of treatment with antituberculosis drugs and
supply/quality Unavailability of certain drugs antiretroviral drugs
[stockouts or delivery disruptions]
Poor storage conditions MDR-TB = multidrug-resistant tuberculosis; TB = tuberculosis;
Wrong dose or combination
Patients: inadequate Poor adherence [or poor direct
problems with IS6110 typing method (144). Further
drug intake observation of treatment]
Lack of information studies are required to understand these issues.
Lack of money [no free treatment
available] Extensively Drug-resistant Tuberculosis
Lack of transportation
Side effects Extensively drug-resistant TB [XDR-TB] is increasingly
Social barriers being reported from several parts of the world (145-148)
Malabsorption including India (149) during the last two years. Among
Substance abuse disorders immunosuppressed patients, XDR-TB has been asso-
Adapted and reproduced with permission from reference 138 ciated with an exceptionally high mortality with very
few survivors as the treatment options are very few in
these patients. The evolution, case definition and
(139,140) have found that MDR-TB is not more
epidemiological aspects of extensively drug-resistant TB
common among people infected with HIV. Factors
[XDR-TB] have been addressed in the chapter
predisposing for increased chances of MDR-TB occurring
“Antituberculosis drug-resistance surveillance” [Chapter 50].
in persons with HIV infection and AIDS are listed in
Table 49.4 (5-7).
MANAGEMENT
Epidemiological evidence reveals the Mycobacterium
tuberculosis strains infecting HIV patients have a different The treatment of MDR-TB and XDR-TB should be
lineage, clustering pattern and dynamics than those undertaken by experienced clinicians at centres equipped
infecting immunocompetent hosts (141). Comparative with reliable, periodically accredited laboratory services
genomics also showed that Mycobacterium tuberculosis for mycobacterial culture and in vitro sensitivity testing
infecting HIV seropositive and HIV seronegative (5-7,150). In the early reports of outbreaks of MDR-TB in
population are distinct with a maximum genetic distance HIV-co-infected patients in hospitals and prisons, the
of 63 per cent (142). Clonal groupings were observed mortality rate was very high, ranging from 70 to 90 per
among Mycobacterium tuberculosis isolates obtained from cent (5-7). However, subsequent studies have documen-
patients with AIDS. However, isolates from HIV sero- ted better outcome in patients with MDR-TB (5-7).
negative individuals were found to be relatively
heterogeneous and nonclonal. Earlier reports by Yang Principles of Management
et al (143), however, could not show any significant
Need for Standard Definitions
differences between the IS6110-based genotypes of HIV-
1-associated isolates and those from immunocompetent No randomized, controlled trials exist addressing the
patients in Tanzania. This may be attributed to inherent issue of the optimal management strategy for MDR-TB
698 Tuberculosis
and XDR-TB. The standardization of definitions for Principles of Treatment

MDR-TB case registration and treatment outcomes
would permit the accumulation of evidence and would When a patient is suspected to have drug-resistant-TB,
facilitate cross-programme comparisons. Table 49.5 lists the sputum, body fluidm, secretion must be subjected to
the standard definitions that are useful in the mycobacterial culture and antituberculosis drug-
management of patients with MDR-TB (151). sensitivity testing [DST]. Depending on the scenario
Table 49.5: Treatment outcome definitions for patients with multidrug-resistant tuberculosis
New MDR-TB patients
MDR-TB patients who have never received TB treatment, or who have received TB treatment for less than 1 month
MDR-TB patients previously treated with only first-line drugs

MDR-TB patients who were treated for more than 1 month with only first-line antituberculosis drugs*†
MDR-TB patients previously treated with second-line drugs

MDR-TB patients who were treated for more than 1 month with at least one second-line antituberculosis drug [with or without first-line
drugs] †
Transfer-in
MDR-TB patients who have been transferred from another DOTS-Plus register to continue treatment. Their outcomes should be
reported to the transferring unit so they can report their outcomes in the cohort in which they originally started MDR-TB treatment
Others
Includes MDR-TB patients who were treated outside DOTS programmes
Cure
An MDR-TB patient who has completed treatment according to country protocol and has been consistently culture-negative [with at
least 5 results] for the final 12 months of treatment‡
Treatment completed
An MDR-TB patient who has completed treatment according to country protocol but does not meet the definition for cure or treatment
failure due to lack of bacteriologic results [i.e., fewer than 5 cultures were performed in the final 12 months of treatment]
Death
An MDR-TB patient who dies for any reason during the course of MDR-TB treatment
Treatment default
An MDR-TB patient whose MDR-TB treatment was interrupted for 2 or more consecutive months for any reason
Treatment failure
Treatment will be considered to have failed if 2 or more of the 5 cultures recorded in the final 12 months are positive, or if any one of the
final 3 cultures is positive. Treatment will also be considered to have failed if a clinical decision has been made to terminate treatment
early due to poor response or adverse events
Transfer-out
An MDR-TB patient who has been transferred to another reporting and recording unit and for whom the treatment outcome is unknown
* It may also be useful to note if patients received a re-treatment regimen

† Patients should be further defined by the outcome of the most recent previous treatment: failure, return after default, relapse, or
transfer-in
‡ A positive culture requires more than 10 colonies on solid media; 2 consecutive positive cultures must be obtained if, less than
10 colonies are detected in the first culture; if the second culture also contains less than 10 colonies, the culture should be interpreted
as positive. If only one positive culture is reported during that time, and there is no concomitant clinical evidence of deterioration, a
patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive negative
cultures, taken at least 30 days apart
TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis
where the patient is being cared for, these patients should DOTS-Plus Strategy
be started on WHO Category II treatment (152) or the
While DOTS is a key ingredient in the TB control strategy,
regimens suggested by the American Thoracic Society
it has been found to be inadequate in populations where
[ATS], the Centers for Disease Control and Prevention
MDR-TB is endemic (158). The WHO and its inter-
[CDC], and the Infectious Diseases Society of America
national partners have been evolving the “DOTS-Plus
[IDSA] (153) while the mycobacterial culture and
for MDR-TB programmes” [Table 49.7] to facilitate the
sensitivty report is awaited. Further therapy is guided
programmatic treatment of MDR-TB in low- and middle-
by the culture and sensitivity report. The treatment
income countries that have adopted the DOTS strategy.
options are shown in Figure 49.12.
The Green Light Committee is a unique partnership
A single drug should never be added to a failing
established by the WHO to lower the prices of and to
regimen. Drugs with potential for cross-resistance should
increase control over second-line antituberculosis drugs
not be used. At least three previously unused drugs to
and close to 50 DOTS-Plus projects are underway across
which there is in vitro susceptibility must be employed
the globe (5,6,159-162).
when initiating treatment (153,154). Recent publications
The Revised National Tuberculosis Control
(155,156) suggest moxifloxacin to be the most potent
Programme [RNTCP] of the Government of India has
among the currently available fluoroquinolones.
also initiated the DOTS-Plus strategy (138,163). In this
The results of a study from Peru (157) suggest that
strategy, 24 RNTCP state level Intermediate Reference
community-based outpatient treatment of patients with
Laboratories [IRLs], accredited to perform culture and
MDR-TB is possible with high cure rates even in resource-
DST are being set up. The RNTCP has initiated the
poor settings.
establishment of the IRLs network in a phased manner
Various drugs that are currently being used for the
across the country, with support from the four National
treatment of MDR-TB are listed in Table 49.6 (6,7,154).
Reference Laboratories at Chennai, Bengaluru, New
The reader is also referred to the chapters “Evolution of
Delhi, and Agra. The treatment of MDR-TB patients is
chemotherapeutic regimens in the treatment of tuberculosis
planned to begin at DOTS-Plus sites established in a
and their scientific rationale” [Chapter 51] and “Treatment
limited number of highly specialized centres, at least one
of tuberculosis” [Chapter 52] for more details regarding
in each state. On the 29th of August 2007, Gujarat became
the adverse drug reactions and other treatment issues
the first state in the country to initiate MDR-TB patients
related to these drugs.
on treatment under RNTCP with its Category IV regimen
(163). Subsequently, another pilot study of MDR-TB
treatment has started in the State of Maharashtra. The
programme is expected to cover the whole country in a
phased manner.
The principles underlying constitution of individuali-
sed regimens design based on DST for first-line
antituberculosis drugs suggested by the WHO are shown
in Tables 49.8A and 49.8B (164). The recommended
duration of treatment is guided by smear and culture
conversion. The minimal suggested duration is for at least
18 months after culture conversion. Extension to 24
months may be indicated in patients defined as “chronic
cases” (6,7,153,154) with extensive pulmonary damage.
Figure 49.12: Treatment strategies for multidrug-resistant The Category IV regimen used in the RNTCP (138,
tuberculosis 163,164) comprises of six drugs, kanamycin [K], ofloxacin
DRS = drug resistance surveillance; DST = drug sensitivity testing
(Ofl), ethionamide [Eto], pyrazinamide [Z], ethambutol
Reproduced with permission from “World Health Organization.
Guidelines for the programmatic management of drug-resistant [E] and cycloserine [Cs] during six to nine months of the
tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health intensive phase and four drugs [ofloxacin, ethionamide,
Organization; 2006 (reference 154)” ethambutol and cycloserine] during the 18 months of the
700 Tuberculosis
Table 49.6: Antituberculosis drugs used in the treatment of multidrug-resistant tuberculosis
Drug Daily dosage
Group 1 First-line oral antituberculosis agents

Pyrazinamide 20-30 mg/kg [1200 to 1600 mg]
Ethambutol 15-20 mg/kg [1000 to 1200 mg]
Group 2 Injectable antituberculosis agents
Capreomycin* 15 mg/kg [750-1000 mg]
Kanamycin 15 mg/kg [750 to 1000 mg]
Amikacin 15 mg/kg [750 to 1000 mg]
Group 3 Fluoroquinolones†
Ofloxacin 7.5-15 mg/kg [600 to 800 mg]
Levofloxacin 500 to 1000 mg
Gatifloxacin 400 mg
Moxifloxacin 400 mg
Group 4 Oral bacteriostatic second-line
antituberculosis drugs
Thioamides‡
Ethionamide 10-20 mg/kg [500 to750 mg]
Prothionamide 10-20 mg/kg [500 to 750 mg]
Cycloserine 15-20 mg/kg [500 to 750 mg]
Terizodone§ 15-20 mg/kg [600 mg]
Para-aminosalicylic acid [PAS] 150 mg/kg [10 to12 g]
* No cross-resistance with other aminoglycosides, such as kanamycin, streptomycin

† Currently, the most potent available fluoroquinolones in descending order based on in vitro activity and animal studies are: moxifloxacin
= gatifloxacin > levofloxacin > ofloxacin = ciprofloxacin. Moxifloxacin is better tolerated and causes fewer adverse events as compared
with other fluoroquinolones
‡ Chemical structure resembles thioacetazone with which there is frequent and partial cross-resistance. However, strains resistant to
thioacetazone are often sensitive to thioamides, but the reverse is seldom the case. More acceptable if it is administered with orange
juice or milk, or after milk, or at bedtime to avoid nausea
§ Terizidone is a combination of two molecules of cycloserine
Table 49.7: Components of DOTS-Plus strategy Similarly, details regarding the management of MDR-
TB in special situations, such as renal failure, pregnancy,
Sustained political and administrative commitment
base, line hepatic dysfunction, among others is also too
Accurate, timely diagnosis through quality-assured culture and
drug susceptibility testing
technical for the general reader who is, anyway, not
Uninterrupted supply of quality assured first-and second-line
expected to undertake the management of MDR-TB on
drugs; appropriate treatment strategies utilizing second-line drugs an individual basis. The interested reader is, therefore,
under strict supervision referred to the websites of the WHO (154), or, the Central
Directly observed treatment TB Division, Ministry of Health and Family Welfare,
Standardized recording and reporting system that enables Government of India (138,163,164) for the latest details
performance monitoring and evaluation of treatment outcome on this topic.
The results from the retrospective study (165) of
continuation phase. Para-aminosalicylic acid [PAS] is MDR-TB patients [n = 204], treated under the Latvian
included in the regimen as a substitute drug if any DOTS-Plus strategy following WHO guidelines, have
bactericidal drug [K, Ofl, Z and Eto] or any two bacterio- been encouraging; 66 patients were cured or completed
static [E and Cs] drugs are not tolerated. treatment, seven per cent died, 13 per cent defaulted,
The details regarding the clinical, microbiological and and 14 per cent did not respond to treatment. Data on
radiological follow-up protocol and schedule are too adverse drug reactions [ADRs] collected from five DOTS-
exhaustive and cumbersome to be listed in this chapter. Plus sites in Estonia, Latvia, Peru, the Philippines, and
Table 49.8A: Suggested regimens for mono- and poly-drug resistant tuberculosis
other than multidrug-resistant tuberculosis
Pattern of drug Suggested regimen Minimum duration of Comments

resistance treatment [months]
H [± S] R, Z and E 6-9 A fluoroquinolone may strengthen the

regimen for patients with extensive disease
H and Z R, E and fluoroquinolones 9-12 A longer duration of treatment should be
used for patients with extensive disease
H and E R, Z and fluoroquinolones 9-12 A longer duration of treatment should be
used for patients with extensive disease
R H, E, fluoroquinolones, plus 12-18 An injectable agent may strengthen the
at least 2 months of Z regimen for patients with extensive disease
R and E [± S] H, Z, fluoroquinolones, plus an 18 A longer course [6 months] of the injectable
injectable agent for at least agent may strengthen the regimen for
the first 2-3 months patients with extensive disease
R and Z [± S] H, E, fluoroquinolones, plus an 18 A longer course [6 months] of the injectable
injectable agent for at least agent may strengthen the regimen for
the first 2-3 months patients with extensive disease
H, E, Z [± S] R, fluoroquinolones, plus an 18 A longer course [6 months] of the injectable
oral second-line agent, plus an agent may strengthen the regimen for
injectable agent for the first patients with extensive disease
2–3 months
H = isoniazid; S = streptomycin; R = rifampicin; Z = pyrazinamide; E = ethambutol

Table 49.8B: Suggested regimens for multidrug-resistant tuberculosis

Pattern of drug resistance Suggested regimen Comments
H-R Z-E-injectable agent-fluoroquinolone One Group 4 agent is sufficient if E and Z susceptibility

[± one or two Group 4 agents]* has been ascertained. Two Group 4 agents* should be
used in extensive disease, or if the DST result is
questionable [i.e., reported susceptibility to E or Z
despite a history of these agents being used in a failing
regimen]
H-R [± S] and E or Z Z or E-injectable agent-fluoroquinolone Only use the first-line agents to which the patient’s strain
[± two or more Group 4 agents]* is susceptible. Use alternative injectable agent if S
resistance is present. More than two Group 4 agents
should be used in extensive disease or if resistance to
E and Z is present or suspected
Group 5 agents† can be considered if an adequate
regimen of four drugs cannot be formed based on DST
H = isoniazid; R = rifampicin; S = streptomycin; Z = pyrazinamide; E = ethambutol; DST = drug sensitivity testing

* Group 4 agents = ethionamide [Eto]; prothionamide [Pto]; cycloserine [Cs]; terizidone [Trd]; para-aminosalicylic acid [PAS];
thioacetazone [Th].
† Group 5 agents = clofazimine [Cfz]; amoxycillin/clavulanate [Amx/Clv]; clarithromycin [Clr]; linezolid [Lzd]
702 Tuberculosis
the Russian Federation (166) showed that, among 818 Global Experience in the Management of Drug-
patients enrolled for MDR-TB treatment, only two per resistant Tuberculosis
cent of patients stopped treatment and 30 per cent
required removal of the suspected drugs from the Multidrug-resistant Tuberculosis
regimen and use of alternative drugs due to ADRs. In the early reports of outbreaks of MDR-TB in HIV-
co-infected patients in hospitals and prisons, the
Monitoring Response to Treatment mortality rate was very high, ranging from 70 to 90 per
Patients receiving treatment for MDR-TB should be cent (5-7). However, subsequent studies have documen-
closely followed up. Clinical, radiological, laboratory, ted better outcome in patients with MDR-TB [Table
and microbiological parameters should be frequently 49.9A] (168-190). These results suggest that community-
reviewed to assess the response to treatment. Addi- based outpatient treatment of patients with MDR-TB is
tionally, considerable attention must be focussed on possible with high cure rates even in resource-limited
monitoring the ADRs (5-7). settings.
Table 49.9A: Global experience in the treatment of drug-resistant tuberculosis
Study Year of Type of Treatment Outcome

(reference) publication DR-TB
Goble et al (167) 1993 MDR-TB [n = 171] Antituberculosis drugs, Of 134 patients with sufficient
individualized treatment + follow-up data, cured 65%,
resective surgery [n = 9] treatment failure 35%
Telzak et al (168) 1995 MDR-TB [n = 25] Antituberculosis drugs, Clinical response 96%; all 17
individualized treatment + patients for whom data were
resective surgery [n = 3] available had microbiologic response
Sharma et al (10) 1996 MDR-TB [n = 19] Antituberculosis drugs, Sputum conversion in 18 of the
individualized treatment 19 patients
Viskum et al (169) 1997 1998 [n = 8] Antituberculosis drugs, 8 of the 9 patients responded
individualized treatment favourably to treatment; 1 patient died
Park et al (170) 1998 MDR-TB [n = 107] Antituberculosis drugs, Of 63 patients with sufficient
individualized treatment + follow-up data, cured 82.5%, treatment
resective surgery [n = 22] failure 17.5%
Avendano et al (171) 2000 MDR-TB [n = 40] Antituberculosis drugs , Bacteriological conversion achieved
individualized treatment + in 85%, died 12%
resective surgery [n = 6]
Geerligs et al (172) 2000 MDR-TB [n = 44] Antituberculosis drugs, Cured 75%, death 14%
individualized treatment +
resective surgery [n = 6]
Yew et al (173) 2000 MDR-TB [n = 63] Antituberculosis drugs, Cured 81%, treatment failure
individualized regimen 14.3%, death 4.7%
Kim et al (174) 2001 MDR-TB [n = 1011] Antituberculosis drugs, Cured 48%, treatment failure
individualized treatment 8.1%, default 39%, transferred
out 4.3%, death 0.3%
Tahaoglu et al (175) 2001 MDR-TB [n = 158] Antituberculosis drugs, Cured or completed treatment
individualized treatment + 77%, default 11%, treatment
resective surgery [n = 36] failure 8%, death 4%
Suarez et al (176) 2002 Chronic TB [n = 466] Antituberculosis drugs, Cured 48%, treatment failure
Of these 298 Standard empirical treatment 28%, default 11%, death 12%
had MDRTB
-Contd-
Table 49.9A -Contd-
Study Year of Type of Treatment Outcome

(reference) publication DR-TB
Mitnick et al (177) 2003 MDR-TB [n = 75] Antituberculosis drugs, Among the 66 patients who completed
individualized treatment + 4 or more months of therapy, cured or
resective surgery [n = 3] completed treatment 83%, death 8%
Narita et al (178) 2001 MDR-TB [n = 81] Antituberculosis drugs Completed treatment 57%,
default 41%, death 32%
Leimane et al (165) 2005 MDR-TB [n = 204] Antituberculosis drugs, Cured or completed therapy
individualized treatment regimen 66%, treatment failure 14 %,
default 13%, death 13%
Nathanson et al (179) 2006 MDR-TB [n = 1047] Antituberculosis drugs, Cured or completed treatment
individualized treatment regimen 69.7%, treatment failure 6.7%,
+ resectional surgery [n = 114] default 10.5%, death 13%
Gandhi et al (180) 2006 XDR-TB [n = 53] Antituberculosis drugs 52 of the 53 patients died
TRC, Chennai (181) 2007 MDR-TB [n = 65] Antituberculosis drugs, Cured 38%, treatment failure
XDR-TB [n = 1] individualized treatment regimen 26%, default 24%, death 12%
Sharma (182) 2007 MDR-TB [n = 172] Antituberculosis drugs, Cured 41.6%, treatment
XDR-TB [n = 1] individualized treatment regimen failure 38.7%, default 15%, death 4.6%
Dhingra et al (183) 2008 MDR-TB [n = 27] Antituberculosis drugs, 13 patients were cured, 10 defaulted,
individualized treatment regimen one died, and 1 was still under treatment
Shean et al (184) 2008 MDR-TB [n = 491] Antituberculosis drugs, Cured or completed treatment
individualized treatment regimen 49%, death 14%, default
29%, treatment failure 5%
Masjedi et al (185) 2008 MDR-TB [n = 43] Antituberculosis drugs, Cured or completed treatment 67.5%,
individualized treatment regimen treatment failure 14%, death 18.6%
Mitnick et al (186) 2008 XDR-TB [n = 48] Antituberculosis drugs, 60.4% patients with XDR-TB
MDR-TB [n = 603] individualized treatment regimen completed treatment or were cured
+ resectional surgery [n = 94; 7 66.3% patients with MDR-TB
patients with XDR-TB and 87 completed treatment or were cured
patients with MDR-TB]
Bonilla et al (187) 2008 XDR-TB [n = 43] Antituberculosis drugs Cured or treatment completed
individualized regimen [n = 37], 49%, treatment failure 14%,
standardized regimen [n = 6] default 19%, death 19%
Kwon et al (188) 2008 XDR-TB [n = 27] Antituberculosis drugs, Overall, cured or completed treatment
MDR-TB [n = 128] individualized regimen 66%, default 10%, treatment failure
+ resectional surgery [n = 35; 22 14%, death 6%
patients with MDR-TB, 13 Treatment success rate [cured or
patients with XDR-TB] completed treastment] was similar
among patients with
MDR-TB [66%] and XDR-TB [65%]
Banerjee et al (189) 2008 XDR-TB [n = 18] Antituberculosis drugs, Among 17 patients with XDR-TB with
MDR-TB [n = 406] individualized regimen known outcomes, 41.2% completed
treatment, 29.4% died, 1 patient
continues to receive treatment
Keshavjee et al (190) 2008 XDR-TB [n = 29] Antituberculosis drugs Among patients with XDR-TB cured or
MDR-TB [n = 579] individualized regimen treatment completed 48·3%,
treatment failure 31%
Among patients with MDR-TB,
cured or treatment completed
66·7%, treatment failure rate 8.5%
DR-TB = drug resistant tuberculosis; MDR-TB = multidrug-resistant tuberculosis; TRC = Tuberculosis Research Centre; XDR-TB =
extensively drug-resistant tuberculosis
704 Tuberculosis
Extensively drug-resistant Tuberculosis to correct remediable factors, such as malnutrition

(6,7,157,165,167,168,175,191).
Initial reports documenting XDR-TB were associated
with an exceptionally high mortality rate. In the outbreak Newer Antituberculosis Drugs
that occurred in a rural area in KwaZulu Natal Province
in South Africa in (180), 52 of 53 patients with XDR-TB Following the introduction of rifampicin, no worthwhile
antituberculosis drug with new mechanism[s] of action
died. Forty four of the XDR-TB patients tested were HIV-
has been developed in the last three decades. Some of
seropositive. The median survival was 16 days from the
the older drugs that are being evaluated again and the
time of diagnosis among the 42 patients with confirmed
newer drugs with potential as antituberculosis agents
dates of death. However, subsequently published data
that are at various stages of development are listed in
[Table 49.9A] suggest higher cure rates.
Table 49.10.
Prognostic Markers Surgery

Table 49.9B summarizes markers of poor prognosis in The role of surgery in the management of MDR-TB is
patients with MDR-TB. Recognition of these factors may discussed in detail in the chapter “Surgery for pleuropulmo-
help clinicians to monitor the patients more closely and nary tuberculosis” [Chapter 55].
Table 49.9B: Markers of poor prognosis in patients with multidrug-resistant tuberculosis

Study Year of No. of subjects Markers of poor prognosis
publication [% HIV-positive]
Park et al (170) 1996 173 [52] Extra-pulmonary involvement

Telzak et al (168) 1999 156 [100] History of prior tuberculosis treatment
Flament-Saillour et al (191) 1999 51 [16] HIV-coinfection, treatment with less than two active drugs,
and knowledge regarding the multidrug-resistant status at
the time of diagnosis
Tahaoglu et al (175) 2001 158 Older age, history of previous treatment with a larger number
of drugs
Drobniewski et al (192) 2002 90 [29]* Immunocompromised status, failure to culture the bacterium
in 30 days or to apply appropriate treatment with three drugs
to which the organism is susceptible, and age
Mitnick et al (177) 2003 75 [1.5%]† Low haematocrit and resistance to pyrazinamide or
ethambutol
Leimane et al (165) 2005 204 [0.5]‡ Previous treatment for MDR-TB, the use of five or fewer drugs
for > 3 months, resistance to ofloxacin, BMI <18·5 at start of
treatment
Holtz et al (193) 2006 167 Treatment outcomes were statistically significantly worse for
patients who did not convert their sputum culture within
2 months. Previous treatment for MDR-TB, high initial sputum
culture colony count, bilateral cavitations on chest radiography,
and the number of drugs the initial isolate was resistant to at
treatment initiation were independent predictors of delayed
sputum conversion
* 23 of the 79 patients tested had HIV infection

† 1 of the 65 patients tested had HIV infection
‡ 1 of the 197 patients tested had HIV infection
HIV = human immunodeficiency virus; BMI = body-mass index [kg/m2]; MDR-TB = multidrug-resistant TB
Updated and adapted from reference 6
Table 49.10: Older drugs and newer agents potentially it is generally believed that malnourished patients are at
useful for the treatment of multidrug-resistant tuberculosis a greater risk of developing post-operative complication.
Older drugs Nutritional assessment and regular monitoring of the
Rifmaycin derivatives nutritional state by a dietician are essential for the
Rifapentine successful management of MDR-TB patients and should
Rifabutin be an essential part of such programmes.
Fluoroquinolones
Ofloxacin
Sparfloxacin POST-GENOMICS EFFORTS TO UNRAVEL
Levofloxacin THE MYSTERIES OF MYCOBACTERIUM
Moxifloxacin TUBERCULOSIS
Gatifloxacin
Newer drugs Mycobacterium tuberculosis is a unique human pathogen
Diarylquinoline with extraordinary capacity to adapt and evolve. It was
R207910/TMC207 almost believed that TB has been conquered with the
Nitroimidazopyran initial discovery of five to six antituberculosis drugs.
PA-824
Today, TB has resurfaced with strains resistant to almost
Nitro-dihydroimidazo-oxazole
OPC 67683 all the drugs available in the market. Co-infection with
Pyrrole HIV-TB remains to be a pestilent combination threaten-
LL3858, LL3522 ing human efforts at TB control.
Macrolides Therefore, it is not surprising that the genetic make
Clarithromycin up of such an organism revealed extraordinary evidences
Telithromycin
of gene duplication, functional redundancy, diversifica-
Oxazolidinones
Linezolid tion, and families of proteins exclusive to itself conferring
PNU-100480 antigenic variation and host immune evasion. The post-
Diamine genomics era that has followed the whole genome
SQ109 sequencing of Mycobacterium tuberculosis is flooded with
Ring substituted imidazoles
information that can be harnessed into an integrated and
Other agents
Thalidomide multidisciplinary science combining transcriptomics,
Pentoxifylline proteomics with structural and functional genomics, with
Levamisole explicit aims of identifying novel drug targets and
Transfer factor developing new therapeutic regime against TB (194).
Inhibitors of transforming growth factor-β [TGF-β] So far, against one successful drug in the market,
Interleukin-12 [IL-12]
thousands molecules are eliminated as failures. This ratio
Interferon-α [IFN-α]
Imiquimod [an oral agent which stimulates the production of success to failure can be dramatically changed by
of IFN-α] harnessing the present genome information. Extensive
progress has been made in comparative genomics and
Based on references 6,7
proteomics that revealed existence of a gene gradient
amongst mycobacterial species and 16 regions of deletion
Nutritional Enhancement [RD] that varied from strain to strain, redefining the
The degree of cachexia is most profound when MDR-TB genealogy and relatedness of virulent and avirulent
occurs in patients with HIV infection and AIDS. Several strains. Absence of RD1 in BCG as compared to other
second-line drugs used to treat MDR-TB, such as PAS, members of Mycobacterium tuberculosis complex could
fluoroquinolones, cause significant anorexia, nausea, account for the attenuation and hence these ORFs could
vomiting and diarrhoea interfering with food intake, be a probable answer to the virulence of pathogenic
further compromising the cachectic state. Therefore, mycobacteria (195,196). Genomic organization studies
nutritional support is a key factor in the care of patients have also revealed that PE and PPE are not only unique
with MDR-TB, especially those undergoing major lung families of proteins in Myobacterium tuberculosis, but
surgery. Though definitive evidence is not yet available, also have specific organization that has functional
706 Tuberculosis
consequences (197). Also substantial genetic diversity TREATMENT OF LATENT MULTIDRUG-RESISTANT

amongst the BCG strains could explain the variability TUBERCULOSIS INFECTION
observed in different vaccine trials against TB and
The TST has been used for the detection of latent TB
provoked the quest for a better vaccine supported by the
infection conventionally. However, the newer interferon-
inputs from comparative proteomics. ‘Lipogenomics’, a
gamma based assays have shown considerable promise
relatively new field, conceived by the existing genetic
in the diagnosis of latent MDR-TB infection. The reader
information has revealed involvement of 250 genes in
is referred to the chapter “Diagnosis of latent tuberculosis
fatty acid biosynthesis in Mycobacterium tuberculosis as
infection: recent advances and future directions” [Chapter 12].
against only 50 in Escherichia coli emphasizing the For contacts thought to be infected with multidrug-
importance of the cell envelope in pathogenesis of resistant isolates of Mycobacterium tuberculosis, no
tubercle bacilli, making it a significant component of satisfactory chemoprophylaxis is available (202). There
systematic studies for drug development (198). Similarly, is no consensus regarding the choice of the drugs and
a set of potent T-cell and B-cell antigens have been the duration of treatment either. The CDC has put forth
recognised that can serve as potential immunogens for guidelines (203,204) for the management of persons
early detection and differentiation of the diseased from exposed to MDR-TB. The two suggested regimens for
BCG vaccinated healthy population. A global approach the treatment of latent MDR-TB infection are as follows:
pertaining to issues related to latency, persistence, [i] pyrazinamide [25 to 30 mg/kg daily] plus ethambutol
containment in granulomas largely relied on signature- [15 to 25 mg/kg daily]; or [ii] pyrazinamide [25 to 30
tagged mutagenesis for genome scale examination of mg/kg daily] plus a quinolone with antituberculosis
phenotypes contributing to virulence. These mutations activity [e.g., levofloxacin or ofloxacin]. The recom-
could be traced to non-lethal, yet persistence factors in mended duration of therapy is 12 months for those
Mycobacterium tuberculosis genome. These approaches patients with underlying immunosuppression and at
have revealed a plethora of mechanisms presented by least six months for all other patients. All patients should
the pathogen to evade host immunity and develop drug be closely observed for at least two years, and a low
resistance. These include iron trafficking (199), cyclic threshold for referral to a centre with experience in
adenosine monophosphate [CAMP] receptor protein as managing MDR-TB should be maintained (203,204).
stress regulator (200,201), among others. Several These issues merit further study in randomized
important techniques, such as microarrays, subtractive controlled studies.
hybridization, signature-tagged mutagenesis, comple-
mentation and selective capture of transcribed sequences PREVENTION OF TRANSMISSION OF
[SCOTS], have been facilitated by the available genomic MULTIDRUG-RESISTANT TUBERCULOSIS
information for elucidating the details of host-pathogen
The prevention of transmission of MDR-TB in health care
interactions, intracellular metabolism, latency, drug-
settings is covered in the chapter “Tuberculosis in health
actions and antigenic variations. Thus, a hitherto
care workers [Chapter 45]”.
unknown and mysterious organism, Mycobacterium
tuberculosis, could be better understood in terms of its
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714 Tuberculosis
Antituberculosis Drug
Resistance Surveillance
50
CN Paramasivan, VH Balasangameshwara
INTRODUCTION The level of initial drug resistance is said to provide

an epidemiological indicator to assess the amount of
With the discovery of streptomycin in the 1940s and
resistant bacterial transmission in a community, as well
isoniazid in the 1950s, chemotherapy became the
as the success or otherwise of the National Tuberculosis
standard method of treatment of tuberculosis [TB]. In
Programme [NTP]. Further, this influences the design of
the early years of the chemotherapy era, it was found
therapeutic regimens, as well as policy decisions (3).
that treatment with a single drug resulted in the
Hence, reliable data on the levels of drug resistance over
development of drug resistance in a high proportion of
the years in various parts of the country would be of great
the patients, with a consequent loss of efficacy of treat-
value.
ment. Hence, combined chemotherapy with two or more
Vigorous implementation of a multi-pronged
drugs given together became the standard practice. At
approach in the treatment of TB resulted in a decline in
present fixed-dose combinations, where two or three
the prevalence of drug resistance in Korea (4) and New
drugs are incorporated in a single tablet or capsule, are
York city (5) in recent years. The information on drug
also widely available. Despite all these advancements,
there was a dramatic increase in the level of initial drug resistance in India is available from well-conducted
resistance in most of the disease endemic countries. studies for only a small proportion of population; the
The response to treatment in patients with multidrug- prevalence of drug resistance in these settings has
resistant Mycobacterium tuberculosis [defined as resistance remained almost static. In many of the drug resistance
to rifampicin and isoniazid, with or without resistance surveys conducted earlier in India, small or non-repre-
to other antituberculosis drugs is very poor and the sentative samples have been studied. Also, there has been
mortality rate is high. Since these patients have to be no clear distinction between primary and acquired
treated with several toxic and expensive second-line resistance, as the history of previous treatment was not
antituberculosis drugs, and may need prolonged hospi- obtained. Despite such limitations, an attempt has been
talization to manage drug toxicity and other complica- made to give an overview of the prevalence of drug
tions, they account for a significant proportion of the resistance in India over the last three decades.
health care resources (1). For the purpose of drug resistance surveillance [DRS]
In recent years, the incidence of human immuno- in TB, the definitions of primary drug resistance and
deficiency virus [HIV] infection has increased enor- acquired drug resistance have been revised by the World
mously all over the world. Patients with HIV infection Health Organization [WHO] and International Union
are known to have an increased risk of developing TB. Against Tuberculosis and Lung Disease [IUATLD] as
The case fatality rate is high in patients with the acquired ‘resistance among new cases’ and ‘resistance in pre-
immunodeficiency syndrome [AIDS], who have associa- viously treated patients’(6). ‘Resistance among new cases’
ted multidrug-resistant tuberculosis [MDR-TB] (2). is defined as ‘the presence of resistant strains of
Antituberculosis Drug Resistance Surveillance 715
Mycobacterium tuberculosis in a patient who, in response literature search suggests high levels of resistance in some
to direct questioning, denies having had any prior areas. However, many of these studies were not based
antituberculosis treatment [for more than one month], on representative samples and failed to distinguish
and, in countries where adequate documentation is between patients who had received antituberculosis
available, for whom there is no evidence of such history’. treatment in the past and those who had not. Further,
For the purpose of surveillance ‘resistance in a previously there was no consensus on definitions and laboratory
treated patient’ is defined as the presence of resistant results were not standardized. The major limitation for
strains of Mycobacterium tuberculosis in a patient who, in the adequate assessment of drug resistance was the
response to direct questioning, admits having been inadequate culture and DST facilities in many parts of
treated for TB for one month or more, or, in countries the world. All these limitations prevented an exact assess-
where adequate documentation is available, in a patient ment of the magnitude of the problem worldwide and
for whom there is evidence of such a history. meaningful comparison of data among various countries.
Since 1994, several countries have established Global project on antituberculosis drug resistance in
National Tuberculosis DRS projects. Those projects have the world represented a coordinated international effort
adopted a standardized methodology for susceptibility (8). It served as a model for surveillance of drug resistance
testing with the assistance of the Supranational Reference in other diseases and resulted in the establishment of
Laboratories [SRL]. Establishing surveillance of drug multinational system for DRS. Yield of reliable results in
resistance at the country level requires strict adherence
this surveillance report came from laboratory
to three principles: [i] the sample of specimens should be
standardization and QA.
representative of the TB patients in the country or
In the year 1998, WHO and IUATLD Working Group
geographical setting under study and the sample size
on Antituberculosis Drug Resistance Surveillance
should be determined to permit standard epidemiological
published the report on the prevalence of resistance to
analysis. It was recommended that antituberculosis DRS
four first-line drugs in 35 geographical settings during
should cover the entire country or geographical area and
the period 1994 to 1996 (8). As per this report (8),
that the sample size is derived from the total number of
resistance to antituberculosis drugs was found in all 35
new sputum-positive cases in that country; [ii] the
countries and regions surveyed and resistance to
patient’s history should be carefully obtained and
available medical records reviewed to clearly determine isoniazid or streptomycin was most common.
whether the patient has previously received antituber- Despite high rates of HIV co-infection in African
culosis drugs. This was felt essential to distinguish countries, the prevalence of drug resistance was generally
between drug resistance among newly diagnosed cases low (8,9). The low level of multidrug resistance was
and drug resistance among previously treated cases; and attributed to the non-availability of control programmes
[iii] the laboratory methods for antituberculosis drug and the relatively late introduction of rifampicin.
susceptibility testing [DST] should be selected from In Western European countries, where TB notification
among those that are internationally recommended. Four rates were low, (10) the median prevalence of primary
DST methods have been standardized and are widely multidrug resistance was less than one per cent. Despite
used throughout the world (7). They are: [i] proportion 28 per cent of patients with TB having co-infection with
method and its economic and standard variants; HIV in Barcelona, Spain, the prevalence rate of multi-
[ii] resistance ratio method; [iii] absolute concentration drug resistance was only 0.5 per cent.
method; and [iv] radiometric method [e.g., BACTEC 460]. The prevalence of MDR-TB among new cases was
Comparability of data resulting from any of the above greater than three per cent in six geographical settings
four methods is assured by the quality assurance [QA] [Argentina, Dominican Republic, Estonia, Latvia, Côte
and proficiency testing performed by the SRL network. d’Ivoire, and Ivanovo Oblast in the Russian Federation]
(8). These findings prompted WHO to establish the
GLOBAL PREVALENCE OF DRUG DOTS-Plus research initiative aiming to assess the
RESISTANT TUBERCULOSIS feasibility and cost-effectiveness of programmatic
Till the 1990s the worldwide magnitude of the problem interventions to manage patients with MDR-TB in
of resistance to antituberculosis drugs is not known. The middle- and low-income countries.
716 Tuberculosis
Subsequently, the second report of the Global Project Israel. Central Europe and Africa, in contrast, reported
was published in the year 2000 (11). This report (11) the lowest median levels of drug resistance. The
contained data from 72 geographical settings involved percentage of re-treatment cases in a NTP emerged as
in the Global Project between 1994 and 1999. It included an indicator of programme performance.
information collected during the period 1996 to 1999 on As in previous phases of the Global Project, a link
the prevalence of drug resistance from 58 geographical was found between poor programme performance, or
settings and trends on drug resistance from 28 insufficient coverage of a good programme, and drug
geographical settings, 20 of which were originally resistance. Previously treated cases, worldwide, were not
included in the first report (11). Among new cases, the only more likely to be drug-resistant, but were also likely
median prevalence of MDR-TB was one per cent [range to have resistance to more drugs than untreated patients.
0% in eight geographical settings to 14.1% in Estonia]. Another significant finding in the Third Global Report
High prevalences were observed in Henan Province, was that, between 1994 and 2002, the surveyed areas
China [10.8%], Latvia [9%], the Ivanovo [9%] and Tomsk represented over one-third of notified TB cases
Oblasts [6.5%] of the Russian Federation, and the Islamic worldwide. However, enormous gaps still existed in
Republic of Iran [5%]. The median prevalence of MDR- many crucial areas, especially countries with a large TB
TB among previously treated cases was 9.3 per cent burden or where available data strongly suggest that
[range 0% in four geographical settings to 48.2% in the there may be a much larger problem, particularly China,
Islamic Republic of Iran]. India, and countries of the former Soviet Union. It was
In the year 2004, the Third Global Report on the concluded that the ability to conduct a drug resistance
antituberculosis drug resistance in the world published survey was indicative of a reasonable level of capacity
(12). This report included the results of survey in 74 of of the TB control services, most importantly, the labora-
77 settings between 1999 and 2002 (12). The report tory service. Thus, it was likely that TB control in some
indicated that as in the two previous surveys, drug- un-surveyed areas was worse than in those surveyed.
resistant TB including MDR-TB was found in all regions The findings of this phase of the Global Project emphasize
of the world. Analysis of almost 90 000 isolates represen- the importance of strengthening TB control worldwide,
tative of the most recent data from countries between by expanding DOTS in order to prevent the emergence
1994 and 2002 confirmed that, globally, more isolates of further drug resistance. Existing cases need to be
were resistant to isoniazid than to any other drug [range managed by NTP, regardless of prevalence, through
0% to 42%]. In general, isoniazid and streptomycin resis- application of the DOTS-Plus, an internationally adopted
tance was more prevalent than rifampicin or ethambutol strategy to control TB and using the Green Light
resistance. Resistance to isoniazid, streptomycin, Committee to ensure quality of second-line drugs and
rifampicin and ethambutol was the most prevalent proper implementation and monitoring. Full adoption
pattern among previously treated cases and the of DOTS was felt vital for stopping the creation of MDR-
proportions of isolates resistant to three or four drugs TB cases. The report (12) recommended that information
were significantly greater among this group than among on drug resistance was urgently needed from un-
new cases. This relationship suggested amplification of surveyed areas of China, India, and the former Soviet
resistance. It appears that isoniazid and streptomycin Union. This was felt particularly necessary in the light
mono-resistance are the main gateways to acquisition of of the prevalence of resistance detected in those countries
additional resistance. and given the high rate of DOTS expansion currently
The prevalence of MDR-TB was exceptionally high underway or planned in these countries. It was felt that
in almost all former countries of the Soviet Union the DRS should be considered as an essential component
surveyed, including Estonia, Kazakhstan, Latvia, of TB control programmes in these settings (12,13).
Lithuania, the Russian Federation, and Uzbekistan. The Fourth Global Report on the antituberculosis
Proportions of isolates resistant to three or four drugs drug resistance in the world has been published in 2008
were also significantly higher in this region. High (14). This report included DST results from 91 577
prevalence of MDR-TB was also found among new cases patients from 93 settings in 81 countries and 2 Special
in China [Henan and Liaoning provinces], Ecuador and Administrative Regions [SARs] of China collected
between 2002 and 2006, representing over 35% of the antituberculosis treatment (14). Since China has reached
global total of notified new smear-positive TB cases. The the global targets for case detection and treatment
Fourth Report included data obtained between 1994 and success, it was felt that the rapid implementation of
2007 from 138 settings in 114 countries and 2 SARs of services for the diagnosis and treatment of MDR-TB was
China. It also included data from 33 countries that have necessary to ensure success of the TB control programme
never previously reported and also included new data and to control transmission of drug-resistant strains.
from the following high TB burden countries: India, In 2006, 118 732 diagnostic were reported among 108
China, Russian Federation, Indonesia, Ethiopia, countries [with 74 % of these tests conducted in the
Philippines, Viet Nam, Tanzania, Thailand, and European Region] (14). The proportion of new cases for
Myanmar. whom DST was done was also highest in the Europe [45
The estimates published in the Fourth Global Report countries with 78% of estimated MDR-TB cases
(14) suggest that 489 139 cases emerged in 2006, and the accounted for in that region], followed by the Americas
global proportion of resistance among all cases was 4.8 [17 countries with 50% of MDR-TB cases accounted in
per cent. China and India [approximately 50%], and the the region]. The South-East Asia Region showed the
Russian Federation [a further 7%] are estimated to carry fewest cases, with only two countries reporting the 0.03
the highest number of MDR-TB cases. The data from the per cent cases accounted for in the region]. The
Fourth Global Report (14) are shown in Table 50.1, proportion of DST for re-treatment cases also followed a
Figures 50.1, 50.2, 50.3 and 50.4A and 50.4B. similar pattern [Table 50.1] (13).
According to the Fourth Global Report (14), the The WHO Report 2008 (15) also indicated that a small
population weighted mean of MDR-TB among all TB number of MDR-TB cases were diagnosed compared
cases was 5.3 per cent [ranging from 0 % in some western with the large number of cases that were estimated to
European countries to > 35 % in several countries of the exist in the respective WHO regions. These observations
former Soviet Union]. The countries of the former Soviet suggest that an enormous amount of work remains to be
Union are facing a more serious and widespread done to improve the availability and provision of
epidemic, since the population weighted average of diagnosis and treatment for MDR-TB.
countries reporting indicates that almost half of all TB These surveillance results suggest link between the
cases are resistant to at least one drug and MDR-TB quality of TB control programmes and levels of drug
accounted for one among every five cases of TB. In this resistance. However, this relationship is complex (17).
region, MDR-TB cases had more extensive resistance
Extensively Drug-resistant Tuberculosis
patterns including some of the highest proportions of
extensively drug-resistant TB [XDR-TB]. A similar high The Centers for Disease Control and Prevention [CDC],
burden of MDR-TB was observed in some provinces in Atlanta, in March 2006 reported the extensively drug-
China, while Western Europe and some countries in resistant tuberculosis [XDR-TB] (16). The XDR-TB is
Africa, reported the lowest proportions of MDR-TB. It is defined as cases in persons with TB whose isolates were
noteworthy that at least one country in all six WHO resistant to isoniazid and rifampicin and at least three
regions has reported greater than three per cent MDR- of the six main classes of second-line drugs, such
TB among new cases. as aminoglycosides, polypeptides, fluoroquinolones,
Data from surveys in 10 of 31 provinces in China over thioamides, cycloserine, and para-aminosalicyclic acid
a ten-year period indicate that drug resistance is (17,18). Subsequently, this definition has been modified
widespread and represent the highest burden of cases and XDR-TB is defined as isolates resistant to at least
in the world. It is estimated that 130 548 MDR-TB cases rifampicin and isoniazid [which is the definition of MDR-
emerged in 2006 accounting for over 25 per cent of the TB], in addition to any fluoroquinolone, and to at least
global burden. The high proportion of drug-resistant TB one of the three following injectable drugs used in
in new cases China suggests transmission of drug- antituberculosis treatment, such as capreomycin, kana-
resistant strains. It is estimated that over 10 per cent of mycin and amikacin (19-25). A summary of the results
the MDR-TB cases that emerged globally in 2006 occurred of that survey, which was published in a Fact Sheet (18),
in patients in China who had no prior history of determined that during 2000 and 2004, of 17 690 TB
718 Tuberculosis
Figure 50.1: Countries/settings with prevalence of any resistance higher than 30% among new cases, 2002–2007
Reproduced with permission from “The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 2002-2007.
Anti-tuberculosis drug resistance in the world. Fourth Global Report. WHO/HTM/TB/2004.343. Geneva: World Health Organization;
Figure 50.2: Countries/settings with prevalence of MDR-TB higher than 5% among new cases 2002-2007
MDR-TB = multidrug-resistant tuberculosis
Figure 50.3: Countries/settings with a prevalence of MDR-TB higher than 30% among previously treated cases, 2002-2007
Table 50.1: World Health Organization region-wise information on the number of countries reporting diagnostic drug
sensitivity testing in 2006 and the estimated multidrug-resistant tuberculosis cases accounted for in each region
Region New cases Re-treatment cases
No. of countries % of estimated No. of countries % of estimated

reporting MDR-TB cases reporting MDR-TB cases
accounted for in accounted for in
that region that region
Africa 8 10 11 14
Americas 17 50 15 65
Eastern Mediterranean 10 11 6 13
European 45 78 40 81
South-East Asia 2 0.03 3 2*
Western Pacific 15 12 12 3
World 97 19 87 19
* Data from India and China excluded because testing of only 26 [India] and 10 [China] re-treatment cases was reported
MDR-TB = mulitdrug-resistant tuberculosis
720 Tuberculosis
Figure 50.4A: Prevalence of multidrug-resistant tuberculosis among new tuberculosis cases, 1994-2007
Reproduced with permission from “World Health Organization. Anti-tuberculosis drug resistance in the world. Report No. 4. WHO/
IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization;
Figure 50.4B: Prevalence of multidrug-resistant tuberculosis among previously treated tuberculosis cases, 1994-2007
Reproduced with permission from “World Health Organization. Anti-tuberculosis drug resistance in the world. Report No. 4. WHO/
IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization;
convenient sample isolates from 49 countries, the XDR- diagnosed cases estimated by different investigators over
TB was approximately 10 per cent and was spread over the past 30 years are listed in Table 50.3.
17 countries. In addition, population-based data on drug In the 1960s Indian Council of Medical Research
susceptibility of TB isolates were obtained from the [ICMR] conducted two nation wide surveys at nine
United States [for the years 1993-2004], Latvia [for the urban chest clinics in India (26,27). The results of the first
years 2000-2002], and South Korea [for the year 2004], survey showed resistance level of 8.2 per cent to isoniazid
where four per cent, 19 per cent, and 15 per cent of MDR- alone, 5.8 per cent to streptomycin alone and 6.5 per cent
TB cases, respectively, were XDR-TB. A total of 12 [10.9%] to both the drugs. The resistance levels among new cases
of 113 MDR-TB strains in Iran were resistant to all eight seen in these two surveys were 14.7 per cent and 15.5
second-line drugs tested and, therefore, were denoted per cent respectively to isoniazid and 12.5 per cent and
as XDR-TB. Retrospective analysis of the cases of XDR- 13.8 per cent respectively to streptomycin.
TB showed that all of them belonged to one of the two A decade later, a study was conducted to assess the
epidemiological clusters, either a single-family cluster [4 prevalence of resistance among new cases in Govern-
cases] or a cluster of close contacts [8 cases] (19). An ment Chest Institute and Chest [Tuberculosis] Clinic of
unpublished report from Tuberculosis Research Centre Government Stanley Hospital, Chennai (28). The results
[TRC], Chennai, has indicated that XDR-TB to be of this study were almost similar to the earlier ICMR
approximately four per cent of 3173 isolates received surveys and the authors reported that the prevalence of
in TRC during the period 2001 to 2004 from chronically resistance among new cases has not risen during the span
ill patients with a prolonged and varying treatment of 10 years.
history. The global burden of XDR-TB is shown in Figures During the 1980s among five reports on primary drug
50.5A (25) and 50.5B (14). The XDR-TB has emerged resistance, while the levels of resistance among new cases
worldwide as a threat to public health and TB control, to isoniazid and streptomycin were similar to that
raising concerns of a future epidemic of virtually reported in earlier studies. Rifampicin resistance started
untreatable TB. appearing in North Arcot, Pondicherry, Bengaluru and
Jaipur but not in Gujarat (29-34). The reason for the
PREVALENCE OF DRUG-RESISTANT emergence of rifampicin resistance during this period
TUBERCULOSIS IN INDIA may be the introduction of short-course chemotherapy
Drug-resistant TB has frequently been encountered in [SCC] regimens containing rifampicin.
India and its presence has been known from the time Further, a higher level of resistance among new cases
antituberculosis drugs were introduced. Lack of to isoniazid was observed among the rural population
comprehensive reports on this subject is mainly due to in Kolar compared to the urban patients contradicting a
limited facilities for culture and susceptibility tests. Much Korean study where a much higher level of initial
of the drug resistance is presumed clinically when resistance was seen among urban patients giving the
patients do not improve or the symptoms return after reason of easy access to the antituberculosis drugs (4).
initial relief where sputum remains positive for acid-fast There was also an increase in the proportion of resistance
bacilli. among new cases to rifampicin [4.4%] encountered in
this rural population. In the early 1990s, a retrospective
study done at New Delhi (35) showed a high level of
Drug Resistance in Newly Diagnosed Cases
resistance among new cases to isoniazid [18.5%] and a
Though drug resistance in newly diagnosed cases is low level of rifampicin resistance.
found to be low in developed countries, it is common in Overall, the prevalence rate of resistance among new
India and varies widely in different regions. The South- cases to isoniazid as a single agent ranged from six per
east Asia region is a major contributor, accounting for cent to thirteen per cent (26-31,33-35) except among the
almost 30 per cent, of the global burden of MDR-TB rural population in Kolar, Karnataka (32) where a high
among new and previously treated cases [Tables 50.2A rate of 26.7 per cent has been reported. Prevalence of
and 50.2B] (14). The data on drug resistance in newly resistance in newly diagnosed cases to streptomycin as
722 Tuberculosis
Figure 50.5A: Global burden of extensively drug-resistant tuberculosis

Reproduced with permission from “World Health Organization. Countries with XDR-TB Confirmed cases to date. Available at URL:
http://www.who.int/ tb/challenges/xdr/xdrmap_oct07_en.pdf. Accessed on October 22, 2008 (reference 25)”
Figure 50.5B: Extensively drug-resistant tuberculosis: global scenario

Reproduced with permission from “World Health Organization. Anti-tuberculosis drug resistance in the world. Report No.4. WHO/IUATLD
Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008
(reference 14)”
Table 50.2A: Proportion of global mutidrug-resistant tuberculosis in new tuberculosis cases

Region No. of estimated Estimated MDR-TB cases
new TB cases
No. % of global total
Established Market Economies 85 729 724 0.3
Central Europe 42 464 416 0.2
Eastern Europe 336 842 43 878 15.4
Latin America 315 216 7 196 2.5
Eastern Mediterranean Region 569 446 16 430 5.8
Africa, low HIV incidence 350 671 5 311 1.9
Africa, high HIV incidence 350 671 43 767 15.3
South-East Asia 3 100 354 85 908 30.1
Western Pacific Region 1 882 930 82 087 28.7
All countries [n = 175] 9 123 922 285 718 100.0

Table 50.2B: Proportion of global mutidrug-resistant tuberculosis in previously treated

tuberculosis cases
Region No. of estimated Estimated MDR-TB cases

new TB cases
No. % of global total
Established Market Economies 5036 413 0.2

Central Europe 8038 785 0.4
Eastern Europe 79 474 36 179 17.8
Latin America 33 856 4 813 2.4
Eastern Mediterranean Region 31 286 9 040 4.4
Africa, low HIV incidence 25 130 3 105 1.5
Africa, high HIV incidence 216 152 14 528 7.2
South-East Asia 363 959 63 707 31.4
Western Pacific Region 289 214 70 601 34.7
All countries [n = 175] 1 052 145 203 230 100.0

a single agent ranged from 1.0 to 5.8 per cent and to For a correct evaluation of primary drug resistance,
rifampicin from 0 to 1.9 per cent (26-35). In many of these standardized methodology should have been used taking
surveys ethambutol susceptibility was not performed. care of the following, namely, eliciting patient history,
In a recently conducted study in Bengaluru (33), the adequate sample size, uniform laboratory methods,
resistance in newly detected cases was 13.7 per cent to external and internal quality control, reliable drugs for
isoniazid, 22.5 per cent to streptomycin; and 2.2 per cent setting up media for DST, use of standard chemicals in
had MDR-TB. The resistance to any drug increased with the preparation of media, etc. Many Indian studies may
age indicating the effect of improper implementation of have limitations related to these methodological
TB control measures in Bengaluru before 1999. issues.
Table 50.3: Summary of studies on resistance among new cases in Mycobacterium tuberculosis isolates from India
724
Study Year No. of Resistance to single drug (%) Resistance to Total Loca-
(reference) isolates multiple drugs (%) resistance tion
tested (%)
Tuberculosis
H S R E T SH HR SHR
9 Urban Centres 1964-65 1838 8.2 5.8 ND ND - 6.5 - - 20.4 Urban
in India (26) [14.7] [12.5]
9 Urban Centres 1965-67 851 15.5 13.8 ND ND - - - - 22 Urban
in India (27)
Chennai (28) 1976 254 10.6 9.5 ND ND ND 4.7 - - - Urban
Gujarat* (29) 1983-86 570 7.9 3.2 0 2.5 0.5 3.3 0 - 20 -
[13.9] [7.4] [4.0] [1.5]
North Arcot (30) 1985-89 2779 13 4 0.07 ND ND 7 0.7 0.9 26 Rural
[2.0]
Puducherry (30) 1985-91 2127 6 4 0.2 ND ND 3 0.4 0.3 13.9 -
[0.9]
Bengaluru† (31) 1980s 436 12.1 1.8 1.8 0 ND 3.6 0.9 0.2 21.1 Urban
[17.4] [5.7] [3.0] [0.5]
Bengaluru‡ (32) 1985-86 588 12.6 1.7 1.5 0 ND 2.9 1.2 0.2 20.5 Urban
[17.4] [4.8] [2.3] [0.5]
Bengaluru (33) 1999 271 13.7 22.5 2.6 1.8 ND 6.6 2.2 1.1 27.7 Urban
Kolar§ (32) 1987-89 292 26.7 1 1 0 ND 2.4 3.2 0.7 34.9 Rural
[32.8] [5.1] [4.4] [1.7]
Jaipur¶ (34) 1988-91 1009 7.6 5.2 1.9 2 ND 1.6 0.7 0.1 19.9 -
[10.1] [7.6] [3.0] [2.6]
New Delhi (35) 1990-91 324 18.5 - 0.6 - - - - - - Urban
H = isoniazid; S = streptomycin; R = rifampicin; E = ethambutol; T = thiacetazone; ND = not done

Figures in square brackets indicate percentage of isolates resistant to a drug along with other drugs. [H] = H+SH+HR+SHR; [S] = S+SH+SR+SHR; [R] =
R+SR+HR+SHR; [E] = E+HE+SE+SHE+HRE; [T] = T+HT
* Multiple drug resistance patterns were also reported for HT [1.0%]: HE [0.7%]: SHE [0.9%]
† Multiple drug resistance patterns were also reported for HE [0.5%]
‡ Multiple drug resistance patterns were also reported for HE [0.6%]
§ Multiple drug resistance patterns were also reported for HE [0.3%]; SHE [1.0%]; HRE [0.3%]
¶ Multiple drug resistance patterns were also reported for SR [0.2%]; SE [0.5%]; SHE [0.1%]
Resistance in Previously Treated Tuberculosis Cases was 63 per cent, out of which 23.5 per cent were resistant
The rates of resistance in previously treated patients are to single drug and 39.5 per cent resistant to more than
invariably higher than the rates of resistance in newly one drug. In a recently conducted study in Bengaluru
diagnosed cases, though data on resistance in previously (38), the multidrug resistance in previously treated cases
treated patients are limited. Studies on resistance patterns was found to be 12.8 per cent and ranged from 8.4 per
in previously treated patients are shown in Table 50.4. cent to 17.2 per cent. The proportion of 12 per cent MDR-
The longitudinal trend of drug resistance in Gujarat TB in previously treated patients appears to be similar
between 1980 and 1986 (34) showed that in treatment in other DOTS implemented areas, such as Hong Kong
failure or relapsed patients, resistance to rifampicin (39) and Nepal (40). The overall rates of resistance in
increased from 2.8 per cent in 1980 to 37.3 per cent in previously treated patients to isoniazid ranged from 34.5
1986 and to isoniazid from 34.5 per cent to 55.8 per cent. to 67 per cent, for streptomycin from 26.0 to 26.9 per cent
From this study (34), it was presumed that high level of and for rifampicin from 2.8 to 37.3 per cent (26-35).
rifampicin resistance was almost entirely acquired. A
Multidrug Resistance
study was conducted by the ICMR (36) to compare the
efficacy of SCC with the conventional [non-SCC] The rate of MDR-TB in new cases in India is very low,
chemotherapy in North Arcot district, Tamil Nadu. The ranging from 0 to 3 per cent [Table 50.3]. The drug
population was examined during their follow-up period resistance in various DRS sites in India conducted by two
to confirm the bacterial quiescence and in turn the national reference laboratories of India between 1985-
efficacy of SCC. It was found that there was an increase 2003, namely Tuberculosis Research Centre [TRC],
in the frequency of resistance in previously treated Chennai and National Tuberculosis Institute [NTI],
patients with 67 per cent resistance to isoniazid, 26 per Bengaluru is shown in Figure 50.6 (33,41-43). The
cent to streptomycin and 12 per cent to rifampicin. In resistance varied from 0.5 to 3.4 per cent. The level of
addition, six per cent of the strains tested were resistant MDR-TB in previously treated cases was less than 13.0
to both isoniazid and rifampicin (36). A study from New per cent except in Gujarat where a high level was
Delhi in the 1990s (35) also showed a higher level of observed [11.4% to 18.5%] (29) [Table 50.4]. In the report
resistance in previously treated patients to isoniazid and from the Institute of Thoracic Medicine, Chennai (37) on
rifampicin, which is almost similar to that of the Gujarat the prevalence of MDR-TB among patients undergoing
report (29). A study conducted by the Institute of Thoracic treatment for varying periods of time at four District
Medicine, Chennai (37) aimed at finding out the Tuberculosis Centres in Tamil Nadu, 20.3 per cent were
prevalence of TB resistance in four District Tuberculosis found to be harbouring multidrug-resistant strains.
Centres of Tamil Nadu, showed that acquired resistance Majority of these patients had irregular and interrupted
Table 50.4: Summary of studies on resistance in previously treated patients in

Mycobacterium tuberculosis isolates from India
Study Year Number Resistance (%) Location

(reference) of
isolates
H S R SH HR SR SHR
Gujarat (29) 1980-86 1574 34.5-55.8 26.3-26.9 2.8-37.3 - - - - -

Gujarat (29) 1983-86 1267 - - - - 11.4-18.5 1.2-3.5 14.5-15.3 -
North Arcot (36) 1988-89 560 67.0 26.0 12.0 19.0 6.0 - - Rural
New Delhi (35) 1990-91 81 50.7 - 33.7 - - - - Urban

Bengaluru (38) 1999-2000 226 4.7-12.1 5.4-13.2 0-3.6 0-1.3 8.4-17.2 0.2.1 0.2-4.2 Urban
H = isoniazid; S = streptomycin; R = rifampicin

726 Tuberculosis
Figure 50.6: Drug resistance data from some surveillance sites in India [1985-2003].
Figures in square brackets indicate prevalence of Multidrug-resistant tuberculosis
treatment owing to the non-availability of drugs (37).

Data documented at the TRC, Chennai (44) from 443
Category II patients from the model DOTS area in
Tiruvallur district of Tamil Nadu [1999-2003] revealed
that the prevalence of MDR-TB was 11.7 per cent. In
another study (45) in HIV-TB co-infected patients from
south India [n = 204], MDR-TB was observed in 4.2 per
cent [7 of the 167] of new cases and 13.5 per cent [5 of
the 37] of previously treated patients.
Data of resistance among new cases from TRC,
Chennai, for the past four decades are shown in the Figure 50.7: Trend of prevalence of drug resistance in newly
Figure 50.7. It is clearly evident that there was a gradual diagnosed cases of tuberculosis in various studies of Tuberculosis
Research Centre [TRC], Chennai
increase in the prevalence of resistance to antituberculosis
H = isoniazid; S = streptomycin; R = rifampcin
drugs among new cases. For isoniazid, the resistance
rates ranged from three to seventeen per cent and for per cent to isoniazid, 9.1 per cent to streptomycin and
streptomycin from three to thirteen per cent. Initial 15.8 per cent to both the drugs. During the 1980s two
resistance to rifampicin started appearing in 1990s and surveys were conducted by the ICMR at Raichur district,
still remains at one per cent. Resistance to more than one Karnataka (46) and North Arcot district, Tamil Nadu (47)
drug is observed to range from none to seven per cent to estimate the prevalence of drug-resistant TB. The
for streptomycin and isoniazid and less than one per cent results of the survey showed a higher level of initial drug
for isoniazid and rifampicin or streptomycin, isoniazid resistance in Raichur District compared to that in North
and rifampicin. Arcot district (46,47). The results of another
The second ICMR survey (27) conducted in the 1960s study (43) in Wardha district of Maharashtra revealed
showed a higher level of drug resistance among those resistance to isoniazid, rifampicin or both drugs to be
with a history of previous chemotherapy and it was 7.0 15.2 per cent, 0.5 per cent and 0.5 per cent respectively.
A recently concluded study (43) in the Jabalpur district that this lower level of drug resistance in this population
of Madhya Pradesh showed resistance in newly could be due to the minimal chance of indiscriminate
diagnosed cases to isoniazid, rifampicin and to both exposure of antituberculosis agents prior to reporting to
drugs to be 16.1 per cent, 1.8 per cent and 1.1 per cent, the hospital. Overall the initial resistance to isoniazid as
respectively. Since 1999, TRC has carried out several single agent ranges from 0.6 per cent to 13.2 per cent, to
operational research studies in the model DOTS area in streptomycin from 2.2 per cent to 7.0 per cent and to
Tiruvallur district of Tamil Nadu, including, measure- rifampicin from none to 1.7 per cent.
ment of drug resistance among patients living in the trial In the Fourth Global Report (13), India reported data
area. Data from the period 1999-2003 revealed resistance from one state, Gujarat, and three districts: Ernakulam
to isoniazid and MDR-TB among new cases to be 10.4 district, Kerala State, Hoogli district, West Bengal State,
and 1.7 per cent, respectively (44). Likewise, in a study and Mayhurbhanj district, Orissa State [Figure 50.8]. Data
(45) on drug resistance carried out in patients co-infected from the nine sites in India show that drug resistance
with HIV-TB [2000-2002], resistance to isoniazid and among new cases is relatively low; however, new data
MDR-TB among new cases were reported to be 13 and from Gujarat indicate that prevalance of MDR-TB among
4.3 per cent, respectively. retreatment cases [17.2%] was higher than previously
Data on the prevalence of drug resistance from Army anticipated and it is estimated that 110 32 new MDR-TB
Hospital, Pune (48) showed a very low level of initial cases emerged in India in 2006, representing over 20 per
resistance to isoniazid and the authors have reasoned cent of the global burden (14). Although plans have been
Figure 50.8: Prevalence of multidrug-resistant TB in new and previously treated cases in South-East Asia region, 2002-2007
Reproduced with permission from “World Health Organization. Anti-tuberculosis drug resistance in the world. Report No.4. WHO/IUATLD
Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008
(reference 14)”
728 Tuberculosis
developed for management of 5000 MDR-TB cases suggest that there is no alarming increase in the incidence
annually by 2010, insufficient laboratory capacity is seen of initial multidrug-resistant cases.
as the primary limitation in the implementation of these A strong TB control programme that can reduce the
plans. incidence of drug resistance in a community and
particularly DOTS, which is cost-effective, proved to be
Treatment Outcome of Drug-Resistant Tuberculosis effective in treatment completion and in turn proved to
be effective against emergence of drug resistance in New
The emergence of drug-resistant strains is known to
York (5). New drugs for TB are unlikely to come up in
reduce the efficacy of treatment. Strains resistant to
isoniazid. streptomycin or both neither pose a major the near future, and hence, the key success remains in
adequate case finding, prompt and correct diagnosis and
problem nor affect the result of treatment in a big way
effective treatment of infective patients for prevention
provided proper regimens are used (49,50). On the cont-
rary, patients infected with organisms resistant to of drug resistance.
The longitudinal studies of TRC, Chennai (43) and
rifampicin, isoniazid or both have a high rate of treatment
many of the above-cited surveys including studies on
failure (30,35,49,50) and this forms a major threat to TB
control programmes, particularly for countries like India the childhood TB show that there is no real threat by the
increase of MDR-TB in India. However, there cannot be
with limited resources. Patients infected with MDR-TB
complacency among health care professionals, since in
strains require longer duration of therapy and may die
of TB or continue to have active TB despite optimal absolute number, considering the existing TB burden and
population of this vast country, even a fraction in the
therapy (2). The reader is referred to the chapter “Drug-
increase of MDR-TB would literally mean millions of
resistant tuberculosis” [Chapter 49]” for more details
regarding the global experience in the treatment of drug- rupees of extra spending in the treatment of such cases.
Reliablility of second-line antituberculosis DST also need
resistant TB.
to be ascertained before they are tried in India (53). Every
physician and health care worker should strictly adhere
The Relevance of These Studies
to the treatment policies of the government and ensure
In view of the results so far observed, there is no clear early diagnosis and completion of treatment under direct
evidence of an increase in the prevalence of resistance observation of a committed DOT provider, which would
among new cases in India over the years. However, eventually result in the reduction in the prevalence of
relatively high prevalence of resistance in previously MDR-TB in the community (54).
treated patients has been reported from Gujarat, New Apart from a strong TB control programme, there is
Delhi and North Arcot district (29,35,36). When also a need for a continuous and/or periodic survey of
compared to the prevalence of drug resistance globally, drug resistance, which will provide information on the
resistance among new cases is found to be marginally type of chemotherapy to be used for the treatment of
lower and a much higher level of resistance in previously patients and also serve as a useful parameter in the evalu-
treated patients is observed in India. The magnitude of ation of current and past chemotherapy programmes
drug resistance problem to a larger extent is due to (5,55).
acquired resistance. The prevalence of MDR-TB is also
found to be at a very low level in most of the regions of DOTS-PLUS
India. Children seldom produce adequate sputum for
culture and sensitivity testing. Resistance pattern The DOTS-Plus is a comprehensive management strategy
observed in strains isolated from children were found to based upon DOTS (57), under development and testing
be similar to those of strains isolated from their adult that includes the five tenets of the DOTS strategy. The
contacts. Studies conducted at the TRC, Chennai in DOTS-Plus takes into account specific issues such as the
paediatric population revealed that resistance to use of second-line antituberculosis drugs that need to be
isoniazid was five per cent to ten per cent; resistance to addressed in areas where there is high prevalence of
streptomycin without resistance to rifampicin was 2.0 MDR-TB. Thus, DOTS-Plus works as a supplement to
per cent to 11.4 per cent (50-52). These observations the standard DOTS strategy. By definition, it is impossible
to conduct DOTS-Plus in an area without having an though as yet no products have been purchased; [iv] a
effective DOTS-based TB control programme in place. plan for convergence of the drug procurement unit of the
DOTS-Plus is not intended as a universal strategy, and GLC mechanism with the GDF was agreed for
is not recommended in all settings. The DOTS-Plus is implementation in 2006; [v] advice to WHO has enabled
intended to be implemented in selected areas with the formulation of new WHO Guidelines for the manage-
moderate to high levels of MDR-TB in order to combat ment of drug-resistant TB (62); [vi] through assistance to
an emerging epidemic (57,58). The DOTS-Plus is being countries, several high TB and MDR-TB burden countries
implemented in Bolivia, Costa Rica, Estonia, Haiti, were approved for MDR-TB management in the fifth
Karakalpakstan [Uzbekistan], Latvia, Malawi, Mexico, round of the Global Fund to Fight AIDS, Tuberculosis
Peru, Philippines and the Russian Federation and Malaria [GF]; [vii] important modifications to the
[Arkhangelsk, Ivanono, Tomsk and Orel Oblasts]. The governance of the Working Group were introduced: drug
DOTS-Plus projects have also been approved for 27 sites resistance to the second line-drugs was included in the
in 24 countries including Georgia, Honduras, Jordan, terms of reference of the Group, the Core Group was
Kenya, Kyrgyzstan, Lebanon, Nepal, Nicaragua, expanded with representatives of the community; and
Romania and Syria (59,60), and are under review in [viii] the first training for consultants on MDR-TB
six countries including Delhi, India. The DOTS-Plus management was conducted at the newly established
projects are also in pipeline for 10 countries, including WHO Collaborating Centre for MDR-TB Control in Riga,
some other sites in India. Latvia (59).
The World Health Organization Working Group on PREVENTION OF MULTIDRUG-RESISTANT

DOTS-Plus for Multidrug-resistant Tuberculosis TUBERCULOSIS IN INDIA’S REVISED NATIONAL
TUBERCULOSIS CONTROL PROGRAMME
The Stop TB Working Group on DOTS-Plus for MDR-TB
has planned to produce feasible, effective and cost- It is well known that resistance levels are higher in areas
effective approaches to the prevention and management with a poorly performing DOTS programmes. Use of
of MDR-TB (61). During 2005, it focussed on developing inadequate regimens and inappropriate direct observa-
new guidelines for MDR-TB management in resource- tion of treatment [DOT] leads to increase in resistance
limited settings, producing the Strategic Plan of the levels in the community. It has been acknowledged that
Working Group for 2006-2015, refining a guide to policy- good treatment is a pre-requisite to the prevention of
making in management of drug-resistant TB and submitt- emergence of resistance. The Revised National Tuber-
ing manuscripts on feasibility and cost-effectiveness of culosis Control Programme [RNTCP], of the Government
MDR-TB pilot projects to peer-reviewed journals. The of India, recognizes that implementation of a good
main achievements during 2005 were: [i] new projects for quality DOTS programme is the first priority for TB
the management of MDR-TB were approved for six control in the country. Prevention of emergence of MDR-
TB in the community is more imperative rather than its
countries and existing projects were expanded. There 47
treatment (63).
projects for management of MDR-TB with a total cohort
size of 12 215 MDR-TB patients in 29 countries; [ii] a
DOTS-Plus in India’s Revised National
manuscript reporting results from the first five Green Light
Tuberculosis Control Programme
Committee [GLC] approved projects was submitted to a
peer-reviewed journal. These results showed that MDR- Provision of DOTS-Plus is a supplementary service under
TB management was feasible and that adverse events were the expanded framework of the DOTS package under
manageable in resource-limited settings; [iii] as part of the RNTCP. Well administered first-line treatment for
prequalification of manufacturers of second-line drugs, susceptible cases is the best method to prevent the
nine manufacturers applied to the WHO prequalification development of resistance in such cases. Therefore, in
project, 14 dossiers were submitted for assessment, and every DOTS implementing unit of the country, DOTS
three inspections took place. The production plants of two would be prioritized above DOTS-Plus with the view
manufacturers of second-line drugs were approved, that DOTS reduces the emergence of MDR-TB, and
730 Tuberculosis
therefore, over time the need for DOTS-Plus also gets DRS protocols as per international guidelines have been
reduced. Timely identification of MDR-TB cases and developed and are under progress with gradual addition
adequately administered Category IV regimens are and re-survey of states over time. The objectives of DRS
essential to stop primary transmission of MDR-TB. in the state setting are to: [i] determine the levels and
Although the standardized drug regimens used by pattern of resistance to first-line antituberculosis drugs
RNTCP are highly effective, with low failure rates of among “newly diagnosed” sputum-positive cases;
around two per cent and six per cent amongst Category [ii] estimate the levels and pattern of resistance to first-
I and II cases, respectively, RNTCP has planned to line antituberculosis drugs among “previously treated
address the issue of the treatment of those pulmonary cases”; and [iii] establish the foundation for routine
TB patients who remain smear-positive following a fully surveillance of drug resistance in order to observe trends
supervised Category II re-treatment regimen. over time. Another objective of nationwide surveillance
The RNTCP views the treatment of MDR-TB patients of drug resistance in India includes strengthening of
as a “standard of care” issue. Recognizing that the laboratory networks through the implementation of an
treatment of MDR-TB cases is very complex, treatment external QA system for smear microscopy and QA of
will follow the internationally recommended DOTS-Plus culture and DST in state laboratories. The plan of action
guidelines and will be done in designated RNTCP DOTS- also includes human resource development and
Plus sites. These sites will be in a limited number of highly enhancement of financial capacity before a nationwide
specialized centres, at least one in each state, which will survey is implemented. Currently there are three NRLs,
have ready access to an RNTCP accredited state-level 16 intermediate reference laboratories [IRLs] or State TB
intermediate reference laboratory [IRL] with facilities for Demonstration and Training Centres in India. The DRS
culture and DST, with qualified staff available to manage protocols for Indian states have adapted economic
patients, using standardized second-line drug regimens variant of proportion method for DST in DRS. The
given under daily DOT and standardized follow-up sample size for population proportionate cluster
protocols, have systems in place to deliver ambulatory sampling [PPS] for each state has been calculated to be
DOT after an initial short period of in-patient care to 1680 patients for ‘new’ smear-positive cases with an
stabilize the patient on the second-line drug regimen, estimated prevalence of two per cent, precision of one
and with a logistics system and standardized information per cent for 95 per cent confidence intervals [CI]
system in place. The DOTS-Plus sites are planned to be including 10 per cent loss, after applying a design effect
initiated in a phased manner similar to that for the of two. The sample size for ‘previously treated’ smear-
establishment of the culture and DST laboratory network, positive cases is 992 patients, estimated prevalence: 12
and these sites will be linked geographically to the per cent, precision: two per cent, 95 per cent CI, 10 per
establishment of the RNTCP accredited IRLs. The DOTS- cent loss after applying a design effect of 2. Intake for
Plus has been developed as an integral component of previously treated smear-positive cases would be from
RNTCP to manage MDR-TB to be implemented through the designated microscopy centres selected for new cases.
the existing programme infrastructure. Intakes for both new and previously treated cases have
The reader is referred to the chapter “Revised National been scheduled to be completed within one year. A
Tuberculosis Control Programme” [Chapter 63] for more national external QA document for Central TB Division
details. has been developed, which has incorporated inter-
national guidelines established in 2002. Primary
Indian Efforts at Antituberculosis Drug Resistance importance has been given for EQA of smear microscopy
Surveillance before start of DRS. A national RNTCP Laboratory
India has developed a plan to conduct nationwide Network Coordination Team consisting of microbiolo-
surveillance of drug resistance in each state. At the gists from national reference laboratories of TRC, NTI
national level, a generic protocol for the Central TB and L.R.S. Institute of Tuberculosis and Respiratory
Division, Ministry of Health and Family Welfare, Diseases, New Delhi and representatives from inter-
Government of India has been developed, as per WHO mediate reference laboratories, Central TB Division,
guidelines in line with international standards (6). The Ministry of Health and Family Welfare, Government of
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734 Tuberculosis
Evolution of Chemotherapeutic
Regimens in the Treatment of
Tuberculosis and Their
Scientific Rationale
51
Rani Balasubramanian, Rajeswari Ramachandran
INTRODUCTION
Tuberculosis [TB] has been a scourge of mankind for
thousands of years and remains one of the deadliest
diseases in the world today. Nevertheless, TB can be cured
in nearly all cases. The only way to stop the spread of
disease in the community is to cure all smear-positive
cases by treatment with appropriate chemotherapeutic
regimens.
SCIENTIFIC BASIS OF TUBERCULOSIS

TREATMENT
Mycobacterium tuberculosis is a slow-growing aerobic
organism with doubling time of 18 hours and can remain
dormant for a long period [Figure 51.1]. Therefore, Figure 51.1: Theoretical basis of chemotherapy of tuberculosis.
prolonged treatment is required to ensure relapse-free Three populations of Mycobacterium tuberculosis are postulated to
cure. The effect of treatment is determined mainly by exist in a tuberculosis cavity, based on their anatomic and metabolic
characteristics. Population A refers to rapidly multiplying bacteria
bacteriological, environmental [anatomical and bio-
found in caseous debris in pulmonary cavities. Compared with
chemical] and pharmacological factors. streptomycin [S], rifampicin [R], and ethambutol [E], isoniazid [H] is
most active against this population. Slowly multiplying bacteria
Bacteriological Factors because of local acidic conditions are referred to as population B.
Pyrazinamide [Z] is the most effective antituberculosis drug active
The Numerical Factor
against this group followed by rifampicin [R] and isoniazid [H].
The number of tubercle bacilli varies widely with the type “Elimination” of populations “A” and “B” results in negative sputum
of lesion. Based on the data on resected lung specimens cultures, typically after two months of treatment. Bacilli in the host
from untreated patients (1), the number of bacilli in a tissue capable of sporadic bursts of metabolism, multiplication
constitute population “C”. This population is a potential source for
medium-sized cavity communicating with the bronchi
relapses. Rifampicin [R] plays a major role in eliminating these
is about 108. Resistant mutants are likely to be present organisms followed by H. Another population of bacilli designated
even before treatment is started if the bacterial population as population “D” are dormant non-replicating bacilli that are not
is larger. This fact must be borne in mind when choosing vulnerable to antimicrobial action and are also considered to be a
the regimen. potential source for relapse
The Metabolic Factor But, in each bacterial population there are bacilli with a
Antituberculosis drugs kill tubercle bacilli that are very low metabolic rate. Some are inhibited owing to a
metabolically active and are multiplying continuously. low pH; others are dormant most of the time and grow,
Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale 735
if at all, only during short periods. These organisms present, but it is not necessary to keep this concentration
remain unaffected by most drugs; only rifampicin or at a constant level. In fact, studies on the role of dosage
pyrazinamide may kill them effectively under certain and serum levels of isoniazid showed that it was both
conditions. They survive even in the presence of potent the peak level and the total exposure to the drug [area
drugs such as isoniazid and streptomycin, in spite of under time concentration] that were important for the
being susceptible to these drugs. These organisms are response to the drug (3). Thus, 400 mg of isoniazid given
called “persisters”. This phenomenon explains to some once daily was therapeutically superior to the same dose
extent why all bacilli are not killed during treatment, and divided into two parts and administered at 12 hour
why drug-susceptible bacilli are coughed up for some intervals (3).
time thereafter. Relapse with drug-susceptible organisms
after being “cured” or endogenous reactivation may Combinations of Drugs
occur due to bacilli that have persisted in residual lesions Regimens should contain a combination of three or more
in a dormant state for a long time. bactericidal drugs, particularly in the initial phase of
treatment so that bacilli that are both susceptible and
Environmental Factors resistant to one drug are killed rapidly by various other
drugs. Treatment of TB disease should never be
The Anatomical Factors
attempted with a single drug. In patients having lesions
The type of tissue harbouring tubercle bacilli may modify like cavities which are likely to contain large numbers of
drug action because all drugs are not able to penetrate bacilli, the regimen should include at least two new drugs
into all tissues and cells or permeate biological to which the bacilli are likely to be susceptible especially
membranes, including the normal blood-brain barrier. for patients who had received antituberculosis drugs
Isoniazid, rifampicin and pyrazinamide readily cross earlier and a single drug should never be added to a
biological membranes, whereas streptomycin fails to failing regimen. Otherwise, treatment failure due to the
enter many cells and is much less effective against emergence of drug resistance is the likely result.
intracellular bacilli than against extracellular bacilli (2). The major landmarks in the evolution of modern
antituberculosis Treatment are given in Table 51.1.
The Biochemical Factors
Important biochemical factors influencing the CURRENT RECOMMENDATIONS FOR STANDARD
antimicrobial effect of a drug are the environmental pH REGIMENS
and the oxygen tension. In cavity walls, the pH is neutral
All treatment regimens should have two phases, an initial
or slightly alkaline, oxygen tension is high and
intensive phase of three or four bactericidal drugs and a
mycobacterial multiplication is rapid. In cavitary lesions,
continuation phase of at least two drugs (4).
all the bactericidal antituberculosis drugs are highly
effective. Streptomycin is best active in a slightly alkaline
Initial Intensive Phase
[extracellular] environment. Mycobacterial growth is
slowed by low oxygen tension. Pyrazinamide, is unique The initial intensive phase is designed to kill actively
amongst antituberculosis drugs in having greater growing and semi-dormant bacilli. This means a shorter
bactericidal activity as mycoabacterial metabolism slows duration of infectivity with usually a rapid smear
down and is also effective in acidic environment. Thus, conversion [80% to 90%] after two to three months of
it is active against mycobacteria inside macrophages treatment. The initial phase of rifampicin-containing
where, the pH is acidic, oxygen tension is low and regimens should always be directly observed in order to
mycobacterial growth is slow. ensure adherence. The initial phase usually comprises
of three to four, or sometimes five drugs, especially for
Pharmacological Factors patients who had failed or relapsed after primary
chemotherapy. If initial resistance rates are high, use of
Dosage
a three-drug regimen has the risk of selecting drug-
Drugs must be given in a dosage large enough to produce resistant mutants, especially in smear-positive
an inhibitory concentration at the site where bacilli are pulmonary TB patients with high bacillary loads. In such
736 Tuberculosis
Table 51.1: Evolution of modern treatment for tuberculosis ethambutol, is of benefit when initial drug resistance may
be present or when the burden of organisms is high (7).
Year Major events
The multiplication of susceptible organisms stops during
1946 Clinical use of streptomycin, monotherapy leads to the first few days of effective treatment, and the total
resistance
number of bacilli in the sputum decreases rapidly,
1948 Double drug regimen [SP] prevents emergence of
drug resistance especially within the first two weeks of effective
1952-55 Introduction of isoniazid and two drug regimens [PH treatment (8).
and SH] The key observations concerning antituberculosis
1958 Data from India suggest that supervised adminis- treatment from laboratory and controlled clinical studies
tration of treatment [direct observation of treatment]
are described below. It is crucial for the outcome of
is essential
1958-67 Emergence of daily administered 3 drug regimens
treatment, especially in patients harbouring large
[STH/TH, SPH/PH, SRH/RH] bacterial populations, to rapidly stop bacterial
1959 Ambulatory chemotherapy is as effective as sanato- multiplication and ensure that drug-susceptible bacilli
rium treatment. There is no additional risk of disease are killed as soon as possible [“early kill”]. This will
to close contacts prevent early deterioration and death in the initial weeks
1961 Peripheral neuropathy, related to isoniazid dose and
of treatment. Furthermore, rapid reduction of bacterial
is more common in slow acetylators
1964 Efficacy of twice weekly SH intermittent regimen population say, from 108 [a number commonly found in
[S2H2] is proved lung cavities] to 103, the likely emergence of new resistant
1969 Twice weekly PH as effective as daily PH mutants will be minimized, even after several
1970 12RE and 2RE/10R1E1 is effective salvage regimen generations of uninhibited multiplications.
1972 Concept of two phase regimens evolves: SRH/R2H2
Appropriate multidrug combinations always contain
regimen proves to be effective
1974 Effective short-course daily regimens of 6 months
two drugs capable of destroying single drug-resistant
including RZ mutants pre-existing in wild strains. Thus, at the outset,
1980 6-month fully intermittent effective short-course in a cavity harbouring a population of 108 bacilli, about
regimens evolved 5 000 isoniazid-resistant and several hundreds of
2001 Possibility of 4-month ultra short-course short streptomycin-resistant mutants could be present. When
effective regimen containing quinolones is explored
the patient is started on treatment, initially all the
Numbers preceding the regimen indicate duration in months; susceptible organisms get killed and also the bacilli
numbers in subscript indicate the number of times the drug is resistant to isoniazid alone for example may get killed
administered per week
by the other drugs. Sometimes, the organisms resistant
S = streptomycin, P = para-aminosalicylic acid; H = isoniazid;
R = rifampicin; T = thioacetazone; E = ethambutol; Z = pyrazina-
to rifampicin may get selected out and start multiplying.
mide Such multiplication may be particularly dangerous in the
early phase of the treatment as it will produce drug-
resistant disease (9). Thus, in patients with initial
situations, a four-drug regimen decreases the risk of
resistance to a single drug [except rifampicin], an initial
developing drug resistance and reduces failure and
treatment with three or four drugs is associated with
relapse rates. Even if patients default after the initial
good response to therapy. The addition of a fourth drug
intensive phase, relapse is less likely.
in the intensive phase may be beneficial in patients who
There is ample experimental and clinical evidence
harbour large numbers of Mycobacterium tuberculosis.
that more than one drug, and particularly a three- or four-
drug regimen, when administered in the initial period
Continuation Phase
of treatment, greatly improves the efficacy of treatment
(5,6). At least two bactericidal drugs, such as isoniazid The continuation phase eliminates most residual bacilli
and streptomycin or isoniazid and rifampicin, are and reduces failures and relapses. Because of a small
required in the initial phase. Pyrazinamide given in the number of bacilli in the beginning of the continuation
initial intensive phase allows reduction in treatment phase, fewer drugs are required as the chance of
duration from nine to six months. A fourth drug, like emergence of drug-resistant mutants is low.
Table 51.2A: Classification of currently used Table 51.2B: Alternative classification of currently used
antituberculosis drugs antituberculosis drugs
First line drugs Group 1 First-line oral antituberculosis agents
Rifampicin Isoniazid [H]
Isoniazid Rifampicin [R]
Pyrazinamide Ethambutol [E]
Ethambutol Pyrazinamide [Z]
Streptomycin Group 2 Injectable antituberculosis agents
Second line drugs Streptomycin [S]
Broad spectrum agents Kanamycin [Km]
Cycloserine Amikacin [Am]
Fluoroquinolones Capreomycin [Cm]
Ciprofloxacin Viomycin [Vi]
Ofloxacin Group 3 Fluoroquinolones
Levofloxacin Ciprofloxacin [Cfx]
Moxifloxacin Ofloxacin [Ofx]
Gatifloxacin Levofloxacin [Lfx]
Rifamycins [other than rifampicin] Moxifloxacin [Mfx]*
Rifabutin Gatifloxacin [Gfx]*
Rifapentene Group 4 Oral bacteriostatic second-line antituberculosis agents
Macrolides Ethionamide [Eto]
Azithromycin Prothionamide [Pto]
Clarithromycin Cycloserine [Cs]
Narrow spectrum agents Terizidone [Trd]*
Capreomycin Para-aminosalicylic acid [PAS]
Kanamycin Thioacetazone [Th]†
Amikacin
Viomycin * The long-term safety and efficacy for multidrug-resistant
Ethionamide tuberculosis [MDR-TB] treatment have not yet been fully confir-
Prothionamide med, and therefore, use is not yet recommended for treatment of
Clofazimine MDR-TB
Para-aminosalicylic acid † Thioacetazone should be used only in patients documented to
Thioacetazone be HIV-negative and should usually not be chosen over other
Other drugs* drugs listed in Group 4
* Listed in Table 49.10
Source: reference 10 continuously. For the first time, it was observed among
patients admitted to randomized controlled clinical trials
Antituberculosis Drugs at the Tuberculosis Research Centre [TRC], Chennai
The classification of antituberculosis drugs is shown in [formerly Tuberculosis Chemotherapy Centre, Madras]
Tables 51.2A and 51.2B (10,11). The reader is referred to that even patients who had consumed less than 80 per
the chapter “Treatment of tuberculosis” [Chapter 52] for cent of the scheduled chemotherapy had remained
more details regarding the dosing schedule and various bacteriologically quiescent during a follow-up period of
therapeutic regimens that are currently used. five years. Subsequently, in vitro experiments demons-
trated that, after a culture of Mycobacterium tuberculosis
is exposed to certain drugs for some time, it takes several
THE SCIENTIFIC BASIS OF
days [the “lag period”] before new growth occurs (12,13).
INTERMITTENT TREATMENT
The long generation doubling time of Mycobacterium
Intermittent regimens are those in which the individual tuberculosis [about 18 hours] and the observation that the
drugs are given at intervals of more than one day, e.g., antituberculosis drugs can kill the tubercle bacilli only
three or two times a week. Originally, it was believed when they are metabolically active, intermittent treat-
that antituberculosis drugs require daily administration ment led to the evolution of intermittent antituberculosis
to maintain drug concentrations at inhibitory levels treatment.
738 Tuberculosis
Table 51.3: Lag in growth of Mycobacterium tuberculosis Table 51.4: Comparison of results at the end of 12 months
after temporary exposure to drugs treatment with streptomycin and isoniazid twice weekly vs
para-aminosalicyclic acid plus isoniazid daily
Drug Concentration Lag [days] after exposure for
[mg/l] Status of disease SH PH
6 hours 24 hours Twice weekly * Daily †
Isoniazid 1 0 6-9
No. % No. %
Rifampicin 0.2 2-3 2-3
Pyrazinamide 50 5-40* 40* Bacteriologically quiescent 68 94 56 85
Ethambutol 10 0 4-5 Bacteriologically active 2 2 9 14
Streptomycin 5 8-10 8-10
Ethionamide 5 0 10 Death from tuberculosis 2 3 1 2
Cycloserine 100 0 408 Total no. of patients 72 100 66 100
Thioacetazone 10 0 0
* SH = streptomycin 1 g intramuscular + oral isoniazid 14 mg/kg
* Depending on the pH of the medium body weight
Source: reference 13 †PH = sodium para-aminosalicylic acid 10 g + isoniazid 200 mg
daily, divided into two equal doses
Table 51.3 shows the lag in the growth of Mycobac-
terium tuberculosis after temporary exposure to different
Treatment was ‘fully supervised’, i.e., each patient first
drugs for varying times. For each bactericidal drug there
had to take isoniazid tablets in the presence of the staff
was a maximum lag [last column] that seems to indicate
[who verified that the tablets had actually been swallo-
the practical limit beyond which the interval between
wed] and then receive the injection of streptomycin. The
two doses should not be extended. Thioacetazone did
results at 12 months are shown in Table 51.4.
not produce any lag, even after exposure for 24 or 96
The intermittent regimen was highly successful and
hours. This suggests that thioacetazone is unsuitable for
perhaps slightly more effective than the daily regimen.
intermittent treatment. Animal studies (13) showed
All the patients admitted to the study had extensive,
conclusively that, with the exception of rifampicin, the
bilateral cavitary disease with sputum heavily positive
longer the chosen interval between doses, the higher the
by direct smear examination. The relapse rates at two-
doses of most of the drugs needed to be. Thus, with high
years were eight per cent for the twice-weekly and 12
doses of isoniazid, a three-day interval was shown to be
per cent for the daily regimen; after four years, the
the optimum, whereas an extension to eight days gave
corresponding figures were 12 per cent and 15 per cent,
significantly worse results. A series of experiments in
respectively. In four out of five patients who relapsed
animal models demonstrated that intermittent adminis-
on the intermittent regimen, the bacilli were susceptible
tration of isoniazid, rifampicin and pyrazinamide
to both isoniazid and streptomycin. These data suggest
actually increased the efficacy of treatment.
that had there been an intensive phase at the start of
treatment, the susceptible bacilli would probably have
Standard Intermittent Regimens
been eliminated.
Although experimental findings cannot be directly In another study (15), the possibility of increasing the
extrapolated to the clinical scenario in humans, these dosing interval to one week among out-patients was
results were promising enough to be explored in clinical investigated at TRC, Chennai. Four intermittent regimens
studies. The first such randomized controlled clinical trial were studied concurrently. The regimen consisting of
[Table 51.4] was undertaken at the TRC, Chennai (14). A streptomycin and isoniazid administered twice weekly,
standard oral regimen of isoniazid plus para-amino- was compared with streptomycin plus isoniazid
salicyclic acid [PAS] twice daily was compared with a administered once weekly. In both regimens, the dosage
twice-weekly regimen of streptomycin plus isoniazid. of streptomycin [0.75 g to 1 g given by intramuscular
The oral regimen was dispensed for self-administration. injection] and isoniazid [15 mg/kg body weight] were
For the intermittent regimens, the patients had to attend the same. The effect of a lower dose [0.75 g] of strepto-
the clinic twice a week at three- to four-day intervals. mycin was studied because it seemed likely that the
smaller dose would be sufficient and better tolerated, sterilizing activities of pyrazinamide and rifampicin
particularly by elderly patients, than the usual 1 g dose. implicating low relapses. The chances of failure due to
The twice-weekly regimen again proved to be highly initial drug resistance are greatly decreased because of
successful and the once-weekly regimen was consider- the multiplicity and potency of the drugs used particu-
ably less effective. Nevertheless, it was rather impressive larly in the intensive phase. Sputum conversion occurred
that, despite severe disease, 71 per cent of patients on rapidly. In view of all these factors it was possible to
the latter regimen achieved bacteriological quiescence evolve highly effective short-course regimens consisting
(15). of rifampicin, isoniazid, and pyrazinamide with
The reasons for the inferiority of the once-weekly streptomycin or ethambutol for a period of two months
regimen were examined. In this analysis, patients were followed by two or three drugs like rifampicin plus
grouped according to the rate of inactivation of isoniazid isoniazid with or without ethambutol or a non-rifampicin
and the dosage of streptomycin. The efficacy of the twice- continuation phase consisting of streptomycin or
weekly regimen was influenced neither by the inacti- thioacetazone plus isoniazid. These regimens were found
vation rate of isoniazid nor by a 25 per cent reduction in to be highly effective with no failures among patients
the dosage of streptomycin. In contrast, the once-weekly with drug-sensitive bacterial population. The relapse
regimen was clearly affected by the rate of isoniazid rates were less than five per cent during a two-year period
inactivation and, to a lesser extent, also by the reduction of follow-up. Majority of relapses occurred within six
months after stopping chemotherapy. In contrast, 12
in the streptomycin dosage. The twice-weekly regimen
month non-rifampicin conventional regimens had an
was, therefore, robust and effective, even without an
overall maximum failure [failure plus relapse] rate of 18
initial intensive phase. The isoniazid inactivation rate also
per cent. Streptomycin resistance was of no consequence
influenced the response to other once-weekly regimens
in the response to treatment among patients treated with
concurrently investigated.
short-course chemotherapeutic regimens. Initially either
From the clinical studies done at TRC, Chennai and
three or four bactericidal drugs were given daily for two
other places, the following conclusions may be drawn
or three months in the initial intensive phase followed
from the experience gained with intermittent treatment
by two or three drugs daily for the subsequent four or
without rifampicin. Twice-weekly regimens containing
six months.
isoniazid in a high dosage [14 to 15 mg/kg] and strepto-
mycin [0.75 g to 1 g] are highly effective, whether given Intermittent Short-course Chemotherapy Regimens
from the outset or after an initial intensive phase of
treatment. Their efficacy in slow and rapid inactivators As the daily SCC regimens were found to be highly
of isoniazid is similar. These regimens can be highly effective, the efficacy of intermittent SCC regimens was
effective in patients with extensive disease and in studied. At first, regimens with a daily intensive phase
populations with a high frequency of rapid inactivators. followed by an intermittent continuation phase were
A once-weekly regimen of isoniazid [15 mg/kg] and studied with the risk of relapse being the key indicator
streptomycin [1 g] after initial daily therapy with isonia- of the effectiveness of the regimen (16). Many regimens
zid and streptomycin given for four weeks, approached achieve nearly 100 per cent cure; relapse was less than
five per cent. A series of studies (17-28) have demons-
the efficacy of the twice-weekly regimen; however, unlike
trated that intermittent treatment following a daily
the latter, it was substantially inferior in rapid
intensive phase–which may be as short as two weeks–is
inactivators, and therefore, cannot be recommended.
highly effective, as long as treatment observation is
Evolution of Short-course ensured.
Six-month SCC regimens achieve smear and culture
Chemotherapeutic Regimens
conversion within two to three months in a majority of
The monumental advance in the chemotherapy of TB in patients. Many regimens achieve a favourable response,
the last three decades has been the development of short- as defined by culture negativity of 97 to 100 per cent
course chemotherapy [SCC] regimens of six to eight (17-28) at the end of treatment. The challenge, however,
months duration as against 12 to 24 months of conven- lies in identifying practical regimens with low [< 5%]
tional chemotherapy. Animal studies had shown high relapse rates.
740 Tuberculosis
Short-course Chemotherapy Regimens in the The prefix ‘4’ refers to the continuation phase of treatment
Treatment of Sputum Smear-positive Pulmonary for four months with rifampicin and isoniazid.
Tuberculosis In the regimen designated 2H3R3Z3E3 /4H3R3 or 2
[HRZE]3/4[HR]3, the prefix ‘2’ refers to the initial phase
Several studies have demonstrated that a six-month SCC
of treatment for two months with isoniazid, rifampicin,
regimen containing rifampicin throughout and
pyrazinamide and ethambutol. The subscript ‘3’ follow-
pyrazinamide in the intensive phase is highly effective
ing the letter[s] indicates thrice weekly administration
in the treatment of sputum smear-positive TB (17-28). In
of the drugs. The prefix ‘4’ refers to a continuation phase
the initial studies, drugs were given daily throughout or
of four months with isoniazid and rifampicin.
during the initial intensive phase at least. Studies
conducted at the TRC, Chennai and Hong Kong Special Short-course Chemotherpay Regimens of Less
Administrative Region of China [Hong Kong SAR] have Than Six Months
shown that fully intermittent regimens are equally
Two five-month regimens [2HRZS/3(HZS) 2 ] and
effective, and that the reduction in adverse reactions is
[3HRZS/2(HZS)2] investigated at Chennai were found
significant, with near 100 per cent efficacy at the end of
to be effective and had low relapse rates [4% to 5%] (16).
the treatment followed by a relapse rate of two to seven
This is the only study that investigated five-month
per cent (21,22,28,29).
regimens consisting of streptomycin for the entire
Thus, these data suggest that newly diagnosed
duration of treatment and acceptable results were
sputum smear-positive pulmonary TB patients should
achieved (16). The efficacy of a three-month regimen [90
be treated with daily or intermittent therapy for six to
doses of RHZS] (30,31) has been studied in patients with
eight months; eight months being required if rifampicin
pulmonary TB. Though this regimen achieved a near 100
is not used in the continuation phase of the treatment.
per cent culture conversion rate at the end of the treat-
The intensive phase should comprise of four drugs
ment, 20 per cent of patients had bacteriologically
including rifampicin and pyrazinamide and should be
confirmed relapse during the follow-up period of five
given for at least two months.
years (31). In contrast, when fewer doses were
administered over a longer duration [thrice-weekly for
Terminology of Standard Tuberculosis
Treatment Regimens 2 months; followed by twice-weekly for 4 months,
making up a total of 63 doses in 6 months], relapse rates
It is essential to familiarize with the terminology used to were only four to six per cent. Thus, the duration for
describe various treatment regimens for TB (4). There which the drugs are administered appears to be of prime
are standard codes for TB treatment regimens. In this importance and not the number of doses. Similarly, four-
nomenclature, each antituberculosis drug has a standard month SCC regimens investigated in Singapore also had
abbreviation [H = isoniazid, R = rifampicin, Z = pyrazina- high relapse rates [8% to 16%] (23-25,31,32). With the
mide, S = streptomycin, and E = ethambutol] and each advent of fluoroquinolones there appears to be a tentative
regimen has two phases. The number before a phase possibilty of reducing the duration of treatment to four
indicates the duration of that phase of treatment in months in patients with pulmonary TB (33). However,
months. A number in subscript [e.g., 3] following a letter more studies are needed to draw firm conclusions.
is the number of doses of that drug per week. If there is
no number in subscript after a letter, then treatment with Optimum Duration of Standard, Non-rifampicin
that drug is on a daily basis. An alternative drug [or Containing Regimens
drugs] appears as a letter [or letters] in parantheses. There are situations where rifampicin is either not
Some examples are described below to illustrate the available or rifampicin and pyrazinamide cannot be given
standard code. In the regimen designated ‘2HRZE/4HR’, to a patient. Before rifampicin and pyrazinamide became
the prefix ‘2’ refers to an initial intensive phase of treat- available, patients were treated for prolonged periods
ment for two months with isoniazid, rifampicin, ranging from 12 to 18 months. For patients with initially
pyrazinamide and ethambutol. As there is no subscript sputum smear-positive TB, practically all-effective
number following the letters, the drug treatment is daily. regimens reach the potential of bacteriological quiescence
within six months of the start of treatment. However, without pathological and/or bacteriological confirmation
relapse occurs in about one-fourth of patients treated with of the diagnosis. This results in over-diagnosis and
streptomycin, isoniazid and thioacetazone daily for six unnecessary treatment of a large number of patients (41).
months (17). Hence if rifampicin and pyrazinamide are not Extra-pulmonary TB may not be considered at all in the
used the total duration should be at least 12 months. differential diagnosis; resulting in delay or deprivation
With reference to study the optimum duration of of treatment (42).
initial supplement of streptomycin or the initial intensive Extra-pulmonary TB is usually paucibacillary and any
phase in long-term treatment, studies in East Africa had treatment regimen that is effective in pulmonary TB is
shown that an initial supplement of streptomycin for likely to be effective as well in the treatment of extra-
eight weeks to the basic regimen of thioacetazone plus pulmonary TB. For the purpose of treatment, extra-
isoniazid daily for 12 months had a success rate of 96 pulmonary TB can be classified into severe and non-
per cent and the emergence of resistance was rare among severe forms. Severe forms of extra-pulmonary TB include
patients who failed treatment. Two weeks of initial meningeal TB, spinal TB [Pott’s disease], neurological-
intensive treatment resulted in 10 per cent of failures, all TB, abdominal TB, bilateral or unilateral, moderate or
with organisms resistant to isoniazid. Patients who extensive pleural effusion, pericardial effusion, and bone
received an initial supplement of streptomycin for four and joint TB involving more than one site. Limited disease
weeks had only a slightly [2%] less favourable bacterio- involving other body sites are classified as non-severe
logical response than those in the eight weeks intensive forms. There are few reports of the use of SCC in the
phase (33). Other studies (34,35) investigating two weeks treatment of extra-pulmonary TB (43). The difficulty in
of initial intensive phase in the long-term treatment did defining a clear-cut “end-point” in assessing the efficacy
not show any contribution to the overall results of the of treatment of extra-pulmonary TB led to varying
regimens. Thus, the optimum duration of intensive phase durations of treatment, and there have been relatively
in a conventional long-term treatment is eight weeks. On few controlled clinical trials in extra-pulmonary TB
the other hand, there is enough evidence that more than (44,45). The principles underlying the diagnosis and
18 months of good treatment produces little additional management of extra-pulmonary TB, therefore, have
benefit, if any, in terms of treatment success or prevention evolved mainly from the experience gained from
of relapse (36). randomized controlled clinical trials for pulmonary TB.
However, studies on some forms of extra-pulmonary TB
SMEAR-NEGATIVE PULMONARY TUBERCULOSIS [e.g., TB of the spine, TB lymphadenitis, abdominal TB
The optimum duration of treatment for smear-negative and brain tuberculoma] have clearly established the
pulmonary TB patients was addressed in studies done efficacy of SCC [6 to 9 months] in both children and
in Hong Kong SAR (37-40). Patients who had five smears adults. Table 51.5 describes the efficacy of treatment
negative for acid-fast bacilli [AFB] and had a chest radio- regimens in different forms of extra-pulmonary TB
graph suggestive of pulmonary TB were treated with two (46-50). The overall favourable response with these
or four months of SHRZ (37-40). Relapse rates were regimens varied from 87 to 99 per cent [Table 51.5].
higher with two to three months of treatment and the Intermittent regimens have been proven to be as effective
study concluded that smear-negative patients require at as daily regimens (46-50).
least four months of treatment. But for consistency and The severe form of extra-pulmonary TB is preferably
to allow a margin of safety, the World Health Organiza- treated with four drugs in the initial intensive phase and
tion [WHO] recommends six-month regimens for the if required, the total duration of treatment can be
treatment of smear-negative pulmonary TB. extended to nine to twelve months, especially in TB
meningitis and neurological-TB. Corticosteroids should
EXTRA-PULMONARY TUBERCULOSIS also be administered to patients with TB meningitis with
neurological impairment, massive pleural effusion, some
Challenges in Diagnosis
cases of TB pericarditis, and possibly other severe forms
Patients with extra-pulmonary TB are often treated of extra-pulmonary TB. Lymph nodes can enlarge, persist
empirically based on clinical and radiological grounds and become superinfected with bacteria in the course of
742 Tuberculosis
Table 51.5: Efficacy of treatment regimens in different forms of extra-pulmonary tuberculosis
Study (reference) Treatment regimens Duration No. of Follow-up Overall

[months] patients period [months] favourable
response [%]
Spinal TB (46) 6HR + Modified 6 78 120 90

Hong Kong Surgery
6HR 6 78 120 94
9HR 9 79 120 99
Pott’s paraplegia (47) Radical surgery +
2HERS/7H2R2 9 20 60 90
2HERS/7H2R2 9 11 60 73
TB lymphadenitis (48) 2H3R3Z3S3/4H2S2 6 168 36 97
Abdominal TB (49) 2HRZ/4HR 6 85 60 94
EHS/HE* 12 93 60 87
Brain tuberculoma (50) 3HRZ/6H2R2 9 47 24 89
3H3R3Z3/6H2R2 9 44 24 91
The number before the letters refers to the number of months of treatment
The subscript after the letter refers to the number of doses per week
* Daily regimen of streptomycin, ethambutol and isoniazid for 2 weeks, followed by ethambutol and isoniazid for rest of the subsequent
12 months
TB = tuberculosis; H = isoniazid; R = rifampicin; E = ethambutol; S = streptomycin; Z = pyrazinamide
TB treatment. Paradoxical reactions or immune documentation of relapse rates of less than four per cent
reconstitution inflammatory syndrome [IRIS] may occur. (46-50).
Generally, no modification or prolongation of
antituberculosis treatment regimen is indicated. SURGERY
Even though treatment gives good results in most
forms of extra-pulmonary TB, there are a few exceptions With the introduction of SCC, primary surgical treatment
such as TB meningitis and spinal TB, where the treatment is less frequently used for the treatment of TB. The current
outcome depends on early initiation of antituberculosis status of surgery in the treatment of TB is discussed in
the treatment. In TB meningitis, particularly, the outcome the chapter “Surgery for pleuropulmonary tuberculosis”
correlates with the stage of the disease at the time of [Chapter 55] and in the respective chapters covering
initiation of treatment; only a minority of patients with various forms of extra-pulmonary TB.
severe disease recover completely (51). Predictors of poor
Monitoring of Adverse Drug Reactions to
outcome include younger age and advanced stage of the
Antituberculous Drugs
disease. However, Donald et al (52) had reported a
mortality rate of 16 per cent and a relapse rate of two per Adverse reactions to antituberculosis drugs [Table 52.3]
cent among 95 children diagnosed to have TB meningitis are relatively rare, but in some patients they may be
treated with a SCC regimen of RHZE daily for six severe. Clinicians who treat TB should be familiar with
months. Similarly, in patients with spinal TB, the time the methods of monitoring adverse reactions. Patients
taken for neurological recovery was not related to the should be closely monitored for signs and symptoms
nature of treatment regimen but appeared to be influen- suggestive of adverse drug reactions. The following are
ced by factors, such as initial motor power, presence or the definitions used to document adverse drug reactions
absence of bed sores and duration of kyphosis (47). [ADRs] and adverse events [AEs] (53).
The long-term efficacy of short-course treatment
regimens of six to twelve months duration in various Adverse Drug Reaction
forms of extra-pulmonary TB has been proven by An ADR is defined as a response to a drug which is
systematic follow-up of patients for five to ten years and noxious and unintended and which occurs at doses
normally used in humans for diagnosis or therapy of abnormal liver functions while on antituberculosis drugs
diseases. The term ADR implies that a causal relationship (54). The reader is referred to the chapter “Antituberculosis
between a medicinal product [drug] and an adverse treatment induced hepatotoxicity [Chapter 54] for more
event, is at least a reasonable possibility [i.e., the relation- details.
ship cannot be ruled out] (53). Peripheral neuropathy is associated with use of
isoniazid and is more likely among persons prone to
Adverse Event develop neuropathy due to other causes. Hyperuricaemia
may occur in patients receiving pyrazinamide but acute
An AE is defined as an untoward medical occurrence in
a patient or clinical investigation subject administered a gout is uncommon. Asymptomatic hyperuricaemia is not
an indication for discontinuing the drug. The reader is
pharmaceutical product and which does not necessarily
also referred to the chapter “Musculoskeletal manifestations
have a causal relationship with this treatment. An AE
can, therefore, be any unfavourable and unintended sign of tuberculosis” [Chapter 24] for more details.
[including an abnormal laboratory finding] symptom,
Treatment of Tuberculosis Under Special Situations
or disease temporarily associated with the use of a
medicinal product, whether or not related to the The reader is referred to the chapters “Granulomaotus
medicinal [investigational] product (53). hepatitis [Chapter 20], “Neurological tuberculosis” [Chapter
21], “Tuberculosis in pregnancy” [Chapter 30], and
Serious Adverse Event “Tuberculosis in chronic renal failure” [Chapter 33] for more
A serious adverse event SAE is defined as a fatal or life details regarding the treatment of TB under special
situations.
threatening event or an event resulting in significant or
persistent disability or incapacity or may necessitate
Clinically Significant Drug Interactions
hospitalization or prolongation of hospitalization or may
Due to Rifampicin
jeopardize the subject and may require medical or
surgical intervention to prevent serious outcomes. Several clinically significant drug interactions are known
Ideally, adults treated for TB should have baseline to occur with rifampicin and these are summarized in
measurements of hepatic enzymes, serum bilirubin and Table 52.5.
creatinine as well as complete blood and platelet counts.
Serum uric acid should be measured if pyrazinamide is TREATMENT OF TUBERCULOSIS IN PERSONS
used and baseline examination of visual acuity should WITH HUMAN IMMUNODEFICIENCY VIRUS
be obtained for patients for whom ethambutol is INFECTION AND ACQUIRED IMMUNODEFICIENCY
prescribed. The purpose of these baseline tests is to detect SYNDROME
any abnormality that would complicate therapy or
require a modified regimen. Monitoring of all adverse The treatment of TB in persons with the human immuno-
reactions to TB medications should be individualized. deficiency virus infection and acquired immuno-
Type and frequency of monitoring should depend on the deficiency syndrome is detailed covered in the chapter
drugs used in a given regimen and the patients’ risk “Tuberculosis and human immunodeficiency virus infection”
factors for adverse reactions, such as, age and alcohol [Chapter 40].
use. Patients should be instructed to report if they
develop any new symptoms. If the symptoms are sugges- Fixed-dose Combinations of Antituberculosis Drugs
tive of adverse reactions, appropriate laboratory testing Fixed-dose combination antituberculosis drugs [FDC],
should be performed. All patients receiving regimens which incorporate two or more drugs into one tablet in
containing isoniazid, rifampicin, and pyrazinamide fixed proportions, have been used since the late 1980s
should be closely monitored for drug induced hepatitis. and are registered in more than 40 countries (55).
The latter may be confused with acute viral hepatitis in Combinations of isoniazid and thioacetazone and
developing nations, therefore, it is essential to check for isoniazid and ethambutol have long been used. For SCC,
markers for viral hepatitis in patients who develop the two most common FDC preparations combine
744 Tuberculosis
isoniazid, rifampicin and pyrazinamide, used in the If at all they are used, only the formulations recom-
intensive phase of treatment, and isoniazid and rifam- mended by the WHO and International Union Against
picin, often used in the continuation phase. Increasingly, Tuberculosis and Lung Disease [IUATLD] should be
a four-drug FDC consisting of isoniazid, rifampicin, used (66). When three- or four-drug FDC are used in the
pyrazinamide and ethambutol is being used (56). intensive phase of treatment, a different two-drug FDC
is used in the continuation phase. If a country is using
Potential Advantages FDC, it will need to provide additional training on drug
procurement, treatment recommendations, and patient
Drug resistance may be less likely to emerge since multiple
drugs are incorporated into the FDC (57-59). Further, with and provider education (55). Although there are potential
advantages in using FDC, the benefits may be difficult
treatment interruption due to default, all drugs will be
to realise given the existing operational, programmatic
stopped, and thus, resistant organisms are unlikely to
emerge. The use of FDC can simplify treatment, will and regulatory constraints. Each country must carefully
weigh the advantages, disadvantages and appropriate
reduce the number of pills to be consumed, and thus,
role of FDC within their programme.
minimise prescription errors and reduce the probability
of monotherapy. Procurement, management and Phenomenon of Drug Resistance
distribution of drugs are simplified by the use of FDC. A
Clinical and laboratory observations and experimental
treatment regimen using FDC may improve patient’d
compliance to treatment (59,60). The use of rifampicin in studies have led to the understanding of development
of drug resistance, its clinical and epidemiological
FDC may reduce inappropriate use of rifampicin for other
significance, and its prevention and control. The pheno-
infections (61). Several studies have shown that the FDC
containing four drugs is bioequivalent to separate menon of resistance was detected when streptomycin
alone was introduced in the treatment of TB in humans
individual drugs at the same dose levels (61-64).
(67). At first a striking improvement in the patient’s
symptoms, together with a rapid decrease in the number
Potential Disadvantages
of bacilli in the sputum occurred. Subsequently, the
The bioavailability [the amount of an ingested drug number of bacilli soon increased again and the patient’s
absorbed into the blood] of rifampicin may decrease condition deteriorated. Bacilli isolated from the sputum
when it is combined with other drugs in the FDC of patients who had received streptomycin alone for a
(61-64). Therefore, use of FDC, particularly in three- and few months continued to grow in vitro in the presence of
four-drug combinations, could result in sub-optimal high concentrations of the drug. This showed that large
therapeutic plasma levels of rifampicin, and thus, could bacterial populations contain a minute proportion of
lead to treatment failures, relapses and/or the generation organisms that are barely or not at all susceptible to a
of rifampicin-resistant strains of Mycobacterium tuberculo- particular drug, even before its administration. The
sis (65). Therefore, only FDC of proven bioavailability susceptible bacteria are killed by the drug, the few
should be used (66). resistant organisms survive and multiply, and their non-
A global mechanism for pre-qualification of FDC has susceptible descendants, generation after generation,
been proposed to ensure that only quality FDC will be replace the susceptible organisms. Thus, clinically
purchased and used. The optimal operational efficiency relevant drug resistance is the result of a selection process.
from using FDC may not be achieved as the doses Resistance to any antituberculosis drug [including
required for all patients receiving treatment will vary rifampicin] develops predictably if the drug is used alone.
with body weight of patients. The WHO recommended This was first described with streptomycin in 1947 as the
dosage schedule for FDC allows for easy adjustment of “fall and rise” phenomenon. Such resistance can develop
dosage by weight. Adverse effects, such as antituber- after relatively brief periods [i.e., over several days] of
culosis drug induced hepatotoxicity, may also necessitate single drug treatment, especially in patients with large
dosing changes. Hence, any TB control programme using numbers of actively replicating bacilli [e.g., in patients
FDC must also supply single drugs for special with extensively active disease or severe immunosup-
circumstances to be used by TB specialists. pression, such as AIDS]. Similarly, resistance would be
expected if only one drug in a regimen is effective [due isoniazid, so that the rifampicin component cannot be
to pre-existing resistance to the other agents of the administered alone.
regimen]. Development of resistance due to addition of The consequences of restricted use of rifampicin are
a single drug to a failing regimen has also been well minimal, because rifampicin is occasionally indicated for
described (68). the treatment of some deep-seated staphylococcal
Multidrug-resistant TB [MDR-TB] caused by isolates infections, and in prevention of meningococcal disease.
resistant to isoniazid and rifampicin with or without Other alternative antibiotics that are available may be
resistance to other antituberculosis drugs is emerging as used in such conditions.
a threat to destabilize the global TB control (69,70).
Extensively drug-resistant TB [XDR-TB] is also being RESEARCH AGENDA AND FUTURE FOR
documented in several parts of the world (71). The reader
TUBERCULOSIS TREATMENT
is referred to the chapters “Drug resistant tuberculosis”
[Chapter 49], and “Antituberculosis drug resistance surveil- Newer Antituberculosis Drugs
lance” [Chapter 50] for more details.
Newer antituberculosis drugs are needed for three
Reasons for Special Precautions to reasons: to shorten or otherwise simplify treatment of
Protect Rifampicin TB caused by drug-susceptible organisms, to improve
the treatment of patients with MDR-TB, and to provide
Rifampicin must be protected because it is the key more effective and efficient treatment of latent
sterilizing drug in short-course treatment (72). With
tuberculosis infection [LTBI] (75). Although treatment
rifampicin, treatment for drug-susceptible disease can
regimens for drug-susceptible TB are effective, they must
be completed in six to nine months [depending on
be administered for a minimum of six months to achieve
companion drugs], with combined rates of failure and
optimal results. Non-adherence to this relatively lengthy
relapse of less than five per cent. Without rifampicin,
course of treatment remains a major problem. To address
treatment must generally be given for at least 12 months
the problem of non-adherence, direct observation of
to achieve low rates of failure and relapse. Resistance to
treatment [DOT], as a component of the DOTS strategy
rifampicin results in a substantial increase in the rate of
is recommended as the standard of care worldwide.
failure and relapse when standard three- or four-drug
However, the administrative and financial burden of
regimens are used (73). In the British Medical Research
providing DOT to all patients is considerable.
Council trials (74), initial resistance to rifampicin was
associated with a rate of failure of 45 per cent during Current treatment regimens for drug-resistant TB
treatment and half of the remaining patients relapsed utilize drugs that are less effective, more toxic, and more
[overall unfavourable treatment outcome of 72%]. This expensive than those used for standard treatment.
is in striking contrast to the experience of patients with Moreover, these treatment regimens often have to be
initial resistance to isoniazid and or streptomycin. When given for 18 to 24 months. Although new drugs that are
rifampicin resistance is present, the minimum required effective against resistant organisms would alone not
duration of antituberculosis treatment with a feasible solve the problem of drug resistance, their judicious use
regimen is 12 to 15 months. If resistance to isoniazid is would greatly improve the treatment of many patients.
also present [i.e., multidrug resistance], then necessary With the advent of newer and more efficient diagnostic
treatment duration is likely to be 18 to 24 months or more. tests for the detection of LTBI, such as the inteferon-
These problems can be prevented by restricting avail- gamma release assays [IGRAs], there is a need for new
ability of rifampicin and related drugs [rifabutin, drugs to provide for safe and effective “short-course”
rifapentine] to TB control programmes [as is done in some LTBI treatment. No truly novel compounds that are likely
developing countries with well functioning program- to have a significant impact on TB treatment are presently
mes], or to licensed or experienced practitioners [as is available for clinical study. Table 49.10 lists some of the
done in many developed and some developing count- newer drugs that are being evaluated for the treatment
ries]; and/or, making rifampicin available exclusively of TB. The reader is also referred to the chapter “Treatment
as a fixed-drug combination in products which include of tuberculosis” [Chapter 52] for more details.
746 Tuberculosis
OTHER INTERVENTIONS TO IMPROVE experimental studies (83). Finally, a study suggested that
THE EFFICACY OF TUBERCULOSIS the administration of vitamin A and zinc to patients with
TREATMENT PROGRAMMES pulmonary TB is associated with an increased rate of
sputum conversion and improvement in chest
A number of other approaches have been suggested that
radiographs (84). Further assessment of nutritional
might lead to improved treatment outcome, including
supplements in TB treatment is indicated.
alternative drug delivery systems and a variety of
methods of immunomodulation and immunotherapy. METHODS TO IDENTIFY AND MANAGE HIGH- AND
Experimental studies have demonstrated that effective LOW-RISK PATIENTS
serum concentrations of isoniazid and pyrazinamide can
be provided through incorporation of drug into slow- The sputum culture positivity at two months appears to
release, biodegradable polymers that are implanted be a marker for an increased risk of relapse for patients
subcutaneously (76). However, there has been little with pulmonary TB. Surrogate markers that could be
apparent commercial interest in pursuing this approach. measured earlier in therapy and have a greater sensitivity
Liposomal encapsulation of antituberculosis drugs has and specificity for a poor outcome could better select high
been suggested as an approach to direct drug to the risk patients for more intensive or longer therapy, thus,
proposed site of infection [i.e., the macrophage] to minimizing the likelihood of relapse. Studies of several
provide more effective and better tolerated therapy; and molecular markers in the sputum have shown promise
for widely spaced treatment interval. Similarly, and deserve further evaluation (85). Conversely, markers
incorporation of drug into inhalable smaller particles that reliably identify patients at lower risk of an adverse
may reduce dose requirements, minimize toxicity, and treatment outcome would be helpful to select patients
deliver drug to the infected alveolar macrophages. for less intense or shorter treatment. Whether or not low-
Although experimental studies have suggested that these risk patients can be treated with shorter regimens using
approaches might be effective, little clinical work has currently available drugs is a topic of considerable
been done in these areas (76,77). Because of possible importance.
detrimental effects of the cytokine, tumour necrosis
factor-α [TNF-α] in HIV-associated TB, there has been DOTS
some interest in the use of drugs, such as thalidomide The WHO (4) and the IUATLD (86) guidelines for the
and pentoxifylline, that block TNF-α production. Studies treatment of TB target, in general, countries in which
have shown that administration of thalidomide improves mycobacterial culture, drug susceptibility testing,
weight gain in both HIV-seropositive and HIV-sero- radiographic facilities, and second-line drugs are not
negative patients with TB (78). Pentoxifylline has been widely available. Both these recommendations are built
associated with reduced circulating HIV viral load in around a national case management strategy called
patients with TB (79). However, the potential side effects “DOTS,” in which DOT is only one of five key elements
of these drugs may outweigh possible benefits. A more (87).
promising intervention is the administration of The essential principles of DOTS strategy are the
“protective” cytokines, such as aerosolized interferon and products of India’s long and distinguished tradition of
subcutaneous interleukin-2, which have shown activity TB research. In the 1950s and 1960s, studies at the TRC,
as adjuncts to chemotherapy in patients with MDR-TB Chennai, demonstrated the efficiency and safety of home
(80,81). Another method of immunomodulation, the use treatment of TB patients without additional risk of
of heat-killed preparations of Mycobacterium vaccae as a disease to close contacts (88). Wallace Fox (89) of TRC,
therapeutic vaccine, has not shown clinically significant Chennai identified the problems related to poor
benefits when carefully evaluated in randomized clinical compliance to treatment and demonstrated the necessity
trials (82). Nonetheless, there continues to be interest in and feasibility of supervised administration of every dose
this approach, especially for patients with advanced of treatment to TB patients and also provided evidence
drug-resistant TB. Other vaccines that lead to expression that intermittent chemotherapy was as effective as daily
of protective cytokines have shown more promise in treatment. In the 1960s, studies at the National
Tuberculosis Institute [NTI], Bengaluru [then Bangalore], tuberculosis in South India. Bull World Health Organ
documented the efficacy and feasibility of case detection 1960;23:535-85.
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Treatment of Tuberculosis 751
Treatment of Tuberculosis
52
WW Yew
INTRODUCTION treatment. This could lead to treatment failure and

development of drug resistance. In the early 1960s, the
Tuberculosis [TB] is one of the most common infectious
experience gained in Chennai [earlier called Madras] and
diseases known to mankind. After some years of neglect,
Hong Kong from collaborative studies between the British
this important global problem is regaining the attention
Medical Research Council and relevant health care
it deserves. Treatment of TB, largely based on drugs, has
authorities demonstrated the effectiveness and efficacy of
been evolving for several decades.
ambulatory antituberculosis treatment (4). Prolonged
hospitalizsation in sanatoria became unnecessary. Fully
HISTORY OF CHEMOTHERAPY OF
supervised chemotherapy, directly observed therapy
TUBERCULOSIS
[DOT], in form of streptomycin and isoniazid given
Chemotherapy for TB became possible only after the intermittently twice per week in the continuation phase,
discovery of streptomycin in 1944. Improvement in after the initial few months of the daily triple-drug therapy
clinical state, sputum bacteriology and radiography was referred to earlier, was utilized. In 1965, rifampicin was
experienced by the patient after two to three months of discovered followed shortly by ethambutol and
therapy with the drug. Unfortunately, these good pyrazinamide. In the 1970s, short-course chemotherapy
responses were short lasting as bacillary resistance to [SCC] was introduced for the treatment of TB (5).
streptomycin would develop after the monotherapy
resulting in disease deterioration again (1). A few years Biological Characteristics of Mycobacterium
later, combined therapy with streptomycin and paratuberculosis and Basis of Short-course
aminosalicylic acid was found to prevent drug resistance Chemotherapy
from developing and achieved better results (2). The Mycobacterium tuberculosis is a slowly growing bacterium,
subsequent introduction of isoniazid as a drug in the and it can also enter a phase of dormancy which is basi-
combination regimen for treating TB formed the basis of cally drug refractory. A patient with TB can harbour four
primary chemotherapy in the 1950s to 1960s (3). The hypothetical populations of organisms. The first popu-
standard regimen then comprised streptomycin, lation is the actively growing extracellular organisms,
isoniazid and para-aminosalicylic acid for a few months which are present in abundance within aerated cavities.
followed by the latter two drugs up to a total period of The second population consists of slow intermittently
18 to 24 months. Para-aminosalicylic acid could be growing organisms in an unstable part of the lesion. The
substituted by ethambutol or thioacetazone depending third population includes organisms surviving in low
on their availability and acceptability in the community. environmental pH, which can occur in inflammatory
Aside from adverse reactions to drugs, patients often lesions or within phagolysosomes of macrophages. The
absconded prematurely or took drugs irregularly when last population refers to the completely dormant orga-
they became symptomless after a few weeks to months of nisms surviving under anaerobic conditions [Figure 51.1].
752 Tuberculosis
The three major actions of antituberculosis drugs (5) Table 52.1: Drug regimens for treatment of new cases of
are: [i] bactericidal action, defined by the ability to kill smear-positive pulmonary tuberculosis
actively growing bacilli rapidly; [ii] sterilizing action, Reference
defined by the capacity to kill the semi-dormant orga-
Standard 6-month daily regimens
nisms; and [iii] prevention of emergence of drug
2 EHRZ/4 HR 6
resistance. 2 SHRZ/4 HR
Isoniazid is the most potent bactericidal drug.
Standard 6-month regimens when directly observed, intermittent
Rifampicin is also important as such. Rifampicin and
chemotherapy can be organized
pyrazinamide are important drugs for sterilizing the TB 2 EHRZ/4 H3R3
lesions and preventing disease relapse. Resistance to an 2 SHRZ/4 H3R3 7
antituberculosis drug is due to spontaneous chromo- 2 E3H3R3Z3/4 H3R3
somal mutation at a frequency of 10-6 to 10-8 mycobacte- 2 S3H3R3Z3/4 H3R3 8, 9
0.5 EHRZ/1.5 E2H2R2Z2 / 4 H2R2 10
rial replications. As mutations resulting in drug resistance
0.5 SHRZ/1.5 S2H2R2Z2 / 4 H2R2
are unlinked, the probability of resistance to all three 2 EHRZ/4 H2R2 11
drugs used concomitantly becomes 10-18 to 10-20. Thus, 2 SHRZ/4 H2R2
the chance of drug resistance becomes practically nil
Alternative less active regimens of longer durations
when three effective drugs are used in combination for
With a highly active initial 4-drug phase
the treatment of TB. Among the first-line antituberculosis
2 EHRZ/6 HT 12
drugs, isoniazid and rifampicin are most effective in 2 SHRZ/6 HT
preventing the emergence of drug resistance (5). 2 EHRZ/6 HE
Streptomycin, ethambutol and pyrazinamide are less so. 2 SHRZ/6 HE
Thioacetazone and para-aminosalicylic acid are the least 2 SHRZ/6 S2H2Z2 13
effective for the purpose. With a less active or no initial phase
2 SHR / 7 HR 14
2 EHR / 7 HR 15
AIMS OF TREATMENT 9 HR 16
The aims of chemotherapy of TB are: [i] to cure patients E = ethambutol; H = isoniazid; R = rifampicin; Z = pyrazinamide;
of TB by the shortest duration of drug administration S = streptomycin; T = thioacetazone;
with minimum interference with their living; [ii] to Number preceding abbreviation for a drug name = month[s] of
prevent death from TB or late sequelae of disease; [iii] to treatment; numbers in subscript indicate the number of doses
prevent relapse of TB; [iv] to prevent emergence of drug administered per week
resistance; and [v] to reduce transmission of disease to

Regimens that do not contain pyrazinamide in the initial
people both within and outside the community.
intensive phase must be given for longer than six months.
The standard terminology used for describing
The relapse rates during six to thirty months post-
antituberculosis drugs and various treatment regimens
treatment are generally less than five per cent. In
are described in the chapter “Evolution of chemotherapeutic
countries or communities with a high rate of initial
regimens in the treatment of tuberculosis and thier scientific
resistance to isoniazid [4% or more] (13), as in most Asian
rationale” [Chapter 51].
countries, a four-drug regimen [for 2 months] followed
by two drugs used simultaneously [for 4 months] is
Treatment of Smear-positive Pulmonary Tuberculosis
recommended [Table 52.1]. This is currently the standard
In the last few decades, a number of effective drug regimen recommended by the World Health Organiza-
regimens have been found, largely through clinical trials, tion and International Union Against Tuberculosis and
for treating newly diagnosed patients with smear- Lung Disease [IUATLD] (17). Furthermore, the
positive pulmonary TB. These regimens are summari- administration of pyrazinamide beyond two months has
zed in Table 52.1 (6-16). not been shown to be of advantage (18,19). However, for
Most regimens are given for a total duration of six individual cases with extensive disease and slow sputum
months, this being currently the shortest required. bacteriological conversion to negative, prolongation of
the administration of pyrazinamide with or without For the treatment of smear-positive relapse cases of
streptomycin or ethambutol beyond two months sounds pulmonary TB as well as retreatment after interruption,
acceptable. Prolongation of the total duration of a eight-month regimen has been recommended by the
treatment can also be considered. Presence of radio- WHO and IUATLD, namely 2SHRZE/1HRZE/5HRE or
graphic cavity and sputum culture positivity after two 5H3R3E3 (17). Bacillary drug susceptibility testing in vitro
months have been found to be factors associated with can help to guide modification of this regimen as
an increased risk of failure and relapse (20,21), and thus required.
possibly justify prolongation of short-course therapy to The use of fixed-dose drug combination [FDC] tablets
a total duration of nine months in individuals possessing comprising two to three and even four drugs can enhance
these characteristics (22). The eight-month regimen ease of prescription for physicians, reduction of inadver-
where streptomycin [S], isoniazid [H], rifampicin [R] and tent medication errors, simplification of drug procure-
pyrazinamide [Z] are administered for two months ment [WHO] and supply, and treatment adherence by
followed by subsequent six months of isonaizid [H] and patients (24). When used properly, FDC tablets should
thioacetazone [T] or ethambutol [E] [2SHRZ/6HT or decrease the risk of development of multidrug-resistant
6HE] combined with hospitalization in the first two tuberculosis [MDR-TB], i.e., TB caused by bacillary
months has been proven to be effective in controlled strains resistant to at least isoniazid and rifampicin in
clinical trials and programme settings in Africa (12). This vitro (25). While FDC tablets by self-administered therapy
regimen is, however, generally not recommended by may serve as an alternative to DOT when the latter cannot
health care authorities in the developed countries. In be practised, the delivery of DOT using FDC tablets
confirmed or suspected human immunodeficiency virus should be advocated as there is still a potential risk of
[HIV] infected patients, ethambutol should be used in emergence of drug resistance when these FDC tablets
place of thioacetazone in light of possibly severe cuta- are taken irregularly (26). The main concern in using FDC
neous reaction to the latter drug (23). There is increasing tablets is the quality and bioavailability of their
indication that thioacetazone should be dropped from component drugs, especially rifampicin (27). This would
the antituberculosis regimens in the developing occur when proper manufacturing conditions and raw
countries, as many of these are experiencing rising HIV materials were not utilized (28). In 1994, the IUATLD
infection rates. Regimens based almost entirely on and WHO issued a joint statement recommending that
isoniazid and rifampicin (14-16) are perhaps only good only FDC of proven good quality should be used in the
for pansusceptible TB with limited bacillary load, and treatment of TB (29).
has to be given for nine months [2HRE/7HR or 9HR]. The WHO and IUATLD have also formulated model
These regimens are usually not applicable in Asian protocols for establishing the bioequivalence of
countries except for patients who cannot tolerate rifampicin in the FDC tablets as compared with single
pyrazinamide. Intermittent regimens comprising two drug reference preparations administered in loose
drugs in the continuation phase, following upon an combinations (30,31). The majority of clinical studies
intensive phase of four drugs given on a daily basis, have found no significant difference between FDC tablets and
been shown to be highly effective [2SHRZ/4H3R3 or individual drugs regarding sputum smear conversion
2SHRZ/4H2R2] (7,11,22). The WHO, however, does not rates and frequency of side-effects and relapses (32).
generally recommend twice-weekly regimens because of Some studies, however, have produced controversial
the higher risk of treatment failure with missing doses results. The Singapore study (33), found higher relapse
(17). Lately, clinical data from China [including Hong rates in patients who received FDC at two years and five
Kong] on 2S3H3R3Z3/4H3R3 also reveal the high efficacy years of follow-up. While more knowledge needs to be
of such a regimen (8,9). Intermittent short-course acquired on the optimal use of the FDC tablets, these
regimens that are administered thrice-weekly have have recently been recommended to be included in the
largely equivalent efficacy to daily regimens. In addition, list of essential drugs (34). Furthermore, the Global TB
they have lower cost, greater feasibility for directly Drug Facility [under WHO] can supply quality drugs,
observed administration under ambulatory settings, and including four-drug FDC to countries requesting assis-
possibly also lower drug toxicity. tance (35).
754 Tuberculosis
DOTS Treatment of Smear-negative

Drug-resistant TB can result from poor patient adherence
and other aspects of failure in implementation of an effec- In many countries, around 50 per cent of patients are
tively functioning TB control programme (36). Although diagnosed as having active pulmonary TB on clinical and
patient characteristics like homelessness, alcohol or drug radiographic grounds, without immediate bacteriological
abuse, behavioural problems, mental retardation, and confirmation (17). In the first smear-negative study in
lack of social or family support are more commonly Hong Kong (43), it was subsequently found that 36 per
associated with non-adherence to therapy, it is often cent of these patients had one or more initial sputum
difficult to identify poorly adherent patients because cultures positive for Mycobacterium tuberculosis. When
underlying reasons for such behaviour are indeed patients were observed until the appearance of radio-
multifaceted and complex (37). The DOT was in fact graphic and/or bacteriological evidence for active
shown to be highly efficacious in ensuring patient disease, 57 per cent of this control group of patients
adherence through experience gained earlier in Chennai required treatment within 60 months. When smear-
and Hong Kong (4). In order to facilitate delivery of DOT, negative, culture-positive patients were treated with two
other concomitant strategic interventions must be to three months of daily streptomycin, isoniazid,
incorporated. Short-course chemotherapy has been rifampicin and pyrazinamide, relapses occurred in 32 per
shown to be the most important component. In 1993, the cent and 13 per cent, respectively, over 60 months of
WHO officially announced the new global strategy for follow-up. The corresponding relapse rates for culture-
TB control known as DOTS (38,39). The DOTS strategy negative patients for these two durations of therapy were
is clearly more than DOT alone. Some randomized eleven per cent and seven per cent respectively. In the
controlled trials have not shown the benefit of DOT second study carried out in smear-negative patients at
(40,41). However, these trials were compromised by Hong Kong (44), which again included 35 per cent of
suboptimal implementation of treatment observation, subjects with sputum cultures initially positive for
with success rates significantly below those of worldwide Mycobacterium tuberculosis, all patients received
programmes of DOTS. Implementation of DOT depends streptomycin, isoniazid, rifampicin and pyrazinamide,
on the setting, facilities, resources and environment. In daily or thrice weekly, for three to four months [culture-
its application, flexibility should be exercised (17). To negative cases] and four to six months [culture-positive
reiterate, the DOTS strategy should be viewed as a cases]. Over 60 months, the combined relapse rates for
comprehensive service, or an integral part thereof, which culture-negative patients who had three and four months
possesses ingredients also inclusive of enablers, of treatment were seven per cent and four per cent,
incentives, education and holistic care that are conducive respectively. The relapse rate for the four-month regimen
to the success of the programme. Regarding holistic care, was two per cent in patients with initially drug-
resolution of social disadvantage particularly poverty is susceptible bacilli and eight per cent in patients with
of paramount importance. Poverty predisposes to the bacilli initially resistant to isoniazid, streptomycin or
development of TB through mechanisms including both. There was no significant difference between the
overcrowding and malnutrition, and TB perpetuates relapse rates among patients allocated four-month and
poverty by increasing the economic burden. In addition, six-month regimens of the same four drugs.
a higher prevalence of multidrug resistance was found The WHO recommends, in the latest guidelines (17),
to be associated with a lower gross national product the use of six-month regimens consisting of daily
[GNP] per capita income (42). With the use of DOTS, isoniazid, rifampicin, ethambutol and pyrazinamide for
treatment success of TB can be optimized and chances two months followed by daily or thrice-weekly isoniazid
of development of drug resistance markedly curtailed and rifampicin for another four months in the treatment
(36,39). Indeed, this strategy should be regarded as the of new cases of smear-negative pulmonary TB (17).
most cost-effective intervention in the control of TB (39). Ethambutol may be omitted during the initial phase of
The reader is referred to the chapters “DOTS: the strategy treatment for some patients with non-cavitary smear-
that ensures cure of tuberculosis” [Chapter 56] and “Directly negative pulmonary TB who are known to be HIV-
observed treatment” [Chapter 57] for more details. negative, and children with primary TB (17). The
American Thoracic Society, Centers for Disease Control The reader is referred to the chapter “Antituberculosis drug
and Prevention [CDC], Infectious Disease Society of resistance surveillance” [Chapter 50] for more details.
America (22) recently recommended four to six months Although DOTS is highly effective in the manage-
of treatment totally for smear-negative pulmonary TB ment of drug-susceptible TB, it is not sufficient for
basing on the culture status of the pre-treatment sputum treating established MDR-TB (50). Even in settings using
(22). 100 per cent DOT, cases with MDR-TB had a higher
failure rate than drug-susceptible TB (51). The frequency
Treatment of Monodrug-resistant of recurrence of disease among MDR-TB declared cure
Pulmonary Tuberculosis after SCC is also high (52). Furthermore, SCC including
standardized retreatment regimens can even cause an
For patients who are subsequently known to harbour
amplification of drug resistance when empiric treatment
bacilli resistant to streptomycin, it would obviously be
reasonable to stick to the conventional short-course courses are repeatedly administered. The treatment
success rates of patients with MDR-TB are generally
regimens just described for treatment of new cases. For
much lower when compared to those of patients with
patients with isoniazid-resistant TB, one of the following
two approaches can be adopted. First, continuation of drug-susceptible disease, namely 56 per cent to 80 per
cent versus 90 per cent or more (53-57). Also, the standard
rifampicin, ethambutol and pyrazinamide for a further
retreatment SCC regimen [US$ 30 to 35] is about 50 per
10 months or rifampicin plus ethambutol for another 12
months after having administered rifampicin, isoniazid, cent more costly than a first-line conventional SCC
regimen [US$20], and the cheapest reserve chemotherapy
ethambutol and pyrazinamide for two months before
regimen comprising second-line and new antimycobacte-
drug susceptibility testing [DST] results are known
(45,46). Secondly, no modification of the initially rial drugs is at least 100 times more costly [US$ 2 000]
(17).
administered four-drug regimen is made, with it being
On the basis of available data, the WHO has recom-
given for a total duration of six months (47). Reducing
the drug components from four to two after two months, mended a three-part response to the global threat of
MDR-TB (58): [i] widespread implementation of DOTS
as in the management of drug-susceptible TB is also
as the cornerstone of good TB control; [ii] improved DST
acceptable for programme purpose, except the relapse
rate would be somewhat higher [10% v 3%] (19). When and surveillance; and [iii] careful introduction of second-
line [reserve] drugs [SLD] after a sound evaluation of
patients are already known to have isoniazid-resistant
cost, effectiveness and feasibility. Figure 52.1 depicts the
disease at the commencement of therapy, a nine-month
regimen comprising streptomycin, rifampicin, concept of the combined chemotherapy strategy in the
control of TB.
pyrazinamide and ethambutol for two months, followed
by rifampicin and ethambutol for seven months, has also
been shown to be effective (48). On the other hand, for
patients with rifampicin mono-resistant disease, which
is generally of rare occurrence in clinical practice aside
from HIV subjects, recommendation has been made to
treat with isoniazid, pyrazinamide and ethambutol for
18 to 24 months (49). Some authorities currently feel that
the duration of treatment can be shortened to nine to
twelve months with addition of a fluoroquinolone to this
three-drug regimen (22).
Treatment of Multidrug-resistant
The WHO/IUATLD global project on antituberculosis Figure 52.1: Combined chemotherapy strategy in the control of
drug resistance surveillance (42) found that drug tuberculosis
resistance was indeed a very widespread phenomenon. TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis
756 Tuberculosis
Preliminary evidence shows that investing in MDR- and ethionamide, after failure of the standard
TB control in middle-income countries is beneficial (59). retreatment SCC regimen that comprised streptomycin,
However, it would not simply be logical for any country rifampicin, isoniazid, ethambutol, and pyrazinamide
or community to divert significant resources to could be cured. Indeed, ofloxacin-containing multidrug
implement treatment strategy for MDR-TB, if a large regimens could give rather impressive cure rates of about
proportion of new infectious cases remain ineffectively 80 per cent in MDR-TB in several reports (55-57).
treated. The new initiative known as DOTS-Plus (60) is Preliminary data from two other reports (64,65) also
currently coordinated by the WHO in partnership with suggest that levofloxacin possibly has better efficacy than
many agencies and institutions worldwide. Thus, for ofloxacin in the treatment of MDR-TB. Among the agents
established MDR-TB, effective treatment should used in the multidrug regimens, the fluoroquinolones
comprise alternative specific and perhaps even ideally are most likely the pivotal drugs with major contribution
individualized SLD regimens. It appears that the most to the efficacy of the regimens. In a retrospective analysis
important determinant in formulating a drug regimen of patients with MDR-TB treated with ofloxacin or
for MDR-TB is the patient’s current drug susceptibility levofloxacin together with similar accompanying drugs
pattern in vitro (54,57). It has been well shown that that principally included aminoglycosides, ethionamide
patients given appropriate drugs based on DST in vitro or prothionamide, pyrazinamide, ethambutol,
had better outcomes (56,61). One practical obstacle to the cycloserine, and para-aminosalicylic acid, resistance to
usefulness of conventional DST in guiding regimen ofloxacin in vitro was found to be a significant variable
modification and design is its prolonged turnaround independently associated with adverse outcomes (57).
time. Rapid DST broth systems based on non-radio- Aside from their efficacy in vivo resulting from good
metric or radiometric technique have brought about bactericidal and sterilizing activities (57,66), though the
improvement in this aspect (62), but these are more costly latter is still apparently inferior to that of pyrazinamide
compared with the conventional ones. Advances in especially in TB patients co-infected with HIV (67),
phenotypic or genotypic technology might help in further fluoroquinolones such as ofloxacin or levofloxacin and
accelerating the delineation of drug resistance in the near ciprofloxacin also have the following favourable
future (62). Besides, the methodology of assessing drug therapeutic characteristics: high peak serum drug
susceptibilities for many SLD is not totally standardized concentration: minimal inhibitory concentration [MIC]
yet, and therefore, there can be an observed discrepancy ratio, good tissue penetration particularly into lungs, and
in microbiological response of the patient and results of good tolerance by patients during long-term adminis-
the DST in vitro (56). More work apparently needs to be tration even at high dosages (57,64,68,69). The good
done in the relevant area (63). The fluoroquinolones, tolerance is therapeutically beneficial and sets the
however, emerge as new antimycobacterial drugs that fluoroquinolones aside from most second-line [reserve]
have consistent activities in vitro, often independent of antituberculosis agents (57). However, interactive
culture medium, inoculum size, and method of assess- toxicities of fluoroquinolones with cycloserine can be of
ment (57). real concern (70).
A patient with MDR-TB should receive a regimen The good patient tolerance of fluoroquinolones is not
comprising at least four to five of these SLD, for the initial a class effect. Sparfloxacin, for example, has better
months, followed by three to four drugs subsequently. antituberculosis activity than ofloxacin or levofloxacin
One regimen recommended by the WHO consists of (71,72). However, potential phototoxicity and cardio-
treatment with ethambutol, ethionamide and prothiona- toxicity can jeopardize its future role in the clinical
mide, ofloxacin or ciprofloxacin, pyrazinamide, and management of MDR-TB (73,74). By the same token, new
aminoglycoside, capreomycin, for six months, with the fluoroquinolones with good antimycobacterial activities,
first four drugs being administered for a further 12 to 18 like moxifloxacin (75-77), sitafloxacin [DU-6859a] (78)
months (17). and gatifloxacin (79,80) might share a similar fate unless
In fact, in a recent large-scale trial in Peru (59), 55 per their safety profiles on long-term use can be established
cent of adherent patients given a similar regimen, namely in the future. Moxifloxacin attracts the greatest interest
kanamycin, ciprofloxacin, pyrazinamide, ethambutol, because of its good oral bioavailability, long half-life
[8-16 hours] and prominent sterilizing capacity (81-83). emergence of cross-resistance among members of this
The Tuberculosis Trials Consortium [TBTC] of CDC, USA important class of drugs (53,72). This has already been
has launched “Study 27” officially to examine the efficacy reported in some communities (89,90), and might have
and tolerance of moxifloxacin by substituting the negative impact on the potential usefulness of emerging
fluoroquinolone for ethambutol in the standard four- members of this drug class with greater antimycobac-
drug, short-course antituberculosis regimen (84). terial activities. It also appears useful to delineate the
Preliminary clinical data have supported the satisfactory correlation of fluoroquinolone-resistance phenotypes
tolerance of moxifloxacin (85). Data from mouse model and genotypes to enable better choice of new fluoroqui-
reveal moxifloxacin to be most efficacious when nolones in the face of MDR-TB caused by ofloxacin-
substituted for isoniazid instead of ethambutol in the resistant bacillary strains (91).
standard first-line antituberculosis drug regimen (86).
The TBTC “Study 28” is evaluating this combination DEVELOPMENT OF NEW ANTITUBERCULOSIS
treatment in a double-blind randomized controlled Phase DRUGS
Two two-month treatment trial. A Phase Three trial New antituberculosis drugs can hopefully offer advances
[REMox TB Trial] to evaluate ability of moxifloxacin- in management of TB in the following areas (92): [i]
based drug regimens to shorten treatment to four months shortening total duration of therapy and significantly
with safety and efficacy not inferior to standard six reducing number of doses administered under the DOTS
months treatment for drug-sensitive pulmonary TB in protocol; [ii] improving treatment success of MDR-TB;
HIV-seropositive and HIV-seronegative adults has been and [iii] providing more effective treatment of latent TB
planned. Further examples of new quinolones that might infection [LTBI].
have roles in antimycobacterial treatment include A new drug for treatment of TB should have desirable
garenoxacin or T-3811ME (87), [a broad-spectrum des- biopharmaceutical, pharmacokinetic and pharmaco-
F(6)-quinolone] and PD161148 [a C-8-methoxyl dynamic properties. Considerations should include oral
fluoroquinolone] (88). The optimum duration of solubility, permeability and compatibility with other
treatment for patients with MDR-TB is currently unclear. agents in combination. Furthermore, its oral bioavail-
While a number of authorities including the WHO has ability, tissue penetration especially into lung, disposition
recommended a total duration of at least 18 months even profile and elimination half-life are also issues of concern.
for HIV-negative patients (17), there is some preliminary Lastly, the MIC and post-antibiotic effect of the drug
evidence that at least a proportion of immunocompetent against Mycobacterium tuberculosis should be superior to
patients who managed to achieve sustained sputum those of existing agents.
culture conversion early in the treatment course could The fluoroquinolones have a role in the management
perhaps be adequately treated with 12 months of of MDR-TB, and possibly also TB in the face of severe
fluoroquinolone-containing regimens (57). It does drug intolerance, such as hepatotoxicity (93). However,
appear, however, that patients who are immuno- their role as primary treatment for TB is uncertain (94).
compromised [including those with diabetes mellitus Other potential new drugs will be briefly discussed
and silicosis], or have extensive radiographic evidence below. Some of these are existing antimicrobial agents
of disease [particularly with cavities], or extensive drug and classes for different indications, while others are
resistance in vitro, or delayed sputum culture conversion novel classes of compounds.
[i.e., after more than 3 months of treatment], or extra- Rifabutin, a spiropiperidyl rifamycin with better in
pulmonary involvement should receive longer than 12 vitro activity against Mycobacteium tuberculosis than
months of treatment. In formulating the optimum rifampicin, has also been shown to have activity against
duration of treatment for MDR-TB, the key factors that some MDR-TB bacillary strains though the cross-
appear to be most relevant are the number of active resistance rate between the two rifamycins is high (95).
agents, their bactericidal capacity, dosage, cost and Indeed, its clinical efficacy in MDR-TB was found to be
toxicity, alongside the anticipated patient adherence (57). disparate among two clinical studies (96,97). The better
Finally, fluoroquinolones must be used with great designed study (96) that compared patients randomized
vigilance in the management of MDR-TB to prevent to receive rifabutin or rifampicin together with similar
758 Tuberculosis
accompanying drugs showed a low culture negativity experience concerning the in vitro (108) and early
rate [20%] even for the rifabutin group. Rifalazil [KRM- bactericidal activity (109) of β-lactam-β-lactamase
1648], a benzoxazinorifamycin, has been found to have inhibitors against Mycobacterium tuberculosis, the role of
MICs about 10-2 those of rifampicin and less than or equal these compounds in the treatment of TB especially MDR-
to 0.25 those of rifabutin against Mycobacterium tuberculosis TB is still uncertain, given the scanty clinical data that
(98). Results were also favourable when it was combined are currently available (110,111). Clofazimine is a
with isoniazid in long-term treatment of murine TB (99). riminophenazine that has been extensively used for
However, it has been shown to possess partial cross- treatment of leprosy and Mycobacterium avium complex
resistance with rifampicin (98), and human Phase Two infection. It has recently been shown to possess in vitro
studies have not demonstrated any significantly positive and in vivo activities against some strains of Mycobacte-
result (100). Rifapentine, a long-acting cyclopentyl rium tuberculosis (112), including drug-resistant ones in
rifamycin, has been shown to yield encouraging results the murine model. A few analogues of this drug, such as
when given with isoniazid in a once-weekly dosing B746 and B4101 were found to have even better activities
during the continuation phase of treating pulmonary TB, under both in vitro and in vivo settings (112). Thus,
though delineation of the optimum dosage of this clofazimine and its analogues might have a place in the
rifamycin to achieve a lower relapse rate is still required management of MDR-TB if sufficient evidence support-
(9,20,21). A prospective, randomized, double-blind study ing their clinical efficacy and tolerance can be established.
(101) on the tolerability of rifapentine 600, 900, and Other examples of new drug classes which might
1200 mg plus isoniazid in the continuation phase of potentially merit further evaluation include oxazolidi-
treatment has suggested that rifapentine 900 mg once- nones (113,114), nitroimidazopyrans (115), and 2-
weekly dosing appears to be safe and well tolerated. This pyridones (116). The oxazolidinones are new synthetic
dosing schedule would have further evaluation in antibacterial agents, and preliminary studies have shown
Phase Three efficacy trials on treatment of LTBI. As for that the compound PNU100480 is as active as isoniazid
1200 mg once-weekly rifapentine, further exploration of (113). Furthermore, preliminary pharmacokinetic data
the safety and tolerability is apparently warranted too in the murine model has shown good oral bioavailability
(101). This approach of utilizing long-acting rifamycin (114). While another member linezolid has demonstrated
can greatly facilitate the delivery of DOTS. However, data some activity against Mycobacterium chelonae in vivo (117),
concerning the unsatisfactory clinical efficacy and its potential clinical use in mycobacterial infections is
development of acquired rifampicin mono-resistance compromised by possible toxicity and high cost. The key
among HIV infected patients given rifapentine therapy compound of the nitroimidazopyran group is PA824
are somewhat disturbing (102). Rifametane, a 3-azino- (115). This lead compound is active against MDR-TB
methyl rifamycin was found to have a superior pharma- strains and exhibits no cross-resistance with existing
cokinetic profile to rifampicin in terms of higher peak antituberculosis drugs. Its site of action is possibly on
serum drug concentration and longer half-life (103). No the synthesis of protein and cell wall lipid. Another class
relevant clinical data are yet available for this new of related compound, namely the nitroimidazoles, with
rifamycin. CGI 17341, an analogue of metronidazole as an important
Aminosidine [paromomycin] is an aminoglycoside example, also has potentially significant antimycobacte-
that has been shown to have activities against Mycobacte- rial activity (118). TMC207, a diarylquinoline that has
rium tuberculosis in vitro (104) and in vivo (104,105). activity against drug-sensitive and drug-resistant strains
Further evaluation of its role in the treatment of MDR- of Mycobacterium tuberculosis, is in clinical phase 2
TB is required. Also, aerosolized aminoglycoside, like development (119,120). Other new antimycobacterial
tobramycin, might have a place in the treatment of TB, compounds, a new pyrrole known as Sudoterb [LL-3858]
and is being further evaluated (106). (121), the compound, SQ-109 [an ethylenediamine] (122)
Clarithromycin, an important macrolide active and OPC-67683 [nitroimidazo-oxazole] (123) have
against Mycobacterium avium complex, was not found to entered clinical Phase One evaluation. It must be stressed
have significant activity against Mycobacterium tuber- that only scanty data concerning the antimycobacterial
culosis (107). Although there has been favourable activities of these agents are currently available.
Methods to design novel drugs based on the structure venture aiming at accelerated discovery and develop-
of a cellular component or genetic material have been ment of antituberculosis drugs to combat this important
repeatedly attempted. One possible target of intervention foe. The vision of this Alliance is provision of new drugs
is the mycobacterial glyoxylate pathway (106) which with equitable access to communities and countries for
involves key enzymes, like isocitrate lyase. It has been better treatment of TB. The Alliance will function as a
shown that the glyoxylate shunt is important for the long- lean, virtual, research and development organization.
term survival of Mycobacterium tuberculosis within The pipeline of research and development of new drugs
pulmonary tissue (124). Another example is concerned essentially consists of relevant basic research, discovery
with the lipids in the mycobacterial cell wall. Thiolacto- of lead compounds, preclinical studies, clinical trials and
mycin, a unique thiolactone antibiotic isolated initially finally technology transfer in drug production. This
from the soil Nocardia species, possesses both in vitro and pipeline is currently filled with gaps accounting for the
in vivo activities against Mycobacterium smegmatis and tremendous length of time required for development of
Mycobacterium tuberculosis (125). The likely targets of new antituberculosis drugs. The formation and
action are fatty acid and mycolic acid biosynthesis (126). functioning of the Alliance may help to overcome some
Recently, a novel antimycobacterial compound N- or all of these obstacles.
octanesulphonyl-acetamide, by acting on similar sites Despite this, the final development of antituberculosis
through mimicking the transit state of the reaction drugs for clinical use is still an arduous task. Efficacy
catalysed by the β-ketoacyl synthase (127), may serve as trials are both complex and time-consuming. Regulatory
a promising lead compound for future antituberculosis authorities require that a new drug must be at least as
drug development. safe and effective as the existing standard therapy to
Aside from new drugs, novel methods of delivery of grant approval for registration for the indication. The
old drugs may facilitate better treatment of TB. Such generally accepted end points for an efficacy trial are the
possible innovative approaches include liposomal cure rate at the end of treatment and the relapse rate
delivery (106) of aminoglycosides and fluoroquinolones, during a two-year post-treatment follow-up. There is thus
implant delivery (106) of isoniazid, and aerosolisation a genuine need for surrogate markers for these
of cytokines (106), aminoglycosides (106), and rifampicin parameters, such as early bactericidal activity (130) as
microparticles (128) for the treatment of TB. well as two-month sputum culture conversion rate (131)
With the advent of gene therapy, a new strategy of and its possible molecular marker[s] (132).
antimycobacterial treatment might be developed in the Expansion of the knowledge in mycobacterial
future. Mycobacteriophages can be used to deliver genomics has offered great potential in drug target
antisense nucleic acids or other materials to combat discovery and birth of new antimycobacterial agents
mycobacteria including the drug-resistant strains (106). (133). In addition, the development of combinatorial
The latest developments in gene transfer technology have chemistry and robotic screening brings promise in the
revealed the possibility of developing preventive or introduction of an era of rational discovery of new
therapeutic vaccines for TB (129). antituberculosis drugs (92).
The lack of interest of the pharmaceutical industry in
pursuit of development of new antituberculosis drugs DOSAGES AND ADVERSE REACTIONS OF
largely results from the conventional notion that the ANTITUBERCULOSIS DRUGS
anticipated financial return would not justify the
immense investment required. To circumvent this The usual dosages of the drugs used in conventional SCC
difficulty, public-private partnerships for the discovery and therapy of MDR-TB are shown in Table 52.2. The
and development of antituberculosis drugs should be the reader is referred to the chapter “Evolution of chemo-
proper direction. In 2000, participants from a number of therapeutic regimens in the treatment of tuberculosis and their
interested parties comprising public organizations as scientific rationale” [Chapter 51] regarding the definitions
well as companies in the private sector joined hands in of adverse drug reactions and related events. The
forming a coalition named Global Alliance for Tubercu- important adverse reactions to these antituberculosis
losis Drug Development (92). This is a not-for-profit drugs are listed in Table 52.3.
760 Tuberculosis
Table 52.2: Usual dosages of antituberculosis drugs
Drug Daily dosage Intermittent dosage
Adults and Adults Adults and children Adults

children*† [mg/kg]
[mg/kg] Weight [kg] Dosage Weight [kg] Dosage
Drugs commonly used in conventional therapy

Isoniazid 5 – 300 mg 10 three times/week – –
15 twice/week – –
Rifampicin‡ 10 < 50 450 mg 10-12 three times/week – 600 mg
> 50 600 mg 10-12 twice/week – 600-900 mg
Streptomycin 12-15 < 50 500-750 mg 12-15 thrice or twice/week < 50 500-750 mg
> 50 750 mg > 50 750 mg
Pyrazinamide 20-30 < 50 1.0-1.5 g 30-40 three times/week < 50 1.5-2.0 g
> 50 1.5-2.0 g > 50 2.0-2.5 g
40-60 twice/week < 50 2.5-3.0 g
> 50 3.0-3.5 g
Ethambutol 15 – 30 three times/week – –
45 twice/week
Thioacetazone 2.5 – 150 mg – – –
Drugs commonly used in therapy for multidrug-resistant tuberculosis
Amikacin 15 750 mg three to five times/week
Kanamycin 15 750 mg
Capreomycin 15 750 mg
Ofloxacin 600-800 mg
Levofloxacin 500-600 mg
Ciprofloxacin 750-1500 mg
Ethionamide 15 < 50 500 mg
Prothionamide [adults] > 50 750 mg
Cycloserine 15 < 50 500 mg
[adults] > 50 750 mg
Para-aminosalicylic 2 g/10 kg < 50 8-10 g
acid > 50 10-12 g
* Some authorities recommend higher dosages of isoniazid, rifampicin, and streptomycin for children
† Drugs for treatment of multidrug-resistant tuberculosis may require split dosing to meet tolerance
‡ Dosage of rifampicin > 600 mg twice per week is associated with higher risk of “flu” syndrome
Although more than 25 per cent of study patients on administration, and is usually mild and self-limited. It
antituberculosis treatment reported at least one type of usually responds well to symptomatic treatment. If a
reaction (18,19,44), most of these were mild and required serious reaction such as haematological, circulatory or
no modification of treatment regimens. Less than 10 per renal in type occurs after administration of rifampicin,
cent of patients required termination or prolonged the drug should be withdrawn and never given again.
suspension of drug[s]. The most common reactions were The initial recommended approach in managing
gastrointestinal or cutaneous in nature (18,19). Adverse gastrointestinal intolerance, not associated with hepatic
reactions mostly occur within the first three months of toxicity, is to change the time of drug administration
the treatment. Peripheral neuropathy caused by isoniazid and/or to administer the drugs with food (22). The
can be prevented by an adequate supplement of former approach often refers to altering the timing of
pyridoxine [vitamin B6] in the at-risk groups. Arthralgia drug administration closer to mealtime. If bedtime
can occur during pyrazinamide administration. It is less administration is eventually desired, self-administered
likely to occur during intermittent than daily therapy has to be given. As for drug administration with
Table 52.3: Adverse reactions to antituberculosis drugs
Drug Reactions
Common Uncommon Rare
Drugs commonly used in conventional therapy

Isoniazid Asymptomatic elevation of Hepatitis Fever
serum hepatic enzymes Cutaneous hypersensitivity Giddiness
Peripheral neuropathy Convulsion
Optic neuritis
Mental symptoms
Haemolytic anaemia
Aplastic anaemia
Lupoid reactions
Arthralgia
Gynaecomastia
Rifampicin Pruritus Hepatitis Shortness of breath
Cutaneous hypersensitivity Shock
Gastrointestinal reactions Haemolytic anaemia
Thrombocytopenia Acute renal failure
Febrile reaction Thrombotic thrombocytopenic
“Flu syndrome” purpura
Pyrazinamide Anorexia Hepatitis Sideroblastic anaemia
Nausea Vomiting Gout
Flushing Arthralgia
Photosensitization Cutaneous reactions
Ethambutol Retrobulbar neuritis Peripheral neuropathy
Cutaneous reactions
Arthralgia
Streptomycin Cutaneous hypersensitivity Vertigo Clinical renal failure
Giddiness Ataxia Aplastic anaemia
Numbness Deafness
Tinnitus
Thioacetazone Gastrointestinal reactions Hepatitis Agranulocytosis
Cutaneous hypersensitivity Erythema multiforme
Vertigo Exfoliative dermatitis
Conjunctivitis Haemolytic anaemia
Drugs commonly used in therapy for multidrug-resistant tuberculosis
Amikacin Hearing damage, Clinical renal failure

Kanamycin vestibular disturbance
Capreomycin Deranged renal function tests
Ofloxacin Gastrointestinal reactions Anxiety Convulsion
Ciprofloxacin Insomnia Dizziness Cutaneous hypersensitivity
Headache
Paraesthesia
Tremor
Ethionamide Gastrointestinal reactions Hepatitis Convulsion
Prothionamide Peripheral neuropathy Depression
Alopecia
Hypothyroidism
Impotence
Gynaecomastia
-Contd-
762 Tuberculosis
-Contd-
Reactions
Drug
Common Uncommon Rare
Cycloserine Dizziness Psychosis Sideroblastic anaemia
Headache Convulsion
Depression
Memory loss
Para-aminosalicylic acid Gastrointestinal reactions Hepatitis Hypothyroidism
Drug fever Haematological reactions
Generalized hypersensitivity
Malabsorption
food, one caveat would be impaired bioavailability of Table 52.4: A suggested protocol for reintroducing antituber-
medications in some patients (134,135). culosis drugs after “disappearance” of cutaneous reaction
When a significant cutaneous reaction resulting from Order of Challenge doses
drug hypersensitivity [allergy] occurs, all drugs must be reintroduction
stopped until the reaction has subsided. Reintroduction Day 1 Day 2 Day 3
of drugs may follow the suggested protocol [Table 52.4]. Isoniazid 50 mg 300 mg 300 mg
The rationale of drug challenge is to identify the drug Rifampicin 75 mg 300 mg Full dose*
responsible for the reaction. The purpose of starting with Pyrazinamide 250 mg 1g Full dose*
a small challenge dose is that if a reaction indeed occurs,
Ethambutol 100 mg 500 mg Full dose*
it will not be as severe as to a full dose. The dose is
Streptomycin 125 mg 500 mg Full dose*
gradually increased over three days. There is no evidence
that this challenge process leads to the development of * as described in Table 52.2
drug resistance. If the initial cutaneous reactions were
rather severe, a smaller initial challenge dose [approxi- tion process can be associated with the risk of develop-
mately one-tenth of the dose shown for day 1] should be ment of drug resistance. If other effective drugs are
given. If a reaction occurs with the first challenge dose, available, it is easier to substitute another drug for the
it is known that the patient is hypersensitive to that drug. one that has caused the reaction except when the disease
When starting to desensitise, it is usually safe to begin is severe and the incriminated drug[s] being the most
with one-tenth of the normal dose. Then the dose is potent and crucial one(s). Desensitization can be
increased by one-tenth each day. If the patient has a mild dangerous for HIV infected patients and is not
reaction to a dose, the same dose [instead of a higher recommended (17).
dose] is given next day. If there is no reaction, the dose is Second-line [reserve] drug regimens on the whole are
to be increased again by one-tenth each day. If the more toxic and can be poorly tolerated by patients. In a
reaction is severe [which is unusual], a lower dose is used study in Hong Kong (57), about 40 per cent of patients
and the dose then increased more gradually. If a reaction experienced adverse reactions of varying severity.
occurs with the second challenge dose as shown in Table However, only half of these patients required modifica-
52.4, desensitization can be started with the first challenge tion of their drug regimens (57). In a study undertaken
dose and then the dose is increased by the amount equal in Peru (136), young patients with little co-morbid disease
to the first challenge dose each day. Some patients may could have these adverse effects largely managed on out-
need antihistamine or steroid to control the severe patient basis. Suspension of an agent only occurred in
reaction. For very severe drug reactions requiring high- 11.7 per cent of patients and discontinuation of therapy
dose corticosteroid therapy, desensitization should not was never required (136).
be attempted. Desensitization is a tedious process and Transient changes in serum bilirubin and alanine
should be performed in specialized centres. Desensitiza- transaminase levels are rather common during antituber-
culosis treatment and may not signify true hepatotoxicity isoniazid] (150-152) during drug biotransformation
(10,18). However, drug-induced hepatotoxicity during [metabolism] in the liver or intestine. Generally speaking,
administration of SCC has been well documented, and rifampicin acts as an enzyme inducer (150) and isoniazid
deaths due to fulminant hepatic necrosis, while rare, have an inhibitor (152). The agents interacting significantly
been reported (137). Patients with underlying liver with rifampicin include anticoagulants, anticonvulsants,
diseases, especially those related to alcohol (138), antiinfectives, cardiovascular therapeutics, oral
hepatitis B (139), hepatitis C (140), and HIV (140), appear contraceptives, glucocorticoids, immunosuppressants,
to be more prone to develop drug-induced hepatic psychotropics, sulphonylureas, and theophylline (150).
dysfunction or toxicity. Other possible predisposing Table 52.5 shows some examples of such drugs involved
factors include old age and malnutrition (138). Hepatitis in clinically significant interactions with rifampicin.
B (141) and hepatitis C (142) are prevalent in Asia, and Isoniazid interacts principally with anticonvulsants,
HIV infection (143) is also surging therein. The benzodiazepines, theophylline, paracetamol and some
populations in some Asian countries are also ageing. food (152). Induction effect with rifampicin can occur
While rifampicin and isoniazid co-administration exhibit between under five to fourteen days (150). Similarly, some
additive risk for hepatotoxicity (144), the contribution of time is required after withdrawal of the rifampicin for
pyrazinamide to hepatotoxic potential in SCC, though the induced enzyme system to return to its baseline
not yet totally clear, is increasingly being recognized activity (151). For inhibition effect, its onset and
(145-147). In the face of extensive disease when delay in disappearance are generally rapid upon institution and
therapy might be detrimental to the patient’s health, the cessation respectively of the inhibitor (150). These pheno-
fluoroquinolone, ofloxacin, can be used with mena are of great relevance in the management of drug
streptomycin and ethambutol as a relatively safe and interactions during antituberculosis treatment. Fluoro-
efficacious interim regimen for treatment (148). Indeed, quinolones can have disturbance of their absorption by a
one randomized clinical trial has also demonstrated the variety of agents especially metal cations (150). Important
safety of an ofloxacin-based regimen in patients with interactions of fluoroquinolones usually result from their
chronic liver disease (149). The hepatotoxic potential of enzyme inhibiting potential or pharmacodynamic
a combination of isoniazid and rifampicin was found to mechanisms (150). The geriatric and immunocompro-
be greater than that of isoniazid, ofloxacin and mised patient populations are particularly at risk of drug
pyrazinamide used together. More work should be done interactions during treatment of their TB. One common
to unravel the potential utility of ofloxacin in this denominator being significant comorbidities and
important setting. The reader is also referred to the concomitant polypharmacy.
chapter “Antituberculosis treatment induced hepatotoxicity
[Chapter 54] for more details. TREATMENT OF EXTRA-PULMONARY TUBER-
The development of antituberculosis therapy related CULOSIS AND OTHER SPECIFIC SETTINGS
renal impairment necessitates the withdrawal of the
incriminated drugs, commonly streptomycin [and other In general, extra-pulmonary TB accounts for about 20 per
aminoglycosides] or rifampicin. cent of all reported cases (17). Lymphatic, pleural, bone
Clinically significant interactions during antituber- or joint disease are the most common, and pericardial,
culosis treatment principally involve rifampicin (150,151), meningeal and miliary forms are more likely to result in a
isoniazid (150,152) and the fluoroquinolones (150). fatal outcome (17). Treatment recommendations are
Interactions between these antituberculosis agents and compromised by the paucity of data from controlled
the co-administered drugs constitute the majority of such clinical trials. Many experts now agree that most extra-
interactions. The consequences can be therapeutic failure pulmonary TB can be treated with the standard six-month
or drug toxicity. Most interactions are pharmacokinetic short-course regimen (17,22,46). Some authorities
rather than pharmacodynamic in nature. The cytochrome recommend nine months of treatment for disseminated
P450 isoform enzymes being a superfamily of more than [miliary] TB and some cases of bone and joint TB (22). In
30 related enzymes are responsible for many drug addition, some experts favour the use for nine to twelve
interactions [especially those involving rifampicin and months of treatment for TB meningitis (22,46).
764 Tuberculosis
Table 52.5: Clinically significant drug mycin and pyrazinamide. A prospective study (154) for
interactions with rifampicin silicotuberculosis undertaken in Taiwan showed that a
Analgesics Cardiovascular drugs nine-month regimen [HRZS for two months followed by
Alfentanil Digitoxin HR for seven months] yielded a success rate of 95 per
Codeine Digoxin cent and relapse rate of five per cent after 18 to 40 months
Methadone Diltiazem of follow-up. This latter regimen was better tolerated in
Enalapril
Anticoagulants comparison with the Hong Kong regimen.
Losartan
Phenprocoumon
Metoprolol For HIV infected patients with drug-susceptible TB,
Warfarin
Mexiletine the standard six-month regimen can result in good
Antidiabetics Propanolol sputum bacteriological conversion and low rate of
Glibenclamide Quinidine treatment failure. But the relapse rate of TB is generally
Verapamil
Glimepiride higher than that in HIV negative patients. Prolongation
Glipizide
Immunosuppressants of therapy to 12 months can result in lower relapse rate
Antiepileptics Corticosteroids but no significant impact on survival (155). The most
Hexobarbitone Cyclosporine recent guidelines of the CDC (156), in USA recommend
Phenytoin Tacrolimus
the minimum duration of treatment to be six months,
Sodium valproate
Psychotropics but that if the clinical or bacteriological response is slow,
Antimicrobials Diazepam treatment should be offered for a total period of nine
Clarithromycin Haloperidol
Midazolam
months, or for at least four months after achievement of
Delavirdine
Doxycycline Nortriptyline culture negativity.
Indinavir Zolpidem Combination regimens of highly active antiretroviral
Itraconazole Zopiclone drugs have improved the prognosis of HIV infected
Ketoconazole
Sundry others patients, but have also complicated the management of
Nelfinavir
Levothyroxine those with concomitant TB. Rifampicin is a stronger
Nevirapine
Saquinavir
Oral contraceptives enzyme inducer than rifabutin. The HIV protease
Tamoxifen inhibitors and some non-nucleoside reverse transcriptase
Theophylline
inhibitors are significant enzyme inhibitors. Interactions
between rifamycins with HIV protease inhibitors and
Patients with silicosis are at risk of developing active non-nucleoside reverse transcriptase inhibitors are
pulmonary TB, and are more difficult to treat because of complex and adjustment of drug dosages is very often
impaired local host defence as well as impeded penetra- required (157). Otherwise, loss of therapeutic efficacy and
tion of drugs into the fibrotic disease sites. In Hong Kong, development of drug toxicity may ensue. To circumvent
a study (153) on such patients showed that with a this, the CDC also lists, a non-rifamycin containing
regimen of H3R3Z3S3, ethambutol being added in the first regimen as a possible alternative, namely the administra-
three months if there was a history of previous chemo- tion of isoniazid, pyrazinamide and streptomycin for
therapy, treatment for six months proved inadequate. A nine months with ethambutol also for the first two
relapse rate of 22 per cent during three years and 33 per months (156). However, there are a number of concerns
cent during five years occurred, compared with only with this latter strategy especially regarding its inferior
seven per cent during three years in patients treated for efficacy and the need to utilize prolonged duration of
eight months. The study also showed slower conversion parenteral therapy. The reader is also referred to the
of sputum bacteriology in the silicotic patients than in chapter “Tuberculosis and human immunodeficiency virus
the non-silicotic ones even when the same four- or five- infection” [Chapter 40] for more details.
drug regimens were given. Only 80 per cent of the studied
group had negative sputum culture at two months after SURGICAL TREATMENT OF MULTIDRUG-
treatment. One additional problem is that about 20 per RESISTANT PULMONARY TUBERCULOSIS
cent of patients experienced adverse reactions to this The most important indication of surgery in the manage-
intensive regimen, with intolerance largely to strepto- ment of TB today is centred on the MDR-TB setting.
Basically, there are three selection criteria for adjunctive

surgery in patients with such disease (158). First,
profound drug resistance in vitro is present, leading to a
high probability of failure or relapse with medical
treatment alone. Secondly, the disease is sufficiently
localized so that its great preponderance could be
resected with expectation of still adequate postoperative
cardiopulmonary capacity. Thirdly, there is sufficient
drug activity to suppress the mycobacterial burden to
facilitate healing of the bronchial stump. Patients must
receive antituberculosis treatment prior to surgery for a
minimum duration of three months (159). If possible,
patients should achieve culture conversion to negativity
before surgery (159,160). Unfortunately, this cannot
Figure 52.2: Activation of macrophage and T-lymphocytes in
always occur (160). In some reports, sputum culture tuberculosis
conversion only occurred after surgery together with APC = antigen presenting cell; Th0 = T-helper type-null lymphocyte;
prolonged duration of drug therapy afterwards. Th 1 = T-helper type-1 lymphocyte; Th2 = T-helper type-2
Ventilation/perfusion scan, pulmonary function test, and lymphocyte; IL = interleukin; IFN-γ = Interferon-gamma
computed tomography [CT] of the chest are important
immunotherapy with low-dose recombinant human
investigations for pre-operative assessment (159). In
interleukin-2 was also found to stimulate immune
patients with suspected pulmonary arterial hypertension,
activation and might enhance the antimicrobial response
right heart catheterization may be needed. Bronchoscopy
in MDR-TB (163). However, this cytokine did not enhance
should be done in patients with suspected broncho-
bacillary clearance or improvement in symptoms in HIV-
stenosis. The nutritional status of the patient should be
seronegative adults with drug-susceptible TB (164). In a
optimized for improving outcome. In experienced hands,
study, aerosolized interferon-alpha [IFN-α] treatment was
the outcome could be rewarding [operative mortality:
found to reduce the sputum mycobacteria colony counts
0% to 3.3%] (159,160). Complications included respira-
in patients with MDR-TB (165). Interleukin-12 [IL-12], a
tory failure, bronchopleural fistulae, infections and other
cytokine amplifying lymphocyte-macrophage activation,
problems of the wound, bleeding, pneumonia, and
may also contribute to the host protective immunity
recurrent laryngeal nerve injury. The cure rate was noted
against Mycobacterium tuberculosis (166-168). Preliminary
to reach 90 per cent or more when combined medical
data concerning the use of heat-killed Mycobacterium vaccae
and surgical modalities were applied in treating selected
[NCTC 11659] in patients with MDR-TB in several centres
MDR-TB patients (159,160). The reader is also referred
have suggested possible efficacy (169). A randomized
to the chapter “Surgery for pleuropulmonary tuberculosis”
clinical trial of this form of immunotherapy in MDR-TB
patients appears warranted. On the other hand, the
efficacy of immunotherapy with Mycobacterium vaccae in
IMMUNOTHERAPY OF PULMONARY
African patients with newly diagnosed pulmonary TB
TUBERCULOSIS
appears somewhat conflicting (170,171). Another potential
Cell-mediated protective immunological response in TB use of immunotherapy in TB is to down-regulate the host
is largely based on macrophage activation and granuloma inflammatory response. When given to patients with
formation that require cytokines especially interferon-γ advanced TB and acquired immunodeficiency syndrome
[IFN-γ] and tumour necrosis factor-α [TNF-α] (106). [AIDS], thalidomide, a potent TNF-α inhibitor, caused
Lymphocyte-macrophage interaction in the immuno- weight gain and decreased viral replication (172). In HIV-
pathogenesis of TB is depicted schematically in Figure 52.2. positive patients with TB, pentoxifylline, which can
The IFN-γ has been shown to have efficacy in lowering suppress TNF-α in cell cultures, resulted in decreased
bacillary load in MDR-TB and nontuberculous mycoplasma HIV ribonucleic acid and improved performance
bacteriosis in anecdotal reports (161,162). Adjunctive scores (173).
766 Tuberculosis
Preliminary data (174,175) are available suggesting that adjunctive corticosteroid therapy could be beneficial
that adjuvant therapy with Mycobacterium w vaccination in causing defervescence, improvement in serum
along with antituberculosis drugs is well-tolerated and albumin, gain in body weight and radiographic improve-
facilitates early sputum conversion. Two large-scale ment more rapidly in TB patients with toxic [immuno-
multicentre trials that are already underway (176,177) logical] reactions. Paradoxical response to antituber-
are expected to provide definitive evidence regarding culosis treatment has been found to improve with
this treatment modality in Category II [treatment failure, corticosteroid treatment (195,196). Such response,
treatment after interruption, relapse] and Category I [new presumably due to immunological awakening, has been
pulmonary TB] patients. reported to be more common among HIV infected
It is clear that the current data on the role of immuno- patients with TB especially following upon initiation of
therapy in MDR-TB are limited. Further evaluation of highly active antiretroviral therapy (188,189,197,198).
this modality of therapy is required (178). Furthermore, corticosteroid treatment was reported to
result in a favourable response in some HIV-infected
CORTICOSTEROIDS AS ADJUNCTIVE patients with disseminated TB (199). More experience
TREATMENT IN TUBERCULOSIS needs to be accumulated.
Aside from replacement therapy in Addison’s disease
THERAPEUTIC DRUG MONITORING IN
[TB-induced adrenal insufficiency] (179), corticosteroids
ANTITUBERCULOSIS TREATMENT
have been found useful as adjunctive therapy for TB in
certain clinical settings (180). Two controlled trials using Therapeutic drug monitoring [TDM] represents an arena
prednisolone have demonstrated benefit in fibrino- of multidisciplinary service where clinicians, clinical
effusive tuberculous pericarditis in terms of survival, pharmacologists and laboratory specialists collaborate
resolution of clinical symptoms and need for repeat in optimizing therapy for patients (200).
pericardiocentesis (181,182). In a double-blind, rando- Serum concentrations of drugs are assessed from
mized, placebo-controlled trial of adjunctive predni- blood samples drawn by direct venipuncture or by an
solone in the treatment of effusive TB pericarditis in HIV- indwelling intravenous catheter. The crucial and
seropositive patients, a significant reduction of mortality practical pieces of information conducive to successful
was observed (183). Data obtained from trials of varying TDM are the actual times of drug-dose administration
degrees of rigour have shown that adjunctive cortico- and blood sampling (200). As the peak serum concen-
steroids offered an advantage over antituberculosis tration may be more important for most drugs, a two-
chemotherapy alone in the management of Stages II and hour post-dose sample can be collected for the purpose
III TB meningitis for survival and/or frequency of (201). For a few drugs, like ethambutol and rifabutin, a
neurological sequelae (184-186). However, change in three-hour time point may approximate the peak better
intracranial pressure or incidence of basal ganglia (201). For cases with suspected delay in absorption, a
infarction was not significantly affected (186). More second sample typically six-hour post-dose, enables
controlled studies can elucidate the utility of steroids assessment of information on the rate and completeness
further. The definitive usefulness of adjunctive cortico- of absorption (201). Blood samples obtained should be
steroid in the management of TB pleuritis has not been promptly centrifuged and the serum harvested and
thoroughly established (187,188). The efficacy of frozen at -20 °C to -70 °C, depending on the duration of
adjunctive corticosteroid in endobronchial TB in adults storage prior to analysis. The drug assay technology
has been equivocal (189,190). There has been some applied should be specific for the drug of interest. The
interesting but anecdotal data on the use of local steroids generally preferred techniques include high-performance
in the management of this condition (191). Preliminary liquid chromatography and gas chromatography (201).
retrospective analysis has suggested that corticosteroid Therapeutic drug monitoring in antituberculosis
administration in combination with antituberculosis treatment, however, is still not yet well developed. The
treatment could reduce morbidity and mortality in areas of potential usefulness of TDM in TB (200) are:
peritoneal TB (192). Two clinical studies (193,194), [i] optimization of therapy to ensure and improve success
including one randomized controlled trial, have shown in specific clinical settings; [ii] management of pharmaco-
kinetic drug interactions; [iii] management of drug- concentrations of drugs are frequently low among HIV
disease interactions; [iv] evaluation of new drug formu- infected patients with active TB compared with healthy
lations; [v] study of influence of dietary contents and volunteers (202,203), HIV-related TB responds well to
antiulcer therapy on bioavailability of drugs; and [vi] conventional antituberculosis regimens (204). Recurrence
monitoring of drug adherence. of TB in patients was also not found to be significantly
The conventional antituberculosis drugs, namely associated with antituberculosis drug levels or HIV status
isoniazid, rifampicin, pyrazinamide, and ethambutol (205).
have relatively predictable pharmacokinetics and are Examples of the second setting mainly include study
generally highly efficacious when given in standard and management of pharmacokinetic interactions of
doses under DOT settings. The usual values of their rifampicin (150,200) [and other rifamycins], as well as
pharmacokinetic parameters are shown in Table 52.6. On isoniazid (150) to a lesser extent. If an interaction is
the other hand, second-line [reserve] agents have suspected to have occurred, one should check the clinical
narrower therapeutic indices [toxic: therapeutic ratios].
situation compatibility especially regarding the time
The consequences of treatment failure of drug-resistant
course. In addition to data retrieval from literature, TDM
TB may prove difficult to manage. So are some toxicities
can be used to confirm the pharmacokinetic interactions.
related to treatment for such disease.
The clinical or pharmacodynamic consequence is then
Examples of the first potentially useful setting
assessed largely in the perspectives of change in efficacy
(22,200,201) include patients with unsatisfactory treat-
or production of toxicity. The TDM can also help to guide
ment response not explained by poor adherence or drug
resistance, malabsorption of antituberculosis drugs in implementation of new treatment strategy.
HIV-seropositive subjects and other settings, scheduling Examples of the third setting largely focus on renal
administration and dosing of second-line [reserve] drugs impairment. Streptomycin, ethambutol, ofloxacin and
in some patients with MDR-TB, and perhaps optimizing cycloserine are drugs that are clearly dependent on the
dosing in selected patients with TB empyema and TB renal route of clearance (200,201), and TDM for these
meningitis. antituberculosis drugs in the face of renal dysfunction
There are still many questions to be answered in terms can be of significant relevance in guiding therapy to
of clinical applicability in the use of TDM in the treatment achieve optimum response and to avoid inadvertent
of TB. The most important limitation is the current lack toxicity. The role of TDM in managing patients with TB
of sufficient data to formulate clinically validated ranges in the face of hepatic dysfunction requires further
for antituberculosis agents (22). One proposed solution delineation (200).
is to employ the distribution of concentrations of a drug The most important example of the fourth setting can
achieved in healthy volunteers as the therapeutic range be found in association with fixed-dose combination
(22,201). However, in practice this approach can still be formulations, where bioequivalence studies are germane
problematic. One important example is concerned with to recommending utility of these compounds for treat-
HIV infected patients. Notwithstanding the serum ment (35).
Table 52.6: Usual pharmacokinetics of conventional antituberculosis drugs

Drug Dose Serum Cmax Serum tmax Serum t½
Isoniazid 300 mg 3-5 mg/l 0.75-2 h 1.5-4 h

Rifampicin 600 mg 7-20 mg/l 2h 3h
Pyrazinamide 25 mg/kg 20-50 mg/l 2h 9h
Ethambutol 15 mg/kg 2-5 mg/l 2-3 h Biphasic: 2-4 h,
12-14 h
Streptomycin 15 mg/kg 35-45 mg/l 0.5-1.5 h 3h
[intramuscular]
Cmax = peak serum drug concentration; tmax = time to peak concentration; t½ = serum half-life
768 Tuberculosis
The shortcomings of TDM principally include the treating pulmonary tuberculosis. Initial report. Am J Respir
time necessary for both patients and health care provi- Crit Care Med 1998;157:1726-33.
10. Cohn DL, Catlin BJ, Peterson KL, Judson FN, Sbarbaro JA. A
ders to obtain and transport blood samples, and the
62-dose, 6-month therapy for pulmonary and extrapulmo-
relatively high cost resulting from the demand for nary tuberculosis. A twice-weekly, directly observed and cost
specialized technology and expertise in measuring serum effective regimen. Ann Intern Med 1990;112:407-15.
drug concentrations. Furthermore, it must be stressed 11. Snider DE, Graczyk J, Bek E, Rogowski J. Supervised six-
that TDM taken in isolation is of limited value, therefore, month treatment of newly diagnosed pulmonary tuberculosis
using isoniazid, rifampin, and pyrazinamide with and
correlation with clinical and bacteriological data is
without streptomycin. Am Rev Respir Dis 1984;130:1091-4.
mandatory (201). 12. Third East African / British Medical Research Council Study.
In conclusion, TDM of antituberculosis agents Controlled clinical trial of four short-course regimens of
apparently provides a new opportunity in the clinical chemotherapy for two durations in the treatment of pulmo-
management of selected patients with TB, with a goal to nary tuberculosis. Second report. Tubercle 1980;61:59-69.
13. Hong Kong Chest Service/British Medical Research Council
improve their outcome. It is likely that TDM will furnish
Study. Controlled trial of 6-month and 8-month regimens in
a new paradigm of care for some patients with TB the treatment of pulmonary tuberculosis: the results up to 24
(200,201). In the coming decade, with further advance- months. Tubercle 1979;60:201-10.
ment in knowledge, technology and expertise, new 14. British Thoracic and Tuberculosis Association. Short-course
horizons and expanding indications of TDM may be chemotherapy in pulmonary tuberculosis. A controlled trial
by the British Thoracic and Tuberculosis Association. Lancet
attained. 1976;2:1102-4.
15. Slutkin G, Schecter GF, Hopewell PC. The results of 9-month
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776 Tuberculosis
Treatment of Latent
Tuberculosis Infection
53
DS Maru, CB Ogbunugafor, S Basu
INTRODUCTION a more proactive approach to tuberculosis [TB] control

be undertaken. As new diagnostic tests develop, as
The huge global reservoir of latent tuberculosis infection
shorter treatment regimens become available, and as the
[LTBI] presents a persistent challenge to the global control
health infrastructure further develops, LTBI treatment
of the disease. It is estimated that the global prevalence
for some even low-to-medium risk patients might be
of LTBI is over 30 per cent, infecting two billion indivi-
more feasible. Successes in the treatment of LTBI among
duals, the vast majority of whom live in resource-poor,
HIV-seropositive individuals suggest that targeted
highly endemic countries. Estimated prevalence in these
treatment in poor countries may be possible. Targeted
countries can reach over 80 per cent (1). It has long been
treatment of recent LTBI is a feasible strategy that has
argued that, in highly endemic, poor countries, scarce
yet to be explored fully. Finally, both national and
antituberculosis resources should be saved for treatment
international finances for TB have been mobilized like
of active cases. Indeed, DOTS is and should remain the
never before, which may provide the resources necessary
focus of public health programmes. In addition to DOTS,
to implement an LTBI treatment programme.
however, it is important to consider strategies to reduce
This chapter seeks to provide a framework for
the huge prevalence of LTBI.
clinicians and public health officials to address these
The strategy that many industrialized countries have
issues among the patient populations with whom they
taken to reduce LTBI has been targeted screening and
work. The chapter also focusses on issues concerning
treatment of high-risk populations. This strategy has
treating LTBI in resource-poor countries whose annual
largely been ignored in poor countries. Delivery of a
TB incidence exceeds 100 per 100 000 individuals.
preventive strategy to asymptomatic individuals that
requires up to one year of daily dosing in poor places
DIAGNOSTIC TESTS
with low health infrastructure and medication delivery
methods is problematic. Furthermore, defining LTBI is The paucity of tools available for the diagnosis of LTBI is
complicated by as much as 60 per cent reactivity to the a central barrier to the implementation of effective
tuberculin skin test [TST], which is commonly used in treatment of LTBI. Given the toxicity and cost associated
rich countries to define LTBI cases. In countries the size with antituberculosis chemotherapy, it is crucial that a
of India or China, the prospects of providing treatment diagnostic test be sufficiently specific while at the same
over six or nine months to 60 per cent of the population time preserving the sensitivity necessary for an effective
would seem completely unfeasible and non-productive. screening programme. The most widely used test, the
Despite these major obstacles, treatment of LTBI may century-old TST, is inadequate on both accounts. This
be an important strategy in certain patient populations. has hampered research in LTBI diagnosis for years; given
The spectre of human immunodeficiency virus [HIV] and the limits of TST as the gold standard, it has been difficult
multidrug-resistant tuberculosis [MDR-TB] require that to adequately assess new diagnostic strategies. The
Treatment of Latent Tuberculosis Infection 777
interferon-gamma release assays that have recently The fundamental statistical consideration on utility
become available, have broadened the possibilities of of these tests as tools for determining LTBI is the positive
LTBI detection. predictive value [PPV] in a given population. Since
environmental mycobacteria are so common in areas
Performance Characteristics of Latent Tuberculosis where TB is endemic (2), specificity is low for the TST,
Infection Diagnostic Tests decreasing the PPV. On the other hand, a high prevalence
of LTBI improves the PPV.
In the absence of a gold standard test for LTBI, approxi- Perhaps of greater clinical relevance than one carrying
mations are made in determining the performance LTBI is that of risk of developing active TB. This risk is
characteristics of these tests [Table 53.1]. highly dependent upon age, history of active TB contacts,
and whether the TST was a recent conversion [Table 53.2]
Tuberculin Skin Test (3,4). Immunosuppressive therapy and HIV infection also
confer as much as 10 times greater risk of activation (3).
The reader is referred to the chapter “Tuberculin skin test” Physicians need to take these issues into account when
[Chapter 11] for more details. they consider particular patients for testing for LTBI.
Interferon-gamma Release Assays TREATMENT REGIMENS
The reader is referred to the chapter “Diagnosis of latent Even as diagnosis is hampered by a lack of sensitivity
tuberculosis infection: recent advances and future directions” and specificity, LTBI treatment is hampered by long,
[Chapter 10] for more details. potentially toxic regimens that are difficult to administer
among asymptomatic individuals. Treatment regimens
for LTBI are listed in Table 53.3. Among HIV-sero-
Table 53.1: Methods to approximate performance charac-
teristics of latent tuberculosis infection diagnostic tests
negative subjects, the effectiveness of isoniazid treatment,
measured by the decrease in TB has been found to range
Sensitivity from 25 to 92 percent; when adherence was high, the
Response among culture-positive TB cases protective efficacy was observed to be close to 90 per cent
Actually determines sensitivity for disease not infection (4). Recently, Churchyard et al (5) computed that, in HIV
May overestimate sensitivity if immune response is weak
infected adults with no previous history of TB, the
in paucibacillary cases
May under-estimate sensitivity if immune response is weak combined efficacy of all TB preventive therapy regimens
owing to TB disease [regardless of TST status], was a 36 per cent reduction in
Long-term risk for developing active TB among subjects with the TB incidence compared with placebo. The greatest
various levels of test reactivity reduction in the TB incidence [62%] was observed among
Does determine the most relevant measure for public health individuals with a positive TST result. Isoniazid alone,
programming: risk
given for six to twelve months, reduced the TB incidence
Requires long period of follow-up and significant epidemio-
logical resources
by 33 per cent overall and by 64 per cent among
individuals with positive TST results (5).
Specificity All the trials evaluating preventive treatment for LTBI
Response among low-risk populations have included individuals with no previous history of
May underestimate specificity if certain members of the
TB. Published evidence also suggests that TB preventive
population have been exposed
May overestimate specificity if low-risk populations are
therapy for HIV infected individuals previously treated
also at lower risk of acquiring environmental mycobac- for TB [secondary preventive therapy] is also effective in
teria reducing TB recurrence (5). However, currently
Long-term risk for developing active TB among subjects with published international guidelines (4) do not endorse the
various levels of test reactivity use of secondary preventive therapy. This issue also
Does determine the most relevant measure for public health merits evaluation in future studies.
programming: risk
Requires long period of follow-up and significant Isoniazid
epidemiological resources
Since the 1950s, randomized, controlled trials have
TB = tuberculosis
evaluated isoniazid regimens in more than 20 trials,
778 Tuberculosis
Table 53.2: Annual risk of developing active tuberculosis*
Age group [years]
0 to 5 6 to 15 16 to 35 36 to 55 Over 56
[%] [%] [%] [%] [%]
Non-conversion positive result

5 to 9 mm 6 4 12 7 7
10 to 14 mm 19 8 15 10 10
> 15 mm 24 14 19 12 12
Recent conversion or contact with
active tuberculosis case
5 to 9 mm 29 6 30 23 12
10 to 14 mm 37 12 37 28 15
> 15 mm 54 12 56 42 17
* Based on data from studies carried out in the United States of America
Adapted from reference: 3
Table 53.3: Treatment regimens for latent [ATS] and Centers for Disease Control and Prevention
tuberculosis infection [CDC] guidelines (4) is nine months, based on extra-
Isoniazid 5 mg/kg [300 mg max] daily for 9 months polations from controlled studies of six-month and
Isoniazid 15 mg/kg [900 mg max] twice weekly for 9 months given twelve-month regimens. These studies have shown
as DOT improved effectiveness of approximately 10 per cent,
Isoniazid 300 mg daily for 6 months during the course of the 12-month regimen. Non-
Isoniazid 300 mg twice weekly for 6 months given as DOT controlled sub-group analyses, however, have suggested
equivalency of the nine-month and twelve-month
Rifampicin 10 mg/kg [600 mg max] with pyrazinamide 15-20
mg/kg [2000 mg max] for 2 months regimens (4).
Rifampicin 10 mg/kg [600 mg max] with pyrazinamide 50 mg/kg Transient elevation of liver function tests can be
[4000 mg max] twice weekly for 2 months given as DOT expected in as many as of 10 to 22 per cent of patients.
Rifampicin 10 mg/kg [600 mg max] daily for 4 months Clinical hepatitis, however, develops at a rate of approxi-
mately one to two per cent in younger individuals with
Note: In paediatric populations, doses are: isoniazid 10-20 mg/
no risk factors, but increases with age, alcohol abuse,
kg [300 mg max] daily, 20-40 mg/kg [900 mg max] twice weekly;
no adjustments for rifampicin necessary chronic viral hepatitis, and HIV to as high as 10 per cent.
DOT = directly observed treatment The recent commercialization of rapid, point-of-care liver
Source: reference 4 enzyme assays, providing costs decline, could make such
monitoring easier in rural areas where laboratory
totaling more than 100 000 patients. These observations
facilities may be lacking. The reader is referred to the
show a clear impact of isoniazid on the development of
chapter “Antituberculosis treatment induced hepatotoxicity”
active TB, with effectiveness [1–relative risk] ranging [Chapter 54] for more details.
from 25 to 90 per cent (6). The high variability in results
is largely due to differences in adherence and baseline
Rifamycin-based Regimens
risk rates. The standard remains a nine-month, isoniazid-
based regimen. Variation in efficacy may also be due to Since adherence and retention have been limited with
variability in hepatic metabolism. This was suggested to otherwise effective isoniazid regimens, the development
be the cause for the null result in one Japanese study (7); of shorter regimens is a priority. These have typically
however, other Japanese studies have shown positive been rifamycin-based regimens. The well-studied is a
impacts similar to those from other countries (8). The two-month regimen consisting of pyrazinamide and
regimen suggested by the American Thoracic Society rifampicin. Owing to concerns over hepatotoxicity, this
combination has not been evaluated in a randomized, (22,23). Additionally, in vitro studies of moxifloxacin and
controlled trial among HIV-seronegative patients. other fluoroquinolones have shown that there appears
Among HIV-seropositive patients, in whom risk is to be no indication of cross-resistance between fluoro-
elevated, the benefits have outweighed these costs. For quinolone resistance and resistance to other antituber-
both ethical and scientific reasons, these regimens must culosis drugs (24). Finally, in a murine model of LTBI,
be compared with standard isoniazid regimens as moxifloxacin was highly effective as part of various
opposed to placebo. Four randomized controlled trials combination treatment regimens, including shorter
involving over 5000 patients have shown statistical duration ones (25).
equivalence to isoniazid regimens (9-12). Following these Widespread use of fluoroquinolones in general
successes, the rifampicin and pyrazinamide regimen practice for other disease indications even though
was piloted in seronegative patients. However, severe patients are actually infected with Mycobacterium
liver injury including deaths were reported among 5.8 tuberculosis, especially inadvertant treatment of smear-
per cent of 1311 patients treated with this regimen negative pulmonary TB with fluoroquinolones due to a
(13-17). Revised guidelines (18) recommended that misdiagnosis of community acquired pneumonia can
rifampicin and pyrazinamide regimen should not actually result in monotherapy for TB (26,27). These
generally be offered to patients with LTBI and the factors may facilitate the emergence of moxifloxacin
clinicians should choose from the alternative regimens
resistance. It is necessary to safeguard the use of
available. The rifampicin and pyrazinamide regimen
moxifloxacin, as it is a valuable addition to the armamen-
definitely should not be used in persons with underlying
tarium of antituberculosis drugs (26,27).
liver disease, history of alcoholism, or isoniazid-
associated liver injury (18). If the potential benefits of
PROGRAMMATIC ISSUES IN LATENT
this regimen outweigh the risk of hepatotoxicity, it should
TUBERCULOSIS INFECTION TREATMENT:
be very carefully employed in selected situations only
THE CASE OF INDIA
by the experts.
At the moment, these regimens have been under- India constitutes one-fifth of the global burden of TB,
studied in paediatric populations, though some and approximately 40 per cent of the population is
uncontrolled data suggest their effectiveness. As such, estimated to have LTBI. The annual risk of developing
these are definitely second-line agents among paediatric LTBI is 1.5 per cent (28-30). The economic losses of TB
populations, except in the case of contact with a known are enormous. In India, three to four months of work is
case of isoniazid-resistant TB. lost if an adult develops active TB, resulting in the loss
Rifabutin, like rifampicin, works by inhibiting the of 20 to 30 per cent of annual household income. If the
enzyme bacterial deoxyribonucleic acid-dependent patient dies as a result of TB, 15 years of productivity are
ribonucleic acid polymerase. The most important use of lost. India was the site of discovery and implementation
rifabutin is among HIV-positive patients at risk for of key chemotherapy regimens, including DOTS, in the
isoniazid-resistant TB. Rifabutin may interact less with control of TB. This, along with a relatively well-funded
protease inhibitors and non-nucleoside reverse higher medical education system that attracts top
transcriptase inhibitors than does rifampicin. students in medical research and practice, provides the
experience necessary to deliver and evaluate such a
On the Horizon: Moxifloxacin-based Regimens programme. Furthermore, India is home to the most
The increased prevalence of MDR-TB has engendered advanced generic drug manufacturing industry in the
an even greater urgency to explore new classes for developing world, which can help to ensure a steady
potential treatments of LTBI. Among the fluoroquino- supply of cheap medicines. For these reasons, India
lones, moxifloxacin shows the greatest promise to date appears well situated to be a global leader in LTBI control.
in the treatment of LTBI. The drug has strong in vitro There are several major barriers to implement the
(19-20) and in vivo activity in non-human models (21), widespread LTBI treatment, however, which have been
and in the treatment of active TB in humans, it has highlighted by some as arguments against such prog-
bactericidal activity comparable to first-line agents rammes.
780 Tuberculosis
Tuberculosis is too Endemic to Treat Latent mycobacteria [NTM] infection, the epidemiological
Tuberculosis Infection evidence suggests that the bulk of them would represent
true LTBI. While these may represent a small reservoir
The real question is not whether LTBI is too endemic but
of LTBI, there is a wealth of data suggesting they should
rather whether false-positive rates for LTBI diagnostics
be treated; indeed, any foreigner who comes to India and
are too high. If, in a given country 40 per cent of the
subsequently converts will be given treatment. At the
citizens are in fact true LTBI cases, and they can be
very least, then, for that 40 per cent of the population
detected with a specific assay, then they should be
that is not reactive at any given moment, it may be
treated. The enormity of these numbers should not be a
prudent to serially, perhaps annually, test them for
deterrent as sub-populations for several diseases that
conversion.
have massive prevalence rates are routinely treated.
Examples include prevalence rates of 30 per cent for HIV
Massive Campaigns to Treat Latent Tuberculosis
in some African communities (31,32), of 50 per cent for
Infection will only Lead to Drug-resistance
diabetes in some American Indian populations (33,34),
of 40 per cent for hepatitis C virus (35,36) among some It has been hypothesized (37) that community-wide
prison populations in the United States. Where there is isoniazid preventive therapy for HIV-TB co-infected
an epidemic, the public health system must treat all individuals will reduce the incidence of TB in the short-
patients affected. term but may also speed the emergence of drug-resistant
However, that largely moral argument may take a TB. A recent review (38) highlighted the paucity of data
secondary role to the very real problem of limited and did not exclude the possibility of an increased risk
resources. This has been the argument with regard to for isoniazid-resistant TB following isoniazid preventive
DOTS that limited resources must focus on smear- therapy. It also emphasized the importance of exclusion
positive pulmonary TB, because that is where the major of active TB prior to isoniazid preventive therapy and
chain of transmission is located. While that is in large continued surveillance for isoniazid resistance.
part true, very rarely in public health is funding a zero- Emergence of drug-resistance is a major concern, but
sum game. That is to say, LTBI treatment, if appropriately should not be a barrier provided appropriate control
marketed, would not drain resources from other areas measures are put into place to prevent this phenomenon.
because the problem of resources is largely one of political There are three major reasons why an LTBI campaign
will as opposed to absolute finances. This is especially would lead to the development of drug resistance. The
true as huge, wealthy multinational donors, led by the major reason, as with any infection, is improper dosing or
Bill and Melinda Gates Foundation, continue to enter into administration. These issues are tied to a lack of
the global public health financing arena. preventative medicine culture that finds origin in socio-
Furthermore, it remains to be seen whether an LTBI political will rather than clinical capability. The key here
programme can be cost-effective, as has been demons- is rigorous education, monitoring, and follow-up. It will
trated in wealthier countries. Given the huge economic also be important to discover once-weekly and short-
burden of TB, efforts aimed at prevention could prove course treatment regimens, which would make adherence
highly cost-effective. and follow-up more likely, as well as even opening the
Now, for example, if 60 per cent of the citizens are possibility of directly observed therapy. The next problem
TST-positive, but only 20 per cent of these are true LTBI would be the development of resistance due to partially
cases, then certainly there is an argument against treating treating active TB. This should be avoided by taking a
all TST-positive cases. This is why there is clearly a need rigorous history and review of symptoms, as well as
for new diagnostic tests. However, this does not mean assessing a chest radiograph prior to starting treatment.
that no TST-positive patients should be treated. The most In any case, all studies employing treatment should
obvious subpopulation are high-risk patients who show have in place sound mechanisms of follow-up so that
recent TST conversion. These are patients that have not any patient who develops active TB should submit
reacted to previous BCG vaccination, the most common samples for drug resistance testing. This will ensure that
reason for a false-positive TST. Although these patients the patient is placed on an appropriate regimen and that
could represent conversion due to nontuberculous the treatment programme is appropriately evaluated.
However, the lack of a ‘gold standard’ for the diagnosis 4. Joint Statement of the American Thoracic Society [ATS] and
of LTBI, costs involved in getting mycobacterial culture the Centers for Disease Control and Prevention [CDC].
Targeted tuberculin testing and treatment of latent tuber-
and sensitivity tested in a reliable, periodically accredited
culosis infection. Am J Respir Crit Care Med 2000;161:S221-
laboratory and the enormity of the task of following up 47.
millions of persons for prolonged periods, all seem to be 5. Churchyard GJ, Scano F, Grant AD, Chaisson RE.
insurmountable hurdles for implementing massive LTBI Tuberculosis preventive therapy in the era of HIV infection:
treatment campaigns in resource-limited settings. overview and research priorities. J Infect Dis 2007;196[Suppl
1]:S52-62.
Rural Health Care Facilities and Personnel are 6. Dooley KE, Sterling TR. Treatment of latent tuberculosis
infection: challenges and prospects. Clin Chest Med
Extremely Lacking
2005;26:313-26.
The provision of adequate rural health care facilities and 7. Bush OB Jr, Sugimoto M, Fujii Y, Brown FA Jr. Isoniazid
personnel is among India’s greatest public health failures, prophylaxis in contacts of persons with known tuberculosis.
and represents a huge barrier to successful implemen- Second report. Am Rev Respir Dis 1965;92:732-40.
8. Chiba Y, Takahara T, Kondo K, Nagashima A. Chemopro-
tation of any public health programmes. Again, however,
phylaxis of tuberculosis for adults in Japan. Bull Int Union
the success of several vaccination campaigns, of nutrient Tuberc 1964;35:91-3.
supplementation, and of DOTS suggests that, in spite of 9. Quigley MA, Mwinga A, Hosp M, Lisse I, Fuchs D, Porter
this, some strides in preventive public health can be JDH, et al. Long-term effect of preventive therapy for
made even in rural areas with poor health facilities. tuberculosis in a cohort of HIV-infected Zambian adults.
AIDS 2001;15:215-22.
10. Mwinga A, Hosp M, Godfrey-Faussett P, Quigley M,
DECIDING WHEN TO TREAT LATENT Mwaba P, Mugala BN, et al. Twice weekly tuberculosis
TUBERCULOSIS INFECTION IN preventive therapy in HIV infection in Zambia. AIDS
HIGH-PREVALENCE SETTINGS 1998;12:2447-57.
11. Gordin F. Short-term tuberculosis prophylaxis is effective in
Clearly, there is not enough evidence to start rolling out persons with HIV. Am Fam Physician 1998;58:948.
LTBI screening and treatment for the general population. 12. Halsey NA, Coberly JS, Desormeaux J, Losikoff P,
For the clinician working in endemic areas, however, Atkinson J, Moulton LH, et al. Randomised trial of isoniazid
there are several options for detecting and treating LTBI. versus rifampicin and pyrazinamide for prevention of
tuberculosis in HIV-1 infection. Lancet 1998;351:786-92.
It is prudent, even in the absence of contact tracing by
13. Centers for Disease Control and Prevention [CDC]; American
public health authorities, for individual clinicians to Thoracic Society. Update: fatal and severe liver injuries
encourage the family and personal contacts of active TB associated with rifampin and pyrazinamide for latent
patients to at least be screened using the TST. If the TST tuberculosis infection, and revisions in American Thoracic
is reactive, the patient is asymptomatic and chest Society/CDC recommendations: United States, 2001. Am J
radiograph is negative, patients can be counselled as to Respir Crit Care Med 2001;164:1319–20.
14. Stout JE, Engemann JJ, Cheng AC, Fortenberry ER, Hamilton
which treatment regimen, if any, would be most
CD. Safety of 2 months of rifampin and pyrazinamide for
appropriate for them. Whichever regimen is started, it is treatment of latent tuberculosis. Am J Respir Crit Care Med
then the duty of the clinician and the health care team to 2003;167:824–7.
ensure that treatment is appropriately adhered to. 15. Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo
J, Vittinghoff E, et al. Short-course rifampin and pyrazinamide
compared with isoniazid for latent tuberculosis infection: a
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Antituberculosis Treatment Induced Hepatotoxicity 783
Induced Hepatotoxicity
54
PK Garg, RK Tandon
INTRODUCTION prophylaxis was evaluated. In this study (11), 20 836

subjects were administered isoniazid in a dosage of 300
In the present era, short-course antituberculosis treat-
mg/day as chemoprophylaxis while 6991 control subjects
ment with standard first-line drugs, namely, isoniazid,
received a placebo. The relative risk of developing
rifampicin, pyrazinamide, ethambutol or streptomycin
hepatotoxicity in patients receiving isoniazid
is the norm and these drugs constitute the essential
chemoprophylaxis for less than one year was found to
components of the DOTS strategy for control of
be 5.2/1000 irrespective of age (11).
tuberculosis [TB] endorsed by the World Health
After these early reports, the United States Public
Organization [WHO] (1). Antituberculosis treatment may
result in adverse effects involving almost all systems in Health Service [USPHS] conducted a large multicentre
the body including the gastrointestinal tract, liver, skin, prospective study (12) in patients receiving isoniazid for
nervous system, otovestibular apparatus and the eyes. chemoprophylaxis to find out the incidence and course
Of these, drug-induced hepatotoxicity [DIH] is an of isoniazid-induced hepatotoxicity (12). In 13 838
important and commonly encountered adverse effect patients, the overall incidence of isoniazid-induced
(2-8). Antituberculosis DIH usually has a benign hepatotoxicity was found to be one per cent with a
course, but may result in serious morbidity and even mortality rate of 0.06 per cent. This high mortality rate
mortality (2-8). resulted in the termination of the study (13). In addition
to patients developing clinical hepatitis, a large
EFFECT OF ANTITUBERCULOSIS proportion of patients had developed asymptomatic
DRUGS ON THE LIVER elevation of transaminases (14).
Usually, isoniazid-induced hepatitis gradually resol-
Isoniazid ves within one to four weeks after stopping isoniazid.
Isoniazid was introduced for the treatment of TB in the However, if the drug is continued, patients may develop
1960s. Initially the hepatotoxic potential of isoniazid was severe hepatitis including fulminant hepatic failure (15).
not recognized. In 1969, however, Scharer and Smith (9) Snider and Caras (16) after reviewing the articles
reported that 10.3 per cent of patients receiving isoniazid published from 1965 through 1989, identified 177 deaths
developed liver function abnormalities. In a large from isoniazid-induced hepatitis among persons taking
study (10) of 2321 patients who were on isoniazid isoniazid alone for chemoprophylaxis in the United
prophylaxis, clinical hepatitis was reported to occur in States. They (16) also found that: [i] deaths from isoniazid
19 [0.8%] cases and overt jaundice in 13 [0.6%] cases with hepatitis are less frequent now than in 1970s;
one death (10). [ii] increasing proportion of deaths occur with increas-
In a randomized, double-blind study (11) the ing age; and [iii] women may be at an increased risk of
incidence of hepatotoxicity due to isoniazid chemo- death.
784 Tuberculosis
Pathogenesis HEPATOTOXICITY DUE TO COMBINATION

The pathogenesis of isoniazid induced hepatotoxicity is TREATMENT OF ACTIVE TUBERCULOSIS
not well-understood. Both dose related toxicity and DISEASE WITH ISONIAZID, RIFAMPICIN AND
hypersensitivity reaction have been considered. The PYRAZINAMIDE
histopathological picture resembles that of viral hepatitis Isoniazid and Rifampicin
and shows hepatocyte necrosis, ballooning degeneration
and inflammatory infiltrate (17). These findings may There is evidence to suggest that DIH occurs with greater
suggest dose related toxicity. Hypersensitivity is consi- frequency and may be more severe when isoniazid and
dered unlikely because of the delayed onset of isoniazid- rifampicin are administered in combination than when
induced hepatotoxicity, absence of symptoms usually either drug is given alone (2,25). Some reports (27,28)
associated with hypersensitivity such as rash, fever, have suggested that hepatitis appeared sooner with
arthralgia and eosinophilia, and no hepatotoxicity on re- isoniazid and rifampicin combination therapy than with
challenge in most cases (18,19). However, in some isoniazid therapy alone, with significant elevation of
patients there is a circumstantial evidence of hypersensi- transaminase levels and hypoprothrombinaemia
tivity to the drug. In these patients, eosinophils are occurring in some patients.
prominent on liver biopsy and hepatotoxicity recurs on More than a decade ago, Steele et al (25) undertook a
re-challenge (19). In addition, lack of direct correlation meta-analysis to estimate the incidence of antituber-
between serum drug levels and hepatotoxicity argues culosis treatment induced hepatotoxicity. A total of 34
against a direct toxic effect (20). clinical studies [22 involving adults and 12 involving
children] published between 1966 and 1989 were
Rifampicin analysed. They found that the incidence of clinical
hepatitis in adults with isoniazid alone was 0.6 per cent,
The major adverse effect of rifampicin therapy is
with multidrug isoniazid regimens without rifampicin
hepatotoxicity. Abnormalities in the liver function tests
1.6 per cent and with regimens containing rifampicin and
are common in patients receiving rifampicin and these
not isoniazid 1.1 per cent. The incidence of clinical
resolve even while the drug continues to be used.
hepatitis in 6 105 patients taking isoniazid and rifampicin
Elevation of bilirubin and alkaline phosphatase levels
combination was 2.6 per cent which was significantly
are characteristic with rifampicin treatment. In several
higher than the incidence in patients taking multiple
published studies (21-24), the reported incidence of
drugs containing isoniazid without rifampicin and those
transaminase elevation and overt clinical hepatitis during
taking multiple drugs containing rifampicin without
rifampicin therapy in the absence of isoniazid varied
isoniazid. Children receiving isoniazid and rifampicin
from 0.6 to 2.7 per cent. On meta-analysis, the mean
combination had a significantly higher incidence of
incidence of hepatitis in 1264 patients on rifampicin
hepatitis [6.9%] compared to those receiving multiple
therapy without isoniazid was computed to be 1.1 per
drug isoniazid containing regimens without rifampicin
cent, significantly lower than the 2.6 per cent observed
[1.6%]. The authors concluded that isoniazid and
with isoniazid and rifampicin combination (25).
rifampicin combination caused more hepatotoxicity than
either of the drugs administered alone and the
Pathogenesis
hepatotoxic effects of these two drugs given together was
Rifampicin-induced hepatotoxicity occurs earlier additive rather than synergistic.
compared to isoniazid and produces a patchy cellular In a retrospective study (29), five of the thirteen ortho-
abnormality with marked periportal inflammation (26). topic liver transplant recipients developed hepato-
Rifampicin-induced hepatitis has been postulated to toxicity. All of them were receiving isoniazid and rifam-
occur as a part of systemic allergic reaction and due to picin as a part of a multidrug regimen for the treatment
unconjugated hyperbilirubinaemia as a result of compe- of TB. In this study (29) patients receiving isoniazid alone,
tition with bilirubin for uptake at hepatocyte plasma or, isoniazid along with ethambutol for chemo-
membrane (26). prophylaxis did not develop hepatotoxicity.
Pathogenesis Other studies (32-36) have suggested that products

of hydrolysis rather than acetylation are the critical toxic
It is not clear as to why is there an increased risk of
metabolites of isoniazid hydrolase. Ellard and Gammon
hepatotoxicity with isoniazid and rifampicin combi-
nation. The answer probably lies in the interaction (32) showed that a small portion of isoniazid is directly
between isoniazid and rifampicin metabolism [Figure hydrolyzed by isoniazid. They (32) also showed that the
54.1]. The metabolism of isoniazid is influenced by both proportion of drug metabolized through this direct
genetic and intercurrent factors. The principal metabolite pathway is greater in slow acetylators than in rapid
of isoniazid, acetyl isoniazid, is converted to monoacetyl acetylators. Sarma and colleague (33) showed that the
hydrazine. This in turn is metabolized by microsomal hepatotoxic action of metabolites of isoniazid is not so
p-450 enzymes to other compounds causing hepato- much due to monoacetyl hydrazine but due to the
toxicity and this effect may be enhanced by rifampicin- hydrazine formed from isoniazid. Rifampicin induces the
induced enzyme induction. Because acetyl isoniazid metabolism of isoniazid by isoniazid hydrolase resulting
formation occurs in larger amounts in rapid rather than in the formation of isonicotinic acid and hydrazine (34).
slow acetylators, it was suggested that rapid acetylators It has been suggested that concomitant administration
are more prone to hepatotoxicity (19). However, of rifampicin and isoniazid could result in increasing
subsequent studies questioned this hypothesis as it was levels of hydrazine and this could provoke hepatotoxicity
shown that monoacetyl hydrazine formed was rapidly especially in slow acetylators (33). This hypothesis is
converted into the less toxic diacetyl hydrazine which supported by the finding of increased hepatotoxicity in
was excreted rapidly (30). Both rapid and slow slow acetylators (35,36).
acetylators excreted similar proportions of monoacetyl There is a considerable debate with regard to whether
hydrazine suggesting that the more rapid formation of the hepatotoxicity is due to the additive effect of isoniazid
monoacetyl hydrazine is compensated by its more rapid and rifampicin or synergistic direct toxic effect of drugs
conversion to diacetyl hydrazine and its excretion in or is a hypersensitivity phenomenon. The first human
rapid acetylators (31). case of a proven hepatotoxic interaction between
Figure 54.1: Pathways of isoniazid metabolism

* Oxidation induced by alcohol and cytochrome P450 2E1
NAT = N-acetyl transferase; GSTM = glutathione S-transferase M
786 Tuberculosis
isoniazid and rifampicin has been reported by Askgaard pyrazinamide-induced hepatotoxicity, whereas, early
et al (37). A 35-year-old black Somalian patient with increases in serum transaminases [usually within first
miliary TB developed hepatotoxicity after a few days of 15 days] are likely to be caused by rifampicin-induced
treatment with isoniazid, rifampicin, pyrazinamide and isoniazid hepatotoxicity (45).
ethambutol. On withdrawing all the drugs, the liver
profile normalized and remained so after isoniazid HEPATOTOXICITY DUE TO TREATMENT OF
challenge. Hepatotoxicity recurred when isoniazid was LATENT TUBERCULOSIS INFECTION
added but it was well-tolerated when rifampicin was re-
introduced without isoniazid. Earlier, the terms “preventive therapy” and “chemo-
In a study from Chandigarh (38), the role of oxidative prophylaxis” have been used to refer to the use of a
stress as a mechanism of hepatotoxicity caused by simple regimen using isoniazid to prevent the develop-
isoniazid and rifampicin was investigated in young ment of active TB disease in persons known or likely to
growing rats. Altered profile of antioxidant enzymes with be infected with Mycobacterium tuberculosis. As these
increased lipid peroxidation indicated that isoniazid and terms were confusing, the term “treatment of latent
rifampicin induced hepatotoxicity appeared to be tuberculosis infection [LTBI]” has replaced these terms
mediated through oxidative stress. It has also been shown in the statement of the American Thoracic Society [ATS]
that rifampicin and isoniazid resulted in an increase in and the Centers for disease Control and Prevention
acetaminophen and isoniazid-induced cytotoxicity in [CDC] (46). Though uncommon in India, targeted
human HepG2 hepatoma cells (39). tuberculin testing and treatment of LTBI is often practiced
in developed countries, like the USA, as per these
Rifampicin, Isoniazid and Pyrazinamide guidelines using isoniazid alone for six or nine months,
or rifampicin alone for four months or the combination
Hepatotoxicity is the most serious side effect of pyrazina-
of rifampicin and pyrazinamide for two months. Because
mide treatment. Earlier pyrazinamide was employed in
of cost-effectiveness, the National Institute for Health and
a dosage of 40 to 50 mg/kg/day for prolonged periods
Clinical Excellence [NICE] guidelines (47) recommend a
and hepatotoxicity developed in about 15 per cent of the
two-step approach, with an initial tuberculin skin test
cases leading to the abandonment of pyrazinamide as a
[TST], followed by an interferon-gamma release assay
first-line drug (40). However, pyrazinamide is presently
test to confirm positivity. Six month course of isoniazid
administered in a dosage of 25 to 35 mg/kg/day. The
or rifampicin or a three-month course comprising of
contribution of pyrazinamide to the development of
rifampicin and isoniazid is recommended for the
hepatotoxicity at this dosage has been controversial. In a
treatment of LTBI (47). In the late 1960s, and the early
large Indian study (41) on hepatic toxicity with short-
1970s, it was observed that a large proportion of the
course regimens containing rifampicin, isoniazid and
subjects who were treated for LTBI with isoniazid
pyrazinamide, there was no indication that pyrazina-
developed asymptomatic elevation of hepatic trans-
mide contributed to the development of hepatotoxicity.
aminases and one per cent to ten per cent developed
However, in some studies (42-45), pyrazinamide was
clinically evident hepatotoxicity (9-13). More recent
found to significantly contribute to the development
evidence suggests that less than one per cent of persons
hepatotoxicity when given along with isoniazid and
receiving clinically monitored isoniazid prophylaxis
rifampicin.
developed DIH (48).
Though the rifampicin and pyrazinamide regimen
Pathogenesis
was well tolerated in human immunodeficiency virus
The exact pathogenetic mechanism of pyrazinamide [HIV]-seropositive patients, after the publication of the
induced hepatic damage has not been clarified as yet. In ATS guidelines (46), severe liver injury including deaths
patients receiving a combination of isoniazid, rifampicin were reported among 5.8 per cent of 1311 patients treated
and pyrazinamide, two patterns of fulminant liver injury with the rifampicin and pyrazinamide regimen
have been observed. Late increases in serum trans- (49-51). Pyrazinamide has often been implicated as the
aminases [usually after 1 month] occur during agent chiefly responsible for this (52). A meta-analysis
(53) compared rifampicin plus pyrazinamide versus Table 54.1: Risk factors for the development of
isoniazid for treatment of LTBI and concluded that the antituberculosis treatment induced hepatotoxicity
former treatment regimen increases the risk of Advanced age
hepatotoxicity especially in non-HIV infected persons. Female sex
Revised guidelines (47,52) recommended that rifampicun
Moderately/far advanced/extensive disease [pulmonary tuber-
and pyrazinamide regimen should generally not be culosis]
offered to patients with LTBI and the clinicians should Hypoalbuminaemia, malnutrition
choose from the alternative regimens available. This
Alcoholism
regimen definitely should not be used in persons with
Underlying liver disease
underlying liver disease, history of alcoholism, or
Hepatitis B virus infection
isoniazid-associated liver injury (52). If the potential
Hepatitis C virus infection
benefits of this regimen outweigh the risk of DIH, it
should be very carefully employed in selected situations Human immunodeficiency virus infection
only by experts. Curiously, the hepatotoxicity rate is Acetylator phenotype
higher among the HIV-seronegative subjects than in HIV- N-acetyltransferase activity
seropositive subjects. Furthermore, rates of DIH that have Glutathione S-transferase activity
been observed with this two-drug regimen are higher
than those observed among patients with active TB who
are treated with three potentially hepatotoxic drugs was more frequent in older patients. However, in another
[isoniazid in addition to rifampicin and pyrazinamide] Indian study (57), it was observed that age had no relation
during the initial intensive phase of two months (54). with antituberculosis treatment induced hepatotoxicity.
These issues merit further study.
Sex
FACTORS IMPLICATED IN THE DEVELOPMENT In some studies (42,44,56,58), elderly females have been
OF ANTITUBERCULOSIS TREATMENT INDUCED reported to be at a higher risk to develop antituberculosis
HEPATOTOXICITY treatment induced hepatotoxicity. However, some
workers believe that the incidence of DIH due to
The fact that antituberculosis drugs cause hepatotoxicity
antituberculosis drugs is not influenced by the gender
only in a small proportion of patients raises the question
of the patients (55).
about some predisposing factors for the development of
antituberculosis treatment induced hepatotoxicity.
Ethnic and Racial Variation
Certain putative factors have been implicated in the
development of antituberculosis treatment induced In Indian patients, a higher risk of DIH due to antituber-
hepatotoxicity [Table 54.1]. These are discussed below. culosis drugs has been reported (41,57,59,60) than in their
Western counterparts (61-63). The risk of DIH, based on
Age data derived from four prospective studies from India
(25) was 11.5 per cent, compared with 4.3 per cent in 14
Isoniazid-induced hepatotoxicity has been correlated
published studies from the West (56).
with age. The incidence of serious hepatotoxicity is rare
below 20 years of age. It was found to be 0.3 per cent in
Genetic Factors
the age group of 20 to 34 years, 1.2 per cent in 35 to 39
years age group and in patients above the age of 50 years, Though several risk factors have been suggested for the
the risk increased to 2.3 per cent (55). Riska (11) found development of DIH due to antituberculosis treatment,
that the relative risk of hepatotoxicity due to isoniazid the role of genetic factors has not been fully evaluated
prophylaxis was 2.8/1000 in patients younger than 35 (63). Sharma et al (64) recently reported the major
years while it was 7.7/1000 in those more than 50 years histocompatibility complex [MHC] class II alleles and
of age. In a case-control study, Pande et al (56) observed clinical risk factors for the development of DIH in
that antituberculosis treatment induced hepatotoxicity 346 north Indian patients with TB receiving
788 Tuberculosis
antituberculosis treatment. Of these, 56 patients [16%] genotype-phenotype correlation study for human NAT2
developed DIH, whereas the remaining 290 patients did has revealed alleles associated with rapid and slow
not. Multivariate logistic regression analysis revealed acetylation. Isoniazid is metabolized to hepatotoxic
that, older age, moderately or far advanced disease, intermediates by the isoenzyme NAT2 and cytochrome
serum albumin less than 3.5 g/dl, absence of human P450 2E1 [CYP2E1]. However, the association of poly-
leucocyte antigen [HLA]-DQA1*0102, and presence of morphic NAT acetylator status and hepatotoxicity
HLA-DQB1*0201 were independent risk factors for the induced by isoniazid is not clear (5). Huang et al (68)
development of DIH (64). reported that NAT2 slow-acetylator status and age were
the only independent risk factors for DIH due to
Acetylator Status and Hepatotoxicity antituberculosis treatment. Additionally, it was also
There is considerable confusion in the literature observed that slow acetylators were prone to develop
regarding acetylator phenotype status and the more severe hepatotoxicity than rapid acetylators (68,69).
development of hepatotoxicity. Rapid acetylators have Ohno et al (70) also reported that NAT2 slow acetylator
been shown to be more susceptible to isoniazid-induced genotype significantly affected the development of DIH
toxic hepatitis (23). On the other hand, in patients due to isoinazid and rifampicin. In another report (71),
receiving regimens containing isoniazid and rifampicin, even after adjustment for acetylator status and age, the
the incidence of DIH was found to be higher in slow CYP2E1 c1/c1 genotype remained an independent risk
acetylators than in rapid acetylators (41,56). However, factor for hepatotoxicity suggesting that CYP2E1 genetic
Gurumurthy et al (65) in a study of 3000 south Indian polymorphism may be associated with susceptibility to
patients receiving various isoniazid containing regimens DIH caused by antituberculosis treatment. While no
demonstrated no relationship between the acetylator association was found between NAT2 polymorphism
phenotype and the incidence of hepatotoxicity. Singh et and DIH due to isoniazid in the treatment of LTBI,
al (66) also did not find any correlation between the genotyping of CYP2E1 polymorphisms was found to be
acetylator status and the development of antituberculosis a useful predictive tool for predicting isoniazid-induced
treatment induced hepatotoxicity. hepatic toxicity (72).
Drug-Metabolizing Enzyme Polymorphisms and Glutathione S-transferase

Predisposition to Antituberculosis Treatment
In a case-control study (73) of polymorphisms at the
Induced Hepatotoxicity
glutathione S-transferase [GST] loci [GSTM1 and GSTT1]
N-acetyl Transferase and Cytochrome P450 2E1 and their relation to the development of DIH due to anti-
tuberculosis treatment, the frequencies of mutations at
N-acetyl transferase [NAT] activity, one of the earliest
GSTT1 and NAT2 genes were not significantly different
pharmacogenetic traits to be recognized, was first identi-
between cases and controls. However, frequency of
fied as the genetically controlled step for the inactivation
homozygous ‘null’ mutation at the GSTM1 gene was
of isoniazid. Molecular genetic studies of NAT in humans
significantly higher among cases suggesting that these
revealed the presence of three loci, two of which encode
mutations could predispose to the development of DIH
distinct enzymes with similar action and the third is a
due to antituberculosis treatment (73). A recent meta-
pseudogene (67). Human NAT1 is found in liver, gut and
analysis (74) concluded that NAT2mt, CYP2E1*1A and
almost all tissues. It acetylates para-aminosalicylate and
GSTM1 null have a modest effect on genetic susceptibility
para-aminobenzoic acid. In contrast, humans NAT2,
to antituberculosis treatment induced hepatotoxicity.
found primarily in the liver and intestinal epithelium,
acetylates substrates, such as isoniazid, dapsone and
Underlying Chronic Liver Disease
arylamine carcinogens. Gene mapping studies in humans
have demonstrated that the NAT genes are located Even though there are reports that patients with known
between 170 and 360 kb at 8p22. The coding region for liver disease can be treated with isoniazid and rifampicin
both NAT1 and NAT2 is 870 bp and is intron less (5,67). containing regimens without undue risk, many workers
Both NAT1 and NAT2 loci are highly polymorphic. The have reported that patients with underlying liver disease
and alcoholics are more prone to develop DIH due to toxicity has been reported in patients with malnutrition
antituberculosis treatment. Gronhagen-Riska et al (58) (80). In another study (81) from India, it has been
studied predisposing factors in hepatitis due to combined observed that mild degree of malnutrition in children
isoniazid and rifampicin treatment and reported that one does not predispose to hepatotoxicity. Singh et al (42)
half of the patients who developed large increases in reported that malnutrition predisposed to the develop-
transaminases [> 150 units/l] were either alcoholics or ment of antituberculosis treatment induced hepato-
had a history of previous liver or biliary disease. The peak toxicity. They also reported that malnourished patients
transaminase and bilirubin levels were higher in patients had received higher than normal dosage of antituber-
who were hepatitis B virus [HBV] carriers than in those culosis drugs per kilogram body weight and suggested
who were not (58). Other studies (11,13) also suggested that this could be one of the reasons for the development
that concurrent and previous biliary disorders and of hepatotoxicity in them.
alcoholism were risk factors for DIH caused by isoniazid.
ANTITUBERCULOSIS TREATMENT INDUCED
Hepatitis and the Human HEPATOTOXICITY AND TYPE OF TUBERCULOSIS
Immunodeficiency Viruses Patients with severe forms of TB have been reported to
In a study (75) involving 43 HBV carriers and 276 non- be at a higher risk of developing DIH than those with
carriers who received antituberculosis treatment, and 86 mild disease (82). Patients with TB meningitis have been
HBV carriers who did not receive antituberculosis observed to have a higher incidence of DIH compared
treatment, the incidence of DIH was significantly higher to those with milder disease (83). Similar findings have
in HBV carriers [34.9%] when compared to non-carriers been reported in studies from India (56). Development
[9.4%] and HBV carriers not given antituberculosis drugs of DIH has been attributed to multiple factors including
[8.1%]. For patients given antituberculosis drugs, HBV hepatic involvement by primary disease, malnutrition,
carriers who developed liver dysfunction were younger more frequent hospitalization and parenteral therapy
and had more severe liver injury compared with non- (41,84). Close biochemical monitoring revealed that the
carriers. By multiple logistic regression analysis, age and diagnosis of antituberculosis treatment induced hepato-
HBV infection were found to be risk factors for DIH toxicity was made frequently in these patients (41,84).
caused by antituberculosis treatment (75).
Sparse literature is available regarding the role of CLINICAL COURSE OF ANTITUBERCULOSIS
hepatitis C virus [HCV] and the HIV in the genesis of TREATMENT INDUCED HEPATOTOXICITY
DIH caused by antituberculosis treatment. Ungo et al (76) While most of the patients with antituberculosis treat-
reported that the relative risk of developing DIH if the ment induced hepatotoxicity have only asymptomatic
patient was HCV or HIV positive was five-fold and four- elevation of transaminases, few develop overt icteric
fold, respectively. If a patient was co-infected with both hepatitis. The onset of hepatitis usually resembles viral
HCV and HIV, the relative risk of developing DIH was hepatitis. In fact, it was emphasized that not all cases of
increased by 14.4-fold (77). In another recent study from presumed antituberculosis treatment induced
Korea (77), DIH developed more frequently in HCV- hepatotoxicity were due to antituberculosis drugs but
seropositive patients with TB [7 of 54 patients, 13%] than many of these cases were acutally due to viral hepatitis
in control subjects [4 of 97 patients, 4%]. These issues
(84,85).
merit further study.
Majority of the cases with antituberculosis induced
hepatitis resolve spontaneously following withdrawal of
Malnutrition
the offending drugs. However, in a substantial propor-
Mehta et al (78) have shown that drug metabolizing tion of patients severe liver damage may occur leading
processes in the liver including acetylation pathways are to acute or subacute liver failure with subsequent
deranged in states of protein energy malnutrition. A mortality. The development of antituberculosis treatment
significant decrease in isoniazid metabolism has been induced acute liver failure has been reported (86) and
demonstrated in kwashiorkar (79). In India, a higher such cases mark the rapidity, severity and the importance
incidence of rifampicin-and isoniazid-induced hepato- of antituberculosis treatment induced hepatotoxicity. In
790 Tuberculosis
the study reported by Singh et al (86), overall mortality Table 54.2: Diagnosis of antituberculosis
in patients with antituberculosis treatment induced drug-induced hepatotoxicity
hepatotoxicity was 12 per cent while it was 75 per cent Guidelines Elevation of Elevation of serum
in patients who developed acute and subacute liver (reference) transaminases bilirubin
failure due to antituberculosis treatment.
ATS/CDC/IDSA Three-fold increase Any increase
(2,87) in ALT over the upper
MANAGEMENT OF ANTITUBERCULOSIS normal limit in patients
TREATMENT INDUCED HEPATOTOXICITY reporting jaundice and/or
hepatitis symptoms such
Diagnosis as nausea, vomiting,
abdominal pain,
When DIH is suspected, the patient receiving antituber- unex-plained fatigue]
culosis treatment should be systematically investigated Five-fold increase in
for other causes, such as viral hepatitis. Due consideration ALT over the upper
must be given to the drug interactions between the normal limit in the
antituberculosis drugs and other drugs administered for absence of symptoms
ERS/WHO/ Five-fold increase in Any increase
co-morbid illnesses which can result in hepatic
IUATLD (88) ALT over the upper
dysfunction. Isoniazid when administered alone normal limit
enhances the toxicity of drugs with hepatotoxic potential HKTBS (3,89) Three-fold progressive Two-fold persistent
such as phenytoin, carbamazepine, valproate, acetamino- escalating increase in increase
phen due to inhibition of several cytochrome P450 ALT over the upper
enzymes. When isoniazid is co-administered with normal limit
rifampicin, the inductive capability of rifampicin exceeds ATS = American Thoracic Society; CDC = Centers for Disease
the inhibitory effect of isoniazid and results in decreased Control and Prevention; IDSA = Infectious Diseases Society of
levels of phenytoin. Other clinically important drug America; ALT = alanine aminotransferase; ERS = European
interactions include decrease in the serum concentrations Respiratory Society; WHO = World Health Organization; IUATLD
of HIV protease inhibitors, non-nucleoside reverse = International Union Against Tuberculosis and Lung Disease;
AST = aspartate aminotransferase; HKTBS = Hong Kong
transcriptase inhibitors, corticosteroids and oral
Tuberculosis Service
contraceptive pill containing ethinyl oestradiol and
norethindrone induced by rifampicin (87). In these
situations, therapeutic drug monitoring may be useful.
guidelines published by the American Thoracic Society
The criteria for the diagnosis of DIH in patients
[ATS], CDC and the Infectious Diseases Society of
receiving antituberculosis treatment according to some
America [IDSA] (2,87) form the basis for the diagnosis
of the published international guidelines are listed in
and management principles listed below.
Table 54.2 (87-89). According to WHO classification (90),
severity of hepatotoxicity is defined as follows: grade 1,
Guidelines for Monitoring Patients Receiving
for any serum ALT level of 51 to 125 IU/l, or 1.25 to 2.5
Treatment for Active Tuberculosis Disease
times normal; grade 2, for any serum ALT level of 126 to
250 IU/l, or 2.6 to 5.0 times normal; grade 3, for any serum Screening for Viral Hepatitis
ALT level of 251 to 500 IU/l, or 5.1 to 10.0 times normal;
The guidelines (2) specifically recommend screening for
and grade 4, for any serum ALT level greater than 500
IU/l, or greater than 10 times normal, or greater than viral hepatitis in a certain group of patients [Table 54.3].
250 IU/l if accompanied by compatible symptoms. This is especially important in developing nations (85).
Ideally, antituberculosis treatment should be indivi-
Monitoring of Liver Functions
dualized according to the body weight and co-morbid
illnesses. Whenever feasible, baseline liver function There is no consensus protocol for monitoring of liver
testing must be done. Consensus guidelines for the functions in patients receiving antituberculosis treatment
management of patients with antituberculosis treatment for active TB disease. be repeated if fever, malaise,
induced hepatotoxicity are yet to be evolved. The recent vomiting, jaundice, or unexplained deterioration occur.
Table 54.3: Patient groups receiving treatment for active Guidelines for Monitoring Patients Receiving
tuberculosis disease in whom screening for viral hepatitis Treatment for Latent Tuberculosis Infection
is indicated
The guidelines (2,87) also recommend that individuals
Individuals who inject drugs
over the age of 35 years who are treated for LTBI with
Persons born in endemic areas of Asia, Africa, the Pacific Islands, isoniazid alone, or isoniazid with rifampicin should have
Eastern Europe, or the Amazon Basin
baseline measurement and scheduled monitoring of ALT
Human immunodeficiency virus infected patients
every other month; or at one, three, and six months in
Persons who may have had sexual or household contact with those taking a nine-month regimen, depending on the
chronically infected individuals
perceived hepatotoxicity risk, effectiveness of patient
Subjects who may have had occupational exposure to infected
education, and the stability of ALT. The WHO and
blood
IUATLD recommend only clinical monitoring for
Chronic haemodialysis patients
hepatotoxicity in patients with TB in low-income
Recipients of clotting factors before 1987; blood or solid organ
countries (46,91,92).
transplants prior to 1992
Patients with undiagnosed liver disease
Infants born to infected mothers Treatment of Tuberculosis in Patients with
Antituberculosis Drug Induced Hepatotoxicity
Source: reference 2
Once the diagnosis of DIH is established, it is essential
to first stop all potentially hepatotoxic drugs till complete
These guidelines (2,87) do not recommend baseline clinical and biochemical resolution of hepatotoxicity
liver function monitoring for healthy patients, but occurs. In the interim period, at least three non-
recommend monitoring of serum ALT and bilirubin in hepatotoxic drugs such as ethambutol, streptomycin and
patients with a possible liver disorder, those with a quinolones [moxifloxacin or ofloxacin] can be used after
history of chronic liver disease [e.g., chronic hepatitis B appropriate checks on renal function and visual acuity.
and C, alcoholic hepatitis, and cirrhosis], patients with After complete resolution of transaminitis, most
chronic use of alcohol, those with HIV infection treated antituberculosis drugs can be safely restarted in a phased
with highly active antiretroviral therapy [HAART], manner. Regarding the safety and wisdom of re-starting
pregnant women, and those who are up to three months the same hepatotoxic drugs which caused hepatitis, the
post-partum, for patients receiving other medications clinical experience has shown that these drugs can be
and for those with chronic medical conditions. The given safely. The re-introduction of antituberculosis
guidelines (2,87) also advocate measuring serum drugs has seldom been systematically studied and a great
transaminases and bilirubin concentrations every two to deal of controversy exists regarding sequence in which
four weeks for the first two to three months, and then as the drugs are to be reintroduced, whether the re-intro-
necessary. These (2,87) suggest that ALT is preferred for duction should be done in full dosage or in gradually
detecting and tracking hepatocellular injury in those who escalating dosage.
develop symptoms of DIH; estimation of AST, serum
bilirubin, and alkaline phosphatase are adjunctive for
Recommendations for Re-introduction of
monitoring chronic liver disease, cholestasis, or severe
Treatment in Patients with Antituberculosis
hepatocellular injury. The upper limits of normal used
Drug-Induced Hepatotoxicity
should be that of the laboratory performing the assay
and the reference limits for enzymes should be adjusted According to the guidelines (2,87), suspected anti-
for age in children and in adults older than 60 years, and tuberculosis drugs can be started one at a time once the
for gender in adults, if available. These guidelines also transaminase levels return to less than two times the
advocate the use of international normalized ratio upper normal. Rifampicin is to be restarted first. If the
periodically as well in patients with severe hepatic liver functions remain normal after one week, isoniazid
impairment. can be added to the regimen. If the liver functions remain
792 Tuberculosis
normal after one week, then pyrazinamide is added. If confirmed in studies with a large sample size. In a study
there is recurrence of symptoms or deterioration of liver from Copenhagen (96), 61 of the 752 [8%] patients with
functions, the last added drug should be stopped. TB [8%] developed DIH. Recurrence of DIH was
Depending on the number of doses taken, bacteriological observed in 16 of these 61 patients [26.2%] on re-intro-
status and the severity of the disease, the treatment may duction of antituberculosis treatment and they required
have to be individualized and extended. In a recent study a modified regimen. In a recent case-control study from
(93) in TB patients with serious liver injury, a 12-month New Delhi (97), four of the 45 patients [9%] had recur-
regimen of ethambutol, and ofloxacin, including rence of DIH after re-introduction of antituberculosis
streptomycin for the first three months, followed by drugs. There was no statistically significant difference
ethambutol and ofloxacin for the subsequent nine in recurrence of DIH in three regimens used for re-
months was well tolerated, and it was effective in 85 per introduction. Low serum albumin was a significant risk
cent of patients. factor for recurrence of DIH (97).
Recurrence of Drug-Induced Liver Transplantation

Hepatotoxicity on Re-treatment
Occasionally, liver transplantation may be required for
Review of published literature suggests that the seriously ill patients with antituberculosis drug induced
recurrence rate of DIH when antituberculosis drugs are acute liver failure (98). However, published literature on
re-introduced ranges from 6.3 to 26.2 per cent (2,87,89,94- this topic is sparse.
96). In a study from New Delhi (86), after resolution of
DIH, re-introduction of isoniazid and rifampicin was
ISSUES TO BE RESOLVED
possible in 41 of 44 patients suggesting that the recurrence
rate of DIH on re-introduction was 6.8 per cent. In Consensus guidelines for the management of patients
another study (94), 55 of the cohort of 1036 patients [5.3%] with antituberculosis treatment induced hepatotoxicity
developed DIH. Treatment was re-introduced in 48 are yet to be evolved (5-8). The re-introduction of anti-
patients and successfully completed in 45 patients tuberculosis drugs has seldom been systematically
indicating that the recurrence rate of DIH on re- studied and a great deal of controversy exists regarding
introduction of antituberculosis treatment was 6.3 per sequence in which the drugs are to be re-introduced,
cent. In a randomized prospective study from Turkey whether the re-introduction should be done using all
(95) patients who developed DIH on antituberculosis drugs at once, in full dosage or sequentially, in gradually
treatment [n = 45] were re-treated with a drug regimen escalating dosage (5-8). Since there is no consensus on
consisting of isoniazid, rifampicin, ethambutol and these issues, large multicentre studies are required to
streptomycin administered by gradually increasing the provide answers to these questions.
number and dosage of the drugs [group I, n= 20]. The
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796 Tuberculosis
Surgery for
Pleuropulmonary Tuberculosis
55
Arvind Kumar, D Dilip, Abha Chandra
INTRODUCTION SURGERY IN THE DIAGNOSIS OF TUBERCULOSIS

Till the time effective antituberculosis treatment was Inspite of the advances in modern methods of imaging
available in the middle of the twentieth century, surgery and diagnosis, a definitive diagnosis of pleural and pul-
was the only therapeutic option for pulmonary tuber- monary TB is not possible in several patients. In this
culosis [TB]. Several operations were devised and setting, surgery is often performed to obtain tissue speci-
practiced with the aim of controlling spread of the men to confirm the diagnosis and exclude underlying
disease and promoting healing of the lesions. With the malignancy.
advent of effective antituberculosis treatment, there has In the series reported by Ishida et al (1), 36 patients
been a gradual decline in the need for surgical inter- who presented with a solitary pulmonary nodule on the
vention in patients with pulmonary and pleural TB. The chest radiograph underwent surgery for the confirmation
of diagnosis. Pre-operatively, lung cancer was initially
human immunodeficiency virus [HIV] infection and
suspected in 21 [58%] of these patients. The histopatho-
acquired immunodeficiency syndrome [AIDS] pande-
logical diagnosis revealed pulmonary tuberculoma in
mic has resulted in the resurgence of TB worldwide.
these patients. In another retrospective study (2) where
Furthermore, multidrug-resistant TB [MDR-TB] is a
thoracotomy was performed to ascertain the aetiological
major public health problem in several parts of the
diagnosis and rule out malignancy, 24 of 31 patients [77%]
world. Because of all these factors, there has been were found to have pulmonary TB. At the Sri
renewed interest in surgery. Presently, there has been Venkateswara Institute of Medical Sciences [SVIMS],
an increase in the number of patients with pulmonary Tirupati, during the period 1996 to 2000, 23 patients with
and pleural TB requiring surgical intervention for a solitary lung lesion in whom TB was suspected pre-
diagnostic or therapeutic purposes. operatively but diagnostic work-up did not reveal an
This chapter deals with the role of surgery in the aetiological clue underwent thoracotomy for the
management of pleuropulmonary TB. Although the confirmation of diagnosis. Of these patients, 15 [65%]
emphasis will be on the operative methods used cur- were found to have TB, five were found to have
rently, the history of development of various surgical bronchogenic carcinoma and three were found to have a
procedures for TB has also been described. fungal ball [aspergilloma] and definitive treatment could
Tuberculosis of the vertebra and the oesophagus be instituted in all these patients.
belongs to the domain of orthopaedics and gastrointesti-
Video-assisted Thoracoscopic Surgery
nal surgery and will not be discussed here. The reader is
referred to the chapters “Skeletal tuberculosis” [Chapter 23] In a study reported from the All India Institute of Medical
and “Abdominal tuberculosis” [Chapter 19] for more Sciences [AIIMS], New Delhi (3), video-assisted thoraco-
details. scopic surgery [VATS] was helpful in confirming the
Surgery for Pleuropulmonary Tuberculosis 797
diagnosis of TB in five of the 18 patients with pulmonary broncho-pleuro-cutaneous fistula, which would drain
pathology, three of the eight patients with mediastinal indefinitely. These procedures are seldom employed in
pathology and one of the five patients with pleural the current era.
pathology. Importantly, VATS was helpful in providing
a definitive diagnosis in all 18 patients with lung The Collapse Therapy Era
pathology, seven of the eight patients with mediastinal
lesions and five of the six patients with pleural pathology The period between the eighth decade of the nineteenth
who would have otherwise undergone diagnostic century and the fourth decade of the twentieth century
thoracotomy (3). In another study from Switzerland (4), marked the era of “bed rest” and “collapse therapy”.
VATS was useful in confirming TB as the aetiological Bed rest was introduced by Dettweitter in Germany
diagnosis in 10 of the 96 patients [10.4%] in whom the and Turban in Switzerland around 1880 (9). By decreas-
pre-operative diagnoses were lung cancer [n = 4], ing the functional residual capacity of the lung, bed rest
empyema [n = 2], Pancoast tumour, pericardial effusion, therapy was thought to decrease the static tension on
pleural mesothelioma, and mediastinal lymphoma [one the walls of the TB cavities. Bed rest also resulted in a
patient each]. Similar observations were also reported decrease in the dynamic traction on the cavity walls by
from Japan (5). Thus, VATS, a minimally invasive decreasing the ventilation and increasing blood flow to
procedure has been found to be of great assistance in the apices of the lung. This caused the cavities to collapse
confirming the diagnosis of TB in recent times. and facilitated healing. Good treatment consisted of bed
rest round the clock, at least during the first few months
SURGERY IN THE TREATMENT OF ACTIVE of treatment. Exercise was gradually increased as and
PULMONARY TUBERCULOSIS when the pulmonary lesion began to come under control.
Even under the most favourable circumstances, a year
Several surgical procedures have been used for the of sanatorium treatment was the rule.
treatment of active pulmonary TB in the era before the During this period, an artificial pneumothorax was
advent of effective antituberculosis treatment. It is likely extensively used by the internists as a treatment for
that several of these so called “historical” procedures may pulmonary TB. The surgeons also became involved later
have relevance in the current scenario as well. to help in the lysis of intrapleural adhesions so as to
enhance the efficacy of pneumothorax (10). The other
The Cavernostomy Era
procedures developed and practiced during this period
During the eighteenth century and the first-half of the included thoracoplasty (11-13), phrenic nerve interrup-
nineteenth century, following the Hippocratic principles tion (14), pneumonolysis with plombage and later with
of laying the abscess cavity open, large TB cavities in the pneumothorax (15,16), and minor pulmonary resections
lungs were opened through the thoracic wall and decortication (17). Several patients are living today
[cavernostomy]. The earliest mention of cavernostomy because they underwent collapse therapy in one or
dates back to 1726 (6). Hastings and Stork (7) reported another form in this pre-chemotherapy era. Although
similar procedures with success in 1844. Thereafter, no most collapse therapy procedures have been abandoned
reports of surgical treatment of pulmonary TB appeared today, some are still in use. The surgeons involved in
in the literature for the next 40 years. The procedure of the treatment of TB patients today should at least be
cavernostomy was revived in 1938 by Monaldi (8) who aware of the older procedures and what they had to offer.
introduced a trocar and a cannula into the lung cavity Collapse therapy was used in about 70 per cent of
through the chest wall, inserted a catheter and applied the sanatorium patients. Only patients with very minimal
suction. Others performed “open cavernostomy” in a lesions or those with bilateral extensive lesions that were
staged manner. At first, rib resection was performed and too advanced for this treatment did not receive collapse
a pack was placed against the parietal pleura for 10 to 14 therapy. The purpose of collapse therapy was relaxation
days to ensure formation of adhesions. In the second of the diseased lung, so as to allow the scar tissue
stage, the cavity was entered and a large drainage tube produced by the natural healing process a better chance
was inserted. This procedure invariably caused TB to contract.
798 Tuberculosis
Phrenic Nerve Paralysis sed by Jacobeus (10). This method was useful only for
thin adhesions which contain only fibrous tissue. Thick
The purpose of phrenic nerve paralysis was to relax the
adhesions which could contain lung tissue or even an
lung and also to “rest” it. Following phrenic nerve para-
extension of a cavity posed a problem as their division
lysis, a rise of the ipsilateral hemidiaphragm occurs,
would result in a bronchopleural fistula [BPF] and
reducing the distance between the apex of the lung and
empyema. The safety of intrapleural pneumonolysis
its base, and thus, relaxing the diseased portion. Since
rested largely on the judgement of the surgeon. In case
the excursions of the diaphragm on the paralysed side
adhesions appeared to be too thick for safe division, it
are reduced, the lung receives more rest. Although
was far better to abandon the attempt at artificial
numerous enthusiastic reports had appeared at that time,
pneumothorax and proceed to perform some other
but, it is difficult to evaluate the benefits of phrenic nerve
collapse therapy procedure. Recently, there has been
palsy in retrospect (14). Cavities at the base of the lung
renewed interest in the usefulness of artificial pneumo-
were thought to have responded more favourably than
thorax in the management of pulmonary TB. In a recent
at any other locations. In the 1930s, this was amongst
report (18), use of additional artificial pneumothorax was
the commonest operations and many thousand proce-
found to be useful in achieving culture negativity in all
dures of phrenic nerve paralysis were performed.
the new cases with cavitary pulmonary TB [n = 56]
compared with 80 per cent observed in the control group
Pneumothorax
[n = 55] who received antituberculosis treatment alone.
The use of an artificial pneumothorax in the treatment Similarly, among re-treatment cases, artificial pneumo-
of pulmonary TB began in the late nineteenth century thorax resulted in culture-negativity in 81 per cent
and came into wide use between 1920 and 1940. In this patients [n = 53] compared with 40 per cent observed in
procedure, a needle was introduced into the chest cavity the control group [n = 50]. The authors concluded that
and air was slowly introduced into the chest to collapse artificial pneumothorax was a useful addition in
the lung using a specially designed pneumothorax managing certain patients with cavitary disease,
apparatus. The procedure was repeated at regular especially those with drug-resistant TB.
intervals until the desired amount of collapse was
achieved. If there were no intrapleural adhesions, the Pneumoperitoneum
pneumothorax relaxed the lung effectively, contraction
For sometime the pneumoperitoneum was used as a
of scar tissue was promoted and the cavity walls could
method of achieving collapse therapy. With pneumoperi-
approximate. The collapse interfered surprisingly little
toneum both hemidiaphragms were elevated to some
with pulmonary function, even when bilateral pneumo-
extent contributing to collapse of the lung. The results of
thoraces were produced. Once a satisfactory collapse by
pneumoperitoneum alone were unpredictable, and
pneumothorax had been obtained, it was usually
therefore, on several occasions it was combined with
continued for two years or sometimes even longer, on
phrenic nerve paralysis to achieve a rise of the hemi-
an ambulatory basis. When the chest radiographs
diaphragm twice as great as could be obtained with either
suggested healing of the TB lesion, refilling of
of the procedures alone. The combined procedures were
pneumothorax was stopped, and the lung re-expanded.
often effective in the closure of a basal cavity.
The normal portions of the lung became overinflated to
compensate for the contracted disease portions. If all
Extrapleural Pneumonolysis
went well, pneumothorax yielded good results but this
was true only in a small percentage of patients. In many When dense intrapleural adhesions prevented the
cases pleural adhesions prevented the induction of induction of pneumothorax, and thoracoplasty did not
pneumothorax leading to its failure. For such cases, seem to be applicable or desirable, an extrapleural
division of these adhesions [intrapleural pneumonoly- pneumonolysis was performed (19). For this procedure
sis] was done to help achieve total collapse of the lung. a small piece of rib was resected under local anaesthesia
This could be done by performing a thoracotomy or by between the scapula and the spine. The parietal pleura
the closed method by using a thoracoscope as populari- was exposed and dissected away from the chest wall by
blunt dissection, creating a space between the apex of muscles would stabilize the chest wall. He also
the lung, covered by both visceral and parietal pleura recommended “positive pressure breathing” during the
and the chest wall. The space, thus, created was filled post-operative period to control paradoxical movement
with some material in order to maintain the collapse of of the chest wall and the mediastinum (23,24). In
the lung so produced. The most common method of paravertebral thoracoplasty procedure, ribs were
maintaining the space was to fill it up with lumps of resected posteriorly from the angle back to the transverse
paraffin. The paraffin eventually became encapsulated process (25). This less extensive procedure had much
with the scar tissue and remained in place permanently lower mortality than Brauer’s and Friederich’s procedure
without causing any problem. Sometimes the wall of a and was more effective than de Cerenville’s technique
TB cavity would slough off because of disruption of its (23-25). Alexander is considered to be the father of
blood supply from pleura during extrapleural dissection, thoracoplasty in the USA. During his early career, he
creating a BPF and ultimately an empyema. Occasionally, himself had contracted pulmonary TB, for which he was
the sloughing of the wall of the TB cavity would lead to hospitalized and was advised bed rest. During the
the paraffin going into the cavity leading to expectoration hospitalization, he wrote the first English text on the
of slivers of paraffin, a condition very difficult to treat. surgical treatment of TB (26). During the subsequent
The other method of maintaining the lung collapse years, he perfected the technique of staged posterior
after an extrapleural pneumonolysis included keeping lateral thoracoplasty with an operative mortality of less
up air refills in which case the procedure was known as than two per cent and cavity closure and sputum
extrapleural pneumothorax (19). This procedure provi- conversion in over 80 per cent cases (27).
ded more extensive collapse than was possible with
Standard thoracoplasty The extent of thoracoplasty will
paraffin. Like intrapleural pneumonolysis, TB empyema
depend on the extent of the disease. An average thoraco-
was a problem in extrapleural pneumonolysis also.
Sometimes the air in an extrapleural pneumothorax plasty may consist of extraperiosteal resection of seven
ribs in three stages at two to three weeks intervals [Figure
was replaced with sterile mineral oil thus creating an
55.1]. There is some deformity with thoracoplasty but
“oleothorax” (19,20). The oil became encapsulated by a
thick fibrous capsule. Sometimes there was exudation of not as much as might be imagined [Figure 55.2]. Since
the clavicles hold the shoulder girdles in place, the
lot of fluid into the space, raising its pressure very high
shoulders remain at the same level. Scoliosis tends to
and leading to BPF and aspiration of this oil into both
the lungs with unfortunate results. occur with thoracoplasty, the convexity of the curve being
towards the thoracoplasty side. However, with proper
Thoracoplasty physical therapy, scoliosis can be minimized and normal
arm movement retained. The results of thoracoplasty in
Thoracoplasty was initially used in the treatment of the closure of TB pulmonary cavities were good on the
empyemas in the 1880s (21). In 1885, de Cerenville (22), whole. In properly selected patients cavity closure and
removed anterior portions of the second and third ribs sputum conversion occurred in 80 to 90 per cent of the
in an attempt to collapse underlying TB cavities. Other patients. The use of thoracoplasty for obliteration of the
variations of thoracoplasty were also tried but none was TB empyemas occupying the entire hemithorax usually
sufficiently extensive to achieve collapse of the under- requires resection of nine or ten ribs. Thoracoplasty is an
lying TB cavities. Brauer (23), is credited to be the first to
effective method for obliteration of empyema. Alter-
have advocated extensive rib resections sufficient to
native procedures include pleuro-pneumonectomy or
collapse the diseased lung. Other workers (23,24),
decortication.
attempted resection of the second through the ninth ribs
along with their periosteum and intercostal muscles. Plombage thoracoplasty During the 1940s it was
However, postoperatively, paradoxical respiration with realized that an excellent collapse of lung could be
respiratory insufficiency was a major problem. The obtained by stripping the periosteum off the ribs and
mortality rate of this operation was 30 per cent. Brauer letting the lung, with parietal pleura, periosteal beds, and
(23) recommended staging the procedure and hypothesi- intercostal muscles and bundles, fall away from the chest
sed that preserving the periosteum and intercostal wall. The advantage of this type of collapse over
800 Tuberculosis
Figure 55.1: Thoracoplasty incision [upper panel centre]. Periosteum of the third, fourth and fifth ribs being peeled off [middle panel left].
Third, fourth and fifth ribs being excised [middle panel right, lower panel left]. The third, fourth and fifth ribs have been removed and the
chest wall has fallen into the cavity obliterating the pleural space [lower panel right]
removal and unroofing of the residual space by resecting

the original ribs was done. By this time regeneration of
ribs from the displaced periosteum would have taken
place and would maintain the collapse. Because of the
possibility of infection or other complications, some
surgeons made it a practice to remove the plombe
routinely after several months. Most others removed the
plombe only if and when the plombage material
migrated. Some others were inclined to remove the
plombe electively only in young patients. A major
disadvantage of an extraperiosteal plombage was that
the subsequent pulmonary resection beneath it, when
necessary, was technically, extremely difficult more so
than with standard thoracoplasty (19). Recently, a new
modality of collapse therapy which uses percutaneous
tissue expanders [the Perthese tissue expander] has been
described (28). Compared with the classical extrapleural
thoracoplasty, long-term complications such as erosion
of major vessels, infection, and migration are likely to be
Figure 55.2: Chest radiograph [postero-anterior view]
showing thoracoplasty on the left side
less with this technique (28).
The Modern Era

extrapleural pneumonolysis is that a more extensive
collapse can be obtained, if desired, and reduction in From 1950s onwards availability of predictably effective
pulmonary function is less, thus, making it suitable for antituberculosis treatment coupled with significant
patients who could not tolerate standard thoracoplasty advances in the fields of anaesthesiology and intensive
or resection because of age, emphysema, or extensive care, blood transfusion, and the availability of potent
disease (19). Substances used to maintain the collapse antibiotics opened the way for much wider applications
[plombe] included Lucite spheres, Ivalon sponges, ping- of surgical methods in the treatment of TB.
pong balls, polythene spheres and sheets, and paraffin. The main operations during this era became
The spheres had to be large enough so that they would resections (24,29,30). Previously proposed operations
not slip between the denuded ribs and the moulded were improved and modified. It was possible to greatly
paraffin had to be introduced in one mass to fit the expand indications for various operations and markedly
extraperiosteal space. The ribs could then be easily spread improve their results. Numerous pulmonary resections
for the introduction of these materials. The advantage of and other operations performed to treat TB during the
this procedure over a standard thoracoplasty was that 1950s provided a powerful impetus to the development
much more collapse could be achieved in one stage of thoracic surgery including cardiac surgery. Although
procedure. On the other hand, the collapse was not as fundamentally, no “new” operations were proposed
satisfactory as with standard thoracoplasty, especially during this period, the previously described operations
for large or medially located cavities. Infection in the were improved upon, refined and the surgical outcome
extraperiosteal space could occur, and migration of the improved dramatically making them more acceptable in
introduced foreign bodies was often reported. Pressure the treatment algorithms of various patients.
necrosis of various adjacent structures by Lucite spheres
Current Status of Surgery
has sometimes produced rather dramatic complications.
Experience with paraffin and polythene spheres has been Antituberculosis treatment sometimes proves ineffective
rather good, better than with Lucite spheres or Ivalon or of little benefit in controlling the disease. This lack of
sponges. For instance, if the paraffin mass migrates, its response may vary from as low as five per cent of all
802 Tuberculosis
patients to as high as 40 to 55 per cent patients (29). This Preoperative Work-up

happens in patients with resistant forms of infection or
The patients to be taken up for surgery for chest TB should
in the treatment of certain forms of TB and its complica-
have reasonably localized disease amenable to surgical
tions or sequelae which are associated with irreversible
resection and they should have adequate cardiopulmo-
morphological changes in organs and tissues. Surgery is
nary reserve to undergo the operation safely. The preope-
indispensable in such patients. In combination with
rative work-up apart from a chest radiograph includes
chemotherapy, surgery can ensure sufficiently radical
computed tomography [CT] of the chest, pulmonary
removal of localized lesions and save the patients life,
function tests and if possible, arterial blood gas analysis.
halt progression of the disease, create better conditions
It has been suggested that ventilation perfusion scan
for reparative processes, restore organ functions and
should also be done on all these patients as it is useful in
promote complete recovery (29,30).
determining the extent and the type of resection to be
Although, there are conflicting views regarding the
performed. The primary role of the ventilation perfusion
exact role of surgery in the overall management of
scan is to confirm that the regions to be resected are
patients with pulmonary TB, most physicians, however,
physiologically inert and contributed minimally to the
consider the use of surgical methods appropriate in the
patient’s respiratory capacity. In addition, sometimes, an
situations outlined in Table 55.1 (31-35).
area which appears normal on chest radiograph and
The presence of a cavitary disease in itself is not an
CT may actually have no function on ventilation scan
indication for surgery unless it is associated with one of
and is best removed than left inside.
these complications. The relative indications for resection
These patients should also have frequent sputum
are listed in Table 55.2.
analysis for smear and culture of mycobacteria. The
Table 55.1: Definite indications for surgery in patients with patients should be reviewed jointly by the physician and
pleuropulmonary tuberculosis the surgeon and they should be started on an intensive
To procure tissue material for confirmation of diagnosis of drug regimen to achieve sputum negativity or at least
tuberculosis reduce the bacterial load to the minimum possible extent
Multidrug-resistant tuberculosis before surgery. Ideally, surgery should be performed
Complications of tuberculosis when the smears and culture have become negative as it
Haemorrhage has a direct bearing on the incidence of bronchial stump
Bronchopleural fistula related complications after surgery.
Empyema Pomerantz et al (31) have reported 65 per cent success
Bronchiectasis in achieving sputum conversion after an average of two
Tracheal or bronchial stenosis and a half months of intensive chemotherapy. Treasure
Broncholiths et al (35) also used intensive preoperative chemothera-
Pulmonary aspergilloma peutic regimen but reported success in turning sputum
negative in much higher number of patients [17 of 19
Table 55.2: Relative indications for surgery in patients with patients; 90 per cent]. They reported that patients with
pleuropulmonary tuberculosis persistent cavities, or disease affecting multiple segments
Destroyed lobe or lung distal to an irreversibly damaged bronchus or a lobe or with total lung destruction were candidates
and subject to repeated tuberculosis or, pyogenic infection who benefited from surgery. Surgical removal of des-
An open negative cavity of significant size [> 2 to 3 cm] in a troyed lung tissue harbouring a large number of bacilli
young person protected from antibiotics by poor blood supply assists
A cavity in an immunocompromised host in converting the sputum negative and helps prevent
Demonstrable nontuberculous mycobacteria multidrug-resistant relapse.
organisms in a cavitary disease that can be resected clearly by It is also recommended that bronchoscopy be per-
lobectomy formed at or before operation to exclude the presence of
Recurrent sputum positive infection in a given segment or lobe, endobronchial disease at the proposed bronchial
even though no macroscopic cavity can be demonstrated
resection margin, as its presence will greatly increase the
Asymptomatic peripheral nodule risk of bronchopleural fistula after resection (24).
Preoperative Preparation extrathoracic skeletal muscle [myocutaneous flap using

latissimus dorsi or serratus anterior] or omentum has
Nutritional Build up been shown to significantly decrease the incidence of this
Most of the patients with chest TB would have been ill complication (2,29,34). These should be used in all cases
for a long time and are in a chronically debilitated of resectional lung surgery for TB.
condition with poor nutritional status. Before taking up The aim of surgery in TB is to remove all the disease-
for surgery, it is important to build up nutrition of these bearing lung tissue at the same time preserving as much
patients. When possible this should be achieved by of normal lung tissue as possible. Sometimes the amount
enteral means by encouraging high protein and calorie of lung tissue remaining after a resection may not be
diet. Sometimes, patients may need hyperalimentation. adequate to fill the entire pleural cavity and may lead to
The value of nutritional build up needs to be emphasized space problems post-operatively. In such cases, a
as it has a direct bearing on the outcome and the concomitant tailoring thoracoplasty is recommended to
complications after surgery. Patients with anaemia and reduce the chances of post-operative space problems (29).
hypoproteinaemia have uniformly poor outcome after The exact procedure to be performed may vary from
surgery. segmental or wedge resection to lobectomy, pneumonec-
tomy or pleuropneumonectomy with or without
Incentive Spirometry myoplasty.
The outcome after surgery can be improved and the

incidence of complications reduced by pre-operative Multidrug-Resistant Tuberculosis
chest exercises in the form of deep breathing and breath- Patients infected with Mycobacterium tuberculosis resistant
holding exercises and incentive spirometry. It is to rifampicin and isoniazid with or without resistance to
important to explain the value of these simple looking other antituberculosis drugs have MDR-TB. Indications
exercises in improving the postoperative outcome to the for surgery in patients with MDR-TB are listed in
patient in detail in order to achieve their maximum Table 55.3.
cooperation and compliance. Several days of such “chest Various procedures performed for patients with
training” helps tremendously in improving the outcome MDR-TB have ranged from segmental resection to
after surgery. pleuropneumonectomy. Pomerantz et al (31) in a series
of 42 patients with MDR-TB reported one postoperative
Principles of Surgery death secondary to acute respiratory distress syndrome.
Double lumen endotracheal tube should be used for There were six late deaths, from two months to four years
anaesthesia in these patients to avoid cross-contami- postoperatively, two of which were related to the
nation of the contralateral lung. Patients with TB often resistant Mycobacterium tuberculosis infection. Only three
have extensive, dense adhesions between pleura and the patients had persistently positive sputum after surgery
lung and it may be impossible to find a plane between and the postoperative sputum smear conversion rate
the pleura and the lung. Additionally, dissecting through
the infected material present in the pleural cavity Table 55.3: Indications for surgery in patients with
multidrug-resistant tuberculosis
increases the risk of postoperative empyema several
folds. Due to these reasons, an extrapleural approach for Drug resistance so extensive that there is a high probability of
pneumonectomy has been suggested (36) which failure or relapse
decreases the morbidity as well as mortality of this Disease sufficiently localized so that the great preponderance of
operation. Dehiscence of the bronchial stump leading to radiographically visible disease could be resected with the
expectation of adequate cardiopulmonary reserve after surgery
BPF and empyema is the most feared and the most
and sufficient drug activity to diminish the mycobacterial burden
common complication after resectional lung surgery for enough to facilitate probable healing of the bronchial stump after
TB with a reported incidence of 25 to 40 per cent (2) in surgery
the past. Reinforcement of the bronchial stump by a
vascularised tissue like intercostal muscle, pedicled
804 Tuberculosis
was over 90 per cent. There was one late death each due patients with MDR-TB. The lesions were bilateral in 16
to renal failure, myocardial infarction, drug overdosage cases, with a preponderance of cavities on one side. Out
and respiratory failure. The major complications were of 27 cases, five patients had unilaterally destroyed lung;
seen in eight patients. Three had wound infection, two 20 patients underwent pneumonectomy [left side 15,
had respiratory failure, one patient each had recurrent right side 5]. Lobectomy operations included bilobectomy
laryngeal nerve palsy and Horner’s syndrome and one superior [n = 1], right lower lobectomy [n = 2], right upper
patient had re-exploration for bleeding. Only one patient lobectomy [n = 3], and left upper lobectomy with superior
who underwent completion pneumonectomy developed segmentectomy [n = 1]. Because of haemorrhage, two
BPF and remained sputum positive. In the past this cases who underwent a right and left pneumonectomy,
subject had undergone lobectomy. As compared to this, respectively, required revision on the first day.
in the group of patients with infection due to drug- Bronchopleural fistula developed in two patients who
resistant non tuberculous mycobacteria [NTM], eight of underwent left pneumonectomy. Apical residual space
the thirty-eight patients operated developed BPF was left in one of the three patients who underwent right
signifying a much higher complication rate in this group. upper lobectomy. Retreatment protocols resulted in
They (31) also reported that among patients with MDR- negative cultures and smears in all patients with an
TB requiring pneumonectomy, it was the left side which average duration of four months [1 to 6 months]. A total
was affected in over 85 per cent cases [left lung syndrome], of four patients [16%] completed a retreatment period of
whereas in cases with NTM infection, there was an even 18 to 24 months with negative cultures. Only one patient
distribution between right and the left sides. Similar was [3.7%] developed relapse in the 17th month of re-
the experience reported by Ashour et al (37). The exact treatment. In 22 patients, sputum culture became
reason for this preferential destruction of left lung is not negative and at the time of reporting of this study, they
known. Whether this is due to the smaller size, more were still on re-treatment. The authors concluded that
horizontal course of the left main bronchus, more limited judicious use of surgery in conjunction with antituber-
peribronchial space, or, other causes is not clear. culosis treatment was useful in the treatment of MDR-
In a study reported by Jouveshomme et al (38), seven TB.
patients underwent collapse therapy with polystyrene In a retrospective study (40), the role of pulmonary
sphere plombage for pulmonary MDR-TB. Four patients resection as an adjunct in the treatment of MDR-TB was
were infected with multidrug-resistant strains of evaluated. Sixty-two patients with MDR-TB were
Mycobacterium tuberculosis, two with Mycobacterium studied, postoperative complications were observed in
xenopi, one with Mycobacterium avium. All patients were 16 patients [23%]. There was one postoperative death.
adequately treated before surgery, had extensive, Eighteen of 24 patients [75%] who were persistently
bilateral cavitary disease and were considered unsuit- sputum positive at the time of operation immediately
able for resection because of extensive disease or converted to a negative sputum smear and culture status.
functional respiratory impairment. Six patients had For all patients who were sputum negative after opera-
active disease at the time of surgery. Collapse therapy tion, 80 per cent remained relapse-free by actuarial
with insertion of six to eighteen spheres resulted in long- analysis.
standing bacteriological conversion in six patients. In another study (35), 19 of the 59 patients who
Collapse therapy was unilateral in six and bilateral in underwent surgery, were operated for MDR-TB. There
one. No immediate postoperative complication or death were two late deaths: one with progressive disease and
was observed. Hospital stay was short [mean 12 days]. massive haemoptysis and the other due to a relapse of
The authors concluded that collapse therapy is a MDR-TB. Of the patients operated on as part of their
conservative alternative therapy in patients with therapeutic regimen for MDR-TB, 17 [89%] of the 19
pulmonary disease caused by multidrug-resistant patients remained culture negative. In a study from South
mycobacteria at high risk of treatment failure and consi- Africa (41) [n = 23] lung resection [pneumonectomy in
dered unsuitable for pulmonary resection. 17 patients and lobectomy in 6] as an adjunct to
Kir et al (39) evaluated the results of resectional antituberculosis treatment was found to be useful in
surgery as an adjuvant therapy in 27 HIV-negative curing 95.6 per cent of patients with MDR-TB. In a study
evaluating the role of adjunctive surgery in patients with chemotherapeutic regimen needs to continue for
MDR-TB in resource-limited setting, such as Lima, Peru prolonged periods after surgery also, probably for well
[n = 121] (42), sustained culture-negative status was over a year, otherwise recrudescence of the disease with
achieved in 74.8 per cent of the survivors and 63 per cent poor survival is a real possibility.
of those followed-up for at least six months after surgery
were either cured or probably cured. Similarly, surgical SURGERY FOR THE COMPLICATIONS OF
resection [n = 23] was found to be useful in achieving TUBERCULOSIS
negative sputum smear conversion in all the patients
Bronchopleural Fistula
with MDR-TB; one patient had a relapse at one year, in
another study (43). Bronchopleural fistula may develop in TB patients
Based on the experience reported in the literature following lung resections or spontaneously in association
about surgery for MDR-TB, it can be concluded that the with lung lesions or empyema. Although the incidence
operation can be performed with a low mortality [below of post-resection fistula in patients with TB has come
3%]. However, the complication rates are high with BPF down from as high as 28 per cent, two or three decades
and empyema being the major complications. Sputum ago, to three per cent or less in recent years (41-43), it
positivity at the time of surgery, previous chest irradi- nevertheless, remains an important problem for the
ation, prior pulmonary resection and extensive lung thoracic surgeon. Also, the non-surgical, spontaneously
destruction with polymicrobial parenchymal contami- occurring BPF continues to be a problem, responsible for
nation are the major factors affecting morbidity and up to 27 per cent of all TB related BPF in one series (45).
mortality. Over 90 per cent of the patients achieve Spontaneous BPF develops due to liquefaction necrosis
sputum negative status postoperatively. Although and rupture of a sub-pleural TB focus. If the fistula is
operation related mortality is less than three per cent, small and effective chemotherapy is instituted, the leak
total deaths due to all causes occur in about 14 per cent may close spontaneously and the lung re-expands as the
patients, which also compares favourably with over 22 pleural air is absorbed. Unfortunately, such is usually
per cent mortality due to TB in a similar group of patients not the case and the leak persists with pneumothorax
treated medically (31). More liberal use of muscle flaps leading to collapse of the underlying lung and ultimately
to reinforce the bronchial stump and fill the residual development of an empyema. It is generally believed that
space has helped significantly in reducing the rates of every patient with active pulmonary TB who develops
BPF, air leaks and residual space problems. These must pneumothorax has a BPF.
be used in patients with positive sputum, when residual Bronchopleural fistula is a serious condition with a
post-lobectomy space is anticipated, when BPF already reported mortality of 23.1 per cent, mostly due to
exists pre-operatively or when extensive polymicrobial aspiration and its complications (44,45). In post-resection
contamination is present. In patients with NTM infection, BPF, the incidence of this complication is highest during
the outcome is poorer as compared to patients with the first three months after surgery, although it can occur
resistant Mycobacterium tuberculosis infection. However, at any time even several years after surgery (46,47). The
these patients should also be operated before the disease risk of aspiration pneumonia is highest during these first
causes extensive destruction of the lung or polymicrobial three months and its incidence decreases dramatically if
infection, when the incidence of complications becomes BPF occurs later than three months after surgery (37).
very high. Adequate dependent surgical drainage is the basic
Thus, surgery is currently recommended for patients principle in the treatment of BPF. Drainage alone may
with MDR-TB whose prognosis with medical treatment result in closure of the fistula in some patients. In patients
is poor. It should be performed after minimum of three with non-surgical, spontaneously occurring BPF
months of intensive chemotherapeutic regimen, associated with pulmonary TB, intercostal tube drainage
achieving sputum negative status, if possible. The should be complemented with intensive chemotherapy
operative risks are acceptable and the long-term survival as all of these patients have active, severe, often sputum
is much improved than that with continued medical positive TB infection. The pulmonary disease may vary
treatment alone. However, for this to be achieved, the in severity from an isolated focus to extensive disease
806 Tuberculosis
with cavities or even bilateral disease. Continuous Table 55.4: Indications for myoplasty in
suction should always be applied to the tube thoraco- the treatment of bronchopleural fistula
stomy and intensive antituberculosis chemotherapy A persistent bronchopleural fistula despite an adequate drainage
continued. These patients, apart from TB infection, have and thoracoplasty
associated secondary pyogenic infection also which is When thoracoplasty alone is not considered to be sufficient to
often polymicrobial and needs antibiotics based on the close the fistula [due to a large residual cavity]
culture reports. Ihm et al (48) analysed 52 patients with In a situation where myoplasty is likely to obviate the need for a
spontaneous BPF of TB aetiology. Of these, 38 patients thoracoplasty altogether
were treated with intercostal tube drainage with chemo-
therapy and the lung re-expanded in 28. On analyzing
of BPF are listed in Table 55.4. For post-pneumonectomy
the factors affecting the success or failure of intercostal
fistulae, reamputation of a long bronchial stump may
tube drainage, they found that the size of the BPF that
sometimes affect the closure especially if the BPF has been
gave rise to pneumothorax was the most important
diagnosed early (49,50). Further resection of the residual
factor. This in turn was influenced by the extent of TB
lung [site of BPF] or thoracoplasty of various types have
disease in the lung. Patients with extensive parenchymal
also been recommended for treating resistant post-
disease, poorly controlled by drugs, had large fistulae,
resectional BPF but these have the disadvantage of
early development of a restrictive peel on the lung and
further compromizing the already compensated cardio-
poor outcome following tube drainage. The initial degree
pulmonary reserve of these patients. On the other hand,
of collapse of the lung had no bearing on the outcome. A
myoplasty, can close the fistula without excision of addi-
short time interval between the onset of pneumothorax
tional lung tissue and with the removal of few, if any,
and chest tube insertion was a favourable factor, but not
additional ribs. Using the myoplasty techniques, a high
dramatically so, and a long interval did not preclude
rate of BPF closure with a low mortality has been reported
success (48).
(49-51).
In patients failing to re-expand the lung following
tube drainage, suction and chemotherapy, thoracotomy
Tuberculosis Empyema
and decortication, with or without lobectomy or pneu-
monectomy or pleuropneumonectomy may be required The term “tuberculosis empyema” has been an all
depending upon the findings at surgery. The timing of inclusive one ranging in meaning from asymptomatic
this procedure is crucial. It is vital to recognize the point pleural effusion to massive, frankly purulent involve-
at which no further headway is being made with tube ment of the pleura with BPF and trapping of the lung.
thoracostomy and chemotherapy and schedule the Simple TB pleural effusion with or without associated
patient for definitive surgery straightaway. parenchymal disease responds rapidly to antituberculo-
In the post-resection BPF, tube drainage alone may sis treatment. Thoracocentesis may be used to confirm
close the fistula in up to 20 per cent patients (49), other- the diagnosis or relieve symptoms of dyspnoea due to
wise definitive surgical procedure is required. For lung compression. Unfortunately, some patients develop
patients with post-lobectomy or post-pneumonectomy a restricting pleural peel with or without secondary
fistula, this may involve dissection down to the lung or pyogenic infection of the pleural fluid. It is suggested
the mediastinum to identify the fistula site and its suture that in these patients, antituberculosis treatment along
ligation. Suture ligation alone has a high failure rate. Use with antimicrobial therapy [according to culture if
of pedicle muscle flaps has been recommended to fill up possible] should be continued till maximum resolution
the empyema cavity and buttress the suture closure of of the parenchymal disease and associated sepsis is
the fistula site. This has been reported successful in over achieved. At that point, an anatomical evaluation of the
75 per cent patients (44). However, it is important that disease status by a CT scan should be done. In case of a
the muscle flap completely fills the empyema cavity. The residual cavity with collapsed lung, surgical intervention
muscles that have been used include intercostals, is indicated and decortication should be performed
pectoralis major, serratus anterior, latissimus, dorsi and [Figures 55.3A and 55.3B]. If the underlying lung is
sacrospinalis. Indications for myoplasty in the treatment grossly diseased or destroyed or fails to expand following
Figure 55.3A: Chest radiograph [postero-anterior view] Figure 55.3B: Chest radiograph [postero-anterior view] of
showing hydropneumothorax on the right side the same patient after decortication on the right side
decortication, pulmonary resection may also be needed. the dependent position. Once stabilization is accomp-
In these situations also, muscle flaps should be liberally lished, diagnostic and therapeutic interventions should
used to obliterate the residual spaces and buttress the be promptly performed because recurrent bleeding
bronchial stump to prevent the development of post- occurs unpredictably. Early bronchoscopy, preferably
resection BPF. The use of myoplasty reduces the need during active bleeding, should be performed with three
for thoracoplasty in many situations or at least reduces goals in mind: to lateralise the bleeding side, localise the
the number of ribs that need to be resected in the specific site, and identify the cause of the bleeding. In
thoracoplasty. those patients with lateralized or localized persistent
bleeding, immediate control of the airway may be
Haemoptysis obtained during the procedure with topical therapy,
Haemoptysis is a frequent complaint in patients with endobronchial tamponade, or unilateral intubation of the
pulmonary TB. Sometimes, the bleeding may be sudden non-bleeding lung. If bleeding continues but the site of
and large in amount, threatening life of the patient. This origin is uncertain, lung isolation or use of a double-
topic has been dealt with in the chapter “Complications of lumen tube is reasonable, provided that the staff is skilled
tuberculosis” [Chapter 35]. in this procedure. If the bleeding cannot be localized
The treatment of massive or life threatening haemop- because the rate of haemorrhage makes it impossible to
tysis has to be immediate and quick. Medical or expectant visualize the airway, emergent rigid bronchoscopy or
treatment is associated with an unacceptably high urgent arteriography is indicated. Numerous reports in
mortality (52,53). The first priority in treating patients the recent past have outlined the value of arteriography
with massive haemoptysis is to maintain the airway, and embolization in the management of haemoptysis (54-
optimize oxygenation, and stabilize the haemodynamic 62). Arteriography and embolization should be used
status. The major question to be answered is whether or emergently for both diagnosis and therapy in patients
not the patient should be intubated for better gas who continue to bleed despite endobronchial therapy.
exchange, suctioning, and protection from sudden Mani et al (54) in a series of 37 patients presenting
cardiorespiratory arrest. If the bleeding site is known, with massive or recurrent haemoptysis of TB aetiology,
the patient should be placed with the bleeding lung in were able to successfully control the bleeding in all the
808 Tuberculosis
33 patients where embolization with gelfoam could be Foci of Residual Disease

performed. In two patients the bronchial artery could
With the many effective combinations of antituberculo-
not be cannulated and in the remaining two embolization
sis agents available presently, there is little, if any,
was not performed because the anterior spinal artery was
medical indication for removing lung tissue, previously
seen to be arising from the bronchial artery trunk. During
six months of follow-up, four of these 33 patients had affected by TB as a prophylactic measure. However,
relapse of haemoptysis. Three were treated by re- sociological and psychological factors may also play an
embolization of the abnormal bleeding vessels while one important role in the treatment of TB. There is an
died due to aspiration. They concluded that the bronchial evidence to indicate that this type of involvement not
artery embolization is an effective method of treatment only constitutes a continuing threat to the patient but
for immediate control of life-threatening haemoptysis. that resection of the affected tissue eliminates this threat,
Similar experience has been reported by others (55,57,59). reduces hospitalization and duration of treatment, and
Sharma et al (57) have reported the use of an indigenous is associated with excellent long-term control of disease
coil embolization for controlling recurrent, massive (52,53). For various reasons, both individual and societal,
haemoptysis secondary to post-TB bronchiectasis. This certain patients are unable to effectively and diligently
method is extremely cheap and highly effective. In maintain the drug treatment regimen. The association
patients with life-threatening haemoptysis, early of antituberculosis drug treatment failure and alcoholism
operation is considered when bleeding has been localized is widely recognized. It is estimated that as many as 40
to one side and embolization is not available or not to 60 per cent of the population of TB sanatoria are
feasible when bleeding continues despite embolization alcoholic (52,53). The problem of alcoholism along with
or it is associated with persistent haemodynamic and its consequences is magnified in the non-hospital
respiratory compromise. However, before surgery it environment. Similarly, patients with psychological
should be ensured that the lesion is sufficiently locali- disorders ranging from psychosis to simple denial of a
zed to be resectable and the patient’s general condition physical disease state to mental incompetence may be
[cardiopulmonary status] does not contraindicate unable to maintain an adequate drug regimen. Resection
thoracotomy and pulmonary resection (52,53). For
of TB foci with the potential to recur if the long-term
patients in whom bleeding has ceased or decreased,
requirements of drug therapy are not met is the logical
emergent intervention may not be necessary. Surgery is
course if such treatment alleviates or reduces the need
the most definitive form of therapy for patients with
for prolonged therapy.
haemoptysis because it removes the source of bleeding.
Whether to proceed with elective surgery in patients with
Tracheal or Bronchial Stenosis,
a major bleed that has stopped or one that is controlled
Broncholiths and Bronchiectasis
angiographically is a difficult decision. Limited data are
available to assist in this decision, even for specific Tuberculosis is a necrotizing infection, and certain
diseases, such as bronchiectasis. Similarly, the long-term patients, although cured of the infectious process, carry
course of patients treated with endobronchial tamponade in their lungs the residuum of this destruction. Patients
or topical therapy is unknown. For patients with inoper- with a destroyed lobe or lung, bronchial stenosis with
able disease, limited cardiopulmonary reserve or bilateral distal recurrent secondary infection and atelectasis,
progressive disease, embolization is the mainstay of bronchiectasis with chronic infection and its conse-
treatment and should be pursued vigorously, even quences, and other similar residua may be candidates
repeating it, if necessary. It frequently controls bleeding for operative intervention. These abnormalities are
for prolonged periods. Majority of patients with life- doubtful indications, however, unless associated with
threatening haemoptysis due to TB have bilateral disease,
significant symptoms that cannot be controlled by current
often with cavitation. Localization of the side and the
medical modalities.
lobe from which the bleeding is originating is of para-
mount importance for therapy. Bronchoscopy performed
Pulmonary Aspergilloma
during bleeding is able to localize it in most of the cases.
However, it needs to be performed quickly when the Pulmonary aspergilloma is often produced in residual
patient is actively bleeding. cavities of TB origin. This topic has been covered in the
chapter “Complications of tuberculosis” [Chapter 35]. The recurrence at the same location was the one who had
surgical treatment of aspergilloma is a much debated refused the antituberculosis treatment after the first
matter. On the basis of having described its spontaneous surgical procedure.
lysis in five to fifteen per cent of cases (63), some authors
advise an expectant attitude for uncomplicated, asympto- Surgery for Complications Caused by Enlarged
matic cases of aspergilloma while others advise that it is Mediastinal Lymph Node Tuberculosis in Children
preferable to treat all aspergillus lesions with respect to
Sometimes, surgical intervention may be required in
the future risk of complications (64). If there are accom-
children with mediastinal lymph node TB for the
panying clinical symptoms, and if the patient meets the management of complications caused by the enlarged
conditions of operability, it is preferable to undertake
lymph nodes. Freixinet et al (70) treated six children, aged
surgical resection taking into account the condition of
two months to three years, who required an invasive
the affected lung. Lobectomy is preferred, although there procedure for the management of complications caused
may also be indications for segmental resection or
by enlarged mediastinal lymph nodes secondary to TB.
pneumonectomy depending on the size of the lesion (64-
Radiological and endoscopic studies revealed bronchial
66). Another surgical technique used, although only in involvement by lymph nodes, with endobronchial
patients with high operative risk, is simple cavernostomy
granulomas and lobar or pulmonary obstruction in four
and extraction of the aspergilloma as well as myoplasty
patients and marked tracheal and oesophageal stenosis
in the treated zone (67). A surgical alternative in cases produced by extrinsic compression in the remaining two.
that precludes operation is intracavitary instillation of
Histopathological study of the lymph node or bronchial
antifungal agents (64). In patients with massive haemop-
samples from the six patients disclosed granulomas with
tysis, embolization of the bronchial arteries is indicated caseous necrosis and Langhans’ giant cells. All children
as a primary recourse before planned surgery. Surgical
were treated with a standard six-month drug regimen
treatment for aspergilloma demands individual, careful
consisting of isoniazid, rifampicin, and pyrazinamide.
validation because it is a complex pathology with high Five of the patients underwent thoracotomy for the
incidence of post-resection complications.
purpose of nodal curettage or excision. In one, right upper
lobectomy and bronchoplasty were necessary. The sixth
Cold Abscess of the Chest Wall
patient was treated by the endoscopic resection of the
Cold abscesses of the chest wall, though uncommonly granulomas. There was no postoperative morbidity, and
encountered in industrialized countries, are common radiologic and endoscopic evidence of resolution of the
problems in areas where TB is highly endemic (68). lesions was observed in all the patients. The authors (70)
Because fine needle aspiration remains an inaccurate felt that, surgical treatment, when performed as an
diagnostic tool and antituberculosis treatment is not adjuvant treatment for tracheobronchial complications
always efficient, chest wall TB cold abscesses remain in stemming from mediastinal TB lymphadenitis, results
most patients a surgical entity. Faure et al (69) described in the resolution of the lesions and has no related
the surgical management of 18 patients with one or more morbidity.
cold abscesses of the chest wall. Before operation, the
diagnosis was confirmed by needle aspiration of the Surgery for Complications of Previous Surgery
abscess only in four patients and presumed in four others. Sometimes, plombage therapy can result in long-term
One patient did not undergo operation after a favourable postoperative complications. The management of these
response to medical treatment. In the other patients, an late complications is challenging and frequently requires
operation was indicated because of lack of response surgical intervention.
[n = 5] and the absence of diagnosis [n = 12]. Management Thomas et al (71) reported an infected axillary sinus
included adequate debridement and a postoperative tract that discharged balls made of an acrylic resin
antituberculosis treatment regimen with prevention of consisting essentially of polymerized methyl methacry-
recurrence in the mind. Follow-up details were available late [lucite] 45 years following performance of an
in 11 of the 17 patients undergoing operation. The only extraperiosteal pneumonolysis and Lucite ball plombage
patient who required a second operation because of for collapse therapy of right upper lobe cavitary TB.
810 Tuberculosis
Surgical extraction of the balls was performed, followed patients in 20 years in a university hospital for thoracic
by a partial decortication of the lung and intrathoracic TB revealed that surgery was necessary in 2.2 per cent of
transposition of a pectoralis major muscle flap to fill the all TB patients seen at that centre (73). The most common
residual pleural space. Primary healing was attained, and indications included TB empyema with or without BPF
the patient was well 18 months after surgery. [Table 55.4]. All procedures were performed under the
Nell et al (72) reported a patient who received a cover of antituberculosis treatment and supportive
plombage in 1947. The patient was admitted to hospital treatment with the aim of resolution of process, oblitera-
with hoarseness of voice. A CT of the chest revealed tion of the empyema space, control of sepsis and
transthoracic penetration of the paraffin plombage with improvement of activity performance. The morbidity was
intrusion into the overlying soft tissue. The patient extensive and mortality was high in major procedures.
underwent excision and debridement of the paraffin wax Good results could be obtained in over 92 per cent cases
mass followed by thoracoplasty. The patient then deve- and only 66.2 per cent on major surgery cases.
loped septicaemia and died due to multiple organ failure After the advent of drug treatment for pulmonary
23 days after the surgical intervention. Early ablation of TB, the operation of thoracoplasty became rare in the
plombage should be considered in order to prevent late developed countries. However, this was not the case in
complications. developing countries like India. Dewan et al (75) reported
results of thoracoplasty in 139 patients. Indications of
SURGERY FOR TUBERCULOSIS: surgery were TB empyema [n = 84], pyogenic empyema
INDIAN EXPERIENCE
[n = 33], post-operative empyema with BPF [n = 8], drug-
Indian experience regarding the role of surgery in the resistant pulmonary TB [n = 2] and recurrent haemop-
treatment of TB is summarized in Table 55.5 (73,74). A tysis [n = 2]. Successful outcome in the form of control of
retrospective analysis of the surgical procedures in 1655 sepsis, closure of BPF, sputum conversion and control of
Table 55.5: Indications for surgery in pleuropulmonary tuberculosis: Indian experience

Variable Lahiri et al (73) SVIMS, Tirupati (74)*
[1970-1990] [1993-2007]
[n = 1655] [n = 355]
No. [%] No. [%]
Tuberculosis empyema with or without 1507 [91.0] 206 [58.0]

bronchopleural fistula
ICT drainage 1507 [91.0] 206 [58.0]
Thoracostoma 56 [3.4] 2 [0.6]
Decortication 45 [2.7] 120 [33.8]
Thoracoplasty 6 [0.4] 5 [1.4]
Continuous short tube drainage† 17 [1.1] 22 [6.2]
Complicated pulmonary tuberculosis 78 [4.7] 149 [42.0]
Pneumonectomy 35 [2.1] 40 [11.3]
Lobectomy 30 [1.8] 71 [20.0]
Segmental wedge resection 3 [0.2] 3 [0.8]
Thoracoplasty 10 [0.6] 2 [0.6]
Bullectomy 0 [0] 7 [2.0]
Cold abscess in the chest wall 54 [3.3] 2 [0.6]
Osteomyelitis of ribs, or sternum 16 [1.0] 7 [2.0]
Aspergilloma 0 [0] 17 [4.8]
Some patients underwent more than one procedure

* Data updated from reference 74
† The intercostal tube was cut short, fixed with a safety pin and left open to atmosphere. This
procedure was used in patients who were either unfit, or could not afford major surgery
ICT = intercostal tube; SVIMS = Sri Venkateswara Institute of Medical Sciences
haemoptysis was achieved in most cases. There were four 16. Schkabgem G. Kongress der Deutschen Gesellschaft fur
deaths in the entire series. The authors concluded that Chirurgie zu Berkub. Int Zbl Tuberk Forsch 1907;2:38.
17. Tuffier TL. De la resection du sommet du poumon. Semin
with the persisting problem of pulmonary TB in the
Med 1891;11:202.
developing countries, thoracoplasty is still an operation 18. Motus IY, Skorniakov SN, Sokolov VA, Egorov EA,
of continued relevance. Pratap et al (76) described the Kildyusheva EI, Savel’ev AV, et al. Reviving an old idea: can
immediate and long-term results of resectional surgery artificial pneumothorax play a role in the modern
in patients with pulmonary aspergilloma. In this series management of tuberculosis? Int J Tuberc Lung Dis
(75), morbidity due to complications was 29 per cent and 2006;10:571-7.
19. Steele JD. The surgical treatment of pulmonary tuberculosis.
the mortality was under three per cent. Ann Thorac Surg 1968;6:484-502.
20. Graf W. Ueber die thoracoplastische totalausschaltung des
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814 Tuberculosis
DOTS: The Strategy that Ensures

Cure of Tuberculosis Patients
56
Thomas R Frieden
INTRODUCTION monitoring and accountability for every patient

diagnosed (8).
On March 24, 1997, the Director-General of the World
In this chapter, the principles, scientific basis, and
Health Organization [WHO], declared that, “The DOTS
experience with implementation of DOTS will be
strategy represents the most important public health reviewed. In addition, the relevance of DOTS in the
breakthrough of the decade, in terms of lives which will context of the human immunodeficiency virus [HIV]
be saved” (1). epidemic, multidrug-resistance and recent epidemio-
Yet DOTS is nothing new. In fact, the essential logical findings will also be reviewed. Since 1993, India
principles of DOTS were first discovered in India at the has adapted and pilot-tested the DOTS strategy as the
Tuberculosis Research Centre [TRC] in Chennai [earlier Revised National Tuberculosis Control Programme
known as Madras] and the National Tuberculosis [RNTCP].
Institute [NTI], Bengaluru [earlier known as Bangalore],
in the 1950s and 1960s. The determination that POLITICAL WILL
tuberculosis [TB] patients need not be hospitalized was
By any measure, the burden of suffering caused by TB in
first proven in Chennai and changed care of TB patients
India and elsewhere is staggering. Globally, there are
worldwide (2). Use of supervised treatment, now known more than nine million cases and 1.7 million deaths from
as directly observed treatment [DOT], in which patients TB in 2006, and nearly 100 million people died of TB in
are observed to take their antituberculosis medications, the twentieth century (9,10). In India, 1000 people die
was shown to be essential in India (3). The efficacy of from TB every day. Tuberculosis affects young adults
intermittent treatment, with medications given two or disproportionately, and it therefore, leaves more orphans
three times a week, was also first shown to be effective than any other infectious disease, impoverishes families,
in India (4). The efficacy of case finding by microscopy and undermines economic development (11). Tuber-
among patients attending health services was also culosis causes nearly one-third of female infertility in
demonstrated in India (5,6). By 2002, India had the largest India (12), and kills more women of reproductive age
DOTS programme in the world, in terms of number of than all causes of maternal mortality combined (9). India
patients treated annually (7). accounts for nearly 20 per cent of all TB cases in the world
The five fundamental principles of the WHO-recom- and cases may increase in India as the population grows
mended DOTS strategy are: [i] Political will; [ii] Case- and the HIV epidemic progresses (13).
finding primarily by microscopic examination of sputa Despite the heavy burden of disease, in many
of patients presenting to health facilities; [iii] Short- countries TB control efforts are poorly funded and
course chemotherapy given under direct observation; supported. Shortages of drugs and equipment are
[iv] Adequate drug supply; and [v] Systematic common and key posts within the TB control programme
DOTS: The Strategy that Ensures Cure of Tuberculosis Patients 815
are often vacant or suffer from low prestige and high recommended by WHO (14). Sputum microscopy is a
staff turnover. It is the responsibility of physicians, as highly specific test and should be the primary tool for
leaders in their communities, to ensure that effective TB diagnosis. In contrast, the unreliability of chest radio-
control programmes exist, and to support and coordinate graph is well-documented; 30 per cent or more of patients
their own efforts with those of TB control programmes. classified as having “active” TB on the basis of chest
Although TB control is a core government function, it radiograph, even by experts, are found not to have TB
cannot be accomplished by any one individual or sector, (15-17). Culture, even where available, has a limited role
but requires communication and collaboration between in diagnosis: a decision taken on the basis of the algorithm
local health authorities, the primary health care system, presented in Figure 56.1 will often be more rapid than
hospitals, medical schools, private physicians, non- one based on culture (18). The technical and logistic
governmental organizations and others. requirements for culture make it unsuitable as a primary
diagnostic tool in developing countries. In addition to
DIAGNOSIS BY SPUTUM MICROSCOPY OF being a specific diagnostic tool, the acid-fast bacilli [AFB]
smear correlates with severity of disease, mortality, and
PATIENTS ATTENDING HEALTH FACILITIES
infectiousness (19,20). Furthermore, it is a low-cost,
Two important concepts are combined in this aspect of appropriate technology which can be done reliably even
the DOTS strategy. First, that diagnosis should be based in remote areas (21). Current technology for serological
primarily on microscopy rather than chest radiograph, and amplification tests on sputum samples is more
clinical examination, or culture, and, second, that case- expensive and less informative than the AFB smear and
finding should be done primarily among patients attend- is not of proven utility in TB control. Future develop-
ing health facilities, and not by active case-finding in the ments in this field may facilitate diagnosis, particularly
community. Figure 56.1 presents the diagnostic algorithm of smear-negative and extra-pulmonary TB cases, and
Figure 56.1: Diagnosis algorithms: standardized management plan for patients with tuberculosis
1 Screening: cough more than 2 to 3 weeks. Diagnosis: clinical signs, symptoms, normal chest radiography
2 Consider other diagnosis
TB = tuberculosis; AFB = acid-fast bacilli
816 Tuberculosis
there are circumstances where culture and sensitivity case detection rates have increased steadily as patients
testing can be useful (22). learn that effective services are available and seek care
The second component of this aspect of the DOTS at government centres (7).
strategy is the approach to case-finding. All too often,
there are efforts to do massive case-finding for TB. These SHORT-COURSE CHEMOTHERAPY GIVEN IN A
efforts result in low cure rates (17,19). This is because PROGRAMME OF DIRECTLY OBSERVED
most patients with active TB seek care, and the few who TREATMENT
do not are less likely to complete treatment (18). This
This principle also has two aspects, both of which are
was well-documented in India more than 30 years ago:
crucial. The efficacy of short-course, intermittent
“Even with the present extremely limited and inadequate treatment has been conclusively demonstrated in
facilities available for the diagnosis and treatment of the controlled clinical trials in India and elsewhere (23-33).
disease, over half of the sputum-positive persons have Short-course treatment has also been documented to be
actually sought assistance at government medical effective for extra-pulmonary TB (34,35). The first series
institutions, motivated by their symptoms” (6). Dr Karel of trials showed that with isoniazid and rifampicin, with
Styblo, who developed the DOTS strategy based in large or without other drugs, a nine-month course of treatment
part on the principles discovered in India, wrote about could be given. The next trials showed that, with addition
this phenomenon: “Well-organized outpatient chemo- of pyrazinamide for the first two months, treatment
therapy, especially if provided free of charge, will attract duration could be reduced to six months, but giving
symptomatic cases from far and wide” (19). pyrazinamide for a longer period of time did not give
Experience with the RNTCP in India demonstrates additional benefit (36). Trials attempting to reduce the
the validity of both aspects of this diagnostic approach. length of treatment to below six months have failed,
In the RNTCP, half of all patients with pulmonary TB indicating that with the currently available medications
are diagnosed on the basis of positive sputum smears, no practical regimen of less than six months duration is
as opposed to less than one out of four in the previous acceptable for patients with smear-positive TB (37,38).
programme. Furthermore, in areas where the prog- Treatment regimens which are recommended by
ramme has been successfully operating for several years, WHO are presented in Table 56.1 (39). As noted above,
Table 56.1: World Health Organization-recommended treatment regimens
Tuberculosis Tuberculosis Initial Continuation
treatment patients phase phase
Category I New smear-positive 2HRZE [2HRZS] 6HE

pulmonary TB; 2H3R3Z3E3 [2H3R3Z3S3] 4HR
New smear-negative pulmonary TB with 4H3R3
extensive parenchymal involvement;
concomitant HIV or new cases of severe
forms of extra-pulmonary TB
Category II Sputum smear-positive relapse; treatment 2SHRZE/1HRZE 5H3R3E3
failure; treatment after interruption 2S3H3R3Z3E3 /1 H3R3Z3E3 5HRE
Category III New smear-negative pulmonary TB 2HRZE 6HE
[other than in Category I]; new less severe 2H3R3Z3E3* 4HR
forms of extra-pulmonary TB 4H3R3*
Category IV Chronic [still sputum-positive after supervised Specially designed standardized or
re-treatment]; proven or suspected MDR-TB individualized regimens
cases
The number before the letters refers to the number of months of treatment. The subscript refers to the number of doses per week
* Under the Revised National Tuberculosis Control Programme of the Government of India, Category III regimen 2H3R3Z3/4H3R3 has
been used with an apparently low failure rate
TB = tuberculosis; HIV = human immunodeficiency virus; H = isonaizid; R = rifampicin; Z = pyrazinamide; E = ethambutol; S =
streptomycin; MDR-TB = multidrug-resistant tuberculosis
it is now well-documented that intermittent treatment weeks of treatment and that he might be tempted to stop
given twice or thrice weekly is as effective as daily taking his medicine, but that to do so might have very
therapy. This should not be surprising, since the doubling serious consequences. Such instruction was repeated at
time of Mycobacterium tuberculosis is 18 to 24 hours, every monthly examination, and at other visits to the
compared with 12 to 20 minutes for most bacteria (40). clinic as well as in the patient’s home, by the doctors, by
In fact, in one animal model, intermittent treatment was the public health nurses, and by the health visitors.
more effective than daily treatment (41). The recent study Further, an attempt was always made to get another
of Chaisson et al (30) is of particular note since the member of the family to watch the patient swallow the
regimen which was used is identical to that of the RNTCP medicine. The explanation was always given in simple
of India for new smear-positive patients, i.e., two months language. “Despite this approach, ensuring self-administra-
of thrice weekly isoniazid, rifampicin, pyrazinamide, and tion was a major problem” (3).
ethambutol, followed by four months of isoniazid and Directly observed therapy is the most difficult and
rifampicin thrice weekly. Cure rates were 87 and 81 per the most controversial aspect of the DOTS strategy. It
cent for HIV uninfected and HIV infected patients, should be clarified that DOTS is the comprehensive five-
respectively. The lower cure rate in HIV infected patients point strategy outlined above, whereas DOT is one
was a result of deaths from non-TB-associated causes. essential component of that strategy. Observation must
The authors concluded that, “thrice-weekly, supervised, be done by a person who is accessible and acceptable to
short-course therapy for TB was highly effective in the patient and who is accountable to the health system
patients with and without HIV infection. Intermittent (14). In some countries [Tanzania, Cambodia], DOT is
therapy was extremely well-tolerated.” However, inter- given in hospital for the first two months (51,52). In
mittent treatment should only be given in a programme various countries, health staff [Nicaragua (53), China (54),
of direct observation of treatment (42). New York City (55)], community volunteers [South
Drugs can only be effective if they are taken (42,43). Africa (56,57)], members of non-governmental
Virtually all clinical studies of short-course chemo- organizations [Bangladesh (58)], religious leaders
therapy were conducted using supervised therapy. It can, [Philippines (59)] or others have given DOT. Each
therefore, be argued that use of unsupervised rifampicin- community has strengths, and the challenge in
containing regimens is experimental and potentially implementing this aspect of the DOTS strategy is to
dangerous. The DOT is becoming the standard of care identify and enlist the support of these strengths. Even
for TB (44-46). A large body of evidence has conclusively in the unstable environment of a refugee camp, DOT has
demonstrated that a large proportion of patients [at least been shown to be feasible (60). In India, health staff
30%] do not take medications regularly as prescribed, including multi-purpose workers and pharmacists have
and that it is not possible to predict which patients will given DOT, as have Anganwadi workers, Dais, commu-
not adhere to treatment (42,43,47-49). This observation nity volunteers, tea vendors, and others (7). Directly
was first made in TB in India (50). Studies from the TRC, observed therapy means more than the mere mechanical
Chennai demonstrated that non-adherence was not procedure of watching patients as they take medications,
related to side effects, dosage, or prior receipt of one year an approach that it likely to fail. Rather, direct observa-
of supervised treatment. Non-adherence was as high tion succeeds through the building of human bonds
with placebo as with active drug. Surprise home visits between patients and health care workers or community
revealed a much greater degree of non-adherence than volunteers, and by transmitting recognition of the value
pill counts or urine tests. The experience was of treatment success for patients and their communities.
summarized as follows: “Every effort was made to obtain It also implies recognition of the responsibility of the
and keep the patient’s co-operation and much time was programme and of the community for successful
spent during several interviews explaining both to the treatment, which is accomplished by providing treatment
patient and to the family the seriousness of the disease with respect for the patient, at convenient times, and in
and the necessity for a long-course of chemotherapy. The appropriate facilities (61).
infectious nature of the disease and the radiographic It may be impossible to arrange DOT for some
lesion was demonstrated to the whole family. The patient patients. In a well-functioning programme, this should
was warned that he would feel much better after a few occur in less than 10 per cent of the cases. In these cases,
818 Tuberculosis
the patient may need to be given self-administered the DOTS strategy because it ensures accountability. The
treatment which a family member may be able to assist information system designed by Dr Styblo of the
the patient in taking. However, assistance by a family International Union Against Tuberculosis and Lung
member, as indicated in the study cited above from the Disease and recommended by WHO is simple but
TRC, is unreliable. There are no examples of successful remarkably robust. This system allows effective prog-
large-scale DOTS programmes in which immediate ramme management as well as operational research (62).
family members have been utilized as the primary DOT At each microscopy centre, a good quality microscope
providers. Organising DOTS may not be simple, but it is and reagents are supplied, and the laboratory technician
only method which, on a programme basis, can ensure a is trained, supervised, and included in a quality control
high cure rate. network. Every patient whose sputum is examined is
recorded in the Laboratory Register. Every patient whose
ADEQUATE SUPPLY OF GOOD QUALITY DRUGS
sputum is found to be positive for AFB and started on
Obviously, for treatment to succeed there must be enough treatment is recorded in the TB Register, and the outcome
drugs for patients to complete prescribed treatment. In of every such patient is recorded. Quarterly reporting of
addition, it is important that drugs should be of good diagnosed cases allows simple but revealing analysis of
quality, with adequate bioavailability. Particular the descriptive epidemiology of TB. Smear-positive
concerns are for the bioavailability of rifampicin in patients are monitored for sputum conversion to negative
combination tablets, particularly when rifampicin and at the end of the intensive phase of treatment, and the
pyrazinamide are combined, and the stability of sputum conversion rate is monitored as an early indicator
ethambutol, which may be compromised by poor quality of programme effectiveness. Finally, the outcome of
packaging or excessive humidity during storage. treatment is systematically recorded in one of six
Combination tablets of proven bioavailability have categories, which are all strictly defined [Table 56.2]. The
the theoretical advantage of preventing monotherapy. global target for cure of new smear-positive patients is
Fixed-dose combination [FDC] tablets incorporate two
85 per cent or more (8).
or more medications into the same tablet and prevent
Information in TB Laboratory Register and the TB
providers and patients from using a single antituber-
Register can be easily checked for internal consistency
culosis drug. This should reduce the likelihood of
and consistency between records, and can also be
development of drug resistance, and should also reduce
externally verified by reviewing sputum slides, inter-
the likelihood of physician prescription error and patient
viewing patients and health workers, and by monitoring
medication error. The FDCs can also simplify treatment
consumption of drugs and supplies.
for patients and logistics for programme managers.
However, FDCs of low bioavailability could result in
RESULTS OF DOTS
treatment failure and drug resistance, and FDCs increase
the cost of antituberculosis drugs (14). The benefits of The DOTS strategy has been implemented successfully
FDCs on a programme basis are difficult to document in a wide variety of countries and contexts. In the United
and, of course, FDCs do not ensure that the drugs will States, Baltimore demonstrated a marked reduction in
be taken. case rates despite a high rate of HIV infection with use
In India, drugs in the RNTCP are being supplied in of DOTS (63). And in New York City, by 1991 half of TB
blister packs in patient-wise boxes containing the entire patients were HIV infected and one in five had multi-
course of treatment. In this way, the patient is assured of drug-resistant tuberculosis [MDR-TB] (64), but DOTS
having drugs available until cure, and no patient can be resulted in a rapid decrease in both TB and in multidrug-
begun on treatment unless a full supply of drugs is resistance (65). Murray et al (51) reviewed experience in
present. Malawi, Mozambique and Tanzania, documenting cure
rates of 86 to 90 per cent. Effective programmes have
SYSTEMATIC MONITORING AND
been established and have continued to function well
ACCOUNTABILITY
even in the context of civil war [Mozambique (51) and
Although record-keeping is often seen as unimportant, Nicaragua (53)]. Application of universal DOT and
an effective system of registering patients is the heart of subsequent adoption of short-course chemotherapy were
Table 56.2: World Health Organization-recommended case definitions

New case
A patient who has never had treatment for TB or who has taken antituberculosis drugs for less than 1 month
Relapse
A patient previously treated for TB for whom treatment has been successful [i.e., who has been declared cured or who has completed
treatment but does not meet the criteria to be classified as cured or as having treatment failure], and is diagnosed with bacteriologically
positive [smear or culture] TB
Treatment after failure
A patient who is started on a re-treatment regimen after having failed previous treatment
Treatment after default

A patient who returns to treatment, positive bacteriologically, following interruption of treatment for 2 months or more
Transfer in
A patient who has been transferred from another TB register to continue treatment
Multidrug-resistant TB
A patient who has active TB with bacilli resistant at least to both rifampicin and isoniazid
Chronic case
A patient who is sputum-positive at the end of a standard re-treatment regimen
Other
All cases that do not fit the above definitions
Smear-positive pulmonary TB
Either: a patient with at least two or more initial sputum smear examinations positive for AFB; or: a patient with at least one sputum
smear examination positive for AFB plus radiographic abnormalities consistent with active pulmonary TB as determined by a clinician;
or: a patient with at least one sputum smear positive for AFB plus sputum culture positive for Mycobacterium tuberculosis
Smear-negative pulmonary tuberculosis

A patient with pulmonary TB that does not meet the above definition for smear-positive TB. This group includes cases without smear
result, which should be exceptional in adults but are relatively more frequent in children.
Treatment outcomes
Cure: Patient who is sputum smear-negative in the last month of treatment and on at least one previous occasion
Treatment completed: Patient who has completed treatment but who does not meet the criteria to be classified as cured or as having
treatment failure
Treatment success: Patient who has either been cured or who has completed treatment
Treatment failure: Patient who is sputum smear-positive at 5 months or later during treatment. Also a patient who was initially smear-
negative before starting treatment and became smear-positive after completing the initial phase of treatment
Died: Patient who dies for any reason during the course of treatment
Default: Patient whose treatment was interrupted for 2 consecutive months or more
Transfer out: Patient who has been transferred to another recording and reporting unit and for whom the treatment outcome is not
known
TB = tuberculosis; AFB = acid-fast bacilli

820 Tuberculosis
associated with a substantial decline in TB in Cuba, to a of drug-resistant cases at a faster rate than these cases
level below that of many industrialized countries (66). can be cured, even if unlimited resources are available.
In Beijing, DOT was implemented in 1978, and short- Although treatment of MDR-TB is difficult and expen-
course chemotherapy was introduced in 1988. Prevalence sive, it may be important for TB control in some contexts.
of smear-positive TB in Beijing decreased from 127 per For disease control, if multi-drug-resistance is present in
100 000 in 1979 to 16 per 100 000 in 1990, a decrease of 17 congregate facilities [e.g., prisons, hospitals] where
per cent annually (54). More recently, a World Bank- immunosuppressed [e.g., HIV infected or malnourished]
assisted project in China has had considerable success. people are present, it is essential to promptly diagnose
New patients were treated with 2[HRZS]3 4[HR]3, and and treat patients with MDR-TB or there can be rapid
retreatment cases with 2[HRZSE]3 6[HRE]3 (66). More spread of the disease. For patient care, in contexts where
than three million patients have undergone sputum resources permit [e.g., targets for case detection and
examinations, and by the end of 2002 more than 1.5 treatment success met and resources in place to continue
million smear-positive patients had been treated, with a DOTS implementation], treatment of MDR-TB can be life-
cure rate of more than 90 per cent. The failure rate in saving and can prevent the further spread of disease.
previously treated patients fell progressively from The reader is referred to the chapters “Drug-resistant
eighteen to six per cent in the first year of the programme. tuberculosis” [Chapter 49] and “Antituberculosis drug-
The programme in China currently covers a population resistance surveillance” [Chapter 50] for details regarding
of 700 million (67,68). In the South-east Asia Region, extensively drug-resistant tuberculosis [XDR-TB].
Bangladesh has had good success in DOTS implemen-
tation, with coverage of the entire country and a cure HUMAN IMMUNODEFICIENCY VIRUS
rate above 80 per cent (69). In India the RNTCP has
Infection with the HIV is the most potent known risk
obtained overall cure rates of 85 per cent, with some areas
factor for progression to active TB among adults (82).
consistently achieving cure rates above 90 per cent (70).
Individuals who are not HIV infected and who become
In addition, DOTS has been shown to be highly cost-
infected with Mycobacterium tuberculosis have approxi-
effective (51,71).
mately a 10 per cent lifetime risk of developing active
TB, compared with a risk of 60 per cent or more in persons
MULTIDRUG-RESISTANT AND EXTENSIVELY
infected with both HIV and Mycobacterium tuberculosis
DRUG-RESISTANT TUBERCULOSIS
(83). Among persons with acquired immunodeficiency
The emergence of drug resistance is a symptom of syndrome [AIDS] who become infected with Mycobacte-
ineffective TB control (72). If patients are prescribed rium tuberculosis, the risk of progression to active TB is
appropriate antituberculosis treatment and take this very high, and the rate is very fast. In outbreaks of TB in
treatment, development of resistance is extremely rare. wards for AIDS patients in the United States, the median
In contrast, in situations where prescribing practices or time from TB exposure to disease was three months, and
case holding or both are poor, drug resistance can in some outbreaks more than one-third of exposed
emerge. Effective treatment programmes can prevent patients developed TB (84).
drug resistance (73,74) and can even result in a decrease The HIV epidemic is a stress test for TB control
in drug resistance if it has emerged; this has been programmes, and can relentlessly reveal programme
documented in Edinburgh [Scotland] (75), Libya (76), weaknesses. Cantwell and Binkin (85) reviewed expe-
Korea (77), Burkina Faso (78), Beijing (79), Texas [USA] rience in 20 countries in sub-Saharan Africa representing
(80), South Africa (81), and New York City [USA] (65). half of the population and 85 per cent of the reported
Treatment of MDR-TB is difficult, expensive, often cases of the region. They (85) found that from 1975 until
unsuccessful, and should only be undertaken with the 1985, case rates decreased by an average of 1.6 per cent
appropriate expertise and resources (72). Prevention of per year. After 1985, with an increase in rates of HIV
the development of drug-resistant TB by ensuring cure infection, case rates increased by an average of 7.7 per
of new smear-positive patients is a much higher public cent per year. Case rates increased approximately twice
health priority than treatment of MDR-TB. This is because as fast in countries with high rates of HIV-seropositivity.
a low cure rate among new cases will result in the creation The increase in case rates after 1985 was much lower in
countries with good quality TB control services. The clear roles and responsibilities for implementing this plan.
authors (85) concluded that improving quality of national This plan must include a clear and practical protocol for
TB programmes “is essential to mitigate the resurgence ensuring that patients who are discharged continue on
of TB in the HIV era.” treatment and complete the course so that they are not
One lesson learned from the unfortunate experience admitted again with infectious, possibly drug-resistant
in the United States and elsewhere is that MDR-TB can TB; [ii] ensure prompt diagnosis; most TB is spread in
spread very rapidly among HIV-infected persons who hospitals by patients whose TB has not been diagnosed
are hospitalized (86-90). This experience has recently and who, therefore, have not begun treatment. Since the
been documented in Argentina (91), Italy (92), South radiographic appearance of TB in HIV infected persons
Africa (93), Spain (94), and Russia (95). Tuberculosis in is often atypical, in areas of high HIV prevalence, all
HIV infected persons, particularly in patients with patients who have chest symptoms should undergo three
advanced HIV-related disease and low CD4+ T-cell sputum examinations for AFB which must be performed
lymphocyte counts, tends to be smear-negative, extra- accurately and reported promptly; [iii] ensure that
pulmonary, and with atypical presentation on chest effective antituberculosis drugs are used, and that the
radiograph and a high [15% to 25%] case fatality rate health staff directly observe the patient to ingest every
(96-98). Nevertheless, patients with HIV respond well to dose. This also means ensuring that a proper history is
appropriate antituberculosis treatment (99,100). Patients taken from patients and that patients who have been
treated for TB in the past are treated with a more intensive
with HIV infection and TB disease survive longer if they
regimen; [iv] keep TB patients in separate wards from
are given short-course chemotherapy [SCC] with
HIV infected patients who do not have TB, with separate
rifampicin-containing regimens compared with patients
air supply [e.g., in different wings or buildings rather
given conventional treatment (101), and longer still if
than on adjacent floors of the same building]. Whenever
SCC is given in a programme of DOT (102,103). Tuber-
possible, TB should be diagnosed and treated on an
culosis appears to hasten the development of AIDS in
outpatient basis; [v] ensure that TB patients who fail to
HIV-infected persons (104,105,106). Use of intermittent
respond to directly observed antituberculosis treatment
treatment for patients with advanced HIV disease and
are not in proximity to HIV infected persons, including
low CD4+ cell counts appears to be associated with an
staff and patients with and without TB. This is important
elevated rate of development of rifampin resistance if because patients who are responding poorly to treatment
the patient relapses (107). However, even among severely may harbour drug-resistant strains of Mycobacterium
immunosuppressed HIV infected patients, relapse and tuberculosis which may spread rapidly among HIV-
development of resistance occurs in fewer than five per infected persons; and [vi] take steps to reduce the concen-
cent of patients. The reader is referred to chapters “Drug- tration of airborne Mycobacterium tuberculosis. Risk to
resistant tuberculosis” [Chapter 49], and “Tuberculosis and patients and staff may be reduced by ensuring that
human immunodeficiency virus infection” [Chapter 40] for patients cover their mouths when they cough or sneeze,
more details. increasing natural sunlight [because the ultraviolet rays
in direct sunlight kill aerosolized bacilli], increasing
PREVENTION OF NOSOCOMIAL SPREAD OF ventilation [e.g., by placing window exhaust fans in rooms
TUBERCULOSIS AMONG HUMAN where TB patients will be treated], and, possibly, by
IMMUNODEFICENCY VIRUS INFECTED PATIENTS careful use of upper-room ultraviolet irradiation. Sputum
collection should be done outside and away from other
Recommendations on the prevention of nosocomial people.
spread of TB have been published by the US Centers for Tanzania and Malawi have had programmes of DOTS
Disease Control and Prevention (108), but some of these for more than 10 years. Despite high rates of HIV infec-
recommendations may be impractical for developing tion, which is present in up to one-third of TB patients,
countries. The basic principles of TB infection control, there has been no evidence of an increased rate of relapse
however, are clear and generalizable. In order to prevent among HIV infected patients, and rates of drug resistance
nosocomial spread of TB, hospitals located in areas with remain low (73,74). Avoiding the creation of drug-resis-
a high prevalence of both HIV and TB should: [i] develop tant TB is the best way to prevent the spread of such
a plan for TB care and infection control, and assign staff strains.
822 Tuberculosis
MOLECULAR EPIDEMIOLOGY 5. Banerji D, Anderson S. A sociological study of awareness of

symptoms among persons with pulmonary tuberculosis. Bull
Molecular tools are being applied to the study of the World Health Organ 1963;29:665-83.
epidemiology of TB, sometimes with surprising results. 6. Baily GVJ, Savic D, Gothi GD, Naidu VB, Nair SS. Potential
One such technology is restriction length polymorphism yield of pulmonary tuberculosis cases by direct microscopy
of sputum in a district of South India. Bull World Health
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Organ 1967;37:875-92.
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cases may result from transmission of infection within Engl J Med 2002;347:1420-5.
the previous two years (109-112). This is a much larger 8. World Health Organization. Framework for effective
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Health Organization; 1994.
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9. World Health Organization. Global tuberculosis control :
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11. World Health Organization. Groups at risk: report on the
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Directly Observed Therapy 827
Directly Observed Therapy

57
Ian Smith
INTRODUCTION from 11 per cent in 1995 to over 61 per cent by 2006 (2,3).
The global treatment success rate had reached 84.7 per
Detecting people with active tuberculosis [TB] and
cent by 2005 (2,3). There is clearly a need to rapidly
achieving high cure rates in these patients is the primary
expand DOTS.
strategy for interrupting transmission of this devastating
disease, and is more effective than other control
WHAT IS DIRECTLY OBSERVED THERAPY?
interventions such as bacille Calmette-Guérin [BCG]
vaccination and preventive therapy (1). In 2006, TB Directly Observed Therapy [DOT] has been widely
caused 1.7 million TB, deaths worldwide of which 98 per advocated as a tool for achieving compliance with
cent occurred in developing countries (2). Although the treatment for patients with TB for many years. Although
incidence of TB is falling in most regions of the world, definitions of DOT vary, in essence, it refers to the act of
the total number of new TB cases registered slow increase a responsible observer holding the drugs and observing
largely due to the human immunodeficiency virus [HIV] each administration (7). Morse (8) further defines the
pandemic in Africa, where TB incidence rates are highest observer as a health care worker or a trained lay person.
(2,3). Use of the terms DOT and DOTS interchangeably has
Results of model programmes in Africa have demon- led to some confusion. For the purpose of this discussion,
strated that the introduction of short-course chemo- and in general, the term DOT refers to the specific activity
therapy [SCC] is one of the most cost-effective interven- of directly observing therapy, i.e., watching the patient
tions available in primary health care (3-5). Based on taking his or her treatment. On the other hand, DOTS is
these experiences, the World Health Organization a “brand name” for effective TB control and incorporates
[WHO] now advocates DOTS as an essential strategy for the five essential elements promoted by WHO (9):
TB control, with an emphasis on improving health service [i] political commitment; [ii] passive case-finding by
performance in the delivery of care to people with TB, sputum smear examination; [iii] standardized regimens
rather than blaming the patient for poor compliance. of SCC with a priority for infectious cases, given under
Unfortunately, few National Tuberculosis Programmes direct observation; [iv] a continuous and uninterrupted
[NTPs] in developing countries have been able to achieve supply of medicines; and [v] a cohort reporting system
and sustain the global TB control targets first promoted to monitor the outcome of treatment. These have been
by WHO in 1991 (6): detecting at least 70 per cent of further simplified to funding, microscopes, observers,
sputum smear-positive cases and achieving a cure rate medicines, and reporting books (10).
of at least 85 per cent among those cases. These targets
were subsequently re-affirmed at the 53rd World Health COMPLIANCE, ADHERENCE OR CONCORDANCE?
Assembly in 2000 (6). By 2006, DOTS has been imple- With the emphasis on a high case-detection and cure rates
mented in 184 countries. Case detection rates followed; as the main objectives of TB control, and awareness that
828 Tuberculosis
low cure rates can lead to an increased prevalence of the will of the provider. She (21) suggests “adherence”
drug-resistant TB and may increase the overall incidence as an alternative term, reflecting the active role of the
of TB, it is not surprising that investigations of comp- patient in the management of their illness. More recently,
liance feature prominently in sociological studies relating the term “concordance” has been suggested, to reflect a
to TB. Numerous studies over the years have documen- relationship between the patient and prescriber, based
ted the poor treatment success rates achieved in many on exchange of information, negotiation and co-opera-
TB programmes all over the world, including India tion, and expressing agreement and harmony (22). In that
(11-13). Although compliance is frequently thought of spirit, this chapter will henceforth use the term
in terms of the patient, Wallace Fox (14,15) identified concordance.
doctor compliance as an issue to be considered. He Default is an equally unpopular word–also implying
showed that treatment failure was commonly attribut- a moral judgement. Rouillon (23) points out that to
able to the failure of physicians to adhere to agreed default is a natural phenomenon, and “the normal
policies and principles of therapy, such as duration of sensible person is the one who defaults”. It is the
therapy, treatment regimen, and hospitalization. Banerji abnormal, perhaps obsessive, individual who continues
(16) echoes the concern that compliance is all too to take medication for months after he or she feels better!
frequently a form of ‘victim blaming’, with patient as She (23) defines default as “an omission on the part of
victim. He identifies health workers and managers as the patient or services, an omission which necessitates a
the main culprits, because of their failure to appropriately corrective intervention, in the interests of the patient
diagnose patients with TB, their inability to implement and/or in those of the community”. All too often the term
and maintain effective TB programmes, and their is used for the patient rather than the services!
dogmatic and aggressive attitudes towards patients who Fortunately, there are those who continue to remind us
discontinue treatment. A clear example of poor doctor that the patient is not the main culprit; Banerji (16) uses
compliance is provided by Uplekar and Rangan (17) who his definition of defaulter: “anyone whose conduct with
reported a study of 102 private practitioners in Mumbai. regard to treatment is contrary to his own good, or to
These doctors (17) used 10 different drug combinations that of society, or to both”, to mark out health admini-
in 80 different regimens of varying duration. This strators as the main problem.
example becomes more salient when combined with the The factors that influence concordance with treatment
fact that India accounts for 20 per cent of the world’s are diverse [Table 57.1]. Some are patient characteristics,
estimated incident TB burden (2) and nearly half of including health beliefs, demographic factors, and cultural
India’s TB patients seek care in the private sector (18). influences. Others relate to the nature of the health
This form of poor compliance is not only reflected in the services, for example, accessibility and appropriateness
treatment of patients, but also in the lack of ability to of health facilities, treatment regimens, and attitudes of
gather standard monitoring and evaluation data from health workers. Factors in the make up of society, can also
the private sector (19). A third level of compliance is be of importance, for example the socio-economic status
illustrated by Grange and Festenstein (20), who describe of the community, and political stability. Finally,
national non-compliance. This lack of political commit- environmental factors may adversely affect treatment
ment is demonstrated by countries failing to adopt or concordance; mountains, rivers, monsoons, poor roads
adequately fund effective TB control measures. and snow can all seriously interrupt treatment supplies,
Compliance must, therefore, be considered in terms of and prevent patients from reaching health services.
the social, cultural and economic context of the Although many studies have tended to focus on
community, and is influenced by political stability, demographic factors, it is clear that health beliefs and
favourable health strategies, standardized control quality of services are two, perhaps more important,
policies, a healthy infrastructure, trained and supervised determinants. An in-depth study from Wardha district
staff, public education and community participation. in Maharashtra State, India, demonstrated the influence
Sumartojo (21) finds compliance a pejorative expres- of health motivation, perceived severity of disease,
sion, carrying the unfortunate connotation of a docile and presence of social support, and satisfaction with the
passive patient, yielding, submissive and subservient to health care provider on treatment concordance (24).
Table 57.1: Factors influencing concordance with 80 per cent treatment success or higher must be inter-
treatment preted with caution, as the factors influencing concor-
The patient dance in the small proportion of patients defaulting from
Demographic
treatment may be quite different from programmes
Age achieving poor cure rates. It might be assumed that in
Marital status programmes achieving high cure rates, the proportion
Ethnic group of patients defaulting due to social problems is high. In
Cognitive/Affective contrast, the main factor influencing treatment
Knowledge about tuberculosis and treatment concordance in programmes with poor cure rates is
Previous experience of taking medicines probably the quality of the health services.
Feeling better/feeling worse/feeling no better
Perceived severity of symptoms IS DIRECTLY OBSERVED THERAPY
Cultural THE ONLY STRATEGY FOR IMPROVING
Health beliefs TREATMENT CONCORDANCE?
Decision making power
The DOT is not the only method used for improving con-
Family and social support
Adverse events [e.g., death in the family] cordance with treatment. Many other interventions have
Contrary advice been promoted, and are summarized in Table 57.2. How-
ever, few of these have been rigorously evaluated, and a
Others
systematic review of different approaches to promote
Substance abuse
Disease [e.g., HIV/AIDS]
adherence to TB treatment was only able to find evidence
Pregnancy for following methods; reminder cards, monetary
incentives, health education, and intensive supervision
The heath service
of staff (25). The many different approaches to improving
National treatment policy
treatment concordance can also be categorized as policing,
Quality of health service
Attitudes of health workers manipulating, exhorting and empowering. Policing
Adverse effects of drugs methods include enforced hospitalization (26) and
Availability of drugs involuntary detention. Some methods are highly
Delivery of drugs to patients manipulative and ethically questionable, for instance
Follow-up of late patients
notifying community leaders, particularly in a culture
Availability of alternative sources of treatment
where TB carries a stigma. Exhortation, including health
Society education for patients (27) and supervision of health
Socio-economic status of the community workers (28) is of value, but these approaches alone gene-
Migration rally do not achieve satisfactory cure rates. Empowering
Educational opportunities
strategies, such as providing a flexible and responsive
Social and political stability
service, developing support groups and social networks,
The environment providing education and economic assistance, are less
Distance easy to develop within the framework of the existing
Season
health services, but provide the key to enabling greater
Methods of transport
concordance with treatment. Depending on the attitude
HIV = human immunodeficiency virus; AIDS = acquired of the personnel providing DOT, and the extent DOT is
immunodeficiency syndrome adapted to the needs of the patient, this strategy can be a
policing or an empowering approach to improving
Any assessment of causes of default must take into treatment concordance.
account the influence of bias. Many published reports The relationship between all the factors involved in
on treatment outcome come from programmes of promoting concordance can be summarized in the form
operational research, which tend to achieve good results. of a simple diagram, known as the “Hold Chain” [Figure
Studies of concordance from such programmes achieving 57.1]. Drawing on the model of the “Cold Chain”
830 Tuberculosis
Table 57.2: Interventions designed to improve treatment and “user-friendly”. The next key element is an effective
concordance regimen, to rapidly and permanently render patients
Treatment non-infectious, and relieve their symptoms without
Standardized regimens of short-course chemotherapy
creating adverse effects. The third link in the chain is
Intermittent chemotherapy DOT, to ensure that patients take treatment until they
Fixed-dose combination tablets are cured. However, good drugs can be misused if health
Blister packaging workers have not been trained how to use them appro-
Calender packaging priately, the fourth link, and will be totally useless if the
Education distribution system fails to procure and deliver them in
Patient counselling a timely fashion to treatment centres–the fifth link in the
Family counselling chain. The final link is education-a high quality service,
Mass media health education good drugs, treatment observers, skilled health workers,
Incentives and an efficient logistics system will be of little benefit if
Financial rewards to patients patients don’t know that medicines for TB are effective
Gifts in kind; lottery tickets, meal tickets, bus tickets and available, and must be taken for a full course of
Loans and economic aid treatment. Such knowledge will spread by word of
Bond and deposits mouth as patients are treated and cured, but can also be
Prepayment schemes
promoted by a programme of health education. Failure
Financial rewards to health workers
Micro-credit schemes to ensure the integrity of any single link will result in a
break in the chain, and loss of treatment concordance.
Operational
The term “Hold” refers not to holding the patient on
Directly observed therapy
treatment, but to holding the health services together!
High quality health services; accessible, acceptable and
appropriate to needs of individual patients and the local culture
Therefore, DOT is one essential link within a combination
Rapid follow up of late patients by health worker or letter of factors which together ensure that patients are given
Doorstep delivery of medicines the maximum opportunity to achieve a successful
Involuntary detention outcome of treatment.
Frequent supervision of health services
Community approaches HISTORY OF DIRECTLY OBSERVED THERAPY

Ex-tuberculosis patients motivating new patients
Community volunteers supervising treatment The history of DOT presents us with a remarkable global
Education of community leaders journey, which begins in Europe, and takes us through
Social incentives Asia, America, and Africa, before finally emerging as a
Treatment contracts [verbal or written] truly international approach to improving treatment
Family involvement concordance. Grange (29) suggests that the earliest
Support groups, self help groups, and social networks documented example of DOT for patients with TB comes
Notification of late patients to community leaders from the eleventh century, when King Edward, the
Certificate of treatment completion
Confessor would lay hands on the afflicted person and
declare “The king toucheth thee, but God healeth thee”.
promoted by the Extended Programme of Immunization A more conventional form of supervised treatment was
to maintain vaccines at the correct temperature from introduced in the 1840s, with the establishment of the
manufacture to the child, the Hold Chain is visualized sanatorium movement in Europe (30). Patients who were
as a series of factors which are inextricably linked. The admitted to these mountain sanatoria were isolated for
first essential component is a quality health service, long periods of time, and subjected to diverse and
which patients trust and use. Low utilization of govern- disciplined regimens of treatment. An early advocate of
ment health services is common in many developing supervised therapy and support to the patient wrote in
countries, as patients prefer to use traditional healers or 1904, “In the solution of the TB programme a plan of
the private sector, both of which may be more accessible supervised home relief must play a chief part” (31).
Figure 57.1: The Hold Chain
The discovery of effective drugs in the 1940’s trans- observations that influenced the development of a
formed the management of people with TB. Perhaps programme of supervised ambulatory care in Hong Kong
because of the long history of sanatorium treatment, the (37). The studies from India therefore, provide the earliest
first patients to be treated with streptomycin, and later example of modern conventional DOT utilising effective
para-aminosalicylic acid [PAS], were all hospitalized for treatment to ensure high cure rates in people with TB.
the full course of treatment (32). The importance of doctor However, the evidence that patients taking treatment for
compliance and of mutual support was emphasized even TB do not pose a threat to their families and communities
at this early stage in the development of TB treatment; a was the primary message that came across from the
footnote to the overview of the first three studies of Indian studies, and ambulatory treatment that was
combined chemotherapy praised the participating rapidly adopted around the developing world was often
clinicians thus; “Only by their constant adherence to a unsupervised.
centrally devised scheme, and by a most remarkable team From Asia we return to Europe, where the principle
spirit on a large scale have these investigations been of supervised treatment was adopted by Stradling and
possible” (32). Poole (38,39) in London, and then travel further west-
In the late 1950s the focus shifted to Asia, and Bayer wards to America, where the call for supervised treat-
and Wilkinson (33) take the story up from here in their ment was taken up by Sbarbaro (40), which he termed
history of DOT. The British Medical Research Council “directly administered” treatment. However, these were
[BMRC] studies conducted by Wallace Fox (34) in Madras lone voices, and the few others who practised supervised
demonstrated that hospitalization was not necessary to treatment usually reserved it for a selected group of
prevent transmission of disease. These findings led to a patients whom they regarded as most likely to default.
shift to ambulatory chemotherapy for people with TB in This was despite awareness of the difficulties in
most parts of the world. However, in an earlier article, predicting treatment concordance (41), a finding which
Fox (35) had identified the problems of poor compliance was confirmed 30 years later in New York (42). Those
with treatment, which later led him to conclude that who argued for “selective” DOT won through (43),
supervised treatment was essential and feasible (36), despite repeated calls for universal DOT (44). Even
832 Tuberculosis
though the United States of America [USA] adopted DOT prescribing health worker (54). However, the simple act
as the standard of care for all people with TB (45), argu- of observing treatment is clearly not the only factor
ments over selective and universal DOT have continued promoting a positive outcome of treatment. Simply
(44,46,47), and consequently has yet to achieve the global having someone to help and encourage you can be of
targets for TB control. The developed world still has much considerable benefit in promoting treatment concor-
to learn from developing countries! dance. Thomas Frieden, originally working in New York
We return to the 1970s to take up the story of DOT in and later with the RNTCP in India, has described the
the developing world. In 1974 WHO published the 9th value of the “human bond” between patient and health
report of the Expert Committee on Tuberculosis (48), worker, emphasizing the value of the social support
which proposed the use of a supervised regimen of provided by a treatment observer. Parallel studies in the
intermittent streptomycin and isoniazid, as a means for field of maternity care have demonstrated the benefits
ensuring patient compliance. However, the next major of a birth attendant to support the mother during labour
step forward in the history of DOT was the development (55). A more appropriate definition of DOT is, therefore,
of SCC regimens given under direct supervision in the a strategy to improve treatment concordance, in which a
International Union Against Tuberculosis and Lung responsible person who is accountable to the health
Disease [IUATLD] supported programme in Tanzania, service observes the patient taking medication correctly,
which was subsequently expanded to a further six and provides the support and encouragement needed
countries in Africa, and to Nicaragua (49). The Tanzania to complete a full course of treatment.
model, developed by Dr Karel Styblo, was based on This relationship between observer and patient helps
hospitalization of TB patients for the intensive phase of to explain why the effect of DOT extends beyond the
treatment. The reasons for doing so were significantly initial period of supervision. In poor treatment prog-
different from the early days; the emphasis was now on rammes, about half of the episodes of default occur in
supervision of therapy, and continuation of treatment the first two months of treatment. For example, 54 per
until the patient was cured. Over the last two decades, cent of defaulting patients attending a rural hospital in
universal hospitalization of patients has been largely Sind, Pakistan, did so in the first two months of treatment
abandoned due to a massive increase in the incidence of (56)–a result which led the authors to call for a
TB resulting from the acquired immunodeficiency synd- programme of supervised treatment. Programmes which
rome [AIDS] pandemic, and the inability of the health have implemented DOTS have been able to demonstrate
services to cope with the large number of patients. The that treatment concordance is maintained through the
principle that has been established is, therefore, not continuation phase, even if the frequency of contact with
hospitalization, but supervision of drug-taking. the health worker is reduced to as little as once every
The role of Dr Karel Styblo in the development of three months (57).
these innovative programmes cannot be understated. The
Countries which have introduced DOT have demons-
principles which evolved here were later adapted and
trated a profound and sustained increase in their
promoted by WHO as DOTS, and adopted in places as
treatment success rates. Cure rates in China were 52 to
diverse as China (50), Nepal (51), New York (52), and
58 per cent before the introduction of DOT, and rose to
India (53) as the Revised National Tuberculosis Control
89.7 per cent in newly diagnosed patients following the
Programme [RNTCP] from the early 1990s. We have,
establishment of a new project of DOTS (50). The
therefore, come full circle. The principles of modern TB
beneficial effects of DOT extend beyond a simple increase
control first developed in India in the late 1950s have
in the cure rate, and positively impact on rates of drug
travelled around the world, and finally returned home
resistance and relapse. In a retrospective study (58)
nearly 40 years later, as DOTS.
comparing 407 unsupervised treatment episodes from
1980 to 1986 with 581 treatment courses of DOT from
HOW DOES DIRECTLY OBSERVED
1986 to 1992 in Texas, USA, the proportion of patients
THERAPY WORK?
with primary drug resistance fell from 13 to 6.7 per cent,
It is well recognised that many patients [perhaps 50 per acquired drug resistance dropped from 14 to 2.1 per cent,
cent] do not take their medication as intended by the and the frequency of relapse declined from 20.9 to
5.5 per cent. The failure rate in previously treated patients Tuberculosis at the District Level” (61), is practised in
fell to 6.2 from 17.6 per cent, following the introduction several countries, for example, Botswana (62), China
of DOT in China (50). (50,63) and is the main method adopted in India,
The cost-effectiveness of ambulatory DOT has also Bangladesh and Nepal. Patients attend the health post
been shown. A study from the Hlabisa Health District in or treatment centre daily [or two to three times a week if
South Africa (59), compared hospitalization with taking an intermittent regimen] and a nominated treat-
ambulatory DOT, and demonstrated that the latter was ment supervisor at the health facility supplies the medi-
2.4 to 4.2 times more cost-effective. A study by Moore cines and watches them take the medication correctly.
and colleagues from Baltimore (60) compared three Completion rates of 83 per cent have been achieved in
different treatment strategies; DOT, unsupervised fixed- India (53), and as high as 92 per cent in Botswana before
dose combination [FDC] tablets, and unsupervised the advent of the HIV pandemic (62). China has achieved
individual tablets. Again, DOT proved to be the most remarkably high cure rates of 89.7 per cent (50).
cost-effective approach. Field-based health workers, such as Village Health
Workers and Community Health Volunteers are utilized
WHO OBSERVES TREATMENT? as treatment supervisors in some programmes, for
example, the TB control programme organized by BRAC,
Five different methods of delivering DOT have been
a non-governmental organization [NGO] in Bangladesh
described, which fit neatly into a hierarchy of supervision
(64). A female health volunteer receives a full course of
[Figure 57.2]. These are hospitalization; ambulatory DOT
treatment for the patient, and either takes the medicines
at a health facility; DOT by a field level health worker;
to the patient each day, or the patient comes to the health
DOT by a community member; and DOT by a relative.
worker. An alternative methodology utilizes specially
Those at the top offer a high level of accountability to
designated mobile treatment supervisors who observe
the health service but are relatively inaccessible for the
treatment at each patient’s home or work place. This
patient; the reverse is true at the bottom.
method has produced excellent results in several cities
Hospitalization of TB patients was widely practised
of North America, such as New York (52) and Baltimore
up to the 1960s and then abandoned in favour of
(65) where treatment supervisors provide a home
ambulatory treatment. It is usually restricted to patients
delivery service of DOT for patients who are unable to
with smear-positive TB, and is often limited to the first
attend a health facility. Few developing countries will
two months of therapy, or, until the patient becomes
be able to adopt this method, for the obvious reason of
smear-negative.
cost.
Ambulatory health facility-based DOT, as recom-
Community leaders have also been advocated as
mended in the WHO training materials “Managing
treatment supervisors. A programme in KwaZulu
utilizing a variety of different supervisors, including
health workers, storekeepers, teachers and other lay
people, has been extensively reported, with treatment
completion rates of over 80 per cent (66-68).
An attractive alternative to observation by health
workers is observation of treatment by family members.
This approach has been utilized in various programmes
in Asia, including Thailand and Nepal, but concerns that
family DOT could easily degenerate into unsupervised
treatment, have led some to call this sloppy DOTS! A
study carried out in several hill districts of Nepal
compared health facility-based daily DOT with family
or community-based DOT and no DOT (69). In the first
group, all patients had daily DOT supervised by
Figure 57.2: The hierarchy of DOT treatment centre staff during the intensive phase. In the
834 Tuberculosis
second group of treatment centres, 75 per cent of super- CHOOSING A DIRECTLY OBSERVED
visors nominated by patients were family or community THERAPY METHOD
members and 13 per cent of patients had no supervisor.
Does each of these approaches work the same? Are all
In the third group, 93 per cent of patients were unsuper-
equally effective? Assessment of the relative value of a
vised and received a monthly supply of medicines.
DOT strategy must be based on the outcome of treatment,
Treatment outcomes demonstrated a profound
with sputum conversion after two months of treatment
difference; cure rates for smear-positive patients were
for early evaluation, and cure rates as the final outcome
91 per cent in the first group, 57 per cent in the family or
measure. Other factors, such as cost, replicability and
community-based DOT group, and 34 per cent in the
sustainability may also be important secondary
unsupervised group. It would appear that the role of a
indicators.
family-based system should be to supplement DOT by a
In the absence of randomized controlled trials [RCTs]
method which provides more accountability, such as
of different DOT strategies, it is difficult to generalize,
DOT at a health facility.
but it would appear that the more accountable approa-
ches achieve higher cure rates. However, such studies
IS DIRECTLY OBSERVED THERAPY ESSENTIAL?
are difficult to interpret, as other confounding factors
The DOT is perhaps the most contentious aspect of DOTS, may be playing a part, such as pre-existing quality of
and arguments continue over the relative value of the health services, level of health worker supervision and
different components of an effective TB control support from NGOs. In contrasting studies of the
programme (7). Can a programme achieve acceptable cure effectiveness of community health volunteers in South
rates without DOT? Although many developed countries Africa, Dick et al (73) showed no additional benefit of
in America and Europe, and several rapidly developing volunteers in improving the treatment concordance of
countries in Asia have been able to demonstrate a decline adults, whereas Wilkinson and Davies (68) have reported
in the incidence and transmission of TB without using superior results from volunteers compared with health
DOT, the following statement from the WHO (70) still workers.
holds true “The only proven way of ensuring adherence Health workers who are opposed to DOT frequently
and achieving WHO global targets is through direct argue that this improvement in cure rates is at the cost of
observation of treatment. In some settings in some case-finding, and suggest that DOT will push people into
countries, other ways of closely supervising treatment taking unsupervised treatment in the private sector. In
have been tried. No developing country has so far fact the reverse is usually true, and case-finding often
demonstrated country-wide application of ways of super- initially increases following the introduction of DOT.
vising self-administered treatment under programme The choice of a particular DOT method depends on
conditions, with success rates equalling those when several factors, including the local socio-cultural
treatment is directly observed”. environment, and the capacity of the health service
In Nepal, unsupervised SCC has been used infrastructure (70).
extensively since the early 1990s. Results from NGO Economic considerations are clearly important, and
supported districts have been excellent, with treatment the ability to pay incentives to health workers who
success rates approaching or exceeding 85 per cent, even diagnose and treat patients until they are cured, such as
in remote and hilly situations. However, these districts in China (50), may be an important factor in encouraging
have received additional manpower and other resources high rates of treatment concordance. A well-developed
that could not be provided in routine programme health service with a high hospital bed to population ratio
conditions by the NTP. Where unsupervised SCC has may allow for hospitalization of patients, though it is
been used in programme conditions in Nepal, the WHO unlikely that many developing countries will be able to
targets have not been achieved (71). Four districts which provide this service for all patients, particularly if the
initially piloted DOT under programme conditions incidence of TB rises with HIV infection and AIDS. The
achieved the WHO target of 85 per cent cure rate (72), burden of disease clearly influences the choice of a DOT
and subsequently DOTS was expanded across the whole strategy, and is related to the total number of TB cases,
country. and the proportion attributable to HIV. In areas of high
HIV endemicity, where community-based care systems studies of antituberculosis treatment regimens were
involving family members, NGOs, and volunteers are conducted under conditions of direct observation of
active in providing care for people with AIDS, selection patients, unsupervised rifampicin containing regimens
of a DOT strategy should take into account these existing are, in effect, experimental! It will also be difficult to
support structures. The NGOs are generally good at conduct an RCT of DOT, the results of which can be
facilitating community participation, though problems generalized to other populations. The DOT is a manage-
remain in ensuring it is maintained, and in replicating ment tool not a drug. It is not a uniform, standardized
this involvement over larger areas. procedure which can be tested easily–there are many
Cultural factors may be significant, particularly where ways of doing DOT.
TB related stigma is common. In these areas a family- A third concern that has been expressed is that the
based system may be the most acceptable to the patient excellent results obtained in pilot projects may not be
and community, and other options that draw attention maintained as DOT expands throughout the country (76).
to the patient’s disease status may be less successful. In Evidence from other developing countries, particularly
cultures in which family members already play an the IUATLD-supported countries, and large countries
important role in providing health care, involvement of such as China (50) and India (53), have demonstrated
the family in providing support to the patient may be an that this is not the case. With good planning and
appropriate way of building on existing cultural norms management, DOT can be expanded to cover national
populations without compromising cure rates.
and values, such as providing DOT in the continuation
phase of treatment.
WHAT IS THE FUTURE OF DIRECTLY
CONTROVERSIES SURROUNDING DIRECTLY OBSERVED THERAPY?
OBSERVED THERAPY
Success with the rapid global expansion of DOT provides
Critics of DOT have claimed that it is paternalistic, and us with hope that the epidemic of TB can at last be
denies patients the right to consume their medicines in contained and eventually reversed. However, many
private (74,75). In contrast, Sbarbaro (40) has argued that challenges lie ahead. Where does the future of DOT lie
the public health rights of the community override the as NTPs endeavour to find more effective ways of
rights of the individual, and the responsibility of public controlling this disease?
health authorities to protect citizens from infectious First, the concept of DOT is expanding to include
diseases is clearly laid down in law. Milburn and treatment observers other than salaried health workers
Cochrane (22) further argue that patients who selectively in the government public health system. Health sector
take some medicines and not others, or erratically take reform, community-based care and rapidly growing
their treatment, are at risk of developing and spreading private health care services create opportunities for other
drug-resistant TB. As DOT has clearly been shown to categories of people to be involved in supervising
produce higher cure rates than unsupervised treatment, treatment. The rapidly growing HIV epidemic in Asia is
it is possible that patients who do not receive DOT could leading to changes in delivery of health services, and
sue their doctor for malpractice in societies where development of community-based support systems for
litigation is common! Arguments against DOT must take people with HIV and TB. The challenge will be to
into account the consequences of not implementing DOT, maintain the level of accountability required to ensure
and require discussions between experts in ethics, law, that patients are cured of their disease.
and public health, and include patient groups. Second, DOT is being further extended to ‘hard to
The second argument against DOT is that it is reach’ populations. These are populations with limited
unproven, i.e., there has been no RCT to demonstrate access to health services, often because of geographical
the efficacy of DOT (74). Although strictly true, it is hard isolation, social isolation, or civil unrest. Innovative ways
to accept this as a valid criticism in light of the cumulative of ensuring DOT for people living in mountainous
evidence of success with DOT in so many countries regions, island communities, and areas affected by snows
around the world. It is hard to see what additional and monsoons will have to be developed (77). Finding
evidence an RCT would provide. As most of the efficacy ways of implementing DOT in prisons (78,79), refugee
836 Tuberculosis
communities (80), and for homeless or nomadic nary tuberculosis in three sub-Saharan African countries.
communities also present different challenges. Lancet 1991;338:1305-8.
5. DeJonghe E, Murray C, Chuan H, Nyangulu D, Salomao A,
Third, the impact of successful DOTS programmes
Styblo K. Cost-effectiveness of chemotherapy for sputum
will be compromised considerably if the majority of smear-positive pulmonary tuberculosis in Malawi,
patients with TB continue to receive their treatment in Mozambique and Tanzania. Int J Health Plann Manage
the private sector. Ways of encouraging private doctors 1994:9;151-81.
and pharmacies to introduce DOT are being developed, 6. Kochi A. The global tuberculosis situation and the new control
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Fourth, DOT is becoming more efficient, and less
7. Squire SB, Wilkinson D. Strengthening “DOTS” through
time-consuming for the patient and the health care
community care for tuberculosis. BMJ 1997;315:1395-6.
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by the Global Drug Facility (81). Regimens are also for effective tuberculosis control. WHO/CDS/TB/2002.297.
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Fifth, the principles of DOT are expanding to other 10. World Health Organization. WHO report on the tuberculosis
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Finally, we must remind ourselves of the problems
13. Datta M, Radhmani MP, Selvaraj R, Paramasivan CN,
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66. Wilkinson D. High-compliance tuberculosis treatment
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Lancet 1995;346:948-9.
67. Wilkinson D, Davies GR, Connolly C. DOT for tuberculosis
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68. Wilkinson D, Davies GR. Coping with Africa’s increasing Royal Soc Trop Med Hyg 1995;89:241-2.
tuberculosis burden: are community supervisors an essential 81. Kumaresan J, Smith I, Arnold V, Evans P. The Global TB Drug
component of the DOT strategy? Trop Med Int Health Facility: innovative global procurement. Int J Tuberc Lung
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69. Mathema B, Pande SB, Jochem K, Houston RA, Smith I, Bam 82. De Cock KM, Wilkinson D. Tuberculosis control in resource-
DS, et al. Tuberculosis treatment in Nepal: a rapid assessment poor countries: alternative approaches in the era of HIV.
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supervision. Int J Tuberc Lung Dis 2001;5:912-9. 83. Wilkinson D, Anderson E, Davies GR, Sturm AW, McAdam
70. World Health Organization. Treatment of tuberculosis: KP. Efficacy of twice weekly treatment for tuberculosis given
Guidelines for National Programmes. WHO/TB/97.227. under direct observation in Africa. Trans Royal Soc Trop Med
Geneva: World Health Organization; 1997. Hyg 1997;1:87-9.
71. Onozaki I, Shakya TM. Feasibility study of a district tuber- 84. Woodward WC. Should DOT be considered for treatment of
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85. Laurence J. Ethical concerns in international HIV clinical trials.
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The AIDS Reader 1997;7:147-54.
72. Malla P, Bam DS, Sharma NR. Preliminary report of four
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Int J Tuber Lung Dis 1997;1:S69. chloroquine and high-dose primaquine therapy for
73. Dick J, Schoeman JH, Mohammed A, Lombard C. Tubercu- Plasmodium vivax malaria acquired in Guyana, South
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treatment. Tuber Lung Dis 1996;77:274-9. patients and physicians. Tuber Lung Dis 1995;76:277-8.
The Role of Medical Colleges in Tuberculosis Control 839
The Role of Medical Colleges

in Tuberculosis Control
58
Jai P Narain, E Cooreman, LM Nath
INTRODUCTION detection of infectious cases as well as high cure and

success rates (4). The DOTS coverage is almost world-
Tuberculosis [TB] continues to remain a major public
wide, compared to only 10 per cent in 1998 (5).
health problem, particularly in South and South-East
This success is possible through the emerging
Asia and sub-Saharan Africa. National Tuberculosis
partnerships in countries in the development of policies,
Programmes [NTPs] have made a major progress in
strategies and plans, in the delivery of services, in
recent years, but still there are many challenges that need
advocacy, communication and social mobilization. The
to be addressed (1).
NTPs are reaching out to other public and private health
Tuberculosis is a curable infectious disease. Control of
care providers in order to improve accessibility and
this communicable disease is possible through a policy
increase the reach of the DOTS services. Implementation
package branded under the name “DOTS”. While DOTS
of DOTS needs to be further widened, without compro-
was initially an abbreviation for Directly Observed Treat-
mising on the quality (1). Further acceleration in DOTS
ment, Short-course, “DOTS” the acronym has now become
expansion and enhancing TB control requires all sectors
synonymous with the entire strategy. Additional elements,
including medical colleges to play their roles,.
necessary for the management and control of multidrug-
resistant tuberculosis [MDR-TB], are part of a broadened
ROLE OF MEDICAL COLLEGES
strategy, known as “DOTS-Plus”. Implementation of these
strategies implies an organizational framework for Medical colleges play a specific, but important role in
effective utilization of the existing tools for diagnosis health care including TB control. Their role is focussed
[sputum microscopy to identify the most important group in four major areas: advocacy, education, service delivery
of patients, the sputum smear-positive pulmonary TB and research (6-8).
cases; and culture and drug susceptibility testing to In spite of the available knowledge and tools for
identify drug-resistant cases], treatment [standardized diagnosis and treatment, TB is still not diagnosed and
short-course chemotherapy] and treatment delivery treated properly in many parts of the world (9). There
through directly observed treatment [DOT] (2). are many reasons for this situation. In several instances,
The DOTS has been recognized as one of the most doctors are to be blamed for poor diagnosis [e.g.,
cost-effective health interventions available today (1-3). inappropriate use of radiology, inadequate use of sputum
Many countries have included the delivery of DOTS microscopy] and treatment [e.g., prescription of
services as a component of essential services packages ineffective and inadequate regimens]. Incorrect doses and
to be made available as a part of primary health care. drug regimens are sometimes prescribed and the
All countries in South-East Asia which have adopted treatment is given for an inadequate period. Patients are
this World Health Organization [WHO] recommended not monitored during the treatment. Neither patients nor
TB control strategy, are showing improving trends in their families are informed about the disease, its
840 Tuberculosis
transmission or treatment. Contacts of smear-positive “Care provider”, who considers the patient holistically,
cases are often not checked. Although the situation is as an individual, as part of a family and as part of the
improving, these weaknesses are still common parti- wider community; and who provides high quality
cularly in the non-DOTS areas, both public and private continuing care within a doctor-patient relationship
(9,10). based on mutual respect and trust;
As a result of this, an enormous amount of resources “Decision maker”, who chooses which technologies to
may be wasted on misdiagnosed or mismanaged
apply in enhancing care in an ethical and cost-effective
patients. The inadequate use of antituberculosis drugs is
fashion.
increasingly leading to the emergence of multidrug
resistance. “Communicator”, who is able to promote a healthy
It is therefore essential to improve the knowledge of lifestyle by effective explanation and advocacy
medical graduates about TB and to train them to acquire appropriate to the cultural and economic context, thereby
the skills necessary for the proper diagnosis and empowering individuals and groups to improve and
management of TB in an individual patient and in the protect their health.
community (11,12). The expanded DOTS strategy will “Community leader”, who having gained local respect
not succeed unless medical practitioners can be trained and trust, can reconcile individual and community health
to manage TB properly. The active participation of requirements and initiate action on behalf of the
doctors in TB control will lead to a change in the attitude community.
of other health care providers and their involvement will
“Manager”, who can work efficiently and harmoniously
be more easily obtained (13-15).
with individuals and organizations inside and outside
Medical colleges must adapt and use their potential
the health care system to meet the needs of patients and
to contribute proactively to shaping the health system.
communities.
By introducing changes in the medical education,
To fulfil these roles, the medical colleges should
research and delivery of care for TB control, medical
provide every medical graduate with the knowledge,
faculties have the unique opportunity to demonstrate
skills and attitudes essential to the management of TB in
their social accountability.
the patient and in the community as a whole. The medical
college should have an effective educational strategy to
Advocacy
provide such ability. The results of the educational
Involvement of medical colleges to support the imple- process should be adequately assessed and evaluated
mentation of the expanded DOTS strategy aims in the before the medical student is allowed to graduate as a
first place at creating an additional constituency of doctor.
support. The senior teaching staff in medical colleges are Specific and essential knowledge, skills and attitudes
generally very influential and respected in the commu- that must be imparted to doctors before they leave the
nity. They can support TB control from different angles. medical college are listed in the Table 58.1.
As captains of health, they facilitate political, legal and The implementation of TB control services is witness-
social change for better treatment of TB patients; as ing a shift from vertical set ups to partially or fully
opinion makers among medical professionals, they are in integrated general health services. Similarly, with regard
a position to effect attitudinal changes. Through acting to health professional, a shift is taking place from the
as role model for medical and paramedical students, they traditional view of human resources development [HRD]
impart a “zeal” among them. And finally, as resource as the organization of a few basic training courses,
persons with access to the latest information, they seldom taking into account educational principles,
continuously update themselves, disseminate correct towards a clearer understanding of HRD more broadly
information and lead the media. in the context of health systems and the subsequent need
to work on the quality aspects of HRD for TB control.
Medical Education Different types of training can be distinguished: pre-
The doctors of the future should possess the following and in-service training. Pre-service training includes the
five aptitudes and should take up their responsibilities training usually provided by medical, nursing or
as a:
Table 58.1: Specific and essential knowledge, skills and available resources, the arrangement of how, when and
attitudes to be imparted to medical students where should be determined by the best possible learning
Basic science of TB process: students should in optimal conditions and
Transmission of the TB bacillus in humans and the immune
circumstances acquire all required competencies as
response efficiently as possible. In the case of TB, how, when and
TB bacteriology where are interdependent. Three educational options can
TB histology be chosen: sequential, fully or partially integrated.
TB in the individual patient
Pulmonary TB in adults
Sequential
Extra-pulmonary TB This has been and is the most widely used form in
Specific aspects of childhood TB
different medical colleges in India, with basic scientific
TB and HIV infection
Treatment and biological aspects taught in the earlier part of the
Prevention curriculum. Traditionally, clinical training comes later.
Public health training is often offered at a separate time,
TB as it affects the community
early, middle or late. Whilst sequential training is easiest
Epidemiology of TB
National TB programme principles
for the teachers, it can leave the student with disjointed
Organization of treatment knowledge and skills, unless substantial time is devoted
Organization of case-finding towards putting together several elements in a “revision
Prevention of TB disease and infection course”.
Evaluation of national TB programmes
TB = tuberculosis; HIV= human immunodeficiency virus Fully Integrated

In this option, modular training is provided in a fully
laboratory colleges. In-service training can be in the form integrated manner. The biomedical and scientific
of initial training [for staff that were not trained in the elements can be integrated with clinical and public health
particular subject before]; advanced training [for selected training, either as part of a module devoted entirely to
staff with higher responsibilities]; retraining [for staff TB or as part of a module devoted to respiratory diseases,
already trained and based on identified needs] and in general. Although modular training is optimal for the
training on new interventions such as MDR-TB, TB and student, considerable reorganization and institutional
human immunodeficiency virus [HIV] co-infection. change is likely to be necessary to implement such
Medical colleges will focus in the first place on pre- training. There is a trend that more and more subjects
service training, i.e., they train the future doctors, after are taught in a modular way.
which they will graduate and start working as medical
practitioners. Medical colleges get increasingly involved Partially Integrated
in in-service training, where the NTPs makes use of the
Some medical colleges provide integrated modular
faculty and training facilities of medical colleges or
training in the fundamental biomedical subjects early in
specialized TB institutes for offering advanced or
the curriculum and follow this in later years with
refresher training for NTP selected staff or as part of a
integrated clinical and public health modules for TB. This
continuous medical education programme. Distant
should be considered as a transitional compromise, the
education programmes are also being developed, with
optimal eventual aim being fully integrated modular
courses being offered in tailored modules.
training.
Within each option, different approaches can be
EDUCATIONAL STRATEGY
considered, such as plenary ex-cathedra lectures in the
Having defined the required knowledge, skills and classroom or lecture theatre; lectures in smaller groups,
attitudes necessary for the twenty-first century medical problem-solving exercises, simulation or role play
professional in TB control, it must be defined how, when exercises, practical work, projects, reading of reference
and where that education should take place. Within the works, text books or specially prepared materials, use of
842 Tuberculosis
audio-visual techniques, among others. Whenever number of students and pressure of work in the hospital
possible, the approaches which favour the active parti- which may make clinical examination as a part of final
cipation of a maximum number of learners should be examinations difficult in some situations. Also possible
preferred. are the assessment of managing patient problems in the
The sites of learning can and should vary. The practical settings, including assessment of training in the
precinct of the medical college is obviously a major site community which should form part of the final exami-
but teaching about TB should also be provided within nation.
chest or general hospitals, usually but not exclusively at Another valid and much favoured method is a
the bedside. Students should also experience and learn constant day-to-day evaluation, with appropriate feed-
about TB at sites in the community. These could include back, of students as they face real and contrived experien-
rural and urban practice area clinics, primary care sites ces during the course of their training. Such continuous
and private health facilities in collaboration with selected assessment could be best used as a method of formative
general practitioners. Distant learning includes that the assessment to promote students learning.
students study at their own pace, usually at their own Finally, it is necessary to bear in mind that no assess-
place. A tutor is assigned who will guide the student from ment method is perfect. Each has advantages and
a distance and get feedback through correspondence. Site disadvantages. Therefore, it is always necessary to use a
visits can be included in distant learning packages. variety of methods. The selection of method should be
Appropriate assessment of students is important for based on the objectives of the course, economy of time
the following three reasons. It is essential to make sure and expense, reliability and validity of the instruments
that medical students at the time of graduation have and the value as a learning tool for the students. Variety
achieved the objectives of the particular course, in this is inevitable in view of the diverse topics being tested
case related to the management of TB in all its manifes- and because it is envisaged that many different depart-
tations including when associated with HIV. Assess- ments of the faculty will be involved. The overall objec-
ments will motivate students and encourage them to tive of producing a doctor competent and confident to
work harder. Assessments can also guide the teachers handle the diagnosis, therapy and overall management
and the students about which part of the course has been of the patient, family and community will be the
successful and which part needs to be improved. collective responsibility of the medical college and not
Traditionally, the assessment has been by conducting of any single department. However, the brunt of the
an examination, which is mainly centred on the theoreti- responsibilities in TB control will lie with the depart-
cal knowledge. The examination can be in the form of ments of microbiology, medicine and other clinical
multiple-choice questions or essay type questions. specialties and community medicine.
However, this does not lead itself to the assessment of
practical skills. There is a need to assess the attitudes and
SERVICE DELIVERY
the ability of young graduates to handle persons who
suffer from the intense trauma of being diagnosed with Major tertiary hospitals are linked to medical colleges.
a stigmatizing, but curable disease. As it is envisaged In addition to their referral function for a large area, they
that different departments and disciplines in the medical may also cater as primary health care facility for people
faculty will be involved in teaching a wide variety of living in the immediate catchment area. These referral
essential elements identified, it is inevitable that a range centres tend to see a more diverse spectrum of pathology,
of student assessment methods will have to be used. The making it more straightforward for students to come in
selection of the most appropriate method of assessment contact with different forms of TB in a relatively short
will depend on validity, reliability, quality and feasibility. time. While the routine TB cases are diagnosed and
The objective structured clinical examination [OSCE] managed in the more peripheral health facilities, difficult
and the objective structured practical examination diagnostic cases and in particular pulmonary smear-
[OSPE] have many features that will help teachers to negative and extra-pulmonary cases, patients co-infected
determine students’ competencies, skills and attitudes. with HIV and childhood TB are relatively over-represen-
However, there may be practical difficulties, such as the ted in the setting of a medical college hospital.
In recent years, NTPs in South and South-East Asia Table 58.2: Involvement of medical colleges in the Revised
have set up TB management units or “DOTS corners” National Tuberculosis Control Programme in India
(16,17). While diagnosis and clinical care is provided In order to streamline the activities of the medical colleges, a
through the clinician, the DOTS corner provides the National Task Force, five Zonal Task Forces and several State
management of the TB patient: patient registration, classi- Task Forces were set up. A core committee has been set up in
fication, follow up, drug supply, referral to a peripheral each medical college with representatives from the faculty and
the RNTCP
health facility and maintenance of records. This DOTS
corner, usually reporting to the district TB officer, thus, The Central TB Division is piloting a “referral for treatment”
mechanism aimed at developing a seamless RNTCP service
provides the vital link between the public health TB between medical colleges and general health services. The
control programme and the individual clinical care RNTCP provides the human resources and logistic support
provided by the hospital in- or out-patient departments. needed to implement and coordinate activities in medical college
The availability of a “demonstration centre” within the hospitals. Laboratory consumables and drugs as well as funds
precinct of a medical college hospital allows an imme- for facility upgradation are being made available. Medical
colleges provide the necessary space, designate faculty mem-
diate exposure to one model of delivering NTP services.
bers for supervision, and avail of staff sensitization programme.
The medical faculty is a primary resource for
By the 2nd quarter of 2008, 263 of the 277 medical colleges
providing technical support for the implementation of have been involved. Medical colleges contribute 15% to 20%
DOTS services within the medical college hospital. Other of the overall number of cases
hospitals, affiliated to or working in close collaboration
RNTCP = revised national tuberculosis control programme;
with medical college hospitals, will also directly benefit
TB = tuberculosis
from this technical support. The medical college and its
hospital serves as training and referral centre. Through
been undertaken or are underway through the involve-
its network with other hospitals, it can assist in ensuring
ment of medical faculties in the WHO South-East Asia
quality of services, including laboratory services. They
region, especially in India. Results from locally
can contribute to the development of guidelines, policies
undertaken research activities will contribute to the global
and strategies, tailored to the needs of the programme
body of evidence in a relevant way. Through research,
and the character of a tertiary hospital. They can provide
evidence is generated which will provide the basis for
assistance with planning, monitoring and reviewing of
making new policies or updating strategies and guide-
TB control efforts. They can also play a role in disease
lines.
and drug resistance surveillance.
The WHO, NTPs and other stakeholders [including
In the context of increasing spread of HIV, medical
medical colleges] are setting the research agenda that will
colleges can play a crucial role in developing a holistic
lead to the best use of currently available diagnostic and
approach to address the issue of HIV-TB co-infection
treatment tools as well as the development of new
[Table 58.2] (18,19). Building a supportive environment
diagnostics, drugs and vaccines. The NTPs in many
starting from the setting of the hospital may have a much
countries are now seeking partnerships with prominent
wider impact. Reducing transmission of HIV and TB
national and international agencies.
within health facilities should be part of the general
Operational research contributes to an improved
infectious control measures applied in large hospitals.
performance of the TB programme, as well as strengthen-
Both the in- and out-patient departments will provide
ing of the health structure. Laboratory quality assurance,
TB curative services. The involvement of the community
integrated care for AIDS patients suffering from TB, drug
health department may also foster community-based
management and surveillance are some examples that
treatment and care for people living with HIV and TB.
will benefit the health system as a whole.
RESEARCH MANAGING MEDICAL EDUCATION AND PRACTICE
Medical colleges traditionally play an important role in
Tuberculosis Task Force
research. Their academic nature implies conducting both
fundamental and operational research in many fields, To respond to the urgent need for students to be properly
including TB. Several operational research projects have trained in TB, a “TB Task Force” should be set up in each
844 Tuberculosis
medical to plan a proper curriculum and teaching Implementation of Tuberculosis Control in Medical
strategy. The Task Force should ensure that: [i] essential Colleges: Indian Experience
knowledge and skills are covered by every teacher in
Medical colleges have been actively involved in the
their respective fields of TB teaching or training; [ii] evalu-
implementation of the Revised National Tuberculosis
ation covers essential knowledge, skills and attitudes;
Control Programme [RNTCP] of the Government of
[iii] progress is made towards the ideal of integrated
India since 2001. This unique experiment has generated
modules, which move from integrated teaching to
a tremendous response and the medical colleges have
integrated learning; and [iv] the content of the curriculum
contributed to nearly 15 to 20 per cent of the overall
and the systems of evaluation are updated according to
number of TB cases diagnosed and treated with DOTS
priorities in the NTPs (20,21).
(22-24). They have shown their involvement in treatment
The composition of the Task Force should be decided
of HIV-TB co-infection. In the future, their continued
locally. It should, however, include a bacteriologist,
involvement by adopting the DOTS-Plus strategy, will
histopathologist, chest physician, radiologist, infectious
help in prevention and management of MDR-TB and
disease physician, a public health physician or official as
XDR-TB (25). In the scenario of developing countries,
well as a representative of the students.
teaching hospitals attached to medical colleges and
The Task Force, through consensus, should agree to
tertiary care medical institutes appear to be excellent
a proposal regarding changes and improvements
places for education of medical students and conducting
requirements. It should then strive to obtain consensus
operational research relevant to the NTPs (22-24).
within the medical college, and particularly the
curriculum development committee or analogue body.
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Public-Private Mix for
Tuberculosis Control
59
Mukund Uplekar, Knut Lonnroth
THE DIVERSE MIX OF HEALTH CARE PROVIDERS speciality centres, such as chest clinics and general public
hospitals. In spite of being a part of the public sector,
In most countries with a significant burden of tuber-
these providers do not always coordinate with NTP or
culosis [TB], DOTS implementation for TB control has
apply DOTS. Many countries have networks of health
been limited largely to public sector services under services for their specific worker populations, such as
National Tuberculosis Programmes [NTPs]. In reality, those run by social insurance organizations or public
however, many patients with symptoms of TB, including sector undertakings like military, railways or mines.
the very poor, do seek and receive care from a wide Private industries may also offer health services for
variety of health care providers outside the network of employees. Provision of diagnosis and treatment by these
NTP services (1). Studies in India, for example, have private and public providers, who manage sizeable
shown that in urban and rural areas alike, 50 to 88 per proportions of TB patients, are often non-standardized
cent of TB patients’ first contact was a private provider and lack an evidence-based approach. Thus, the TB
(2,3). Various factors such as gender, stigma, convenient patients they serve are not only deprived of the benefits
location, indirect costs such as loss of wages, transport of DOTS but are also subject to mismanagement which
costs, etc., and patient perception of the NTP care played could contribute to a growing incidence of multidrug-
a major role in determining the patient’s decision to first resistant-TB [MDR-TB] or extensively drug-resistant TB
visit a non-NTP provider (4). The NTP services were not [XDR-TB] (5) and undoing the TB control efforts of NTPs.
preferred due to inconvenient opening hours, long wait- Since the introduction of DOTS in the early 1990s, a
ing times, lack of information and patient perceptions of great deal of progress has been made in global TB control.
poor quality of care at government hospitals and DOTS However, the global TB targets-detecting at least 70 per
centres (2). cent of the infectious cases and curing 85 per cent of them
The magnitude and the role of non-NTP providers, were missed twice, first in the year 2000 and then in 2005,
both private and public, vary greatly from country to signalling that TB control efforts, although impressive,
country. Some countries have a large private medical were not sufficient. It became clear that the Stop TB
sector that provides services to all segments of Partnership targets and the TB related Millennium
population, rich and poor. Private providers also include Development Goals [MDG] of halving the prevalence
practitioners who may not be formally qualified, such and mortality of the disease by 2015 would not to be met
as traditional healers in rural areas and informally trained if current efforts were not intensified. This led to the
practitioners in urban slums. Civic groups working with development of the new Stop TB Strategy of the World
disadvantaged communities and non-governmental Health Organization [WHO]. Systematic involvement of
organizations [NGOs] provide TB care in many countries. all relevant health care providers in delivering effective
Urban areas in most countries have a mix of public sector TB services to all segments of the population is among
providers, which include medical college hospitals, the essential components of the Stop TB Strategy (6,7).
Public-Private Mix for Tuberculosis Control 847
PUBLIC-PRIVATE MIX from NTPs, professional medical and nursing societies,

academic institutions, NGOs, HIV-focussed
In order to address this apparent weakness of exclusion
organizations, and to create peer pressure for providers
of a large proportion of health care providers from efforts
to conform to the principles of PPM as well as to serve as
to control TB, WHO and partners embarked the Public-
the basis for pre-service and in-service training.
Private Mix [PPM] for DOTS [PPM DOTS] initiative in
Professional societies and associations in many countries
the mid 1990s. The term ‘PPM DOTS’ represents a
including India have endorsed ISTC and are working
comprehensive approach to engage all relevant health
with the NTPs to put them in practice (Philip Hopewell,
care providers in DOTS implementation. It encompasses
personal communication).
all forms of public-private [between NTP and the private
sector], public-public [between NTP and other public
THE PUBLIC-PRIVATE MIX EVIDENCE BASE
sector care providers] and private-private [e.g., between
an NGO or a private hospital and the neighbourhood A considerable amount of knowledge and field expe-
private providers] collaboration for the common purpose rience on how to undertake PPM for TB care and control
of ensuring provision of standard TB care in a now exists. The WHO conducted a global assessment of
community. the role of private providers in TB control in 1999-2000
In 2001, the global DOTS Expansion Working Group (5). The assessment helped to both underscore the need
[DEWG] of the Stop TB Partnership established a and identify possible approaches for NTPs to work with
subgroup on PPM for DOTS Expansion [PPM Subgroup] the private sector to initiate and sustain productive
with its secretariat based in WHO, Geneva. The subgroup collaboration. As a second step, WHO helped to set up
has helped develop practical tools for PPM (8). It has also or formalize local PPM initiatives at diverse sites in Asia
enabled the development of new PPM initiatives in and Africa during 2000-2002. A systematic documenta-
several settings, reviewed and discussed barriers to scale tion of processes and outcomes of these and other projects
up PPM, helped conduct systematic documentation and provided evidence for their feasibility and effectiveness
evaluation of processes and outcomes of PPM projects (8,14-17).
to provide evidence for the feasibility, effectiveness and World Health Organization and the partners of the
cost effectiveness of PPM (9-11). PPM subgroup have since continued to conduct
Originally, PPM was a strategy for DOTS expansion. operational research on a large number of PPM projects.
However, PPM is also relevant for improving manage- To date, over 50 PPM initiatives have been implemented
ment and control of MDR-TB including XDR-TB as well in 14 countries, of which over 30 have been evaluated,
as for expanding TB and human immunodeficiency virus these include diverse projects linking NTPs to various
[HIV] collaborative activities. To reflect this, the PPM care providers, like non-qualified village doctors,
subgroup has re-labelled PPM DOTS to “PPM for TB care informal and formal private practitioners, private general
and control”. practitioners, specialist chest physicians, public and
“Engaging all care providers” is one of the new and private hospitals, and NGOs. Treatment outcomes have
essential components of WHO’s Stop TB Strategy been evaluated for over 20000 TB patients in 15 initiatives.
launched in 2006 (6). It is also a prominent element of Treatment success rates in the projects that provided
the Global Plan to Stop TB 2006-2015 developed by the drugs free of charge to patients were between 75 and 90
Stop TB Partnership (12). Many countries are now scaling per cent. The impact on case detection has also been
up PPM in line with the Stop TB Strategy and the Global evaluated in several PPM initiatives. All these initiatives
Plan. Addressing and expanding PPM for TB care and have shown an increase in case detection ranging from
control should get a further boost by the recently develo- 10 to 60 per cent (18).
ped International Standards for Tuberculosis Care [ISTC] Cost and cost-effectiveness analyses undertaken for
(13). These standards address the basic elements of three well-established initiatives in India showed that
diagnosis and treatment of TB with a series of straight- DOTS delivered through a variety of public and private
forward statements that are backed by evidence. ISTC providers was at least as cost-effective as DOTS delivered
could be used to secure a broad base of endorsements exclusively by the public health sector, and that the
848 Tuberculosis
approach was much more cost-effective as compared Table 59.1: Some categories of health care providers who
with TB treatment provided in the conventional non- manage tuberculosis symptomatics and patients
DOTS private health sector. Moreover, PPM significantly Public health care providers
reduced the financial burden on TB patients [mainly by General hospitals
providing drugs free of charge] and facilitated their Speciality hospitals and academic institutions
access to quality TB care (14,15). Data from Bangladesh, Health institutions under state insurance schemes
Health facilities under government corporations and ministries
India and Myanmar indicate that PPM helps to reach
Prison health services
the poor when providers used by them are also involved Army health services
(19-21).
Private health care providers
In conclusion, evidence emerging from the field shows
Private hospitals and clinics
that PPM for TB care and control is a feasible, productive Corporate health services
and a cost-effective approach to improve case detection Non-governmental organization hospitals and clinics
and treatment outcomes as well as to foster equity in Individual private physicians, nurses, midwives, clinical
access to care and financial protection for the poor. officers, etc.
Pharmacies and drug shops
Practitioners of traditional medical systems
IMPLEMENTING PUBLIC-PRIVATE MIX Informal, non-qualified practitioners
World Health Organization with the help of the PPM
subgroup has developed a guiding document to help countries depending on nature of the provider mix, their
countries develop national PPM strategies and opera- willingness to take on different tasks, the status of NTP,
tional plans (18). The document, the essence of which is patient preferences, and the health regulatory frame-
summarized below, does not provide a blueprint for work.
implementing PPM, but sets out the essential steps To illustrate, an NTP should be in a position to carry
required to develop national PPM strategy and out all the tasks; a medical college or a public, voluntary
operational guidelines. Country adaptation is essential or private institution may also be able to undertake most
to identify the most suitable model. The standard country clinical and public health tasks. Individual providers
level PPM approach, therefore, involves three major including pharmacists and non-physicians may be able
steps: [i] conduct a situation assessment; [ii] develop to refer suspects and, at times, supervise treatment while
operational guidelines; and [iii] implement. trained physicians could diagnose and categorize
patients as well as initiate treatment. The NTP would be
National Situation Assessment expected to fill the gaps and weaknesses by supporting
The steps involved in a situation assessment includes to: or taking on the tasks those other providers are unwilling
[i] make a list of all health care provider groups including, or unable to carry out. In all settings, it is essential that
for example, public, voluntary, academia, private- NTP is responsible for covering the main part of the cost
qualified, private non-qualified, etc.; [ii] determine if they of diagnosis and treatment. As a minimum, NTP should
are presently linked with NTP and, if so, what is their provide anti-TB drugs free of charge to providers who
current role in TB control; [iii] assess what potential should dispense them free of charge to patients. The NTP
contribution the providers can make; and [iv] identify should also develop and maintain strong stewardship
input required to optimize their contribution. capacity to guide and oversee the newly joined private
It is essential to map out all relevant public and and public providers. The generic PPM model [Figure
private health care providers in a given setting and 59.2] entails that the government-run NTP assumes the
identifying suitable roles for different providers in TB responsibility of funding, regulating and monitoring,
control. Table 59.1 lists possible providers types to map while the day-to-day collaborative implementation may
out. Figure 59.1 provides an example of options for task be carried out by the local unit of NTP itself or by relevant
mix and role division for different types of providers. non-NTP providers.
The scheme depicted in this figure is only a suggestion, In order to ensure that all relevant stakeholders are
and the suitable task mix will vary across and within involved in developing a national strategy for PPM, the
Figure 59.1: Indicative task mix for different provider categories. Shaded cells correspond to tasks
that could be taken up by respective provider type
TB = Tuberculosis
NTP should constitute a task force, coalition or coordi- Developing Operational Guidelines
nation committee with broad representation of various
groups as indicated in Table 59.2. This body can act as National policy and operational guidelines on PPM
an interface between NTP and other providers. It may should be developed and implemented as an iterative
also advise NTP in carrying out various tasks, such as process: policy leading to preparation of operational
advocacy, sensitization, training, supervision, quality guidelines to help phased implementation and results
control, monitoring and evaluation. In some settings, the of implementation feeding back into policy for any
issue of diagnosis of smear-negative and culture-negative revision required. Developing and using draft policies
forms of TB has been effectively addressed by establish- and guidelines first may facilitate rapid implementation.
ing diagnostic committees comprising relevant local Based on experience and evidence gathered, subsequent
experts. revisions may be undertaken.
850 Tuberculosis
Defining the Task Mix for Different Providers

Building on the situation assessment discussed above
[Figure 59.1], roles and responsibilities for different
providers need to be clearly defined, while providing
different options so that the guidelines provide sufficient
flexibility for local adaptation.
Developing Practical Tools to Help Implementation

The examples of practical tools include laboratory request
form, referral-for-treatment form, feedback or back-
referral form, transfer form, laboratory register, TB
register and the TB treatment card. Most of the tools could
be adaptations of those used routinely by NTP.
Figure 59.2: Generic PPM model. A generic PPM structure
emerging from PPM DOTS field projects. The national government
Develop a Training Strategy
formulates a PPM policy in consultation with the stakeholders. A The training strategy should be based on the defined task
co-ordination mechanism helps to bring the public and the private mix, and target NTP staff as well as various provider
sectors together, agree on implementation schemes and maintain
types to be involved.
dialogue. A local DOTS agency-public, private or voluntary-
implements DOTS through a network of willing health care providers
Developing Standards for Certification of Providers
in an area
PPM = public-private mix; PP = private provider; While the criteria for certification and de-certification
MoU = memorandum of understanding
should be related to the specific task options for
respective providers, these criteria should be similar for
Table 59.2: Public-Private Mix, DOTS:
stakeholders at national, provincial and local levels the public and private sectors. The certification may be
informal initially and may gradually evolve into a formal,
Ministry of Health, its departments and sub-national counterparts
standardized procedure.
Other ministries such as Ministries of Labour, Interior, Defence,
etc.
Developing Incentives and Enablers
Health insurance organization
Drug regulatory authority Financial compensation may be necessary for providers
Academic institutions who manage a large number of TB suspects and cases.
Social welfare programme for the poor and marginalized However, evidence shows that individual private
Professional organizations practitioners who have few TB patients at any time, and
Hospital associations, Pharmacy associations etc. voluntary organizations providing TB care may find in-
National and international NGOs involved in TB service delivery kind, non-monetary incentives sufficient to enter into
Drug industry collaboration with NTP (22). Some examples of effective
Consumer organizations non-monetary incentives include: access to free TB drugs;
an opportunity to serve society through free care for the
NGOs = non-governmental organizations; TB = tuberculosis
poor; access to free training and continuing education;
There are seven essential elements of operational free microscopy services, opportunity to deliver high
quality services; recognition due to formal association
guidelines for PPM. These are described below.
with a government programme; and potential to expand
Formulating Objectives business as a result thereof.
These may include: [i] increase in case detection;
Monitoring and Evaluation Plan
[ii] improved treatment outcomes; [iii] improved access
for the poor; and [iv] reduced financial burden for It is important to monitor the process of PPM in relation
patients. to defined objectives and evaluate the process in order
to fine-tune PPM strategies and implementation plans of the nature of individual and institutional providers, a
in a stepwise manner. first contact with the providers will be required to
understand their current and potential contribution to
Implementation Proper TB control. During these visits, relevant NTP staff should
also provide general information about the local TB
As discussed above, the national guidelines need to be
programme and convey the desire to begin collaboration.
flexible enough to allow for local adaptation, the logical
Information obtained on different providers during the
steps of which are: [i] preparation; [ii] mapping and first
prioritization of providers for active collaboration and
contact with providers; [iii] selection of providers; [iv]
their training are important steps that require serious
implementation proper; and [v] advocacy and communi-
cation. thought in local implementation. Some common
principles should be given consideration. Institutional
Preparation providers are likely to give a higher yield of cases but
will also require greater time and attention on the part
A clear, written message from the top NTP management of senior NTP staff. These may include medical colleges,
on the importance and priority of PPM is the first pre- general public hospitals, corporate health care institu-
requisite before local implementation begins. Operational tions, institutions under health insurance organizations,
guidelines, including guidance on local implementation, among others.
should preferably be made available. Draft sensitization Private practitioners may not be handling a large
and training materials should be ready for use. The number of cases individually but it may be possible to
implementation tools, including any new formats and identify and target first the ones handling a large number
adapted NTP registers and reports, should be handy. of suspects and cases. Chest physicians with large
Most importantly, NTP staff must be oriented about PPM; practices may belong to this category. Since private
their tasks and responsibilities should be defined and a practitioners may be the first port of call for most people,
plan of implementation should be available according involving them will have additional benefits like
to locally defined objectives for PPM. A local task force, reducing diagnostic delay and cost of care for patients.
equivalent to national task force, may be established to The poor are likely to first approach NGOs operating in
engage all relevant partners in planning and implemen- poor areas, non-physicians like pharmacists, non-
tation at local level. Such a local task force might also be qualified providers and traditional healers. Approaching
given operational responsibilities towards sensitization, these types of providers might help in providing the poor
training, supervision and quality control. with better access. In some communities, female patients
may prefer female care providers. Involving female care
Mapping on Local Level and providers may help to address gender differentials in
First Contact with Provider case detection. Involving other public sector institutions
The local NTP unit should have a map of its area to enable within and outside the Ministry of Health may require a
marking of all public and non-public providers on it. In parallel process of getting approvals and directives from
many settings and in large urban areas, such maps may their top regional or national management. After initial
have to be prepared with a physical listing and verifi- mapping, first contact and sensitization, it should be
cation of all types of health care providers. Other public possible to identify tough-to-tackle providers. It is
health and development programmes and NGOs worthwhile making a beginning with willing providers
working in the local area may be able to assist in this before spending energies on those reluctant to
task. In dealing with private providers, using a neutral collaborate.
interface such as a local NGO or a civil society institution
Implementation Proper
has been found to expedite both provider enrolment and
programme implementation. Depending on the local The method of launching PPM locally will vary from
context and resources, mapping, making the first contact setting to setting. A proper launch with fanfare may be
with the provider and sensitization may or may not be inspiring to both NTP staff and other care providers and
combined. While mapping will provide a general idea may boost their initial commitment. In the beginning,
852 Tuberculosis
PPM should be seen by both public and private counter- collaboration open and transparent and may also help
parts as a ‘learning- by-doing’ exercise. A key require- minimize the possibilities of misuse and malpractice. The
ment, therefore, for NTP staff in particular, would be to NGOs with expertise in communication and social
give a fair amount of time and input patiently before mobilization may provide useful assistance in
expecting great outcomes. It is important that NTP staff communicating with both providers and patients. Locally
stick to their commitment and diligently follow whatever appropriate advocacy and communication methods and
is mutually agreed upon. The referral routines should materials should be used giving due consideration to the
be adhered to and proper records maintained. Any social stigma attached to the disease and to those
irregularity on the part of collaborating providers with suffering from it.
regard to adherence to guidelines, providing quality care In conclusion, in different country settings, different
and maintaining proper records, if found, must be types of private as well as public providers operate
brought to their notice immediately but gently, and outside NTPs. They include informal village doctors,
corrective measures taken to avoid recurrence. Also, in private general practitioners, large public hospitals,
early stages, some form of documentation of the process specialist physicians, NGOs, medical colleges, corporate
should be maintained. Notes of problems that may arise health services, etc. Since WHO is embarking on the
and are locally identified should be made and forwarded global PPM project, several initiatives in different
to senior NTP management. This could help in better countries have successfully engaged diverse health care
understanding the process of collaboration and also providers in TB care and control. Evidence from such
contribute towards any future revision of operational initiatives shows that the diversity of settings and
guidelines. Continuous dialogue between involved provider types regardless, there are some common steps
partners is necessary to address identified problems and required to set up productive collaborations with the
potential tensions. Proper use of the practical tools and wide array of public and private care providers, steps
process and outcome indicators referred to above will
that have been outlined in brief in this chapter. Evidence
help monitor the progress and evaluate the outcome of
also indicates that once PPM is successfully implemented,
PPM.
it can contribute not only to increased case detection and
Advocacy and Communications cure rates for NTPs, but also to improved access to quality
TB care and to cost savings for patients.
A good NTP is self-advocating, both for patients and for
National Tuberculosis Programme is primarily
other care providers. It has been observed that as the
responsible for planning and implementing a PPM
services improve, more and more patients get attracted
strategy. However, PPM can never happen without the
to them. This also helps in improving the image of the
involvement and commitment by the providers that
programme among other care providers. A successful
constitute the PPM in health care. Furthermore, expe-
and strong NTP is in a better position to elicit collabora-
tion from other care providers. To generate and sustain rience has shown that individual private or NGO sector
interest in PPM, advocacy should be directed both at NTP institutions can play an igniting role for PPM, and take
managers and staff and their counterparts among other the lead even before NTP has started to plan for PPM.
private and public provider groups. Improvements in Even individual physicians, especially chest specialists
communications are required at two levels-inter-provi- who are local opinion leaders, can take the lead and
der communication and patient-provider communica- catalyse further action from NTP. The ISTC is a tool
tion. The NTP staff may need input to learn to designed primarily for practitioners who are operating
communicate effectively with diverse provider groups outside the public health domain. It is foreseen that the
and all care providers would benefit from lessons in standards will be an important tool for clinicians to start
improving their communication and interaction with TB become actively involved in national TB control efforts,
suspects and cases. Providing information to patients on and take the lead when necessary and appropriate. The
the availability of TB services in the public and private reader is referred to the chapter “The International
sectors and the charges they may or may not need to pay Standards for Tuberculosis Care” [Chapter 67] for more
for different services offered would help make the details.
ACKNOWLEDGEMENT private mix subgroup for DOTS expansion. WHO/HTM/

The authors acknowledge the assistance provided by Hannah 12. World Health Organization. Stop TB Partnership. The Global
Monica Yesudian in the preparation of this manuscript. Plan to Stop TB, 2006-2015. Actions for life: towards a world
free of tuberculosis. WHO/HTM/STB/2006.35 Geneva:
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854 Tuberculosis
Building Partnerships
for Tuberculosis Control
60
Nani Nair, J Kumaresan
INTRODUCTION WHO began to promote an approach (11) that combined

key elements from early work carried out at the
In the mid 1980s and into the 1990s, the world saw a 20
Tuberculosis Research Centre [TRC], Chennai [then
per cent increase in global notification rates for tuberculosis
called Madras] (12) and the National Tuberculosis
[TB], spurred in part by rising human immunodeficiency
Institute [NTI] Bengaluru [then called Bangalore] (13) in
virus [HIV] infection and acquired immunodeficiency
India, with practical tools for field implementation that
syndrome [AIDS] prevalence in many parts of the world
had been developed and successfully implemented by
including the South-East Asia [SEA] Region (1-4).
Dr Karel Styblo of the International Union Against TB
Tuberculosis was and continues to be the leading cause of
and Lung Disease [IUATLD] in Malawi and Tanzania
death due to infectious diseases globally today (5). This
(14,15). The elements of the approach were outlined in
led the Forty-fourth World Health Assembly in 1991 to
the “Framework for effective tuberculosis control”
adopt a resolution [WHA 44.8] that urged member
launched by WHO in 1994 (16) and these elements, in
countries to intensify TB control as an integral part of
1995 were packaged together as the DOTS strategy (17).
primary health care and called for the establishment of
global targets for TB control (6). The targets set were to During the next few years, the strategy, actively
cure at least 85 per cent of all sputum smear-positive cases promoted worldwide by the WHO and the IUATLD and
detected annually and detect at least 70 per cent of all cases hailed by the World Bank as one of the most cost-effective
estimated to occur annually, by the year 2000. The of health interventions began to be increasingly adopted
principle on which these targets was based was that early by more countries (18). By 2007, 202 out of 212 countries
detection of infectious cases and effective treatment and territories had adopted and were implementing
leading to cure would reduce the prevalence of TB by half DOTS (19).
over the next five years thereby reducing transmission,
A GLOBAL PARTNERSHIP FOR
and thus, the incidence of new infections (7). At that time
TUBERCULOSIS CONTROL
less than 20 countries globally had effective control
programmes in place (8). In India, for example, a Despite good progress in DOTS expansion and increased
programme review in 1992 showed that only 30 per cent funding for TB control, the first global monitoring report
of patients with TB were being diagnosed; of these, only on progress with DOTS published by the WHO in 1997
about one-third were being cured (9). (20) showed clearly that the targets for TB control were
Recognizing that decades of neglect, combined with not going to be achieved by 2000. While treatment success
deficiencies in national control programmes was contri- rates were close to 80 per cent, the percentage of
buting to the increasing morbidity and mortality due to infectious cases being detected lagged behind at 11 per
TB around the world. The World Health Organization cent of all estimated cases.
[WHO] in 1993, therefore, took the unprecedented step In 1998 the WHO, therefore, convened an “adhoc
of declaring TB a global emergency (10). At the same time committee on the TB epidemic” to analyse the reasons
Building Partnerships for Tuberculosis Control 855
for slow progress towards targets and make recommen- The Global Partnership to Stop TB today comprises
dations to the global community to accelerate progress of a membership of over 300 institutions and individuals
(21). Among the recommendations made by the adhoc and is a result of a paradigm shift in global thinking on
committee were the creation of a global charter among TB as being purely a concern for public health, to thinking
all key partners and countries with the highest burdens of TB as a health concern with political, social and
of disease [22 countries account for 80 per cent of global economic dimensions. The partnership is also a result of
TB burden], involvement of the private sector and com- a recognition that different partners, not all of whom are
munities in national TB control efforts and the creation necessarily directly involved in health of TB control bring
of a global drug facility. different strengths to conquering the multidimensional
Later that year, Dr Gro Harlem Brundtland, then challenges posed by TB (30). The Global Partnership to
Director-General of the WHO, launched the Stop TB Stop TB through the Global Plan to stop TB, based on
Initiative founded on the principle of a global partnership the Stop TB strategy launched by WHO in 2006, aims to
to address the lacunae pointed out by the adhoc com- eliminate TB as a public health problem, a goal that has
mittee and to accelerate action against TB control (22). eluded the world despite there being effective means to
As a result of the efforts of the newly launched Stop control it since the 1950s. Its mission is to ensure that
TB Initiative (23), several events with far reaching impli- every TB patient has access to effective diagnosis,
cations on global TB control followed in rapid succession treatment and cure; to stop the transmission of TB
in 2000 and 2001. A ministerial conference on TB and worldwide; to reduce the inequitable social and economic
sustainable health involving several global partners and burden of the disease; and to develop and implement
ministers of health, finance and planning from countries new preventive, diagnostic and therapeutic tools and
with the highest TB burden, was held in Amsterdam in strategies to eliminate TB. In the nearer term, it aims to
March 2000 leading to the landmark “Amsterdam meet the World Health Assembly’s targets for 2005 and
Declaration” to stop TB. In May 2000, the World Health the G-8 targets for 2010, which are incorporated into the
Assembly endorsed the formation of a global partnership United Nations’ Millennium Development Goals for
for TB control and, at the same time, considering that 2015.
most countries had not reached the targets set in 1991, Seven technical working groups advance the work
postponed these targets to 2005 (24). of the Stop TB Partnership in the following areas: DOTS
In 2001 a structure for a global Stop TB partnership expansion; DOTS-Plus for the treatment of the patients
was developed [Figure 62.4] and this was endorsed at with multidrug-resistant tuberculosis [MDR-TB]; TB and
first meeting of the Stop TB Partners forum in HIV; new TB drug development [Global Alliance for TB
Washington in October 2001 (25). At this first forum of Drug Development]; new TB diagnostics development,
the partnership, then comprising of 80 partners and and new TB vaccine development [TB Vaccine Develop-
high-burden countries endorsed the Washington ment Coalition] and advocacy communication and social
Commitment to Stop TB, committing themselves to the mobilization [ACSM].
2005 targets and to specific actions as outlined in the Different coalitions of partners are contributing to
global plan to stop TB (26). Also in 2001, the G-8 at their these different areas of work. The WHO plays a lead role
26th summit in Okinawa (27), committed to reducing in the DOTS Expansion Working Group and guides the
TB deaths and prevalence by half by 2010 and in the 22 High Burden Countries in making detailed national
same year, the United Nations at its Millennium plans for DOTS implementation. The Working Group
Assembly, adopted the Millennium Development Goals on DOTS-Plus for MDR-TB aims to develop an
which included under one of its targets, the halting and affordable, effective and evidence based response to
reversal of the incidence of TB by 2015 (28). In January MDR-TB in resource-poor settings. It has succeeded in
2002, the Global Fund to Fight AIDS, TB and Malaria reducing the price of second-line TB drugs by up to 90
[GFATM] was set up as a financial instrument to per cent through the use of competitive, pooled
resource activities aimed at control of these three procurement. The Working Group on TB/HIV has the
diseases (29). TB control was now firmly established mandate of reducing the burden of TB in population with
on the global health agenda. high prevalence of HIV.
856 Tuberculosis
The three research and development Working

Groups are making substantial progress. The Global
Alliance on TB Drug Development is an independent
public-private partnership that aims to accelerate the
discovery and development of new TB drugs that shorten
and improve treatment, and are affordable by low-
income countries.
The Global TB Drug Facility [GDF] is another vital
arm of the partnership (31). It aims to supply quality TB
drugs to allow for continued DOTS expansion in many
of the high burden countries that still lack resources to
procure these. The working group on Advocacy and
Communications and social mobilization and task force
on Finance and Resource Mobilization provide common
support for the various activities of the Stop TB
Partnership. Figure 60.1: Case detection and treatment success rates, South-
East Asia Region, 1997-2006
TUBERCULOSIS IN THE SOUTH-EAST ASIA Source: “Annual report on TB in the SEA Region, WHO/SEA, 2007
REGION (reference 34)”
The SEA Region of WHO bears the highest burden of TB services have been consistently higher than 85 per cent,
globally, with 38 per cent of the world’s TB cases being while case detection rates continued to rise steadily in
in this Region [Figure 4.3A]. Five of the 22 countries with most member countries. The current case detection rate,
the highest TB burden globally namely, Bangladesh, i.e., the percentage of cases being registered under DOTS
India, Indonesia, Myanmar and Thailand belong to this
Region and together, account for 95 per cent of the three
million new cases of TB and the nearly half a million
deaths that occur every year in the Region. The incidence
of disease is the highest in the economically productive
age groups between 15 to 54 years, with 80 per cent of all
new smear-positive cases being reported among people
in this age group (32,33). This poses significant threat
not only to health; but also to social and economic
development in the Region.
Progress with Tuberculosis Control

The Region, however, has made remarkable progress
with DOTS since the strategy was introduced in Member
Countries in the early 1990s. National TB Control
Programmes [NTPs] in the eleven countries of the WHO
SEA Region and particularly the five high burden Figure 60.2: Case detection and treatment success rates achieved
countries, Bangladesh, India, Indonesia, Myanmar and by member countries in South-East Asia Region in 2007
Thailand have rapidly expanded DOTS to ensure that BAN = Bangladesh; DPRK = Democratic People’s Republic of
good diagnostic and microscopy services were made Korea; IND = India; INO = Indonesia; MAV = Maldives; MMR =
Myanmar; NEP = Nepal; SRL = Sri Lanka; THA = Thailand; TLS =
available to the entire population of the people in the Timor-Leste; SEAR = South-East Asia Region
region by 2006. Treatment success rates in areas and Source: “Annual report on TB control, National TB Programmes
programmes offering DOTS diagnostic and treatment SEA Region member countries, December 2007 (reference 36)”
against the total number of new smear-positive cases International Developmental Partners in the Region
estimated to occur annually is above 68 per cent [Figure Countries in the SEA Region are fortunate to have strong
60.1] (34). Much of the progress in case detection in the vibrant ties with several international development
Region is attributable to increasing case detection in partners and donors who are funding and technically
India, which alone contributed to 67 per cent of the global supporting countries in the Region, some with the highest
increase in case detection in 2002 (35). Figure 60.2 (36) burdens of disease and the least ability to pay. Figure
shows the treatment success rates being achieved by 60.3 shows the major donors and partner agencies
national programmes under DOTS in the countries of providing technical and financial support for TB control
the SEA Region. in countries in the SEA Region.
Figure 60.3: Major donors and partners supporting tuberculosis control in South-East Asia Region
ADB = Asia Development Bank; AusAID = Australian Government Overseas Aid Programme; BNMT = Britain Nepal Medical Trust; BRAC
= Bangladesh Rural Advancement Committee; CDC = Centres for Disease Control and Prevention, Atlanta, USA; CIDA = Canadian
International Development Agency; DFB = Damien Foundation Belgium; DFID = UK Department for International Development; EBF =
Eugene Bell Foundation; GDF = Global Drug Facility; GFATM = Global Fund to fight AIDS, TB and Malaria; Gorgas = Gorgas TB
Initiative; INF = International Nepal Fellowship; JICA = Japan International Cooperation; Agency; KNCV = Royal Netherlands Tuberculosis
Association; LEPRA = a medical development charity that evolved from the British Empire Leprosy Relief Association; LHL = Norwegian
Association of Heart and Lung Patients; MSH = Management Sciences for Health; NORAD = Norwegian Agency for International
Development; NLR = Netherlands; PATH = Programme for Appropriate Technology in Health; PSI = Population Services International;
RIT = Research Institute for Tuberculosis [Japan]; SAARC = South Asian Association for Regional Cooperation; TBCTA = Tuberculosis
Coalition for Technical Assistance; IUALTD= International Union Against TB and Lung Disease; USAID = United States Agency for
International Development; WB = World Bank; WHO = World Health Organization; 3DF = 3 Diseases Fund
858 Tuberculosis
National Partnerships for Tuberculosis Control decades. Strong presence at international forums has led
in the South-East Asia Region to increasing recognition of the influence they can wield
and their potential to contribute.
It had long been recognized in the Region that public
health systems alone could not deliver health care to all. The Bangladesh Rural Advancement
Health systems in the Region were already overstretched. Corporation, Bangladesh
Countries in the Region did not have sufficient sustain-
able resources to meet the basic health needs of their An outstanding example of a successful government
populations (37). Many were undergoing a difficult and NGO collaboration to stop TB is in Bangladesh. The
process of health sector reform in order to address this Bangladesh Rural Advancement Committee [BRAC]
(42) and the Damien Foundation, Bangladesh, together
and increase access to primary health care services
with seven major NGOs in the country are providing
including DOTS to those who were least able to pay for
DOTS services to over 90 per cent of the population.
services (38).
Their responsibilities in TB control include dissemi-
nation of TB information to communities; identifying
NON-GOVERNMENTAL ORGANIZATIONS AND
and diagnosing TB suspects; providing DOTS and
TUBERCULOSIS CONTROL
following up TB patients during and after treatment
The role of non-governmental organizations [NGOs], completion.
for example, in leprosy elimination (39), rehabilitation The nucleus of the BRAC TB Control Programme is
of the physically handicapped and more recently in the the utilization of community-based voluntary health
prevention and care of the HIV-affected (40) have workers, called Shastho Shebikas. These are local women,
strengthened both government and community beliefs averaging 25 to 35 years of age, most having no formal
that NGOs can indeed deliver and what is more, deliver education but trained by BRAC on essential health
most effectively. Their role in TB prevention and control activities including TB control. Their responsibilities in
has been no less significant (41). The DOTS strategy relation to TB control are: [i]to disseminate information
itself, considered the most cost-effective strategy to about TB to the community; [ii] to identify suspected
combat TB today was first developed by a NGOs, the patients and refer them to diagnostic centres for a sputum
IUATLD. smear examination; to ensure directly observed
Traditionally, provision of TB treatment services has treatment; [iii] to dispense medication during the initial
been the most common area for collaboration. However, and continuation phases; and [iv]to follow up on TB
with the advent of DOTS, national government organiza- patients during and after treatment completion.
tions participation in stopping TB has taken on even An individual who is diagnosed with TB signs a
greater importance. Being closer to the communities they contract with BRAC, witnessed by two community
serve, being more credible, dependable and more integra- members including Shastho Shebikas, and pays a bond of
ted in the services they provide, NGOs have a distinct takas 200 [US$5], to ensure that he or she completes the
edge over Government workers in convincing TB treatment. This amount is returned to the patients if they
suspects to undergo diagnostic tests, take their medicines complete their prescribed treatment regimen and they
regularly and report for the prescribed follow ups to pay takas 125 to the Shastho Shebikas for her work in
ensure complete cure. They have a comparative advant- identifying patients and ensuring that the patients take
age over the public sector in flexibility, commitment, their medication daily.
drive, and a sense of urgency for change. Among the Treatment outcomes in the areas covered by BRAC,
multitudinal ways in which NGOs can partner national are very impressive. The cure rate has been over 85 per
programmes effectively in stopping TB, there is, cent since 1995 and as high as 91.7 per cent in some areas.
however, one that stands out most prominently. The Case detection rates have also been high at close to 60
NGOs have a major role to play in advocacy and per cent in these areas with the proportion of women
mobilizing government and community support to stop among the total number of cases diagnosed as well as
TB. Through building a powerful lobby, NGOs can wield the proportion of sputum-positive cases to the total cases
their power to influence the future of TB. The role of being higher in the case of this community-based TB
NGOs has increased significantly over the past two programme.
The reader is also referred to the chapter “Non- initial diagnosis, counselling and treatment of TB patients
governmental organizations and tuberculosis control” at the Mahavir Hospital, patients were referred back to
[Chapter 61] for more details. identified DOTS centres within easy walking distance
of their homes. Flexible timings were also ensured.
THE PRIVATE HEALTH SECTOR AND The results of this programme have been outstanding.
TUBERCULOSIS CONTROL Nearly two-thirds of the patients were referred by the
In many high TB-burden countries, there is evidence that private practitioners in the project area and women
a substantial proportion of TB suspects and patients seek accounted for nearly half of all smear-positive cases.
care from private and non-government providers National goals of 75 per cent case finding and a cure rate
(43-49). Most of these providers used unstandardized of more than 92 per cent among new smear-positive
diagnostic and treatment protocols resulting in incorrect patients have been achieved. This experience shows that
diagnosis, and poor treatment outcomes, with the risk a strategy of collaboration between the public and private
of developing drug-resistant TB (44). Furthermore, in the sectors is feasible and cost-effective.
absence of any legislation to notify these cases, most
Kathmandu Valley, Nepal
patients were not being reported. There were serious gaps
in the perceptions and practice of private providers (45). The NTP in Nepal had extended the DOTS strategy to
Developing partnerships with health providers outside 75 per cent of the country by end 2000. With cure rates
the government health system, and especially with well over 85 per cent, it was appropriate to focus on the
private health providers was, therefore, critical to private sector before the HIV epidemic and the develop-
progress with DOTS. The reader is referred to the chapter ment of multi-drug resistance became major concerns.
“Public-private mix for tuberculosis control” [Chapter 59] for Indirect evidence had shown that case detection in the
more details. public sector was around 50 per cent, with nearly 70 per
cent of antituberculosis drug inputs being accounted for
Examples of ongoing Public-Private Initiatives in by the private sector. Private-public collaboration was
Tuberculosis Control in the Region considered especially important in urban areas in view
of rapid population growth, high burden of disease,
Mahavir Trust Hospital, Hyderabad, India weaker public health services with a rapidly expanding
In a joint effort between the Government and the private private sector and the availability of over-the-counter
sector, a charitable specialty trust hospital, Mahavir antituberculosis drugs. A model for service linkage with
Hospital in Hyderabad, India undertook a project private practitioners was, therefore, developed in one
involving individual private practitioners in the DOTS municipal ward, Lalitpur, in the Kathmandu valley (51).
programme (50). This project, initiated in 1995, currently The Lalitpur Municipality has a population of 200 000
covers a population of 500 000 in the city. Following a and was selected since it was close to Kathmandu. One
basic situation analysis where it was found that up to 80 hundred private practitioners were involved in this
per cent of patients sought treatment in the private sector project. Following needs assessment and interviews with
and that most private facilities were not following private practitioners, a working group as well as local
national guidelines for either diagnosis or treatment, an DOTS committees consisting of all stakeholders were
intervention, first to sensitize private practitioners to the created. Standard case management protocols were
programme, and then to develop a model for collabora- developed and private practitioners were trained. Service
tion, was developed with the charitable trust hospital providers [microscopy centres, treatment centres and
functioning as an inter-phase between the government sub-centres] were identified. These included five urban
and individual private practitioners. DOTS treatment centres and four diagnostic centres.
A campaign was launched to inform local physicians Health workers, volunteers and social workers were
about DOTS and to create a mechanism for referral of trained to implement DOTS and late patient tracing
TB patients with the assurance that the private practi- mechanisms were developed with NGO support.
tioner would continue to be the patient’s primary care- Feedback to private practitioners was arranged through
provider. A referral card was developed, and following periodic private practitioner clinic visits. An informal
860 Tuberculosis
Coalition Against Tuberculosis [CAT] involving the are to sensitize private providers to the DOTS
District Health Office, NGOs, the local municipality and philosophy; [vi] sufficient supervision monitoring of
members from the community was formed. private providers is required; this is ultimately the
Private practitioner referrals have contributed responsibility of the government sector; and [vii]
significantly to case-finding for the NTP. Presently, nearly providing drugs free of charge to patients improves
a fifth of new registered cases by the NTP in Lalitpur are treatment outcome, promotes equity and is also a tool
referred by the private practitioners. Treatment success for steering private providers through formal or informal
rates in the project area rose to over 90 per cent showing “drugs for performance contracts”.
that by sensitizing the private practitioners and providing These initial pilots are now spurring the formulation
appropriate information, it is possible to build on the of national policy on public-private partnership for NTPs
strengths of local health services. around the Region. India is among the first countries in
These examples prove that it is possible to induct the Region to frame a national policy and develop guide-
private health care providers into public health program- lines for the involvement of private providers in DOTS
mes with an intermediary organization coordinating (52). At the present time, however, the scale of public-
between NTPs and private providers. The NTP fulfils a private collaboration is insufficient to show a demonstr-
stewardship role ensuring technical support, training, able impact on national case finding and treatment
quality microscopy services and antituberculosis drugs. outcomes. Efforts need to be directed at scaling-up
A strong referral and feedback system coupled with successful initiatives without diluting the benefits
regular supervision to offer support [rather than exercise accrued from the small-scale projects.
control] remains at the heart of a sustainable collabo- The corporate sector could play an important role and
ration. has a tremendous potential to mobilize additional
Long-term sustainability can be ensured by maintain- resources. Its involvement in health care delivery,
ing motivation among private practitioners, leaving the research and development of new drugs and diagnostics
“ownership” of their patients with them, and allowing and human resource development could be very
some degree of autonomy within the DOTS framework. promising.
Building then on the strengths of the private providers
emerges as a successful and replicable proposition. MEDICAL COLLEGES AND THEIR ROLE
Some common determinants of success that emerged IN THE FUTURE OF TUBERCULOSIS CONTROL
from a detailed cross-site analysis of public-private mix
[PPM] DOTS projects are: [i] government commitment The NTPs did not initially attempt to reach out to medical
to PPM is the sine qua non of the partnership; the schools and provide them with the necessary information
government should finance and provide stewardship to to make a useful contribution in DOTS implementation.
PPM operations, in particular, it should subsidize drug The medical academia on their part perceived national
costs; [ii] it is important to invest time for dialogue programme practice as having been simplified to the
between all stakeholders in order to build trust and to point of being ineffective, and therefore, preferred
achieve a high level of agreement on common goals for individualized treatment regimens over the broad-based
PPM; when conflicts of interest exist, they need to be approach advocated by the NTPs. As a result, the
identified early and discussed openly; [iii] using an NGO, strengths of the DOTS strategy as practised by the NTPs
or a medical association or some such intermediary in the use of microscopy for diagnosis, standardized
ground may facilitate collaboration, especially when treatment regimens, ensuring follow-up and account-
there is an initial distrust between government sector, ability through recording and reporting, were introduced
NTP and private providers; [iv] improvement in referral in very few medical colleges. An attitudinal change was
and information systems through simple practical tools needed to bridge the gap between internationally-
is an essential component both for the effective accepted national programme strategies and medical
operationalization and evaluation of PPM; [v] training teaching and practice (53,54). The reader is referred to
is crucial; it is as important to assure that NTP staff the chapter “The role of medical colleges in tuberculosis
members are sensitized to the PPM philosophy, as they control” [Chapter 58] for details.
DOTS AT WORKPLACES society through a credible demonstration of corporate

Tuberculosis affects people of all ages, but the hardest social responsibility and an improved image in relation
hit are those between 20 and 45 years of age, men and to customers, potential buyers etc.
women who are at work during the most economically
DOTS at Workplaces – An Example From Bangladesh
productive years of their lives. Out of 2.5 billion people
in employment worldwide, over 50 per cent are at risk Bangladesh: Tuberculosis Control in the Chittagong
of developing active TB in their lifetime. The business Export Processing Zone
sector, therefore, has a large stake in controlling TB. The
illness imposes great costs on employers with disruption Chittagong is the largest industrial city in Bangladesh,
of work, reduced productivity, high treatment costs, and and therefore, attracts a large number of people seeking
in addition, significant indirect costs that are expended work. There are over 600 garment factories in the city in
for replacement and retraining of workers. addition to industries in the Chittagong Export
On the other hand, business and industry can actively Processing Zone [CEPZ]. These garment factories alone
contribute by identifying TB suspects within their employ 1.8 million workers, 80 per cent of whom are
workforce, referring them for diagnosis, and helping females, between the ages of 15 to 35 years. Recognizing
affected employees to be treated in order to prevent the that health facilities at individual factory premises were
spread of TB both at the workplace and by extension, in inadequate, the Bangladesh garment manufacturers and
communities. A workplace may be more of a community, exporters established two health centres with one doctor
than even the neighbourhood in which people reside. and one nurse at each. Forty-three DOTS treatment
Most workers spend a significant proportion of their centres, seven of which function also as diagnostic
waking hours in their places of work. In some situations, centres, were also established. These centres were
the workplace may also be where workers live. The dire established through collaboration between the NTP, the
need to introduce TB control services in workplaces may city corporation, local NGOs and the National Anti-TB
be stronger than in any other. Employers must, therefore, Association of Bangladesh, [NATAB]. Tuberculosis cases
help provide access to information and support sick identified at the health centres are referred to nearest
workers and link TB control with other workplace issues, NTP centre.
such as HIV/AIDS, elimination of other occupational Within the CEPZ, operated by Bangladesh Export
health hazards, like silicosis. Processing Zone Authority [BEPZA], there are 117
Employers and their organizations can play a vital industries, employing 83589 workers, mostly young
role in promoting and implementing TB control activities. women. The Youngone Group in Bangladesh, which
Workers and their organizations can collaborate in these produces and exports sportswear including garments,
activities and advocate for the needs of employees, shoes, nylon fabrics, quilting and luggage, operates
including access to health care and observance of ethical within the CEPZ. It employs 24000 employees of which
aspects of employment. Strategies are needed to ensure 80 per cent are females in age group between 18 to 30
maximum ‘buy-in’ by various partners in workplace TB years, coming from many different districts in
control. Experiences from workplaces in a number of Bangladesh. Tuberculosis was found to be common
settings in Asia and elsewhere have demonstrated that among these factory workers. The medical staff also
implementing DOTS has been both successful and cost- recognized that most workers concealed their illness for
effective. The DOTS programme can easily be built on fear of loosing their jobs. Those with TB in the CEPZ
the existing health services being offered to workers and either had to attend the CEPZ hospital, or the nearest
sustained through supervision and monitoring of all TB NTP centre - as a result, most workers suffering from TB
cases through management systems which are in place preferred to consult private practitioners. This resulted
at workplaces (55-56). in most being treated incompletely. Recognizing that
The introduction of TB control practices into the these workers were among the most vulnerable to TB on
workplace, therefore, offers several benefits, like a account of close regular contact with affected workers,
healthier workforce, reduced medical costs, higher work the management of Youngone Industries decided to
morale, higher productivity, an enhanced image in establish a DOTS centre at Youngone Industry in the
862 Tuberculosis
CEPZ. So far the Youngone Industries have registered international recognition, and a better corporate image.
186 cases of TB among its workers, of whom a third were There is growing interest at the CEPZ hospital in
smear-positive cases. establishing DOTS centre under NTP, due to the initiative
As a result of this initiative, the company enjoys the by the Youngone Group. Youngone is also interested in
economic benefit accruing from increased work efficiency establishing a wider partnership to address TB-HIV co-
and better morale among its workers, national and infection (57).
Table 60.1: Community-based care in delivery of DOTS services

Year Setting Coverage Community involved Components of care Effectiveness
provided
1982 Tribal hamlets in Hamlets = 62 Literate tribal youth Identification of sympto- Increase in case-
Tamil Nadu, India Population: matics; sputum collection finding by 20%
96000 and drug dispensing;
transportation
1987 Rural villages in Villages = 44 Dais [Traditional Identification of 600 symptomatics
Tamil Nadu, India birth attendants] symptomatics; collection identified in 5 years
and transportation of [sputum positive cases
sputum samples; 2.8%] cure rate = 85%
distribution of drugs;
monitoring drug
consumption.
1990 Urban and Rural Lay and church Observation of Cure rate in rural
settings, Philippines group volunteers treatment areas = 90% cure rate in
urban areas = 80%
1991 Rural Thanas in Community health Identification of sympto- Improvement in case-
Bangladesh workers matics; referral and finding; cure rate = 66.3%
follow-up drug distribution
and monitoring of drug
consumption; default
retrieval; health education
1992 Hill districts in Nepal Traditional healers Identification of Improvement of out-
symptomatics patient attendance in
PHIs
One-third of diagnosed
patients are referred by
healers
1996 Rural and urban Through-out Village doctors Direct observation Cure rate among
provinces the country treatment new sputum positive
patients = 90% cure rate
among previously treated
patients = 81%
1997 Slum areas in 46000 Student volunteers Drug dispensing; chasing Treatment completion
Madurai city in of defaulters rate = 83%
Tamil Nadu, India Default retrieval
successful on 57%
occasions
1997 Rural community Social workers and Direct observation of Cure rate = 85%
National Demonstration community workers treatment and default
Centres, Nepal retrieval
PHIs = Peripheral health institutes

THE MEDIA AND TUBERCULOSIS CONTROL services at the community level through greater
community involvement and indeed active participation
The NTPs in the SEA Region recognize that the media in delivering DOTS services are essential for future
has a very significant role in stopping TB. Through sustainability. Community-based care in a number of
advocacy, publications, broadcasts and social settings has been demonstrated to be very cost-effective.
mobilization activities, the media does not merely Table 60.1 (58) shows the key features of nine studies
heighten public awareness about TB and mobilize a undertaken between 1978 and 1997 in several Asian
demand for TB services, but also carries out the critical countries.
advocacy effort needed to build the political will The studies reveal that community TB services have
necessary for governments to sustain effective TB control. been explored in various socio-cultural settings and that
Forging partnerships with the media is easier today a range of communities have been involved with diffe-
than ever before. The media has changed its image. It no rent means. All these projects point out the acceptability
longer remains a passive observer, merely feeding facts of services and record that the effectiveness is better than
to apathetic audiences. With rising health literacy, the that of programmes operating only through public health
media is beginning to respond to the peoples’ demand institutions.
for more and more information on health matters. It is The NTPs need to involve communities on a wider
beginning to look more critically at the multi-dimensional scale, ensuring first that quality services are in place
determinants of health in the world today. TB is within the public health system.
undeniably one of the major health concerns in the A new vision, based on partnerships is clearly
region. The NTPs need to provide the media with factual essential to build national capacities to deliver health for
information to make TB more visible in the eyes of the all and to deal with the many different but interconnected
government and the people, to caution on the dangers forces involved in delivering health services, including
of ignoring the worsening epidemic and to highlight the DOTS. These needed to encompass all the requirements
efforts being made and successes with the DOTS strategy for delivering effective health services including human
in beginning to overcome one of the biggest public health resources, financing and service infrastructure. In order
challenges of today. DOTS promises high cure rates for to increase the reach of DOTS to all, several initiatives
those afflicted with TB. The media offers some of the most have been taken around the world and in the SEA Region
cost-effective ways to inform people of the signs and to build partnerships with other sectors—the private
symptoms of TB, to avail themselves of the free TB health sector, NGOs, business and industry, medical
diagnostic and treatment services and to create a demand schools, the media and with civil society have all being
for these services. involved to widen the resource base, reach and utilization
“PANOS” is a media agency with an interest in of DOTS. These partnerships have helped to integrate
highlighting health issues (59). The agency held two the strengths of individual partners into national and
regional workshops for the print media from SEA Region. local programmes, initiated pilots that have then been
International and regional experts on TB and its control developed into regular programmes and enhanced
explained various aspects of the disease to the national capacities to deliver primary health care. Wider
participating journalists. These efforts of PANOS resulted and more inclusive partnerships need to be forged to
in a spate of articles in national dailies and weeklies in meet the manifold challenges posed by TB, both globally
many Asian countries during subsequent years and in a and in the SEA Region.
book, “Stopping A Killer”.
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Non-governmental Organizations
and Tuberculosis Control
61
Ian Smith
INTRODUCTION Across the region, NGOs and governments have developed

a diverse array of innovative approaches to implement
We live in a changing world. Relationships and roles are
DOTS, the World Health Organization [WHO]
being redefined, as barriers are broken down, and
recommended control strategy for TB, in response to the
organizations discover new ways of working together.
TB epidemic. The Revised National Tuberculosis Control
Vocabulary is changing to reflect these developments,
Programme [RNTCP], Government of India reported that
and words and phrases like “...networking ...cross-cutting 2946 NGOs were participating in the programme in
issues ...multisectoral ...coalitions ...partnership 2008 (1). International NGOs directly support TB control
...collaboration ...” occur with increasing frequency in activities in 46 of the 75 districts of Nepal, and the Nepal
documents and discussions. Antituberculosis Association [NAA], one of the oldest
These are not simply cliches born of the latest trends national NGOs in the country, has activities in 28 districts.
in health development fashion but they reflect the vision In Bangladesh, NGOs provide services in the majority of
and action of organizations striving to find ways of thanas, under contractual agreements between the
increasing efficiency and effectiveness. These organi- Government of Bangladesh [GoB], the Bangladesh Rural
zations understand that vertical approaches to service Advancement Corporation [BRAC], an indigenous NGO
delivery are inefficient, that selfish competitiveness must in Bangladesh and the Leprosy Co-ordinating Committee
be replaced by a rational and equitable distribution of [LCC], and provide treatment to over 70 per cent of patients
resources, and that collaboration creates synergism, i.e. registered in the country.
multiplying the positive impact of endeavours. National antituberculosis associations have played
Previous distinctions separating government and an important role in the history of TB control and continue
non-government, public and private, are disappearing to be active in many countries of the region, such as
as organizations learn to work together, and value the Bangladesh, India, Nepal and Sri Lanka. Roles have
contributions of each other. This is seen clearly in the changed through, and many national and international
partnerships that have developed between government NGOs are moving from their traditional roles of education
and non-governmental organizations [NGOs] to fight and service provision, supported by voluntary contribu-
communicable diseases. Within the South-East Asia tions, to community, development and advocacy, with
Region, NGOs make a vital contribution to disease control grant aid from funding agencies, including governments
that is increasingly recognized by governments and (2,3).
international development partners. Formal partnerships between governments and
Tuberculosis [TB] control provides an excellent illust- NGOs are developing rapidly. The Global Partnership
ration of the value of these partnerships. Tuberculosis is to Stop TB, established in 2000, now comprises 450
a devastating disease, killing over a million people a year partner organizations, the majority of which are NGOs
in the region, and infecting over a third of the population. (4). Stop TB is also promoting the development of national
Non-governmental Organizations and Tuberculosis Control 867
partnerships, and has produced several tools to facilitate Tuberculosis is a Human Rights Issue
this process (5). In large countries, particularly those with
The effect of TB is disproportionately great on people who
a federal government system, partnerships at the state or
have been deprived of some of their basic rights, such as
district level may be more effective in ensuring
prisoners and refugees (13).
collaboration, and evidence of the strengths and
weaknesses of such coordination mechanisms is Tuberculosis is a Gender Issue
increasingly becoming available, for example from Pune
and Mumbai in Maharashtra, India (6,7). Fewer women are registered for TB treatment than men
A major catalyst to the development of national (14). One contributing factor is that women have less
coordination mechanisms involving NGOs has been the access to health care services. Tuberculosis is the single
Global Fund to Fight AIDS, Tuberculosis and Malaria biggest killer of young women. Tuberculosis in men also
[GFATM] (8). It was established in 2001, as an innovative has a profound effect, on the well-being of women and
approach to increase funds to tackle these three diseases. families.
A key element in the grant-making process of the GFATM
Tuberculosis is a Child Health Issue
is the endorsement of funding proposals by the Country
Coordination Mechanism [CCM], which also oversees Children get TB, but also suffer when their parents fall
implementation of the grant. The rules require that CCMs ill and die from TB.
incorporate representatives from civil society, including
local NGOs, and people living with the diseases (9). The Tuberculosis is a Development Issue
effectiveness of CCMs is being watched closely, with The effects of TB are felt most seriously by the poor and
particular attention being given to the role and involvement the poor get TB more than the rich. The DOTS can
of NGOs (10). contribute to economic development. A study (15) from
South-East Asia showed that every dollar invested in TB
WHY SHOULD NON-GOVERNMENTAL control gives a ’return’ of $55 [about Rs. 2475] to the
ORGANIZATIONS BE CONCERNED community over a 20-year period. Specific initiatives are
ABOUT TUBERCULOSIS? needed to ensure that the poor are not excluded from
Several factors have led to recognition by many NGOs effective TB control services (16).
that they need to play an important role in the fight against
DOTS is a Means to Improving
TB.
the Overall Quality of Health Services
Tuberculosis Causes a Huge Burden of Disease, The DOTS is an integrated approach to TB control at the
Suffering and Death district level of the health service. Introducing DOTS is a
means to improvements in laboratory services, logistics,
Many NGOs have a mandate to address health problems,
health management information systems, training and
and TB is one of the most serious threats to the health of supervision.
people of South-East Asia, with more than three million
people developing the disease in the region every year (11). The Government Alone Cannot
Defeat Tuberculosis
DOTS is Cost-Effective
Besides the government health services, other sectors such
Tuberculosis control tops the list of interventions in as NGOs and the private sector have a vital role in the
primary health care. Effective TB treatment costs only $3 national effort to control TB. In many countries, less than
to $7 [about Rs 135 to Rs 315] for every health year of life 50 per cent of TB patients are diagnosed and treated in
gained (12). government health services.
868 Tuberculosis
The NGOs make a unique contribution at the commu- their existing skills and experience. For example, an NGO
nity level. The NGOs are well-suited to participate in the running hospitals or clinics would probably want to
national effort because of their credibility, access to develop effective TB diagnosis and treatment services.
communities, access to vulnerable populations, and On the other hand, organization involved in community-
greater flexibility of work. based care for people with human immunodeficiency virus
[HIV] infection and acquired immunodeficiency syndrome
HOW CAN NON-GOVERNMENTAL ORGANIZATIONS [AIDS], would probably want to incorporate community
BE INVOLVED IN TUBERCULOSIS CONTROL? DOTS.
Three basic principles govern the role of NGOs in TB
EXAMPLES OF NON-GOVERNMENTAL
control. These concern responsibilities roles, and
ORGANIZATION APPROACHES TO TUBERCULOSIS
approaches [Table 61.1].
CONTROL
First, governments retain the primary responsibility
for maintaining and improving public health. Effective The diversity of approaches adopted by NGOs working
TB control demands a co-ordinated approach with in TB control is reflected in the following section, which
standardized diagnostic, treatment, and information attempts to categorize and describe the characteristics of
systems. The government must, therefore, take a lead in different strategies. All of these complement the TB
developing and maintaining these systems. The NGOs, control activities of the government, and can make a
along with the government and other agencies, become major contribution to preventing transmission of TB,
part of the national tuberculosis programmes [NTPs], and strengthening health services, and supporting communi-
follow the same policies. ties and people with TB. These different approaches are
Secondly, the role and nature of many NGOs has not mutually exclusive, and a combination will often be
changed in recent years. Organizations have recognized required.
that their primary role is to facilitate and support and to
help build capacity of individuals, communities and Service Delivery
governments (17). This is particularly important in TB
The traditional model for NGO involvement in TB control
control. Tuberculosis will not be eradicated in the short- has been service delivery through TB clinics and
term, it will probably take at least 50 years. Few NGOs
hospitals. Many NGOs in South-East Asia are still
can be committed to provide services for that period of
involved in this way and continue to make important
time, and recognize they must support and help
contributions to TB care (18). In a service delivery
communities and governments develop and maintain the
approach, the NGO is responsible for diagnosing and
services that are essential for TB control. This is true of
treating people with TB. Treatment services may be
most health and development problems, and illustrates specifically for TB patients, for example a TB clinic or a
the need for long-term commitment to sustainable TB
tuberculosis hospital. Alternatively, services may be
control.
provided as part of general health services, for example,
Thirdly, greatest success is achieved when organiza-
in a hospital or health centre.
tions select and approach that builds on their existing
The NGO health services are often of a high quality,
strengths. There is no ideal model for NGO involvement
and popular with patients. However, a service delivery
in TB control, but many alternative approaches, and the approach requires long-term commitment, and has
most suitable one will depend on the nature of the NGO.
several other disadvantages [Table 61.2].
Organizations will be most successful if they build on
Health Service Management Support
Table 61.1: Principles of non-governmental organizations
involvement in tuberculosis: strengths Some NGOs prefer to avoid service delivery, and choose
Facilitate and support community action
to support the development of effective government health
services. They recognize that successful TB control
Building on existing strengths
programmes depend on good management, particularly
Integrating DOTS in ongoing programme activities
for laboratory services, logistics and monitoring. These
Table 61.2: Disadvantages of non-governmental between government health services and local
organizations health services communities. Some countries have established district
General hospitals often have few or no community-based staff and
DOTS committees, to facilitate the introduction and local
cannot do defaulter tracing. Cure rates in general hospitals are supervision of DOTS. Tuberculosis control can also be
often poor linked with other community development activities, such
Service delivery is expensive because of the need to employ large as community-based care, income generation, literacy and
numbers of staff micro-credit. Many NGOs are committed to a community-
Many hospitals charge fees for services, for example smear based approach, in which members of the community
microscopy, whereas most National Tuberculosis Programmes themselves take responsibility for identifying their own
have a policy of free diagnosis and treatment for tuberculosis needs, planning interventions, implementing activities,
patients and monitoring and evaluating outcomes.
Strong NGO health services sometimes may impede the People with TB live in families and communities.
development of the capacity of government health services These communities, in villages, towns, cities, slums, and
Service delivery is unpopular with donors and may be difficult to factories provide valuable social support to the members
sustain of the community. Community-based care of people with
NGO = non-governmental organization; NTPs = National chronic illness has become popular, as communities
Tuberculosis Programmes; TB = tuberculosis recognize that health services provided by institutions,
such as health posts and hospitals, are limited in their
organizations help government staff carry out the capacity to provide adequate support within the home
management aspects of TB control, for example, needs or local community. Relatives and neighbours already
assessment, planning, training, supervision, drug supply, provide the majority of care; community-based care is a
quality assurance of sputum smear examination, and means of facilitating this existing system, and providing
reporting. This support is in the form of skills develop- support to care givers. A basic principle of TB control is
ment for government staff, and systems development to provision of care as close as possible to the patient’s home,
improve the efficiency and effectiveness of government often in the community to which the patient belongs.
services. It is less costly than a service delivery approach, Community volunteers, local leaders, civil service
does not require a long-term commitment, and involves organizations, colleagues in the work place, religious
capacity building; enabling government health workers leaders, shopkeepers, teachers and many others can be
to improve the quality of their work. Success relies on actively and usefully involved in helping cure TB (19,20).
development of a close working relationship with There are two types of community-based care. The first
government health services based on mutual trust and type is care by outreach workers from the health services,
support. A weak health service infrastructure, frequent or from NGOs. These are often salaried health workers or
transfer of government health workers, and a wide gap social workers, and may have been recruited from within
between the salaries and incentives of NGO workers and the community. The second method is by volunteers from
government staff may hamper the development of this within the community [often as part of an NGO initiative].
relationship. Community-based care workers provide support,
observation of treatment, nursing care, and education.
Community Participation and Experience from Bangladesh (21) has demonstrated the
Community-based Care cost-effectiveness of this approach, which achieved similar
cure rates at one-third less the cost than through a health
It is communities that are most affected by the TB epidemic, facility based approach (21).
and it is communities that have most to gain from effective Community-based care has become popular in recent
TB control measures. Involvement of the community is a years as a result of the HIV epidemic. Many people with
key principle of TB control, because communities are most AIDS also have TB, and NGOs working in community-
aware of local needs and circumstances, and most able to based care for people with AIDS have discovered that they
identify effective ways of delivering DOTS. Communities need to know as much about TB as HIV infection and
can identify local solutions to local problems, such as AIDS. Tuberculosis is a treatable condition, and treating
means of organizing observation of treatment. The NGOs an AIDS patient for TB can make a very significant contri-
can make an important contribution by facilitating links bution to the quality and duration of life.
870 Tuberculosis
Education on behalf of people affected by a disease of disability.

However, organizations specifically for TB patients are
Health education, information and communication [HEIC]
rare. The reasons are shown in Table 61.3.
is an important strategy in TB control. Many people with
The potential for involving people with TB in existing
TB lack awareness of the basic symptoms of TB. Even if
self-help groups is great. These include micro-credit
they do know about symptoms, they may not know that
diagnosis and treatment is freely available through groups, adult literacy groups, and organizations for people
government or NGO health services or that TB can be cured. affected by HIV infection and AIDS.
However, education of the community about TB treatment
may have a negative impact, if treatment services are not Table 61.3: Reasons for the rarity of
organizations for tuberculosis patients
widely available or are of poor quality. Provision of DOTS
must go hand in hand with an education programme. Tuberculosis is no longer a chronic disease; so most patients do not
There are many different ways of communicating identify themselves as belonging to a group of long-term sufferers,
with the exception of those with HIV-related TB, and those with
messages about TB, for example, mass media [television
MDR-TB
and radio], printed materials [posters and pamphlets],
Stigma may discourage people from identifying themselves as having
and drama [puppet shows, street theatre]. One of the most
TB
important ways is by word of mouth. Health workers can
Relatively few people with active tuberculosis live in the same
play an important role in sharing information about TB
geographical location [except in urban areas]
during conversations with patients and people in the
Disadvantaged groups in society often have less experience in
community. advocating on behalf of themselves
Advocacy TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis;

The main role of advocacy in TB control is to draw the
attention of policy makers, donors and the media to the
magnitude of the TB epidemic, and to the benefits of
DOTS. Many organizations have been most effective in Research
advocating on behalf of groups in society who are The principles underlying the DOTS strategy were first
disadvantaged due to social status, disease, gender, age, developed by an international NGO—the International
race, etc. Recently, these organizations have recognized Union Against Tuberculosis and Lung Disease [IUATLD]
that people affected by TB are often the most disadvant- (22). Commitment to research has enabled many NTPs
aged in society, and that advocacy on their behalf is vital around the world to develop excellent TB control
in order to develop and maintain effective TB control programmes in their own countries, NGOs with resources
programmes. and a capacity for innovation and flexibility have the
World Tuberculosis Day [March 24th] provides a opportunity to conduct research. However, there is often
global opportunity to advocate for and with patients and a conflict between the need for standardization to ensure
programmes to raise awareness and increase commit- that everyone follows national policies and the need for
ment to DOTS. Around the world, organizations and innovation to improve the way TB control services are
individuals organize events to commemorate the
organized. Any deviation from NTP policy is only
anniversary of the discovery of Mycobacterium tuberculosis
acceptable if it is agreed beforehand with the national
by Robert Koch in 1882.
authorities, and if it is part of a well-run research, designed
to find solutions to important problems in the TB
Patient’s Organizations
programmes. Research must be relevant to the needs of
There has been a rapid growth in self-help groups and the NTP and must be scientifically rigorous. It must not
patients’ organizations in the last few years, particularly hamper programmes by deviating attention and resources
for people with HIV infection and AIDS and other chronic away from the primary purpose of introducing and
illnesses. Such groups have many benefits, providing a maintaining excellent TB control services. Tuberculosis
social network for patients and their families, information research does not have to be expensive. Important
and education about specific conditions, and advocacy information can be gained simply and quickly by
analyzing information in the routine recording and private practitioners, and act as the interface between the
reporting system. public and private sectors.
Partnerships with the Private Sector Human Immunodeficiency Virus/Acquired

Immunodeficiency Syndrome Organizations
In many countries of South-East Asia, the majority of people
and Tuberculosis Control
with TB are initially diagnosed and treated by doctors
working in the private sector (23). This can cause serious Tuberculosis is closely linked to HIV infection. People who
problems for the NTPs, as poorly treated patients are a are co-infected with TB and HIV have a very high risk of
source of infection in the community, and may develop developing active TB, up to about 10 per cent a year. In
multidrug-resistant tuberculosis. Characteristics of poor many countries of South-East Asia, over 50 per cent of
management of TB patients in the private sector are shown people with AIDS have active TB. There is also a strong
in Table 61.4. link between TB control and prevention of AIDS. Treating
Governments have three alternatives for improving the people with TB and HIV infection prolongs their life,
care of patients in the private sector. These are: education, reduces suffering, and prevents the spread of TB to other
people. The reverse is also true; if HIV increases, then the
Table 61.4: Characteristics of poor management of number of people with TB also rises. So preventing the
tuberculosis patients in the private sector
spread of HIV is good for TB control.
Diagnosis by chest radiograph, without smear examination, leading Organizations involved in HIV/AIDS prevention and
to over-diagnosis of smear-negative TB and under diagnosis of care may not be fully aware of the close links between
smear-positive TB.
TB and HIV, and may not have experience in supporting
Over-use of unnecessary and expensive tests people with TB (24). However, the close relationship
Under-treatment; too few drugs, short duration, inadequate doses between the two infections means it is important that
Over-treatment; prolonged duration HIV/AIDS organizations take urgent steps to learn about
No supervision of treatment TB [and vice-versa], and find ways of integrating TB control
No follow-up of late patients activities into their work. Both programmes can serve as
Inappropriate monitoring of treatment by chest radiograph identification points for the two diseases and formally
Inadequate treatment records link with cross-referral of patients. Organizations involved
No reporting in prevention of spread of HIV infection can develop
educational approaches to help increase awareness of the
TB = tuberculosis
links between HIV and TB. However, it is important that
such educational approaches do not use fear to influence
people. Creating fear may have a limited effect in the short-
collaboration and legislation. The NGOs have an important term, but in the long-term can create stigma, and make life
role to play in establishing links between the public and even harder for people with HIV and TB.
private sectors in the first two of these approaches (2). The
NGOs can educate private practitioners to adopt NTP SUCCESSFUL PARTNERSHIPS
diagnostic and treatment policies, and encourage them to
The NGOs involved in TB control do not exist in isolation,
refer patients for DOTS. In addition, NGOs may be able to
they form part of the NTP, which includes the
provide diagnostic and treatment services to which private
community, the government, the private sector, and
practitioners can refer patients. The NGOs can also provide
other NGOs. Successful participation in the NTP is
outreach workers in the community for follow-up of late
facilitated by information, collaboration and co-
patients, and may be able to assist with recording and
ordination.
reporting of patients managed in the private sector. Links
with national and local branches of medical associations,
Information
with chest physicians, para-medical workers, pharmacists
and other associations may be possible. The NGOs can A successful programme relies on a steady flow of
also help to facilitate the development of networks of information. The successful programme will generate
872 Tuberculosis
information that it can share with others. Equally, a good Table 61.5: Key to successful networking
programme needs information to ensure that it is up to
Shared ownership
date with current developments in TB control. Sources of
Consensus
information include newsletters, journals, books,
Openness
conferences, meetings, training courses, and the World
Wide Web. Transparency
Communication
Collaboration
There are many existing and potential partners working though voting may be needed at times. Networks also have
in TB control. Collaboration, working together, is an to define the membership. This will usually be open, with
effective way of strengthening partnerships, reducing few restrictions or pro-qualifications, other than interest
costs, sharing resources and skills, and maximizing the or involvement in TB control. Prior agreement on the scope
value of the contributions of different agencies. of discussions within the network will help to prevent
meetings from deviating from the main purpose.
Co-ordination Appointment of a secretary responsible for arranging
Co-ordination, keeping each other informed, is important meetings, preparing and distributing the agenda, and
to avoid duplication of effort. Networks are groups of keeping minutes of discussions, will help to increase the
individuals and organizations that meet and communi- effectiveness of meetings. “Turf wars”, in which
cate together, and facilitate effective co-ordination. Most organizations compete for resources or areas of work, can
networks have formed to share information, co-ordinate be very destructive. These can be avoided by frequent
activities, and advocate for action. Learning organizations communication and maintaining a commitment to
are always keen to listen to others, to find out what works, openness and transparency in dealing with government
and to share failures as well as successes. The rapid and donors.
increase in the number of NGOs working in TB control, The potential and need for NGO involvement in TB
and the growth of information technology, has resulted control is even greater than ever. The challenge of the TB
in a profound change in the way information is shared. epidemic, the recognized relationships between TB and
Many local and national TB networks have developed poverty, human rights, women’s health, and child health,
in recent years, such as the Tuberculosis Control Network together with the added threats of HIV infection and AIDS
[TBCN] in Nepal and the LCC in Bangladesh. and drug resistance, demand urgent attention from
Networks are needed at each level. In the commu- organizations committed to health and development.
nity, networks of patients in self-help groups can offer Opportunities for involvement are many, and most
mutual support to one another. At the district level, organizations will be able to find an approach that builds
groups of NGOs can co-ordinate activities. At the on their existing skills and experience. Community
national level, networks can share information and participation and co-ordination with the government and
resources, and co-ordinate research, education and other NGOs are key principles that will ensure
advocacy activities. success (25).
There are some basic principles for successful net-
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874 Tuberculosis
Global Tuberculosis Control:

The Future Prospects
62
D. Fraser Wares
“At the midpoint of the 20 th century, tuberculosis was shown that by using multi-drug chemotherapy virtually
recognized by all as the “White Plague”, undeniably the most all TB patients could be cured.
dreaded enemy of the human race by any measure. Whether In 1956, the Tuberculosis Chemotherapy Centre
measured by prevalence, cost, social consequences, sheer misery [TCC], now called Tuberculosis Research Centre [TRC],
or any yardstick, I believe that any observer of the time would was opened in Madras [now called Chennai], India under
consider the bacillus of tuberculosis as the enemy number one the joint auspices of the Indian Council of Medical
of the human race. None of us – myself included – believed Research, the Madras State Government, the WHO and
that its control could be attained by medical means within this the British Medical Research Council. Through pioneer-
20th century.” ing studies in the 1950s and 1960s, the TCC demonstrated
Professor H. Corwin Hinshaw the safety and efficacy of ambulatory TB treatment, the
Pioneer tuberculosis researcher at the Mayo Clinic, USA in effectiveness of intermittent chemotherapy, and the
the 1950-60s [quote from the introduction to his unfinished feasibility and necessity of directly observed treatment
book titled “Conquest of a Plague”] (3,4). In the 1960s, the National Tuberculosis Institute
[NTI] in Bengaluru [earlier known as Bangalore], India
INTRODUCTION documented the importance of TB detection through
sputum smear microscopy in primary health centres (5).
Pre-1992
During the 1960s, rifampicin, pyrazinamide and
In 1960, the eminent figure in the field of tuberculosis ethambutol were added to list of drugs effective against
[TB] Sir John Crofton, felt confident during a lecture at TB. Slowly over the next two decades, the threat of TB
the Royal College of Physicians of London to state that: faded from the every day concerns of people in the
“I believe that we now have the weapons to defeat TB developed world. Work in the 1970s and 1980s led by
finally and completely,….”(1). In the same year as Sir doctors such as Karel Styblo and Annik Rouillon of the
Crofton delivered his lecture in London, the World International Union Against TB and Lung Disease
Health Organization [WHO] at its seventh meeting [IUATLD], had begun to show that the principles laid
stressed that “tuberculosis was the most important out by the ground-breaking research of the previous two
specific communicable disease in the world as a whole, decades could also be implemented in developing
and its control should receive priority and emphasis by countries, such as Tanzania (6).
the WHO and governments” (2). Important discoveries Yet in 1990 and 1991, reports were being published
of drugs to treat TB, namely streptomycin, isoniazid and drawing attention to the fact that during the previous
para-aminosalicylic acid [PAS], had been made in the five years, there had been an ominous resurgence of TB,
two decades prior to Sir Crofton’s statement. Work by especially in sub-Saharan Africa (7). Between the mid
Crofton and colleagues in Edinburgh, Scotland (1), had 1980s and 1990, global notification rates had risen by
Global Tuberculosis Control: The Future Prospects 875
20 per cent (8). In October 1990, at a meeting of represen- Development Agency, reviewed the National TB
tatives of TB control programmes from all over the world Programme. The Programme review showed that only
convened by the WHO, Africa was described as “lost” 30 per cent of patients were diagnosed, out of which only
to the epidemic of co-infection of human immunodefi- 30 per cent were treated successfully (16). It had already
ciency virus [HIV] and TB (9). In an article in the Lancet been pointed out that such poor results of chemotherapy
that took its title, “Is Africa lost?”, from the WHO’s may slow down the natural decline of TB, worsen the
experts’ comments, the prominent authors stated “In epidemiological situation by keeping infectious cases
conclusion, we are facing one of the greatest public-health alive to continue to transmit infection, and may lead to
disasters since the bubonic plague” (9). The HIV was an increase in the prevalence of drug resistance (17).
stated to have “caused the greatest deterioration in the How had this situation arisen given the optimism of
[TB] epidemiological situation in the last 100 years” (10). the previous decades? There were a number of factors to
In India, where a National TB Programme had been explain the resurgence of TB, or at least its halting decline,
initiated in 1962 and into which short-course chemo- over the preceding two decades. Crucially, TB had come
therapy [SCC] had been introduced since 1983, a study to be neglected as a public health issue by many countries
from south India showed mortality and failure rates of and the international health community. In indus-
28 per cent and 31 per cent, respectively amongst a cohort trialized countries, advances in TB treatment had led to
of patients during 1986-88 (11). Only 40 per cent of a relatively quick disappearance of the disease as a public
patients completed treatment, with this non-completion health problem. The fact that the disease still had a huge
impact on the poor in developing countries had slipped
of treatment resulting in over a four-fold increase in
out of sight of the international health community. Many
mortality and two-fold increase in the failure rate when
of these countries were in addition struggling to provide
compared with patients who had completed treatment.
basic public services such as health services, due to the
In 1990, the Commission on Health Research for
deterioration in their socio-economic conditions,
Development stated that “The magnitude of the TB
increasing poverty, mounting debt and an ever growing
problem is matched only by its relative neglect by the
population whose needs had to be met. Tuberculosis as
international community” (12). The next year, in an
a priority issue became less visible because of both WHO
important global overview WHO repeated this message
taking a strong step towards integration of programme
when it stated that “This report confirms the staggering
functions and as a consequence of the health sector
global magnitude of the TB problem and the urgent need
reform movement (18). In 1989, just before the
to revive antituberculosis control programmes through- establishment of a new TB Unit at the WHO, only two
out the world” (13). It was estimated that in 1990, nearly staff were responsible for WHO work on TB control
8 million new cases of TB and 2.9 million deaths due to worldwide (18). International funding for TB control
TB occurred worldwide, making TB then the leading work was minimal, and little, if any, important research
infectious cause of death in the world. The TB notification was being conducted into new drugs, diagnostics or
rates in the 1990s had doubled or tripled in some African vaccines for TB.
countries, such as Malawi, Tanzania and Zimbabwe, in The spread of HIV and acquired immunodeficiency
as short a period as 10 years. syndrome [AIDS], especially in sub-Saharan Africa, was
In another important paper published in 1991, it was playing an important role in further increasing TB
estimated that 1.7 billion people, i.e. a third of the human morbidity and mortality [Figure 62.1] (19-22). Social and
population, were infected with the tubercle bacillus (14). economic deterioration in countries of the former Soviet
Over 95 per cent of the estimated eight million new cases Union, with a resultant collapse of their public health
and 2.9 million deaths were occurring in the developing services, had led to a dramatic rise in TB morbidity and
world. At the same time, less than 15 countries world- mortality [Figure 62.1] (23). In the USA, the rise in TB
wide were capable of reporting on treatment outcomes, notifications in the mid-1980s prompted the awakening
less than half of TB cases were covered by proper of public health and TB experts in that country [Figure
treatment services, and less than half of the cases treated 62.2] (24,25). Identified reasons for the increase in the
were cured (15). In 1992, the Government of India, USA were growing urban poverty, TB control being given
together with WHO and the Swedish International low priority with resultant deterioration of the TB control
876 Tuberculosis
Figure 62.1: Trends in TB case notification rates, 1980-2000 in Africa and former Soviet Union
THE RESPONSE: THE DOTS STRATEGY

Understanding the natural history of TB disease is key
to the development of effective control strategies for the
disease. In the absence of effective treatment, case fatality
of TB was extremely high, around 50 per cent (29,30).
An untreated smear-positive pulmonary TB individual
remains, on an average, infectious for approximately two
years, and then dies or recovers (31). In those two years,
Figure 62.2: Reported tuberculosis cases United States, a single patient infects on an average 20 contacts (32). Of
1979-1999 these infected contacts, on average two persons
Reproduced with permission from “Schneider E, Castro KG. eventually break down with active disease, of which one
Tuberculosis trends in the United States, 1992-2001. Tuberculosis will have smear-positive pulmonary TB (33). In this way,
the chain of transmission of TB essentially remains
programme infrastructure and poor TB control practices, steady, reflecting, in itself, a well-adjusted host-parasite
and the burgeoning HIV epidemic (25). However, it soon relationship between man and Mycobacterium tuberculosis.
became clear that a growing percentage of cases notified Early detection of infectious cases and effective treatment
annually in the USA were among recent immigrants from leading to cure reduces the infectious period consi-
low income and high TB burden countries HBCs, a direct derably, and thus, reduces transmission, thereby
consequence of the worldwide neglect of TB control reducing the incidence of new infections.
(26,27). Many other industrialized countries were also The failure to introduce effective treatment program-
seeing an increase in TB cases and driven by the similar mes in developing countries, by application of ambula-
factors of increased urban poverty, increase of TB cases tory therapy using standard chemotherapy regimens for
seen amongst immigrants from HBCs and HIV (28). The smear-positive TB cases, had meant that the chain of
finding that in industrialized countries, an increasing transmission had continued unchanged in these
percentage of TB cases were amongst immigrants countries. This despite an international consensus on the
from HBCs, began to generate awareness that no overall control strategy as expressed in the WHO Expert
sustainable TB control could be reached in the USA and Reports on TB in 1964 and 1974 (34,35). The most
many Western European countries without properly important reason had been the failure to cure the sources
addressing the global TB epidemic. of infection that were identified.
In an article in 1991, Dr Arata Kochi, the newly Association [KNCV], such as Benin, Malawi,
appointed head of WHO’s TB programme, highlighted Mozambique, Nicaragua and Vietnam. They also
three major programmatic deficiencies that had to be included countries with a long history of adequate control,
overcome: inadequate treatment services, high rates of such as Algeria, Chile, Cuba and Uruguay. Finally there
failure to complete treatment, and the worldwide absence were two countries, China and Peru, in the initial phase
of adequate governmental surveillance and monitoring of implementation of programmes that would become
systems (14). It was also recognized that bacille Calmette- successful models later in the decade (39).
Guérin [BCG] did not have a significant impact on A major boost to global TB control efforts was the
reducing transmission of infection and that renewed publication of the World Bank’s 1993 Development
emphasis had to be given to the treatment of infectious Report, in which TB chemotherapy was called “one of
cases, especially those whose sputum was smear positive. the most cost-effective of all health interventions” (40).
The WHO began to promote an approach that had been This official endorsement by the World Bank of the
successfully implemented by Karel Styblo of the IUATLD importance of investing in TB control influenced financial
in some of the poorest African countries, like Malawi and policies in many countries. Also in the same year, WHO
Tanzania. The approach was based on the concepts declared TB a global emergency, an unprecedented step
expressed in the 9th Report of the WHO Expert in public health and WHO’s own history (41). Soon
Committee on TB from 1974 (35). The prime objective of afterwards in 1994, launched the “Framework for Effec-
TB control programmes was to be the improvement of tive Tuberculosis Control” which laid out the five essen-
the cure rate of all patients under treatment, but most tial elements of a TB control policy package (42). These
importantly of the smear-positive cases. During field five elements were: [i] government commitment to
implementation of these theoretical concepts in Tanzania, sustainable TB control; [ii] diagnosis through sputum-
Styblo added the practical tools necessary to evaluate smear microscopy mainly among symptomatic patients
programme performance. The results showed that, even self-referring to health services; [iii] standardized SCC
in a very poor country, it was possible to achieve high provided under proper case management conditions,
cure rates (6,36). Inspired by these observations, WHO including direct observation of treatment [DOT]; [iv] a
requested all countries to focus on cure rates and achieve functioning drug supply system ensuring a regular,
at least 85 per cent cure rates, and, later, expand TB uninterrupted supply of all essential antituberculosis
services to detect more cases once the cure rates were drugs; and [v] a recording and reporting system allowing
permanently high (14). assessment of treatment results from all patients
In May 1991, the 44th World Health Assembly met in registered. A year later, in 1995, this package was branded
Geneva and adopted a resolution [WHA 44.8] which: under the name “DOTS” – the Directly Observed
[i] urged member States to intensify TB control as an Treatment, Short-course strategy for TB control.
integral part of primary care using the new WHO strategy
elaborated on the basis of the IUATLD approach;
PROGRESS SINCE 1992
[ii] encouraged international partners to continue to help
control TB by collaborating with National Programmes; During the mid-1990s, there was rapid progress in global
and [iii] requested the establishment of global targets (37). TB control. The DOTS strategy was aggressively
The targets set were to cure 85 per cent of sputum smear- marketed, and soon became widely adopted by inter-
positive patients under treatment, and detect 70 per cent national agencies and countries themselves and one of
of such cases by the year 2000. If these targets were met, the most well-known brands in health (43). The number
it was calculated that the result would be a 40 per cent of WHO member countries adopting the DOTS strategy
decrease in infected contacts. This would lead to a rapid continued to grow throughout the 1990s (44). Countries
decrease in the prevalence of TB, which in turn would were encouraged to adopt the strategy by the demons-
lead to a decrease in the incidence of the disease (38). tration that it was effective at achieving high cure rates
In 1992, less than 20 countries were implementing a and by an increasing media interest in TB (45). At the
sound TB control strategy that would later be called the same time, available external funding for TB control
DOTS strategy. These included the countries assisted by increased from $16 million in 1990 to $50 million in 1996,
the IUATLD and the Royal Netherlands Antituberculosis and up to $190 million in 2000 (18).
878 Tuberculosis
However, despite the rapid adoption of DOTS and recommendations which included: creation of a “global
the increased finances available, following the establish- charter” among all key partners and the endemic
ment of a global surveillance and monitoring system and countries to co-ordinate efforts more effectively; a proper
the publication of the first monitoring report by the WHO balance between integration of TB control services and
in 1997, it became apparent that the targets set for the specificity, and between decentralization and centralized
year 2000 were not going to be reached (46). The report functions; involvement of private sector and communi-
showed that only 11 per cent of all estimated cases were ties in TB control activities; creation of a “global drug
being treated under DOTS programmes, leaving nearly facility”, and strengthening of health information
nine out of ten either untreated or managed through systems related to TB control activities.
other TB control practices. The cure rate among those In November 1998, the new WHO Director-General
cases treated under DOTS in 1995 was 78 per cent (46). launched the Stop TB Initiative [Table 62.1] with found-
That the targets were not going to be met were largely as ing members comprising the American Lung Associa-
a result to the very slow pace of DOTS expansion in the tion ALA, the American Thoracic Society ATS, the
22 HBCs, who are home to 80 per cent of the global IUATLD, the KNCV, the United States’ Centers for
incident cases. Disease Control and the WHO. Other organizations soon
In view of the slow pace of DOTS implementation, joined. A clarion call in the fight against TB, its purpose
in early 1998 WHO convened an “Ad-hoc Committee is to support partners in fulfillment of the vision and
on the TB Epidemic” to discuss the TB situation in mission of the global movement.
countries with respect to the Year 2000 targets and to
make recommendations for rapid control. The Commit- Mission of the Stop TB Initiative
tee highlighted six major issues which in their view were The mission of the Stop TB initiative is: [i] to ensure that
impeding global TB control efforts, namely: insufficient every TB patient has access to effective diagnosis,
political will and commitment; lack of financing or treatment and cure; [ii] to stop the transmission of TB;
ineffective use of financial resources; lack of trained [iii] to reduce the inequitable social and economic toll of
human resources; lack of good management at prog- TB; and [iv] to develop and implement new preventive,
ramme level in many countries; problem in quality and/ diagnostic and therapeutic tools and strategies to stop
or supply of antituberculosis drugs; and weakness of TB.
information systems (47). Also HIV-associated TB and Much has happened in the years since the launch of
multidrug-resistant TB [MDR-TB] were recognized by the Stop TB Initiative in 1998. As a result of the Initiative’s
the Committee as two key epidemiological challenges cultivation of high level support for accelerated action
that needed to be tackled urgently with effective inter- against TB in the HBCs, a Ministerial Conference on
ventions. In response to the issues highlighted, the Tuberculosis and Sustainable Development was
Committee made a number of specific as well as general convened in Amsterdam in March 2000. On World TB
Table 62.1: Excerpt from the remarks of World Health Organization Director-General Brundtland at the Global Congress on
Lung Health and the 29th International Union Against Tuberculosis and Lung Disease World Conference, Bangkok, November
1998
“Today I invite you to participate in a new Stop TB Initiative led by WHO. This initiative is at its very beginning. It is founded on
partnership. Only with your and others’ participation will we be able to address the real problems of TB in Asia and the rest of the world.
We need to reach out to the TB community but also beyond it – to the UN family, to the private sector and civil society. Tuberculosis is
relevant to organizations that deal with human rights, women’s rights, poverty, prisoners and labour markets
The initiative will develop a global action plan for TB control which identifies the role for different partners. It will focus on a global charter
to secure commitments to improve TB control from Heads of State of endemic countries, international organizations, and donors. It will
develop mechanisms to ensure global access to quality, fixed dose combination TB drugs
Urgent action focussed on high burden countries, the emerging drug resistance problem and management of TB control in settings of
high HIV prevalence is also planned. The initiative will support a balanced agenda for global TB research focussing on short- and long-
term results”
TB = tuberculosis; WHO = World Health Organization; UN = United Nations; HIV = human immunodeficiency virus
Day 2000 [24 March] ministers from 20 of the world’s 22 all types “to support and to participate in the global
HBCs, adopted the landmark Amsterdam Declaration partnership to stop TB by which all parties co-ordinate
to Stop TB [Figure 62.3]. Along with the members of the activities and are united by common goals, technical
Stop TB Initiative, the delegates from the 20 HBCs strategies, and agreed-upon principles of action” (50).
pledged to “develop and implement a global partnership At the same World Health Assembly, the global TB
agreement” through which “individuals, governments, targets set for 2000 were reconsidered. As most countries
private organizations and industry” could all contribute had failed to meet the targets set in 1991, the World
to efforts against TB (48,49). “Recognizing the enormity Health Assembly under resolution WHA 53.1, postponed
of the task ahead and the huge amount of resources the targets to 2005.
required….” the conference participants – ministers and The momentum of the Amsterdam Declaration led
high level representatives of the Organization for to the establishment of a Global DOTS Expansion Plan
Economic Co-operation and Development [OECD] [GDEP] in May 2001 (51). The GDEP promotes national
governments, international development organizations, inter-agency co-ordination committees and formulation
non-governmental organizations [NGOs] and bilateral of five-year DOTS expansion plans in line with global
donors – made the following commitments to meet the targets. It provided a template to mobilize the human
targets for global TB control by 2005: [i] to develop and/ and financial resources required to achieve the global
or strengthen the TB component of national development TB control targets, working through strengthened
plans; [ii] to ensure universal access to TB drugs through national health systems. At the first GDEP meeting in
improved procurement and distribution; [iii] to accelerate November 2000, only nine countries had comprehensive
Research and Development, and delivery of new tools plans, while three others were under preparation. By
and incentives for the development of TB diagnostics, 2001, 20 of the 22 HBCs had comprehensive national
drugs and vaccines; and [iv] to establish a Global Fund plans, with the last two to be finalized in January 2002.
for TB. Within the GDEP, an assessment of global financial needs
In May 2000, the World Health Assembly endorsed for TB control had been conducted, and this was
the idea of a Partnership, calling upon organizations of estimated at $1.2 billion per year. It was further estimated
that there was a funding gap of at least $300 million that
needed to be mobilized (52).
Also in March 2001, the Global TB Drug Facility [GDF]
was launched. The main goal of the GDF is to supply the
high quality antituberculosis drugs needed to rapidly
expand DOTS coverage in many HBCs that lack the
resources or mechanisms to procure such drugs. It aimed
to provide drugs to treat at least 10 million patients by
2005, thereby assisting countries to reach the global
targets by 2005.
A structure for the Stop TB Partnership was soon
devised [Figure 62.4] and was endorsed at the First Global
Partners’ Forum held in Washington in October 2001
[Figure 62.5]. In addition to the Stop TB Co-ordinationg
Board and Partnership Secretariat, six Working Groups
were set up to advance the work in vital technical areas,
namely DOTS Expansion; DOTS-Plus for MDR-TB; TB
and HIV; New TB Drug Development [Global Alliance
for TB Drug Development]; New TB Diagnostics
Development; and New TB Vaccine Development [TB
Vaccine Development Coalition]. A Task Force on
Figure 62.3: Amsterdam Declaration to Stop TB, 24 March 2000 Advocacy and Communications and a parallel body on
880 Tuberculosis
movement to Stop TB. Also at the Forum, the Partners

and the HBCs – some 80 countries and organizations –
endorsed the Washington Commitment to Stop TB,
committing themselves to the 2005 targets of 70 per cent
case detection and 85 per cent treatment success under
DOTS, and pledging specific actions to reach these targets
(55).
As TB became more visible on the international
agenda and gained momentum, additional sets of targets
were developed. At the 26th G8 Summit in Okinawa,
Japan, in June 2000, the eight major industrialized
countries discussed health related issues and committed
themselves to reducing TB deaths and TB prevalence by
50 per cent by 2010 compared with levels in the year 2000
Figure 62.4: Structure of the Stop TB Partnership (56). In the same year, member states of the United
TB = tuberculosis; WHO = World Health Organization; HIV = human Nations reaffirmed their commitment to sustaining
immunodeficiency virus; MDR-TB = multidrug-resistant development and eliminating poverty at the Millennium
tuberculosis; R & D = research and development Assembly of the United Nations. The Millennium
Development Goals were adopted and included to
“combat HIV/AIDS, malaria and other diseases” (57).
More specifically, TB was to be halted and the incidence
of TB reversed by 2015.
The Global Partnership to Stop TB now has over 250
organizations participating in it. The DOTS Expansion
Working Group [DEWG] has published the Global
Expansion Plan, assisted all 22 HBCs to prepare detailed
national plans for DOTS Expansion and gives support
to the countries as they implement these plans, and has
assisted in the establishment and functioning of Inter-
Agency Co-ordinating Committees in HBCs. By 2005,
DOTS has been implemented in 187 countries covering
nearly 89% of the world’s population (58-62).
Subsequently, the new Stop TB strategy 2006, and the
Global Plan to Stop TB, 2006-2015 (63) have been
announced. The reader is referred to the chapter
“Epidemiology: global perspective” [Chapter 4] for more
Figure 62.5: First global Stop TB Partners’ Forum, details regarding these topics.
Washington 2001 Through the WHO/IUATLD Global Drug Resistance
Surveillance Project, surveys in 72 countries have shown
Finance/Resource Mobilization provide common that MDR-TB is present globally and represents a major
support for the various areas of the Global Partnership constraint to TB control, especially in a few settings
(53). named “hot spots” (64,65). These “hot spots” included
At the Forum, the Partnership also unveiled the the Baltic Republics of Estonia and Latvia, parts of the
Global Plan to Stop TB 2001-2005, a budgeted, consensus Russian Federation and China, Iran and the Dominican
based five-year business plan (54). It estimated that $9.1 Republic. After much debate, in 1999 the international
billion would be necessary between 2001 and 2005 to community established the Global Working Group on
expand DOTS, adapt it to the challenges of HIV and DOTS-Plus for MDR-TB, which was responsible for
MDR-TB, develop new tools, and strengthen the global identifying solutions to the control of MDR-TB (66,67).
The establishment of good TB control by standard 1.9 million patient treatment courses, worth over $23
“DOTS” strategy is now seen as the sine-qua-non for million, approved. Twenty-seven countries had to date
DOTS-Plus. Much work has been done since 1999, in received the grants of TB drugs from the GDF. Through
exploring whether programmes can effectively introduce centralized, pooled procurement, the prices of
expensive second-line drugs into their routine activities antituberculosis drugs have been reduced by approxi-
under “DOTS-Plus” projects and guidelines for mately a third with the average drug cost per patient for
establishing DOTS-Plus projects were published by a full six-month regimen now standing at around $12
WHO in 2000 (68). Currently, projects are implemented (73).
in Peru, Latvia, Estonia, the Philippines and three oblasts In January 2002, the Global Fund to Fight AIDS,
[provinces] in the Russian Federation. The results of a Tuberculosis and Malaria [GFATM] was set up as a
country-wide project in Peru are promising and suggest financial instrument, complementary to existing prog-
that MDR-TB can be effectively managed under routine rammes addressing these three diseases. The purpose
conditions, using long regimens with second-line drugs of the Global Fund is to attract, manage and disburse
with reasonable adherence and cure rates (69). additional resources through a new public-private
The establishment of the DOTS-Plus Working Group partnership that will make a sustainable and significant
has succeeded in placing second-line antituberculosis contribution to the reduction of infections, illness and
drugs on the WHO Essential Drug List [EDL]. This listing death, thereby mitigating the impact caused by HIV/
on the WHO EDL and through the use of competitive, AIDS, TB and malaria in countries in need, and contri-
pooled procurement under the Green Light Committee buting to poverty reduction as part of the Millennium
[GLC], a committee appointed from amongst the Development Goals. By January 2004, US$2.1 billion
Working Group members, has resulted in a reduction of had been committed from the three rounds of Global
the price of second-line drugs by up to 90 per cent (70). Fund financing, of which over US$350 million [17%]
In addition as the Working Group aims to develop an had been approved for TB control activities. These funds
affordable, effective and evidence-based response to will be disbursed to the respective countries over the
MDR-TB in resource-poor settings, the GLC has been next two years (74).
tasked to control global access to the reduced cost second- The funding situation of TB control activities signi-
line drugs via an application process from potential ficantly improved in the year 2002. The total budget
DOTS-Plus project sites, with the purpose of ensuring requirement for 2003 in the 22 HBCs was calculated at
that misuse does not create further resistance (71). The $481 million, of which $52 million [11%] was not
GLC has now been subsumed under the GDF which has available at the time of the publication of the Seventh
now taken on this additional function. The reader is also WHO Annual Report on Global TB Control (44). The
referred to the chapters “Antituberculosis drug resistance anticipated funding gap for 2003 was lower than that
surveillance” [Chapter 50], “Drug-resistant tuberculosis” reported for 2002, and the approval of applications to
[Chapter 49] for more details. the GFATM from a number of HBCs to fund TB control
The Working Group on TB/HIV has developed a new activities would have further reduced the funding gap.
strategic framework to reduce the burden of TB/HIV (72). In 2002, WHO issued “An Expanded DOTS Frame-
Working Group members are now assisting countries to work for Effective TB Control” (75). The original
put the framework into practice and promote colla- framework dated from 1994 (42), and since then many
borative activities between TB and HIV/AIDS program- challenges had been identified which had impeded
mes. The three research and development Working sustainable implementation and expansion of TB control
Groups [Global Alliance for TB Drug Development, New activities. Many of these stem from a weak political will
TB Diagnostics Initiative and New TB Vaccine Initiative] failing to elicit the required health system and societal
are making substantial progress in their work on the response to control TB. General public health services
medium- and long-range solutions to the TB problem. needed to enhance their capacity to sustain and expand
In its first two years of operations, the GDF completed DOTS implementation without compromising the
six rounds of grant applications, 69 applications for grants quality of case detection and treatment. Community
of TB drugs were reviewed, with 46 applications and over involvement in TB care and a patient-centred approach
882 Tuberculosis
is needed, emphasizing and promoting to improve both [iii] standardized SCC to all cases of TB under proper
access to and utilization of health services. Collaboration case-management conditions including direct
and synergy among the public, private and voluntary observation of treatment. Proper case management
sectors are seen as essential to ensure accessible and conditions imply technically sound and socially
quality-assured TB diagnosis and treatment. The increas- supportive treatment services; [iv] uninterrupted supply
ing impact of HIV on the incidence of TB, especially in of quality-assured drugs with reliable drug procurement
sub-Saharan Africa, called for new partnerships and and distribution systems; and [v] recording and reporting
approaches. A surge of drug-resistant forms of TB in the system enabling outcome assessment of each and every
former Soviet Union and several other parts of the world, patient and assessment of the overall programme
required effective implementation of the DOTS strategy performance.
to prevent the development of new MDR-TB cases in The expanded framework also contained some addi-
addition to measures to cure existing MDR-TB cases, i.e., tional areas of key operations. These included: informa-
DOTS-Plus activities. Sustaining DOTS programmes will tion, education, communication and social mobilization;
also entail their integration into primary health care and involving private and voluntary health care providers;
adaptation to ongoing reforms within health sectors economic and financial planning; and operational
around the world. research.
Recognition had been made that it was now necessary In 2003, WHO also published the third edition of the
to widen the scope of the DOTS strategy and make it a Guidelines for National Programmes (82). Reflecting the
comprehensive support strategy – support to all new challenges facing TB control, the third edition
providers, patients and people to tackle the problem of included separate chapters on the management of
TB. It laid equal emphasis on technical, managerial, social chronic and multidrug-resistant cases, TB and HIV
and political dimensions of DOTS. It acknowledged infection, and TB in children.
access to TB care as a human right and recognized TB
control as a social good with large benefits to society. CURRENT SITUATION
Cost savings for DOTS countries can be substantial, as After the unprecedented activity of the last decade
indeed for the community – a study in Thailand found directed towards the goal of global TB control, where do
that for every US $1 invested by the government in TB we stand today?
control, the community gained US $50 over a 20-year Tremendous progress has been made and remarkable
period (76,77). Per capita costs of implementing DOTS successes have occurred. The reader is referred to the
may be as low as US $0.05 in some low-income countries chapter “Epidemiology: global perspective” [Chapter 4] for
(78). These, and the findings of others, underscored the details regarding the expansion of DOTS worldwide, and
contribution TB control makes to poverty alleviation by its current status. Death rates under DOTS programmes
reducing the great socio-economic burden that the are often dramatically lower than non-DOTS
disease inflicts on the poor (79-81). programmes, and DOTS has saved more than one million
The expanded framework reinforced the five essential lives in the last 10 years (83).
elements of the original DOTS strategy, and applied to Significant declines in TB have been seen in a number
HIV-related and drug-resistant forms of TB as well. The of countries that have been implementing DOTS for some
five elements of the expanded framework were: [i] sus- years. Mathematical modelling estimates that where TB
tained political commitment to increase human and incidence is stable and HIV absent, a control programme
financial resources and make TB control a nation-wide which reaches the WHO targets of 70 per cent case
activity, integral to the respective national health system; detection and 85 per cent cure would reduce the
[ii] access to quality-assured TB sputum microscopy for incidence rate by 11 per cent per year [range 8% to 12%/
case detection among persons presenting with, or found year] and the death rate by 12 per cent per year [9% to
through screening to have, symptoms of TB [most 13%/year] (84,85). At a seven per cent annual decrease,
importantly prolonged cough]. Special attention is incidence would be halved in 10 years. Reaching WHO
necessary for case detection among HIV infected people targets by the year 2010 would save 23 per cent [15% to
and other high-risk groups, e.g., people in institutions; 30%] or 48 million cases by the year 2020 (84). As stated
by Dye et al (84) “The potential impact of chemotherapy

[delivered as DOTS] on TB is greater in many developing
countries now than it was in industrialized countries
50 years ago. To exploit this potential, case detection and
cure rates urgently need to be improved in the principal
endemic countries of the world”. The predictions of the
mathematical model are now borne out by practical
experience in Peru, which had implemented a DOTS-
based programme in 1990 and has achieved high rates
of case detection and cure. The incidence of pulmonary
TB has been seen to be decreasing by at least six per cent
a year and the number of deaths during the 1990s were Figure 62.7: Decline in tuberculosis deaths, Peru 1987 to 1999
cut by more than half [Figures 62.6 and 62.7] (86). Source : reference 86
China has also experienced dramatic declines in case
prevalence as DOTS coverage and treatment success
reached very high levels [Figure 62.8] (87,88). Deaths in
those counties of China that are implementing the DOTS
strategy have prevented at least 46 per cent of the TB
deaths that would otherwise have occurred (89).
India, the country with the largest TB problem in the
world (44), has made tremendous progress in TB control
through the implementation of the Revised National
Tuberculosis Control Programme [RNTCP] – an adap-
tation of the DOTS strategy to local conditions (90,91).
Starting in late 1993 with five pilots sites covering a
population of 2.35 million, by the year 2006 the RNTCP
covered the whole country, the fastest expansion of any Figure 62.8: Reduction of tuberculosis prevalence in DOTS
areas, China 1990-2000
programme in the history of DOTS (90,92-94). The reader
is referred to the chapter “Revised National Tuberculosis
Control Programme” [Chapter 63] for the more details
regarding the achievements of the RNTCP.
Since 2001, annually India has treated more patients
under DOTS than any other country in the world, and
has been the largest contributor to the global case load
(43). Treatment outcomes have been maintained at a high
level since the inception of the RNTCP, with a cure rate
of between 84 to 86 per cent in those patients treated
from the start of 2001 onwards. The mortality in the
RNTCP has reduced to four per cent as compared to 20
to 30 per cent in the earlier National TB Programme
(11,95).
However, the estimates of the global situation suggest
that in 2000 there were 8.3 million new TB cases (44,96).
Incidence rates in sub-Saharan African countries average
Figure 62.6: Decline in tuberculosis incidence, Peru 1980-2000 about 300 per 100 000 population, but in absolute terms,
Source: reference 86 60 per cent of all cases were in Asia. Nine percent of all
884 Tuberculosis
new TB cases in adults were attributable to HIV infec-

tion, but in sub-Saharan Africa, this proportion was
31 per cent. Twelve percent of the TB deaths were attri-
butable to HIV, with TB being the cause of death of
11 per cent of all adult AIDS deaths. It had already been
estimated earlier that without more intensified TB control
activity globally, the annual TB incidence was expected
to increase by 41 per cent [21% to 61%] between 1998
and 2020, from 7.4 million to 10.6 million cases per
year (84).
The increase in geographical coverage of DOTS
programmes does not seem to have translated directly
into gains in case detection. More precisely, overall case
detection from DOTS and non-DOTS areas has remained
at around 40 to 50 per cent since 1980. The progression Figure 62.9: Progress towards 70 per cent case detection,
1994-2003
in case detection under DOTS has mainly been associated
Open circles mark the number of smear-positive cases notified
with gains in cases in DOTS areas from cases previously under DOTS 1995 to 2003, expressed as a percentage of estimated
from non-DOTS areas, and not solely recruiting patients new cases in each year. Closed circles show the total number of
who were never detected and/or notified i.e., most smear-positive cases notified [DOTS and non-DOTS] as a
patients recruited by DOTS programmes are those that percentage of estimated cases
would have been detected and treated anyway in the WHO = World Health Organization
public health system (44,97-98).
Case detection under DOTS has progressed in a linear
fashion over the past years, with an average of 130 000 If the low case detection is due to a problem with the
additional cases being enrolled annually, and at the numerator, where are the missing cases? First, they may
current rate of progression, the 70 per cent case detection just simply be in the community and not presenting to
target will not be attained until after 2010 [Figure 62.9] any health facility, if DOTS programmes and hence the
(22). Some have suggested that even after 2010 the target TB services, are not easily accessible to the population
is not likely to have been reached as the DOTS prog- [Figure 62.11]. DOTS geographical coverage refers to the
rammes expand to the harder-to reach groups (100). percentage of national population that lives in an
There is the possibility that the case detection rates may administrative area, such as a district or province, where
even plateau at 40 to 50 per cent, if additional strategies DOTS services are provided. Full DOTS coverage in any
to detect and notify new cases are not widely given country does not mean that all care providers in
implemented urgently. However, this global analyses did this country follow the DOTS strategy, but only that
not take into consideration the recent rapid progress in governmental health services can provide it. Not all
DOTS expansion such as that made by India in the Years governmental health service facilities may, however,
2002 to 2003, which has led to an acceleration in global provide DOTS services. For example in some countries,
case detection [Figure 62.10]. only specialized TB clinics actually provide DOTS
The low case detection rates seen could, however, be services, excluding a range of facilities including both
due to either the denominator [estimated annual number out-patient and hospital primary health-care services. A
of new smear-positive cases in a given country] being whole range of factors, including geographical or
too high or from the numerator [number of smear- financial, may mean that the population does not have
positive case notifications] being too low. The number access to services.
of TB cases has been estimated on several occasions, with Secondly, cases may be missed within DOTS
the results being similar and consistent (7,13,96,101,102). Programmes if staff do not suspect or diagnose cases
Hence it is unlikely that the low case detection is due to correctly. Thirdly, cases may be missed as they remain
problems with the denominator at a global level. unreported, if DOTS programmes do not notify all cases
are thus often not reported and a substantial proportion

of TB cases may be missed (103). Fifthly, if all the public
health systems are not implementing the DOTS
programme, cases may be missed. For example in China,
the hospital system, which diagnoses a large number of
TB cases, remains largely separate from the DOTS
programme, resulting in a lower than expected case
detection rate [Figure 62.12] (87,104). In addition, patients
may be simply being seen and treated under a non-DOTS
TB control programme.
Finally, the patient may seek advice and treatment
from the private health sector, ranging from pharmacies,
Figure 62.10: Case detection increasing within DOTS areas in quacks, private practitioner’s clinics or private hospitals.
India
Many developing countries, especially in Asia, are seeing
a rapid expansion of the private health sector. For
example it is estimated that 80 per cent of households in
diagnosed. Furthermore, in some settings there may be India choose the private sector for care of minor illnesses
a reluctance to register all cases, especially those deemed and 75 per cent for major ones (105). Hence many people
by the staff to have a high risk of not completing with TB symptoms and disease seek treatment from the
treatment. Fourthly, if not all the public health services private sector, which may provide poor quality diagnosis
and systems are fully linked, cases may be missed. For and treatment (106). In general, there is little co-ordina-
example, prevalence rates are often high amongst tion between the public and private sectors in many low
prisoners, but usually the prisons’ medical services are income HBCs and cases managed in the private sector
the responsibility of the Ministry of Justice and rarely usually go unreported to the national TB programmes.
are they linked efficiently with the general health services Serious differences in perception are seen between those
in the community under the Ministry of Health. Cases practitioners in the public and private sectors, and co-
ordination of activities, especially those related to public
health activities, is rare (107,108). If the private sector is
not involved in TB control activities by national TB
programmes, a significant proportion of cases may be
missed.
Figure 62.12: Improving case detection in China

Figure 62.11: Why may tuberculosis cases be “undetected”? TB = tuberculosis
TB = tuberculosis Source: reference 104
886 Tuberculosis
Priorities for Action Table 62.2: Priorities for action that were listed to achieve
2005 global targets
Financial gaps are progressively decreasing, but in many
Improve, monitor and maintain quality of DOTS
settings, weaknesses of the general health systems, rather 100 per cent geographical coverage, involvement of all MoH
than of specific TB activities, are emerging as major care providers
constraints. Four major constraints to DOTS expansion Comprehensive budgets, with increased utilization of those
were identified at the DEWG meeting held in late 2002, resources being made available
namely: inadequate human resources, in terms of Identification of non-financial constraints
number of staff and especially qualified staff; lack of a Widen access to DOTS
Quality governmental health services accessible to all
strategy to cope with decentralization of the health
Patients’ constraints identified and solutions provided [IEC,
system; non-compliance of the private sector with the enablers, incentives etc.]
DOTS strategy; and inadequate or weak health
Collaboration with partners
infrastructures (22). The lack of collaborative activities Non-MOH governmental systems and services
between the HIV and TB programmes was also Non-governmental sector: private practitioners, NGOs,
highlighted in countries with a high prevalence of HIV. academia, etc.
Top priority for action remains geographical DOTS Increase community/user awareness
expansion within governmental health structures [Table MoH = Ministry of Health; IEC = Information, Education and
62.2]. Access to all public health services should be Communication; NGOs = Non-governmental organizations
ensured during this process. However, there is an urgent
need to address the limited capacity within health
high cure rates [Table 62.2]. These include engagement
systems. Regardless of the increases in funding now
of communities, social mobilization, strengthening of
available to TB control programmes, the lack of human
primary care services, co-ordination with other care
resources is likely to become a key issue to controlling
delivery systems and involvement of the private sector.
TB. As TB control is essentially a management problem,
A framework to involve private practitioners in TB
TB control programmes need more than anything else,
good managers. Trained supervisory staff is crucial as control activities has been developed by WHO, and
effective, independent supervision at all levels is also key describes the strategy known as “public-private mix
to success. Governments in the 22 HBCs must address [PPM] DOTS” (112). The guiding principle is that all
the human resources crises that many of them face. This patients should have easy access to DOTS, including free
may, however, be doubly difficult as many countries are antituberculosis drugs, regardless of the provider that
undertaking health sector reforms, during which there they seek care from. The national TB programme should
are many risks to TB control activities as well as a number provide free drugs and quality microscopy services,
of opportunities (109). Technical considerations are a public or private, and expect adherence to agreed
primary consideration of national and international TB standard practices in return from the private providers.
control programmes; the DOTS strategy requires strict A number of HBC countries, notably India and the
technical rigour in order to achieve its goals and it must Philippines, have already developed policy documents
not compromise on its core principles, especially in the and have PPM projects up and running (113,114). Results
face of rapid health sector reform. To support govern- from a number of PPM projects in India have shown
ments in this, the DEWG has performed a survey on overall positive results, although some weaknesses
human resources in all HBCs, and in 2004-2005 persist but appear manageable [Figure 62.13] (115-117).
organized a series of workshops for country level human Recently, the International Standards for Tuberculosis
resource focal persons. Guidelines on human resource Care have been published where the desired standards
development and expanding DOTS in the context of a for care of patients with TB outside the National
changing health system, have recently been published Tuberculosis programmes, especially in the private
by WHO (110,111). sector, have been published. The reader is referred to
The above activities must be coupled with innovative the chapter “International Standards for Tuberculosis Care”
approaches to increase case finding whilst maintaining [Chapter 67] for more details.
Scaling up of services at the community level and effectively and with reasonable outcomes. There is,
greater involvement of the community are essential for however, a continued need to bring new resources in for
future success (79). Community-based TB care in a TB control in general, including for MDR-TB treatment.
number of settings has been demonstrated to be highly Multidrug-resistant TB and extensively drug-resistant TB
cost-effective and may generate demand for TB services [XDR-TB] can be a useful advocacy tool as a means of
and care by the community in addition to providing bringing in previously untapped public and private
support to patients (118,119). resources to TB control (66). This then needs to be
Generating community awareness about TB is translated into the wider implementation of the DOTS-
important and has traditionally been approached Plus management strategy, but with continued strict
through information, education and communication adherence to the guidelines laid out for such projects.
[IEC] activities. However, translating information into a Recently, XDR-TB has emerged as a new threat for global
change of behaviour is the ideal goal. A framework for attempts at TB control and efforts are underway in
social mobilization, known as Communication for several countries across the globe to tackle this new
Behavioural Impact [COMBI] has been developed to emerging threat (121).
achieve this goal. The COMBI is a strategic approach to The HIV pandemic, with the biological and epidemio-
social mobilization that uses a blend of communication logical interactions between TB and HIV, today presents
strategies based on situational market analysis, all a major challenge to TB control in high HIV-prevalence
directed at the achievement of a specific behavioural goal. settings. Where the prevalence of HIV infection is high,
It has been successfully used in Zanzibar to prevent it is unlikely that TB treatment alone will be able to
lymphatic filariasis (120). The COMBI activities for TB reverse the rise in incidence of TB seen and will require
control are currently being conducted in Kenya and one more than simply implementing the DOTS strategy
state [Kerala] in India, with the aim of prompting people widely (96,122,123). To reduce the number of TB cases in
with a persistent cough to visit health centres for TB a community, there is an urgent need to implement a
diagnosis, and thereby help increase case detection. strategy extended from the standard DOTS one which
The threat of MDR-TB is much better quantified today combines intensified case-finding and treatment to cure
than a few years ago, with a sound international in order to reduce the transmission of TB, coupled with
surveillance system for drug resistance prevalence comprehensive, effective HIV prevention with wide-
having been established. Prices of second-line drugs have scale implementation and availability of integrated
been drastically reduced, and pilot DOTS-Plus projects counselling and testing centres [ICTC], and care includ-
have shown that programmes can adequately introduce ing the wider availability of antiretroviral therapies in
and manage these drugs under routine conditions cost- low-income countries in order to reduce transmission of
HIV.
Enhanced TB case-finding could be considered in
specific groups among whom rates of TB are higher than
the general population, such as attendees at ICTC or
household members of HIV-seropositive TB patients
(124,125).
In order to reduce reactivation of latent TB infection,
current WHO recommendations are that in settings with
a high prevalence of dual HIV/TB infection, TB
preventive therapy should be offered to HIV co-infected
individuals if they can undergo adequate screening to
rule out active TB disease in order to avoid its use in
such cases (126). However, due to the lack of ICTC, and
Figure 62.13: Case detection rates, all cases and new smear
positive, Kannur district, Kerala, India 2000-02 the difficulties in excluding people who already have
Tot = total; Sm+ = smear-positive; q = quarter active TB disease, the use of preventive therapy is not
Source: reference 115 routine in any HBCs. Furthermore, the durability of the
888 Tuberculosis
efficacy of TB preventive therapy is unresolved, with of the operationalization of combined TB/HIV reduction
studies in areas of high transmission showing that activities. The ProTEST uses enhanced integrated
protection may not extend for more than two to three counselling and tesing as an entry point for a series of
years beyond the end of the treatment, and there is at activities that aim to reduce HIV transmission and TB
most a short prolongation of life (127-129). However, for incidence. Evidence-based information for TB/HIV
the individual living with HIV, it is one of the few collaborative interventions has been collected through
interventions proven to reduce morbidity in the absence the ProTEST projects in Malawi, South Africa and
of antiretroviral therapy. A number of studies have also Zambia (141).The lessons learnt from these sites have
shown efficacy of secondary preventive therapy i.e., informed the expansion and implementation of similar
preventive therapy in individuals who have a history of TB/HIV activities, and collaborative TB/HIV activities
previous TB disease, in HIV infected individuals in are now being expanded in many countries (72). With
communities with a high incidence of TB (130,131). Long- further collaboration, TB and HIV control programmes
term isoniazid might therefore serve as chemopro- are accentuating their own strengths and are learning
phylaxis, as well as treating latent infection, but the from each other. Evidence is now beginning to appear
efficacy of such an approach has not yet been that although overall incidence rates of TB are extremely
documented. Use of antiretroviral drugs will also be difficult to contain, good TB control programmes may
beneficial in reducing reactivation of TB in individuals, still be able to maintain stable incidence rates of TB
with studies in Brazil and South Africa showing among HIV-seronegative individuals living in
reductions in TB incidence (132-134). populations with high prevalence of HIV (142). This may
Any strategy that successfully reduces HIV trans- also imply that TB transmission rates can be kept
mission will benefit TB control. In the context of the constant, with important implications for the control of
combined epidemics of TB and HIV, the two most TB in the coming decades. Preventing TB disease and
important strategies are ICTC, and implementation of deaths, among HIV infected individuals, however, will
anti-retroviral drugs. Studies have shown that people require the implementation of additional interventions
who accepted HIV counselling and testing were more to increase access to HIV-testing, antituberculosis
likely to change their sexual behaviour in ways predicted preventive therapy, and anti-retroviral drugs.
to reduce HIV transmission compared to those who According to the recently published update, the
received health information alone (135). Economic revised global estimate of people living with HIV/AIDS
evaluations suggest that this intervention should be one has been downsized to 33.2 million, a reduction of 16
of the main pillars of any HIV prevention programme per cent compared with the estimate of 39.5 million in
(136-138). Voluntary HIV testing identifies HIV-sero- 2006 (143,144) . While this is good news, it should not
positive individuals who are a target for both enhanced result in complacency, and all efforts at HIV-TB control
TB case-finding and for TB preventive therapy. As must be continued.
discussed above, the implementation of anti-retroviral The reader is also referred to the chapter “Tuberculosis
therapy [ART] will have direct effects on TB. In addition, and human immunodeficiency virus infection” [Chapter 40]
as ART can dramatically reduce plasma levels of HIV, for more details.
which correlate closely with infectivity, individuals Finally, as primary care is often too poorly supported
taking ART are therefore likely to be less infectious in to guarantee adequate diagnosis and treatment of a
regard to transmission of HIV. How to deliver ART to variety of respiratory illnesses, including TB, the WHO-
those individuals infected with HIV in low-income sponsored Practical Approach to Lung Health [PAL]
countries who need them, is a major challenge. To strategy aims to assist in the delivery of standardized
address this challenge, WHO in 2003 launched the ‘3 by syndromic management of common respiratory diseases
5 Initiative’ with the aim of getting three million people (145). The strategy leads to improved diagnostic capacity
on ART by the end of 2005 (139). However, this aim could and ensures correct, cost effective treatment of priority
not be eventually achieved (140). respiratory diseases (146). As a consequence, the strategy
Co-ordination at country level between HIV and TB is likely to increase the detection of TB cases. The strategy
programmes is essential, as are specific interventions to targets multi-purpose health workers in lower-middle
tackle TB and HIV. The ProTEST project is one example and middle-income countries, and is being implemented
in Chile, Morocco and some provinces in South Africa logy in the community. The primary task of global TB
(147). This may be the natural evolution of well struc- control over the next five to ten years is to dramatically
tured DOTS programmes towards supporting primary reduce TB deaths, shorten the duration of illness and
care in countries with good health services, such as Chile decrease the incidence of disease – in that order. By 2010,
and Morocco. the International Development Target is to reduce TB
Global TB control is complex. However, we must not deaths and TB prevalence by 50 per cent, and by 2015
forget how far we have come in the last decade - today the incidence of TB is to be reversed (56,57). Further
TB is fully curable, the means to deliver an effective cure progress will require the continued rigorous and
is available through the DOTS strategy, and each cure dedicated application of current technology by all
means reduced transmission. Tuberculosis can be partners committed to the fight to stop TB. To achieve
controlled – if appropriate policies are followed, effective the longer term goals, will, however, require newer
clinical and public health management is ensured, and diagnostic techniques, drugs and vaccines which can be
there are committed and co-ordinate efforts for its control utilized in those areas where TB remains a public health
from within and outside of the health sector (148). Rapid problem (151-153).
expansion of effective TB control services is urgently
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894 Tuberculosis
The Revised National

Tuberculosis Control
Programme [RNTCP] 63
Reuben Granich, LS Chauhan
EPIDEMIOLOGY BRIEF HISTORY OF TUBERCULOSIS

CONTROL IN INDIA
Tuberculosis [TB] remains a serious public health
problem in India, accounting for nearly one fifth of the A number of significant scientific and public health
global burden (1). India has more people with active TB discoveries at the Tuberculosis Research Centre [TRC]
than any other country in the world. Each year, there in Chennai [earlier called Madras] and the National
are approximately 1.8 million new cases of TB disease, Tuberculosis Institute [NTI] in Bengaluru [earlier called
of which nearly 800 000 are highly infectious [smear- Bangalore] in the 1950s and 1960s respectively laid much
positive] TB; two persons die from TB in India every three of the foundation for DOTS which is the international
minutes – more than 1000 every day, and approximately modern-day standard care for TB control.
370 000 people each year (1). The socioe-conomic impact Tuberculosis control in India has a long and illustrious
of TB in India is devastating and more women die of TB past (6). In the early 1900s TB was recognized as a serious
in India than from all causes of maternal mortality problem and the first open-air sanitarium for treatment
combined (1,2). Most TB patients are in the economically and isolation of TB patients was founded in 1906 in
productive age group. India continues to incur huge costs Tiluania, near Ajmer, followed by one in Almora two
due to TB amounting to nearly US$ three billion and 300 years later (3). In 1912, magnitude of the problem was
million in indirect and direct costs respectively. Over 300 recognized through a resolution regarding TB at the All
000 children annually have to leave school as a result of India Sanitary Conference in Madras (7). Although it was
their parents’ TB and more than 100 000 women are recognized that TB prevalence was alarmingly high in
rejected every year by their families on account of their various parts of the country, understanding of the extent
having TB (1,2). of the problem was limited by a lack of reliable
According to the recent estimates of TB burden by surveillance data. The introduction of tuberculin skin
the World Health Organization [WHO] (3), the incidence testing helped to clarify the situation and surveys carried
of smear-positive TB is 75 and all forms of TB is 168 per out in Assam, Bengal, Bihar and Madras showed
100 000 population, prevalence of all forms of TB in India tuberculin positivity ranging from 11 to 33 per cent in
is 299 per 100 000 population. India’s TB problem is persons aged below 15 years and 70 per cent in those
further compounded by an estimated 2.5 million people aged over 15 years (6). Longitudinal surveys carried out
infected with human immunodeficiency virus [HIV], TB in 1939 in south India also provided insight about the
being the most common opportunistic infection amongst magnitude of TB problem (8). In 1946 the Bhore
HIV-infected individuals (4,5). Ironically, TB persists as committee estimated that about 2.5 million patients
a major health problem in spite of the fact that many of required treatment in the country while only 6000 beds
the basic scientific precepts of the WHO recommended were available (8). Countrywide bacille Calmette-Guerin
DOTS strategy were discovered in India. [BCG] campaigns in the 1940s revealed that TB infection
The Revised National Tuberculosis Control Programme [RNTCP] 895
was widespread and also helped to increase the level of In the 1950s and 1960s, research at the TRC in Chennai
awareness among public health authorities and the demonstrated that domiciliary treatment was as effective
general public. and less costly than in-patient treatment for TB (10).
Without effective treatment, progress in TB control Additionally, use of directly observed treatment [DOT],
was minimal and despite an active sanatorium in which patients are observed taking their medications,
movement, millions of TB patients remained largely was shown to be essential (11). These seminal findings
untreated. Lack of effective antituberculosis led to a radical change in thinking regarding TB care
chemotherapy meant that the main line of treatment worldwide (12). Indian researchers also pioneered the
relied on good food, open air and dry climate. Under efficacy of intermittent treatment where medications
these conditions, treatment took a second place to were successfully given two to three times a week (13).
diagnosis. Improved case-finding using microscopy among patients
By 1920, public opinion gained a momentum for attending health services was also demonstrated in India
effective measures for control of TB. India became a (14-15).
member of the International Union Against Tuberculosis In 1962, these and other path-breaking sociological
[IUAT] in 1929 and the antituberculosis movement grew and epidemiological studies led to the establishment of
with support from the government. The Tuberculosis the National Tuberculosis Control Programme [NTP] in
Association of India [TAI] was established in 1939 and 1962. The NTP was implemented nationwide in a phased
the Directorate General of Health Services established a manner through the establishment of District TB Centres,
TB division in 1946. In 1939, the TAI recommended the urban chest clinics and in-patient beds. The NTP
Organized Home Treatment Scheme as the best developed a substantial infrastructure and significantly
compromise under the prevailing circumstances. raising awareness about TB. However, after implementa-
Additionally, TB control was included in the tion for two decades, it was observed that the drug
government’s five-year plans. Work with BCG started adherence levels were not satisfactory. Short-course
in India as a pilot project in two centres in 1948 and in chemotherapy was introduced in 1985. Despite this
1949 it was extended to cover schools in almost all states intervention, ensuring drug supply and adherence
of India. A BCG Vaccine Production Centre in Guindy, continued to be a problem and programme goals to
Chennai was set up in 1948 and WHO and United control TB were not achieved.
Nations Children’s Fund [UNICEF] provided assistance In 1992, a comprehensive joint review of the TB
for introducing mass BCG vaccination. The Government programme in India by members of several organizations
of India also established clinical, domiciliary and after including the Government of India, WHO and Swedish
care services, TB training, demonstration and research International Development Agency [SIDA] found that
centres, and provided beds for isolation and treatment. less than half the patients with TB received an accurate
Research and training, received new support in 1955 with diagnosis and that less than half of those were effectively
the establishment of the Tuberculosis Chemotherapy treated (16). Laboratory services were under-utilized,
Centre, Madras, now called the TRC, Chennai, and in treatment regimens were unnecessarily complicated,
1959, the NTI, Bengaluru. drug shortages were common, and completion of
In the 1940s, streptomycin and para-aminosalicylic treatment was not systematically assessed. Importantly,
acid [PAS] were introduced in the developed countries, the NTP had not made significant epidemiological
followed by thioacetazone and isoniazid in the 1950s. impact on the prevalence of TB. Therefore, the Revised
This gave a global impetus to Tuberculosis treatment and National Tuberculosis Control Programme [RNTCP],
control. In 1951, these drugs were tried out on a small based on the WHO-recommended DOTS strategy, was
number of patients at the New Delhi TB Centre, and started in 1993.
subsequently followed by others. The monumental
National Sample Survey [NSS] on TB carried out by TECHNICAL FOUNDATION
Indian Council of Medical Research [ICMR] between The goal of RNTCP is to cure at least 85 per cent of new
1955 and 1958 revealed that TB was equally distributed smear-positive cases of TB and to detect at least 70 per
in the urban and rural populations (9). cent of such patients, after the desired cure rate has been
896 Tuberculosis
achieved (3). The RNTCP encompasses the five principles antituberculosis drugs including the use of a patient-wise
of the DOTS strategy and builds on the significant boxes which contains a full course of medication for an
infrastructure under the NTP including a network of 446 individual which serves to preclude interruption of
District TB Centres, 330 TB Clinics and more than 47 600 therapy for patients; [iv] use of intermittent [thrice
TB beds. Community-based care is emphasized and weekly] regimens ensuring direct observation of every
infrastructure and management established by the NTP dose of treatment in the intensive phase and at least the
are strengthened under RNTCP by identifying a sub- first dose of the week in the continuation phase; and [v]
district supervisory unit known as TB Unit [TU] and systematic monitoring, supervision and cohort analysis.
adding a supervisory team consisting of the treatment Health care providers are trained to ask all patients
supervisor and laboratory supervisor called as Senior attending health care facilities if they have had a cough
Treatment Supervisor [STS] and Senior TB Laboratory for three weeks or more [Figure 63.1]. These TB suspects
Supervisor [STLS] respectively. Additionally, a medical then have three sputum smears [spot, morning, spot
officer is allocated for TB control activities in addition to sputum smears] examined over a two-day period. If two
his/her other functions. These three individuals at the of the three smears are positive for acid-fast bacilli [AFB],
sub-district management unit [i.e., TU] oversee opera-
tions for approximately 500 000 population which on an
average includes five Designated Microscopy Centres
[DMC]. Supervisory staff can be augmented in difficult,
remote, hilly and tribal areas. A district as per its
population may have one or more TUs which are super-
vised by a District TB Officer [DTO]. Sub-centres covering
a population of 5000 are staffed by health care workers
who can provide TB treatment under direct observation.
Observation of treatment by a family member is not
acceptable under the programme. However, RNTCP is
flexible in identifying the DOT providers who are
accessible and acceptable to the patient and accountable
to the system. The DOT provider can be a medical or a
para-medical personnel or a community volunteer or
someone from the non-governmental organizations
[NGOs] and private sector facility involved in the
programme. In urban areas with limited infrastructure
special arrangements have been made by including one
treatment observer [TB Health Visitor] per 100 000
population on contract. Necessary transport facility is
provided to the districts for regular supervision and
effective logistic management.
Proper supervision, modular training, and regular
Figure 63.1: Patient categorization under the Revised National
cross-checking of work plays a key role in maintaining
Tuberculosis Control Programme*
quality services. The RNTCP has placed an emphasis on
* The algorithm is expected to be revised in future. As per the proposed
assuring high cure rates and carefully expanding case changes, any person with cough for 2 weeks or more [in place of “3
detection activities after achieving the acceptable cure weeks or more”] will be considered as a “TB suspect”; 2 sputum
rates i.e., 85 per cent among new smear-positive patients specimens, 1 of them being an early morning specimen [in place of
“3 sputum smears”] will be required for diagnosis; 1 of the 2 sputum
initiated on treatment. Basic RNTCP principles are: [i] specimens positive will be considered as “smear-positive TB” [in
political commitment to ensure adequate funds, staff, and place of “2 or 3 positive”]; and specimens with scanty bacilli will be
other key inputs; [ii] diagnosis primarily by sputum considered positive. Emphasis has been given to a quality assured
laboratory. The reader can check http://www.tbcindia.org for the latest
smear microscopy of patients presenting to health details
facilities; [iii] regular and uninterrupted supply of TB = tuberculosis
then treatment is started. If all three smears are negative, districts are submitted via the internet and a quarterly
then a course of antibiotics is offered for one to two weeks surveillance report at the national level is generated
and then a repeat sputum smear examination is done within two months of the close of the quarter. Districts
followed by a chest radiograph if the repeat sputum are encouraged to perform TU specific analyses to
smear is found to be negative. If only one smear is highlight good performance and areas that need
positive or symptoms persist after the antibiotics, then attention [e.g., case detection, default, etc.,]. Likewise,
also, a chest radiograph is obtained. A standardized the yearly report is compiled and disseminated to
system of categorization and treatment regimens are used programme staff and others in a time bound manner. A
to manage patients under RNTCP [Table 63.1]. All central staff team reviews the quarterly reports and
regimens are given as thrice weekly intermittent provides feedback directly to the states and districts. The
regimens. Although the emphasis is on treating infectious RNTCP is planning to start a web-based surveillance
smear-positive patients, if three smears are negative and system that should facilitate better data management,
there is no response to one to two weeks of antibiotics, provide timely and useful feedback for end users, and
then a chest radiograph is taken after a repeat sputum an increased access to data for states and DTOs. Through
examination. If the chest radiograph is consistent with training, direct supervision and internal evaluations,
TB, the patient is started on treatment for TB [Figure 63.1]. RNTCP emphasizes the importance of meticulous record
One of the greatest strengths of the RNTCP is the keeping and accuracy. It also encourages a transparent
recording and reporting system. Based on the patient analysis of the data at all levels and actively uses the
treatment card, the laboratory register and the TB information to make programme and policy decisions.
register, this simple but robust system ensures Large-scale implementation of the RNTCP began in
accountability for each and every patient initiated on 1998 with a ‘soft’ loan of US$ 142 million from the World
treatment. Quarterly Cohort reports on case-finding, Bank (17). The five-year credit period starting May 1997
sputum conversion and treatment outcome are compiled was later extended until September 2005. In addition,
from the TB register at TU and district level which are the RNTCP is supported by bilateral donors including
analysed and sent to the state and central levels. the UK Department for International Development
Remarkably, around 95 per cent of quarterly reports from [DFID], Canadian International Development Agency
Table 63.1: Revised National Tuberculosis Control Programme treatment regimens

Category of treatment Type of patient Regimen*
Category I New sputum smear-positive 2H3R3Z3E3 + 4H3R3

Seriously ill† new sputum smear-negative
Seriously ill† new extra-pulmonary
Category II Sputum smear-positive relapse 2H3R3Z3E3S3 + 1H3R3Z3E + 5H3R3
Sputum smear-positive treatment failure
Sputum smear-positive treatment after default
Others‡
Category III New sputum smear-negative, not seriously ill 2H3R3Z3 + 4H3R3
New extra-pulmonary, not seriously ill
* The number before the letters refers to the number of months of treatment. The subscript after the letters refers to the number of doses per
week
† Seriously ill also includes any patient, pulmonary or extra-pulmonary TB who is HIV-seropositive and declares his/her sero-status to the
categorizing/treating Medical Officer. For the purpose of categorization, HIV testing should not be done
‡ In rare and exceptional cases, patients who are sputum smear-negative or who have extra-pulmonary TB can have relapse or treatment
failure. This diagnosis in all such cases should always be made by a Medical Officer and should be supported by culture or histopathological
evidence of current, active TB. In these cases, the patient should be categorized as ‘Others’ and given Category II treatment The dosage
strengths are as follows: H = isoniazid [600 mg]; R = rifampicin [450 mg]; Z = pyrazinamide [1500 mg]; E = ethambutol [1200 mg]; S =
streptomycin [750 mg]. Patients who weigh 60 kg or more receive additional rifampicin [150 mg]. Patients who are more than 50 years old
receive streptomycin [500 mg]. Patients who weigh less than 30 kg receive drugs as per body weight
Patients in Categories I and II who have a positive sputum smear at the end of the initial intensive phase receive an additional one month of
intensive phase treatment
898 Tuberculosis
[CIDA], Global Drug Facility [GDF], Global Fund to fight districts each month. Technical support is provided from
AIDS, TB and Malaria [GFATM], and United States three central institutes including Lala Ram Sarup [LRS]
Agency for International Development [USAID]. Institute of Tuberculosis and Respiratory Diseases, New
Technical support is provided by WHO, with a network Delhi, NTI, Bengaluru and the TRC, Chennai. These
of consultants deployed at the national, state and district institutes work in close liaison with RNTCP and play a
levels to provide technical support and assistance in key role in setting national priorities, training, carrying
monitoring the programme. The second phase of RNTCP out operational research [OR] and also in assisting the
is in progress since October, 2005. As per analysis of the Programme in its monitoring and evaluation activities.
Joint TB Programme Review of 2003, RNTCP is highly The RNTCP actively collaborates and contributes to
economical, costing on an average less than two rupees Global DOTS expansion efforts through dissemination
[5 US cents] per capita per year (18). of its training manuals, scientific research and
Policy direction, supervision, surveillance, drugs and participation in key working groups and international
microscopes are provided by the Central Government. meetings. Finally, it works closely on technical matters
States receive funds for further distribution to Districts with the WHO, Centers for Disease Control and
for carrying out day-to-day activities. Additionally, Prevention [CDC], Atlanta, Royal Netherlands
higher level state staff receives training from the Centre. Tuberculosis Association [KNCV] and the International
They are also provided guidelines and modular training Union Against Tuberculosis and Lung Disease
materials to train staff in the field [Table 63.2]. [IUATLD].
The RNTCP has invested heavily and has also made
significant strides in maintaining and improving the
DRUG PROCUREMENT AND MANAGEMENT
delivery of quality DOTS [Table 63.3]. Regular reviews
of the programme at the state and district level are a key A strong drug procurement and management system is
component of the process. In addition to the routine critical to the success of RNTCP. Medicines or packaging
supervision and monitoring by the programme staff, each materials that lack effectiveness or appear to be of poor
state conducts internal evaluation of two districts in a quality can seriously undermine confidence in the
quarter. Central evaluations are conducted by the team Programme. Every link in the supply chain, from
from the Central TB Division to evaluate one or two manufacturer to patient must be quality assured. Over
Table 63.2: Number of staff trained under Revised National Tuberculosis Control Programme in the year 2006
Category of staff Sanctioned In Place In place and % Trained in

trained in RNTCP
RNTCP
Second MO-DTC 511 392 337 86

MO-TC [TU] 2365 2238 1918 86
MO [at BPHC/PHC/CHC/Others] 76556 64191 49112 77
STS 2415 2351 2231 95
STLS 2448 2373 2254 95
All LTs [including DMCs] 25582 21829 16921 78
LT/Microscopist of DMC 12134 11689 11006 94
TO 1302 1114 975 88
Pharmacist 35759 30458 19997 66
MPHS 47194 37784 28523 75
MPHW 245370 217997 173746 80
TBHV 2383 2104 1889 90
RNTCP = Revised National Tuberculosis Control Programme; MO = Medical Officer; DTC = District TB Centre; MOTC = Medical
Officer TB Centre; TU = TB Unit; DMC = Designated Microscopy Centre; STS = Senior Treatment Supervisor; STLS = Senior Tuberculosis
Laboratory Supervisor; LT = Laboratory Technician; TO = Treatment Organizer; BPHC = Block Primary Health Centre; CHC = Community
Health;Centre; PHC = Primary Health Centre; MPHS = Multipurpose Health Supervisor; MPHW = Multipurpose Health Worker, TBHV
= TB Health Visitor
Table 63.3: Performance of Revised National Tuberculosis Control Programme: case detection [2007], smear conversion [4th quarter 2006 and 1st to
3rd quarter 2007] and treatment outcomes [2006]
State State Total Annual New smear- Annual new smear- % New No. of new Cure rate Treatment
population patients total positive positive case sputum smear-negative of new success
[in 100 000] registered case patients detection rate positive out of cases registered smear- rate of
covered for detection registered total new for treatment postive new smear-
by RNTCP* treatment† rate for pulmonary patients positive
treatment No. % cases patients
Andaman and Nicobar 4 775 193 256 64 85 51 248 86 86

Andhra Pradesh 813 111304 137 49099 60 81 60 32563 85 87
Arunachal Pradesh 12 2746 232 890 75 100 55 732 86 87
Assam 295 36766 125 16324 55 74 61 10536 85 86
Bihar 923 79619 86 30834 33 45 52 28034 75 83
Chandigarh 10 2411 232 736 71 75 60 489 86 86
Chhattisgarh 233 27504 118 10598 46 57 49 11092 84 87
D and N Haveli 3 390 153 127 50 62 61 82 82 82
Daman and Diu 2 337 184 98 54 67 51 95 87 92
Delhi 166 49058 296 13695 83 87 60 9047 85 86
Goa 16 2104 133 645 41 51 53 574 72 73
Gujarat 556 80399 145 34856 63 78 75 11699 87 87
Haryana 234 35591 152 13116 56 59 63 7607 84 85
Himacha Pradesh 65 13611 210 4978 77 81 66 2621 88 89
Jammu and Kashmir 120 12392 103 4932 41 43 66 2538 85 87
Jharkhand 296 36133 122 16164 55 73 58 11774 85 89
Karnataka 568 67630 119 25956 46 61 62 15884 76 78
Kerala 339 24397 72 10915 32 64 70 4694 81 83
Lakshadweep 1 15 22 6 9 12 55 5 71 71
Madhya Pradesh 680 80410 118 30424 45 56 55 25122 82 85
Maharashtra 1055 142792 135 55571 53 66 60 37461 85 86
Manipur 26 4885 188 1064 41 55 36 1893 85 85
Meghalaya 25 4857 194 1447 58 77 57 1097 81 82
Mizoram 10 2177 225 689 71 95 57 513 91 91
Nagaland 22 3079 143 1193 55 74 59 846 89 90
Orissa 395 49285 125 21689 55 65 63 12831 81 86
Puducherry 11 1383 131 636 60 80 76 201 80 81
The Revised National Tuberculosis Control Programme [RNTCP]
-Contd-
899
Table 63.3 -Contd-
900
State State Total Annual New smear- Annual new smear- % New No. of new Cure rate Treatment
population patients total positive positive case sputum smear-negative of new success
[in 100 000] registered case patients detection rate positive out of cases registered smear- rate of
covered for detection registered total new for treatment postive new smear-
by RNTCP* treatment† rate for pulmonary patients positive
treatment No. % cases patients
Tuberculosis
Punjab 263 35875 136 14093 54 56 65 7717 83 85

Rajasthan 635 111700 176 41155 65 81 55 33095 87 89
Sikkim 6 1538 262 493 84 112 64 279 86 86
Tamil Nadu 658 86113 131 33359 51 68 58 24075 82 83
Tripura 35 2573 74 1460 42 56 76 466 86 90
Uttar Pradesh 1874 245106 131 99606 53 56 56 77060 83 86
Uttarakhand 94 13406 143 5398 58 61 62 3356 88 89
West Bengal 868 107226 123 50133 58 77 69 22539 86 87
Grand total 11310 1475587 130 592635 52 70 60 398865 84 86
* Projected population based on census population of 2001 is used for calculation of case-detection rate
† Total patients registered for treatment includes new sputum smear-positive cases, new smear-negative cases, new extra-pulmonary cases, smear-positive re-treatment
cases and ‘others’
Estimated new smear-positive cases/100 000 population based on annual risk of tuberculosis infection [ARI] data for North Zone [Chandigarh, Delhi, Haryana, Himachal
Pradesh, Jammu and Kashmir, Punjab, Uttar Pradesh, Uttarakhand] = 95; East Zone [Andaman & Nicobar, Arunachal Pradesh, Assam, Bihar, Jharkhand, Manipur,
Meghalaya, Mizoram, Nagaland, Sikkim, Tripura, West Bengal] = 75; South Zone [Andhra Pradesh, Karnataka, Lakshadweep, Puducherry, Tamil Nadu] = 75; West Zone
[Chhattisgarh, Dadra & Nagar Haveli, Daman & Diu, Goa, Gujarat, Madhya Pradesh, Maharashtra, Rajasthan] = 80; Orissa = 85; Kerala = 50
Values for shaded cells are not expected
The Central TB Division, Government of India updates these data annually. The reader can access the updated information from the “TB India” report of the current year
available at the URL: http://www.tbcindia.org
the last few years, significant improvements in stocks at each GMSD and SDS are monitored through
packaging, inspection, supply, storage and quality receipt of monthly statements regarding the quantities
control practices and procedures have been achieved. issued during the month, stock in hand and stock of
Due to significant improvement in the information expiry dates.
systems and tracking, procurement according to World Drug quality is assured in a number of ways
Bank specified guidelines, an uninterrupted supply of including: [i] samples from each drug batch are taken
quality antituberculosis medicines is maintained by the and quality of drugs is tested prior to their clearance for
programme. Drug stock tracks the best possible dispatch by the manufacturers; [ii] checking of random
utilization estimate and drug procurement plans are samples from state and central government store houses;
prepared to ensure a 12-month buffer stock at the [iii] Central and State Drugs Inspectors intermittently
national level. Improved blister pack designs in patient- take samples from districts, in addition to when they
wise boxes have also been introduced and have proven receive specific complaints; and [iv] use of an indepen-
to be extremely effective. The availability of drugs in dent laboratory for quality assurance of antituberculosis
patient-wise boxes ensures availability of full treatment drugs.
course for every patient who is started on treatment. The Drug supply system and quality are the backbones
innovative development and use of patient-wise boxes of a strong national TB programme. The RNTCP takes
have enhanced patients’ confidence in the public health several measures to assure that patients receive an un-
system and has simplified drug procurement and interrupted supply of quality antituberculosis drugs. A
management.
web-based drug logistics management system is under
The RNTCP drugs are procured from an agency
development to increase efficiency of the current paper-
selected through International Competitive Bidding
based reporting system. Additionally, an independent
[ICB] process. Presently, procurements are being handled
laboratory hired under the programme for testing
by United Nations Office for Project Services [UNOPS].
random and requested samples is serving as an impor-
The Central TB Division [CTD], Directorate General of
tant link in the quality control chain.
Health Services, Ministry of Health and Family Welfare,
Government of India, calculates requirements, delivery
schedule, technical specifications and consignee details. DOTS EXPANSION
Tender is floated by procurement agents following ICB
The RNTCP began operations in 1993 in five pilot sites
procedures.
in Delhi, Gujarat, Kerala, Maharashtra and West Bengal,
For long-term sustainability of RNTCP, antituber-
culosis drugs logistic management has been decentrali- covering a population of 2.35 million. Piloting allowed
zed with capacity building of states and districts by for further refinement of the inputs [e.g., training
establishing state, district and TU level drug stores and modules, logistics, staffing, infrastructure, supervision,
training of staff in drug logistic management. State Drug recording and reporting ] needed to establish a successful
Stores [SDS] serve to facilitate drug distribution by programme under field conditions. The Programme then
reducing lead-time and greatly reduce the risk of stock- progressively, but slowly, expanded to cover 13.9 million
out and expiry. in 1995 and 20 million in 1996. Large scale expansion of
Drugs are issued to the districts from the SDS on the DOTS services in India began in 1997 after a successful
basis of Quarterly Programme Management Reports pilot, which established the technical and operational
which are tallied with the District’s Case-Finding Report. feasibility of the strategy. Thereafter, the RNTCP
The PWBs of defaulters, treatment failure or dead expanded rapidly, covering 50 per cent of the population
patients are re-constituted so that the drugs from these in 2002; full nation-wide coverage [covering over 1.1
patients are not wasted. A three-month buffer stock is billion population] was achieved in March 2006 [Figures
maintained at each district by a system of projections of 63.2 and 63.3]. Presently more than 1 600 000 patients
future utilization and supply needs of districts. Drugs had been placed on treatment. The reader can access
are issued to SDSs from Government Medical Store http://www.tbcindia.org for the latest figures on this
Depots [GMSDs] by the CTD on the basis of Programme topic. This remarkable expansion of RNTCP is the fastest
Management Report [PMR] of the state. In addition, drug expansion in the history of DOTS.
902 Tuberculosis
Figure 63.2: Population in India covered under DOTS and total tuberculosis
patients put on treatment each quarter
Qtr = quarter
Quality of services was the main focus of RNTCP while In participating institutions, roughly two to three per
expansion of DOTS was taking place in several states. cent of out-patients are screened for TB. Smear micro-
Therefore, systematic appraisal of each district was done scopy, a much more reliable method of identifying
prior to start of service delivery. The appraisal process persons with TB [chest radiographs are non-specific for
ensured that each district maintains a minimum standard TB], now forms the basis for diagnosis. The proportion
before starting RNTCP service delivery [Figure 63.4]. of chest symptomatics who are smear-positive largely
depends on referral practices. Although significant
PROGRAMME PERFORMANCE progress has been made in the area of case detection,
RNTCP has a number of initiatives [e.g., collaboration
The RNTCP has made a significant contribution to public
with the private and corporate sectors, medical college
health capacity-expansion by training more than 500 000
task forces, community-based DOT providers, urban
health personnel of various cadres using a modular
DOTS, etc.,] designed to increase DOTS delivery to
approach and the purchase of over 12 000 binocular
persons suffering from TB. The RNTCP has made addi-
microscopes. Since its inception in 1997, the programme
tional efforts to reach marginalized communities and
has initiated more than eight million TB patients on
internal and cross-border migratory populations.
treatment and prevented over 1.4 million TB deaths.
Every month more than 120 000 patients are initiated on
LABORATORY NETWORK AND
treatment. The programme has evaluated more than 36
QUALITY ASSURANCE
million people with suspected TB. The RNTCP results
over the years have consistently met the international Under the RNTCP, a DMC has been established to cater
benchmark of a treatment success rate of more than 85 the need for approximately 100 000 population [50 000
per cent among new smear-positive pulmonary TB cases. for tribal, difficult and mountainous areas]. Each DMC
Case detection rates are close to the global targets of 70 is staffed by a RNTCP trained laboratory technician (2).
per cent [Figure 63.5]. During 2007, more than 6.48 The Programme provides assistance to improve
million symptomatic persons were screened for TB free laboratory facilities e.g., supply of a binocular microscope
of charge and more than 1.47 million patients were and essential laboratory consumables. By the end of 2007,
initiated on treatment [Figure 63.6]. there were more than 12 500 DMCs working under
Figure 63.2: DOTS Implementation Status in India by District, 2007
Figure 63.3: The Revised National Tuberculosis Control Programme laboratory network
NRL = National Reference Laboratory; IRL = Intermediate Reference Laboratory; TU =TB Unit; MC = medical
college; DMC = Designated Microscopy Centre; EQA = external quality assurance; DTO = District Tuberculosis
Officer; STLS = Senior TB Laboratory Supervisor
904 Tuberculosis
Figure 63.5: Annualized new smear-positive case detection rate and treatment success rate in DOTS areas, India, 1999 to 2008.
Population projected from 2001 census. Estimated number of new smear-positive cases = 75/100 000 population per year
Qtr = quarter
Figure 63.6: New smear positive and total patients treated under
the Revised National Tuberculosis Control Programe 1998-2007
RNTCP. Within respective districts, quality of the sputum sputum smear microscopy services, a review of the
smear microscopy work is ensured by the STLS based at existing RNTCP quality assurance protocol was done in
the TB Unit level and at the district level by the DTO and 2003 with the technical input from NTI, TRC, LRS
at the state level by the Intermediate Reference Labo- Institute and WHO. This review culminated in a national
ratory [IRL] staff. The STLS is expected to visit all [usually level consensus meeting held in August 2003, with the
5 DMCs per STLS] within their respective TU area at least specific objectives of developing an updated RNTCP
once in a month. protocol for EQA of sputum smear microscopy services.
The laboratory network in the respective state is The meeting also addressed the issue of capacity building
overseen by the State TB Cell [STC] headed by the State to do population-based drug resistance surveillance in a
TB Officer, and staff from the State TB Training and number of states. A comprehensive sputum smear
Demonstration Centres [STDC]/IRL. Sanctioned staff microscopy quality assurance protocol that includes on
posts at the STDCs and IRL include a microbiologist, site evaluation, RBRC and panel testing has been
epidemiologist, statistician and laboratory technicians. developed and more than 90 per cent of the districts are
The STDCs are increasingly involved in training implementing the quality assurance protocol
activities and assisting the STC in supervision, [Figure 63.4 ]
monitoring and evaluation of the RNTCP, including
quality assurance of the laboratory services provided by INFORMATION, EDUCATION AND
RNTCP. COMMUNICATION
At the national level, the CTD is assisted by the NTI,
Bengaluru and the TRC, Chennai, LRS Institute of Information, education and communication [IEC] and
Tuberculosis and Respiratory Diseases, New Delhi and advocacy communication for social mobilization [ACSM]
National JALMA Institute of Leprosy and Other are important and crucial components of RNTCP. During
Mycobacterial Diseases, Agra [the acronym JALMA RNTCP I, the focus was on local initiatives, as entire
stands for ‘Japanese Leprosy Mission for Asia’, a Tokyo country was not covered under RNTCP. From 2000,
based voluntary organization that originally managed when more than 50 per cent of the population was
this centre], and all these serve as National Reference covered under DOTS, the programme focussed on large
Laboratories [NRLs]. The NRLs provide training and scale media activities for awareness generation.
supervision of the laboratory-related activities performed The RNTCP II aims to widen the scope for providing
by the STDCs in their role as intermediate level standardized, good quality treatment and diagnostic
laboratories at the state level. services to all TB patients in a patient-friendly environ-
ment, in whichever health care facility they seek
Laboratory Quality Assurance treatment. The IEC approach has an important role in
Although many practitioners in India still rely on clinical popularising this aspect.
examination and/or non-specific chest radiographs to An effective RNTCP ACSM strategy is in place, in
establish a diagnosis of TB, under RNTCP, the core of order to maintain high visibility of TB and RNTCP
the DOTS strategy relies on a bacteriological diagnosis amongst policy makers, opinion leaders and community,
and follow-up of cases by sputum smear microscopy. As and hence sustained long-term political and adminis-
the laboratory provides the foundation for the trative commitment and greater community involvement
programme and ensures quality of the sputum smear to RNTCP. Advocacy and communication are central and
microscopy services, it is a high priority for the RNTCP. integral part of the Phase II TB Project.
Following the recommendation from the programme The focus of IEC in RNTCP is on three main areas,
review of 2000, RNTCP developed a quality assurance i.e., awareness generation, advocacy, and patient-provi-
protocol which included on-site supervision, panel der communication and counselling [Table 63.4]. Goals
testing, and random blinded rechecking [RBRC] of of ACSM include supporting TB efforts by : [i] improving
routine slides. On-site supervision is routine and districts case detection and treatment adherence; [ii] combating
also participate in a RBRC process. stigma and discrimination, [iii] empowering people
On the basis of the new international guidelines in affected by TB; and [iv] mobilizing political commitment
2002 (19) for the external quality assessment [EQA] of and resources for TB.
906 Tuberculosis
The programme has clearly defined communication Central Internal Evaluations [CIE], to prioritize linking
strategy identifying objectives [communication needs]; the IEC activities to the programme objectives and issues
target groups [communication players], and media in the districts and developing a mechanism to review
options to reach target groups [communication tools]. and monitor this component.
The emphasis is on decentralized planning at the state
and districts level in order to have need based locally TUBERCULOSIS AND HUMAN
relevant communication initiatives. To support states and IMMUNODEFICIENCY VIRUS
also to maintain synergy and uniformity of messages,
India is among the world’s 22 high TB burden countries
the Centre has developed prototype communication
and with an estimated 2.5 million people living with
material which can be adapted in the field. The RNTCP
HIV/infection, acquired immunodeficiency syndrome
is probably the first disease control programme in the
[AIDS] has the third highest estimated number of HIV
country to have a web-based IEC resource centre on the
infected people in the world (5). Approximately 40 per
official RNTCP website to house more than 300 types of
cent of people living with HIV/AIDS [PLHIV] in India
material. Designated staff has also been provided in the
are also infected with Mycobacterium tuberculosis. As HIV
states and at the district level.
is the most powerful risk factor for progression from
At the Central level. Advocacy and IEC Unit draws
infection with Mycobacterium tuberculosis to active TB
supports from an expert group known as IEC Advisory
disease (20), the dual epidemic of HIV and TB results in
Group. This ‘think tank” has members from Centres of
increased TB related morbidity and mortality.
excellence, the fields of communication, social develop-
The RNTCP services have expanded rapidly across
ment and research and media. Similar arrangement has
India and in the absence of the HIV epidemic, it might
been recommended for the states by the programme.
have been expected to reduce the incidence of TB by five
The programme has identified areas that need per cent a year or more at least for the first few years
attention. The IEC baseline document has been develo- after full coverage was achieved, and possibly slow down
ped which has information on knowledge, attitudes and after that as the epidemic ages. Even though the
practices among different target audiences and also has prevalence of HIV in India is an order of magnitude less
baseline information on capacity of states and districts than it is in East and southern Africa, it is likely that
in planning and implementation of IEC activities; it also without improvements in TB control associated with the
identifies areas that need to be strengthened. The RNTCP programme, HIV would have given rise to an
programme is drawing plans to address these issues. additional five million TB cases and 2.5 million AIDS
There is also plan to develop standardized training deaths between the years 1990 and 2010. Analyses from
modules for training of IEC Officers, Communication a recent WHO-RNTCP-National AIDS Control
facilitators, involve members of IEC Advisory Group in Organization [NACO] modelling exercise indicate that
Table 63.4: The focus of information, education and RNTCP may be able to contain the impact of AIDS in
communication in the Revised National Tuberculosis Control terms of TB control and maintain the overall incidence
Programme of death rates due to TB at the current level over the next
Awareness raising to increase understanding about TB amongst 10 years (21). As a direct result of the RNTCP programme
The public so that they make use of RNTCP services it is likely that the number of TB cases will in fact decrease
Practitioners across the country so that they know about correct
by about two million while the number of deaths will
TB diagnosis and treatment and they refer patients to DOTS decrease by about 100 thousand during this period, even
services, or become DOT providers themselves with the AIDS epidemic. Without HIV/AIDS, the
Advocacy to develop political, administrative and community-level RNTCP would have reduced these numbers by about
commitment to TB control in India 4.5 million and 1.4 million, respectively. When combined
Patient-provider communication and counselling to assist patient effect of HIV epidemic and impact of RNTCP is consi-
compliance with the treatment regimen, to enhance the reputation dered together, modelling suggests that RNTCP would
of a patient-friendly service, and to encourage patients and their compensate for the impact of HIV on TB over the long-
families to become advocates for the programme
term (21).
TB = tuberculosis; DOT = directly observed treatment; RNTCP = Collaboration between TB and HIV programmes is
Revised National Tuberculosis Control Programme essential to mitigate the high morbidity and mortality
from TB among PLHIV and dampen the potential actual total TB case load is to be found amongst children.
negative impact that the HIV epidemic will have on TB As per the WHO report 1996 (24), globally 1.5 million
control in India. Standard regimens of RNTCP, new cases and 130 000 deaths due to TB per year amongst
particularly if supervised properly, are as effective in children have been estimated. However, these figures
HIV-seropositive as in HIV-seronegative patients (22). may underestimate the true size of the problem. Child-
Treatment with DOTS can significantly prolong the life hood TB prevalence reflects the community prevalence
of HIV-infected persons (23), prevent drug resistance, of sputum smear-positive pulmonary TB, the age-related
and by quickly rendering a person with TB disease non- prevalence of sputum smear-positive pulmonary TB, the
infectious, blunt transmission and the concomitant prevalence of childhood risk factors for disease and the
increase in TB cases. Providing treatment under DOTS stage of the TB epidemic.
for patients with TB and HIV may be the most important Proper identification and treatment of infectious cases
medical intervention widely available for most patients will prevent childhood TB. However, often childhood
in India. Curing TB in HIV/AIDS patients will both TB is afforded a low priority by National TB Control
improve their quality of life and reduce the spread of programmes since there are diagnostic difficulties, cases
TB. Increasing access to care and antiretroviral therapy are rarely infectious, resources are limited, there is often
[ART] for eligible TB patients with HIV infection is also a misplaced faith in BCG and a lack of data on treatment.
a priority for the NACO and RNTCP. However, this rationale disregards the impact of TB on
Recognizing this, the Government of India has childhood morbidity and mortality. Children can present
already taken important steps to strengthen the co- with TB at any age, but the majority of cases present
ordination between RNTCP and the NACO across the between the ages of one and four years. The disease
country with special focus to states with the highest usually develops within one year of infection. Active TB
burden of HIV in the general population. The key areas disease is likely to be disseminated in children who
of focus are: [i] sensitization of the key state and district develop the disease early. In children, the pulmonary to
policy makers to highlight the importance of HIV-TB co- extra-pulmonary TB ratio is 1:3 and pulmonary TB is
infection; [ii] development of training modules on HIV- usually smear-negative. The prevalence of pulmonary
TB for different level of health functionaries of both TB is normally low between the ages of five and twelve
programmes; [iii] joint training programmes on HIV-TB years. Thereafter, the prevalence increases in adolescence
for different categories of programme and field staff; [iv] in whom the presentation of pulmonary TB resembles
referral linkages between the service delivery sites of that seen in adults (25).
National AIDS and TB control programmes; [v] estab- Reliable data on the burden of all forms of TB amongst
lishment of state and district co-ordination committees children in India are not available and most surveys that
to monitor the progress of collaborative activities; have been conducted have focussed on pulmonary TB.
[vi] development of IEC material on HIV/TB at the Additionally, no significant population based studies on
national level; [vii] cross-involvement of NGOs partici- paediatric extrazpulmonary TB are available. In 2006, of
pating in the National AIDS Control Programme [NACP] the 1.4 million total patients registered for treatment
and the RNTCP. under RNTCP, 64 697 were paediatric cases. Procurement
To further strengthen this collaboration and improve and distribution of paediatric drug boxes for improved
the access to care for co-infected patients, OR on TB/ care of paediatric cases had been initiated in early 2007
HIV has been prioritized. A number of OR projects have and are now being used for treating paediatric patients
been undertaken. This includes the establishment and in all states and union territories.
evaluation of decentralized delivery of cotrimoxazole To seek consensus on improved case detection and
preventive therapy [CPT] for HIV positive TB patients, improved treatment outcomes for all diagnosed paediat-
establishment of referral linkages between decentralized ric TB cases, a workshop of national and international
RNTCP services and ART centres. paediatricians with expertise in childhood TB and TB
control programme managers on the “Formulation of
MANAGEMENT OF PAEDIATRIC TUBERCULOSIS
guidelines for diagnosis and treatment of paediatric TB
The actual global disease burden of childhood TB is not cases under RNTCP” was held in New Delhi in 2003 (3).
known, but it has been assumed that 10 per cent of the As a result of the workshop the “Consensus Statement
908 Tuberculosis
on Management of Paediatrict TB” (26) was formulated given in Tables 63.5A and 63.5B. Intermittent short-
and the same is being followed all over the country. course chemotherapy given under direct observation, as
advocated in the RNTCP, should be used in children. To
Diagnosis assist in calculating required dosages and administration
Children presenting with fever and/or cough for more of antituberculosis drugs for children, the medications
than three weeks, with or without weight loss or no are now made available in the form of combipacks in
weight gain; and history of contact with a suspected or patient wise-boxes, linked to the child’s body weight.
diagnosed case of active TB disease within the last two In patients with TBM on Category I treatment, the
years will be considered to be “suspect cases with four drugs used during the intensive phase should be
pulmonary TB”. Diagnosis of pulmonary TB will be isoniazid, rifampicin, pyrazinamide, and streptomycin.
based on a combination of suggestive clinical presen- Continuation phase of treatment in TBM and spinal TB
tation, sputum examination wherever possible, chest with neurological complications should be given for six
radiograph [postero-anterior view], tuberculin skin test to seven months, extending the total duration of treat-
[Mantoux test] using 1 tuberculin unit [TU] purified ment to eight to nine months. Corticosteroids should be
protein derivative [PPD] RT23 with Tween 80, considered used initially to reduce inflammation in hospitalized
to be positive if induration is greater than 10 mm after cases with TBM and TB pericardiitis and tapered
48 to 72 hours; and history of contact as described in the gradually over six to eight weeks. Any child who is to be
diagnostic algorithm. Diagnosis of TB in children should started on category II treatment should be examined by
be made by a medical officer. Where diagnostic diffi- a paediatrician or a TB expert.
culties are faced, referral of the child should be made to
a paediatrician for further management. The existing Treatment of Latent Tuberculosis Infection
RNTCP case definitions will be used for all cases diag-
Asymptomatic children under six years of age, exposed
nosed. The use of scoring systems is not recommended to an adult with infectious [smear-positive] TB, are given
for use in diagnosis of pediatric TB patients currently. six months treatment with isoniazid [5 mg/kg body
weight].
Treatment of Paediatric Tuberculosis
The DOTS is the recommended strategy for treatment of PRIVATE SECTOR

TB and all paediatric TB patients should be registered In India, with one of the largest private health care sectors
under RNTCP. Recommended treatment regimens are in the world and almost one third of the global burden
Table 63.5A: Revised National Tuberculosis Control Programme treatment regimens for paediatric patients
Treatment category Type of patient Regimen*
Category I New smear positive; seriously ill smear negative; 2H3R3Z3E3/4H3R3

seriously ill extra-pulmonary
Category II Previously treated smear positive [relapse, treatment failure, 2H3R3Z3E3/1H3R3Z3E3/5H3R3E3
treatment after default]
Category III New smear negative and extra-pulmonary, not 2H3R3Z3/4H3R3

seriously ill
* The number before the letters refers to the number of months of treatment. The subscript after the letters refers to the number of
doses per week
In children, seriously ill sputum smear-negative pulmonary TB includes all forms of sputum smear negative pulmonary TB other than
primary complex. Seriously ill extra-pulmonary TB includes TB meningitis, disseminated TB, TB pericarditis, TB peritonitis and intestinal
TB, bilateral extensive pleurisy, spinal TB with or without neurological complications, genitourinary TB, and bone and joint TB
Not seriously ill sputum smear negative pulmonary TB includes primary complex. Not seriously ill extra-pulmonary TB includes lymph
node TB and unilateral pleural effusion
H = isoniazid; R = rifampicin; Z = pyrazinamide; E = ethambutol; S = streptomycin; TB = tuberculosis
Table 63.5B: Guidelines for use of paediatric patient wise boxes under the Revised National Tuberculosis Control
Programme
Product Code Product Description Strength Unit

Product Code-13 Treatment box for paediatric Each combi-pack of Each multi-blister calender Treatment box
category [6-10 Kg]. Each Schedule-5, containing combi-pack of Schedule-6
treatment box contains 24 combipacks 1 tablet of rifampicin [75 containing 3 tablets of
of Schedule-5 in one pouch mg]; 1 tablet of isoniazid rifampicin [75 mg each];
and 18 multi-blister calendar [75 mg]; 1 tablet of 3 tablets of isoniazid [75 mg
combi-pack of Schedule-6 in ethambutol [200mg]; and each]; and 4 tablets of
another pouch 1 tablet of pyrazinamide pyridoxine [5 mg each]
[250mg]
Product Code-14 Treatment box for paediatric Each combi-pack of Each multi-blister calender Treatment box
category [11-17 Kg]. Each Schedule-7, containing: combi-pack of Schedule-8,
treatment box contains 24 combipacks 1 tablet of rifampicin containing 3 tablets of
of Schedule-7 in one pouch [150mg]; 1 tablet of rifampicin [150 mg each];
and 18 mult i-blister calendar isoniazid [150mg]; 1 tablet 3 tablets of isoniazid
combi-pack of Schedule-8 in of ethambutol [400mg ]; [150mg each]; and 4
another pouch and 1 tablet of tablets of pyridoxine [5 mg
pyrazinamide [500mg] each]
Product Code-15 Treatment box for prolongation of Each combi-pack of Treatment box
intensive phase of paediatric Schedule-5, containing
cases [6-10 kg, 18-25 kg]. Each 1 tablet of rifampicin [75
box containing 5 pouches and mg]; 1 tablet of isoniazid
each pouch containing 12 blister [75 mg]; 1 tablet of
combi-packs of Schedule-5 ethambutol [200mg]; and
1 tablet of pyrazinamide
[250mg]
Product Code-16 Treatment box for prolongation Each combi-pack of Treatment box
of intensive phase of paediatric Schedule-7 containing
cases [11-17, 18-25 kg and 26-30 1 tablet of rifampicin
kg]. Each box contains 5 pouches [150mg]; 1 tablet of
and each pouch contains 12 isoniazid [150mg];
blister combi-packs of Schedule-7 1 tablet of ethambutol
[400mg]; and 1 tablet of
pyrazinamide [500mg]
The formulations used in RNTCP are rifampicin [75/150 mg]; isoniazid [75/150 mg]; ethambutol [200/400 mg]; pyrazinamide [250/ 500
mg]
For the purpose of treatment, the paediatric population is divided into four weight bands: 6-10 kg; 11-17 kg; 18-25 kg; and 26-30 kg
The antituberculosis drugs for paediatric patients are available in the form of generic patient wise boxes i.e., Product Code-13 and
Product Code-14. Product Code-15 and Product Code-16 would be available for the prolongation of the intensive phase, if required and
also to facilitate conversion of the boxes into Category II and for reconstitution, if required
The generic patient wise boxes, would be used for the paediatric patients in the following manner: a child weighing 6-10 kg would
require one box of Product Code-13; a child weighing 11-17 kg would require one box of Product Code-14; a child weighing 18-25 kg
would require one box of Product Code-13 and one box of Product Code-14; a child weighing 26-30 kg would require two boxes of
Product Code-14
In case, any patient is to be placed on Category II or III, the following steps will have to be taken to convert the generic boxes into a
Category II or III box. For children to be placed on Category II, prolongation pouches would be added for prolongation of the intensive
phase. For the extra one month of continuation phase, a prolongation pouch would be added after removing the pyrazinamide tablets
from the prolongation pouch. For the other four months of continuation phase blisters, ethambutol tablets will need to be added which
can be used from the supplies of loose drugs under the programme. Streptomycin injection [750 mg] supplied under the programme
shall be used for such patients and the dosage would be as per body weight. For children who are to be put on Category III, the
ethambutol tablets will be removed from the intensive phase blisters
910 Tuberculosis
of TB, most patients with chest symptoms first consult RNTCP TB cases. The corporate sector has also begun to
private practitioners [PPs] (27,28). Unfortunately, TB is collaborate and over 120 corporate sector units are
often inaccurately diagnosed and ineffectively treated in involved in RNTCP including sugar mills in Uttar
the private sector (28-33). This can result in diagnostic Pradesh, the tea gardens in North-East and West Bengal,
delay, prolonged infectiousness, drug resistance, poor Coal India in West Bengal and some of the other major
treatment outcomes, and higher relapse rates. Although houses of industry. Additionally, the Indian Business
often sharing a common patient with similar objectives, Alliance is a coalition recently formed by the Global
there are often considerable misunderstandings between Health Initiative of the World Economic Forum. The
the private and public sectors regarding TB management objective is to bring together these companies to work
(34). Consequently, the RNTCP has made efforts to with Government of India to improve TB control.
develop partnerships with health providers outside the Members include Reliance, Larsen and Tourbo [L & T],
government health system, and in particular with the Aditya Birla, Confederation of Indian Industry [CII],
private health sector and NGOs. The goal is to raise the Tata, Hindustan Lever Limited [HLL], and other
standard of care and provide a seamless more effective corporate houses. As part of this effort to expand
TB control environment for patients by improving access collaborations, Government of India has started a public-
to quality TB care in either the public or private sector. private mix initiative in 14 large urban areas with the
In 2001, the RNTCP has developed official policy support of the CIDA and technical assistance from WHO.
guidelines for involvement of NGOs and PPs in the This ground-breaking initiative includes technical
programme. The policy guidelines for NGOs and PPs consultants who are dedicated to establish and improve
involvement provide a menu for collaboration on public-private sector collaborations and is expected to
different levels of service delivery including referral, IEC, significantly strengthen the partnership between the
DOT provision alone, and operating a DMC with or private health sector and TB control activities in India.
without provision of DOT. To improve collaborations The CTD conducted a three-day Consultation on
with the private sector, the RNTCP has started a number Revision of NGO/PP Guidelines in January 2008 in Delhi
of initiatives including the provision of CMEs, seminars, to improve the collaboration with private sector in all
workshops, lectures and conferences on RNTCP and the aspects of RNTCP implementation. Subsequently, in
DOTS strategy. A national conference, was held at the August 2008, the CTD brought out the RNTCP Revised
All India Institute of Medical Studies [AIIMS], New Delhi Schemes for NGOs and Private Providers [Table 63.6]
in 2001 to share experiences and discuss modalities for (49) to meet the challenges of the present day programme
private sector involvement in the RNTCP. District and implementation. These guidelines have been
State TB Control Societies are encouraged to include implemented with effect from October 1, 2008.
representatives from NGOs and PPs as members of the
respective society. State/district action plans for ACADEMIC SECTOR
implementation of the RNTCP include plans for NGO
involvement. Finally, RNTCP is engaged with the Indian India has over 277 medical colleges and over 18 000 new
Medical Association [IMA] and the Indian Association doctors graduate annually. Through research, academic
of Paediatrics [IAP] and has co-edited a number of work and practical training, medical colleges play a major
articles discussing RNTCP in the Journal of the Indian role in establishing the standard of care for managing
Medical Association (35-48). TB. Additionally, as referral centres of excellence, medical
Thousands of NGOs, PPs, and RNTCP staff have colleges treat a significant number of TB cases. The
recognized the potential benefit of RNTCP for their RNTCP recognizes the challenge and importance of
patients and have developed formal and informal introducing DOTS principles as the standard of care into
collaborations. To date, about 2 400 NGOs and more than both the training and clinical care practices of medical
17 000 PPs are officially providing RNTCP services. professionals. In order to further integrate medical
Evaluation and documentation of some of these prog- colleges into the national effort to control TB, the RNTCP
rammes have shown that case detection and notification has made it a priority to involve medical colleges and
can increase significantly and that patients’ outcomes are their hospitals in the RNTCP. Under RNTCP, the District
similar between the public and privately managed Health Society is authorized to provide a medical officer,
Table 63.6: Revised schemes for the involvement of non-governmental organizations and private providers in the Revised
National Tuberculosis Control Programme
ACSM Scheme: TB advocacy, communication, and social mobilization

SC Scheme: sputum collection centre/s
Transport Scheme: sputum pick-up and transport service
DMC Scheme: Designated Microscopy Cum Treatment Centre [A & B]
A. Designated Microscopy and Treatment Centre for a NGO/Private lab
B. Designated Microscopy Centre [microscopy only]
LT Scheme: strengthening RNTCP diagnostic services
Culture and DST Scheme: providing quality assured culture and drug susceptibility testing services
Adherence scheme: Promoting treatment adherence
Slum Scheme: Improving TB control in urban slums
Tuberculosis Unit Model
TB-HIV Scheme: delivering TB-HIV interventions to high HIV risk groups
TB = tuberculosis; ACSM = advocacy, communication, and social mobilization; SC = sputum collection; NGO = non-governmental
organization; LT = Laboratory Technician; DST = drug susceptibility testing; HIV = human immunodeficiency virus
Detailed description of these schemes can be accessed at “Central TB Division. Revised Schemes for NGOs and Private Providers.
Available at URL: http://www.tbcindia.org/pdfs/New%20Schemes%20NGO-PP%20140808.pdf. Accessed on October 12, 2008
(reference 49)”
a laboratory technician and a TB health visitor to the patient friendly services, improving provision of DOT,
participating medical college with a DMC and a DOT etc.].
centre. In addition, RNTCP supplies laboratory Currently, 263 of the 277 medical colleges are
consumables and supplies, binocular microscopes [for involved in the RNTCP and all have established a Core
government medical colleges], drugs for patients and Committee to oversee the functioning of a DMC and
funds for civil works for improving the laboratory DOT centre within the medical college. To further
facilities in medical colleges. integrate the services, RNTCP has started a “referral for
In 1997 a national consensus conference on TB was treatment” mechanism to develop seamless
held in Delhi and following this initiative the RNTCP communications between the medical colleges and the
organized a series of sensitization seminars, and national general health services so that all TB patients diagnosed
level workshops at Central TB Institutes for the training at medical college receive RNTCP services [e.g., DOTS]
of medical college faculty staff. In 2002, the AIIMS hosted at the most convenient location to the patient. Although
national-level meetings and seven premier medical establishing meaningful participation in RNTCP by the
colleges in different zones of the country were identified academic sector requires additional efforts by all
as nodal centres to take the lead in establishing academic involved, there is now a growing professional consensus
sector for nation-wide participation in RNTCP (41,50). in India regarding the efficacy of RNTCP’s DOTS-based
A national task force, five zonal task forces and several strategy.
state-level medical college task forces were formed. Core
activities include: [i] training and teaching RNTCP as part RESEARCH
of CME courses to undergraduates, medical students, The RNTCP is founded on basic scientific principles
faculty, paramedical staff ; [ii] implementing RNTCP in largely discovered in India and TB research plays an
the medical college including establishing DMC and important role in determining the future direction of its
DOTS centres, strengthening laboratory infrastructure, TB control efforts (37). Although an impressive amount
involvement in quality assurance and the management of research is published each year from India on TB, a
of difficult cases; [iii] advocacy regarding RNTCP relatively small proportion addresses practical difficulties
through sensitization of professional bodies including of TB control in India. To fill up this gap, the RNTCP has
the IMA; [iv] design and implementation of OR that is established an OR agenda [Table 63.7] and a funding
focussed on answering key issues facing RNTCP efforts mechanism for OR proposals from interested researchers
to control TB [e.g., increasing case detection, providing (3). Proposals are screened by a committee consisting of
912 Tuberculosis
Table 63.7: Priority operational research agenda for Revised National Tuberculosis Control Programme
Improving DOTS Implementation
Prospective, community-based long-term cohort study of patients registered and treated under RNTCP, evaluating multiple key treatment-
related questions
Risk factors for death, default, and failure under RNTCP
Evaluation of the impact of migration on treatment outcomes
Treatment outcomes among patients with co-morbidities [e.g., diabetes mellitus, HIV infection]
Treatment outcomes among patients with drug-resistant TB [other than MDR-TB]
Prevalence of recurrent TB due to either relapse or re-infection
Risk factors for recurrent TB, including relapse [i.e., reactivation] and reinfection
Health seeking behaviour and reasons for delay in diagnosis among TB patients in vulnerable populations, including tribals and urban
slum dwellers
Pilot test of “2+2” [2 weeks cough and 2 sputum specimens] for TB suspect identification and initial evaluation in high and low workload
settings
Rapid retrospective evaluation of risk factors for Category II treatment default
A cluster of randomized controlled trials of innovative and cost-effective programme interventions to reduce treatment default
Evaluation of family-DOT in paediatric TB patients using paediatric patient-wise boxes
Rapid retrospective evaluation of the impact of treatment interruptions on treatment outcomes
Improving DOT: what modifiable factors are associated with higher quality of DOT in different settings?
Evaluation of patient reasons for initial default, and the effectiveness of programme interventions to prevent initial default
MDR-TB
Prevalence of MDR TB in Category I failures, Category II entry, and Category II patients who are smear-positive at 3 months, and
association of MDR-TB with past history of antituberculosis treatment [including whether it was DOTS or self administered non-DOTS
treatment]
Evaluation of innovative methods of community-based DOT provision for the delivery of RNTCP Category IV treatment
TB-HIV
Evaluation of the optimum screening modality for intensified case finding for TB disease in Antiretroviral Treatment and Care and
Support Centres
Reasons for loss of TB suspects referred from integrated counselling and testing centres [ICTCs] to designated microscopy centres
[DMCs]
ACSM
Health marketing to private providers – what messages change behaviour?
PPM
Quality of TB diagnosis and care among private sector physicians
RNTCP = Revised National Tuberculosis Control Programme; TB = tuberculosis; OR = operational research; DOT = directly observed
treatment; HIV = human immunodeficiency virus; PPs = private practitioners; ACSM = advocacy communication for social mobilization;
PPM = public-private mix; MDR-TB = multidrug-resistant tuberculosis
internal and external experts. Funds have also been made study of the RNTCP infrastructure and implementation
available to states for inviting proposals and funding mechanism (3).
research activities in their respective states. Completed
research projects include annual risk of TB infection [ARI] Measuring Epidemiological Impact
studies, drug-resistance surveys, baseline studies on the The ARI estimates in India are available from studies
accessibility and utilization of RNTCP services by various conducted in smaller geographical areas over the last 30
marginalized sectors [e.g., scheduled castes/scheduled years. Recently, the NTI, Bengaluru in collaboration with
tribes, women, people living with HIV/AIDS], and a the TRC, Chennai completed a countrywide cross-
sectional survey, which for the first time provides current ment of MDR-TB and subsequent XDR-TB is through
national and regional estimates of the ARI in India. maintaining and improving quality of the RNTCP DOTS
National estimate of ARI prior to 2000 was 1.7 per cent and more importantly promote the rational use of first-
and estimate based on National ARI survey [2001 to 2003] and second-line antituberculosis drugs amongst all
is 1.5 per cent (51,52). health care providers. The national programme has
The ARI in urban areas [2.1] was higher than rural initiated the DOTS-Plus services for management of
areas [1.2 to 1.3]. The zonal estimates are applied to the MDR-TB in Gujarat and Maharashtra in August 2007 and
states that constitute the zone for calculating the in Andhra Pradesh in October 2008. These services will
incidence estimates used for monitoring case detection. be introduced in other states across the country in a
Finally, to monitor trends and impact of RNTCP on the phased manner by 2009 to2010.
TB burden, a repeat survey using a zonal sampling
approach will be undertaken in approximately five years. Joint Monitoring Missions
National ARI survey to estimate incidence has been
External reviews by national and international
initiated during the period 2007 to 2009.
authorities have played an important role in monitoring
These data can then be used with corroboration from and evaluating RNTCP’s progress. As a follow-up to the
community-based prevalence studies and notification
1992 review that prompted the revised programme, a
data to estimate the RNTCP’s impact on TB epidemiology
review conducted in February 2000 found the RNTCP
in India. implementation to be a success, with a striking increase
in the proportion of patients cured (17). The 2000 review
Drug Resistance Surveillance
recommended rapid expansion of quality RNTCP
Monitoring population-based levels of drug resistance services to cover the entire country by 2005 in order to
among TB patients can help a programme to better make a significant impact on the TB epidemic. A follow-
understand whether it is being effective since program- up review to assess progress, technical policies and
matic lapses [e.g., interrupted drug supply, inappropriate performance was jointly organized by the Government
regimens, poor adherence to DOT] can lead to increased of India and the WHO in September, 2003. A team of 20
levels of resistance (53-55). Rifampicin resistance and national experts [from IMA, National Institute of Health
multidrug-resistance [defined as resistance to both and Family Welfare, leading medical colleges, central TB
rifampicin and isoniazid with or without resistance to institutes, NGOs and programme staff from state and
other antituberculosis drugs] among new patients started district level] and 22 international TB experts from CIDA,
to appear in the 1980s, and has been less than three per CDC, DANIDA, DFID, GDF, GFATM, IUATLD, KNCV,
cent in most studies (56). The TRC, Chennai in USAID and WHO conducted this review. From five states
collaboration with the NTI, Bengaluru using the WHO/ selected, three districts were randomly selected and one
IUATLD guidelines conducted a number of population- district was conveniently selected adding up to a total of
based studies in districts across India which has provided 20 districts. Two DMCs were randomly selected from
valuable information about primary drug resistance each of the 20 districts.
(56,57). The reader is referred to the chapter At the time of 2003 review, a population of 740 million
“Antituberculosis drug resistance surveillance” [Chapter 50] had access to DOTS and nearly 2.4 million patients had
for further details on this topic. been placed on treatment with over 85 per cent treatment
A major challenge for the programme in achieving success. The review appreciated the extraordinary rapid
the goal of TB control is multidrug-resistant TB [MDR- expansion while maintaining high levels of treatment
TB] and the emerging threat of extensively drug-resistant success, and noted that it was highly economical. The
TB [XDR-TB]. Although the community based Drug RNTCP has expanded faster than any other effective TB
resistance surveillance [DRS] conducted in Gujarat and control programme in the history of DOTS, and its visi-
Maharashtra recently estimated the prevalence of MDR- bility has increased both nationally and internationally.
TB to be around three percent amongst new cases, in Good infrastructure and management systems for TB
terms of absolute numbers the burden is quite significant. control have been established and more than 500 000 staff
The most effective means of preventing further develop- have been trained. As a result, case detection rates are
914 Tuberculosis
increasing and cure rates remain high. The teams found programme which should strive to ensure that all
that overall the recording and reporting is excellent and patients have access to care remains a challenge and
that the published data at the central level reflect the many patients still face significant economic and social
programme activities in the field, including diagnosis of barriers to access care. Combining maintenance and
cases and outcomes of treatment. The RNTCP provides improvement of already existing DOTS services to
treatment that is free, intermittent and directly observed. difficult and hard to reach areas will require considerable
Significant initiatives at central, state and local levels have planning, monitoring and supervision.
resulted in greater involvement of NGOs, PPs and Another challenge is ensuring that adequate
medical colleges. The Joint Monitoring Mission held in resources are in place to sustain the Programme activities.
September 2003 provided valuable guidance for the Adequate resources have been ensured till 2011 in
RNTCP over the past four years. RNTCP II. However, long-term sustainability to achieve
The third Joint Monitoring Mission was undertaken the ultimate goal of TB control will require careful
in 2006 that was jointly organized by the Government of planning.
India and WHO in October 2006, consisting of a team of One of the thrust areas for RNTCP is filling up the
24 national experts. The team observed that the vacancies of key staff arising from time to time. The cost-
programme service delivery is well integrated into the effectiveness of DOTS and benefits of the Programme
health system, there is a well established effective drug are clear and warrant further investment of resources.
logistic management system, quality assured drugs are The significant direct and indirect costs to patients due
available throughout the country free of charge, EQA to TB further supports the argument for strengthening
has been implemented in the microscopy network, the public health sector services. For example, sputum
smear microscopy has a pivotal role to play in diagnosis
coordination between RNTCP and TB-HIV is evidenced
and follow-up of TB patients and full-time trained
in a joint action plan and a plan to address MDR-TB is
laboratory technicians are essential for all RNTCP DMCs.
prepared.
Though the CTD is directly supporting appointments of
an important proportion of these staff, the states also need
THRUST AREAS to take the initiative in making staff appointments, as
eventually they will need to manage and support the
The following topics are considered as ‘thrust areas’ for
programme. The framework of National Rural Health
the RNTCP which is facing significant challenges in its
Mission [NRHM] calls for convergence and integration
efforts to control TB in India.
which is a positive development for RNTCP and can
Planning for the provision of quality TB services to a
improve equitable access and convenience of services.
population of over one billion is a daunting task. To
Another thrust area is to successfully decentralize
maintain and improve the existing standards of care
some of the core managerial responsibility for running
involves a significant number of activities. Specifically, the programme to the states while maintaining quality.
this means assuring that quality DOTS is being provided To ensure effective administration, accountability and
which will include screening several million people each sustainability of the programme, the states will need to
year, performing almost 100 000 smear examinations increasingly shoulder responsibility for running the
every day and providing an uninterrupted supply of programme. As a step towards decentralization of
quality antituberculosis drugs under supervision to more programme management, the capacity of the states has
than 1.4 million cases each year. The RNTCP has been developed for technical and financial monitoring.
consistently shown treatment success rates of around 85 The State TB Officers and accountants at the respective
per cent, whilst case detection rates have gradually STCs have been trained in financial management and
increased to 70 per cent in 2007. India has demonstrated procurement in addition to the routine STO training
that with the right combination of political commitment, curriculum under RNTCP. Capacity at state level to plan,
adherence to technical standards, managerial capacity supervise and monitor TB control requires more
and partnership, rapid large-scale expansion of services attention. Increased supervision is required at all levels
with good results are possible in TB control. However, to ensure proper programme functioning. Although
establishing that the patient is the “VIP” of the recording and reporting is a strong component of the
programme, the capacity to analyse, interpret and Management of MDR-TB is also an important
improve performance based on findings is limited. challenge. Although the overall proportion of patients
Another challenge for RNTCP is to increase case with MDR-TB is relatively low when compared with
detection and improve the standard of care through other “hot spots”, there are a significant number of
collaboration with other key partners including other patients with MDR-TB in India. Effective implementation
governmental public health providers, the corporate of RNTCP is the most effective means of preventing
sector, academia, PPs, NGOs, large para-statal organi- development of MDR-TB. The RNTCP recognizes that
zations such as the Railways, Employees State Insurance indiscriminate use of second-line drugs under non-DOTS
Service [ESIS], and TB hospitals. The largely unregulated conditions is widespread and is actively planning its
private sector is sizeable and provides a substantial national strategy regarding the issue of drug resistance.
proportion of outpatient care, and this care is of inconsis- Plans include bolstering state capacity to perform drug
tent quality (31). Although there has been progress in resistance testing, widening drug resistance surveillance
involving large and growing private sector, their efforts, and making arrangements to provide second-line
involvement is not yet sufficient to provide maximal drugs. Establishment of the planned accredited network
benefit to patients. A number of key partnerships are of IRLs for quality controlled culture and drug suscepti-
emerging including the significant involvement of the bility testing [DST] to diagnose MDR-TB is a challenge
medical colleges, some parts of the corporate sector, ESIS
to the programme.
and Railways, NGOs and PPs.
India is a large country with varied populations,
The sixth thrust area is advocacy, communication and
cultures, beliefs and socio-economic status across the
social mobilization in order to maintain high visibility
country. TB as a disease and its management is often
of TB and RNTCP amongst policy makers, opinion
viewed differently depending on the various socio-
leaders and community and hence, sustain long-term
cultural-economic conditions prevailing in India today.
political and administrative commitment and greater
Despite the major challenges inherent in providing care
community involvement in RNTCP. The goal of ACSM
across the diversity of modern India, the RNTCP and its
is to support TB efforts by [i] improving case detection
partners have made significant advances in establishing
and treatment adherence; [ii] combating stigma and
a quality DOTS-based programme. For millions of patients
discrimination; [iii] empowering people affected by TB;
and [iv] mobilizing political commitment and resources the RNTCP has delivered on its promise of free and
for TB. By doing so, it aims to widen the scope for effective care for TB. However, the RNTCP is entering a
providing standardized, good quality treatment and new and challenging phase to improve patient
diagnostic services to all TB patients in a patient-friendly management and treatment outcomes by further
environment decentralizing DOT and making treatment observation
Another area of thrust is the TB-HIV co-infection. more convenient to patients, particularly in slum and tribal
Addressing this issue requires close coordination bet- areas. What is also required by the programme is to
ween the TB and HIV/AIDS programmes and steps have improve the capacity of the supervisors at all levels to
been taken to ensure a joint action plan. Cross-referral evaluate and use programme data for action to improve
linkages between service delivery sites TB and AIDS the performance.
control programme have been established across the An effective DOTS programme in Peru has been
country. A large number of HIV infected TB patients are documented to result in a seven per cent decrease in TB
being routinely identified and initiated on DOTS. incidence per year (58). However, this rate of decline is
However, providing optimal access to HIV care including dependent on a number of factors including the presence
antiretroviral therapy, to these TB patients co-infected of HIV/AIDS and the contribution of recent transmis-
with HIV, remains a challenge as HIV care is relatively sion. Although the impact of RNTCP on disease incidence
centralized. Another area of thrust for TB/HIV collabora- will be known once ARI results will be available in 2009-
tive activities is addressing needs of marginalized 2010, there is a high likelihood that with the active
populations with high risk for HIV, such as commercial support of patients, the community, health authorities,
sex workers, men who have sex with men, etc. Due to providers, and policy makers, RNTCP should be able to
various social factors reaching out to these populations achieve its goal of controlling TB to the extent that it is
remains a challenge, requiring a distinct approach no longer a major public health problem in India.
916 Tuberculosis
ACKNOWLEDGMENTS 14. Banerji D, Anderson S. A sociological study of awareness of

symptoms among persons with pulmonary tuberculosis. Bull
The authors wish to thank Mr Avijit Choudhary, Mr Santosh World Health Organ 1963;29:665-83.
Kumar, WHO TB technical team, TB patients and health care 15. Baily GV, Savic D, Gothi GD, Naidu VB, Nair SS. Potential
workers across India who have markedly improved TB control yield of pulmonary tuberculosis cases by direct microscopy
in India. of sputum in a district in South India. Bull World Health
Organ 1967;37:875-92.
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918 Tuberculosis
Tuberculosis Vaccine
Development: Current Status
and Future Expectations 64
Anil K Tyagi, Bappaditya Dey, Ruchi Jain
INTRODUCTION the fight against this infectious disease in children in

developing countries (2). In India, the BCG vaccine
Tuberculosis [TB] is one of the most fatal infectious
laboratory was established in Chennai, Tamil Nadu, in
diseases, which continues to be a major global health
1948 to aid BCG immunization programme in the
problem. Despite all the available drugs and regimens,
country and to supply BCG to some neighbouring count-
there is a general perception that in the absence of an
ries. Though Pasteur strain remains the international
effective TB vaccine, the real control of TB on a worldwide
reference strain of BCG (3), owing to the variations in
basis is unlikely. Although a vaccine represents one of
production and preservation methodologies in different
the most efficacious and potent defenses against
countries, BCG strains with genotypic and phenotypic
infectious diseases, a perfect vaccine against TB that
differences have emerged. Variations in these strains
would be most effective in the control of this disease has
have been observed with respect to tuberculin conversion
eluded us all the time. Unfortunately, bacille Calmette-
rate, frequency of adverse reactions and even vaccine
Guérin [BCG], the currently used vaccine that was
efficacy ranging from 0 to 80 per cent (4-6). Nevertheless,
developed more than 80 years ago, has generated little
more than three billion children all over the world have
protection and a great deal of controversy.
been vaccinated with BCG. Although several studies
have been carried out with different doses of BCG, in
THE BACILLE CALMETTE-GUERIN VACCINE
diverse age groups and populations and through various
HISTORY: SCIENTIFIC FABLE AND THE LESSONS
routes such as oral, per-rectal, parenteral, subcutaneous,
LEARNED
and conjunctival route, these studies have yielded
The BCG, the only available and widely used vaccine different results (7-11) and the intradermal route for
against TB, was developed by Calmette and Guerin vaccination with BCG still remains the standard
between 1908 and 1921, from a Mycobacterium bovis strain international protocol. Considering the importance of
by serial weekly passages for 13 years (1). Based on the lung immunity in TB, many investigators (12-16) have
encouraging results in infants during the next four years, also employed intranasal route for BCG vaccination and
BCG was distributed around the world and its use as a have reported either an equivalent or a better protection
preventive vaccine against TB was encouraged. By 1948 than the intradermal route in various animal models.
more than 10 million immunizations were carried out Despite the global use of BCG, skepticism about its
and in the First International BCG Congress held in the efficacy and safety has persisted. A major setback
same year in Paris, it was concluded that BCG vaccination occurred in 1929 in Lubeck Germany, where 72 out of
was effective in preventing TB. In 1974, BCG vaccination 251 BCG vaccinated children died of TB, though later it
was included in the expanded immunization programme was revealed that the particular BCG vaccine preparation
of the World Health Organization [WHO] to strengthen was contaminated with the virulent Mycobacterium
Tuberculosis Vaccine Development: Current Status and Future Expectations 919
tuberculosis ‘keil’ strain (17). Other than the most frequent majority of these are saprophytic water or soil-borne
and mild side effect of BCG vaccination like local organisms. Mycobacterium tuberculosis is described as a
indurations and regional suppurative adenitis (18), the slow growing, strictly aerobic, lipid rich, hydrophobic,
only serious complication observed is disseminated BCG acid-fast bacilli [AFB], which exhibits true cording.
disease, seen in some children with human immuno- Mycobacterium tuberculosis is a strict aerobe and requires
deficiency virus [HIV] infection (19). However, the most special enriched media for its growth in vitro.
persistent controversy remains its variable efficacy in Multifactorial reasons for its slow growth include, the
different human populations. Till date, a number of relative impermeability of the cell envelope, aberrations
controlled BCG efficacy trials and one controlled trial in nucleic acid synthesis, presence of weak promoter
with BCG re-vaccination have been carried out. The signals and a single ribosomal ribonucleic acid [rRNA]
results of these major trials have been extensively operon. In addition, several other factors such as the
reviewed by Bloom and Fine (20), Colditz et al (21) and genomic organization with 41 per cent of the genes being
Comstock (10); and several reasons for the variable transcribed in the direction opposite to that of replication
efficacy of BCG have been proposed, such as variations (27), may also contribute to its slow growing nature.
in strains, defects in preparation, environmental There is a compelling evidence to suggest that in addition
influences [exposure to sunlight, poor maintenance of to the innate virulence of the bacilli, the host responses
cold chain], genetic or nutritional differences among the play an important role in determining the clinical
populations studied or exposure to environmental
manifestation and ultimate outcome of infection. The
mycobacteria and methodological differences among the
availability of genome sequence of Mycobacterium
major trials (22). Based on the published data, a quanti-
tuberculosis [4 411 526 bp], which encodes nearly 4000
tative meta-analysis of BCG efficacy revealed that it
putative open reading frames [ORFs], has brought a
reduces the risk of TB by 50 per cent among the vaccina-
paradigm shift in the approaches employed for cellular,
ted group (21). A recent meta-analysis (23) of effect of
biochemical and immunological dissection of this
BCG vaccination on childhood TB, meningitis and
pathogen. However, in spite of the rapid progress made
miliary TB worldwide, found BCG vaccination to be a
during the last two decades, towards understanding the
highly cost-effective intervention against severe
molecular nature of Mycobacterium tuberculosis several
childhood TB, and it was recommended that it should
important questions still need to be answered before a
be retained in high-incidence countries as a strategy to
rational approach for the development of a TB vaccine
supplement the chemotherapy of active TB. Although,
repeated BCG vaccination is a common practice in many can be anticipated.
countries [those in Eastern Europe] for prevention of TB
and leprosy, its effectiveness is yet to be evaluated (20). IMMUNOLOGY OF TUBERCULOSIS
A trial at Malawi comparing single, repeated and a
The reader is referred to the chapter “Immunology”
combination of BCG and killed Mycobacterium leprae
vaccine, concluded that a single BCG vaccination confers
50 per cent or more protection against leprosy, but not
against TB; a second vaccination added appreciably to COMPLICATIONS ASSOCIATED WITH HUMAN
the protection against leprosy, without providing any IMMUNODEFICIENCY VIRUS INFECTION AND
protection against TB (24). The inadequate and variable ACQUIRED IMMUNODEFICIENCY SYNDROME
protective efficacy imparted by BCG in different The prevalence of childhood TB is relatively low even in
populations poses a difficult question about the optimum highly endemic areas. However, with increasing
effectiveness of new vaccines, thus, demanding their incidences of HIV infection in children, it has become a
testing in diverse populations (25).
matter of serious concern whether to immunize these
infected children with BCG or not, which may accelerate
UNIQUE FEATURES OF THE PATHOGEN
the course of HIV infection (28-32) and may cause severe
Tubercle bacillus, the most virulent and pathogenic disseminated mycobacteriosis (33). Along with local
species of its kind, belongs to the genus Mycobacterium, adverse reactions, various forms of lymphadenopathy
which contains at least 100 different species (26); a were reported in patients with severe immunocompro-
920 Tuberculosis
mised condition, and in almost all of the cases adverse understanding of TB. Each animal model has its strengths
effect of BCG appeared only after the manifestation of and weaknesses with a varying degree of extrapolation
clinical symptoms of HIV infection (33). The BCG of their research findings in humans. Nevertheless, all
vaccination is known to protect individuals from deve- these animal models resemble the some important facets
loping extra-pulmonary TB, such as meningitis and of the human TB in one-way or the other.
miliary TB (34). By contrast, HIV infection has been First, animals can be easily infected by pulmonary
observed to reduce the efficacy of BCG against the route depositing a few virulent tubercle bacilli directly
development of extra-pulmonary TB (35). Thus, due to in to the alveolar spaces, which precisely epitomizes the
lack of sufficient studies to understand the effect of BCG way humans acquire infection. Secondly, various stages
vaccination in HIV-seropositive and -seronegative of disease progression in TB, such as, granuloma
children and inadequate understanding of BCG and HIV formation, liquefaction, cavity formation and haemato-
interdependence, WHO has recommended to disconti- genous spread can be easily studied in some of the animal
nue BCG vaccination in HIV infected children (36). models, especially in guinea pigs, rabbits and non-human
Immunodeficiency caused by HIV infection consider- primates. Various features of TB such as fever, weight
ably increases the risk of developing TB. During HIV loss, respiratory distress and radiological abnormalities,
infection, the progressive decline in CD4+ T-lymphocyte can also be observed in these animal models. If left
count, especially of the Th1 subtype with a shift towards untreated, infected animals may eventually die of
Th2, results in failure to control most of the invading pulmonary insufficiency, a fate typical of human TB
opportunistic organisms; Mycobacterium tuberculosis patients. The strong T-cell mediated immune responses
being the robust of all is often the earliest to break the as evident by a delayed type hypersensitivity [DTH] in
host defense (37). Besides the potentiating effect of HIV guinea pigs further substantiate the fact that animal
on progression of TB, generation of cytokines like tumour models have a significant similarity to humans. Due to
necrosis factor-α [TNF-α] during control of TB infection analogy of animal models and humans in terms of their
may act as a potent enhancer of HIV replication resulting susceptibility and resistance to TB, the disease process
in an increased viral burden (38). Furthermore, the and the consequences, the former can be successfully
immune response generated during active TB has been used for screening new antituberculosis vaccine as well
shown to prime peripheral blood cells and enhance their as chemotherapeutic agents.
susceptibility to HIV infection (39).
Mouse Model of Tuberculosis
CONTRIBUTION OF VARIOUS ANIMAL MODELS IN
Amongst various animal models of TB, mouse model is
THE UNDERSTANDING OF TUBERCULOSIS
the most popular and has particularly stood the test of
IMMUNOLOGY AND DEVELOPMENT OF VACCINES
time. Inbred mouse strains have undoubtedly provided
Animal models have played a great role in the field of a huge wealth of information regarding the basic mecha-
vaccine development. They provide invaluable insights nisms of immune responses, which have subsequently
into the human system owing to the striking similarities been shown to draw a significant similarity with humans.
between human and animal physiology. Unlike any other The evidence for involvement of lymphocytes in mediat-
disease, contribution of different animal models to TB ing immunity to TB was successfully shown by the ability
research has a long-standing history that can be traced of whole blood and spleen homogenates [from an
back to the time of Robert Koch. Moreover, TB being an infected mice] to transfer DTH to a naive mice (40). It
extremely complex disease with diverse clinical was also observed that CD4+ cells, when adoptively
outcomes, it requires adequate animal models that can transferred, conferred immunity to TB (41) and a popula-
mimic the disease process in humans. This would help tion of CD4+ memory cells also remains in the system
in understanding the pathogenesis of TB, mechanism of after clearance of the infection by chemotherapy (42).
host defense and would aid in evaluating prospective Further, a seminal work in mouse model by Cooper and
prophylactic and therapeutic TB vaccines and drugs. The Flynn (43) and Flynn et al (44) firmly established the
animal models, such as mouse, guinea pig, rabbit, and importance of Th1 pathway in the expression of
non-human primate have vastly contributed to our protective immunity. The mouse data have also shown
a potential role for CD8+ (45), CD4-/CD8- (46) and γ/δ aspects of TB, mice model has only been recommended
T-cells (47) in generating immune response to TB for the first-order screening of vaccine candidates, due
vaccines. In fact, there are several instances, where to differences in its pathology in comparison to humans.
findings originally obtained in the mice model have later Hence, as the protection in mouse model does not
been verified in humans. For example, knock out mice guarantee its reproducibility in humans, the efficacy of
deficient in interferon-γ [IFN-γ] and interleukin-12 [IL- new vaccines needs to be validated in other models of
12] genes were found to be highly susceptible to experimental TB.
Mycobacterium tuberculosis infection akin to patients with
hereditary deficiency in IFN-γ and IL-12 signalling. Mice Guinea Pig Model of Tuberculosis
with deficient TNF-α signalling exhibited similarity with
Guinea pig model of low-dose, airborne infection with
rheumatoid arthritis patients who developed reactivation
virulent Mycobacterium tuberculosis has been used for
TB on treatment with anti-TNF-a monoclonal antibodies. decades to elucidate events in the pathogenesis of pulmo-
The most evident similarity is observed with dramatically
nary TB and mechanism of vaccine induced resistance.
increased incidence of primary and secondary TB in
Guinea pig is currently one of the most useful models of
knock-out mice devoid of CD4+ T-cells, thus, mimicking human TB for evaluation of new vaccines. The primary
HIV infection (48).
reason for this preference stems from the ability of guinea
The usefulness of the mouse model has grown pigs to initially develop strong immunity, which
tremendously over the last two decades due to avail- eventually results in considerable tissue damage, leading
ability of a vast database of reagents, like monoclonal to the formation of granulomas as seen in humans. These
antibodies to T-cell surface markers, primers and probes granulomas then undergo an extensive caseation necrosis
for the growing array of cytokines and chemokines. eventually killing the animal. Moreover, guinea pigs are
Moreover, advancement in the field of transgenic expres- sensitive to tuberculin skin testing and can be used to
sion, gene knock-out, gene knock-in [both constitutive determine vaccination induced DTH reaction.
and conditional] technologies, along with the availability On infection of lungs with Mycobacterium tuberculosis,
of large variety of mouse mutants with defined immune a considerable host tissue remodelling occurs to thwart
deficiencies have immensely helped the scientific off the infection by permitting the correct influx of
investigations dissecting the precise nature of immune lymphocytes and macrophages. But this necessary lung
response to Mycobacterium tuberculosis infection. The tissue consolidation results in the death of the infected
mouse genome sequence has further helped in designing animals due to pulmonary insufficiency. Thus, a short-
genome-based experiments to pin-point the importance term reduction in bacillary load may not be the most
of key genes involved in innate and adaptive immunity important criterion and a long-term survival and imp-
against TB and understanding the role of downstream roved pathology in the guinea pig model may provide a
signalling pathways. better picture of efficacy of a vaccine. Further, in contrast
Although mouse model provides a huge advantage to mice model, guinea pigs like humans have a group
in terms of cost effectiveness, it fails to completely mimic of CD1+ molecules that are responsible for the presenta-
the entire spectrum of human TB. The granulomatous tion of mycobacterial glycolipids to a specialized T-cell
pathology induced in mice in response to TB infection is population. These CD1+ molecules have been shown to
very different to that observed in humans and other present mycolic acids, lipoarabinomanan and other
naturally susceptible hosts as mice are innately resistant components of the mycobacterial cell wall to human
to TB and generate a strong cellular immune response T-cells in vitro. Thus, guinea pigs can be employed to
against TB infection, which controls bacterial growth and investigate the role of these glycolipids in protection and
disease progression. Mice develop granuloma with the pathology.
aggregation of lymphocytes towards the centre, which The guinea pig model has also been employed to
is in striking contrast to humans and guinea pigs wherein study the effect of malnutrition on TB, which is known
lymphocytes form a peripheral ring with arrangements to induce a state of immunodeficiency. The precise
of macrophages towards the centre (49-54). Thus, despite mechanism of interference with the immune responses
its definite advantages in the study of immunological and compromised antimicrobial resistance that results
922 Tuberculosis
from malnutrition has also been elucidated by using contribution of various cell populations in mediating
guinea pig model. McMurray and colleagues (54) have protection against the disease.
documented a series of immunological abnormalities
associated with protein deficiency in guinea pigs, which, Non-human Primate Model of Tuberculosis
when viewed in a clinical context, mimic the situation, On comparative assessment of all the existing models of
where malnutrition in humans results in an increased TB, non-human primates like Rhesus monkey,
susceptibility to TB. Malnutrition is known to impair Cynomolgus monkey, etc., were found to mimic several
several aspects of mycobacterial antigen-specific aspects of human TB (57). Apart from the susceptibility
peripheral T-cell function including lymphocyte prolife- to natural infection with a range of mycobacterial species,
ration (53), interleukin-2 [IL-2] production (54), expres- non-human primates are very similar to humans in terms
sion of the CD2+ marker (55), and the ability to mount a of granuloma architecture and various stages of disease
DTH response (56). These immunological alterations, progression (58-61). These similarities are based on the
which seem to be associated with the loss of vaccine presence of several common molecules in non-human
induced and naturally acquired resistance to pulmonary primates and humans. For example, non-human
TB in the guinea pigs, can serve as suitable surrogate primates [Rhesus monkey] and humans share the
markers for protection. However, sufficient evidence to presence of functional major histocompatibility complex
substantiate their utility is lacking at present. The only [MHC] molecules, which bind specifically to myco-
way to correlate the immunological readouts with protec- bacterial peptides (62,63). Further, both humans and non-
tive efficacy [as measured by bacillary load and effect on human primates have CD1+ molecules in common that
survival of guinea pigs following infection] is to carry are required for presenting several non-peptide
out a mass screening of vaccines with varying efficacy mycobacterial products to the T-cells (64-66). Besides, in
in the guinea pig model, followed by a statistical primates the course of infection can be easily followed
regression analysis. This would help in identification of up by chest radiograph, weight loss, as well as by
immune responses required for protection. Furthermore, performing a variety of immunological assays, which
to screen new TB vaccine candidates, an ideal animal provide a detailed insight into the disease progression.
model would be one in which BCG efficacy is suboptimal, It has also been further developed to study HIV and TB
thus, providing room for improvement. Though, several co-infection (67,68), which would help understanding the
genetically engineered mice strains are available, these disease pathogenesis and treatment of HIV-related TB
are probably too impaired immunologically to provide (69,70). However, several critical disadvantages have
an optimal window for efficacy evaluation. Thus, a reserved this model only for the final stage of vaccine
moderately protein-deficient guinea pig has been evaluation. The disadvantages, such as, high cost,
proposed as an ideal animal model for testing the efficacy requirement of extensive biohazard containment facility,
of new vaccines. difficulty in handling and maintenance of disease-free
Most of the vaccine candidates are first screened in colonies of these primates, which are extremely suscep-
mice model of TB and only promising candidates are tible to mycobacterial infections, have resulted in the
taken up for screening in guinea pigs. But this strategy testing of only a few candidate vaccines in primates till
of prioritizing any vaccine candidate should be analysed date.
very carefully as there are chances of loosing those Langermans and colleagues (71) using the Macaque
candidates, which though may not be efficacious in mice model showed that protection against a high dose of
but may have tremendous potential in guinea pigs which Mycobacterium tuberculosis infection could be achieved in
resembles humans more closely. But despite several Cynomolgus monkeys with BCG vaccination, although
advantages, guinea pig model of TB suffers from few no such protection was observed in case of Rhesus
disadvantages that have precluded its use as a first-order- monkeys. Though Rhesus and Cynomolgus monkeys are
screening model. These include [i] high cost and require- closely related species they differ markedly in their
ment of extensive biosafety level III [BSL III] animal susceptibility to Mycobacterium tuberculosis infection and
facility; and [ii] paucity of immunological reagents BCG induced protection; these two species, thus,
required to track down the immune responses and represent the two extremes of the degree of protection
induced by BCG in humans. Since most of the vaccines of the disease. Hence, it may be advisable to first test
need to be compared to BCG, Cynomolgus can be very promising vaccine candidates in this model to generate
useful for evaluation of subunit and deoxyribonucleic sufficient data before including them for human trials.
acid [DNA] vaccines, whereas live attenuated vaccines
[like recombinant BCG] may show a clear improvement Deciphering the Mystery Behind an Array of
over BCG in Rhesus monkeys (71). Recently, haemagglu- Immune Responses to Vaccination and Infection
tinating virus of Japan-liposome encapsulating a
Numerous meta-analyses based on several BCG efficacy
combination of DNA vaccines expressing heat shock
trials in humans have resulted in some important
protein 65 [HSP65] and IL-12 has been tested in observations concerning the susceptibility to infection
Cynomolgus monkeys. In the same study, a recombinant and elicitation of immune responses. Different human
BCG harbouring the 72f fusion gene [r72f BCG] when populations respond differently to immunization as well
used in Cynomolgus monkeys exerted a significant as Mycobacterium tuberculosis infection. Various host
prophylactic effect against Mycobacterium tuberculosis factors, variability in the BCG strains, and differences in
infection (72). A vaccine based on the 72f fusion protein the virulence of Mycobacterium tuberculosis strains
has entered Phase I clinical trial after evaluation in represent some of the multifactorial reasons for the
Cynomolgus monkeys (73). Another subunit vaccine, apparent variability in the protective efficacy of BCG.
which is now in Phase I clinical trial is a fusion protein The role of host factors is well exemplified by the fact
of 85B and early secreted antigen 6 [ESAT-6] which, when that only 10 per cent of the exposed individuals actually
tested in non-human primate model using dimethyl develop the disease and rest 90 per cent are efficiently
dioctadecylammonium bromide/monophosphoryl lipid able to control the infection, which may remain latent
A [DDA/MPL] and in adjuvant system no. 02A [AS02A] for many years (75). Though till date there is no strong
of Glaxo SmithKline as adjuvants, induced a strong evidence in favour of the genetic bias for susceptibility
protective immune response. Both the formulations to TB in humans, some epidemiological investigations
resulted in substantial reduction in bacillary load in lungs suggest that susceptibility to TB may be under some
and significantly improved lung pathology. Furthermore, genetic control (76). For example, although complete
a very good correlation was observed between the inability of BCG to provide protection in Chingleput trial
disease severity and weight loss with elevated levels of (77) could suggest an underlying genetic bias for these
immunoglobulin M [IgM] and immunoglobulin G [IgG] results, a case-control study on immigrant Asian
responses to several mycobacterial antigens, such as community in UK revealed far greater protection in
culture filtrate protein 10 [CFP 10], HSP-X [alpha immigrant Asians in UK than those in Chingleput, South
crystalline] and MPT83. Along with higher levels of India. Thus, genetic bias might not really have been at
T-cell activation, an increased level of ESAT-6 specific least the primary reason for the observations in
IFN-γ was detected during infection (74). Though the Chingleput trial where BCG exhibited zero per cent
studies in Macaque model have tremendously helped efficacy (77,78). Indeed the contribution of other factors,
gaining an insight into the immune responses and like age, nutritional status, co-existence of other diseases,
pathogenesis associated with human TB, it suffers from immune status, etc. may play an important role in
some key limitations like inclusion of only a small determining the risk of developing TB. Besides, in specific
number of animals in the study and difficulty of subpopulations, like infants or persons with immuno-
maintenance, etc., for long-term experiments. With the deficiency, the occurrence of TB was found to be much
availability of more BSL III containment facilities, it higher than those in the general population (79-82). Apart
should gradually become feasible to include a larger from HIV co-infection, infections like, schistosomiasis
number of animals with longer experimental schedules and hookworm infection have been found to adversely
in future studies. affect the progression of TB. Co-infection with these
As primate model can reproduce several important parasites modulates the immune system of the host by
aspects of human TB, improvement in this model will down- regulating the T-cell responses against
help in deciphering the disease pattern, immune res- mycobacterial antigens, thereby resulting in a reduced
ponses, and pathology associated with different phases protection by BCG immunization against TB (83-85).
924 Tuberculosis
Apart from the host genetic factors and differences would be highly beneficial, if the number of variables
in BCG strains, which result in an enormous variability, arising from the host, pathogen and the vaccine is
there is an emerging evidence that various Mycobacterium minimized in order to obtain uniform results.
tuberculosis strains may vary in their genetic composition
as well as phenotype and, thus, may substantially affect IDENTIFICATION OF VACCINE TARGETS
the evaluation of vaccine candidates. The Beijing strain IN THE POST-GENOMIC ERA
of Mycobacterium tuberculosis, for example, which is one The publication of the genome sequence of Mycobacterium
of the most prevalent strains in Asian countries, has been tuberculosis H37Rv in 1998 was a giant leap in under-
implicated in TB outbreaks in BCG vaccinated popula- standing the biology of the tubercle bacilli in particular
tions and has been found to be frequently associated with and Mycobacteria in general (27). The application of
drug resistance (86). This strain has also been found to functional genomics to the vaccine development
be much more virulent in mice than the laboratory strain programme has tremendously accelerated the process
Mycobacterium tuberculosis H37Rv, which is normally of defining the complete set of immunodominant
used in the guinea pig and mouse models of Mycobacte- antigens and has provided the means for their discovery,
rium tuberculosis infection. Thus, evaluation of new production and manipulation. Further, sequencing of the
vaccines against the challenge of Beijing strain requires genomes of six Mycobacterium species has opened several
serious consideration. Recently, Castanon-Arreola and new vistas and has significantly helped the process of
colleagues (87) have reported that a recombinant BCG identification of vaccine candidate by inter-species
strain over-expressing the 38kDa antigen of Mycobacte- comparison of the genome sequences (91-93). Moreover,
rium tuberculosis [an otherwise under-expressed antigen it has also helped to understand the source of antigenic
in conventional BCG strains] was able to provide better variation among different strains of Mycobacterium
protection against a Beijing strain of Mycobacterium tuberculosis. In a recent finding, Pro-Glu [PE] and Pro-
tuberculosis than BCG. The enhanced protective efficacy Pro-Glu [PPE] proteins have been proposed as the source
of recombinant BCG was not apparent when of antigenic variation, which may most likely affect the
Mycobacterium tuberculosis H37Rv was employed as the interaction of the bacilli with the host cell. Application
challenge organism (87). The mechanism of influence of of microarray technology has revealed a repertoire of new
various strains of Mycobacterium tuberculosis on the final stage specific antigens of Mycobacterium tuberculosis,
outcome of the TB pathogenesis is not yet known. But, which are expressed in different phases of infection.
with the rapid development of the molecular genetic tools Specifically, the identification of deleted regions from the
such as restriction fragment length polymorphism genome of Mycobacterium bovis that are absent in the
[RFLP], random amplification of polymorphic DNA currently used vaccine strain, will allow identification
[RAPD] fingerprinting and microarray techniques, of antigens responsible for pathogenicity and persistence
characterization of virulence determinants in the various (94). Unlike the conventional targeted gene knock-out
strains of Mycobacterium tuberculosis should be possible methodology, application of techniques like transposon
in the near future. mutagenesis and signature tagged mutagenesis has made
Various strains of BCG that have been used all over it possible to screen a large number of mutants to
the world for immunization have also been implicated simultaneously screen for their in vivo growth and
as a major cause of the heterogeneity observed in the virulence in experimental animal models (95-99). This
protective efficacy of BCG. Support for this hypothesis has lead to identification of virulence genes, which can
has accumulated from several direct evidences; for be further assessed for their vaccine efficacy in a suitable
example, a significant difference between the protective animal model. Two other areas, namely subunit and
efficacies of the Paris and Japanese BCG strains was nucleic acid vaccines have also been significantly
revealed in the studies carried out in Hong Kong (88,89). benefited from the genome sequencing of Mycobacterium
The Tice BCG strain imparted 75 per cent protection in a tuberculosis. For example, several secreted or surface
trial involving high-risk infants in Chicago, although in exposed proteins, which are widely used as vaccine
several other studies carried out in the United States, it candidates were discovered based on the presence of
failed to show any significant protection (90). Hence, it specific sequences or motifs. This in silico analysis to
identify new vaccine candidates, which is termed as humans, these animals were given a very high dose of
‘reverse vaccinology’, has tremendously boosted the infection (101,102). It clearly indicates that at this high
entire vaccine development programme. It has also dose of infection, the amount of antigen available to the
provided access to the entire repertoire of Mycobacterium immune system was enough to generate immune
tuberculosis antigens. With the application of advanced responses necessary for protection against reinfection.
immunoinformatic tools, several antigenic secretory Thus, to out-perform Mycobacterium tuberculosis, a vaccine
proteins and their potent T-cell epitopes have been should induce a more potent immune response than the
identified for the development of novel protein, peptide natural infection. Figure 64.1 depicts various stages of
or epitope based vaccines. While the identification of new the disease progression, where specific intervention
antigens as prospective vaccine candidates is an essential strategies like drugs and vaccines can be used. The
primary step in vaccine designing, this will have to be various vaccination strategies that have emerged in the
followed by understanding the role of these antigens in last two decades are listed in Table 64.1.
mycobacterial infection, disease process and resolution.
Recombinant bacille Calmette-Guérin
VARIOUS STRATEGIES FOR THE DEVELOPMENT
It is well acclaimed that BCG protects children against
OF TUBERCULOSIS VACCINES
childhood TB. Hence, instead of replacing BCG with
Despite the lack of a perfect understanding about another vaccine, it would be wise to improve the current
protective immunity and effector mechanisms involved vaccine by expressing in it the immunodominant
in TB, there are several reasons to believe that a better antigens involved in pathogenesis, persistence and
TB vaccine is biologically possible. Less than 10 per cent immunomodulation. Alternatively, BCG can be
of the two billion individuals infected with Mycobacterium employed in a prime boost strategy. Thus, without
tuberculosis develop the disease, which in many cases is hampering the childhood immunization programme, a
promoted by immunodeficiency, such as a concurrent recombinant BCG vaccine would help in improving the
HIV infection (100). This strongly supports the argument protective efficacy against adult pulmonary TB. Along
that the immunocompetent host is well equipped to keep with its potent immunoadjuvant property, high degree
the pathogen in check. However, reactivation of of safety for human use and the availability of expression
persistent tubercle bacilli in asymptomatic individuals systems that provide enhanced and stable expression of
suggests that natural infection with Mycobacterium genes in mycobacteria, BCG became a very attractive
tuberculosis does not provide complete sterility or vehicle for the development of new recombinant BCG
protection against reinfection. Possibly, during natural vaccines. In addition, several ways have been devised to
exposure, humans are infected with a very few Myco- enhance the expression or secretion of a protein in to the
bacterium tuberculosis bacilli. Hence, in an immuno- extracellular milieu (103-112). Apart form the restoration
competent host the immune response generated against of the lost genes, like ESAT-6 and MPB-64, which are
the infection is sufficient enough to clear the system of absent from BCG, several other antigens like major
this small number of bacilli. However, it does not secretory 30-32 kDa protein, 38 kDa lipoprotein etc. have
provide complete sterilization, leaving behind very few been expressed in BCG and analysed for their protective
bacilli in dormant state. In these conditions, only a efficacy in mice and guinea pig models of TB (113,114).
negligible amount of antigen is available to the immune However, such an approach should be employed
system resulting in depletion of the memory pool of cautiously as over-expression of the genes involved in
lymphocytes, which require a continuous contact with pathogenesis might result in a BCG strain with enhanced
the antigen for their maintenance in an activated or virulence. For example, re-introduction of the complete
primed state (101). As a result, during reinfection, the region of difference 1 [RD1] locus, although resulted in
immune system is not able to generate appropriate a better protection in immunocompetent mice, it was
immune response to kill the infecting bacilli. However, found to be virulent in immunocompromised mice. Also,
under identical conditions primary infection with over-expression of antigens like 19kDa lipoprotein in
Mycobacterium tuberculosis did provide protection against BCG have resulted in an overall change in the
reinfection in mice. But, unlike the natural infection in immunomodulatory nature of BCG, resulting in loss of
926 Tuberculosis
Figure 64.1: Different stages of Mycobacterium tuberculosis infection and intervention strategies. The figure illustrates the heterogeneity
in terms of the outcome of infection in different individuals and various stages of the disease progression, where specific intervention
strategies like drugs and vaccines can be used
TB = tuberculosis; HIV = human immunodeficiency virus; MDR-TB = multidrug-resistant tuberculosis
Table 64.1: Various vaccination strategies that emerged in BCG strains. These regions encode 129 ORFs including
the last two decades several regulatory genes as well as some of the highly
Recombinant BCG immunodominant antigens (94,125). This has provided
Live attenuated mutants and auxotrophs of Mycobacteirum a rationale for the development of live vaccines using a
tuberculosis Mycobacterium tuberculosis background rather than
Nontuberculous mycobacterial vaccines Mycobacterium bovis BCG background. Such strains can
Subunit vaccines be developed by either: [i] producing auxotrophic
mutants of Mycobacterium tuberculosis with limited
DNA vaccines
replication capacity in immunocompromised subjects; or
Epitope based vaccines
[ii] by disrupting virulence genes necessary for host-
Prime boost immunization strategy
pathogen interaction (126).
BCG = bacille Calmette-Guerin; DNA = deoxyribonucleic acid A number of auxotrophic Mycobacterium tuberculosis
mutant strains developed by random transposon-
protective immune responses induced by BCG alone mutagenesis, signature tagged mutagenesis, illegitimate
(115,116). recombination and allelic exchange-homologous
An efficient antituberculosis immunity relies upon a recombination have been assessed for their protective
Th1 immune response which has led to the development efficacy in experimental animal models (124,127-131). For
of rBCG vaccines expressing human Th1 cytokines like example, a leucine auxotroph of Mycobacterium tuber-
IFN-γ, interferon-α-2β [IFN-α-2β], IL-2, IL-12, interleukin- culosis that was severely attenuated in severe combined
18 [IL-18] and granulocyte-macrophage colony- immunodeficiency syndrome [SCID] mice was comp-
stimulating factor [GM-CSF] (117-121). In most of these letely cleared from mouse organs within a few weeks of
studies, though the recombinant strains showed immunization. However, at least two doses were
improved Th1 response, their protective efficacy is yet required to elicit significant protection in immuno-
to be assessed in an appropriate animal model. Though competent C57BL/6 mice. Due to its excellent safety in
BCG is known to induce a detectable cytolytic T- immunocompromised mice, this appears to be an
lymphocyte [CTL] response (122), its inability to access excellent candidate vaccine for its use in immunodeficient
class I antigen-processing pathway significantly has individuals (132). The methionone, tryptophan and
necessitated procedures to augment CD8+ T-cell res-
proline auxotrophs of Mycobacterium tuberculosis have
ponse. Recently, an rBCG strain expressing listeriolysin
been found to be highly attenuated and confer protection
of Listeria monocytogenes, which forms pores in the phago-
equivalent [proline] to or better [tryptophan] than BCG
lysosomal membrane, has been reported to escape to the
against Mycobacterium tuberculosis infection in DBA/2
cytoplasm, thereby promoting antigen processing by
mice (129). Similarly, a double auxotroph of Mycobacte-
class I pathway resulting in a greater cytotoxic T-cell
rium tuberculosis [leucine and pantothenate] has also been
response and a better protection against Mycobacterium
shown to provide a significant protection against
tuberculosis infection (123). This vaccine is now
Mycobacterium tuberculosis infection (124). The panCD
undergoing Phase I clinical trial for its protective efficacy
mutant of Mycobacterium tuberculosis [genes required for
against TB.
de novo biosynthesis of pantothenate] was observed to
be highly attenuated in immunocompromised SCID and
Live Attenuated Mutants and Auxotrophs of
IFN-γ deficient mice and has proven to be much safer
Mycobacterium tuberculosis
than BCG. The mutant provided significant protection
The development of Mycobacterium tuberculosis mutants against Mycobacterium tuberculosis with a single
as vaccine candidates primarily relies upon the assump- immunization eliciting significant memory response as
tion that the vaccine strain should be antigenically as evident from the fact that the protection persisted even
identical as possible to the disease-causing organism seven months after immunization (133). For the develop-
(124). By comparative genomics, it has been revealed that ment of an ideal auxotrophic mutant, at least two or more
in comparison to Mycobacterium tuberculosis 16 defined unlinked genes should be deleted to reduce the
regions [RD1-RD16] are deleted from the currently used probability of reversion. However, such mutants should
928 Tuberculosis
be able to survive inside the host for sufficient time to protection as compared to BCG in the mouse model
generate an efficient immune response. Such auxotrophic (147,148). In another approach, killed Mycobacterium w
mutants that are antigenically indistinguishable from the [Mw] caused reduction in the bacillary load in mice and
wild type Mycobacterium tuberculosis would target the prevented formation of granulomatous lesions in guinea
appropriate antigen presenting cells during their pigs (149,150). A study from north India revealed
residence in the host (20). protective efficacy of Mw against leprosy. The follow-up
A second approach relies on attenuation of Mycobacte- studies in the same population showed that Mw also
rium tuberculosis genes required for virulence. Till date reduced the incidence of TB in this population by 61.5
several virulence genes have been identified, knocked per cent (151). Furthermore, with the advent of compara-
out and the mutants assessed for their growth in vitro tive genomics, sequencing of these NTM would aid in
and in vivo (134-139). These knockout strains were found the development of these viable or killed NTM as a
to have differences in their virulence and growth vaccine against TB.
characteristics. For example, Mycobacterium tuberculosis
mutants deficient in dormancy associated genes replicate Subunit Vaccines
in mice lungs in an unconstrained manner early after Subunit vaccines represent one of the most popular
infection, but cease to grow at later stages due to their
approaches for vaccine development. Subunit vaccines
impaired dormancy gene programme (134). Some
against Mycobacterium tuberculosis mainly comprise of
knockout strains have been shown to induce much less secretory [culture filtrate proteins] and non-secretory
pathology in guinea pigs in comparison to the parental
proteins or lipids and carbohydrate antigens derived
strain despite a growth rate that was comparable with
from Mycobacterium tuberculosis cell wall but also includes
the parental strain (135). vaccines based on non-mycobacterial vectors, like
Due to its highly pathogenic nature, development of
attenuated pox virus and adenovirus. Most of the
attenuated strains of Mycobacterium tuberculosis requires
vaccines included in this class have been identified by
careful consideration of two important aspects. As far as screening purified fractions or 2-D gels with antiserum
possible, the original strain should contain a complete
collected from TB patients or by analysing T-cell response
repertoire of antigens and attenuation should result in a
against these antigens and are expected to be inherently
fine balance between attenuation and immunogenicity, safe. However, these traditional ways of antigen
as over-attenuated bacilli may be devoid of key antigens
discovery are now being replaced by new techniques,
necessary for protective immunity.
such as comparative genome and proteome analysis,
which has tremendously accelerated the process of new
Nontuberculous Mycobacterial Vaccines
antigen discovery. For example, a recent screen has
Nontuberculous mycobacteria [NTM] that are closely identified 34 antigens that are expressed in Mycobacterium
related to Mycobacterium tuberculosis have been evaluated tuberculosis but not in BCG. Further testing of these
for their vaccine efficacy in various animal models and antigens as DNA vaccines identified an antigen, which
human trials. The close phylogenetic relationship of these alone conferred as much protection against Mycobacte-
organisms with Mycobacterium tuberculosis renders them rium tuberculosis infection as BCG. Lately, some new
antigenically similar to the pathogen. Apart from having bioinformatic tools like MHC-I antigenic peptide
the adjuvant-like property, these NTM are non-patho- processing prediction [MAPPP], Epimatrix etc., have
genic even in immunocompromised individuals. enabled MHC-I epitope identification. These advances
Mycobacterium microti when used in a prophylactic mode are likely to pave the way for the development of more
conferred 77 per cent protection [equivalent to BCG] specific epitope based subunit vaccines (152).
against TB infection in infants (140,141). Several studies Mycobacterium tuberculosis changes its antigenic
have also been carried out with killed/live or repertoire when it shifts from an active state to a dormant
recombinant Mycobacterium vaccae in both prophylactic non-replicating state. Thus, it can be advocated that for
and immunotherapeutic modes resulting in protective a prophylactic vaccine, the candidate antigens should
efficacy comparable to BCG (142-146). In a separate comprise of proteins that are rapidly secreted during
study, Mycobacterium habana exhibited improved early infection. On the other hand, the proteins associated
with dormancy-induced genes would serve better for a context of TB, as the protective immunity against
post-exposure vaccine. Indeed a vaccine that includes Mycobacterium tuberculosis is primarily dependent on the
antigens from both the classes is most likely to protect cellular fraction of the immune system (48). The DNA
individuals from various populations with different age vaccine allows continuous expression of a particular
groups and exposure levels. The widespread use of BCG antigen, thereby exposing the immune system to the
in neonates and its apparent efficacy against paediatric antigen for a prolonged time. The usefulness of DNA
TB has made it difficult to replace BCG with a new vaccines has led to the development of a variety of
vaccine. Thus recently, the focus of TB vaccine research methods for their delivery to a desired site in the host.
has shifted towards using these subunit vaccine Direct injection, electroporation or gene-gun based
candidates as a boosting agent in populations that have delivery into muscles, delivery to the respiratory mucosa
already been immunized with BCG. using liposome encapsulated DNA vaccines etc., are in
The apparent inability of the subunit vaccines to common use for delivery of DNA vaccines these days.
mount a strong T-cell response has accelerated the Expression of antigens by DNA vaccines and their
process of adjuvant discovery required to induce a potent subsequent processing and presentation along with the
Th1 response by these subunit vaccines and new MHC class I molecules mimics the antigen-processing
adjuvants like DDA, MPL-A and AS02A of Glaxo Smith pathway followed by an intracellular pathogen. Several
Kline], which are potent modulators of T-cell responses, DNA vaccines have been developed in the last decade
and have been evaluated for their efficacy against TB in
have now been shown to better enhance the immuno-
various animal models. The DNA vaccination with genes
genicity and protective efficacy of several subunit
encoding the members of Ag85 complex of Mycobacte-
vaccines than traditional adjuvants (153,154). In a recent
rium tuberculosis and 65 kDa heat shock protein of
report, ESAT-6 by itself failed to stimulate the adaptive
Mycobacterium leprae conferred protection equal to BCG
arm of immune response, but stimulated protective
(160,161). A significant protection [equivalent to BCG]
immune responses equivalent to BCG when injected
was also observed in case of ESAT-6, MPTP64 (162), PstS
along with a mixture of DDA and MPL-A (155). These
(163), a PPE protein (164), immunogenic protein [MPT70]
two adjuvants have already been declared safe for human
(165) and 19kDa antigen (166) when used as DNA
use (156). The fusion protein 72f when used along with
vaccines in mouse model of experimental TB. The
an adjuvant containing a saponin derivative from Quillaja advancements in the field of recombinant DNA
saponaria [QS21] mixed with MPL-A exhibited very technology have facilitated simultaneous expression of
promising results in several animal models and now more than one gene using a mammalian expression
represents the first subunit vaccine to enter a clinical trial. vector. The DNA vaccines based on fusion of antigen
Another recombinant protein resulting from the fusion Ag85B with either ESAT-6 or MPT64 gene conferred
of antigen 85B and ESAT-6 has also entered clinical trials protection better or equivalent to BCG (167,168).
in the year 2006. Moreover, co-expression of co-stimulatory molecules,
such as different cytokines and chemokines, inclusion
DNA Vaccines of CpG motifs in the DNA vaccine backbone has helped
The DNA vaccines, the latest entry in the field of vaccine in enhancing immunogenicity of DNA vaccines.
development, have quickly emerged as one of the most Modifications in the mode of delivery would further
promising advancements in the field of vaccine improve the transfection ability of DNA vaccines, thereby
discovery. The surprising observation that immunization enhancing the expression levels and consequently
with naked DNA could direct the immune system immunogenicity of the associated antigen (169). For
towards stronger and persistent cellular and humoral example, elicitation of improved immunogenicity has
immune responses attracted many scientists towards this been reported with the coating of DNA plasmid with
area (157-159). Intramuscular injection of a mammalian gold particles and their delivery by a gene gun (170,171).
expression vector encoding a desired gene, results in the
Epitope Based Vaccines
expression of corresponding protein, which subsequently
induces a potent cellular immune response against the Immunodominant T-cell epitopes play a crucial role in a
encoded antigen. This is especially advantageous in the naturally occurring immune response. Recently,
930 Tuberculosis
strategies for exclusive delivery of immunodominant a heightened response to the secondary exposure of the
T-cell epitopes of a single or multiple proteins have antigen has been utilized to develop effective prime boost
emerged. One of the potential advantages of this epitope- vaccination strategies against TB. Repeated adminis-
based approach includes higher safety, as it helps in tration with the same vaccine [called homologous boost-
getting rid of the unwanted, toxic or immunosuppressive ing] has proved to be relatively inefficient at boosting
regions from a protein. This also provides the oppor- cellular immunity, instead it generates a very strong
tunity to appropriately engineer epitopes to elicit a humoral response. This has been especially observed in
desired immune response. However, such epitopes need case of BCG, which, when administered repeatedly
to be identified by employing either the new tools of offered little benefit in humans as well as in various
bioinformatics or by screening the T-cells derived from animal models. Besides, these studies (192-195)
TB patients at various stages of disease progression by demonstrated that the mycobacterial sensitization
in vitro assays employing different overlapping peptides dramatically lowers the efficacy of BCG with little
of a protein (172,173). Moreover, comparative genomics protection. Prior sensitization to environmental
and new bioinformatic tools have helped identification mycobacteria and consequent immunity to BCG might
of conserved epitopes across various pathogenic be responsible for an early clearance of BCG, before it is
organisms, which can be incorporated along with the able to mount a sufficient immune response. In order to
Mycobacterium tuberculosis epitopes to generate a multi- circumvent this problem, ‘heterologous boosting’ came
purpose vaccine. This approach can prove to be into being, which involves sequential administration of
extremely beneficial, if the specificity of T-cells isolated vaccines with appropriate intervals using different
from exposed but asymptomatic individuals is charac- antigen-delivery system such that the immune system is
terized against a vast array of peptides isolated from primed to the antigen using one vector and is then
Mycobacterium tuberculosis proteome. These peptides can boosted with the same antigen delivered through a
be further assessed for their immunogenicity in the form different vector. The key strength of this strategy lies in
of a multivalent epitope-based vaccine (174). At present, the greater level of immunity it induces in comparison
several investigators are using the bioinformatic ‘genome to single vaccination or homologous boosting. With the
mining’ tools for identification of putative secretory emergence of new strategies involving adenovirus and
proteins and immunodominant peptides from poxvirus in heterologous prime boost vaccination
Mycobacterium tuberculosis genome and assessing their schemes, synergistic effects can be achieved instead of
immunomodulatory potential in vitro (174-176). Till date, an additive effect generally observed in case of
many immunodominant proteins like 38 kDa (177,178), homologous boosting (196-198). This synergistic
30-32 kDa antigens (179-181), 19 kDa lipoprotein (182), enhancement of immunity to the target antigen is
ESAT-6 family (183), HSP65 (184), MPB70 (185,186), 28 reflected by an increased number of antigen-specific
kDa haemolysin (187), 24 kDa LppX (188), MPT51 (189), T-cells and selective enrichment of high avidity T-cells.
16 kDa protein (190) and PE and PPE family of proteins Moreover, it also induces an elevated level of both CD4+
(191) of Mycobacterium tuberculosis have been screened and CD8+T-cell response (196). The tremendous power
for immunodominant T-cell epitopes and some of them of prime-boost was recently highlighted in a murine
have also been assessed for immunogenicity in vitro and model, wherein, intranasal vaccination of mice with BCG
in animal models, but protective efficacy of these epitope- followed by a booster of a recombinant Vaccinia virus
based vaccines is yet to be confirmed. After the avail- expressing antigen 85A resulted in a nearly 300-fold
ability of an effective delivery system, a multi-epitope- reduction in bacillary load in the lungs following aerosol
based vaccine could have the potential of being the safest infection with Mycobacterium tuberculosis (199). This
means of immunization. would mimic the situation where a gradually declining
immunity of BCG can be enhanced by boosting with a
Prime Boost Immunization Strategies candidate antigen specifically recognized by memory
The concept of ‘boosting’ the immune responses traces immunity. Amongst different strategies involving
its history back to the era of Louis Pasteur. The fact that various antigens and delivery approaches, the prime
the immune system once primed with an antigen elicits boost strategy described above represented the only
successful immunization, significantly prolonging the The BCG dose not perform satisfactorily against adult
survival of guinea pigs in comparison to BCG TB. A possible reason for this may stem from the fact
immunization (200). The protective efficacy of this that the antimycobacterial memory response generated
vaccination strategy is currently being evaluated for its by BCG immunization during childhood may be
efficacy in Cynomolgus monkeys. With these rendered ineffective by continuous exposure to environ-
encouraging results, this vaccine became the first of the mental mycobacteria resulting in the development of
new generation TB vaccines to enter the human trials either immune tolerance or a diversion of the immunity
(201). Moreover, it has been found to be innocuous and towards Th2 or Treg arms. In these adults, any attempt
immunogenic in mycobacterially naive healthy to stimulate the previously generated immune responses
volunteers and is now being tested in BCG vaccinated would be ineffective. Thus, it would be a better option to
populations. generate a new primary response followed by a booster
Apart from the viral vectors, which have been highly to elicit an adequate anti-mycobacterial immunity (205).
recommended as boosting agents, subunit vaccines Although, detailed studies need to be carried out, success
including both recombinant proteins and DNA vaccines of these heterologous prime boost immunization
are now being used to boost the immunity imparted by strategies has generated optimism for the development
BCG. Brooks and colleagues (202) observed that with of effective antituberculosis vaccines in future.
increasing age, mice vaccinated with BCG gradually lose
their capacity to resist an aerosol infection with IMMUNOTHERAPEUTIC APPROACH TO
Mycobacterium tuberculosis. However, if these mice are COMBAT TUBERCULOSIS
boosted with the Ag85A protein [with MPLA as an
adjuvant] in midlife, it restored back the resistance in Current strategies for TB control are based on trans-
elderly mice to levels equivalent to young ones; with mission reduction by treatment of active cases and
reduced pathological damage and bacillary load in the prevention of disease by prophylactic vaccination. The
lung. available chemotherapy comprises of a very lengthy
Recently, a comparative assessment of Mycobacterium treatment schedule [6 to 9 months] with a combination
tuberculosis and Mycobacterium bovis BCG genome and of four drugs isoniazid, pyrazinamide, rifampicin and
proteome, revealed an interesting pattern; wherein, ethambutol. This therapy, although successful per se,
homologue of Rv3407 of Mycobacterium tuberculosis was often fails due to lengthy treatment regimens, which are
although present in the BCG genome, the encoded protein difficult to follow in most of the developing countries,
was present exclusively in Mycobacterium tuberculosis where TB is a major public health problem. Moreover,
proteome (203). The DNA vaccine encoding Rv3407, such non-compliance can often lead to relapse and
when evaluated for its efficacy in mouse model as a
emergence of drug resistance. Thus, a significant
boosting agent after BCG vaccination, improved the
reduction in treatment schedule is likely to provide many
protection offered by BCG along with prolonged survival
fold advantages; such as, cost effectiveness, reduced
of Mycobacterium tuberculosis infected guinea pigs over
incidence of drug resistance and latent infections.
two years.
Besides the use of BCG as the priming agent, several However, unless a difficult goal of a shorter chemothera-
efforts to develop other heterologous prime boost immu- peutic regimen is achieved, use of immunotherapy to
nization strategies are underway. Immunization with boost the immune system of infected patients as an
DNA vaccine encoding ESAT-6 as a priming agent along adjunct to chemotherapy can provide a significant relief.
with a booster of recombinant ESAT-6 protein signi- It may not only reduce the prolonged chemotherapy
ficantly improved the immunogenicity of DNA vaccine period but may also eliminate dormant bacilli and
inducing an enhanced antigen specific Th1 response consequently prevent reactivation. Additionally, a
(204). Though these vaccination protocols need to be reduction in the conversion of reinfection into active
evaluated for conferring protective efficacy in various disease may be another possible spin off (206).
animal models, the promising subunit vaccines would Immunotherapy can also be used to down-regulate a
definitely find their use in the immunocompromised highly exaggerated immune response in patients with
individuals, where live vaccines based on viral or severe disease. An exaggerated pathological damage in
bacterial vectors pose problems. active pulmonary TB, which stems from a localized and
932 Tuberculosis
a systemic production of high levels of Th1 cytokines term application of immune adjunctive agents. Apart
like IFN-γ or TNF-α, can be reduced by a targeted from characterization of the immune responses involved
suppression of these cytokines by using neutralizing in protection against TB, identification of newer immuno-
antibodies. Besides, the use of systemic immunotherapeutic agents, their delivery mode and dosage will
suppressing agents, like corticosteroids etc. can also definitely help in shortening the prolonged chemo-
produce similar effects. However, in the use of these therapy period and an effective management of the
immunomodulators an extreme care should be taken to disease in future.
avoid an increased suppression of the immune system,
which may have unfavourable consequences (207). ROLE OF DIAGNOSTICS IN THE DEVELOPMENT
With growing evidence for the role of various Th1 AND ASSESSMENT OF NEW VACCINES
cytokines, like IFN-γ, IL-2, IL-12, and IL-18 etc., in protec- Tuberculosis being a very complex disease with a diverse
tive immunity against TB, several immunotherapeutic range of pathological and bacteriological outcomes, an
strategies using Th1 cytokines have been developed. For ideal diagnostic test for TB should be able to precisely
example, an aerosol delivery of IFN-γ was found to distinguish between various stages of the diseases.
produce clinically encouraging response in treating However, none of the currently available diagnostic tests
multidrug-resistant TB [MDR-TB], although the effect fulfils these criteria. Apart from the need to develop
was transient (208,209). In other studies (210,211), robust diagnostic assays for an early detection of TB
treatment with GM-CSF along with IFN-γ successfully infection, a focussed and a coordinated effort is also
treated patients with refractory central nervous system required to develop tests for evaluating the efficacy of
MDR-TB. Recently, a cocktail of six recombinant proteins promising vaccine candidates undergoing pre-clinical
[6 antigens: 85B, 38kDa, ESAT6, CFP21, Mtb8.4, and trials. At present, in most of the TB vaccine trials, vaccine
16kDa] along with IFN-γ and Ribi adjuvant [monophos- efficacy has been evaluated by differentiating between
phoryl lipid A-trehalose dicorynomycolate {MPLA-TD}] protected and unprotected subjects on the basis of various
conferred a significant protection against Mycobacterium surrogate immunological markers and clinical and
tuberculosis infection in mice model (211). Besides, IL-2 radiological features.
immunotherapy in MDR-TB patients resulted in a The diagnosis of TB is primarily based on clinical
significant immune activation and reduced bacillary symptoms like, cough for more than two to three weeks,
burden (212). However, in a separate study (213), no haemoptysis, fever, weight loss and loss of appetite, chest
significant reduction in the clinical symptoms was radiographic features and a DTH response to tuberculin
observed when IL-2 was used as an immunotherapeutic skin test [TST] (219,220). The confirmatory tests comprise
agent in adults suffering from drug-susceptible TB. of identification of AFB in the sputum and in other body
Recently, immunotherapy with a combination of two fluids by direct smear and conventional culture methods.
DNA vaccines [Ag85A and PstS-3] in mice model along These techniques suffer from serious limitations of low
with chemotherapy was found to prevent exogenous sensitivity and specificity apart from being time con-
reinfection as well as endogenous reactivation (214). In suming. The development of new diagnostic techniques
a separate study (215), supplementing the chemotherapy based on lipid profiling (221), hybridization with specific
with DNA vaccine encoding the Mycobacterium leprae gene probes (222-227), polymerase chain reaction [PCR]
HSP60 resulted in a significantly reduced duration of RFLP based methods (228-232) and new immunological
treatment. In an alternative approach, the use of the NTM assays involving both cellular and humoral responses,
Mycobacterium vaccae as an immunotherapeutic agent have overcome these limitations to some extent.
successfully enhanced the Th1 response. However, the As purified protein derivative [PPD] is comprised of
expected improvement in the treatment of HIV infected many proteins present in Mycobacterium tuberculosis,
adults with pulmonary TB was not observed (216-218). Mycobacterium bovis BCG and other NTM, infection with
Although adjunctive immunotherapy is reasonably Mycobacterium tuberculosis, exposure to environmental
effective, it still poses serious problems, such as, high mycobacteria and vaccination with BCG can all cause
cost, occasional occurrence of adverse and serious positive TST. In addition to this, TST cannot distinguish
adverse events and induction of tolerance during long- between latent infection and active disease. Thus, it has
proved to be of limited value in evaluation of the efficacy developing countries with limited resources. Thus,
of vaccine candidates especially those based on BCG, serious efforts are required to develop improved cost-
attenuated Mycobacterium tuberculosis, or other attenuated effective diagnostic methods for an early detection and
or killed mycobacterial species. These limitations of PPD treatment of infected individuals as well as to shorten
can be circumvented by developing new reagents for skin the necessary follow-up phase of TB vaccine trials.
test, which will help in specifically measuring the DTH
response elicited exclusively by Mycobacterium KEY ISSUES SURROUNDING NEW
tuberculosis infection. Several efforts have been made till TUBERCULOSIS VACCINES
date to identify Mycobacterium tuberculosis specific
Expectations from a New Vaccine
antigens that elicit DTH responses to develop an effective
skin test based diagnostics (233,234). Apart from TST, Last decade has clearly witnessed a sudden resurgence
assays based on cellular [T-cell] and humoral immune in the field of TB vaccine research; nearly 200 new vaccine
responses are showing promising results. For example, candidates have already been evaluated for their efficacy
measurement of IFN-γ secreting T-cells specific for in various animal models and five most promising
Mycobacterium tuberculosis antigens like ESAT-6 and candidates have entered the Phase I clinical trials. These
CFP10, when used together, successfully detected vaccine candidates have shown encouraging results in
Mycobacterium tuberculosis infected patients with various animal models including the non-human primate
remarkable specificity (235,236). The reader is referred model. However, success in various animal models does
to the chapter “Diagnosis of latent tuberculosis infection: not always guarantee effectiveness of a vaccine in human
recent advances and future directions” [Chapter 12] for more trials. Moreover, TB being a chronic disease with diverse
details. clinical and pathological outcomes in different
Staining for AFB, the most widely used method individuals, it may be unwise to expect a single vaccine
provides a simple and a fast means for detection of active to work efficiently in all these different situations (238).
TB but its sensitivity is too low and limited to the presence Hence, in order to test these vaccine candidates, target
of at least 104 bacilli per ml of sputum (224,225). Also, populations have to be carefully chosen, which may
any pathogenic and saprophytic mycobacterium, which involve focussing in areas with a high prevalence of TB.
shows acid-fast staining, may interfere with an accurate A geographically endemic area or an epidemiological
detection of Mycobacterium tuberculosis. Hence, enormous group at greater risk of infection may represent an
efforts are underway for the development of diagnostic appropriate choice for such trials. Several criteria that
procedures that can detect Mycobacterium tuberculosis should be satisfied by a TB vaccine recommended for
directly in the clinical specimens in a minimum possible human use are listed in Table 64.2.
time with greater specificity and efficacy. Several PCR
and hybridization based methods utilizing Mycobacterium Groundwork for Human Trials
tuberculosis specific nucleic acid probes have been Since evaluation of a candidate vaccine in human trials
developed in the last few years and are now available requires an elaborate infrastructure, human resources,
commercially. The examples include, MTD test [Gen- substantial funding and is time consuming, prior evalu-
Probe, San Diego, CA], Amplicor test [Roche Molecular ation of candidate vaccines in animal models requires
System] and Probe tech Direct TB-a strand displacement stringent criteria so that only promising candidates are
amplification [SDA] test [Becton and Dickinson], among taken up for human trials.
others (237). With the availability of genome sequence Mass screening of large number of vaccine candidates
of Mycobacterium tuberculosis, oligonucleotide probes in a single programme using a standardized protocol for
specific for various clinically relevant mycobacteria have the identification of promising vaccine candidates has
been developed which are now been regularly used for been a long cherished dream. The National Institutes of
the identification of various clinical isolates (223,227). Health [NIH]–pre clinical TB vaccine screening prog-
Although, these new methods are rapid, procedural ramme and the European Union [EU] TB vaccine
complexity and requirement of a huge infrastructure and integrated project, which are working towards this goal,
technical support may not encourage their use in the have already tested more than 150 vaccine formulations
934 Tuberculosis
Table 64.2: Essential criteria for human tuberculosis vaccine
It should be able to induce a long-lasting and a heightened protective immune response against infection with virulent tubercle bacillus
Apart from preventing the primary infection, a vaccine should also block the reactivation of dormant or latent TB infection
As the infection with Mycobacterium tuberculosis itself does not generate a sufficient protective immunity against reinfection, a new TB
vaccine is therefore expected to generate an immune response, which is qualitatively and quantitatively very different from the natural
infection. A new vaccine meant to be used as a post-exposure vaccine is expected either to clear the bacilli without generating any
occult signs of disease due to vaccine induced inflammation in the background of ongoing TB infection or it should be able to modulate
the immune response in such a way that it aids in clearing bacillary load in lungs of patients undergoing antituberculosis treatment
The new vaccines should be innocuous enough to safely immunize the neonates as well as the immunocompromised individuals, as
these represent a population, which is highly susceptible to mycobacterial infections
Since the uniform success of BCG against childhood TB would make its replacement in the immunization programme almost impossible,
the new vaccine strategies should either be based on BCG or be evaluated in the background of a pre-existing BCG induced immunity
The resource crunch and inadequate technical support faced by developing countries, which indeed would consume the major proportion
of the new vaccine, would necessitate that a new vaccine should be inexpensive, easy to store and transport, and should have a long
shelf life with an ease of administration
TB = tuberculosis; BCG = bacille Calmette-Guerin
for their protective efficacy. However, the basic protocols period of time with a greater degree of accuracy and
followed by the two programmes differ in several confidence (241). In order to efficiently translate the basic
aspects. The NIH pre-clinical screening programme uses research findings into the clinical assessment, it would
a low dose aerosol mouse and guinea pig model. In require: [i] focussed and coordinated effort of multidis-
mouse model, efficacy of the vaccine candidates is ciplinary expertise or networks, like mycobacteriologists,
assessed on the basis of their ability to reduce the bacillary epidemiologists, clinical trial specialists, vaccine
load in lungs after a specified period of Mycobacterium biologists, etc.; [ii] an appropriate trial site along with
tuberculosis infection. The guinea pig model on the other availability of a detailed knowledge of TB epidemiology
hand employs an open-ended survival based assay of the trial site; [iii] availability of volunteers with nega-
extending up to a period of more than two years. Indeed, tive TST and with no history of BCG vaccination.
in addition to the survival time, reduction in lung However, the criteria for volunteers in the endemic areas
pathology represents an important selection criterion for may require different considerations based on the
a promising vaccine. In contrast to NIH protocol, EU-TB available epidemiological knowledge; [iv] cost-effective
vaccine cluster programme employs a high-dose guinea and easy to perform robust diagnostic assays, expertise
pig infection model. Since, BCG vaccination protects in data compilation and interpretation would also be
guinea pigs against low dose infection, a greater required for a precise data analysis; and [v] appropriate
stringency is required to compare the efficacy of various financial resources, support from governmental and non-
vaccines, which is met by extending the time point of governmental organizations.
euthanasia up to 26 weeks post-infection. In these
conditions, as BCG vaccinated animals are overwhelmed VACCINES IN PHASE I CLINICAL TRIAL
by the high dose of infection, vaccines that outperform
At present nine most promising vaccine candidates have
BCG are chosen for human trials (239,240). Figure 64.2
passed the regulatory hurdles and entered the Phase I
depicts the protocol used for screening of vaccine
clinical trials with encouraging results. These include:
candidates.
[i] MVA85A, a modified vaccinia virus based vaccine
overexpressing Ag85A [University of Oxford/Emergent
Human Trials: New Challenges
Biosolutions] (242); [ii] rBCG30, a recombinant BCG
In planning the human trial of a candidate vaccine, expressing Ag85B [UCLA School of Medicine/Aeras]
several regulatory and operational issues need to be (114); rBCGΔureC:Hly + , a urease C deficient and
addressed to ensure completion of the trial within a short listeriolysin O secreting BCG [Max Planck Institute for
Figure 64.2: Variables involved in the screening of vaccine candidates. The figure depicts the protocol used for screening of vaccine
candidates in a prophylactic mode against infection with Mycobacterium tuberculosis and the different parameters that are used as a
measure of immunogenicity and protective efficacy
i.d. = intradermal; s.c. = subcutaneous; i.m. = intramuscular; i.v. = intravenous; IFN-γ = interferon-γ; IL = interleukin; TGF-β = transforming
growth factor-β
Infection Biology/Vakzine Project Management] (243); the first candidate TB vaccine to enter clinical trial. For
[iv] Mtb72f, a fusion protein of two proteins encoded by this, based on IFN-γ ELISPOT test, volunteers without
Rv1196 and Rv0125 from Mycobacterium tuberculosis prior exposure to mycobacteria were included in the
[GlaxoSmithKline] (244); [v, vi] Ag85B-ESAT6, a fusion study. Safety and immunogenicity data emerging from
protein of ESAT6 and antigen 85B in adjuvant system these studies are quite encouraging. Besides, a prime
H1/IC31 [Statens Serum Institut/Sanofi Pasteur] and boost vaccination strategy involving BCG as the priming
LTK 63 [Statens Serum Institut/Novartis] respectively agent and MVA85A as a booster was also used to assess
(245,246); [vii] Advac expressing Ag85A, Ag85B and safety and immunogenicity of this heterologous prime-
TB10.4 [Aeras] (247); [viii] HyVac4/IC31, a fusion protein boost immunization regimen. In addition, a parallel trial
of Ag85B and TB10.4 [Statens Serum Institut, Sanofi is also being conducted in a TB endemic area in West
Pasteur and Aeras] (248); and [ix] rBCG [Aeras] Africa.
overexpressing Ag85A, Ag85B and TB10.4 [Aeras] (248). For the first Phase I trial of rBCG30, 30 subjects were
Modified vaccinia virus [MVA85A], based vaccine enrolled at two sites, and at both sites the vaccine was
overexpressing Ag85A of Mycobacterium. tuberculosis, was found to be safe and well tolerated by the volunteers.
936 Tuberculosis
Phase I trial of both the fusion protein based vaccines is against bovine TB would be a viable option in controlling
near completion. Mycobacterium bovis based human infections in addition
to reducing the burden of bovine TB. Several recombinant
IMPACT OF ZOONOSIS ON TUBERCULOSIS BCG strains, subunit vaccines and DNA vaccines
VACCINE DEVELOPMENT expressing Mycobacterium tuberculosis antigens have also
Zoonotic diseases in humans include all the diseases that been assessed for their efficacy in bovine model against
are acquired from or transmitted to any other vertebrate Mycobacterium bovis infection. Prime boost vaccination
animal. Among the various zoonotic diseases, TB strategies using DNA vaccines encoding HSP65, HSP70
represents one of the most common diseases transmitted and Apa as priming agent followed by a booster of BCG
to humans. Although, Mycobacterium tuberculosis is the have provided a substantial evidence that this regimen
causative agent of human TB, a significant proportion of can provide better protection in calves than either of the
human infections are caused by Mycobacterium bovis – vaccine when used alone (252). In another strategy,
the aetiological agent of bovine TB. The pulmonary TB Vordermeier et al (263) reported substantial protection
caused by both Mycobacterium tuberculosis and Myco- in cattle immunized with BCG followed by a booster of
bacterium bovis are clinically indistinguishable with modified MVA85A and attenuated fowl pox strain FP9
similar radiographic and pathological features (249). [FP85A], expressing Ag85A. Furthermore, a combination
Extra-pulmonary disease due to Mycobacterium bovis is of DNA vaccines encoding Ag85B, MPT64 and MPT83
mainly caused by drinking and handling of contaminated when tested for their efficacy using DDA as an adjuvant,
milk, which results in cervical lymphadenopathy and was found to be highly effective in controlling bovine
chronic intestinal and skin lesions. In many African and TB (264).
Asian countries, where cattle are an integral part of social Apart from developing vaccines against both human
life, close physical contact between humans and infected and bovine forms of TB, control of zoonotic TB in India
animals leads to a significant proportion of human TB of and other developing countries needs coordination
bovine origin. In the past, several incidences of human between the human and bovine TB vaccine development
TB caused by Mycobacterium bovis were reported from programmes along with strict regulatory measures. In
South Africa (250-253), Latin America (254,255) and some some industrialized and developed countries, animal TB
of the Asian countries. The proportion of human TB in control and eradication programme, together with milk
UK due to Mycobacterium bovis was estimated to be 3.1 pasteurization have drastically lowered the incidence of
per cent of all the forms of TB (256). Similarly in Latin TB caused by Mycobacterium bovis in both animal and
America, two per cent of the total pulmonary cases and human population (265,266). However, a developing
eight per cent of extra-pulmonary TB cases were reported country like India, which has the largest livestock popula-
to be caused by Mycobacterium bovis (257). In a recent tion in the world, has no effective control and eradication
study from India (258), analysis of cerebrospinal fluid programmes for bovine TB. In addition to development
from patients suffering form TB meningitis revealed that of effective vaccines against both human and bovine TB,
in comparison to Mycobacterium tuberculosis [2.8%], 17 per specific identification strategies for different species of
cent of the samples were found to be positive for Mycobacterium, will aid in detection of TB cases of diverse
Mycobacterium bovis of TB due to Mycobacterium bovis origin, which would help in developing effective treat-
infection has also been reported in HIV -seropositive TB ment strategies. As the degree of cattle movement in a
patients. For example, in France, 1.6 per cent of TB cases country also enhances the incidence of TB and other
in HIV-seropositive patients were due to Mycobacterium zoonotic diseases, strict surveillance of animal migration
bovis based infection (259). On the other hand, cases of may help in bringing down incidence rate (267).
Mycobacterium tuberculosis infection in cattle have also In conclusion, despite the lack of a perfect
been reported from India as well as some of the European understanding about protective immunity and effector
countries, though the incidence rate was not very high mechanisms involved in TB, there are sufficient reasons
(260,261). to believe that a better vaccine is really possible. Although
As the performance of BCG in preventing bovine TB several key questions related to TB still need to be
is doubtful, devising an effective vaccination strategy answered, and hence, a rational approach for the
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Ethical and Legal Issues in Tuberculosis Control 947
Ethical and Legal Issues

in Tuberculosis Control
65
John Porter
Scientific thought succumbed because it violated the first law methods for TB are violating the first law of culture, and
of culture, which says that the more man controls anything, therefore, making TB more uncontrollable. Is this why
the more uncontrollable both become we have an increasing international problem with multi-
Tyler SA (1) drug-resistant TB [MDR-TB] and extensively drug-
resistant TB [XDR-TB]?
INTRODUCTION The field of ethics, because it is to do with questions
about ‘how we ought to live’ (3), provides a framework
In the early years of the twenty-first century, increasing
which is included in the other disciplines which address
links are being made between communities, countries
health care issues and is also a useful tool for creating a
and continents. There are more opportunities for us to
framework with which to untangle the dilemmas that
witness life in other places and to view and review our
occur around the treatment and ‘control’ of people with
own structures and perceptions of the way we live and
TB. The morality of the individual is intimately connected
to learn from people of different cultures and religions.
with the ethics of the medical and public health fraternity
This new ‘internationalism’ brings with it increasing
and both of these entities also link with the legal profes-
‘complexity’ and an added importance for each of us to
sion and the law [Figure 65.1]. The law and the legal
review our own beliefs and perceptions in order to allow
increasing co-operation and understanding.
In the field of public health, there are discussions
aimed at widening the scope of health care beyond the
treatment of diseases, like tuberculosis [TB], to a broader
concept of ‘the creation of health’; that health is an entity
that communities and societies have the opportunity of
developing (2). This broader perception uses biomedical
health care concepts and systems, but adds to them by
including other disciplines, like anthropology, environ-
mental sciences, ethics and human rights. It is anticipated
that the result of this fusion, created through inter-
disciplinary work, will be a change in biomedicine’s
perception of health and health care. Now, those of us
working in TB control have an opportunity to view our
control measures from different perspectives. Perhaps it
is time to take note of the quotation at the beginning of
the chapter and to consider whether the current control Figure 65.1: Ethics and the law
948 Tuberculosis
system provide a framework within a society to ‘assist sophisticated treatments and medications to treat
and protect people’ (4); protecting the rights of indivi- illnesses, like TB. From the time that, Koch discovered
duals but at the same time protecting the rights of the tubercle bacillus in 1882, there has been an
institutions and organizations, like professional medical understanding that TB is caused by Mycobacterium
bodies. The basic function of the law is to establish legal tuberculosis and that destroying the bacillus with drugs
rights, and the basic purpose of the legal system is to would provide an appropriate treatment. With the
define and enforce these rights (5). Ethics is not separate development of streptomycin and the subsequent
from the law, it is an integral part of the legal system development of other antituberculosis drugs, short-
and how laws are made and enforced. course chemotherapy [SCC] was developed; a solution
This chapter looks at TB control from the perspectives for controlling TB worldwide had been found (9).
of ethics and law. It begins with an introduction to the However, by the early 1990s, there were signs of
two disciplines and then applies them to the current increasing TB cases in all countries associated with the
international strategy for TB control. The ‘ethical’ issues movement of people from high to low TB prevalence
of TB are addressed through highlighting the potential countries, the increasing spectre of human immuno-
problems for a TB patient who is seeking care through deficiency virus [HIV] infection and acquired
the health care system [relationship with the health care immunodeficiency syndrome [AIDS], and decreasing
worker and interaction with the health care system etc.,]. funds to support public health infrastructures to control
The legal issues concentrate on groups of people at high TB (9). In the early 1990s, the World Health Organization
risk for TB [e.g., alcoholics, prisoners, etc.,] to try to [WHO] developed the DOTS strategy to try to improve
untangle the legal problems. Examples from India, the the uptake of TB control measures around the world,
United States and the United Kingdom are used to particularly in order to combat the increasing problem
provide the context for the discussion. of MDR-TB. The strategy includes: government
commitment to a national programme; case detection
BACKGROUND through ‘passive’ case-finding [sputum smear micro-
scopy for pulmonary TB suspects]; SCC for all smear-
Public Health and Tuberculosis
positive pulmonary TB cases [under direct observation
The control of infectious diseases is an important part of for at least the initial phase of treatment]; regular,
public health policy. In most countries, TB control is the uninterrupted supply of all essential antituberculosis
responsibility of public health departments. Public health drugs; and a monitoring system for programme
is ‘the science and art of preventing disease, prolonging supervision and evaluation (10,11).
life and promoting health through the organized efforts The international strategy for controlling TB, has been
of society’ (6). A more succinct definition comes from developed from a science base and has been created from
the Institute of Medicine in the United States, which says many disciplines including medicine, epidemiology and
that public health is ‘what we, as a society, do to assure the basic science. Now, however, with several new TB
the conditions for people to be healthy’ (7). Both drug and vaccine candidates, which are in various stages
definitions imply an imperative to balance the needs of of trials and testing, the health care fraternity is having
the individual with the needs of the population in the to look at the basic human behavioural issues in TB
control of infectious diseases. Inherent in this, as in all control. The issues of how individual patients interact
balances, is a tension, and this tension often engenders with health care systems, and in particular, how they
debate and even conflict between decision makers. The interact with health care workers (12,13). For a person to
framework of ethics can assist in developing a course of complete their six months of antituberculosis treatment,
action to resolve these conflicts by providing clarification they need to be supported and cared for and this requires
of the questions and a system for weighing alternatives strong health systems. This is a basic function of health
through ethical debate (8). care provision but one which has been increasingly
During the past one hundred and fifty years, scientific neglected with the rise of the rapid technological
structure and discourse have framed the development approaches to treating disease. Are the current TB control
of technological medicine which has produced methods consistent with the broad public health agenda
of preventing disease and promoting health? Is there susceptible population requires the use of medication to
sufficient emphasis on the care of TB patients in order to prevent the development of a disease [treatment of latent
promote or create health? All of these questions become TB infection].
increasingly difficult and complex with the increase in The four principle methods for controlling TB are
prevalence of HIV in communities and its link with TB stated to be: the improvement of socio-economic condi-
(14). tions, case-finding and treatment, chemoprophylaxis and
bacille Calmette-Guérin [BCG] vaccination (16).
Infectious Disease Control and Tuberculosis Although the improvement of socio-economic conditions
undoubtedly has a major impact on TB (17), in public
Methods for the control of infectious diseases have been
health terms TB control focusses on finding infectious
developed principally through the study of epidemio-
cases [sputum positive] and treating them so that they
logy. The perspectives of biomedical scientists have are no longer infectious to others. This is the method for
dominated thinking in this area, and the control methods disrupting transmission, it concentrates on the individual
currently used reflect this focus. Epidemiologists look at with the aim of treating the person and protecting the
the interaction between the agent, host and environment, community from further infection and disease. As has
and the main strategies for control are to attack the source already been mentioned, the current international TB
[e.g., the treatment or isolation of cases and carriers]; to control strategy is DOTS. Part of the strategy is direct
interrupt transmission [e.g., environmental and personal observation of treatment [DOT] which has been
hygiene, vector control]; or to protect the susceptible established to prevent the development of drug-resistant
population [e.g., immunization, chemoprophylaxis] strains of TB. The ‘direct observation’ component of the
[Table 65.1] (15). strategy introduces ethical issues around the right to
The categories, attacking the source and protecting ‘control’ individuals with TB, in order to protect the
the susceptible population, both relate to the treatment majority [community].
of patients. Attacking the source refers to the treatment But is case finding and treatment sufficient? Although
of a case of disease: the patient is treated [a benefit to it makes scientific and logical sense to concentrate on
him or her] and the population is protected from being infectious TB cases, are there not other social, environ-
infected by him [a benefit to the population]. A person mental and economic issues that need to be considered?
with infectious pulmonary TB needs to be treated not What about structural interventions for example?
only for his or her benefit but also for the benefit of the Structural factors within the field of human immuno-
public health, to prevent further transmission of deficiency virus [HIV] infection have been broadly
Mycobacterium tuberculosis to others. Protecting the defined as physical, social, cultural, organizational,
community, economic, legal or policy aspects of the
environment that impede or facilitate persons’ efforts to
Table 65.1: Main strategies for control
of infectious disease
avoid infection (18). With the increasing complexity of
health care, the requests for a broad perception of health,
Attack source Interrupt Protect susceptible and with the increasing inter-disciplinary nature of
transmission people
public health work, there is an opportunity to re-evaluate
Treatment of Environmental Immunization the current control measures. Are these control measures
cases and carriers hygiene for TB appropriate? Are they sensitive to the needs of
Isolation of cases Personal hygiene Chemoprophylaxis people with TB? Can they be improved to ensure the
Surveillance of Vector control Personal protection rights and dignity of all patients?
suspects
Control of animal Disinfection and Better nutrition ETHICS
reservoir sterilization When one speaks of ethics, one might be speaking from
Notification of cases Restrict population – one or a combination of three mutually interconnected
movements perspectives: [i] the study of ethics; [ii] the adherence to
ethical guidelines laid down by governments and
professional bodies; and [iii] the application of ethical
950 Tuberculosis
principles in daily life (19). The ethical process is not a phenomenon. When applied to health one consequence
once-and-for-all, nor a once-in-a while pursuit. On the of the ‘utilitarian’ approach is the generation of
contrary it forms part of our day-to-day interactions and interventions which are geared towards maximising
is an integral part of our public health interventions (19). majority over individual benefit (19).
In the study of ethics, philosophers develop theories
about the interaction between moral values and the ways Ethics in the East
in which societies operate. Morals—the values and norms
It is difficult to locate the Eastern tradition in the
that frame societies’ ideas about ‘right’ and ‘wrong’—
historical, abstract and formal theories of ethics that have
are inherently cultural constructions. All cultures and been developed in the West. Ethics in the East is framed
societies have moral codes, but because these are
by the religions of Islam, Hinduism and Buddhism as
culturally and historically contingent, they shift and
well as many others.
change over time. The work of moral philosophers both In the Brahmanical-Hindu and Jaina traditions for
reflects and to some extent informs this process.
example, it is recognized that ethics is the ‘soul’ of the
With the increasing co-operation and collaboration
complex spiritual and moral aspirations of the people,
between countries in public health research, this cultural co-mingled with social and political structures forged
and historical contingency is important to understand.
over a vast period of time. This accounts for the cultures
People’s perceptions and understanding of TB, ethics and
profuse literature in wisdom, legends, epics, liturgical
the law, are framed by the cultural values and historical texts, legal and political treatises. There are a variety of
background of the society in which they live. The moral
ethical systems within the Hindu tradition, but the
construct used in some societies is seen as ‘absolute’; for
tradition itself contains within it a diverse collection of
example, certain religious texts dictate the ‘way the social, cultural, religious and philosophical systems (23).
community ought to live’, whereas in others, moral
The highest good is identified with the total harmony of
values are seen as ‘relative’ and more flexible, being seen
the cosmic or natural order, characterized as rita: this is
to be different according to the context of the situation the creative purpose that circumscribes human
in which the ethical dilemma arises. Each community
behaviour. The social and moral order is, thus, seen as a
needs to be understood in terms of its history and cultural
correlate of the natural order. This is the ordered course
values. of things, the truth of being or reality [sat] and hence the
‘Law’ (24). The convergence of the cosmic and the moral
Ethics in the West
orders is universally commended in the all-embracing
In the western industrialized world, there has been a shift category of dharma, which becomes more or less the
in moral thinking from absolute to relative values: from Indian analogue for ethics (23). What counts as ‘ethics’
a deonotological model of ethics to a utilitarian model. The then although in appearance naturalistic, is largely
utilitarian theories suggest that answers to moral normative; the justification usually is that this is the
questions on right and wrong depend solely on the ‘divined’ ordering of things, and hence, there is a
nature of the consequences of those actions or proposed tendency also to view the moral law as absolute.
actions, whereas deontology relates to moral rules not
related to consequences, from the Greek word deon Ethics Principles and Tasks
meaning duty (20). Although to some extent framed In the development of international guidelines for the
within the Judaic Christian religious traditions, the ethical control of infectious diseases like TB, the western
theories and models developed in the west attempt to philosophical model tends to dominate the process. There
be ahistorical, abstract and formal. is, however, continuing research to try to develop an
It has been argued that the ‘utilitarian’ structure has appropriate set of international ethical principles (25).
emerged with the growth of technology in the North (21). In 1994 at the 38th Council for International Organiza-
If one accepts Bell’s definition of technology as ‘the effort tions of Medical Sciences [CIOMS] Conference in Ixtapa,
to transform nature for utilitarian purposes’ (21,22), one a declaration was issued describing the emergence of
may then step back for a moment and look at the bioethics as a global and multilayered enterprise and ‘the
profound social and moral dilemmas inherent in this need to continue to work towards an ethics of health
which calls on us to consider the interconnections among have a moral obligation to respect the autonomy of others
all of our choices and actions that affect the health status as long as it is compatible with equal respect for the
of people anywhere’ [CIOMS, Declaration of Ixtapa] autonomy of all those potentially affected. According to
(26,27). the Western philosopher Kant, respect for autonomy
There have been suggestions as to how ethics can be means ‘treating others as ends in themselves and never
used in practice to assist with ethical dilemmas in merely as means’ to some [externally defined] end (20).
medicine and public health. Beaufort and Dupuis (28) The person with TB is an autonomous individual, a
have suggested that the ethical process might be used decision maker, and the decisions that they make about
to: [i] clarify concepts, [ii] analyse and structure their treatment should be respected not only by the health
arguments, [iii] weigh alternatives; and [iv] provide care worker with whom they are interacting but also by
advice on an “appropriate” course of action. Another the health care system that is providing the treatment.
way of looking at ethical argument is that it can assist us The quality of the relationship between the patient and
to identify the obstacles that prevent us from acting the health care provider is a key to the provision of
“morally”. Once these obstacles have been identified, it appropriate TB treatment.
is easier to find ways of overcoming them.
As human beings we are moral agents: we interact Beneficence and Non-maleficence
daily with our family, friends, colleagues and acquain-
There is always a need to balance the effort to help and
tances, and these interactions are framed by the values
and norms that prevail in our society. By going to our the risk of causing harm. The traditional Hippocratic
jobs, taking care of our families and talking to our moral obligation of medicine is to provide beneficence
neighbours, we are acting as engaged participants in our with non-maleficence: net medical benefit to patients
moral community. As health care workers we are moral with minimal harm. Once again, the relationship
agents, too. In this we do not stop engaging with our between the health care provider and the patient deter-
moral community, but we expand the boundaries of that mines whether there is a net benefit to the TB patient. It
community: at this level we also interact with our profes- is also important to remember, however, that the health
sional ethics and with the legal system of the wider care provider will be more able to provide support and
society (29). be beneficent to the person with TB if they are appro-
The four principles which currently dominate inter- priately supported in their job by the organization or
national bio-ethical debate are: respect for autonomy, system that employs them. So, although the relationship
beneficence, non-maleficence and justice (30). These between health care worker and the patient is important,
principles-plus attention to their scope [i.e., how and to the relationship of the health care worker with their
whom they apply] provide the basis for a rigorous consi- employer is also part of the process of ensuring beneficent
deration and resolution of ethical dilemmas. Although and non-maleficent care.
they do not provide “rules”, these principles can help
public health workers make decisions when moral issues Justice
arise. In effect they make a common set of moral commit- Justice refers to the moral obligation to act on the basis
ments, a common moral language, and a common set of of fair adjudication between competing claims. Equality
moral issues (20) more visible and more accessible. These is at the heart of justice, but as Aristotle argued, justice is
principles are considered to be prima facie: they are more than mere equality—people can be treated unjustly
binding unless they conflict with other moral principles. even if they are treated equally (31). Equity entails
They are outlined briefly below. treating no portion of the population in a dispropor-
tionate manner. Inequity, then, is a descriptive term used
Autonomy
to denote existing differences between groups or
Autonomy, “self-rule”, although perceived differently individuals in the distribution of or access to resources.
in different cultures, is an attribute of all moral agents. However, inequity also denotes the reasons behind and
Autonomy gives one the ability to make decisions on the responsibilities for underlying conditions of inequality.
basis of deliberation. Autonomy is also reciprocal: we As such, it is inherently a statement of justice (32).
952 Tuberculosis
People with TB need to be treated fairly and justly. If person’s freedom may result in harm to another (8). This
a community wishes to prevent the spread of TB, patients is known as the ‘harm principle.’ The nineteenth century
need to have access to a health care structure that philosopher John Stuart Mill defined this principle in the
provides them with treatment and care. This access needs following way: ‘The only purpose for which power can
to be available to all TB patients equally. be rightfully exercised over any member of a civilized
community, against his will, is to prevent harm to others.
The Application of Ethics in Public Health His own good, either physical or moral, is not a sufficient
Little has been written in regard to moral issues in public warrant’ (37). This principle provides the ethical and legal
health (33) or the application of ethics to public health foundation for establishing public health programmes
decision making. In 1980, Shindell (34) suggested that a designed to require those with communicable diseases
public health intervention should: [i] relate to a well- to behave in ways that are likely to reduce the risk of
understood disease aetiology; [ii] be feasible; and transmission.
[iii] entail only an appropriate trade-off of the rights of
the individual against the benefits that accrue to the THE LAW
population. It is the third point that leads to moral debate
and a tension between public health and civil liberties. What is It and What does It do?
In infectious disease control, interventions usually relate
The values that are contained within a community help
to diseases with a well-understood aetiology. The
to define the legal statutes that are created. Ethics and
feasibility of a particular intervention will depend on the
the law are intimately connected [Figure 65.1]. The legal
details of the disease outbreak [location, numbers,
system in every country is unique, although it may use
demographic character of people involved, etc.,] and the
certain structures or processes, like ‘common law’, as a
possibility of using standard control measures to
foundation (5).
intervene. In TB control, the aetiology of the disease is
It is useful to have a working definition of the law to
fairly well understood, the intervention [case finding and
assist with the legal issues that pertain to TB control.
treatment] is feasible and there is an accepted [taken for
Wing (5), from the United States, states that the law is
granted] trade-off between the rights of the individual
‘the sum or set or conglomerate of all of the laws in all of
and the benefits of the population.
the jurisdictions: the constitutions, the statutes and the
Public health interventions tend to embody an
imbalance of power and capacity between the imple- regulations that interpret them, the traditional principles
menters and the recipients. Public health professionals known as common law, and the judicial opinions that
decide when and where to intervene, and normally what apply and interpret all these legal rules and principles’.
the intervention will consist of. It is presumed that Wing (5) argues that the law is also the legal profession
whatever “harm” the intervention may impose on indivi- and the legal process – legislatures and their politics and
duals is out-weighed by the “good” it will bring to the finally ‘the law is what it is interpreted to be’.
population as a whole. This form of practice does not The basic function of the law is to establish legal
exemplify respect for the autonomy of the people at the rights, and the basic purpose of the legal system is to
receiving end of the intervention (35,36). Hall (36) has define and enforce those rights. Legal rights are the
argued that although individuals surrender some degree relationships that establish privileges and responsibilities
of personal freedom in exchange for membership of a among those governed by the legal system. Finally, some
society, ‘individual autonomy remains to some degree’. rights are protected, not by statute or regulation, but by
He (36) states that this residual autonomy is not addre- an understanding and application of the prevailing ethics
ssed within public health and suggests that the utilita- in an area. In general, ethics are regulated through
rian support for the practice of public health whatever sanctions are imposed against censured
must be subordinated to the deontological rights of the behaviour by peers or colleagues. These statements
individual. underlie the essential link between ethics and the law,
Within liberal democracies it is generally accepted but, ‘it is normally accepted that ethics are something
that the state may intervene when the exercise of one more than the law’ (38).
Legislation for Infectious Disease Control Legislation for the control of diseases like TB can have
in the United States and United Kingdom a range of ‘control’ measures, from ‘an order to complete
treatment’, to ‘an order for detention while infectious’
Surveillance of infectious diseases began in the United
(42). In New York City in 1993, the health code was
States in 1874 in Massachusetts, when the State Board of
revised to permit ‘compulsory actions to protect the
Health instituted the first state-wide voluntary plan for
public health’ in relation to TB (42). The types of regula-
weekly reporting of the prevalence of diseases by
tory action included: order for examination for suspected
physicians. By the turn of the century, the forerunners
TB as out-patient or in detention; order to complete
of the Public Health Service had been established, and
treatment; order for DOT; written warning of possible
laws in all states required that certain communicable
detention; order for detention while infectious; order for
diseases be reported to local authorities (39). During the
detention while non-infectious; discharge from detention
period 1940 to 1970, states added many diseases to their
before cure [for non-infectious patient] (43).
mandatory lists. Even in states that did not enact
legislation to require additional reporting, surveillance Legislation in India
and reporting efforts were broadened during this period
through state regulation or directives from the state In India, health regulation is a responsibility of each state.
health commissioners (40). The central government has some authority but the laws
In the United Kingdom, the Infectious Disease are created through the state legislature; each state can
Notification Act of 1988 amended the Infectious Disease make and enforce its own laws. Central government can
[Notification] Extension Act of 1899 which required also develop health legislation but has to depend solely
compulsory nation-wide notification of certain infectious on each state to enforce it.
diseases [but not TB]. In England and Wales, this list was Just before independence in 1948, the Bhore commit-
re-enacted with modifications on a number of occasions tee (44) produced recommendations on health laws
and the current ‘notifiable diseases’ are contained in including statements on the control of infectious diseases.
section 10 of the Public Health [Control of Disease] Act While showing great concern for the measures required
of 1984. Notification of TB is contained in Schedule 1 of to prevent and combat the spread of diseases between
the 1988 Regulations. provinces, it made recommendations for giving the
The law for infectious diseases has two parts: central government some legal powers in line with those
surveillance and control; with control being further existing in the United States at the time. Public Health
Acts were recommended for the central as well as state
subdivided into control of the environment [in its widest
governments to bring together existing legal provisions
sense to include premises and articles] and control of
relating to health, to modify sections of the laws which
people. The control of actions by people is contained in
required change in the interest of promoting efficient
both the 1984 Act and the 1988 Regulations, and the
administration and to incorporate new provisions
powers are wide ranging, from exclusion to incarceration.
necessary for the health programmes recommended by
Section 10 of the 1984 Act allows the proper officer of
the Bhore Committee. However, in keeping with the
any district to request any person to discontinue work
government policy of doing as little legislation in the field
‘with a view to preventing the spread’ of TB and if they
of health as possible, such a consolidated act was never
fail to do so, this may be an offence under section 19 of
adopted (38).
the 1984 Act. Under the powers contained in section
32[1][a] a person can be requested to leave his or her
TUBERCULOSIS CONTROL - ETHICAL ISSUES
residence and under section 32[1][b] compulsory removal
can be effected, under a court order, to alternative The following section looks at the ethical issues and
accommodation when any infectious disease occurs in a dilemmas within the treatment and control of a person
house. In addition, provisions are included in the 1984 with TB. It focusses on the interaction between the patient
Act to allow compulsory removal to and incarceration and the health care provider, the interaction of the patient
in a hospital if the person is considered a serious risk with the health care system, and on the separate stages
(41). of TB treatment from the problems of access to the
954 Tuberculosis
systems established for monitoring and follow-up. Many

of the ethical questions that arise in the control of TB are
to do with relationship, particularly the relationship
between the patient and the health care provider whether
that person be a nurse, physician, community worker or
manager; but also the broader interaction of the patient
with the overall health structure.
In public health decision making, there is always the
issue of balancing the rights of the individual versus the
rights of the population. Each of us is inextricably linked
Figure 65.3: Determinants of risk of tuberculosis
to the community in which we live and what happens to
us affects the wider community. Our individual morality society. ‘The law is there to assist and protect people’
is interlinked with the ethics of the public health system (4). It can be argued that in the case of TB, the rights of
[in this case the TB control programme] and with the the individual are justifiably sacrificed for the overall
laws of the state [Figure 65.2]. good of the population (45). As stated above, however,
In the case of TB control, the biomedical model has ethics demands a balance: while infected people have a
established that a person with sputum positive TB is
right to be treated with dignity, worth, value and respect,
infectious to others, and is therefore, capable of transmitt-
they have a duty not to spread the infection to others
ing the infection with the risk of the development of TB
(46).
disease. However, it is important to remember that the
determinants of risk for TB are personal, societal and Relationship of a Tuberculosis Patient with the
programmatic [Figure 65.3]. The main ethical issue, Health Care Provider
therefore, in TB control is the perspective on this balance
A patient with TB wants both to understand what is
between the individual, and the community in which
wrong with them and to receive treatment. A person with
she or he lives; the balance between accepting the
a persistent cough will seek advice from members of their
autonomy of the individual versus the process of justice
community who they know to have knowledge of health
and equity. The official process of justice in a society is
and disease. In some places this person will be the local
provided through the legal system which through the
traditional healer, in others it will be a physician
law courts provides a structure for people to be heard
practising in the private or government health system.
and also develops the laws to govern and protect the
The relationship that is developed with this person and
with the health care system to which they belong will
dictate how the person is treated and whether they are
treated with dignity and respect.
The whole ‘context’ of where a person comes from,
their socio-economic conditions and level of education
is essential for the health care worker to understand.
Without an attempt to understand the patient’s
perspective, health care providers will be unable to
provide an appropriate service. How far does the person
have to travel to come to the health facility? Can they
afford to come? What is their job and how is it being
affected by their illness? How can the health care worker
provide a relationship of trust?
Compliance and Adherence
Figure 65.2: Ethics of tuberculosis control programme,

Compliance can be defined as the extent to which a
law and morality person’s health related behaviour coincides with medical
advice (47). When seeking care patients carry out their Improved adherence to TB therapy will depend on
own “cost-benefit analyses”, balancing out their under- an improved understanding of the social epidemiology
standings of the severity of the illness, its impacts on their of TB. Wherever it occurs TB is a disease of poverty. There
family members and their ability to obtain access to is a strong evidence that the poorest compliance occurs
treatment, against the other conflicting priorities and in the poorest communities (49). It is, therefore, essential
demands of daily life. Patients with acute TB tend to that the social and economic factors involved in non-
comply with treatment because of the desire to get well compliance are understood and appreciated. Compliance
and to be free from troubling symptoms of fever, cough will only be improved if these factors are taken into
and night sweats. Compliance after the initial phase of account. As Farmer (50) has noted, “those least likely to
treatment, when the patient feels well, is more difficult comply are those least able to comply” with treatment.
to ensure. The balance of benefits and priorities has In the United States and other industrialized nations TB
shifted from an immediate benefit to the patient to a more is concentrated among the elderly and people from
abstract [from the patient’s perspective] benefit to the minority ethnic groups, many of whom are poor and
community. From the patient’s point of view the “costs” have compromised access [social, physical and economic]
of staying on treatment once symptoms have to care (14,51). The main TB burden, however, occurs in
disappeared may well out-weigh the benefits, which the developing world where TB cases occur across a wide
must be difficult to assess. Thus, while the “failure” of spectrum of society (52,53).
patients to comply with maintenance therapy may Direct Observation of Treatment
appear to be irrational from the physicians’ or health care
workers’ perspective, it is intelligible when seen from As has already been mentioned in the background to this
the patient’s point of view (48). chapter, DOT is part of the international DOTS strategy
Ethically, compliance relates to the interaction for TB control (10). But, DOT has potential difficult ethical
questions relating to coercion and control, an imbalance
between the autonomy of the TB patient and the bene-
between the autonomy of the individual patient and the
ficence of the health care worker. Although health care
control exerted by the health care worker in the system.
workers may be trying to ‘do good’ and to avoid harm
It can be argued that ‘if a person’s health related
to the patient, however, they have difficulty acting as
behaviour does not coincide with medical advice, then
independent moral agents because they are participants
it is appropriate to ensure that it does’ (19).
in a health structure, and are therefore, bound to uphold
The ethical, legal and Constitutional principles that
the ethics of that structure [Figure 65.2]. As members of
justify efforts to control TB in the United States are broad
professional organizations and players in TB
enough to justify efforts to ensure that all patients with
programmes, they are expected to conduct themselves
TB are treated until cured. Legal commentators have
in a particular manner, to follow the regulations of the endorsed the goal of treatment to cure (44,54,55). There
programme, and to encourage patients to take and has been controversy, however, over the nature of the
complete their treatment until cured. Cure is the goal, public health interventions that might be employed to
the outcome measure, which health care worker are achieve this goal and the extent to which the legal and
obliged to bring about. But there is a danger inherent in ethical principles that guide medical and public health
this process. At some stage the health care worker’s practice should constrain those interventions (8).
compliance to the system may lead to coercion of patients: In the United States, DOT has proven effective in
the end [cure] may come to justify any means taken to increasing rates of treatment completion (56,57) and in
reach it, even if those means transgress against respect decreasing the prevalence of drug resistance and relapse
for the autonomy of patients. If patients are treated in communities in which it is used (58). It was initially
autonomously, then it must be accepted that they may recommended for persons with poor records of treatment
choose not to follow the ‘orders’ of the system. The adherence and for those whose demographic or
relationship between the health care worker and the psychological profile suggested a high risk of failure.
patient, the trust and respect between them and the Now, however, DOT has emerged as a standard of care
success of their communication are vital for ensuring an (57). This change has come about because of the rise of
ethical approach to TB treatment (12,13). drug resistance in the United States.
956 Tuberculosis
In the United States, it has been argued that because Those opposing direct observation may feel that it
DOT is standardized [is the same for all patients], the initial threatens this very important relationship. It is not that
treatment decisions should not violate the principle of DOT is wrong. In fact, the DOT is a rational approach to
justice, and should thus preclude acts of discrimination the delivery of TB drugs. The problem comes, however,
(59). The fact that all patients start their post-hospitalized with the abuse of power that is potentially inherent in a
treatment under a common programme of supervision relationship between a powerful medical worker and a
should help to reduce the stigma of being under sick vulnerable patient (19).
treatment and create an effective public health plan for
the control of TB. Yet is it reasonable to assume that such Interaction and Relationship of a Tuberculosis
a programme will be equally appropriate in all settings, Patient with the Health Care Structure
no matter how socially or economically diverse? Does [Official and Unofficial]
DOT respect the autonomy of individuals everywhere In every country there is a health care structure whether
in the same way? Indeed universal DOT has been
official or unofficial. In some, it is organized and
challenged as an unethical intrusion on autonomy, as
controlled by the government [regulated system], and
‘gratuitously annoying’ (60), as a violation of the Consti- in others it is a system established through traditional
tutional requirement that the least restrictive measure
systems of medicine and health care [unregulated
be used, and as contrary to the requirements of the
system]. Increasingly, the health care systems in many
Americans With Disabilities Act [That decisions involv- countries are being administered through a mixture of
ing restrictions on those with disabilities be based on an
public and private providers.
individualized assessment] (61). The DOT has also been
criticized on the basis that it is resource and manpower The Health Care Structure
intensive, and so may be wasteful of scarce resources
(59,62). For a health care system to work and to provide appro-
It has been argued that the discourse of direct priate care for people, it must be consistent with the
observation is one of domination and control of the health underlying health beliefs and social norms of the
care worker over the patient (63). In ethical terms, it can community (64). If the government does not provide
be argued that the approach fails to respect the autonomy appropriate health care for communities, they will
of the person with TB. The ‘care relationship’ between establish their own systems. The rise of the private sector
patients and providers should, in ethical terms, be in countries in Asia is an example. The ethical issues that
characterized by a balance between the autonomy of the relate to health care structures are to do with the rights
TB patients and the beneficence or non-maleficence of of individuals to have a system of health care provided
the health care worker and should lead to net benefit for them by government. In western industrialized
with minimal harm. If the health care worker attempts countries, governments are considered to have a duty to
to force the patient into a type of treatment which they provide systems of health care for the population and
do not understand or agree with, then the relationship individuals consider that it is their right to be provided
becomes coercive. with a service.
A person goes to a medical practitioner because he is
Access
sick and wants to get well. The practitioner has access to
technology and knowledge that the patient needs. It is While it is important for health care to be consonant with
an inherently unequal relationship. Yet this relationship patient belief systems, it must also be accessible to them
is also the key relationship in health care. In TB control, in physical, geographic and economic terms (50,65). Not
the discipline of ethics helps to frame this relationship all people have equal access to health care structures and
in order to ensure that this inequality is not abused. it is usually the most vulnerable groups [e.g., displaced
Indeed codes of conduct are an important part of ethics populations, the poor, the unemployed, etc.,] that find it
in medicine. The stronger this relationship the more most difficult to use the health care services (66). In terms
appropriate the care provided. This relationship is of ethics, it is important to look at the relative autonomy
destroyed if power is abused. of people with TB within their community, the balance
between beneficence and non-maleficence, the net gain enable the development of solutions which meet the
for being enrolled in TB treatment [the DOTS strategy, needs of the system as well as the needs of the patients
for example], and finally whether they are treated justly. and the communities in which they live.
Social and Cultural Burden Treatment and Drugs

How people use the health care system [‘treatment Once the patient has accessed the system and been
seeking’] relates to cultural as well as social and economic diagnosed with TB, she or he needs to be provided with
factors. While the burden of TB has been well defined a regular supply of antituberculosis drugs. This requires
from the epidemiological perspective, there have been a system to have been developed to ensure that there is a
surprisingly few attempts to define the social and regular drug supply. For this to be achieved, questions
economic burden of TB (52). Similarly, there are only a need to be asked about the type of health care system
limited number of studies on the actual costs or economic established in a country. It asks governments to be
consequences of TB borne by families, communities, and committed to dealing with TB and to ensuring an
economies in the developing world (67). Nevertheless, appropriate management and distribution system for TB
it is apparent that not all people are equally able to access drugs. It is not simply the uninterrupted supply of drugs
health care structures (50). This is a question of equity. that is important, however, it is also the access to those
Ethical processes are critical in promoting equity. ‘Equity- drugs by the people who need them.
promoting action in the health sector must put the needs
and interests of the poorest and most vulnerable at their Monitoring
heart, as the relatively worse health outcomes of this
Monitoring and evaluation of the TB system is obviously
group in comparison with other groups are most often a
essential and can either promote equity and efficiency
function of circumstances beyond their control’ (68). or seriously detract from it (10,11). It is important, for
example, that health care workers are able to perform
Stigma
the tasks and achieve the targets they are being evaluated
Another issue which needs to be highlighted when on: the criteria for evaluation need to be realistic and
considering a patient’s interaction with the health care appropriate for particular contexts and given the real
structure as well as the ethics of the ‘passive case-finding’ constraints faced on the ground. Recent operations
approach [The health care system waits ‘passively’ for research in India, for example, indicate that targets set at
patients to present with TB rather than ‘actively’ looking the national and international level may be placing
for patients] advocated in TB control strategies is stigma. stresses on health care workers that do not promote the
TB carries a social stigma. It is also a disease which affects care of patients (12,13,69).
the most marginalized, most poor and most vulnerable Ethical questions that need to be asked in relation to
groups in communities, the very groups who tend to monitoring and evaluation include: Is the system just and
have the least autonomy. Although it is clear that the equitable? Does the system respect both the TB patients
effects of stigma on passive case-finding needs to be and the health care workers that care for them? Does the
better understood, there is evidence which indicates that system encourage health care workers to identify
it will have an effect on delaying treatment-seeking and problems or does it penalize them for ‘not doing it right?’
that it may substantially constrain the ability of young Problems need to be identified and dealt with positively.
people and women in particular to seek and obtain care This is the art of making difficult problems soluble, a
(67). Passive case-finding is the method of waiting for process which Medawar called the ‘art of the soluble’
people with TB to present to health facilities rather than (70). After all it is through tackling problems that we find
actively going out to find cases. a process of engagement and integration between people
Passive case-finding may well be sound in public with TB, their communities, districts, states, government
health terms, and even in macro-economic terms, but the and the international community (71).
ethical implications need to be taken into consideration The international DOTS strategy makes sense
as well. Considered and well-informed debate should scientifically, but if the emphasis is only on targets rather
958 Tuberculosis
than the process developed to achieve these targets, then ‘ethics, principles and tasks’ it has already been stated
health care workers and patients may be used as ‘means’ that inequity denotes the reasons behind and
to achieving a particular ‘end’: they may be abused. A responsibilities for underlying conditions of inequality,
system needs to be established in which both patients and it is therefore, inherently a statement of justice (32).
and providers are respected. The health service is, after Ethical processes are critical in promoting equity (29,68).
all, there to provide a service for patients. A danger of
having inappropriate targets for the health care worker Legal Processes Affect the Minority of
is that they will focus on attaining these targets rather Tuberculosis Patients
than on caring for the patient. This may lead to coercion A study conducted in New York City and published in
by the health care worker of the patient, or to the
1999 indicates that between 1992 and 1997, legal action
exclusion of the patient from the system. Targets need to
was required only for a minority of patients with TB (42).
be adapted to the local community situation and made In 1993, because of the increasing rates of TB and cases
appropriate to them.
of MDR-TB, the New York City Department of Health
As noted above, ethics requires people to treat each
updated its Health Code to permit compulsory action to
other as ends in themselves and not merely as the means protect the public health. From this date, the
to achieving a particular outcome ‘end’ (72). Concentrat-
Commissioner of Health could issue orders compelling
ing on the moral and social aspects of a monitoring
a person to be examined for suspected TB, to complete
system will help to ensure that this is achieved, that treatment, to receive treatment under direct observation,
people are respected and TB patients are not abused in
or to be detained for treatment (43). The types of regula-
the process. ‘The provision of social services has a strong
tory action ranged from ‘an order for examination for
person element: the quality of service depends heavily suspected TB’ to ‘an order for detention while infectious’.
on the attitudes of the people undertaking it, and it is
The study by Gasner et al (42) evaluated legal actions
hard to monitor. Service provisioning, furthermore, often
in TB control and showed that regulatory orders were
involves a position of power over users. Hence the issued for less than four per cent of the 8000 TB patients
importance of professional ethics’ (73).
treated between 1993 and 1995. The paper strikingly
highlights the social and demographic characteristics of
TUBERCULOSIS CONTROL - LEGAL ISSUES those who were detained [‘the outliers’]; of the 304
The next section focusses on some legal issues contained patients who required regulatory action, 211 [69%] were
within the current TB control strategy. The examples used black, 68 [22%] were Hispanic, 21 [7%] were white and 4
are from a western legal perspective. [1%] were Asian. Human immunodeficiency virus
In the industrialized world the legal cases that are infection was documented in 147 cases [48%]. One
reported in the literature tend to relate to the loss of civil hundred and fifty-two [50%] had a history of
liberties. For example, in order to protect ‘the majority’, homelessness, 128 [42%] had used injection drugs, 183
the legal system is used to ‘control’ people with TB who [60%] had used ‘crack’ cocaine, 191 [63%] had a history
fail to follow public health recommendations and of alcohol abuse and 145 [48%] had a history of
regulations to prevent the spread of Mycobacterium incarceration (42).
tuberculosis (8). These people are a minority of cases but
High Risk Groups
affect certain groups who are themselves ‘minorities’; for
example, the homeless, ethnic minorities, drug users and In ethics there is a dictum which states ‘ought implies
alcoholics (19). It can be argued that these people are the can’ (8). It can be argued, therefore, that a person cannot
‘outliers’ of a community, people who live on the fringes be held ethically accountable for failing to adhere to
of society and who are not seen as part of the majority moral or legal standards [e.g., TB treatment], if he or she
i.e. they are different from ‘the norm’. If ‘equality’ is the cannot do so, or if he or she faces insuperable obstacles
only aspect of justice that is important, then it could be to adherence. This statement highlights the plight of the
argued that this situation is appropriate. However, the most vulnerable groups in our communities (52).
question of equity is also important. In the section on Ethically it is important to consider the duties of the
community to support these groups of vulnerable people and treat frequently neglected populations residing in
to ensure that they are appropriately treated for TB, but jails and prisons throughout the developing world’ (78).
perhaps more importantly, to find ways of preventing Prisoners have been confined to prison through the
them from acquiring TB. legal system in a particular country, but it is the
This ethical principle of ‘ought implies can’ compels responsibility of the government system which manages
us to recognize that the elimination of impediments that the prisons to ensure that prisoners are treated and cared
impinge on the capacity of an individual to cooperate in for appropriately [duties]. In the case of TB, this means
his or her own care for TB is essential and we need to both ‘establishing the conditions in which people can be
look for appropriate structural interventions (18). For healthy’ in prisons [i.e., no overcrowding, poor nutrition
example, homeless persons cannot reasonably be etc.,] as well as providing appropriate treatment of TB
expected to comply with their treatment unless they are cases when they arise. In many countries, the primary
provided with a secure residence, and in many cases with reason for the higher prevalence of Mycobacterium
other social supports (8). This is echoed in social science tuberculosis infection and increased incidence of TB
research which indicates that those with strong disease within prisons is the disproportionate number
community or familial support are more likely to adhere of inmates who are otherwise at high risk for acquiring
to a full course of TB therapy (64,67,74,75). The New York infection and developing active disease (78).
City Tuberculosis Working Group (61) has argued that The discussion of ethical and philosophical matters
‘the government that fails to provide adequate social in health care is not new. Over two thousand years ago
supports for the most vulnerable loses the legal, as well the writings of Hippocrates debated the duties of doctors
as the moral, authority to threaten with a deprivation of towards their patients and the community. However, the
liberty those whose behaviour poses a health risk’. last three decades of the twentieth century and the start
Thus, the laws we develop in our communities and of the twenty-first have seen a dramatic transformation
societies are a reflection of how we see the world, of the in medical ethics. What has been limited in the past to
values we use to frame our legal system; and in the case codes of professional conduct became in the 1960s the
of TB control, how we perceive and deal with these new academic discipline called biomedical ethics or
vulnerable groups of TB patients. Is it not easier to bioethics (27). By the 1980s bioethics had included the
develop a law which confines high risk groups to ensure societal debate encompassing discussions about priority
that they do not spread the disease to the larger setting and health care reforms. Now, in the 1990s, a new
population than to address the difficult, some may say phase is evolving which transcends health care matters,
impossible, social questions of homelessness? Is there not encompassing the full range of health determinants. This
also the moral responsibility of the society to try to find phase has moved towards the ‘bioethics of population
ways of supporting these groups of people to prevent health’ with a focus on the broader ethical issues in public
them from acquiring TB without resorting to health such as social justice, equity, sustainable health,
coercion and control? Indeed if we are to believe Tyler’s sustainable living, globalization and environmentalism
statement (1) at the beginning of the chapter, our efforts (79). As was stated in the introduction, the 1990s and
to control TB patients in this way may be making the TB early 2000 is witnessing increasing ‘internationalism’ and
situation worse. ‘complexity’ and the increasing need to address cross-
cultural ethical issues as well as the theoretical and
Prisons
practical convergence of public health and human rights
Incarceration is the final legal action that can be taken to (80). This is highlighted in the spectre of the HIV
ensure that a person with TB takes their medication. pandemic and the research being conducted in this area,
However, prison itself is an important site for the which is driving an international agenda that is forcing
transmission of TB as demonstrated by recent outbreaks individuals and governments to address broad ethical
of MDR-TB in prisons in the United States, Spain and concerns about research and control.
Russia (76,77). These outbreaks have called for ‘inter- At the 38th CIOMS Conference in 1994, a Declaration
national efforts to ensure effective global initiatives to was issued describing the emergence of bioethics as a
control TB in these settings; strategies to screen, diagnose, global and multi-layered enterprise. The following
960 Tuberculosis
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Tuberculosis: Some Web-based Resources on the Internet 963
Tuberculosis: Some Web-based

Resources on the Internet
66
Anju Sharma, NC Jain
INTRODUCTION 17 millions [248%] in North America. Africa had only

51 million [3.5%] users. The World Wide Web is very
Internet is the newest and fastest growing medium for
expensive in most of the developing countries including
information flows. Internet growth is ever accelerating,
India. In India, less than per cent population has access
which indicates that the Internet is still in its expansion
to World Wide Web and most of them live in States and
phase. It provides information and data from all over
Union Territories like Delhi, Karnataka, Maharashtra,
the world in a few seconds. It is a worldwide, publicly
Tamil Nadu and a few metropolitan cities. If one looks
accessible series of interconnected computer networks
at Internet penetration rates [% population] in the world
that transmit data by using the standard Internet Protocol
North America tops the tally with 73.6 per cent
[IP]. It is also known as a “network of networks” that
penetration followed by Australia/Oceania [59.5%] and
consists of millions of smaller domestic, academic,
Europe [48.1%]. Asia has only 15.3 per cent penetration
business, and government networks, which together
carry various information and services. Most information rate while Africa has the least of 5.3 per cent only. As per
these days in fact, is available online and an increasing one estimate the World Wide Web contains about 170
number of people worldwide now have access to the terabytes [1 000 000 000 000 bytes or 1012 bytes] of
Internet (1). information on its surface (3).
Internet and the World Wide Web [www] are not How much new information is actually created each
synonymous. The Internet is a collection of inter- year? More that 90 per cent of new information is stored
connected computer networks, linked by copper wires, on magnetic media, primarily hard disks. Film represents
fiber-optic cables, and wireless connections. In contrast, seven per cent of the total, paper 0.01 per cent, and optical
the World Wide Web is a collection of interconnected media 0.002 per cent. The amount of new information
documents and other resources, linked by hyperlinks and stored on paper, film, magnetic, and optical media has
Uniform Resource Locators [URLs]. The World Wide been increasing every year. This is what is called
Web is one of the services accessible via the Internet, information explosion. Despite this development, the
along with many others including e-mail, file sharing amount of information printed on paper is still
and others (2). If one takes into account all web accessible increasing, but the vast majority of original information
information, there are about 550 billion web connected on paper is produced by individuals in office documents
documents and 95 per cent of this information is available and postal mail, not in formally published titles such as
publicly as in 2007. books, newspapers and journals.
As of June 30, 2008, 1.463 billion people were English language is the dominant language if one
using the Internet according to Internet World Stats. Of looks at the distribution of web sites. Currently, only 50
these, 578 millions [39.5%] Internet users were in Asia, per cent of all Internet users are native English speakers,
followed by 384 millions [26.3%] in Europe and though English web sites continue to dominate with
964 Tuberculosis
approximately 78 per cent of all web sites and 96 per cent possible for a lay person, a patient or otherwise, to know
of e-commerce web sites being in English. It is not possible about the diseases like TB (4) , acquired immuno-
to estimate what percentage of web sites have their origins deficiency syndrome [AIDS] (5) , and various other
in the English speaking countries or others (2). resources (6) with just a click of mouse.
The Internet has now become an essential Here are some of the sources on the Internet which
infrastructure in the health environment. It provides an provide information about tuberculosis. This is a
abundance of resources such as communication services compilation based on information available on PubMed
[http://www.ncbi.nlm.gov/enterez/query.fcgi], Google
including electronic mail and discussion groups; direct
[http://www.google.com], Google Scholar [http://
access to scientific and health-related information
scholar.google.com/], Scirus – for scientific information
resources, including digital libraries. There are enumer-
only [http://www.scirus. com/], IndMed [http://
able number of web sites available these days providing
indmed.nic.in/], medIND [http://medind.nic.in/], and
information, both authentic and otherwise, to public, various published and other internet resources. This
researchers, clinicians, experts and whosoever is collection is not based on any guidelines or criteria but
interested to know about health related issues, policies, mainly our experience in the area of biomedical
new infections, emerging and re-emerging infections, communications. The list can never be complete, the
diseases and medical research currently being done deletions as well as additions will be a continuous
globally. There was a time when there were no means process. There may be problems about authenticity of
for general public to know about the etiology, pathogene- information at certain sites though we have tried to
sis, treatment, preventive measures of tuberculosis [TB], include only the authentic web sites.
the white plague, as it was known as. Now with a burst Some important and useful web resources on TB are
of all kinds of information on the Internet it has become listed below:
Books
Tuberculosis 2007 – From Basic Science to Patient Care, J C Palomino, S C Leao, V Retacco [Editors], [http://tuber-
culosistextbook.com]
ebooks
Opportunistic infections – Treatment and prophylaxis. Totowa: Humana Press; 2003
Schlossberg D. Tuberculosis and nontuberculosis mycobacterial infections. 5th edition, Philadelphia: The McGraw-
Hill Co.,Inc; 2006
Reports
Anti-tuberculosis drug resistance in the world WHO report [http://www.who.int/tb/publications/who_htm_tb_
2004_343/]
A research agenda for childhood tuberculosis. Improving the management of childhood tuberculosis within national
tuberculosis programmes: research priorities based on a literature review WHO/HTM/TB/2007.381. [http://
whqlibdoc.who.int/hq/2007/WHO_HTM_TB_2007.381_eng.pdf]
Communicable Disease Report CDR Weekly [http://www.hpa.org.uk/cdr/]
Global tuberculosis control - surveillance, planning, financing, WHO Report 2007/WHO/HTM/TB/2007.376 [http://
www.who.int/tb/publications/global_report/2007/en/index.html]
Clinical Trials/ Registers

ATM Clinical Trials Registry [http://www.atmregistry. org/]
Australian New Zealand Clinical Trials registry [ANZCTR] [http://www.anzctr.org.au/]
Clinical Trials Registry – India [http://www.ctri.in/]

ClinicalTrials.gov, A service from US National Institutes of Health [http://clinicaltrials.gov/]
Current Controlled Trials [http://www.controlled-trials.com/]
metaRegister of Controlled Trials [mRCT] [http://www.controlled-trials.com/mrct/]
PhRMA Clinical Study Results Database [http://www.clinicalstudyresults.org/]
The Cochrane Central Register of Controlled Trials [http://www.mrw.interscience.wiley.com/cochrane/
cochrane_clcentral_articles_fs.html]
UNIM Clinical Trials Registry [UNIM – CTR] [http://www.umin.ac.jp/ctr/]
WHO International Clinical Trials Registry Platform, ICTRP [http://www.who.int/ictrp/en/]
Drug Development, Vaccines and Diagnostics

AERAS Global TB Vaccine Foundation [AERAS] [http://www.AERAS.org ]
Aeras Global TB Vaccine Foundation, Developing New Tuberculosis Vaccines for the World [http://www.aeras.org/].
Bill and Melinda Gates Foundation [BMGF] [http://www.gatesfoundation.org/GlobalHealth]
European Commission TB Vaccine Cluster [http://www.pasteur.fr/recherche/EC_TBvaccine/]
Foundation for Innovative New Diagnostics [FIND], Geneva, switzerland [http://www.finddiagnostics.
org/]
Global Alliance for TB Drug Development [http://www.tballiance.org/about/mission.php]
KNCV Tuberculosis Foundation [KNCV] [http://www.kncvtbc.nl/]
South African Tuberculosis Vaccine Initiative [http://www.satvi.uct.ac.za/]
TBVAC - TBVAC is a cluster for tuberculosis vaccine developments composed of academic teams and industrial
partners possessing complementary expertise. The major objective of the TBVAC project is to identify, develop and
evaluate in pre-clinical and clinical Phase I trials new and improved vaccines [http://www.tb-vac.org]
TB Vaccine Testing and Research Materials Contract, Colorado State University [www.cvmbs.colostate.edu/
microbiology/tb/top.htm]
Tuberculosis Statistics
Indiana State Department of Health, Indiana Tuberculosis Reports [http://www.in.gov/isdh/dataandstats/
tuberculosis/tb_index.htm]
Minnesota Department of Health, TB Statistics [http://www.health.state.mn.us/divs/idepc/diseases/tb/stats.html]
Morbidity and mortality statistics regarding tuberculosis in India [http://openmed.nic.in/787/].
Texas Department of State Health services Tuberculosis Statistics [http://www.dshs.state.tx.us/idcu/disease/tb/
statistics/]
Tuberculosis and HIV: Statistics and Demographics , The Body The Complete HIV/AIDS Resource [http://
www.thebody.com/index/treat/tubercul_stats.html]
Tuberculosis Data and Statistics, Department of Health, New York State [http://www.health. state.ny.us/statistics/
diseases/communicable/tuberculosis/]
966 Tuberculosis
Tuberculosis- India [http://www.indiastat.com/india/ShowData.asp?secid=17800andptid=77 andlevel=3]

Tuberculosis Statistics in the United States [http://tuberculosis.emedtv.com/tuberculosis/tuberculosis-statistics-
in-the-united-states.html]
Tuberculosis Statistics, Communicable Disease Service Tuberculosis Control Program New Jersey [http://
www.state.nj.us/health/cd/tbstats/]
Professional Associations/Organizations
American Lung Association [ http://www.lungusa.org/site/pp.asp?c=dvLUK9O0Eandb=22542]
American Lung Association of California [http://www.californialung.org/]
American Thoracic Society [http://www.thoracic. org/]
California Tuberculosis Controllers Association, CTCA [ http://www.ctca.org/]
Centers for Disease Control and Prevention, Atlanta, USA [http://www.cdc.gov/]
Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Nirman Bhawan,
New Delhi, India [http://www.tbcindia.org]
Foundation for Innovative New Diagnostics [FIND], Geneva, Switzerland [http://www.finddiagnostics.
org/]
Francis J. Curry National Tuberculosis Center [www.nationaltbcenter.edu/]
Indian Council of Medical Research, New Delhi, India [http://www.icmr.nic.in]
International Union against Tuberculosis and Lung Diseases [IUATLD] [http://www.iuatld.org/], IUATLD – Official
publications; contains abstracts and some full-text articles for free
Japan Anti-TB Association Research Institute of Tuberculosis [http://www.jata.or.jp/eindex.htm]
John Hopkins Center for Tuberculosis Research, USA [http://www.jhsph.edu/dept/IH/Centers/TB_Research.html]
National Institute of Allergy and Infectious Diseases [NIAID], Tuberculosis [http://niaid.nih.gov/publications/
tb.htm] , NIAID, Fact sheet and brochures about TB research and training opportunities
National Institutes of Health, USA [http://www.nih.gov/]
National Prevention Information Network NPIN, CDC, USA [http://www.cdcnpin.org/scripts/index.asp]
National Tuberculosis Controllers Association, USA [http://www.ntca-tb.org/]
National Tuberculosis Institute, Bangalore, India [http://ntiindia.kar.nic.in/]
New Jersey Medical School Global Tuberculosis Institute [http://www.umdnj.edu/globaltb/home.htm]
SAARC Tuberculosis and HIV/AIDS Centre [http://www.saarctb.com.np/tuberculosis.php]
Stanford Center for Tuberculosis Research, USA [http://www.stanford.edu/group/molepi/]
TBC India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India.
[http://www.tbcindia.org/]
The Sanger Center [http://www.sanger.ac.uk/]
The Tuberculosis Association of India, New Delhi, India http://tbassindia. org
Tuberculosis Research Centre [ICMR], Chennai, India [http://trc-chennai.org] Permanent Institute of the Indian
Council of Medical Research, WHO Collaborating Centre for Tuberculosis Control – Institution that conducts
randomized controlled clinical trials to evaluate principles of chemotherapy
World Health Organization, Geneva, Switzerland [http://www.who.int/en/]
Newsletters/Magazines
Division of Tuberculosis Elimination - DTBE Newsletters [http://www.cdc.gov/tb/newsletters.htm]
FIND Newsletters [http://www.finddiagnostics.org/news/newsletters/]
Hartland National TB Center Newsletters [http://www.heartlandntbc.org/newsletters.asp]
Stop TB Partnership Newsletters [http://www.stoptb.org/resource_center/communique_and_newsletters.asp]
TB Alliance Newsletters [http://72.3.224.152/newscenter/newsletters/]
Glossaries/Dictionaries
Division of Tuberculosis Elimination [DTBE], CDC, USA – Questions and Answers Glossary [http://www.cdc.gov/
tb/faqs/qa_glossary.htm]
Health Glossary – Tuberculosis [http://www.singhealth.com.sg/HealthMatters/HealthGlossary/Tuberculosis.htm]
TB Dictionary /A-Z [http://www.tbalert.org/tuberculosis/TBDictionary.php]
Advocacy
California Department of Public Health TB Advocacy and Partners [http://www.cdph.ca.gov/programs/tb/Pages/
AdvocacyandPartnersTBCB.aspx]
Stop TB Parternership Advocacy, Communication and Social Mobilization Working Group [http://www.stoptb.org/
wg/advocacy_communication/default.asp?AM=ACSM]
Tuberculosis Advocacy Report, WHO/CDS/TB/2003.321 [http://www.who.int/tb/publications/
advocacy_report_2003/en/index.html]
Scientific Literature on Tuberculosis

Community contribution to TB care: practice and policy. Geneva, World Health Organization, 2003 [WHO/CDS/
TB/2003.312] [http://www.wqlibdoc.who.int/hq/2003/WHO_CDS_TB_2003.312.pdf]
Current TB News [http://www.hopkins-tb.org/news/index.shtml#top], Summaries prepared by the Centers for
Disease Control and Prevention [CDC] and presented by Johns Hopkins Center for Tuberculosis Research – Weekly
summaries of scientific articles and lay media reports
Division of Tuberculosis Elimination, CDC [http://www.cdc.gov/nchstp/tb/pubs/pem.htm], CDC – Access to
articles, fact sheets, guidelines and other publications
The Connections [http://www.cdcnpin.org/connect/start.htm], CDC National Prevention Information Network –
Access to information about the relationship between TB and HIV and sexually transmitted diseases
The Global Plan to Stop TB, 2006–2015: methods used to assess costs, funding and funding gaps. Geneva, Stop TB
Partnership and World Health Organization, 2006 [WHO/HTM/STB/2006.38] [http://www.stoptb.org/globalplan/
assets/documents/GlobalPlanFinal.pdf]
Tuberculosis literature from the World Heath Organization http://www.int/gtb/publications/index.html]
– Access to WHO documents, books, articles and other publications
968 Tuberculosis
Search Tools
Med Help International [http://www.medhelp.org]
Medline Plus [http://www.nlm.nih.gov/medlineplus/]
Medind [http://medind.nic.in]
Medscape [http://www.medscape.com/], Search tool to access peer-reviewed information from articles, conference
summaries and other publications.
National Library of Medicine Gateway [http://gateway.nlm.nih.gov/gw/Cmd]
PubMed [http://www.ncbinlm.nih.gov/entrez/query.fcgi], National Center for Biotechnology Information at the

National Library of Medicine. National Institutes of Health [NIH] – Search tool to access literature citations and
links to full-text journals
Google [http://www.google.co.in/]
Yahoo [http://www.yahoo.com/]
Scopus [http://www.scopus.com/scopus/home.url]
Epidemiological Data
Global Tuberculosis Control Report [http://www.who.int/gtb/publicaions/globrep00], WHO – Epidemiologic and
TB control data from different countries; data since 1998 available
Global tuberculosis control: surveillance, planning and financing. Geneva, World Health Organization, 2008 [WHO/
HTM/TB/2008.393] [http://www.who.int/tb/publications/global_report/2008/en/index.html]
Morbidity and Mortality Weekly Report [MMWR], [http://www.cdc.gov/mmwr/distrnds.html], CDC –
Epidemiologic data based on weekly reports form the health departments
WHO: Antituberculosis Drug Resistance in the World [http://www.who.int/gtb/publications/dritw/index.htm],
WHO – Drug resistance surveillance data, obtained by WHO and IUATLD
Literature for Lay People

Frequently asked questions [FAQ] [http://www.cdc.gov/nchstp/tb/faqs/qa.htm], CDC – FAQ; also contains a
glossary of terms
Columbia University – Summary of TB pathogenesis and management; has a Spanish language version. [http://
www.cpmc.columbia.edu/resources/tbcpp/abouttb.html]
Tuberculosis [http://www.lungusa.org/diseases/lungtb.html], American Lung Association – FAQ. What You Need
to Know about Tuberculosis
Management of Tuberculosis [Recommendations, Guidelines and Decision-making Algorithms]

ATS-CDC-IDSA Guidelines for treatment of tuberculosis [http://www.thoracic.org/sections/publications/
statements/pages/mtpi/rr5211.html]
A guide to monitoring and evaluation for collaborative TB/HIV activities. Geneva, World Health Organization,
2004 [WHO/HTM/TB/2004.342 and WHO/HIV/2004.09]. [http://whqlibdoc.who. int/hq/2004/WHO_
HTM_TB_2004.342.pdf]
CDC. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings 2005,
Morbidity and Mortality Weekly Report [MMWR] 54/RR-17 . Atlanta, GA , USA : Department of Health and Human
Services, Centers for Disease Control and Prevention ; 2005.p.147. [http://www.cdc.gov/mmwr/PDF/rr/rr5417.pdf]
CDC-NCHSTP-Division of TB Elimination : Major TB Guidelines [http://www.cdc.gov/nchstp/tb/default.htm] –
Technical articles on tuberculosis
CDHS/CTCA JOINT GUIDELINES. Targeted Testing and Treatment of Latent Tuberculosis Infection in Adults
and Children [http://www.ctca.org/guidelines/index.html]
CDHS/CTCA JOINT GUIDELINES. Guidelines for the Treatment of Active Tuberculosis Disease, 2003 [http://
www.ctca.org/guidelines/IIA1treatmentactivetb.pdf]
CDHS/CTCA JOINT GUIDELINES, 1999. Guidelines for the Follow-Up and Assessment of Persons with Class B1/
B2 Tuberculosis [http://www.ctca.org/guidelines/IIA7bnotification.pdf]
Diagnosis Standards and Classification of Tuberculosis in Adults and Children [http://www.cdc.gov/nchstp/tb/
pubs/tbfactsheets/1376.pdf], American Thoracic Society [ATS] and CDC – Diagnostic strategies in various risk
populations and classification of TB based on pathogenesis
Guidelines for the Prevention of Tuberculosis in Health Care Centers for Resource-Limited Settings [http://
www.who.int/gtb/publications/healthcare/index.htm] WHO –Infection control guidelines designed to reduce the
risk of nosocomial Mycobacterium tuberculosis transmission within health care facilities in resource-limited settings
Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization,
2006 WHO/HTM/TB/2006.361 [http://whqlibdoc.who.int/publications/2006/9241546956_eng.pdf]
Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among
adults and adolescents, Recommendations for HIV-prevalent and resource-constrained settings. WHO/HTM/TB/
2007.379 and WHO/HIV/2007.1 [http://whqlibdoc.who.int/hq/2007 WHO_HTM_TB_2007.379_eng.pdf]
Interim Policy on Collaborative TB/HIV Activities, Geneva, WHO, 2004. WHO/HTM/TB/2004.330; WHO/HTM/
HIV/2004.1 [http://whqlibdoc.who.int/hq/2004/WHO_HTM_TB_2004.330.pdf]
Major Tuberculosis Guidelines [http://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/maj_guide.htm], CDC –
Updated CDC guidelines for TB management in different settings
National Institute for Health and Clinical Excellence, Clinical Guideline 33, Tuberculosis, clinical diagnosis and
management of tuberculosis, and measures for its preventionand control, March 2006 [http://www.nice.org.uk/
nicemedial/pdf/CG033niceguideline.pdf]
New technologies for TB control: a framework for their adoption, introduction and implementation
WHO/HTM/STB/2007.40 [http://whqlibdoc.who.int/publications/2007/9789241595520_eng.pdf]
Prevention and Treatment of Tuberculosis among Patients with HIV [http://aepo-xdv-www.epo.cdc.gov/wonder/
prevguid/m0055357/m0055357.asp], CDC – Guidelines for the diagnosis, treatment and prevention of TB among
adults and children coinfected with HIV
Recommendations for Prevention and Control of Tuberculosis among Foreign-Born Persons [http://www.cdc.gov/
epo/mmwr/preview/mmwrhtml/00054855.htm], CDC –Recommendations for preventive therapy, diagnosis, and
management for TB in the foreign-born
Role of BCG vaccine in the Prevention and Control of Tuberculosis in the United States [http://www.cdc.gov/epo/
mmwr/preview/mmwrhtml/00041047.htm], CDC – Considerations and recommendations regarding the use of
BCG vaccine in the United States
970 Tuberculosis
Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection [http://www.cdc.gov/epo/mmwr/

preview/mmwrhtml/rr4906a1.htm], CDC – Recommendations for tuberculin testing and treatment of latent infection
The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. Anti-tuberculosis drug
resistance in the world. Third global report. Geneva, World Health Organization, 2003 [WHO/HTM/TB/2004.343;
more information about the project can be found at: http://www.who.int/tb/dots/dotsplus/surveillance/en/
index.html]
TB Treatment Guidelines in PDA Format, Division of Tuberculosis Ellimination, National Center for HIV/AIDS,
Viral Hepatitis, STD and TB Prevention, CDC, Atalanta [http://www.cdc.gov/tb/pubs/PDA_TBGuidelines/
default.htm]
Treatment of Tuberculosis : guidelines for national programmes, 3rd edition, 2003,WHO/CDS/TB/2003.313, Geneva,
[http://www.who.int/tb/publications/cds_tb_2003_313/en/index.html] WHO Tuberculosis and Air Travel:
Guidelines for prevention and control [second edition, 2006] – WHO Global Tuberculosis Programme, Geneva
[http://www.who.int/entity/tb/publications/2006/who_htm_tb_2006_363.pdf]
Updated Guidelines for the Use of Rifabutin or Rifampin among HIVInfected Patients Taking Protease Inhibitors or
Nonnucleoside reverse transcriptase inhibitors [NNRTIs] [http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/
mm4909a4.htm], CDC – Updated data about drug-drug interactions between anti-TB drugs and antiretroviral agents
Research Databases
BioHealthBase – Mycobacterium – Pathogen – Genome Database [http://www.biohealthbase.org/GSearch/
statsAutomation.do?decorator=Mycobacterium]
BioTech Science – Mycobacterium Genomic Resources [http://biotech.icmb.utexas.edu/pages/science/
mycobacterium.html]
Entrez-PubMed [http://www.ncbi.nlm.nih.gov/Entrez/index.html], National Center for Biotechnology Information]
NCBI – Integrated access to biomedical literature, nucleotide and protein sequences, along with 3-dimensional
protein structures, complete genomes, and population study data sets
Sequence of Mycobacterium tuberculosis CDC1551 [http://www.tigr.org/tigr-scripts/CMR2/
GenomePage3.spl?database=gmt], The Institute for Genome Research [TIGR] – Sequence and annotation of CDC1551,
a clinical isolate from Kentucky/Tennessee region
Sequence of Mycobacterium tuberculosis H37Rv [http://www.sanger.ac.uk/Projects/M_tuberculosis/], Sanger
Center – Sequence and annotation of H37Rv [laboratory strain]
TubercuList [http://genolist.pasteur.fr/TubercuList/] Pasteur Institute – Data of DNA and protein sequences derived
from H37Rv, linked to annotations and functional assignments
EuroTB: Surveillance of tuberculosis in Europe [http://www.eurotb.org/]
Research Groups Interested in Tuberculosis

Action TB [http://www.uct.ac.za/depts/mmi/lsteyn/glaxo.html], Department of Medical Microbiology, University
of Cape Town and Groote Schuur Hospital – Multinational research initiative to develop new effective, anti-TB
drugs
NIAID’s Tuberculosis Antimicrobial Acquisition and Coordinating Facility [TAACF] [http://www.taacf.org/],
NIAID TB programme – Organization that screens compounds in high quality in vitro and in vivo assays, provided
at no cost to the compound supplier
Policy Research and Development [http://www.who.int/gtb/policyrd/index.htm], WHO –WHO research agenda

Sequella Global Tuberculosis Foundation [http://www.sequellafoundation.org/index.asp], Sequella Foundation –
Foundation focused on applied research to develop tools to control TB; currently interested in vaccine development
Stanford Center for Tuberculosis Research [http://molepi.stanford.edu/], Stanford University – Research group
focused on molecular epidemiology studies of TB; the Web site also includes software for analyzing DNA
fingerprinting and DNA microarray data.
The Atlanta Tuberculosis Prevention Coalition [http://www.emory.edu/MED_INF/ATPC/atpc.html], The Atlanta
Tuberculosis Prevention Coalition – Organization interested in operational research in the management of TB
The Global Research Tuberculosis Initiative [http://www.globalforumhealth.ch/docs/forum3doc391.htm], Global
Forum for Health Research – Organization that promotes health policy research
Trudeau Institute [http://www.trudeauinstitute.org/], Trudeau Institute – Independent research institute interested
in human immune response against TB
Resources for Research, Teaching and Training

Francis J. Curry National Tuberculosis Center [http://www.nationaltbcenter.edu/ National Tuberculosis Center
[CDC] – Tuberculosis Control Program Training Center
GrantsNet [http://www.grantsnet.org/], Supported by Howard Hughes Medical Institute and American Association
for the Advancement of Science [AAAS] – Search tool to find funds for training and grants in biomedical sciences;
also contains grant-writing tools and tips
IUATLD [http://www.iuatld.org/], IUATLD – Information about conferences and courses Upcoming events in TB
[http://www.cdc.gov/nchstp/tb/calendar.htm], CDC – Calendar with TB-related events
National Institutes of Health [NIH] [http://grants.nih.gov/grants/], NIH – NIH guide for grant writing, research
contracts, and research training
National Tuberculosis Center [http://www.umdnj.edu/ntbcweb/], New Jersey Medical School – Calendar of courses
and conferences, and general information about TB and Direct Observed Therapy [DOT] strategy
Self-Study Modules of Tuberculosis [http://www.cdc.gov/phtn/tbmodules], CDC –Training material and self-
evaluation, teaching material
Tuberculosis Academic Awards [http://www.nhlbi.nih.gov/funding/training/ tbaa/], National Heart, Lung and
Blood Institute [NHLBI] – Information about awards to stimulate development and improvement in the quality of
TB-related medical curricula, and education for health care workers
Tuberculosis Research Activities, NIAID [http://www.niaid.nih.gov/dmid/tuberculosis/], NIAID – Information
about research goals, resources, blueprints, meeting information, and links
Tuberculosis.Net [http://tuberculosis.net/], Montefore Medical Center – Didactic teaching material
Wellcome Trust Grants [http://www.wellcome.ac.uk/en/1/gra.html], Wellcome Trust Foundation – Organization
that offers grants for research in biomedical topics
Information about Regulatory Action

State Tuberculosis Control Offices [http://www.cdc.gov/nchstp/tb/tboffices.htm], CDC –List of contact information
of state TB control programs in United States
State Tuberculosis Control Programs [http://www.cdc.gov/nchstp/tb/tbwebsites.htm], CDC – State TB control
programs, including regional epidemiological and surveillance data
972 Tuberculosis
Tuberculosis Handbook [http://www.who.int/gtb/publications/tbhandbook/index.htm], WHO – Synthesis of

the general principles and practical approaches for TB control developed by the WHO Global Tuberculosis Program
Tuberculosis Respiratory Protection Program in Health Care Facilities [http://www.cdc.gov/niosh/99-143.html],
NIOSH – Practical guide to initiating and running a TB respiratory protection program in health care facilities
What is DOTS? [http://www.who.int/gtb/publications/whatisdots/index.htm], WHO –Guide to understand the
WHO recommended TB control strategy known as DOTS
General Tuberculosis Web Sites

American Lung Association: TB [http://www.lungusa.org/diseases/lungtb.html] – General TB factsheet
Ask NOAH About: Tuberculosis, Bureau of Tuberculosis Control, New York City Department of Health [http://
www.noah-health.org/english/illness/tb/nycdoh/nycdohtb1.html] – Tuberculosis questions and answers
BCG Vaccine [http://www.drgreene.com/960520.html] – Dr. Greene discusses the effectiveness of the BCG vaccine
Brown University TB/HIV Research Laboratory [www.brown.edu/Research/TB-HIV_Lab/]
Centers for Disease Control and Prevention - Division of Tuberculosis Elimination [http://www.cdc.gov/nchstp/
tb/]
Columbia-Presbyterian Medical Center: TB Resources [http://www.cpmc.columbia.edu/resources/tbcpp/] – Basic
factsheets and articles on tuberculosis including TB : Getting Cured and Skin Test
Contact Investigation in a Worksite Toolbox [http://www.nationaltbcenter.edu/catalogue/epub/index.cfm?
tableName=ciTBox] – This toolbox compiles instruments and resources for use during a worksite contact investigation.
Using these materials, TB control staff will be able to follow step-by-step instructions for contact, implementation,
and follow up; develop protocols for inclusion of a worksite in an investigation; and adapt standard templates for
local use. The toolbox provides letters, forms, policies, and referenced materials
EuroTB [www.eurotb.org/] – Programme aims to collect, analyse and publish epidemiological information on
tuberculosis in Europe, with the aim of improving tuberculosis control
Francis J. Curry National Tuberculosis Center [http://www.nationaltbcenter.edu/] –The Online Learning section
includes knowledgable factsheets on testing and treatment of TB in a Question and Answer format. Pediatric
Tuberculosis is an excellent QandA on TB testing in children, including BCG and testing recommendations
General Information on TB [http://www.heartscreen.com/tb.html]
International adoptions pose extra TB problems, on Dr. Ellen Aronson’s website [http://members.aol.com/
jaronmink/tb2.htm]
Medical Library of the American Medical Association [AMA] [http://www.medem.com/search/
article_display.cfm?path=n:andmstr=/ZZZH7LZK1AC.htmlandsoc=AMAandsrch_typ=NAV_SERCH] – Good
introduction to TB and symtoms in children
MEDLINEplus Tuberculosis [http://www.nlm.nih.gov/medlineplus/tuberculosis.html] – The world’s largest
medical library, the National Library of Medicine at the National Institutes of Health
Merck Manual Home Edition [http://www.merck.com/pubs/mmanual_home/sec17/181.htm] – Diagnosis,
treatment and prevention
MMWR [USA] - Disease trends [http://www.cdc.gov/mmwr/distrnds.html]
New Jersey Medical School Global Tuberculosis Institute [http://www.umdnj.edu/globaltb/home.htm]
Questions and Answers about Tuberculosis [http://www.cdc.gov/tb] – This material discusses TB transmission,
differentiates between latent TB infection and active TB disease, and describes how multidrug-resistant TB develops
[http://www.cdc.gov/nchstp/tb/faqs/pdfs/qa.pdf]
Sanger Center [http://www.sanger.ac.uk/Projects/M_tuberculosis/] – Sequence and annotation of H37Rv,
[laboratory strain]
Self-Study Modules on Tuberculosis: Modules 6-9 [Module 6: Contact Investigations for Tuberculosis] [www.cdc.gov/
nchstp/tb/pubs/ssmodules/module6/ss6contents.htm] – This instructional packet [and web-based course] includes
a series of four print-based modules addressing TB contact investigation, case management, and confidentiality.
Module 6 focuses on contact investigations. [http://www.cdc.gov/nchstp/tb/pubs/ssmodules/pdfs/6.pdf]
Shelters and TB: What Staff Need to Know [http://www.nationaltbcenter.edu] – This videotape and guide are
designed for shelter staff about how to prevent the spread of TB. This video describes what TB is, how it is spread,
what to do when staff suspects someone with TB, how to develop and implement a TB infection control policy, and
how shelters and health departments can work together to create a healthy and safe environment for staff and
clients
Stanford Center for Tuberculosis Research [http://www.stanford.edu/group/molepi/index.html] – Summary of
research, list of publications, and information about international tuberculosis research
Stop TB [http://www.stoptb.org/] – A global movement to accelerate social and political action to stop the
unnecessary spread of tuberculosis around the world
StopTB Partnership [http://www.stoptb.org]
Target Tuberculosis [http://www.targettuberculosis.org.uk] – A UK charity targeting the causes and effects of
tuberculosis overseas
TB - General Information [fact sheet] [http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250010.htm] – This
tuberculosis fact sheet provides basic information about tuberculosis for patients and the general public. [http://
www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250010.pdf]
TB Alert [http://www.tbalert.org/] – A charity designed to increase awareness of tuberculosis and provide resources
for service work and research for tuberculosis in developing countries
TB in cattle - Department for Environment, Food and Rural Affairs [http://www.defra.gov.uk/animalh/tb/
index.htm]
TB in Homeless Shelters: Reducing the Risk through Ventilation, Filters, and UV [http://www.nationaltbcenter.edu]
– This guideline provides directors and facility managers of homeless shelters and other shelter workers with
information on reducing the risk of TB transmission through ventilation, filters, and use of ultraviolet germicidal
irradiation. [http://www.nationaltbcenter.edu/catalogue/downloads/tbhomelessshelters.pdf]
The Acid Fast Club [http://www.nibsc.ac.uk/afc/] – Provides opportunities for people doing research on the
pathology and bacteriology of tuberculosis to meet and discuss their work
The British Lung Foundation [http://www.britishlungfoundation.org/] – The only charity in the UK that funds
research into the prevention, diagnosis, treatment and cure of all lung diseases
The Immunisation website [http://www.immunisation.org.uk/article.php?id=43] – It contains information on
immunisation and vaccines, and is published by the Department of Health and for the NHS
The Institute of Genome Research [TIGR] [http://www.tigr.org/tigr-scripts/CMR2GenomePage3.spl?database=gmt]
– Sequence and annotation of CDC1551, a clinical isolate from Kentucky/Tennessee region
974 Tuberculosis
The International Union Against Tuberculosis and Lung Disease [http://www.iuatld.org/] – A non-profit, non-
governmental voluntary organisation founded in 1920. Its members, organisations and individuals throughout the
world are dedicated to the prevention and control of tuberculosis and lung disease, to disseminating information
about the hazards of smoking and to the promotion of overall community health
The Public Health Research Institute [PHRI] Tuberculosis Center [http://www.phri.org/programs/
program_tbcenter.asp]
Think TB [http://www.cdc.gov/nchstp/tb/pubs/Posters/ThinkTB.htm] – This poster, available in English and
Spanish, lists the symptoms of TB. [http://www.cdc.gov/nchstp/tb/pubs/Posters/images/NTEngPage.pdf]
TubercuList World-Wide Web Server [http://genolist.pasteur.fr/TubercuList/] – Provided by Institut Pasteur
Tuberculosis Control – INDIA [http://www.tbcindia.org/]
Tuberculosis Education and the Congregate Setting Contact Investigation: A Resource for the Public Health Worker
[http://www.umdnj.edu/ntbcweb/tbsplash.html] – This resource was developed for use by public health workers
who provide TB education in congregate setting contact investigations. In addition to explaining how to effectively
plan and conduct a successful TB education session, it contains: [1] a PowerPoint presentation on the basics of TB; [2]
a list of TB-related terms, defined appropriately for lay audiences; [3] frequently-asked-questions [FAQ] sheet specific
to contact investigations; [4] a pull-out TB fact sheet; and [5] an evaluation to assess the effectiveness of the TB
education session. [http://www.umdnj.edu/ntbcweb/docs/congregate/CongregateSetting.pdf]
Tuberculosis- Get the Facts! [http://www.cdc.gov/nchstp/tb/pubs/pamphlets/getthefacts_eng.htm] – This
pamphlet, in English and Spanish, provides basic facts about TB transmission, infection, and the tuberculin skin test
for patients and the general public. [http://www.cdc.gov/nchstp/tb/pubs/pamphlets/TBgtfctsEng.pdf]
Tuberculosis Contact Investigations in Congregate Settings: A Resource for Evaluation [http://www.umdnj.edu/
ntbcweb/tbcontact.htm] – This resource is designed for use in the evaluation of tuberculosis [TB] contact investigations
in congregate settings. It provides explanatory text and tools for assessing health care worker performance and
skills as well as programmatic outcomes of contact investigations in congregate settings. [http://www.umdnj.edu/
ntbcweb/docs/Contact%20Investigations.pdf]
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WHO Global Tuberculosis Control Report [http://www.who.int/tb/publications/global_report/]
WHO Regional Office for Europe centralized information system for infectious diseases [CISID] [http://
www.data.euro.who.int/cisid/]
World Health Organization [WHO] Tuberculosis Site [http://www.who.int/gtb/index.htm] – An international
overview forTB detection and treatment
World Health Organization Tuberculosis - Stop TB Department [http://www.who.int/tb/en/], World Health
Organization Health topics – Tuberculosis [http://www.who.int/topics/tuberculosis/en/]
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American Journal of Respiratory and Critical Care Medicine [http://ajrccm.atsjournals.org], American Thoracic
Society – Official publication; contains abstracts and some full text articles for free
Annals of Medicine [http://www.annals.org/]
Annual Review of Microbiology [http://arjournals.annualreviews.org/loi/micro?cookieSet=1]
Antibiotics and Chemotherapy [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=showproductsand
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BMC Pulmonary Medicine [Electronic Resource] [http://www.biomedcentral.com/bmcpulmmed]
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British Journal of Clinical Pharmacology [http://www.bjcp-journal.com/]
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Indian Journal of Medical Sciences [http://www.indianjmedsci.org/]
Indian Journal of Pathology and Microbiology [http://www.iapm.net/journal.htm]
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International Journal of Clinical Pharmacology and Therapeutics [http://www.clinnephrol.com/]
International Journal of Clinical Pharmacology and Therapeutics [http://www.clinnephrol.com/index.php?id=93]
International Journal of Clinical Practice [http://www.blackwellpublishing.com/ijcp_enhanced/]
International Journal of Leprosy and Other Mycobacterial Diseases: Official Organ of the International Leprosy
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International Journal of Medical Microbiology [http://www.sciencedirect.com/science/journal/14384221]
International Journal of Tuberculosis and Lung Disease [http://www.ingenta.com/journals/browse/iuatld/ijtld]
Irish Journal of Medical Science [http://www.ijms.ie/]
JAMA: the Journal of the American Medical Association. [http://jama.ama-assn.org/]
Journal of Acquired Immune Deficiency Syndromes [http://www.jaids.com/]

Journal of Applied Microbiology [http://www.ingenta.com/journals/browse/bsc/jam]
Journal of the Association of Physicians of India [http://www.JAPI.org]
Journal of Clinical Microbiology [http://www.wt-group.com/jcm2008.html]
Journal of HIV Therapy [http://www.ccspublishing.com/j_aids.htm]
Journal of Infectious Diseases [http://ucp.uchicago.edu/JID/home.html]
Journal of Medical Microbiology [http://jmm.sgmjournals.org/]
Journal of Postgraduate Medicine [www.jpgmonline.com/]
Journal of the Indian Medical Association [http://www.jimaonline.org.in]
Journal of the Royal Society of Medicine [http://www.jrsm.org/]
Journal of Thoracic Imaging [http://www.thoracicimaging.com/]
Lancet Infectious Diseases [http://www.thelancet.com/journals/laninf ]
Magnetic Resonance Imaging Clinics of North America. [http://www.mri.theclinics.com]
Medical Microbiology and Immunology [http://www.springer.com/journal/430]
Microbial Drug Resistance [Larchmont, N. Y.] [www.liebertpub.com/publication.aspx?pub_id=44]
Microbial Pathogenesis [http://www.elsevier.com/wps/product/cws_home/622915]
Microbiological Research [http://www.sciencedirect.com/science/journal/09445013]
Minerva Medica [http://www.minervamedica.it/journals2.t]
MMWR. Morbidity and Mortality Weekly Report [http://www.cdc.gov/mmwr/]
MMWR. Recommendations and Reports [http://www.cdc.gov/mmwr/mmwr_rr.html]
MMWR. Surveillance Summaries: Morbidity and Mortality Weekly Report. Surveillance Summaries/CDC
[www.cdc.gov/mmwr/mmwr_ss.html]
Molecular Microbiology [http://molmic35.biol.rug.nl/]
Morbidity and Mortality Weekly Report [http://www.cdc.gov/mmwr/]
Nature Medicine [http://www.nature.com/nm/]
Nature Reviews Drug Discovery [www.nature.com/nrd/]
Nature Reviews Microbiology [www.nature.com/nrmicro/]
Nigerian Journal of Medicine: Journal of the National Association of Resident Doctors of Nigeria [http://
www.nigerjmed.com/]
Nippon Rinsho. Japanese Journal of Clinical Medicine [http://www.nippon-rinsho.co.jp/]
Paediatric Respiratory Reviews [http://www.elsevier.com/wps/product/cws_home/623066]
Papua and New Guinea Medical Journal [http://www.pngimr.org.pg/png_medical_journals.htm]
Pharmacology and Therapeutics [http://www.elsevier.com/locate/pharmthera]
978 Tuberculosis
PLoS Medicine [http://medicine.plosjournals.org]

Postgraduate Medical Journal [http://pmj.bmj.com/]
Postgraduate Medicine [http://www.postgradmed.com/journal.htm]
Preventive Medicine [http://www.elsevier.com/locate/issn/0091-7435]
Proceedings of the American Thoracic Society [http://www.thoracic.org/publications/pats/pats.asp]
Pulmonary Pharmacology and Therapeutics [http://www.elsevier.com/wps/product/cws_home/622936]
QJM: Monthly Journal of the Association of Physicians [http://qjmed.oxfordjournals.org/]
Respiratory Care [http://www.rcjournal.com/]
Respiratory Medicine [http://intl.elsevierhealth.com/journals/rmed/]
Saudi Medical Journal [http://www.smj.org.sa/]
Singapore Medical Journal [http://smj.sma.org.sg/smjcurrent.html]
South African Medical Journal [http://www.ajol.info/journal_index.php?jid=76]
Southern Medical Journal [http://www.sma.org/smj/]
The American Journal of Medicine [http://www.amjmed.com/]
The Ceylon Medical Journal [http://www.infolanka.com/CMJhome/]
The European Respiratory Journal: Official Journal of the European Society For Clinical Respiratory Physiology
[http://erj.ersjournals.com/]
The Indian Journal of Chest Diseases and Allied Sciences [http://medind.nic.in/iae/iaem.shtml]
The Indian Journal of Medical Research [http://www.icmr.nic.in/ijmr/ijmr.htm]
The International Journal of Tuberculosis and Lung Disease: the Official Journal of the International Union Against
Tuberculosis and Lung Disease [http://www.iuatld.org/full_picture/ en/educ_materials/ijtld/ijtld.phtml]
The Journal of Antimicrobial Chemotherapy [http://jac.oxfordjournals.org/]
The Journal of Clinical Investigation [http://www.jci.org/contents-by-date.0.shtml]
The Journal of Experimental Medicine [http://www.jem.org/]
The Journal of General and Applied Microbiology [http://www.iam.u-tokyo.ac.jp/JGAM/general.htm]
The Journal of International Medical Research [http://www.jimronline.net/]
The Journal of Laboratory and Clinical Medicine [http://www.elsevier.com/wps/product/cws_home/623309]
The Journal of Pharmacology and Experimental Therapeutics [http://jpet.aspetjournals.org/]
The Journal of the Association of Physicians of India [http://www.japi.org/previous_issue.asp]
The Medical Clinics of North America [http://www.medical.theclinics.com/]
The Lancet [http://www.thelancet.com/]
The Medical Journal of Australia [http://www.mja.com.au/]
The National Medical Journal of India [http://www.nmji.in/the%20Journal/the_journal.htm]
The New England Journal of Medicine [http://www.nejm.org/JHome.htm]

The New Zealand Medical Journal [http://www.nzma.org.nz/journal/]
The Nigerian Postgraduate Medical Journal [http://www.galenicom.com/ca/medline/journal/ 1117-1936/]
The Practitioner [http://www.practitioner.com]
The West Indian Medical Journal [http://www.mona.uwi.edu/fms/wimj/]
The Yale Journal of Biology and Medicine [http://www.med.yale.edu/yjbm/]
Thorax [http://thorax.bmj.com/]
Transactions of the Royal Society of Tropical Medicine and Hygiene [http://www.rstmh.org/]
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3. Internet World Stats. Available URL: http://www. internet-
content may be of permanent-unchanging, permanent-
worldstats.com/stats.htm. Accessed on October 4, 2008.
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be aware of this possibility and should attempt further AIDS. Indian J Med Res 2005;121: 611-9.
6. Jain NC. Some important medical resources available on the
refined search to locate the URL if the listed link does
Internet. Curr Sci 2003;84:1170-1.
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980 Tuberculosis
International Standards for

Tuberculosis Care (ISTC)
67
Reproduced with kind permission of Dr PC Hopewell from URL://http://www.who.int/tb/publications/2006/istc_report.pdf. Accessed on
October 20, 2008
International Standards for Tuberculosis Care [ISTC] 981
982 Tuberculosis
984 Tuberculosis
986 Tuberculosis
988 Tuberculosis
990 Tuberculosis
992 Tuberculosis
994 Tuberculosis
996 Tuberculosis
998 Tuberculosis
1000 Tuberculosis
1002 Tuberculosis
1004 Tuberculosis
1006 Tuberculosis
1008 Tuberculosis
1010 Tuberculosis
1012 Tuberculosis
1014 Tuberculosis
1016 Tuberculosis
1018 Tuberculosis
1020 Tuberculosis
1022 Tuberculosis
1024 Tuberculosis
1026 Tuberculosis
1028 Tuberculosis
1030 Tuberculosis
1032 Tuberculosis
1034 Tuberculosis
1036 Tuberculosis
1038 Tuberculosis
Index
Note: “T” indicates table. For example, “T21.1” would be Table 1 in chapter 21
A pathology 88 Adrenocortical reserve in tuberculosis

treatment effect of malnutrition 554
Abdominal tuberculosis antituberculosis treatment 290 effect of rifampicin on corticosteroids
anal tuberculosis 281 surgery 290 554
bile duct tuberculosis 295 tuberculosis of appendix 281 estimation of 554-558
classification 274, T19.1 tuberculosis of mesentery and its in HIV-TB co-infection 558-559
diagnosis contents 276 Amikacin 737, 760, T51.2A, T51.2B, T52.2
ADA estimation 286,288 tuberculosis of small bowel and colon Antiretroviral drugs 579-583
ascitic fluid examination 286, 288 clinical features 278-279, T19.3, co-administration of HAART and
barium studies 283 T19.4 antituberculosis treatment 582-
colonoscopy 289 diffuse colitis 278 583, T40.7
computed tomography, and hypertrophic 277 highly active antiretroviral therapy
285-287 pathology 84-87, 277-278 [HAART] 579-583
fine needle aspiration cytology 289 sclerotic 278 non-nucleoside reverse transcriptase
interferon-gamma estimation 288 ulcerative 277 inhibitors [NNRTIs] 580-581,
inverted umbrella sign ulcerohypertrophic 278 T40.5
[Fleischner’s sign] 283 Acetylator status 788 efavirenz [EFV] 580-581, T40.5
laparoscopy 289 Acid-fast bacilli [AFB], demonstration nevirapine [NVP] 580-581, T40.5
peritoneal biopsy 289 by staining methods 162-164 nucleoside reverse transcriptase
polymerase chain reaction 288 Acute lung injury [ALI] in tuberculosis inhibitors [NRTIs] 580-581,
positron emission tomography after initiation of antituberculosis T40.4
288 treatment 537 lamivudine [3TC] 580
scintigraphy 288 definition 532 stavudine [d4T] 580
serodiagnosis 288 diagnosis 538 zidovudine [ZDV] 589
Stierlin’s sign 284 imaging findings 539 nucleotide reverse transcriptase
string sign 284 in cavitary pulmonary tuberculosis inhibitors [NtRTIs] 583-584,
ultrasonography 285 537 T40.7
duodenal tuberculosis 280-281 in miliary tuberculosis 535 protease inhibitors [PIs]
gall bladder tuberculosis 297 in tuberculosis pneumonia 535-536 amprenavir 583, T40.7
gastric tuberculosis 280 incidence 535 atazanavir 583, T40.7
gastrointestinal tuberculosis management fosamprenavir 583, T40.7
epidemiology 276-277 antituberculosis treatment 539 indinavir 583, T40.7
pathogenesis 276 corticosteroids 539-540 lopinavir 582-583, T40.7
hepatobiliary tuberculosis 296, T20.4 mechanical ventilation 539 nelfinavir 583, T40.7
in children oxygen therapy 539 ritonavir 582-583, T40.7
clinical manifestations 617 prognosis 540 saquinavir 582-583, T40.7
role of surgery 617-618 pathogenesis 532-534 therapy for individuals co-infected
in HIV/AIDS 282 predisposing factors 535 with HIV and tuberculosis 581-
oesophageal tuberculosis 279-280 Addison’s disease 553-554 582, T40.6, T40.7
pancreatic tuberculosis 281 Adenosine deaminase, estimation of rifabutin based regimens 582-583,
pathology 85-90 in ascitic fluid 171, 286 T40.7
peritoneal tuberculosis in cerebrospinal fluid 310 rifampicin based regimens 582-583,
acute 276 in pericardial fluid 334 T40.7
chronic 276 in pleural fluid 171, 250, 252-253, Antituberculosis drugs
clinical features 275-276, T19.2 T17.1 adverse drug reactions, due to 761-773
epidemiology 275 Adjuvant BCG treatment of urinary T52.3
pathogenesis 275 bladder cancer, and arthritis 379 monitoring 742-743
1042 Tuberculosis
reintroduction following resolu- for extra-pulmonary tuberculosis Calmette, Albert 10

tion of 741-742 Candidate genes in tuberculosis 137-138,
cutaneous reactions 762, T52.4 for pulmonary tuberculosis 740- T8.5
hepatotoxicity 791-792 741 Capreomycin 696, 737, 759-760, T49.1,
capreomycin 760, T52.2 of less than six months 740 T51.2A, T51.2B, T52.2
resistance, and tlyA gene 696, terminology of 740 Case definitions
T49.1 streptomycin 691-692, T49.1, T52.2 for MDR-TB 698, T49.5
classification of 737, T51.2A, T51.2B resistance and rpsL gene 691 WHO recommended, for tuberculosis
contraception and 446-447 resistance and rrs gene 691 819, T56.2
current recommendations for also see under individual drugs Categorization of patients under RNTCP
standard regimens Annual risk of infection [ARI] 22-24, 896, T63.1, T63.5A
continuation phase 736-737 30-31, 43 Cavernostomy 797
intensive phase 735-736 Assman foci 81 Choroidal tubercles 420, 423, 496
development of new drugs 757-759 Atypical mycobacteria Choroidal tuberculosis 423-425
dosages 759-760, T52.2 see under “Nontuberculous myco- Chronic meningitis
ethambutol 692-693, 760, T49.1, T52.2 bacteria” aetiology 315
resistance, and arabinosyl Azithromycin 737, T51.2A definition 315
transferase genes 693 clinical evaluation 315-316
fixed-dose combinations 743-744 B diagnostic studies
cutaneous reaction, protocol for neuroimaging studies 316
BCG test 182 meningeal biopsy 316-317
reintroduction after 762, T52.4
BCG vaccination management 317
fluoroquinolones 693-694, 760, T49.1,
history of 918-919 Ciprofloxacin
T52.2
malnutrition, and 649 see under “Fluoroquinolones”
hepatotoxicity, and
skin lesions, due to 392, T25.2 Clarithromycin 737, T51.2A
see under “Hepatotoxicity due to
Bed rest therapy 10 Clofazimine 737, T51.2A
antituberculosis treatment”
Bhowali, King Edward Sanatorium 12 Compound palmar ganglion 370
intermittent treatment
Blood groups, and susceptibility to Computed tomography in
scientific basis of 737-738
tuberculosis 127 abdominal tuberculosis 285-287
short-course chemotherapy
Bone and joint tuberculois breast tuberculosis 437
regimens 739-740
see under “Skeletal tuberculosis” chronic meningitis 316
standard regimens 738-739
Breast tuberculosis female genital tuberculosis 458
isoniazid 688-691, 777-779, 783-786,
classification of 436, T29.2 genitourinary tuberculosis 471
T49.1, T52.2 intracranial tuberculomas 318
clinical features 435-436
resistance, and miliary tuberculosis 501
differentiation from carcinoma
ahpC gene 688-691 pulmonary tuberculosis 201-207
breast 438
kasA gene 689-691 radiculomyelitis 324
epidemiology 434
katG gene 688-691 single, small, enhancing lesions [SSEL]
investigations 436-437
oxyR gene 689-691 320
computed tomography 437
moxifloxacin spinal tuberculosis 346-348
fine needle aspiration cytology 437
for treatment of latent MDR-TB tuberculosis meningitis 308
magnetic resonance imaging 438
infection 779 Congenital tuberculosis 79, 218, 296,
mammography 436
resistance, and gyrA gene 694 598-599
open biopsy 438
newer drugs 705, T49.10 Conjunctival tuberculosis 421-422
ultrasonography 437
ocular toxicity, and 429 Corneal tuberculosis 422
mode of infection 434-435
pyrazinamide 693, T49.1, T52.2 Consumption 11
treatment 438
resistance, and pncA gene 693 Crohn’s disease, differentiation from
Broadbent’s sign 333
rifabutin tuberculosis 88, T5.8
Bronchoalveolar lavage
resistance 688 Cryptic miliary tuberculosis 497
in lower lung field tuberculosis 230
rifampicin 685-688, 760, 777-779, 783- Culture filtrate protein-10 [CFP-10] 189-
in miliary tuberculosis 505-508
786 T49.1, T52.2 192, 606-607
in pulmonary tuberculosis 222-223
drug interactions 743, 764, T52.5 Cutaneous tuberculosis
Broncholith 520
reasons to protect 745 BCG vaccination, skin lesions due to
Bronchopleural fistula 522, 805-806
resistance, and rpoB gene 685-688 400
short-course chemotherapy regimens clinical features
basis of 751-752
C
acute miliary tuberculosis of the
evolution of 739-740 Cavernolith 520 skin 385
Index 1043
apple jelly nodules 385, 421 systematic monitoring and standardized definitions 697-698,
lupus vulgaris 385-387, 421 accountability 818 T49.5
scrofuloderma 387-388 global expansion, current status 58, Drug susceptibility testing
tuberculosis chancre 385 60, 901 direct methods 169
tuberculosis cutis orificialis 388-389 HIV co-infection, and 820-822 E-test 170
tuberculosis gumma 388 results of 818-820 indirect methods
tuberculosis verrucosa cutis 387 DOTS-Plus Strategy 699-700, 728-730 absolute concentration method
diagnosis 391-392 Drug induced hepatotoxicity [MIC method] 170
epidemiology 384 see under “Hepatotoxicity, due to MBBacT system 170
in immunocompromised hosts 391 antituberculosis treatment” proportion method 170
treatment 393 Drug induced liver injury resistance ratio method 170
tuberculids see under “Hepatotoxicity, due to microscopic-observation drug-
criteria for diagnosis 389 antituberculosis treatment” susceptibility assay [MODS]
erythema induratum 390 Drug-resistant tuberculosis 170, 311
erythema nodosum 390 acquired resistance
lichen scrofulosorum 389 see under “resistance among E
multiple episodes of Sweet’s
previously treated cases” E-test 170
syndrome 391
drug efflux pumps, and develop- Early secreted antigen-6 [ESAT-6] 109,
papulonecrotic tuberculids 390
ment of 695-696 188-191, 196, 606-607
Cycloserine 737, 760, T51.2A, T51.2B,
drugs used in the treatment of 700, Echocardiography 335
T52.2
T49.6 Empyema thoracis 806-807
global experience in the management Endobronchial tuberculosis
D of 702-704, T49.9A bronchography 238
Direct repeats [DR] 661-662, 683 global prevalence 715-721 bronchoscopic appearances 236-238
Directly observed therapy management clinical course 234
adherence 827-829 DOTS-Plus strategy 699-700 epidemiology 232
basic concept 827 monitoring response to treatment in HIV infection 238
choice of method 834-835 702 in lower lung field tuberculosis 238
compliance 827-829 nutritional enhancement 705 Indian experience 239
concordance 827-830 principles 697-699 investigations 234-238
factors improving 829, T 57.1 regimens for drug-resistant microscopic appearance 233
interventions for improving 830, tuberculosis, other than MDR- NTM, and 239
T57.2 TB 701, T49.8A pathophysiology
controversies surrounding 835 regimens for MDR-TB 701, T49.8A macroscopic appearance 233
future 835-836 treatment of latent MDR-TB mechanisms of endobronchial
history of 830-832 infection 706 infection 232-233
hold chain 831 molecular basis of development of treatment 239-240
observation of treatment 833-834 resistance to 685-696 Endometrial tuberculosis 451
Disseminated tuberculosis capreomycin 696, T49.1 Enterobacterial repetitive intergenic
see under “miliary tuberculosis” ethambutol 692-693, T49.1 consensus [ERIC] sequences 683
DOTS Strategy746, 876-877 fluoroquinolones 693-694, T49.1 Epidemiology
and improving the overall quality of drug-resistant tuberculosis
isoniazid 688-691, T49.1
health services 867 in India 721-728
pyrazinamide 693, T49.1
and MDR-TB 820 MDR-TB 715-720, 725-728
rifampicin 685-688, T49.1
and XDR-TB 820 XDR-TB 717-721
rifabutin 688 prevalence in newly diagnosed
at work places 861-862 streptomycin 691-692, T49.1
cost-effectiveness 867 cases 721-724
molecular epidemiology 682-684 prevalence in previously treated
fundamental principles
potential causes 696, T49.2, T49.3 cases 725
adequate supply of good quality
primary resistance epidemic prediction
drugs 818
see under “resistance among new see under “mathematical
diagnosis by sputum microscopy
815-816 cases” modelling”
political will 814-815 prognostic markers 704, T49.9B epidemiological load
short-course chemotherapy given resistance among new cases 714-715 evidence from animal models
under direct observation 816- resistance among previously treated 18-19
818 cases 714-715 force of infection 22
1044 Tuberculosis
global scenario Female genital tuberculosis retrograde urethrography 471

current status 58, T4.1A, T4.1B clinical presentation 452-453 ultrasonography 471
historical trajectory 57-58 epidemiology 449-450 urine examination 467
global targets 63-64 pathogenesis voiding cystourethrogram 470
goals of intervention 25-28 computed tomography 458 epidemiology 463
HIV co-infection, and 60-62 diagnosis 453-459 in children
India endometrial biopsy 454 clinical presentation 614-615
annual risk of infection [ARI] endometrial tuberculosis 451 role of surgery 615
30-31, 43 fallopian tube tuberculosis 450 in females
current status 43, 894 hysterosalpingography 455-456 see under “Female genital tuber-
distribution area-wise 33-34 hysteroscopy 456-458 culosis”
distribution as per socio-economic laparoscopy 456-458 in males
criteria 37-38 magnetic resonance imaging 459 tuberculosis of the epididymis
epidemiological trends 40-44 mycobacterial isolation 454-455 466-467
incidence, age-wise 34-36 ovarian tuberculosis 451-452 tuberculosis of the kidney 465-466
mathematical modelling 44 polymerase chain reaction 459 tuberculosis of the penis 467
prevalence, age-wise 34-36 serodiagnosis 458-459 tuberculosis of the prostate 467
prevalence, gender-wise 36-37 tuberculosis of Bartholin gland 452 tuberculosis of the testis 466
prevalence of pulmonary tuber- tuberculosis of the cervix 452 tuberculosis of the urethra 467
culosis 31-38 tuberculosis of the vulva and pathogenesis 463-465
Indian studies vagina 452 tuberculosis of the ureter 466
Madanapalle study 27 ultrasonography 458 tuberculosis of the urinary bladder
National Sample Survey 16-17, 28 pregnancy following treatment, of 460 466
in vitro fertilization 460 treatment
New Delhi study 30
tuboplasty 460 antituberculosis treatment 471-472
Studies in Bengaluru area 29
treatment 459-460 surgery 472-477, T32.3
Tuberculosis Prevention Trial 29-
Fleischner’s sign 283 Ghon’s complex
30
Fluorescent amplified fragment length see under “primay complex”
indices and definitions
polymorphism [FAFLP] 683 Giant cells
annual risk of infection [ARI]
Fluoroquinolones 693-694, 737, 760 T49.1, foreign body
22-24
T51.2A, T51.2B, T52.2 Langhans’ 67, 69, 76, 83, 95
death 21-23
Friedrich’s sign 332 Global plan to stop TB 63,64
incidence of disease 21-23
Granuloma 67-68, 116-117
incidence of infection 21-23
G also see under “granulomatous
prevalence of disease 21-23 inflammation”
prevalence of infection 21-23 Gaenslen’s test 368 Granulomatous hepatitis
issues in measurement Gatifloxacin aetiology 294-295, T20.1
active case detection 55-56 see under “Fluoroquinolones” clinical presentation 295
case notification 55 Genetic susceptibility to tuberculosis differential diagnosis 296-298
geographical heterogeneity 56 ABO blood groups, and 127 idiopathic 301
mathematical modelling 44,56-57 racial differences 127 laboratory abnormalities 295-296
passive case detection 55 twin studies 127 pathological types 295
progress of infection 19 Genitourinary tuberculosis prognosis 302
tuberculosis epidemic, course of 19-21 clinical presentation 465-467, T32.2 treatment 301-303
Epituberculosis 79, 218 diagnosis Granulomatous inflammation 68-70
Erythema nodosum 390 arteriography 470 Guérin, Camille 10
Ethambutol 692-693, 737, 760, T49.1, computed tomography 471
T51.2A, T51.2B, T52.2 cystoscopy 471 H
Ethionamide 737, 760, T51.2A, T51.2B intravenous urography 469
Extensively drug-resistant tuberculosis magnetic resonance urography 470 Haematological manifestations
see under “XDR-TB” microbiological methods 468 AIDS, and 548-549
percutaneous antegrade anaemia 542-544
F pyelography 470 bone marrow changes 546-547, T37.3
plain radiograph 468-469 coagulation abnormalities 545
Faber’s test 368 polymerase chain reaction 468 drug-induced 547-548
Fall and rise phenomenon 744 retrograde pyelography 470 leucocyte changes 544
Index 1045
NTM infection, and 547 N-acetyl transferase and commercially available assays,
pancytopenia 545 cytochrome P450 2E1 788 characteristics
platelet abnormalities 543-545 sex 787 QuantiFERON®-TB Gold® 190
Health care workers and tuberculosis type of tuberculosis 789 T-SPOT.TB® test 190
controlling 637-641, T45.2 underlying chronic liver disease guidelines for use 192
early diagnosis and treatment 637- 788-789 implications for resource-limited
639 Hippocratic succusion 220 settings 195
preventive strategies 639-641 HIV/AIDS International standards for tuberculosis
factors influencing nosocomial and complications 919-920 care [ISTC] 980-1038
transmission 635-637, T45.1 and tuberculosis Intracranial tuberculosis
HEPA filters and individual see under “Tuberculosis and HIV diagnosis 318
protection 640- 641 infection” epidemiology 317-318
IGRAs and detection of LTBI 635 Hold chain 831 imaging studies 318
infection control measures 639-641 Home sanatorium study 13 management 318,320
occupational hazard 634 Huebschmann foci 78 magentic resonance spectroscopy 319
PAPR filters and individual Human immunodeficiency virus pathology 317
protection 640-641 infection
prognosis and outcome 322-323
recognition of transmission imaging 213-214
sequelae 323
interferon-gamma release assays Human leucocyte antigen
Iron metabolism 542-543, 548
635 biological functions 131
IS6110 659-662, 683-685, 697
tuberculin skin test, and 634-635 disease associations 131-132
Isoniazid 688-691, 737, 760, 777-779,
risk assessment 637 Hysterosalpingography 455-456
783-786, T49.1, T51.2A, T51.2B,
risk of infection 635 T52.2
treatment of latent tuberculosis I
infection 642
ultra-violet [UV] radiation, use of 641 Immunogenetics of tuberculosis J
Health education 747 family studies 135
Johne’s disease 107
Hepatotoxicity, due to antituberculosis HLA class I association studies
also see under “Mycobacterium avium
treatment 133-135, T8.3
sub-species paratuberculosis”
clinical course 789-790 HLA-DR2 in mycobacterial diseases
due to isoniazid and rifampicin 784- 135-137
786 non-HLA genes 137 K
due to isoniazid, rifampicin and population studies Kanamycin 737, 760, T51.2A, T51.2B,
pyrazinamide 786 HLA class I association studies T52.2B
due to treatment of latent tuber- 132-133, T8.2 Kasauli , Lady Linlithgow Sanatorium 12
culosis infection 786-787 Immune reconstitution inflammatory Kinyoun’s method 162
effect of antituberculosis drugs on syndrome [IRIS] 406-407, 497, 583-584 Koch’s lymph 10
the liver 783-784 also see under “IRIS” Koch’s phenomenon 105
liver transplantation, and 792 Immune response genes 127-128 Koch, Robert 9-10
management Innate immunity Koenig’s syndrome 85
diagnosis 790, T54.2 interferon-gamma 112 Kussmaul’s sign 333
guidelines for monitoring 790-791 interleukin-1 beta 112
recommendations for re-intro- interleukin-4 112 L
duction of treatment 791-792 interleukin-6 111
treatment of tuberculosis in interleukin-10 112 Laboratory diagnosis of tuberculosis
patients who developed interleukin-12 112 animal inoculation 167
hepatotoxicity 791 interleukin-18 112 collection and transportation of
recurrence of 792 transforming growth factor-beta 113 clinical specimens
risk factors for development tumour necrosis factor-alpha 110-111 bronchoscopic secretions 161
acetylator status 788 Interferon-gamma, estimation of cerebrospinal fluid 161
age 787 in ascitic fluid 171, 288 serous fluids 161
ethnic and racial variation 787 in pericardial fluid 334 sputum 160-161
genetic factors 787 in pleural fluid 171, 253 tissue 161-162
glutathione S-transferase 788 Interferon-gamma release assays urine 161
hepatitis viruses 789 and detection of LTBI 191-192, 635, direct demonstration of mycobacteria
HIV 789 776-777 in extra-pulmonary specimens
malnutrition 789 biology 188 163-164
1046 Tuberculosis
fluorescent staining 163 Lower lung field tuberculosis gas exchange, and 502-504
Kinyoun’s method 162 bronchoscopy, and 229-230 imaging findinsgs
Petroff’s method 163 clinical features 228 chest radiograph 499-500
with Gabett’s solution 162 investigations 229-230 computed tomogrpahy 501
Ziehl-Neelsen stain 164 management 230 magnetic resonance imaging 501
Genotype assays prevalence 227-228, T15.1 ultrasonography 501
GenoType Mycobacteria Assay 169 terminology of 227 immune reconstitution inflammatory
GenoType MTBDR Assay 169 Lymph node tuberculosis syndrome [IRIS] 497
immunodiagnosis 167-169 clinical features 398-399 immunological abnormalitites 505-508
in patients with HIV infection 399 in HIV infection and AIDS 497
antibody detection tests 167
epidemiology 397-398 in immunosuppressed patients 497
antigen detection 168
diagnosis laboratory findings
flow-through filter tests 168
cytopathology 403-404 haematology 498
lipoarabinomannan [LAM] in histopathology 403-404 serum biochemistry 498
urine test 168 imaging 401 miliary pattern on chest radiograph
isolation of mycobacteria by culture molecular and other methods 404 513, T34.11
BACTEC radiometric system 165 diffrential diagnosis 401 prognosis 512-514
colony characteristics 165 in children 618 pulmonary functions, and 502-504
culture characteristics 165 pathogenesis 398 rare manifestations 497
culture media 165, T10.3 treatment 405-407 treatment 511-513
mycobacteria growth indicator IRIS, and 406-407 corticosteroids, and 513
tube [MGIT] 165 Moxifloxacin
mycobacteriophage-based detection M see under “Fluoroquinolones”
tests 166 Multidrug-resistant tuberculosis
Manget, John Jacob 493
nucleic acid amplification tests case definitions 698, T49.5
Madanapalle, Union Mission
amplified Mycobacterium drugs used in the treatment of 700,
Tuberculosis Sanatorium 12
tuberculosis direct test 168 Magnetic resonance imaging in T49.6
ligase chain reaction [LCR] 168 breast tuberculosis 438 factors implicated in the causation
loop mediated isothermal chronic meningitis 316 696, T49.2
amplification [LAMP] 168 female genital tuberculosis 459 global prevalence 715-721
nucleic acid probes 168 intracranial tuberculomas 318 in the immunocompromised 696-697
polymerase chain reaction [PCR] miliary tuberculosis 501 management
168 radiculomyelitis 324 DOTS-Plus strategy 699-700
polymerase chain reaction single, small, enhancing lesions global experience in the manage-
sequencing 169 [SSEL] 320 ment of 702-704, T49.9A
rapid liquid tuberculosis culture spinal tuberculosis 346-348 immunotherpay 765-766
see under “mycobacteria growth tuberculosis meningitis 308 monitoring response to treatment
inhibitor tube” Major histocompatibility complex 702
Septi Chek Acid-fast Bacilli 165 central genes nutritional enhancement 705
see under “class III genes” principles of treatment 697-699,
Langhans Theodore 67
class I genes 128-129 755-757
Latent tuberculosis infection
class II genes 130 regimens for treatment 701,
interferon-gamma release assays
class III genes 130-131 T49.8A
[IGRAs], and detection of 191-
Major polymorphic tandem repeats surgery, for 764-765, 803-805
192, 635, 776-777
[MPTR] 683 prevalence, in India 725-728
programmatic issues, India and 779- prevention, in India’s RNTCP 729-730
Microscopic-observation drug suscepti-
782 prognostic markers 704, T49.9B
bility assay [MODS] 170, 311
regimens for treatment of 777-779, standardized definitions 697-698,
Miliary tuberculosis
T53.3 T49.5
atypical manifestations 497, T34.4
treatment in high prevalence settings bronchoalveolar lavage 505-508 treatment of latent MDR-TB infection
781 cardiopulmonary exercise testing 706, 779
treatment of latent MDR-TB infection 505 treatment outcome 728
779 clinical presentation 494-497 also see under “MDR-TB”
tuberculin skin test , and diagnosis complications 513 Musculoskeletal manifestations of
of 186-188, 776-777 cryptic miliary tuberculosis 497, T34.5 tuberculosis
Levofloxacin diagnosis 508-511 arthralgias, antituberculosis treatment
see under “Fluoroquinolones” epidemiology 493 induced 379
Index 1047
changing clincal pattern 376 Mycobacterium bovis 102-103 Mycobacterium terrae 666, 669
clinical setting for suspecting 374-376 Mycobacterium arupense 666, 670 Mycobacterium triviale 666, 669
diagnosis 379-380 Mycobacterium aubaganense 666, 670 Mycobacterium thermoresistible 666, 669
indications for synovial biopsy Mycobacterium avium intracellulare 393, Mycobacterium tuberculosis
379-380 407, 666-668 antigenic structure 104
epidemiology 374 Mycobacterium avium sub-species bacteriocins 105
imaging 379 paratuberculosis 107, 666 biochemical properties 104
nontuberculous mycobacterial Mycobacterium bohemicum 666, 670 cell wall 103
infections, and 378-379 Mycobacterium bolletti 666, 670 culture characteristics 103-104
panniculitis associated with tuber- Mycobacterium canariasense 666, 670 host immune response 124-125
culosis 377-378 Mycobacterium celatum 666, 669 morphology 102-103
Poncet’s disease 376-377 Mycobacterium conspicuum 666, 669 mycobacteriophages 105
reactive para-infectious arthritis Mycobacterium diernhoferi 666, 670 pathogenesis 105
see under “Poncet’s disease” Mycobacterium elephantis 666, 670 postgenomics efforts and 705-706
rheumatic syndromes 374, T24.2 Mycobacterium fortuitum-Mycobacterium susceptibility to physical and
chemical agents 104
treatment 380 chelonae complex 666, 669
virulence in animals 104
unusual presentations, of 378 Mycobacterium chelonae 394, 666
Mycobacterium ulcerans 106, 392, 668
Myocardial tuberculosis 339 Mycobacterium fortuitum 394, 666
Buruli ulcer disease 392
Mycobacteria Mycobacterium fortuitum, third
Mycobacterium vaccae 669, 670
biochemical properties biovariant complex 666, 670
Mycobacterium w 107, 928
arylsulphatase test 166 Mycobacterium boenickei 666, 670
Mycobacterium woliniskyi 666, 670
catalase at room temperature 166 Mycobacterium brisbanense 666, 670
Mycobacterium xenopi 666, 668
catalase at 68 oC 166 Mycobacterium houstonense 666, 670
neutral red test 166 Mycobacterium neworleansese 666, 670
niacin test 166 Mycobacterium parascrofulaceum 666, N
nicotinamidase activity 167 670 National Task Force [NTF] 639, 902, 911
nitrate reduction 166 Mycobacterium porcinum 666, 670 National Tuberculosis Institute,
peroxidase test 167 Mycobacterium genavense 666, 669 Bengaluru 13-14
pyrazinamidase activity 167 Mycobacterium goodii 666, 670 Natural resistance associated
susceptibility to p-nitrobenzoate Mycobacterium gordonae 393, 666, macropahge protein [Nramp1]
167 Mycobacterium haemophilium 393, 666, 669 see under SLC11A1
susceptibility to pyrazinamide 167 Mycobacterium heckeshornense 666, 670 Neelsen, Freidrich 71
susceptibility to TCH 167 Mycobacterium interjectum 666, 668 Nitrate reduction test 166
classification of 102, T6.1 Mycobacterium kansasii 394, 666, 668 Neurological tuberculosis
culture media Mycobacterium malmoense 666, 669 classification 304, T21.1
Dubos’ medium 164 Mycobacterium marinum 106-107, 392, role of surgery, in children 622-623
liquid media 164 666, 669 New Delhi Tuberculosis Centre 12
Loeffler serum slope 164 fish tank granuloma 392, 666 New Stop TB Strategy 63
Lowenstein-Jensen medium 164 swimming pool granuloma 392, 666, Night cries 344, 351
Middlebrook’s medium 164 Mycobacterium neoaurum 666, 669 Nonphotochromogens 103
Pawlowsky’s medium [potato Mycobacterium palustre 666, 670 Nontuberculous mycobacteria
medium] 164 Mycobacterium paratuberculosis 106, 666, classification 103, T6.2
solid media 164 668 clinical manifestations 670
Sula’s medium 164 Mycobacterium parmense 666, 670 cutaneous lesions due to 393
Sutton’s medium 164 Mycobacterium phocaicum 666, 670 diagnosis 670-674
Tarshis medium [blood medium] Mycobacterium pseudoshottsi 666, 670 culture methods 672
164 Mycobacterium scrofulaceum 393, 668, 666 histopathology 672
high performance liquid chromato- Mycobacterium septicum 666, 670 identification of isolates 672-674
graphy [HPLC], and Mycobacterium shottsi 666, 670 monitoring for toxicity 675
identification of 169 Mycobacterium simiae 666, 668 treatment 676, T48.6
saprophytic 107 Mycobacterium smegmatis 107, 666, 669, distribution in the environment
Tween 80 degradation 166 670 665-667
Tween hydrolysis 166 Mycobacterium szulgai 394, 666, 668 lymphadenitis, due to 399-401, 407,
Mycobacteria growth indicator tube Mycobacterium terrae complex 666, 669 T26.6
[MGIT] 165 Mycobacterium nonchromogenicum 666, in children 618-620
Mycobacterium abscessus 393, 666 669 prevention 676, T48.5
1048 Tuberculosis
pulmonary disease 671 People living with HIV/AIDS [PLHIV] progression 78-80
species 666, T48.1A 574, 579, 586 role of surgery in children 620-622,
causing infection in humans 666, also see under “Tuberculosis and T43.3
T48.1B HIV infection” Psoas abscess 344, 345-347
Nutrition and tuberculosis Photochromogens 103 Pyrazinamide 693, 737, 760, T49.1,
adjuvant immunotherapy 651-652 Polymorphic GC-rich sequences [PGRS] T51.2A, T51.2B, T52.2
clinical implications and interventions 683
diagnosis 649-650 Primary complex 72, 217
malnutrition and BCG vaccine 649
R
Primary tuberculosis 72-78 T5.6
cycle of hunger and disease 652-653 at rare sites Rajayakshma 7
impact of nutrition eye 74 Ranke complex 72
clinical evidence 647-648 skin 74 Rapid growers 103
evidence from animal models gastrointestinal tract 74-75 Reactivation and reinfection tuberculosis
646-647 genitourinary tract 75 clinical presentation 657-658
impact of tuberculosis on nutrition liver 74-75 distinguishing treatment failure and
648-649 head and neck 75 exogenous reinfection 661-663
isonaizid and vitamin B6 deficiency Prosector’s warts 217 molecular epidemiology 659-661
650 Prothionamide 737, 760, T51.2A, T51.2B, natural history of tuberculosis
monitoring nutritional status 652 T52.2 infection 656-657
natural history of tuberculosis in Pulmonary tuberculosis pathogenesis 658
malnourished patients 650 complications Reactive nitrogen intermediates [RNIs]
nutritional interventions in active amyloidosis 529 114
tuberculosis 650-651 aspergilloma 521-522 Reactive oxygen intermediates [ROIs]
chronic respiratory failure 527-528
113
cor-pulmonale 528
O Restriction fragment length polymor-
endobronchitis 524
phisms [RFLP] 661-662, 683
Ocular tuberculosis enteritis 525
Revised National Tuberculosis Control
choroidal tuberculosis 423-425 fungus ball 521-522
Programme [RNTCP]
conjunctival tuberculosis 421-422 haemoptysis 519
academic sector, and 910-911
corneal tuberculosis 422 in HIV-seropositive patients 523
advocacy communication for social
diagnosis 427-428 laryngitis 525
mobilization [ACSM] 905-906
eye lid tuberculosis 421 open-negative syndrome 525
post-tuberculosis bronchiectasis categorization of patients under
in HIV infected patients 427
524 RNTCP 896, T63.1, T63.5A
iritis and iridocyclitis 425
pulmonary artery hypertension DOTS expansion, and 901-902
endophthalmitis 425
528-529 drug procurement and management
panophthalmitis 425
pulmonary function changes 527 system 898-901
orbital tuberculosis 422-423
Rasmussen’s aneurysm 519-520 HIV-TB co-infection, and 906-907
primary 420
scar carcinoma 527 information, education and commu-
secondary 420
spontaneous pneumothorax 525 nication [IEC] 905-906
scleral tuberculosis 422
tracheitis 524-525 laboratory network and quality
treatment 428-429
diagnosis 220-222 assurance 902-905
tuberculosis of the lacrimal system 422
fibreoptic bronchoscopy, and 222- medical colleges, and 910-911
tuberculosis of the uveal tract 423
223 management
Oesophageal tuberculosis 279-280
differential diagnosis 223-225, T14.1 treatment of adult tuberculosis
Open-negative syndrome 525
natural history 217-219 897, T63.1
Orthotopic neobladder 473, 475-476
physical signs 220- 221 treatment of paediatric tuberculosis
Ofloxacin
cracked pot sound 220 907-908, T63.5A, T63.5B
see under “Fluoroquinolones”
Hippocratic succussion 220 performance of 902, 899-900, T63.3
myotactic irritability 220 private sector, and 908, 910
P post-tussive suction 220 quality assurance 902-905
post-primary 81-85, 218-219 research, and
Para-aminosalicylic acid 737, 760, imaging in 207-212 drug resistance surveillance 913
T51.2A, T51.2B, T52.2 symptoms 218-220 Joint Monitoring Missions 913-914
Parotid gland tuberculosis 414 primary 78-79, 81, 217-218 measuring epidemiological
Parrot’s law 72 epituberculosis 79, 218 impact 912-913
Pott’s paraplegia imaging in 201-207 priority areas 912, T63.7
see under “spinal tuberculosis” in adults 80 thrust areas 914-915
Index 1049
staff trained in 898, T63.2 osseous granular type 342 infection of bone 343
technical foundation 895-898 synovial exudative [caseous] type management
Rice bodies 369 343 antituberculosis treatment 349
Rich focus 95 synovial granular type 343 surgery, indications for 349, T23.3
Rifabutin 688, 737, T51.2A tuberculosis of the ankle joint and foot paraplegia in extension 345
Rifampicin 685-688, 737, 760, 777-779, clinical features 360 paraplegia in flexion 345
783-786 T49.1, T51.2A, T51.2B, management 361 paraplegia [Pott’s paraplegia] 344
T52.2 pathology 359-360 pathology 343-344
drug interactions 743, 764, T52.5 radiological features 361-362 radiological features 345-348
“flu syndrome” 760 tuberculosis bursitis 370 Spleen, tuberculosis of 76, 281-282
reasons to protect 745 tuberculosis of the elbow joint Sputum smear microscopy 162-163
resistance, and rpoB gene 685-688 clinical features 364 grading 163 T10.1, T10.2
Rifapentene 737, T51.2A management 364-366 Stierlin’s sign 284
Roentgen, Wilhelm Conrad 10 pathology 364 Streptomycin 691-692, 737, 760, T49.1,
Runyon classification 103 radiological features 364 T51.2A, T51.2B, T52.2
tuberculosis of the hip joint resistance and rpsL gene 691
clinical features 351-352 resistance and rrs gene 691
S String sign 284
stage of advanced arthritis 352
Salivary gland tuberculosis 414 stage of early arthritis 352 Surgery
Scotochromogens 103 stage of synovitis 351-352 for active pulmonary tuberculosis
Scrofula 7, 397 management 354-355 current status 801-802
Silicotuberculosis pathology 351 extrapleural pneumonolysis 798
clinical features 271 radiological features 352-354 phrenic nerve paralysis 798
diagnosis 271-272 pneumoperitoneum 798
tuberculosis of the knee joint
epidemiology 269-270 pneumothorax 798
clinical features 356-357
pathogenesis 270-271 preoperative work-up 802-803
management 358-359
prevention 272 the cavernostomy era 797
pathology 355
the collapse therapy era 797
radiographic findings 269 radiological features 357-358
thoracoplasty 799-801
silicosis tuberculosis of the sacroiliac joint
for complications of pulmonary
accelerated 269 clinical features 367-368
tuberculosis
acute 268-269 management 368
aspergilloma 808-809
bronchoalveolar lavage 269 pathology 367
bronchial stenosis 808
chronic 268 radiological features 368 bronchiectasis 808
complications 269 tuberculosis of the prosthetic joint 371 broncholiths 808
treatment 272 tuberculosis of the shoulder joint caused by mediastinal lymph-
Simon foci 78 clinical features 362 adenopathy 809
Single, small, enhancing brain lesions management 363-364 cold abscess of chest wall 809
on CT, and seizures pathology 362 foci of residual disease 808
aetiology 320 radiological features 362-363 for complications of previous
definition 320 tuberculosis of the spine surgery 809-810
management 321 see under “Spinal tuberculosis” haemoptysis 807-808
neuroimaging 321 tuberculosis of the wrist joint Indian experience 810-811
Skeletal tuberculosis clinical features 366 tracheal stenosis 808
at rare sites management 367 for confirmation of diagnosis of
acromioclavicular joint 368 pathology 366 tuberculosis 796
clavicle 369 radiological features 366 video-assisted thoracoscopic
ilium, ischium and ischiopubic SLC11A1 145-146, 151, 543 surgery 796-797
ramus 369 Spinal tuberculosis for MDR-TB 803-805
scapula 369 cervical spine involvement, and bronchopleural fistula, and
sternoclavicular joint 368 410-411 805-806
sternum and ribs 369 clinical features 344-345 for tuberculosis empyema 806-807
symphysis pubis 369 differential diagnosis 348 Susceptibility to tuberculosis
prognosis 343 18FDG-PET scan 371
candidate genes
types formation of cold abscess 343 interferon-gamma 150
osseous exudative [caseating] grading of paraplegia 345 interleukin-12/interleukin-23/
type 342-343 imaging diagnosis interferon-gamma pathway 150
1050 Tuberculosis
linkage studies 152-153 multidrug-resistant tuberculosis 755- hypercalcaemia 564-565

major histocompatibility complex 757, 764-766 hypothalamus involvement, and 516
152 RNTCP regimens for adult tuber- immune effector mechanisms against
mannose binding lectins 152 culosis 897, T63.1 113-114
SLC11A1 151, 543 RNTCP regimens for paediatric immunoevasion 119
vitamin D receptor 151-152 tuberculosis 907-908, T63.5A, immunomodulators in 119-121
genetic studies in human populations T63.5B immunopathogenesis 108-109
Mendelian susceptibility to myco- smear-negative pulmonary tuber- in arts and literature 10-11
bacterial disease [OMIM 209950] culosis 754-755 in the Vedas 7-8, 10
149-151 smear-positive pulmonary tuber- innate immunity 109-113
host-pathogen interplay 144 culosis 752-754 laboratory related safety issues 171
mouse models 145 therpeutic drug monitoring 766-768, non-genetic factors influencing the
adhesion molecules 148 T52.6 incidence 126-127
cellular immunity 146 WHO regimens 816, T56.1 perinatal 73-74
chemokines 147 Tuberculin skin test pituitary involvement, and 516
cytokines 146-147 administration 186-187 placental transmission of 442-443
major histocompatibility complex
adverse effects 176 primary 72-78, T5.6
150
bacille Calmette-Guerin vaccination, tobacco smoking, and 72
mouse knock-out models 146
and 177 treatment, scientific basis of 734-735
pattern recognition receptors 148
booster phenomenon 181 vitamin D deficiency, and 565-566
qualitative trait locus analysis
conversion 181 well known victims of 11-12, T2.1
148-149
dosage 175 Tuberculosis and HIV infection
SLC11A1 studies 145-146
pathogenesis 144 epidemiological uses 182 clinical presentation 576-578
population variability 143 false-positive and false-negative drug-resistant tuberculosis, and
Syndrome of inappropriate antidiuretic reactions 179 584-585
hormome secretion [SIADH] 497, 562 Heaf test 173 extensively drug-resistant tuber-
historical background 174 culosis [XDR-TB], and 585
T immunological basis 174 in children 578
in HIV-seropositive persons 179 diagnosis 578
Tabes mesenterica 86 infection with environmental epidemiology 574-576
Takayasu arteritis 339 mycobacteria, and 176-177 management of HIV-TB co-infection
T-cell subsets with an immunoregulatory interpretation 179-180 579-584
role Mantoux test 173 antituberculosis treatment 580-581
gamma-delta T-cells 117 newer tuberculins 182 BCG vaccination, and 585
natural killer T-cells 117-118 old tuberculin 171 controlling tuberculosis trans-
Treg-cells 118 reading of the test 176 mission 585
Terizidone 737, T51.2B reversion 181 highly active anti-retroviral
Thioacetazone 737, 760, T51.2A, T51.2B,
sarcoidosis, and 182 treatment [HAART],
T52.2
skin changes 175 and 579-580
Thyroid gland tuberculosis 563-564
standard tuberculin skin test, IRIS, and 583-584
Tobacco smoking and tuberculosis 72
administration of 175 prevention 585-587
Toll-like receptors, and innate immunity
Tine test 173 repsonse to treatment 582-583
110-111
tuberculins 174 Tuberculosis Association of India 12
“Tree-in-bud-appearance” 210, 234-235
Treatment of tuberculosis Tuberculosis Tuberculosis control
adjunctive corticosteroid treatment acquired T-cell mediated immune community contribution to 863
766 mechanisms 114-115 ethics
aims of 752 altered water and electrolyte adherence 954
categorization of patients under metabolism, and 562-563 application in public health 952
RNTCP 896, T63.1, T63.5A and diabetes mellitus 568 autonomy 951
DOTS, and 754 case definitions, for 819, T56.2 beneficence 951
extrapulmonary tuberculosis 763-764 CD4+ and CD8+ T-cells, and 115-116 compliance 954
history of 751 classification 66-67, T5.1 direct observation of treatment 955
in patients who developed hepatotoxi- diabetes mellitus, and 566-568 in the east 950
city 791 generalized 76-77 in the west 950
monodrug-resistant tuberculosis 755 infection, events during 109 justice 951
Index 1051
non-maleficence 951 service delivery 868 Tuberculosis in chronic renal failure

principles and tasks 950-951 successful networking 872, T61.5 clinical presentation
relationship of a patient with the The Bangladesh Rural Advance- during haemodialysis 480-482, T33.1
health care provider 954 ment Corporation 858 diagnosis 484
relationship of a patient with the private health sector, and 859, 871 following renal transplantation 482-
health care structure 956-958 progress in South-East Asia region 484, T33.2
global partnership for 854-856 856-858 magnitude of the problem 480
global tuberculosis control National parternships 858 management 484
current situation 882-885 public health and tuberculosis 948-949 antituberculosis drug dosage, and
DOTS strategy, and 876-877 public-private mix, and 485-486, T33.4
pre-1992 874-876 diverse mix of health care prognosis 489
priorities or action 886-889 providers 846 treatment of active tuberculosis in
progress since 1992 877-878 evidencce base 847-848 patients on dialysis treatment
Stop TB Initiative, mission of the examples of ongoing public- 486
878-882 private initiatives treatment of active tuberculosis in
HIV/AIDS organizations, and 871 Kathmandu Valley, Nepal 859- renal transplant recipients 488
in India 860 treatment of LTBI in patients on
history of 11-12, 894-895 Mahavir Trust Hospital, dialysis treatment 487-488
infectious disease control and Hyderabad, India 859 treatment of LTBI in renal
tuberculosis 949 implementing transplant recipients 488
legal issues details, regarding 851-852 nontuberculous mycobacterial
high risk groups 958-959 developing operational guide- infection, and 489
prisons 959-960 lines 849-851 pathogenesis 479
legislation for infectious disease national situation assessment Tuberculosis in head and neck region
control 953 848-849 diagnosis 416
media, and 863 PPM DOTS 847, T59.2 imaging, and 416
medical colleges, and 839-841, 860 Tuberculosis in children impact of HIV infection 417
advocacy 840 clinical features indications for surgery, in 418,T27.2
continuing education 844 extrathoracic tuberculosis 593-594 tuberculosis of larynx
educational strategy 841-842 intrathoracic tuberculosis 592-593 clinical features 413-414
guidelines development 844 diagnosis diagnosis 416
Indian experience 844 interferon-gamma release assays epidemiology 413
medical education 840 606-607 pathogenesis 412, 525
research 843 laboratory tests 594-596 pathology 413
service delivery 842-843 novel culture systems and tuberculosis of nasal cavity 416
Tuberculosis Task Force 843-844 detection methods 608-609 tuberculosis of oral cavity 412
Non-governmental organizations nucleic acid amplification tests tuberculosis of pharynx 414
[NGOs], and 609-611 tuberculosis of the ear
advocacy 870 radiology 594 clinical manifestations 415
child health issue 867 scoring systems, and 596 pathogenesis 415
co-ordination 872 screening for disease 603 primary infection 414
collaboration 872 serological diagnosis 606 tuberculosis of the nasopharynx 415
community care 869 traditional methods 607-608 tuberculosis of the paranasal sinuses
community participation 869 drug-resistant tuberculosis, and 415
development issue 867 596-597 turban epiglottis 413
education 870 epidemiology 591 tuberculosis of the salivary glands 414
examples of NGO approaches natural history 592 treatment 417-418
868-871 transmission 591-592 Tuberculosis in pregnancy
gender issue 867 treatment 597-600 breast feeding, and 446
health service management corticosteroids, and 598 clinical presentation 441-442
support 868 monitoring of therapy 599-600 diagnosis 444-445
human rights issue 867 of a child in contact with an adult effect of pregnancy on tuberculosis
information 871-872 with tuberculosis 599 442-443
patients’ organizations 870 of infants born to a mother with effect of tuberculosis on pregnancy
research 870 tuberculosis 598 443-444
1052 Tuberculosis
epidemiology 441 diagnosis development, impact of zoonoses on

management of infants born to a cardiac catheterization 336 936-937
mother with tuberculosis 446, 598 chest radiograph 333 DNA vaccines 929
treatment of active tuberculosis 445- echocardiography 335 epitope based vaccines 929-930
446 electrocardiogram 333 expectations from a new vaccine 933
treatment of latent tuberculosis imaging 336 human trials
infection 446 pericardial biopsy 334-335 groundwork for 933
Tuberculosis in the elderly pericardial fluid ADA estimation new challenges 934
clinical features 627-630 334 identification of vaccine targets 924-
extra-pulmonary tuberculosis 629 pericardial fluid analysis 333-334 925
generalized tuberculosis 629 pericardial fluid IFN-gamma immune responses to vaccination
HIV infection, and 630 estimation 334 923-924
pulmonary tuberculosis 627-628 differential diagnosis 333 immunotherapeutic approach 932
diagnosis 630 pathogensis 330-331 live attenuated mutants and auxo-
epidemiology 625-626 treatment trophs of Mycobacterium tuberculosis
latent tuberculosis infection 626-627 antituberculosis treatment 336 927-928
corticosteroid treatment 337
reactivation and reinfection 626 nontuberculous mycobacterial
pericardiocentesis and pericardi-
treatment 630-632 vaccines 928-929
ectomy 337
adverse effects, of 631 prime boost immunization strategies
Tuberculosis radiculomyelitis
of HIV-TB co-infection 631 930-931
clinical features 323
of LTBI 631-632 recombinant BCG vaccine 925-927
CSF examination 323
treatment ex-juvantibus [trial role of diagnostics 932-933
imaging studies 324-325
treatment] 631 management 325 strategies for development 925, T64.1
Tuberculosis meningitis pathology 323 Vaccines in phase I clinical trial 934-936
clinical features 306-307 Tuberculosis Research Centre, Chennai Vagina, tuberculosis of 452
clinical staging system 307, T 21.4 12-13 Variable number of tandem DNA
complications 314-315 Tuberculosis tenosynovitis 369-370 repeats [VNTRs] 660
corticosteroids, and 313 TUNEL immunostaining 114 Viomycin 737, T51.2A, T51.2B
CSF examination 308-311 Vulva, tuberculosis of 452
diagnosis 307-311 U
differential diagnosis 307, T21.5 W
HIV infection, and 307 Ultrasonography in
abdominal tuberculosis 284 Waksman, Selman 10
pathogenesis 305
female genital tuberculosis 458 Web-based resources tuberculosis
pathology 305-306
genitourinary tuberculosis 471 963-979
treatment 311-314
miliary tuberculosis 501 World Tuberculosis Day 10
Tuberculosis osteomyelitis 370-371
Tuberculosis pericarditis United Nations Millennium Develop-
clinical features ment Goals 63,64 X
Urethra, tuberculosis of
ascites precox 333 XDR-TB 697, 717-22
Broadbent’s sign 333 global experience in the manage-
chronic constrictive pericarditis 332 V ment of 702-704, T49.9A
Friedrich’s sign 332 Vaccine
Kussmaul’s sign 333 development , animal models, and Z
pericardial effusion 331 guinea pig model 921-922
subacute effusive-constrictive mouse model 920-921 Ziehl, Franz 71
pericarditis 331-332 non-human primate model 922 Ziehl-Neelsen stain 164

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Contributors i

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

Typeset at JPBMP typesetting unit

S.K. Agarwal V.H. Balasangameshwara

A.N. Aggarwal Rani Balasubramanian

Praveen Aggarwal Sharmistha Banerjee

Jason Andrews Surya Bhan

Rajesh Bhatia S. Datta Gupta

V.K. Chaddha Sajal De

P.K. Garg Arun K. Gupta

S.K. Jindal Arvind Kumar

Rajnish Joshi Ashok Kumar

A.N. Malaviya T. Mohan Kumar

Madhukar Pai Rajeswari Ramachandran

C.N. Paramasivan Ruma Ray

A.K. Rai Ashu Seith

Anju Sharma Ramnath Subbaraman

Ian Smith J. Veen

Pradeep Venkatesh D. Fraser Wares

Mario C. Raviglione M.D.

20. Granulomatous Hepatitis 294

41. Tuberculosis in Children 591

62. Global Tuberculosis Control: The Future Prospects 874

INTRODUCTION logical data on TB that were lacking in the pre-1990 period

INTRODUCTION Holmes referred to the disease as “white plague” (6).

Changes resembling those caused by TB have been DIAGNOSIS

TUBERCULOSIS IN ARTS AND LITERATURE

Andhra Pradesh in 1915. With the advent of the National

TB burden was enormous it was not possible to

Figures 2.6: National Tuberculosis Institute, Bengaluru: A. Entrance. B. Avalon building

Figure 2.7: A brief history of TB

INTRODUCTION where in India was carried out by Frimodt-Moller (4) to

Figure 3.2: Change with time in the number [log10] of Mycobacterium

Figure 3.3: Natural history of tuberculosis

Figure 3.4: Secular curve of epidemics

descending limb and a steady endemic phase. The whole

ARI = annual risk of infection

Incidence of smear- Prevalence of Incidence of smear Prevalence of

Most Advanced* 12-15 15 1.0 1.0

Table 3.6: Annual risk of infection in various areas in India

Kerala TB Association (49) Kerala, Trivandrum 1991-92 0.75

*numbers in square brackets indicate 95 per cent confidence intervals

1. Population: 1000 million [850 million in 5+ years age, 85%]

Prevalence of Tuberculosis cases

46 178 79 444 199 44 4.8

*Allowing for the time dynamics following intervention, as in 2001

34 years, is a phenomenon also seen in some of the

10-14 35 [0.88] 14 [0.3] 8 [0.20] 3 [0.07]

* Figures in square brackets indicate % of total cases

through a system of a preferential intervention dynamics,

Age [years] Total Non- DOTS DOTS

Table 3.11: Prevalence of culture-positive pulmonary tuberculosis by occupation

Urban and rural Sex ratio [M:F]

Table 3.12: Annual incidence of sputum culture-positive tuberculosis cases

Epidemiological class Annual Incidence of C+ Proportional contribution to

Tuberculin-negative N 63.1 0.41 17.8

Period Prevalence of ARI Prevalence

Appendix Table 3.4: Model states

Appendix Table 3.5: Varying epidemiological observations by areas in India

Worst case-scenario Best case-scenario

Areas Chennai slum, Bengaluru area

U = urban; R = rural; ARI = annual risk of infection; TB = tuberculosis

Appendix Table 3.6: Uses of epidemiology as applicable to tuberculosis situation in India