Tuberculosis in Children

Essentials of
TUBERCULOSIS IN CHILDREN
Essentials of
4th Edition
Vimlesh Seth MD FAMS FCAI FISCD

Senior Consultant
Formerly, Senior Professor and Head
Department of Pediatrics and
Chief Division of Tuberculosis, Pulmonology
Rheumatology and Intensive Care Unit
All India Institute of Medical Sciences (AIIMS)
New Delhi, India
SK Kabra MD DNB
Professor and Incharge
Division of Tuberculosis and Pulmonology
All India Institute of Medical Sciences (AIIMS)
New Delhi, India
Foreword
Peter R Donald
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Essentials of Tuberculosis in Children
2011, Jaypee Brothers Medical Publishers
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First Edition
Second Edition
Third Edition
Fourth Edition
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1997
2001
2006
2011
ISBN 978-93-5025-252-9
Typeset at
Printed at
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Dedicated to
My husband
Professor SD Seth
for his constant encouragement
and moral support
My grandchildren Ushmita and Udbhav
for helping me proactively
to become computer friendly
for easing my editorial
work for the book
Contributors
AK Gupta MD
Professor and Head
Department of Radiodiagnosis
All India Institute of Medical
Sciences
New Delhi, India
E-mail: arun676@hotmail.com
Alexey Kruk MD
Department of Public Health
Oxford University
United Kingdom
E-mail: bjmarais@sun.acza
A Maheshwari MD
Assistant Professor
Department of Pediatrics
Kalawati Saran Children Hospital
Lady Hardinge Medical College
New Delhi, India
E-mail: anejas@hotmail.com
Alka Beotra PhD
Scientific Director
National DOPE Testing Laboratory
JN Stadium, Lodi Road
New Delhi, India
E-mail: drabeotra@rediffmail.com
Anju Seth MD
Professor
Division of Endocrinology
New Delhi, India
E-mail: anju_seth@yahoo.com
Arvind Bagga MD FIAP FAMS
Professor
Sciences
New Delhi, India
E-mail: arvindbagga@hotmail.com
Ashok Rattan MD
Chief Executive
Fortis Clinical Research Ltd
Advisor, Religare SRL, Fortis
Escorts, Delhi and NCR
E-mail:
ashok.rattan@fortis.cro.com,
ashok.rattan@srl.in
Ashu Seith Bhalla MD
Associate Professor
Sciences
New Delhi, India
E-mail: ashubhalla1@yahoo.com
Atin Kumar MD
Assistant Professor
Radiodiagnosis
JPNA Trauma Centre
Sciences
New Delhi, India
E-mail: dratinkumar@gmail.com
Bansidhar Tarai MD
Lab Manager
Microbiology, Immunology and
Molecular Biology
Quest Diagnostics India Private
Limited
Gurgaon
Haryana, India
E-mail: bansisss@gmail.com
Ben J Marais MRCP FCP M (Med)
Professor
Department of Pediatrics and Child
Health
Faculty of Health Sciences,
Tygerberg Hospital
Health Sciences, Stellenbosch
University
PO Box No. 19063
7505 Tygerberg, South Africa
E-mail: bjmarais@sun.ac.za
BN Upendra MS
Assistant Professor
Department of Orthopedics
Sciences, New Delhi, India
BR Thapa MD
Professor and Chief
Division of Pediatric
Gastroenterology Hepatology and
Nutrition
Postgraduate Institute of Medical
Education and Research (PGIMER)
Chandigarh, India
E-mail: brthapa1@yahoo.co.in
Daphne Ling
Department of Epidemiology
and Biostatistics
MC Gill University , Quebec, Canada
Donald A Enarson MD, FRCP (Edin)
International Union Against
Tuberculosis and Lung Disease
68 boulvard Saint-Michel
Paris 75006 France
E-mail: union@iuatld.org
Formerly Chair in Clinical
Pharmacology
Indian Council of Medical Research
and Professor and Head
Department of Pharmacology
All India Institute of Medical Sciences
New Delhi, India
E-mail: drsdseth@yahoo.com
drsdseth@gmail.com
H Simon Schaaf MBChB (Stell) MMed
Ped (Stell) DCM (Stell) MD Ped (Stell)
Professor of Pediatrics
Desmond Tutu TB Centre
Health, and Tygerberg Childrens
Hospital, Faculty of Health Sciences
Stellenbosch University
PO Box 19063, 7505 Tygerberg
South Africa
E-mail hss@sun.ac.za
viii
Harleen MS Grewal MD PhD DTMH
Professor and Senior Consultant
The Grade Institute Section for
Microbiology and Immunology
University of Bergen, Norway
E-mail: harleen.grewal@cih.uib.no
Heidi Syre PhD
Scientist, The Grade Institute Section
for Microbiology and Immunology
University of Bergen, Norway
E-mail: harleen.grewal@cih.uib.no
J Cunningham MD FRCP
Medical Officer, WHO/CDS/TDR/PRD
Unicef/UNDP/World Bank/WHO
Special Program for Research in
Tropical Diseases, 20 Appia Ave
Geneva-27, Switzerland
E-mail: cunninghamj@who.int
JB Sharma MD DNB FRCOG
Associate Professor
Department of Obstetrics and
Gynecology
New Delhi, India
E-mail: jbsharma2000@gmail.com
JL Stanford MD
Head, Division of Bacteriology
School of Pathology
University College and
Middlesex School of Medicine
63-67, Riding House Street
London WIP 7PP, UK
K Gopinath PhD
Scientist
Division of Clinical Microbiology
Department of Laboratory Medicine
New Delhi, India
E-mail: kgnath@gmail.com
Kusum Verma MD
Senior Pathologist
Sir Ganga Ram Hospital, New Delhi
Formerly Dean, Professor and Head
Department of Pathology
New Delhi, India
E-mail: ic_verma@vsnl.com

LS Chauhan MD
Senior Dy Director-General (TB)
Central TB Division
Directorate General of Health
Services and Family Welfare
Government of India
Nirman Bhawan, New Delhi, India
E-mail: ddgtb@rntcp.org
Madhukar Pai MD PhD
Assistant Professor and CIHR New
Investigator
Department of Epidemiology and
Biostatistics
McGill University 1020 Pine Ave
West
Montreal, QC H3A IA2, Canada
E-mail: madhukar.pai@mcgill.ca.
Madhulika Kabra MD
Additional Professor
Sciences
New Delhi, India
E-mail:
madulikakabra@hotmail.com
Manju Ghosh PhD
Research Scientist
Division of Genetics
Sciences
New Delhi, India
E-mail:
mghosh_aims@rediffmail.com
Md Khurshid Alam Hyder
Medical Officer (TB)
Tuberculosis Control
World Health Organization
Regional Office for South-East Asia
World Health House
Indraprastha Estate
Mahatma Gandhi Marg
New Delhi, India
E-mail: hyderk@searo.who.int
Nani Nair MD
Regional Adviser TB
World Health Organization
Regional Office for South-East Asia
New Delhi-110002, India
E-mail: nairn@searo.who.int
Neena Khanna MD
Professor
Department of Dermatology and
Venereology
New Delhi, India
E-mail: neena_aiims@yahoo.co.in
Nimrat Bawa
Diplomat of American Boards
(Pathology)
Director Technical Affairs
Auroprobe Laboratories
C-229, Defence Colony
New Delhi, India
E-mail: auro@auroprobelab.com,
drbawa@hotmail.com
Nulda Beyers MBChB(Stell) FCP(SA)
PhD(Stell) MSc(Med)(UCT)
Professor TB/Community Project

International Union Against
Tuberculosis and Lung Disease
68 boulevard Saint-Michel
Paris, France
E-mail: nb@sun.ac.za
OP Semwal MBBS DCH
Former, Research Associate
New Delhi, India
Now: Senior Consultant Pediatrics
E-mail: semwalop@gmail.com
Pawan Rawal MD DM
Senior Research Associate
Nutrition
Education and Research (PGIMER)
Chandigarh, India
E-mail: drrawal2005@yahoo.co.in
PK Dave MS
Senior Consultant
Department of Orthopedics and
Director
Rockland Hospital, New Delhi
Former Director and Professor of
Orthopedics
Ansari Nagar, New Delhi, India
E-mail: prakash_kotwal@hotmail.com
ix
Contributors
Contents
PM Udani (Late) MD DCH
Professor Emeritus
Institute of Child Health, JJ Group
of Hospitals
Mumbai, Maharashtra, India
PP Kotwal MS
Professor and Head
Department of Orthopedics
New Delhi, India
E-mail: prakash_kotwal@hotmail.com
PR Donald MBChB (Stell) DCH (Glasg)
DTM&H (Lond) FCP(SA) FRCP (Edin) MD
(Stell)
Emeritus Professor of Pediatrics

Health
and Tygerberg Childrens Hospital
Faculty of Health Sciences
PO Box 19063
E-mail: prd@sun.ac.za
Prashant Mathur DCH DNB PhD
Scientist D
Division of Noncommunicable
Diseases
New Delhi, India
E-mail: mathurp@icmr.org.in,
drprashant.mathur@gmail.com
Rachna Seth DCH DNB
Assistant Professor
New Delhi, India
E-mail:
drsandeepseth@hotmail.com
Rajni Sharma
Assistant Professor
Division of Endocrinology
Kalawti Saran Children Hospital
New Delhi, India
E-mail: anju_seth@yahoo.com
Rakesh Lodha MD
Assistant Professor
Sciences
New Delhi, India
E-mail: rlodha1661@gmail.com
Ravi Angara MD
Senior Resident
Nutrition
Education and Research
Chandigarh, India
E-mail: brthapa1@yahoo.co.in
Robert P Gie MD
Desmond Tutu TB Center and
Department of
Pediatric and Child Health
Stellenbosh University
South Africa
E-mail: bjmarais@sun.ac.za
Rohit Sarin DTCD MD
Head
Department of TB Control and
Training
Lala Ram Sarup Institute of
Tuberculosis and Related Diseases
Sri Aurobindo Marg
New Delhi, India
E-mail: drsarin@yahoo.com
Roli Mathur PhD
Scientist C
Division of Basic Medical Sciences
New Delhi, India
E-mail: rolimat@yahoo.com,
rolimat@gmail.com
Ruchi Sood PhD
Research Scientist-Infectious
Diseases
New Drug Discovery Research
Ranbaxy Research Laboratories
Plot No. 20, Sector 18
Udyog Vihar, Industrial Area
Gurgaon, Haryana, India
E-mail: ruchi.sood@ranbaxy.com
S Rasool MBBS
Research Officer
Regional Research
Institute of Unani Medicine
Jamia Nagar
New Delhi, India
Sandeep R Mathur MD
Assistant Professor
Department of Pathology
New Delhi, India
E-mail:
drsunnymathur@yahoo.com
Sangeeta Sharma MD
Specialist and Head
LRS Institute of TB and Respiratory
Diseases
New Delhi, India
Sarman Singh MD
Professor
Clinical Microbiology Division
Department of Laboratory Medicine
Sciences
New Delhi, India
E-mail- ssingh56@hotmail.com
S Aneja MD
Director Professor
New Delhi, India
E-mail: anejas@hotmail.com
SD Seth MD
Advisor Clinical Trials Registry
India
National Institute of Medical Statistics
New Delhi, India
Seemab Gulati MD
Associate Professor
New Delhi, India
Email: sheefaligulati@gmail.com

S Mukhopadhyaya MD
Senior Radiologist
Formerly Professor and Head
New Delhi, India
E-mail:mukherjee@touchtelindia.net
SK Kabra MD DNB
Professor
New Delhi, India
E-mail: skkabra@rediffmail.com
Suneeta Mittal MD FRCOG
Professor and Head
Department of Obstetrics and
Gynecology
New Delhi, India
E-mail: suneeta_mittal@yahoo.com
S Kumar
Head of Laboratories
Auroprobe Laboratories
E-mail: eduprobe@gmail.com
S Kuhn MD
Consultant in Pediatrics
Infectious diseases at
Alberta Childrens Hospital
1820 Richmond Road SW
Calgargy, Alberta, Canada
E-mail:
susan.kuhn@calgaryhealthregion.ca
Tahmeed Ahmed MBBS PhD
Senior Scientist and Head
Nutrition Programm
Dhaka, Bangladesh
E-mail: tahmeed@icddrb.org
V Kalra MD
Senior Consultant
Pediatric Neurology
IP Apollo Hospital
Sarita Vihar, New Delhi
Email: kalra_veena@hotmail.com
Vimlesh Seth MD
Senior Consultant in Pediatrics
Formerly Senior Professor and
Head
Sciences
New Delhi, India
E-mail: vimleshseth@gmail.com,
vimleshseth@yahoo.com
YK Amdekar MD
Senior Consultant Pediatrics
151, Tushar, 14th Road
Chembur, Mumbai, Maharashtra,
India
E-mail: ykasya@gmail.com
Foreword
The epidemic proportions of tuberculosis in many countries was identified as a global emergency in 1993. Despite a
considerable increase in international efforts aimed at tuberculosis control and investment in tuberculosis research,
the perverse influence of HIV-infection combined with the effects of poverty and economic recession have combined
to ensure that the failure to control tuberculosis remains a cause for concern for National Tuberculosis Control
Managers in many countries. The magnitude of the problem is daunting and has been exacerbated by the appearance
of an increasing proportion of MDR-TB and the threat of XDR TB; under the lengthening shadow of HIV, the dream
of controlling, not to speak of eradicating TB has moved far into the future. Against this background, childhood
tuberculosis may appear to be a minor problem, but the percentage of tuberculosis occurring in children is estimated
to vary between 15% in low income countries to below five percent in United States and European countries, while
in high density peri-urban slums, the proportion may rise to much more than 20% in some cases. Even in developed
countries, MDR and XDR tuberculosis are an ever-present threat due to the increasing mobility of people across
international boundaries.
The problem of the diagnosis of tuberculosis in children remains a significant obstacle and is worsened in
severe forms of extrapulmonary diseases such as osteoarticular disease and meningeal tuberculosis. The lack of
standard case definitions and low priority accorded to childhood tuberculosis in the public health agendas of many
countries are persistent problems. Nonetheless, it is pleasing that the problems of childhood tuberculosis have recently
received increasing attention from the various agencies including the World Health Organization (WHO).
The belief that tuberculosis in children is not a significant cause of transmission of infection is also not true if
viewed from a long-term perspective; a significant proportion of children in the younger and vulnerable age group
who are infected by an adult source case will very often not receive preventive therapy and will later develop
infectious adult-type tuberculosis, especially during adolescence and this is particularly likely to happen in
communities with a high incidence of HIV-infection. Globally, it is estimated that 1.5 million new cases and 130,000
deaths due to tuberculosis per year occur in young children. Of the total deaths due to tuberculosis, 95% occur in
developing countries. It has been rightly emphasized that tuberculosis control programs should recognize tuberculosis
as a disease of the family and community rather than only the individual and that tuberculosis infection and disease
in children of all ages should be managed simultaneously with the evaluation and management of other family
members and members of the extended family and household and not in isolation.
It is thus pleasing that children are now specially included in the Revised National Tuberculosis Control
Programme (RNTCP) and that antituberculosis agents will become available on a weight-for-age basis. Suboptimal
dosing still remains possible and the lack of child-friendly preparations makes the accurate treatment of under-fiveyear-old children difficult and it is this group that is subject to more serious forms of disseminated disease. Within
financial constraints, active contact tracing of under-five-year-old children is now recommended and will be facilitated
by a family or household-orientated approach.
In addition to these welcome innovations, the early diagnosis and management by directly observed shortcourse treatment (DOTS) of all sputum microscopy smear-positive patients, whether children, adolescents or adults,
remains an important cornerstone of any tuberculosis control program as does the administration of BCG to infants.
Although BCG vaccination has a limited effect and prevents mainly disseminated forms of tuberculosis, efforts to
develop a new improved vaccine are gathering momentum.
One of the characteristics of tuberculosis in children, in contrast to adults, is the wide spectrum of manifestations
and there is a great need to create a greater understanding of this spectrum to fully appreciate the specific problems of
childhood tuberculosis. This book should thus be welcomed by the childhood tuberculosis community throughout the
world. In this book, Vimlesh Seth, herself a well-known international figure in this field, has brought together
63 eminent scientists and clinicians who have contributed 44 outstanding chapters that address most of the manifestations
of childhood tuberculosis. Dr Seth has made a considerable contribution to the better management of childhood
tuberculosis; included in her many activities are participation in two consensus reports (1997 and 2004) and a third that
appears in this book that summarizes the deliberations of pediatricians, program managers and laboratory workers
relating to childhood tuberculosis.
xii

In addition, attention is drawn to the neglected areas of tuberculosis in girls at adolescence and in children with
cancer and two chapters discuss pitfalls in diagnosis and management of childhood tuberculosis, and lacunae and
experience of managing children under the National Program (DOTS). The place of contact surveillance has been
highlighted and forms of extrapulmonary tuberculosis, such as neurotuberculosis, have been illustrated with a large
number of clinical pictures from children of various ages in the different stages of disease. The chapter on imaging
is exhaustive and based on data of pediatric TB clinic over five decades at All India Institute of Medical Sciences
(AIIMS), New Delhi, India.
The book is a valuable resource not only for the pediatric fraternity but also for all practitioners who treat children;
and it should find a place not only in libraries of medical colleges but also in Pediatric and Community Medicine
Departments. It is very reader-friendly and organized for easy consultation by both undergraduates and postgraduates
who need to know more about childhood tuberculosis. Appropriately in an age when the epidemic of HIV continues
to spread, there is a chapter on the organization of a pediatric and HIV clinic in the pediatric department of medical
college and how this can contribute to the collection of information about tuberculosis and HIV for the National Data
Base about disease in children and so influence the design of future policies for diagnosis and management. Frequently
asked questions relating to childhood tuberculosis and BCG are addressed and this is of great practical value. Dr Seth
is to be congratulated on the successful compilation of a formidable compendium of information about childhood
tuberculosis which will be of value, throughout the world wherever tuberculosis is a significant problem.
Peter R Donald
MBChB (Stell) DCH (Glasg) DTM&H (Lond) FCP(SA) FRCP (Edin) MD (Stell)

Department of Paediatrics and Child Health
and Tygerberg Childrens Hospital
Tygerberg, South Africa
Preface to the Fourth Edition

Tuberculosis (TB) continues to be the worlds most important infectious cause of morbidity and mortality among
adults. Nearly nine million people develop tuberculous disease each year and 1.7 million die every year (WHO,
2007). Detection rates are low and morbidity and mortality is high in children also. Over the last five years, the
incidence and prevalence of TB in children has not decreased. The reason is that on the preventive front, the same
strategies: (i) diagnosis and treating sputum smear-positive cases in adults and (ii) mass BCG vaccination of newborns
and infants are being practised. These have not proved effective to a significant extent because of the concurrent
addition of HIV/AIDS infection, MDR-TB and even XDR-TB. The latter two conditions need aggressive treatment in
children along with their source cases, which are usually adults in the family.
On the diagnostic front, with the significant advances at molecular level, there has not emerged a single test for
diagnosis, that too are not cost-effective requiring huge finances and high level of technical expertise. At best, they
are categorized only supportive tests.
In the contact survey, addition of IGRAs, with the basis of release of interferon after incubation of whole
blood or separated T-cells with CFT 10 peptides and ESAT-609 antigen of tubercle bacilli has been well researched.
The two tests are quantiFERON-. TB and T-SPOT.TB; ELISPOT. These again cannot be used as the tests for diagnosis
as they emphasize that they are only comparable to the existing tuberculin test, the advantages over tuberculin test
are: (i) require only one visit of the patient, (ii) previous BCG vaccination does not interfere and, (iii) presence of
nontuberculous mycobacteria in the environment does not vitiate the results. However, their main advantage is
their use in contact tracing for which they have been extensively used.
In the basic format of the book there are seven sections. In each section a number of new chapters have been
added, contributed by specialists in their respective field. In total there are 44 chapters with 63 contributors from
India and abroad. In the 1st three sections namely history, epidemiology and microbiology and immunopathogenesis,
the chapters have been updated including the latest details at the molecular level in all aspects. In the clinical spectrum,
for TB and HIV coinfection there are two chapters with one giving detailed dosage schedule of antiretroviral drugs.
The other significant additions are tuberculosis at adolescence, particularly in female children in whom it can
be a prelude to the development of sterelity later in life. Chapters on cutaneous and endocrine manifestations are the
other additions. The chapter on TB in children with cancer has highlighted the point why TB is not a scurge in these
children. However, one should be in the lookout for this, particularly when the presentation of complications in
cancer are unusual and do not improve with conventional antibiotics used for the commonly occurring superadded
infections. In the management section, the chapters on antituberculosis drugs have been completely revised and
updated to facilitate the readers to understand various regimens used in the clinical spectrum of TB in children
specially HIV/TB coinfection and MDR-TB. Pharmacokinetics of all antituberculosis drugs have been updated from
literature review along with the experience at Pediatric department of All India Institute of Medical Sciences (AIIMS)
with 1st-line agents. Chapter on lacunae and experience of DOTS in the management of children has been included.
The Indian Academy of Pediatrics (IAP) in the third Consensus Statement has highlighted some reservations about
management of HIV and TB coinfection and MDR-TB by general pediatricians. They have emphasized that these
two aspects need management by experts in the field. Advances up to 2010 have been included making all the
chapters well referenced with the latest literature.
The book will be useful to both undergraduates and postgraduates. Departments of Community Medicine of
Medical colleges and Tuberculosis Hospital will also benefit from the efforts of the authors. It will be a useful reference
book for Program Managers of the Tuberculosis Division of Ministry of Health and Family Welfare, Government of
India; Departments of Health Research and Indian Council of Medical Research, Biotechnology of the Government
of India. Chapters on research priorities and ethics involved in clinical trial will facilitate pediatricians to write high
quality scientific projects on TB in children to have research grant from funding agencies. Details of how to get
National Data Base of TB and its coinfection with HIV/AIDS are necessary. This will help in making changes in
policies in their management from time to time. Further, it will help to make some facilities exclusively for children
such as medicine boxes in the four to five weight categories as per age. A chapter exclusively for how to organize a
TB/HIV clinic for pediatrics has been elucidated with detailed case record forms and instruction for the junior
doctors attending the clinic to achieve goal in this direction. In toto, this book will serve as a very useful treatise
regarding all aspects of TB in children.
Vimlesh Seth
SK Kabra
Preface to the First Edition

The prevalence of active tuberculosis in India is 15 to 25 per 1,000 population, of which 25 percent are infectious.
About 3.4 million children in the country have tuberculosis of which 94 million are at risk of infection. Nearly 40
percent of the children by the age of 6 years and 80 percent by the age of 16 years develop tubercular infection. The
annual rate of infection is 3 percent.
There is resurgence of tuberculosis both in the developed and developing countries due to the increasing
occurrence of HIV/AIDs, even children being not spared. With the availability of effective chemotherapeutic agents,
a large number of children with pulmonary primary complex are overtreated and badly planned regimens are given
to children with tuberculous meningitis, as there are no specific guidelines for the management of tuberculosis in its
varied clinical spectrum. Ultimate control of tuberculosis rests on the development of shorter courses of chemotherapy,
and availability of vastly improved diagnostic methods.
Trinity of functions of the faculty of All India Institute of Medical Sciences is patient care, teaching and research.
For all this, there is always a need to have literature on the latest developments about epidemiology, diagnosis
(newer investigations) and treatment of any disease. Tuberculosis is one of the worlds most neglected health crises.
In this treatise, attempt has been made to address the problem of tuberculosis stating from epidemiology in
various settings (hospital and community), review of recent diagnostic methods, particularly the role of nonculture
techniques in the diagnosis of paucibacillary tuberculosis of children. Based on my work in the immunology in
children having tuberculosis, a clinico-immunoradiological profile has been defined. Work on the pharmacokinetics
conducted in my laboratory has helped me to design antituberculosis drug regimens for varied clinical spectrum on
sound scientific basis. The chapters on BCG vaccination and tuberculin test have exhaustively reviewed. There is a
chapter on practical problems in the form of questions and their answers. There is a whole lot of data on Indian
children practically about all aspects of tuberculosis in this book.
The book is intended to be used by general practitioners treating children, pediatricians in practice, faculty of
pediatrics and community medicine of medical colleges, postgraduate students and the policy makers of the
Government of India for its National Tuberculosis Control Program. Specific guidelines on diagnosis and management
of the children of an infectious adult can be formulated which should be incorporated in the National Tuberculosis
Control Program of Government of India and other developing countries.
My most sincere and grateful thanks are due to all the contributors from India and abroad for having presented
the various topics in a comprehensive and authoritative manner. My special thanks are due to Dr OP Semwal for his
painstaking effort and assistance in giving finishing touch to the book.
Able secretarial assistance of Miss Rita Sharma, Mrs Kanta Chawla and Mr Ashok Kumar is gratefully
acknowledged.
Thanks are also due to Shri JP Vij, Chairman and Managing Director of M/s Jaypee Brothers Medical Publishers
Pvt. Ltd., for the publication of this book. I gratefully acknowledge the sincere efforts of Mr Ghuman, Production
Manager, for ensuring a very high quality of the book and bringing it out in such a short-time.
Vimlesh Seth
Acknowledgments
I owe my gratitude to all the contributors for their painstakingly written chapters in an excellent, simple and lucid
style, very well referenced and updated with thorough illustrations.
We acknowledge the efforts of Shri Jitendar P Vij, Chairman and Managing Director of M/s Jaypee Brothers
Medical Publishers (P) Ltd, for publishing the book. We also acknowledge the meticulous work and sincere efforts
of Mr Tarun Duneja (DirectorPublishing) and Mrs Samina Khan, for ensuring quality of this edition. We are thankful
to Mr Bir Singh for his untiring secretarial assistance. He worked even on weekends to meet the deadline.
About the Review of the Previous

Edition of the Book
The appearance of the book and contents are really outstanding.
Peter R Donald
E-mail: prd@sun.ac.za
No Western books on pediatrics have provided a comprehensive update on the subject of childhood tuberculosis,
especially in the context of the developing world.
Professor Vimlesh Seth herself has written most of the early chapters on epidemiology, diagnosis,
immunopathogenesis, and the immunology of BCG vaccination and the tuberculin test. These chapters are readable,
comprehensive, and well referenced. There have been many recent advances in mycobacterial immunology and it is
to Professor Seth's credit that she has managed to be so concise. This is an excellent book.
Anthony Costello
Senior Lecturer
Archives of Disease of Children 1991; 66: 1006
Contents
Section 1: Introduction
1. History of Tuberculosis ............................................................................................................... 3
Vimlesh Seth, SK Kabra
History of Tuberculosis ......................................................................................................................................... 3

History of Tuberculosis Control in India ............................................................................................................ 4
Sanatoria in India ....................................................................................................................................................5
Tuberculosis Association of India ........................................................................................................................ 5
Tuberculosis Control Program in Independent India ....................................................................................... 5
History and Development of International Cooperation in the Conquest of Tuberculosis ........................ 6
Section 2: Epidemiology
2. Global Epidemiology of Pediatric Tuberculosis .................................................................. 11
Md Khurshid Alam Hyder, Nani Nair, Tahmeed Ahmed
Presentation of Pediatric TB ................................................................................................................................ 11
TB in the World .....................................................................................................................................................13
Effect of Migration ................................................................................................................................................16
3. Interaction of Epidemiological Factors................................................................................... 19

Donald A Enarson, Nulda Beyers
Determinants of Tuberculosis in Children ........................................................................................................ 21
Evaluation of Interventions with Reference to Children ................................................................................ 21
Eradication of Tuberculosis .................................................................................................................................22
4. Epidemiology: Special Reference to Children ...................................................................... 26

Pyramid of Childhood Tuberculosis .................................................................................................................. 26

Disease Burden in Children ................................................................................................................................ 28
Determinants of Infection and Disease ..............................................................................................................30
Drug-resistant Tuberculosis ................................................................................................................................ 32
Trends in Tubercular Disease .............................................................................................................................33
HIV and Tuberculosis .......................................................................................................................................... 34
Molecular Epidemiology ..................................................................................................................................... 34
Actions Being Taken in India .............................................................................................................................. 36
xviii
Section 3: Microbiology and Immunopathogenesis

5. Mycobacterium Tuberculosis ................................................................................................... 41
Sarman Singh, K Gopinath, Ruchi Sood, Ashok Rattan
Taxonomy ..............................................................................................................................................................41
Description of the Genus ..................................................................................................................................... 42
6. Nontuberculous Mycobacteria ................................................................................................. 57

Sarman Singh, K Gopinath, Ashok Rattan
Taxonomy ..............................................................................................................................................................57
Classification of NTM on the Basis of Pigment Production ........................................................................... 57
7. Immunology of Tuberculosis: Basic Aspects and Relevance for

Immunodiagnostic Tests ........................................................................................................... 66
Heidi Syre, Harleen MS Grewal
The Immune System .............................................................................................................................................66
8. Clinicoimmunological Profile .................................................................................................. 90

Vimlesh Seth
Immune Reconstitution Disease Associated with Mycobacterial Infections ...............................................96
Section 4: Clinical Spectrum

9. Pulmonary Tuberculosis ......................................................................................................... 101
Transmission .......................................................................................................................................................101
Pathophysiology ................................................................................................................................................. 101
Risk of Infection to Disease in Infants and Young Children ........................................................................102
Natural History of Tubercular Infections........................................................................................................102
Principles of Disease .......................................................................................................................................... 102
Clinical Features ................................................................................................................................................. 107
Clinical Features/Scoring Systems .................................................................................................................. 108
Methods to Diagnose Latent Tuberculosis Infection ..................................................................................... 115
Diagnostic Algorithm for Pulmonary Tuberculosis ......................................................................................115
10. Tuberculous Lymphadenitis .................................................................................................. 122

Ben J Marais, PR Donald
Epidemiology ...................................................................................................................................................... 122

Pathogenesis ........................................................................................................................................................123
Clinical Findings and Diagnosis .......................................................................................................................123
Treatment ............................................................................................................................................................. 126
11. Abdominal Tuberculosis ......................................................................................................... 128

BR Thapa, Pawan Rawal, Ravi Angara
Causative Organisms .........................................................................................................................................128
Ulcerative Type ...................................................................................................................................................130
Stricturous/Hypertrophic type ........................................................................................................................130
Contents
12.
xix
Presentation According to Site of Involvement .............................................................................................131

Techniques for Definitive Diagnosis ................................................................................................................132
Abdominal Ultrasound ......................................................................................................................................137
CT Abdomen .......................................................................................................................................................139
Newer Modalities ...............................................................................................................................................142
Differentiating ATB from Inflammatory Bowel Disease (IBD) .................................................................... 143
Neurotuberculosis ................................................................................................................... 150
12.1. Pathology and Pathogenesis .................................................................................................. 150

PM Udani
Magnitude, Changing Clinical Patterns and Syndromes Specially in BCG-vaccinated Children .........150
Abdominal Tuberculosis ...................................................................................................................................150
Pathological Aspects .......................................................................................................................................... 151
Specific Conditions .............................................................................................................................................154
Pathological Basis of Various Syndromes ...................................................................................................... 156
12.2. Clinical Manifestations, Diagnosis and Management ..................................................... 161

Satinder Aneja, A Maheshwari, Vimlesh Seth
Special Scenarios ................................................................................................................................................. 174
Tuberculoma of Brain .........................................................................................................................................175
Spinal Tuberculosis in Children .......................................................................................................................177
12.3. Case Studies ............................................................................................................................... 180

PM Udani, S Gulati, Rachna Seth, V Kalra, Vimlesh Seth
Profile of TBM in Children Modified by BCGDr PM Udanis Experience .............................................180
Profile of TBM: AIIMS Experience ...................................................................................................................185
13. Osteoarticular Tuberculosis ................................................................................................... 200

PP Kotwal, PK Dave, BN Upendra
Joint Involvement ...............................................................................................................................................200

Tuberculosis of the Hip Joint ............................................................................................................................204
Tuberculosis of the Knee Joint ..........................................................................................................................206
Tuberculosis of the Ankle and Elbow ..............................................................................................................207
Tuberculosis of the Short Long Bones ............................................................................................................. 207
Tuberculosis of the Spine (Potts Spine) ..........................................................................................................207
14. Genitourinary Tuberculosis ................................................................................................... 214

Arvind Bagga
Clinical Presentation .......................................................................................................................................... 214
Diagnosis ..............................................................................................................................................................215
Therapy ................................................................................................................................................................215
15. Tuberculosis and the HIV Infection ..................................................................................... 218

15.1. TB in HIV Infected Children.................................................................................................. 218
BJ Marais, PR Donald
Epidemiology ...................................................................................................................................................... 218

Tuberculosis and the HIV Infection .................................................................................................................218
Diagnosis ..............................................................................................................................................................219
Treatment ............................................................................................................................................................. 219
xx
15.2. Tuberculosis and HIV Infection ............................................................................................ 222

Vimlesh Seth, Rakesh Lodha
Epidemiology of HIV-tuberculosis .................................................................................................................. 222

Prevalence of Tuberculosis in HIV-infected Children ..................................................................................223
Pathogenesis ........................................................................................................................................................224
Differential Diagnosis ........................................................................................................................................227
Treatment of TB ..................................................................................................................................................230
Treatment of Children........................................................................................................................................231
Prognosis ..............................................................................................................................................................234
16. Tuberculosis and Childhood Malignancy ........................................................................... 241

Rachna Seth
Immunology of Tubercular Infection ..............................................................................................................241

Risk Factors ..........................................................................................................................................................243
Diagnosis..............................................................................................................................................................243
Pulmonary Tuberculosis and Bone Marrow Transplant (BMT) Recipients ...............................................244
Short-course Chemotherapy and Reactivation of TB ....................................................................................245
Clinical Characteristics and Treatment Responses of Tuberculosis in
Patients with Malignancy Receiving Anticancer Therapy ...........................................................................245
17. Unusual Manifestations of Tuberculosis............................................................................. 248

Vimlesh Seth
Tuberculosis of Eye and Conjunctiva ..............................................................................................................248

Hematological Complications ..........................................................................................................................249
Esophageal Tuberculosis ...................................................................................................................................250
Tuberculous Otitis Media and Mastoiditis .....................................................................................................250
Isolated Hepatic Inferior Vena Cava Thrombosis in a Case of Tuberculosis ............................................251
Cement kidney: Renal Tuberculosis ................................................................................................................251
Primary Tuberculosis Clinically Presenting as Gingival Enlargement: A Case Report ...........................251
Simultaneous Tuberculous Meningoencephalitis in Two Siblings ............................................................. 251
Childhood Tuberculosis Diagnosed and Managed as Asthma: A Case Report ........................................252
Tuberculosis of the Breast in an Adolescent Girl ...........................................................................................252
Esophageal Stent Improves Ventilation in a Child with a Bronchoesophageal
Fistula Caused by Mycobacterium tuberculosis................................................................................................. 252
Pituitary Stalk Tuberculosis .............................................................................................................................. 252
Multifocal Skeletal Tuberculosis ......................................................................................................................252
BCG Related Complications .............................................................................................................................. 253
18. Cutaneous Tuberculosis .......................................................................................................... 255

Neena Khanna, Seemab Rasool
Epidemiology ...................................................................................................................................................... 255

Etiology ................................................................................................................................................................255
Pathogenesis ........................................................................................................................................................255
Classification .......................................................................................................................................................255
Unusual Patterns of Tuberculosis ....................................................................................................................259
Diagnosis of Cutaneous Tuberculosis ............................................................................................................. 259
Treatment of Cutaneous Tuberculosis ............................................................................................................. 260
Contents
xxi
19. Adolescent Tuberculosis: Prelude to Future Infertility .................................................... 263

Suneeta Mittal, JB Sharma, Sangeeta Sharma
Treatment ............................................................................................................................................................. 269
20. Endocrine Manifestations of Tuberculosis ......................................................................... 273

Anju Seth, Rajni Sharma
Endocrine Effects of Tuberculosis Due to Chronic Systemic Disease .........................................................273

CNS Tuberculosis ...............................................................................................................................................273
Adrenal Tuberculosis .........................................................................................................................................274
Thyroid Tuberculosis .........................................................................................................................................275
Pancreatic Tuberculosis ..................................................................................................................................... 275
Genital Tuberculosis ...........................................................................................................................................275
21. Congenital Tuberculosis ......................................................................................................... 277

Vimlesh Seth
Pathophysiology ................................................................................................................................................. 277

Diagnostic Criteria for Congenital Tuberculosis ...........................................................................................279
Investigations ...................................................................................................................................................... 280
Treatment ............................................................................................................................................................. 281
Section 5: Diagnosis
22. Pitfalls in Diagnosis and Treatment of Childhood Tuberculosis ................................... 287
YK Ambdekar, Vimlesh Seth
Pitfalls in History Analysis ...............................................................................................................................287
23. Tuberculin Test ......................................................................................................................... 296

History .................................................................................................................................................................. 297

Tuberculins ..........................................................................................................................................................297
Composition ........................................................................................................................................................ 297
Immune Basis of Tuberculin Reactivity ..........................................................................................................298
Tuberculosis and Immune System ...................................................................................................................299
Administration of Tuberculin Test ...................................................................................................................300
Infection with Nontuberculous Mycobacteria ................................................................................................301
BCG Vaccination ................................................................................................................................................. 301
Variables Affecting Interpretation ...................................................................................................................302
24. Newer Tuberculins: Profile in Developing Countries ...................................................... 310

JL Stanford
The Reagents .......................................................................................................................................................310

Skin Test and the Assessment of Vaccine Efficacy ........................................................................................314
Development of New Vaccines ........................................................................................................................315
New Tuberculins and Diagnosis of Mycobacterial Disease ......................................................................... 315
Studies of Close Contacts of Patients with Disease .......................................................................................316
Detection of Risk Factor ..................................................................................................................................... 317
Prevaccination Skin Tests ..................................................................................................................................318
xxii
25. Laboratory Diagnosis of Mycobacterial (Tuberculosis) Infection in Children ............ 322

25.1. Conventional Methods ............................................................................................................ 322
Bansidhar Tarai, Nimrat Bawa, Sarman Singh, Ashok Rattan
The Diagnostic Challenges ................................................................................................................................322

Tuberculin Skin Test (Mantoux Test)...............................................................................................................323
Radiology-based Approaches ...........................................................................................................................324
Fine Needle Aspiration Cytology (FNAC) .....................................................................................................324
Conventional Lab Diagnosis .............................................................................................................................324
Immune-based Diagnosis ..................................................................................................................................329
Novel Culture Systems and Detection Methods ............................................................................................331
Diagnosis of TB in HIV Infected Children ...................................................................................................... 331
25.2. Molecular Diagnostic Methods .............................................................................................. 332

S Kumar, Bansidhar Tarai, Nimrat Bawa, Sarman Singh, Ashok Rattan
Commercially Available Assays.......................................................................................................................334
Identification of Mycobacterial Species from Culture by Molecular Methods.......................................... 336
Molecular Methods for Detecting Drug Resistance in Mycobacterial Strains ...........................................337
26. Imaging of Tuberculosis in Children ................................................................................... 344

Ashu Seith Bhalla, A Kumar, AK Gupta, S Mukhopadhyaya
Pulmonary Tuberculosis ....................................................................................................................................344

Imaging Modalities ............................................................................................................................................344
Imaging Findings ................................................................................................................................................345
Prediction of Activity of Tuberculous Lesion ................................................................................................. 353
Follow-up ............................................................................................................................................................. 353
Intracranial Tuberculosis ...................................................................................................................................354
Urinary Tract Tuberculosis ...............................................................................................................................358
Abdominal Tuberculosis ...................................................................................................................................361
Osteoarticular Tuberculosis .............................................................................................................................. 362
27. Pathologic Spectrum ................................................................................................................ 368

Sandeep R Mathur, Kusum Verma
Pathologic Spectrum of Tuberculosis in Children .........................................................................................368
Spectrum of Morphologic Changes .................................................................................................................373
28. New Approaches to TB Diagnosis in Children .................................................................. 380

Ben J Marais, Daphne Ling, Madhukar Pai
Screening Child Contacts for Active Disease ................................................................................................. 380
Approaches to Confirm Active Disease ..........................................................................................................382
Section 6: Management
29. Principles of Therapy ............................................................................................................... 395
Microbiological Principles .................................................................................................................................395
Contents
xxiii
30. Antituberculosis Drugs: First-line Agents ........................................................................... 403

Vimlesh Seth, SD Seth, OP Semwal
Classification of Drugs .......................................................................................................................................404

Acute Toxicity of Isoniazid ...............................................................................................................................409
Rifampicin (Rifampin) .......................................................................................................................................410
Streptomycin .......................................................................................................................................................412
Pyrazinamide ...................................................................................................................................................... 414
Ethambutol ..........................................................................................................................................................415
31. Antituberculosis Drugs: Second-line and Newer Agents ................................................ 427

Second-line Agents .............................................................................................................................................427

Fluoroquinolones ................................................................................................................................................430
Newer Rifamycin Derivatives ..........................................................................................................................434
Beta-Lactams with Beta-Lactamase Inhibitors ...............................................................................................436
Tuberactinomycin ...............................................................................................................................................436
Macrolides ...........................................................................................................................................................436
Phenazines ...........................................................................................................................................................437
Cycloserine ..........................................................................................................................................................438
Aminoglycosides ................................................................................................................................................439
Capreomycin .......................................................................................................................................................439
Miscellaneous Agents ........................................................................................................................................440
Phenothiazines ....................................................................................................................................................441
Nitroimidazopyrans ...........................................................................................................................................441
Oxazolidinones ...................................................................................................................................................442
The New Investigational Drugs .......................................................................................................................442
32. Antituberculosis Drugs: Pharmacokinetics ......................................................................... 449

Vimlesh Seth, Alka Beotra, SD Seth, OP Semwal
General Aspects ..................................................................................................................................................449

Factors Responsible for Altered Drug Response in Children ......................................................................452
Various Factors which Change Pharmacokinetics ........................................................................................453
Pharmacokinetics of Antitubercular Drugs in Relation to Various Factors ...............................................458
Isoniazid ...............................................................................................................................................................461
Rifampicin ............................................................................................................................................................463
Pyrazinamide ...................................................................................................................................................... 464
33. Pharmacogenetics of Tuberculosis ........................................................................................ 471

Manju Ghosh, Madhulika Kabra
What is Pharmacogenetics? ...............................................................................................................................471
34. Management of Tuberculosis ................................................................................................. 476

Commonly Used Drugs ..................................................................................................................................... 476

Drug Regimens ...................................................................................................................................................476
Categories and Drugs Regimen under DOTS ................................................................................................478
Corticosteroids in Tuberculosis ........................................................................................................................478
Monitoring of Treatment ...................................................................................................................................479
Monitoring for Side Effects ...............................................................................................................................480
xxiv
35. Consensus Statement on Childhood Tuberculosis 2010 IAP

Working Group on Tuberculosis........................................................................................... 484
YK Ambdekar
Objectives ............................................................................................................................................................. 485

Recommendations ..............................................................................................................................................485
Current Trends in Chemotherapy of TB under Revised National TB ........................................................490
Management of a Neonate Born to a Mother with Tuberculosis ................................................................493
Gaps in Knowledge ............................................................................................................................................493
36. Drug-resistant Tuberculosis in Children ............................................................................. 497

36.1. Drug-resistant Tuberculosis ................................................................................................... 497
HS Schaaf, PR Donald
The Development of Drug-resistance and Discovery of Basic Principles of
Drug-resistant Tuberculosis .............................................................................................................................. 497
Drug-resistant Tuberculosis in Children .........................................................................................................497
36.2. Multidrug-resistant Tuberculosis ......................................................................................... 504

Epidemiology ...................................................................................................................................................... 506
Management of Patients who have Drug-resistant Disease ......................................................................... 511
37. Organization of Pediatric Tuberculosis and HIV Clinic .................................................. 522

Vimlesh Seth
Starting Tuberculosis Clinic for Children .......................................................................................................523

Instructions for Resident Doctor ......................................................................................................................524
Flow of Patients in TB Clinic .............................................................................................................................525
New Cases ...........................................................................................................................................................525
Check List for the Senior Resident Doctor on Follow-up Visit ....................................................................526
Annexure I ...........................................................................................................................................................529
Annexure II ..........................................................................................................................................................537
Annexure III
Annexure IV ........................................................................................................................................................541
Annexure V ..........................................................................................................................................................546
Section 7: Prevention and Control of Tuberculosis

38. Bacillus Calmette-Guerin (BCG) ........................................................................................... 555
38.1. Bacillus Calmette-Guerin (BCG) Vaccination .................................................................... 555
Need for BCG Vaccination ................................................................................................................................555
Bacillus Calmette-Guerin (BCG) .......................................................................................................................555
38.2. BCG VaccinationFrequently Asked Questions .............................................................. 574

Vimlesh Seth
Annexure
Instruction Sheet for BCG Immunization Section .......................................................................................... 574
Contents
xxv
39. Latent Tuberculosis ................................................................................................................. 589

39.1. Latent Tuberculosis in Children and Adolescents............................................................. 589
Vimlesh Seth, J Cunningham, SM Kuhn
Latent Tuberculosis ............................................................................................................................................ 589
Approach to Latent Tuberculosis Infection ....................................................................................................595
Treatment of Latent Tuberculosis Infection ....................................................................................................597
39.2. Symptoms-based Screening of Child Tuberculosis Contacts

Improved Feasibility in Resource Limited Settings .......................................................... 602
Alexey Kruk, Robert P Gie, H Simon Schaaf, Ben J Marais
40. Tuberculosis Control Program in ChildrenLacunae and Experiences ....................... 612

Rohit Sarin, Sangeeta Sharma
Issues and Lacunae .............................................................................................................................................612
41. Prospective of Prevention, Diagnosis and Management of

Tuberculosis in the National Program ................................................................................. 616
LS Chauhan
Burden of Disease ...............................................................................................................................................616
42. Frequently Asked Questions about Tuberculosis .............................................................. 634

The Broad Status of Tuberculosis at Present in the World ...........................................................................634
Practical Point ...................................................................................................................................................... 639
Treatment of TB Patients ...................................................................................................................................646
43. Ethical Issues and Concerns about Tuberculosis Research in Children ....................... 652
Roli Mathur, Prashant Mathur, Vimlesh Seth
Ethics, Human Health and Research ...............................................................................................................652
Tuberculosis Diagnosis, Treatment, Control, Prevention, Eradication and Ethics ...................................657
44. Tuberculosis in Children: Research Priorities .................................................................... 661

Vimlesh Seth
Research in Pediatric Practice ...........................................................................................................................661

Tuberculosis in Children: Research Priorities ................................................................................................661
Epidemiology ...................................................................................................................................................... 662
Diagnosis ..............................................................................................................................................................662
Treatment ............................................................................................................................................................. 663
Contact-Screening and Management ...............................................................................................................663
Index ............................................................................................................................................ 665
SECTION 1
INTRODUCTION
History of Tuberculosis
History of Tuberculosis
INTRODUCTION
Tuberculosis, described with different names Kings evil,
phthisis, Rajyakshma, Tapedic, etc. appears to be a disease
as old as human history. Bones of prehistoric man dating
back to 8000 BC have shown typical changes of
tuberculosis.1 A bone from Neolithic period (5000 BC)
found in the region of Heidelberg, likewise shows evidence
of tuberculous changes.2 It has been described in India as
early as 3000 BC. In Rigveda which is dated 2000 BC,
tuberculosis has been described as Yakshma. Sushruta
described the disease and observed it was difficult to treat.3
Findings in certain Egyptian mummies clearly indicate
that spinal caries existed around 2400 BC.3
The oldest legal text in the world formulated by the
Babylonian monarch Hammurabi in 1948 to 1905 BC and
engraved in cuneiform script on a stone pillar, now kept
at the Louvre in Paris mentions a chronic lung disease
which was probably tuberculosis.4 A unique bacteriological finding of acid-fast bacilli in smears taken from
psoas abscess in the astonishingly well preserved
mummy of an Inca child from around 700 BC, clearly
documents a case of tuberculosis of the lumbar spine.5
In Greek, literature description of tuberculosis
appears around the time of Hippocrates (460-377 BC).
He first described tubercle (Phymata) in the tissues of
cattle, sheep and pigs. The Hippocratic school considered
pulmonary pthisis a hereditary rather than infectious
disease.2
Aristotle (384-322 BC) described scrofula on the skin
of phthisic pigs. He believed phthisis to be contagious
even though general opinion at that time tended to the
alternative theory that the disease was hereditary.6
Around the start of the common era, Aretaeus of
Capadocia described pulmonary consumption as a
disease with purulent chronic sputum and generally poor
prognosis. Galen (131-201) suspected contagious nature
of phthisis and warned against intimate contact with
consumptives. Caelius Aurelianus, a Roman physician
of 5th century, described clinical details of phthisis.
Reviewing consumption over the course of history,
it is clear that upsurges of the disease have always
followed the development of new urban structures
drawing large numbers of people into confined space.
Fracastonius of Verona (1478-1553) reserved the term

phthisis exclusively for pulmonary consumption.4
There have been many other names used over the
centuries for M.tuberculosis-related diseases. The term
tuberculosis relates to the tubercles which were first
associated with the disease in the 17th century, in Holland
by Franciseus de la Boe, better known as Dr Sylvius.
Consumption
Tuberculosis
Kings evil
Tuberculosis of neck and

lymph glands
Tuberculosis
Tuberculosis of the skin
Tuberculosis of lymph
glands inside the abdomen.
An illness of children
caused by drinking milk
from TB infected cows.
Now uncommon as milk
is pasteurized/ boiled in
India
Chronic wasting away,
the original Greek name
for tuberculosis
Tuberculosis of spine
Tuberculosis of neck
lymph glands,
progresses slowly with
abscesses and fistulas
develop. Young persons
disease
Tuberculosis
Tuberculosis of the bone.
Long/lung sickness
Lupus vulgaris
Mesenteric disease
Phthisis
Potts disease
Scrofula
White plaque
White swelling
In the previous era, tuberculosis was aptly named as

captain of the ship of death. Many great literary and art
figures died of tuberculosis and millions of victims never
lived long enough to acquire fame. Its most famous victim
was English poet John Keats who died in 1821 at the age of
26 years. Some other famous victims of tuberculosis
include French painter Antoin Walteare (1684-1721),
American philosopher Henry David Thoreu (1817-1862),
Russian writer Antoin Chekhov (1860-1904), Polish composer
Frederic Chopin and South American liberator Simon Bolivar
(1783-1830). The renowned Indian personalities who died
Section 1 Introduction
of this disease include KL Sehgal, the famous singer of
yesteryear and Kamla Nehru, wife of the first Prime
Minister of India, Jawahar Lal Nehru. These deaths
occurred before the availability of chemotherapy.7
The term tubercle was coined by Franciseus Sylvius
(1614-1672). He noticed tubercles in the lungs of people
with phthisis. The term tuberculosis was introduced by
Laurent Bayle (1774-1816) whereas Benjamin Martin (1720)
suggested that tuberculosis may be an infectious disease.
Frascatorious (1483-1553) postulated that this disease
maybe transmitted in human population by air-borne
living particles. This particle was named contagium
vivium. In 1868, Villemin (1827-1892) demonstrated in a
series of experiments that tuberculosis was caused by a
specific agent and that it could be transmitted from man
to animals by inoculation with infected material. Robert
Koch in 1882 identified this specific agent of Villemin.
However, the generic name Mycobacterium was proposed
by Lehmann and Newman in 1896. Koch formulated the
following four postulates (Kochs postulates):
The given organism must be found regularly in the
diseased tissue of the infected person or animal.
The organism must be capable of being grown in pure
culture.
The pure culture must produce the disease when
administered to experimental animals.
The organisms must be found in the experimentally
produced disease, and be capable of being recovered
again in pure culture.7
In 1890, Koch discovered tuberculin and called it a
remedy for tuberculosis, which was not to be.
Nevertheless, tuberculin became an important diagnostic
tool. The theory of allergy, on which Albert Calmette and
Camille Guerin subsequently developed Bacillus Calmette
Guerin (BCG) vaccine, was evolved by Kochs
observation of the altered behavior of infected organisms
when challenged with subsequent infection (Kochs
phenomenon). Koch thought that a successful vaccine
would be a living attenuated vaccine rather than an
inactivated one, and various attempts were made by
many workers including Koch himself to obtain such
attenuated strains. However, only the artificially
attenuated bovine strain of Calmette and Guerin (BCG)
was finally produced by subculturing for 13 years (about
230 times). BCG vaccine was first used in 1921 as a
preventive tool. The discovery of streptomycin by
Waksman in 1944 revolutionized the treatment from
bed rest, good nutrition and fresh air to effective
chemotherapy. In the subsequent three decades, the
conventional long-term therapy was replaced by the
more effective short-course (6-9 months) chemotherapy,
mainly with the discoveries of rifampicin, ethambutol,
and rediscovery of pyrazinamide in the early seventies.
Soon after the establishment of WHO in 1947, TB was

given the highest priority with a focus on BCG
vaccination that was the only widely available control
measure at that time. In late 1950s, WHO resources
assisted in the establishment of vertical programs in high
incidence countries. Beginning 1980s with various control
measures it was hoped that TB will finally get controlled.
However, in early 1990s, TB began its resurgence in
several indus-trialized countries. In 1993 report, the
Director General of WHO declared TB to be a global
public health emergency. In subsequent years, Directly
Observed TreatmentShort-course (DOTS) emerged as
public health breakthrough measure. Millennium
Development Goals (MDGs) for TB Control envisage to
reduce TB prevalence by half by year 2015. To create more
awareness World TB day is celebrated every year on 24th
March all over world.8
Though there is lot of effort to control tuberculosis,
new challenges are also emerging. In 1980s, TB was
considered to be well controlled illness in industrialized
countries. With arrival of HIV infection, there was
resurgence of TB.9,10
Other major challenge that has emerged over last three
decades include epidemic of HIV infection and HIV TB
co-infection, these illnesses enhance progression of each
other and due to drug interaction treatment becomes
difficult. 11,12 There is changing clinical spectrum of illness,
relative increase in extrapulmonary tuberculosis has been
documented.13 Another important challenge include
emergence of multidrug resistant and extensively drug
resistant tuberculosis.14-17
Advances have occurred in the diagnostic tests for
tuberculosis. Important developments in microbiology
include development of newer culture media. With better
understanding of immunology and molecular biology of
Mycobacterium tuberculosis, newer diagnostic tests are being
developed.18,19 Polymerase chain reaction and interferon
gamma release assay (IGRA) are some of them that are
going to play an important role in diagnosis of TB.
HISTORY OF TUBERCULOSIS CONTROL IN INDIA

India may be the birth place of one of the deadliest killers
of tuberculosis. In a first of its kind study called,
Predominance of Ancestral Lineages of Mycobacterium
tuberculosis in India that examined the diversity for
presence of TB strains, a joint team of Indian and French
scientist found that ancestral strains of the TB bacterium
was widespread in India. This is an indication that this
might be the reservoir for TB from which more recent
strains evolved and spread to other countries. Although
India has the highest prevalence of TB world-wide, the
genetic diversity of the bacterium in India was largely
unknown. This made a joint team from the Institute
Pasteur, Paris, Center for DNA Finger Printing and
Chapter 1 History of Tuberculosis

Diagnostics, Hyderabad, Tuberculosis Research Center,
Chennai, and the National JALMA Institute for Leprosy
and Allied Mycobacterial Diseases, Agra. They collected
91 isolates originating from 12 different regions spread
across the country. The samples were analyzed by
genotyping with several tests and found highly
congruent groupings. The four independent sets of
markers made possible a clear definition of the three
prevalent lineages which corresponded to the ancestral
strains, an East African Indian, Delhi and the more
modern and virulent Beijing genogroups. In order to
study this diversity, strains obtained from patients in
India between 1997 and 2002 were analyzed. The
excellent congruence observed between the four
independent sets of genetic markers used here lends
strong support to the assignment of different prevalent
lineages. Sayed E. Hasmain said We have over 2500
strains of TB in their laboratory. After short listing the
91 signature samples, he found that most Indians are
suffering from the treatable and less harmful ancestral
TB bacterium. This makes the scientists believe that India
is the origin for the disease. The virulent modern strain,
Beijing strain, is present in very few numbers. This leads
to an important study of the migration of Indian suffering
from TB to other countries. Scientists from CDC Atlanta,
Division of Tuberculosis Elimination (ADTE) have
suggested that the US change its guidelines and make
tests mandatory for all foreign- born nationals. Hence it
is likely that all foreign born Nationals living in the
United States of America including Indians, would soon
be undergoing regular test for latent tuberculosis. At
present only those foreign born nationals who have
stayed in America for more than five years undergo TB
skin testing and treatment of latent tuberculosis. An eight
member committee headed by Kevin P. Cain, Director
of the TB division at CDC Atlanta collected data on all
TB cases listed in the US National TB Surveillance
database to understand why the number of annual cases
of TB reported in US born residents declined by 93% from
1993 to 2004, while those among foreign born cases
increased by 5%.India has reported 557 TB cases which
figured predominantly in the list of countries of origin
of immigrant residents which had the largest number of
TB cases in 2004 after Mexico (1976) and Philippines (829).
India was followed by China (352), Haiti (248), South
Korea (219), Guatemala (190), Ethiopia (69) and Peru (59).
Interestingly nearly 375 Indians who were diagnosed
with TB were living in US for more than five years.
SANATORIA IN INDIA
A christian mission formed the first open-air sanatorium
for the treatment and isolation of tuberculous patients
(girls from schools and orphanages) in 1906 near Ajmer.
In 1908, another sanatorium of its kind for women and
girls was founded in Almora (Uttar Pradesh). This was
followed by the one in Madanapalle in South India. Later,

many sanatoria were opened by private societies. The
Bhowali Sanatorium was established by the Government
of India in 1911, and was named King Edward Sanatorium. Subsequently, many tuberculosis dispensaries in
different parts of India were opened.20
TUBERCULOSIS ASSOCIATION OF INDIA

Tuberculosis Association of India was established on 23rd
February, 1939. The association set up information and
statistical bureau. The main aim was to encourage the
establishment of the clinics, dispensaries, sanato-ria and
education of the public.
In relation to pediatrics, Indian Academy of Pediatrics
(IAP) formed a Subspeciality Chapter of Tuberculosis in 1989
under the leadership of Late Dr PM Udani.21 Indian
Council of Medical Research (ICMR) has also formed a
separate committee for defining priority areas of research
in tuberculosis in children.
A multicentric study in the form of a Task Force
Project was established by ICMR with Vimlesh Seth as
the Convenor for the various centers. Five centers were
financed by Indian Council of Medical Research (now a
part of an Independent Department of Health Research
of Government of India as an independent body in the
Ministry of Health with Director General of Council as
Secretary Health Research since 2008).
The objectives of these centers were mainly two:
To define the uniform criteria of diagnosis of
tuberculosis in children.
To do clinical trial of short-course chemotherapy
according to the severity of tuberculosis in children.
As a follow-up of these, under the auspices of
Tuberculosis Chapter in Indian Academy of Pediatrics
three expert group meetings were held in 1997 22 ,
200423 and 2010.24 Guidelines/Consensus Statement
on Diagnosis and Management of Tuberculosis in
Children were also formulated by the National
Tuberculosis Control Program (RNTCP). It resulted in a
joint statement of TB division of Ministry of Health and
Family Welfare and experts from Indian Academy of
Pediatrics.25
The spade work has also been done by the
International Union Against Tuberculosis and Lung
Disease (IUATLD), Paris, and by 1990, the International
Conference guidelines by WHO have been laid down
regarding the diagnosis and treatment of tuberculosis of
various types in children in 2006.26
TUBERCULOSIS CONTROL PROGRAM

IN INDEPENDENT INDIA
A Tuberculosis Division in the Directorate General
of Health Services of Ministry of Health and Family
Welfare, Government of India, headed by an Advisor in
Section 1 Introduction
Tuberculosis, was established in 1947. The major
emphasis was on control of the bacillary form of tuberculosis,
and BCG vaccination. With the annual rate of infection of
3 to 4 percent in India, some 94 million children aged
between 0 to 4 years are exposed to the risk of infection
and 3.64 million in this age group are infected annually.26
These numbers will increase substantially because these
estimates were projected when the population of India
was taken as 700 million (1981 census) which is more
than 1000 million at present. Hence, it is felt that simultaneously, the attention needs to be given to child
population as well. To this effect, as mentioned above,
ICMR, IUATLD and WHO are making efforts.
The other activities of the National Tuberculosis
Program of the Government of India, besides BCG
vaccination, are:
Establishment of clinics and domiciliary services
Establishment of training and demonstration centers
Provision of beds for isolation and treatment
Facilities for after care and research.
The activities in this direction have been in the form
of undertaking National Surveys, establishment of
Tuberculosis Research Centre at Madras (Chennai) and
National Tuberculosis Institute at Bangalore (Bengaluru).
Besides, there are separate hospitals for tuberculosis in
major cities and tuberculosis dispensaries in districts.
Training of Community Health Workers and scheme to
provide ambulatory diagnostic and therapeutic services
at the door step are also part of its activities.
It was reported by WHO in 1999 that by the existing
National Tuberculosis Control Program only 30 to 50
percent of those diagnosed with TB were being cured.
The rest were continuing to transmit the infection and
TB remained unattended in children. To tackle this
problem now a committee has been formed involving
WHO experts, program managers in the Health Ministry
and renowned pediatricians from Indian Academy of
Pediatrics who have made guidelines for management
of tuberculosis in children. India is one of the first
countries in the world that included children in national
tuberculosis control programs. Now for children there
are weightwise boxes of medicines.
HISTORY AND DEVELOPMENT OF INTERNATIONAL

COOPERATION IN THE CONQUEST OF TUBERCULOSIS
With the birth of World Health Organization in 1947, a
global approach to tackle the problem of tuberculosis was
made. BCG vaccination campaign which started
separately, is now a part of Universal Immunization
Program and forms an important component of National
Health and Child Health services. There was a period of
turmoil when, from Chingleput study in South India it
was interpreted that BCG is not effective against bacillary
form of tuberculosis. However, later with realization of

limitation of the study on BCG and with the opinion of
pediatricians, it was decided that mass BCG vaccination
should be continued in infants because Chingleput study
did not include children below five years. Moreover,
what causes morbidity and mortality in children is the
hematogenous spread in the form of miliary and
meningeal tuberculosis as a complication of primary
infection. There are ample studies in the medical
literature (India) to prove that BCG vaccination does
provide protection against these severe forms of
tuberculosis, though to variable extent. The advent of
most of the antituberculosis drugs around fifties has
changed the whole concept of treatment of tuberculosis
and with the introduction of rifampicin and
pyrazinamide, it was expected that tuberculosis would
be controlled in the coming years. The concept of shortcourse chemotherapy with rifampicin and killing of
persister bacilli with pyrazinamide, has revolutionized
the treatment. However, with the occurrence of
concurrent infection with HIV, and poor compliance to
antitubercular drugs leading to the emergence of resistant
strains, the problem of multidrug resistant tuberculosis
(MDR-TB) is on the rise. This has to be kept in focus for
the early suspicion and diagnosis of MDR-TB as well as
the proper drug therapy for adequate period. Another
important challenge include emergence of extensively
drug resistant tuberculosis (XDR-TB). The WHO global
program committee and the concerned authorities in the
developed and developing countries are keeping vigil
on these aspects.
REFERENCES
1. Ayvazian LF. History of tuberculosis. In Reichman LB
Hershfield (Eds): Tuberculosis. New York: Dekker 1993.
2. Herzog H. History of tuberculosis. Respiration 1998; 65:
5-15.
3. Menon MPS (Ed). History of tuberculosis. In Pulmonary
Tuberculosis, 2nd edn. New Delhi: National Book Trust
1987; 8-14.
4. Keers RY. Pulmonary Tuberculosis. A Journey Down the
Centuries. London: Bailliere-Tindall 1978.
5. Dubos R. The romance of death. Am Lung Assoc Bull
1982; 68: 5-6.
6. Garrison FH. An Introduction to the History of Medicine.
Philadelphia: Saunders 1913.
7. Kanai K. History of tuberculosis and the related research.
In Introduction to Tuberculosis and Mycobacteria.
SEAMIC publication no. 60. Tokyo, South-East Asian
Medical Information Center/ International Medical
Foundation of Japan 1991; 1-3.
8. Yesudian HM, Raviglione MC. World Tuberculosis Day
2009: partnership for TB care. Indian J Med Res 2009;
129:215-8.
9. Glynn JR. Resurgence of tuberculosis and the impact of
HIV infection. Br Med Bull 1998; 54: 579-93.
Chapter 1 History of Tuberculosis

10. Centre for Disease Control and Prevention (CDC). Progress
toward the elimination of tuberculosisUnited States,
1998. MMWR Morb Mortal Wkly Rep 1999; 48:732-6.
11. Rajasekaran S, Chandrasekar C, Mahilmaran A, et al. HIV
coinfection among multidrug resistant and extensively
drug resistant tuberculosis patientsa trend. J Indian
Med Assoc 2009; 107: 281-2.
12. El-Sadr WM, Tsiouris SJ. HIV-associated tuberculosis:
diagnostic and treatment challenges. Semin Respir Crit
Care Med 2008; 29: 525-31.
13. Kabra SK, Lodha R, Seth V. Tuberculosis in children
what has changed in last 20 years? Indian J Pediatr 2002;
69 Suppl 1:S5-10.
14. Mohapatra PR, Khurana AK, Janmeja AK. MDR-TB in
children: need for clear guidelines. Int J Tuberc Lung Dis
2009;13:1578-9.
15. Schaaf HS, Moll AP, Dheda K. Multidrug- and
extensively drug-resistant tuberculosis in Africa and
South America: epidemiology, diagnosis and
management in adults and children. Clin Chest Med
2009;30:667-83.
16. Shenoi S, Friedland G. Extensively drug-resistant
tuberculosis: a new face to an old pathogen. Annu Rev
Med 2009; 60:307-20.
17. Banerjee R, Schecter GF, Flood J, et al. Extensively drugresistant tuberculosis: new strains, new challenges.
Expert Rev Anti Infect Ther 2008; 6:713-24.
18. Pai M, OBrien R. New diagnostics for latent and active
tuberculosis: state of the art and future prospects. Semin
Respir Crit Care Med 2008; 29: 560-8.
19. Kabra SK, Lodha R, Seth V. Some current concepts on

childhood tuberculosis. Indian J Med Res 2004; 120:
387-97.
20. Rao KN. History of tuberculosis. In Rao KN (Ed): The
Textbook of Tuberculosis, 2nd edn. Vikas Publishing
House, New Delhi 1981;3-15.
21. Udani PM. Tuberculosis of children in India. Paediatr
Clin, India 1983;18:11-42.
22. Treatment of Childhood Tuberculosis. Consensus
Statement Recommendations of Indian Academy of
Pediatrics 1997, in Seth Vimlesh, Kabra SK (Eds) Essentials
of Tuberculosis in Children 3rd edn. Jaypee Brothers
Medical Publishers (P) Ltd, New Delhi 2006; 543-47.
23. IAP Working group Consensus Statement of IAP
working group. Status report on diagnosis of childhood
tuberculosis. Indian Pediatrics 2004;41:146-55.
24. Amdekar YK. Consesus statement on childhood
tuberculosis and working group of Tuberculosis. Indian
Academy of Pediatrics. Indian Pediatr 2010;47:41-55.
25. Management of Pediatric Tuberculosis under the revised
National Tuberculosis Control Programme (RNTCP). A
joint statement of the central TB Division, Directorate
General of Health Services, Ministry and experts from
Indian Academy of Pediatrics, in Seth Vimlesh, Kabra
SK (Eds): Essential of Tuberculosis in Children 3rd edn.
Jaypee Brothers Medical Publishers P (Ltd.), New Delhi
2006;543-8.
26. World Health Organisation. Guidance for National TB
programs on the management of tuberculosis in children.
WHO, Geneva, Switzerland WHO/ HTN/ TB/2006:371.
SECTION 2
EPIDEMIOLOGY
Global Epidemiology of Pediatric Tuberculosis
Interaction of Epidemiological Factors
Epidemiology: Special Reference to Children
Global Epidemiology of Pediatric

Tuberculosis
Md Khurshid Alam Hyder, Nani Nair, Tahmeed Ahmed
INTRODUCTION
Tuberculosis (TB) is one of the most widespread
infections affecting almost one-third of the worlds
population. The disease is an important cause of
morbidity and mortality among both adults and children,
especially in developing countries. It is the first infectious
disease to be declared a global health emergency in 1993.
According to the WHO report 2009,1 globally, there
were an estimated 9.27 million ancient cases of TB in 2007.
This is an increase from 9.24 million cases in 2006, 8.3
million cases in 2000 and 6.6 million cases in 1990. Most
of the estimated numbers of cases in 2007 were in Asia
(55%) and Africa (31%), with small proportions of cases
in the Eastern Mediterranean Region (6%), the European
Region (5%) and the Region of the Americas (3%). The
five countries that rank first to fifth in terms of total
number of cases in 2007 are India (2.0 million), China
(1.3 million), Indonesia (0.53 million), Nigeria (0.46
million) and South Africa (0.46 million). Of the
9.27 million incident TB cases in 2007, an estimated 1.37
million (15%) were HIV-positive; 79% of these HIVpositive cases were in the African Region and 11% were
in the South-East Asia Region. Although the total number
of incident cases of TB is increasing in absolute terms as
a result of population growth, the number of cases per
capita is falling. The rate of decline is slow, at less than
1% per year. Globally, rates peaked at 142 cases per
100000 population in 2004. In 2007, there were an
estimated 139 incident cases per 100 000 population.
Incidence rates are falling in five of the six WHO regions
(Table 2.1).
In 2000, 8.3 million incident cases of TB were reported;
an estimated 11 percent were children and the reported
proportion of TB occurring in children ranged from 3-25
percent.2 The percentage of TB cases occurring in children
is estimated to be below 5 percent in the United States
and European countries.2 However, developed countries
have witnessed a resurgence in TB due to immigration
of people from countries with high incidence of
tuberculosis. In the report in 2009 by WHO there is
no separate mention of children as TB notification
even among new smear-positive cases in DOTS areas.
These figures are available only for 2002, and given in
Table 2.2.
It is not easy to estimate the TB burden in children.

Challenges for doing so include difficulties in establishing
a definite diagnosis, the increased presence of
extrapulmonary disease in young children, the lack of a
standard case definition, and the lower priority given
to childhood TB on the public health agenda compared
to adult TB.3 WHO data for TB in children are specified
only for smear-positive cases. Data available is only upto
2002 (Table 2.2). As children are rarely smear-positive,
except at adolescence as reported recently which
represents only a minor fraction of the total cases. The
focus on smear-positive cases under the DOTS strategy,
also leads to underdiagnosis of TB in children. An
accurate rate of tuberculosis in children is therefore
unknown.
Early identification and successful treatment of cases
of TB is currently the most effective means to protect
children from infection with M. tuberculosis. While the
DOTS strategy is showing encouraging results in a few
developing countries, there is much less evidence of
a similar impact in low-income countries. Sustained
efforts in Beijing Municipality, China, where DOTS was
introduced in 1978, have been able to reduce the
prevalence of TB in children, and particularly lifethreatening forms such as TB meningitis.4
PRESENTATION OF PEDIATRIC TB
Tuberculosis is caused by mycobacteria. M. tuberculosis
is the most frequently found organism, to a lesser extent
also M. bovis and M. africanum. In most cases, the
infection is transmitted from pulmonary smear-positive
cases (open cases) to other people. Patients are
classified as smear-positive if acid-fast bacilli (the
mycobacteria) can be demonstrated in sputum. Children
are rarely smear-positive, hence are much less likely to
be a source of infection for others. However, children
can transmit M. tuberculosis, as has been documented
in large school-based and community outbreaks.5,6 They
are more likely to develop disease after infection and
are significantly more likely to develop extrapulmonary and severe disseminated disease than adults. These
clinical observations apparently reflect fundamental
differences in the immune systems of young children
and adults.7
792 378
909 820
555 064
889 278
1 745 394
1 776 440
6 668 374
AFR
AMR
EMR
EUR
SEAR
WPR
Global
9 273
2 879
295
583
432
3 165
1 919
139
363
32
105
49
181
108
177
171
353
48
297
330
782
142
431
171
495
168
150
132
92
120
102
104
91
92
83
72
46
7 423
168
98
228
311
948
223
378
181
290
392
110
1 962
1 306
528
460
461
353
314
297
255
245
157
Number
1000s
4 062
1 188
157
259
190
1 410
859
3 245
66
53
49
49
42
40
39
37
37
32
21
873
585
236
195
174
159
135
133
115
109
68
Number
1000s
61
150
17
47
21
81
48
77
76
142
26
120
136
298
62
174
75
219
76
75
44
102
131
358
100
163
81
130
174
48
Per
100,000
pop
per year
Smearpositive
Incidence and prevalence estimates include TB in people with HIV.

b
Prevalence of HIV in incident TB cases of all ages.
Source: Ref. 1Global Tuberculosis Control Report, 2009.
4 201 761
High-burden
countries
1. India
1 169 016
2. China
1 328 630
3. Indonesia
231 627
4. Nigeria
148 093
5. South Africa
48 577
6. Bangladesh
158 665
7. Ethiopia
83 099
8. Pakistan
163 902
9. Philippines
87 960
10. DR Congo
62 636
11. Russian
142 499
Federation
12. Vietnam
87 375
13. Kenya
37 538
14. Brazil
191 791
15. UR Tanzania
40 454
16. Uganda
30 884
17. Zimbabwe
13 349
18. Thailand
63 884
19. Mozambique
21 397
20. Myanmar
48 798
21. Cambodia
14 444
22. Afghanistan
27 145
Population
1000s
Per
100,000
pop
per year
Incidencea
All forms
13 723
3 766
348
772
456
4 881
3 500
11 301
192
120
114
136
132
95
123
108
79
96
65
3 305
2 582
566
772
336
614
481
365
440
417
164
Number
1000s
206
475
38
139
51
280
197
269
220
319
60
337
426
714
192
504
162
664
238
283
194
244
521
692
387
579
223
500
666
115
Per
100,000
pop
per year
Prevalencea
all forms
HIV
1 316
357
33
97
56
497
276
1 058
18
10
5.9
12
13
6.9
10
10
5.4
11
8.2
302
194
86
79
18
70
53
46
36
45
20
Number
1000s
Table 2.1: Estimated epidemiological burden of TB, 2007
20
45
3.6
17
6.3
28
16
25
20
26
3.1
29
41
52
15
45
11
77
30
26
15
37
53
38
44
64
28
41
72
14
Per
100,000
pop
per year
Mortality
456
378
7.9
7.7
8.1
40
15
339
3.1
15
2.5
20
16
28
3.9
17
0.9
1.8
0.0
30
6.8
5.4
59
94
0.4
23
1.4
0.3
6.0
5.1
Number
1000s
positive
6.8
48
0.9
1.4
0.9
2.3
0.8
8.1
3.5
39
1.3
49
52
213
6.0
82
1.9
13
0
2.5
0.5
2.4
40
193
0.3
28
0.9
0.3
10
3.6
15
38
11
3.5
9.8
4.6
2.7
14
8.1
48
14
47
39
69
17
47
11
7.8
0
5.3
1.9
3.0
27
73
0.3
19
2.1
0.3
5.9
16
HIV Prev.
Per
in incident
100,000 TB casesb
pop
per year %
HIV
negative
12
Section 2 Epidemiology
13
Chapter 2 Global Epidemiology of Pediatric Tuberculosis

Table 2.2: TB notification in children among new smear-positive cases in DOTS areas (2002)
WHO region
Boys (0-14)
Africa
The Americas
Eastern Mediterranean
Europe
South-East Asia
Western Pacific
Total
Girls (0-14)
Total (0-14)
All ages
% children
7 926
834
1 415
156
2 741
1 000
9 471
988
1 544
201
4 540
1 280
17 397
1 822
2 959
357
7 281
2 280
958 365
134 267
179 594
134 917
954 727
680 750
1.8
1.4
1.6
0.3
0.8
0.3
14,072
18,024
32,096
3,042,620
1.1
The risk of developing TB disease after infection with

M. tuberculosis is, in the absence of HIV co-infection,
estimated to be between 5 and 10 percent in adults, 15
percent in adolescents, 24 percent in children below five
years and as high as 43 percent in children under one year.8
If children develop TB disease, it happens more often early
after infection (progressive primary infection). The factors
that determine a childs risk of developing disease include
younger age, malnutrition, recently acquired infection, and
immune suppression, particularly due to measles or HIV
infection.2 The incubation time (time between infection and
symptoms) generally varies between one to six months.9
If they do not develop disease during childhood, infected
children represent part of the pool from which future adult
TB cases will arise. Children infected with TB also indicate
that recent transmission of TB has occurred in the
communities where they are living.
Pulmonary Tuberculosis
As a result of exposure to TB, a primary parenchymal
lesion called Ghon focus develops in the lung with spread
to the regional lymph nodes. The disease process is
contained at this stage in most cases by the resultant cellmediated immunity. Progression of disease in some
children occurs by: 1) extension of the primary focus with
or without cavitary lesions; 2) the pathological processes
caused by the enlarging lymph nodes, or by 3) spread
through lymphatic and/or hematogenous spread.10
Extrapulmonary Tuberculosis
Extrapulmonary tuberculosis (EPTB) refers to TB of
organs other than the lungs. EPTB is common among
children and the most common forms include TB
lymphadenopathy, TB meningitis, TB effusions (pleural,
pericardial and peritoneal) and spinal TB. According to
WHO the ratio of pulmonary and EPTB in children is
usually around 1:3. However, a retrospective study in
Brazil found that among under-15 children, pulmonary
TB was most frequent (57.8%), EPTB occurred in 24.4%
of the cases, while both forms occurred together in
17.8%.11
Diagnosis of TB infection in children is based on a
positive Mantoux test without signs or symptoms of the
disease, and with a normal chest X-ray.2 Diagnosis of TB

disease in children, however, is difficult because (1)
routine sputum smear microscopy rarely identifies TB
in children: children under the age of ten rarely
expectorate sputum for evaluation; if they do, they may
be less subjected to sputum-microscopy; (2) the Mantoux
test may be negative if the child is malnourished; (3) since
cavitary lesions due to pulmonary TB are rare in children,
chest X-rays are not always helpful except at adolescent
age group.12 If sputum is tested, they are less likely to be
smear-positive compared to adults. Approximately 95
percent of children of less than 12 years old with TB are
smear-negative.13 Gastric aspirates have also a low
specificity: they are positive on smear in 20 percent of
the cases and on culture in 50 percent.14 Gastric aspirates
are often limited to hospital settings in urban areas, as is
the case with mycobacterial culture. This leads to an
underdiagnosis of TB in children as efforts to confirm a
diagnosis are often not made. Cases diagnosed outside
public programs are also less likely to be reported. Case
definitions for research or surveillance are rarely based
on bacteriology. A number of scoring systems are used
based on clinical symptoms, Mantoux test, contact history
and X-ray film of chest. An autopsy study carried out in
Zambia found that 20 percent of children dying of
respiratory disease had evidence of TB, which in many
cases was only diagnosed post mortem.15
WHO does not routinely collect segregated age data
for smear-negative and extrapulmonary cases. This
means that 80 percent of child TB cases cannot be
retrieved in the reported data. The proportion of child
TB varies enormously between countries. In low-prevalence countries, this may be less than five percent,
whereas in some high prevalence countries, it could be
more than four times higher. Detailed information of TB
in children is available from few countries only.
TB IN THE WORLD
Europe
Tuberculosis cases in the WHO European Region make
up less than 5 percent of the global disease burden.16 Casenotification rates vary enormously between countries in
the Region: 3 per 100,000 in Cyprus and Iceland versus
14
178 per 100,000 in Kazakhstan. Most countries in Western
Europe have notification rates below 10 per 100,000, while
some countries in Eastern Europe including the former
Soviet Union report case-detection rates of more than 100
per 100,000 (Fig. 2.1).
Case-notification rates have fallen in France and UK
since 1980 and remain fairly constant in the last five years.
Many Eastern European countries have steadily increasing
TB notification rates. TB data on children are scarce. The
region reported only 551 smear-positive patients in the
age group 0 to 14 years, in both DOTS and non-DOTS
areas. Fifty percent of those came from two countries:
Kazakhstan and Romania. Childhood TB increased more
than threefold in Latvia: from 43 to 144 cases between 1991
and 2000, or an increase in rate from 7.5 to 38.9 per 100,000.
In 2000, childhood TB accounted for 8.4 percent of all TB
cases in Latvia. TB incidence in children has also increased
in the Russian Federation.
Although the proportion of child TB cases is lower in
Kazakhstan than in France, this may be due to
underdiagnosis or underreporting. The substantially
higher share of young adults in Eastern Europe indicates
that children are more exposed to TB from their parents
or their caretakers. Younger TB patients are more likely
than older TB patients to have young children sharing
their household environments.17
Specific changes are also occurring in the pattern and
distribution of child TB cases in the United Kingdom.18
While TB notifications have marginally increased in UK,
they have substan-tially increased in London city.
London alone contributes now 40 percent of all TB cases
in UK. Some areas in London have TB notification rates
of more than 100 per 100 000. Child TB has also increased
every year since 1988. There is also a shift towards more
TB in black African children in UK, whereas the proportion of pediatric cases from the Indian subcontinent
has decreased (44% for black African and 21% for
children from the Indian subcontinent in 1998, while it
was 23% and 50% respectively in 1993). TB in children is
also dramatically increasing in UK due to immigration.
Sixty-six percent of the African children with TB in UK
were born abroad, and developed the disease within five
years after entering the country. Although less
Fig. 2.1: Distribution of TB in the World, AFR-Africa, AMR-The Americas,

EMR-Eastern Mediterranean, EUR-Europe, SEAR-South East Asia,
WPR-Western Pacific (new smear-positive cases 2003)
pronounced, a similar pattern is visible in other urban

centers in UK, with a greater proportion of cases
identified among ethnic minorities.
Other countries in Western Europe report a similar
pattern. Child TB in Stockholm has risen from <1 per
100 000 in 1991 to 5.8 per 100,000 in 1995.19 Fifty percent
of the children with TB were born in Africa. A study from
Copenhagen carried out between 1984 and 1993, showed
that 70 percent of children diagnosed with TB had
immigrant parents.20
Africa
TB case notification in the WHO Africa Region has
increased dramatically in recent years. This is to a large
extent attributable to HIV/AIDS. Although the
population base in African countries is relatively smaller
than the large Asian countries, not less than nine African
countries are found among the 22 high-burden TB
countries (which carry 80% of the global TB burden).
Several African countries have the largest estimated rates
for TB in the world, more than countries in Asia or the
Western Pacific.
Among African countries, South Africa notified the
highest number of TB cases in 2002, both in absolute
number and as a rate per 100000. The notification rates
in South Africa and Zimbabwe are almost three times
those of other high-burden countries. Countries in SubSaharan Africa have witnessed a substantial increase in
TB case notification over the last ten years.21 Two-thirds
of the countries with case rates among children of more
than 5 per 100 000 are located in Sub-Saharan Africa.
In a recent cross sectional survey of latent TB infection
in Cape Town area, only 4.7% had low grade TST
responses of 1-9 mm. The proportions of individuals with
TST 10 mm was 28.0% in the 5-10 year age stratum and
88.0% in the 31-35 year age stratum.22
The incidence in children is much more difficult to
estimate due to lack of systematically collected data. As
most of the African countries have resource-poor health
services, accurate diagnosis of TB in children becomes
even more difficult. As part of the DOTS strategy, several
TB programs in the region rely entirely on sputum-smear
microscopy for diagnosis of TB. This indicates that TB in
children in Africa is both underdiagnosed and underreported. The validity of the scarcely available data is
also not guaranteed.
It is clear however that, in Sub-Saharan Africa, child
TB has a larger share in the overall TB case load compared
with other regions. A study published in 2002 estimates
that childhood TB may represent up to 20 percent of
all TB cases.23 Another study from an urban community
in the Western Cape Province, South Africa, found
that 39 percent of the total cases was younger than 14
years.24

In the United Republic of Tanzania25 and Kenya,26
repeated surveys to estimate the annual risk of
transmission of infection (ARTI) show an increase in areas
where TB notification was the highest. The areas with
the high prevalence rates for TB had also high prevalence
rates of HIV infection.
South-East Asia
The WHO South-East Asia Region consists of six
countries in South Asia (Bangladesh, Bhutan, India,
Maldives, Nepal and Sri Lanka), four countries in SouthEast Asia (Indonesia, Myanmar, Thailand and TimorLeste) and one country in North-East Asia (DPR Korea).
With 26 percent of the global population, these 11
countries carry 34 percent of the global TB burden. India,
Indonesia and Bangladesh are in the top four among the
22 high burden countries. India alone had an estimated
1.7 million TB cases in 2002. Although Maldives has the
lowest TB rate, the rate of this island nation is still twice
that of Western Europe.
There is little information on rates of childhood TB in
the region. Rates of infection have also been used to
estimate the disease burden in a community, given the
limitations of using notification data for this purpose.27
A study by the TB Research Centre, Chennai found an
ARTI of 2 percent in Chingleput district, Tamil Nadu,
India.28 This figure has not changed for the last 30 years,
suggesting that the TB risk for children is not increasing.
It is estimated that approximately ten million children
per year in India alone are at risk of being infected with
TB because of close contact with a smear-positive adult.29
A survey in Indonesian health facilities showed
pediatric cases ranging between 5 and 28 percent of all
TB cases, with the median age of child TB between 4 and
7.7 years old.30
Eastern Mediterranean
TB case notification rates in this part of the world have
remained stable or have even fallen in recent years.
Overall contribution of this region to the global TB
disease burden is only 4 percent.
Only two countries in this region belong to the 22
high burden countries: Afghanistan and Pakistan. Both
countries are severely under-reporting, with less than 20
percent of the estimated cases being notified to WHO.
Very little information from this region is available
with regard to childhood TB.
The Americas
The case-notification rates have remained fairly constant
since 1980 or went even down in most recent years. It
was 40 per 100,000 in the early eighties, while the current
figure stands at 27 to 28 per 100,000.
15
Brazil, the only country of this region belonging to

the 22 high-burden countries, is also seeing a steady
decrease in case-notification since 1998. The US Centers
for Disease Control and Prevention (CDC) reported an
estimated overall TB rate in the USA of 5.6 per 100,000 in
2002. This is the lowest figure since reporting began more
than fifty years ago.31
Data on childhood TB are available mainly from USA,
thanks to the comprehensive notification system by
CDC.2 TB in children is based on a positive tuberculin
skin test, a complete set of diagnostic investigations, signs
and symptoms compatible with TB, and treatment with
two or more anti-TB drugs. The USA experienced a rise
in the overall TB case rate from 1984 to 1992, in
conjunction with the declining public health
infrastructure and the rising epidemic of HIV. However,
the number of pediatric TB cases rose in this period with
40%, twice the increase reported for the population as a
whole.32 Later, pediatric TB fell from 3.1 in 1992 to 1.5
per 100,000 in 2001. However, the share of children
among all TB cases has remained unchanged at 6 percent
during this period. As in UK, children belonging to ethnic
minority groups have a disproportionate share. Children
belonging to the Hispanic, black, non-Hispanic and Asian
or Pacific Islander communities developed TB disease
much more compared to Caucasian children.33,34
In 2001, half of the TB cases reported to CDC occurred
in individuals born outside the USA. In California, the
overall rates of pediatric TB have been falling since 1992;
this decline was most important in children born
overseas. Foreign-born children accounted for 42 percent
of all childhood TB in California between 1985 and 1995.
In San Diego, in over 90 percent of US-born children
under-5 with TB, a source case could be identified from
a highly endemic country or had a primary household
language different from english.35
Western Pacific
Figures in the Western Pacific Region are dominated by
one country, China. There were an estimated 1.5 million
TB cases in 2002 in China, ranking the country second in
the world, after India. The estimated TB rate however, is
moderately high: 113 per 100,000. Most other countries
in the region have estimated rates in the same range. Only
Cambodia has rates comparable to Sub-Saharan African
countries. Apart from China, countries in the region
report very few smear-positive children to WHO: 2,280
of whom 1,881 are in China.
A study in Australia shows how immigration from
high-prevalence countries contributes significantly to the
disease pattern within a low prevalence population.36
Notification rates were highest in children born overseas,
while 51 percent of Australian born children with TB
were from non-English speaking households.
16
EFFECT OF MIGRATION
The effect of migration from resource-poor countries to
developed countries has been well studied with active
TB surveillance programs. This movement has a
tremendous impact on TB in developed countries.
Tuberculosis has been dubbed a re-emerging epidemic,
which was thought to have almost entirely disappeared
from the developed countries. This has been documented
extensively in USA, Australia, UK and Canada. In this
last country, the overall risk of TB was found to be twelve
times higher in immigrants compared to people born in
Canada.37 Similar results have been documen-ted in
Switzerland 38, Germany 39 and Spain.40 Molecular
epidemiological studies undertaken in Norway and UK
suggest that many of the new TB cases in immigrants are
due to reactivation of infections acquired abroad.41-43
Immigrant children in developed countries are at
much higher risk of developing TB com-pared to children
born in the country. Recent arrivals may have been
exposed to TB in their country of origin. Those children
are more likely to be exposed to TB either by traveling
back to their country of origin or because of living in
close contact with infectious adults within their homes.
HIV and TB
HIV has a tremendous effect on TB, particularly in SubSaharan Africa. TB rates have increased following an
increase in HIV. HIV is known to increase the risk of
developing TB disease after infection. It is considered one
of the principal reasons for the resurgence of TB in this
region.
There is limited information on the impact of HIV on
pediatric TB rates. It seems likely that it has contributed
to the increasing rate of disease in children in high
prevalence countries. HIV disproportionately affects
young, economically active people who are more likely
to have young children.
The number of children with TB coinfected with HIV
has also increased. A study from Rio de Janeiro, Brazil
shows an increase from 23 to 31 percent between 1995
and 1999.44 A similar phenomenon has been documented
from South Africa, where 48 percent of children with
culture proven pulmonary TB were coinfected with
HIV.45
While it is clear that HIV-positive children are more
vulnerable for developing the disease after infection, it
is not yet proven if HIV makes them more vulnerable of
being infected. Increased childhood TB rates are
associated with increased rates of disease among HIV
infected adults in the community. As TB is the most
common opportunistic infection in HIV-infected adults,
those adults are more likely to progress to TB disease.
Although HIV-positive TB patients show more smearnegative pulmonary and extrapul-monary disease, the
absolute number of smear-positive cases increases also

substantially, which enhances exposure to and spreading
of the infection to HIV+ and HIV people alike.46 HIV in
adults may be an indirect risk factor for TB in children.47
TB diagnosis in HIV+ children is even more difficult
in resource-poor countries. Tuberculin skin test may
become negative due to HIV-associated anergy. The
clinical presentation of pulmonary TB overlaps with other
opportunistic pulmonary infections and HIV related
illnesses and may therefore, also be overdiagnosed.48 The
child may have TB and other pulmonary diseases
concurrently, and thus initially improve with a broadspectrum antibiotic course.40 The treatment outcomes of
HIV+ TB children are also worse due to a higher
mortality. A study in Ethiopia showed that the mortality
during TB treatment in HIV+ children was six times
higher than in HIV-negative children.49 Similar results
were obtained from studies in the Cte dIvoire. 50
Children with TB and HIV coinfection also appear to have
higher relapse rates.
A major difference between children and adults with
HIV is the time of infection. Most adults have been
infected with M. tuberculosis prior to their HIV infection.
Tuberculosis disease may thus represent a reactivation
of a latent infection. Most children are perinatally infected
with HIV. Exposure to and infection with TB occurs
usually later. TB in children with HIV may therefore,
occur at a later age, as young children with HIV are at a
high-risk of morbidity and mortality from other
respiratory diseases before they are infected with TB.51
MDR-TB
Drug-resistant TB may be acquired due to inadequate
previous treatment episodes. Such failure cases may
spread resistant bacilli. Primary resistance occurs in
people who are resistant to anti-TB drugs without being
treated. Resistant children generally are primary
resistant, as they are less likely to have been treated
before.52 There were estimated 0.5 million cases of multidrug-resistant TB (MDR-TB) in 2007. The countries that
rank first to fifth in terms of total number of MDR-TB
cases are India (1,31,000), China (1,12,000), the Russian
Federation (43,000), South Africa (16,000), and
Bangladesh (15,000). By the end of 2008, 55 countries and
territories had reported at least one case of extensively
drug-resistant TB (XDR-TB).1 No such data is available
for children. It is however, very difficult to document
drug resistance in children due to lower rates of
microbiological confirmation in children. The diagnosis
of resistant TB in children is often made on demonstrating
resistance in an adult index case. There may be a strong
correlation with a suspect index case in low risk countries.
In high prevalence countries however, multiple exposure
within the same household, with a drug-sensitive index

case, does not rule out primary drug resistance in a
child.
There is no evidence that drug resistant bacilli would
lead to increased infectiousness or increased risk of
progressing to disease after infection.53 In general, the
incidence and types of resistant organisms found in
children will reflect the resistance pattern of organisms
circulating in the community.54 A South African study
conducted between 1994 and 1998 found 5.6 percent
isoniazid resistance and 1 percent multidrug resistance
(isoniazid and rifampicin) in culture-positive TB
children.55 These figures were similar to what was found
in the adult population during the same period. Data
from UK also shows similar resistance patterns in
children and adults.
CONCLUSION
Tuberculosis remains a major problem of public health
with a high morbidity and mortality. The internationally
recommended DOTS strategy focuses on identifying and
treating smear-positive cases, as a way of prioritizing
infectious cases and focusing interventions on cutting the
transmission.
Yet little is known about the global impact of
childhood tuberculosis. The overall majority of TB in
children is ignored when limiting our attention to smear
or culture-positive cases only. The number of children
suffering or dying from TB is unknown. Data are rather
scarce, and if available, they document mainly findings
in developed countries. Migration is the main reason for
the resurgence of TB in industrialized countries, while
HIV is the main cause fuelling the TB epidemic in
resource-poor, high-burden TB countries. Most children
with TB are not identified through national surveillance
systems; they often represent the more severe complications. TB in children is also a sentinel marker for active
transmission of TB within communities.56
HIGHLIGHTS
Childhood TB contributes 5 to 15 percent of total
TB cases.
Estimates of TB in children are gross under estimates
as most surveys report smear-positive cases only.
Childhood TB has a larger share in Sub-Saharan
Africa.
Immigrant children are more prone to develop TB
as compared to those born in that country.
REFERENCES
1. Global Tuberculosis Control Report. 2009. Available
from: URL http://www.who.int/tb/publicatons/
global/2009/pdf/fullreport.pdf. Accessed April 4, 2009.
2. Nelson LJ, Wells CD. Global epidemiology of childhood
tuberculosis. Int J Tuberc Lung Dis 2004; 8:636-47.
17
3. Kabra SK, Lodha R, Seth Vimlesh. Childhood

tuberculosis: what has changed in last 20 year. Indian J
Pediatr 2002; 69: S5-10.
4. Enarson DA. Children and global tuberculosis situation.
Paediatr Respir Rev 2004; 5(Suppl A): S143-5.
5. Eamramond P, Jaramillo E. Tuberculosis in children:
reassessing the need for improved diagnosis in global
control strategies. Int J Tuberc Lung Dis 2001;5:594-603.
6. Curtis AB, Ridzon R, Vogel R, et al. Extensive
transmission of Mycobacterium tuberculosis from a child.
N Engl J Med 1999;341:1491-5.
7. Lewinsohn DA, Gennaro ML, Scholvinck L, et al.
Tuberculosis immunology in children: diagnostic and
therapeutic challenges and opportunities. Int J Tuberc
Lung Dis 2004;8:658-74.
8. Miller F, Seal R, Taylor M. Tuberculosis in children.
Boston: Little Brown, 1963.
9. Feigin R, Cherry J. Textbook of Pediatric Infectious
Diseases, 4th edn. Philadelphia: WB Saunders; 1998.
10. Guidance for national tuberculosis programmes on
the management of tuberculosis in children: World
Health Organization. Available at: WHO/HTM/TB/
2006.371.
11. Franco R, Santana A, Matos E, et al. Clinical and
radiological analysis of children and adolescents with
tuberculosis in Bahia, Brazil. Braz J Infect Dis 2003 ;7:
73-81.
12. Ahmed T, Sobhan F, Ahmed AMS, et al. Childhood
tuberculosis: a review of epidemiology, diagnosis and
management. Inf Dis J Pak 2008;17:52-60.
13. Jereb JA, Kelly GD, Porterfield DS. The epide-miology
of tuberculosis in children. Sem Pediatr Infect Dis
1993;4:220-31.
14. Khan EA, Starke JR. Diagnosis of TB in children:
increased need for better methods. Emerg Infect Dis 1995;
1: 115-23.
15. Chintu C, Mudenda V, Lucas S. Lung diseases at
necropsy in African children dying from respiratory
illnesses: a descriptive necropsy study. Lancet
2002;360:985-90.
16. WHO Report 2004. Global Tuberculosis Control.
Surveillance, Planning, Financing.
17. Rieder HL. Epidemiology of tuberculosis in children.
Annales Nestl 1997;55:1-9.
18. Atkinson P, Taylor H, Sharland M, et al. Resurgence of
pediatric tuberculosis in London. Arch Dis Child
2002;86:264-5.
19. Eriksson M, Bennet R, Danielsson N. Clinical
manifestations and epidemiology of childhood
tuberculosis in Stockholm 1976-95. Scand J Infect Dis
1997;29:569-72.
20. Rosenfeldt V, Paerregaard A, Fuursted K, et al.
Childhood tuberculosis in a Scandinavian metropolitan
area 1984-93. Scand J Infect Dis 1998;30:53-7.
21. Walls T, Shingadia D. Global epidemiology of pediatric
tuberculosis. J Infect 2004;48:13-22.
22. Wood R, Liang H, Wu H, et al. Changing prevalence of
tuberculosis infection with increasing age in high-burden
townships in South Africa. Int J Tuberc Lung Dis
2010;14:406-12.
18
23. Donald P. Childhood tuberculosis: out of control? Curr
Opin Pediatric 2002;8:178-82.
24. Van Rie A, Beyers N, Gie R, et al. Childhood tuberculosis
in an urban population in South Africa: burden and risk
factor. Arch Dis Child 1999; 80:433-7.
25. Tanzanian tuberculin study collaboration, Tuberculosis
control in the era of the HIV epidemic: risk of tuberculosis
infection in Tanzania, 1993-1998. Int J Tuberc Lung Dis
2001;5:103-12.
26. Odhiambo J, Borgdorff M, Kiambih F. Tuberculosis and
the HIV epidemic: increasing annual risk of tuberculosis
infection in Kenya, 1986-1996. Am J Public Health
1999;89:1078-82.
27. Styblo K. The relationship between the risk of
tuberculosis infection and the risk of developing
tuberculosis. Bull Int Union Tuberc 1985;60:117-9.
28. Tuberculosis Research Centre. Trends in the prevalence
and incidence of tuberculosis in South India. Int J Tuberc
Lung Dis 2001;5:142-57.
29. Chakraborty A. Problem of tuberculosis among children
in the community: situation analysis in the perspective
of tuberculosis in India. Indian J Tuberc 1999;46:91-103.
30. Manissero D. Personal communication with author.
31. CDC. Reported tuberculosis in the United States 2001.
Atlanta: US Department of Health and Human Services,
CDC; 2002.
32. Starke J. Childhood tuberculosis: ending the neglect. Int
J Tuberc Lung Dis 2002;6:373-4.
33. Ussery XT, Valway SE, McKenna M, et al. Epidemiology
of tuberculosis among children in the United States.
Pediatr Infect Dis J 1996;15:697-704.
34. Saiman L, San Gabriel P, Schulte J, et al. Risk factors for
latent tuberculosis infection among children in New York
City. Paediatrics 2001;107: 993-1003.
35. Kenyon T, Driver C, Haas E, et al. Immigration and
tuberculosis among children in the United States
Mexico, county of San Diego, California. Paediatrics
1999;104-8.
36. Heath T, Roberts C, Winks M, et al. The epidemiology of
tuberculosis in New South Wales 1975-1995: the effects
of immigration in a low-prevalence population. Int J
Tuberc Lung Dis 1998;2: 647-54.
37. Long R, Sutherland K, Kunimoto D, et al. The
epidemiology of tuberculosis among foreign-born
persons in Alberta, Canada, 1989-1998: identification of
high-risk groups. Int J Tuberc Lung Sis 2002;6:615-21.
38. Barrazone C, Hofer M, Nussle D, et al. Childhood
tuberculosis at a Swiss university hospital: a two year
study. Eur J Pediatr 1993;152:805-9.
39. Felten MK, Rath T, Magdorf K, et al. Childhood
tuberculosis in Germany between 1985 and 1994:
comparison of three selected patient groups. Int J Tuberc
Lung Dis 1998;2:797-803.
40. Del Rosal T, Baquero-Artigao F, Garca-Miguel MJ, et al.
Impact of Immigration on Pulmonary Tuberculosis in
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
Spanish Children: A Three-Decade Review. Pediatr Infect

Dis J 2010 Mar 5. [Epub ahead of print].
Dahle U, Sandven P, Heldal E, et al. Molecular
epidemiology of Mycobacterium tuberculosis in Norway. J
Clin Microbiol 2001;39:1802-7.
Hayward A, Goss S, Drobniewski F, et al. The molecular
epidemiology of tuberculosis in inner London. Epidemiol
Infect 2002;128:175-84.
Maguire H, Dale J, McHugh T, et al. Molecular
epidemiology of tuberculosis in London 1995-1997
showing low rate of active transmission. Thorax
2002;57:617-22.
Alves R, Ledo A, Cunah A, et al. Tuberculosis and HIV
co-infection in children under-15 years of age in Rio de
Janeiro, Brazil. Int J Tuberc Lung Dis 2003;7:198-9.
Jeena P, Pillay P, Pillay T, et al. Impact of HIV-1
coinfection on presentation and hospital-related
mortality in children with culture pulmonary
tuberculosis in Durban, South Africa. Int J Tuberc Lung
Dis 2002;6:672-8.
Thomas P, Bornschlegel K, Singh T, et al. Tuber-culosis
in human immunodeficiency virus-infected and human
immunodeficiency virus-exposed children in New York
City. Pediatr Infect Dis J 2000;19:700-6.
Jones D, Malecki J, Bigler W, et al. Paediatric tuberculosis
and human immunodeficiency virus infection in Palm
Beach County, Florida. Am J Dis Child 1992;146:1166-70.
Graham SM, Coulter JBS, Gilks CF. Pulmonary disease
in HIV-infected African children. Int J Tuberc Lung Dis
2001;5:12-23.
Palme I, Gudetta B, Bruchfeld J. Impact of human
immunodeficiency virus I infection on clinical
presentation, treatment and survival in a cohort of
Ethiopian children with tuberculosis. Pediatr Infect Dis
J 2002;21:1053-61.
Mukadi Y, Wiktor S, Coulibaly I, et al. Impact of HIV
infection on development, clinical presentation and
outcome of tuberculosis among children in Abidjan, Cte
dIvoire. AIDS 1997;11:700-6.
Schaaf HS, Cotton MF, de Villiers GS, et al. Clinical
insights into the interaction of childhood tuberculosis and
HIV in the Western Cape. S Afr J HIV Med 2000;7:33-5.
Schaaf HS, et al. Transmission of multidrugresistant
tuberculosis. Pediatr Infect Dis J 2000; 19:695-9.
Tiexeira L, Perkins MH, Johnson J. Infection and disease
among household contacts of patients with multi-drugresistant tuberculosis. Int J Tuberc Lung Dis 2001;5:321-8.
Steiner P, Rao M. Drug-resistant tuberculosis in children.
Sem Pediatr Infect Dis 1993;4:275-82.
Schaaf H, Gie R, Beyers N, et al. Primary drug-resistant
tuberculosis in children. Int J Tuberc Lung Dis
2000;4:1149-55.
Bloch A, Snider D. How much tuberculosis in children
continue to be neglected? Am J Public Health 1986;76:
14-5.
Interaction of
Epidemiological Factors
Donald A Enarson, Nulda Beyers
INTRODUCTION
No one could say that tuberculosis is not a serious
problem today. It is the most frequent cause of death from
a single disease in the world among those aged 15 to 49
years, and the main cause of death in people living with
HIV/AIDS. Deaths due to tuberculosis are equivalent to
the crash of a jumbo jet every hour of every day.
The distribution and trend of tuberculosis in the world
has been extensively described in other publications.1-3
The epidemiology of tuberculosis has been described over
many years by a series of eminent investigators.4-12
According to WHO report 2009,13 globally there were an
estimated 9.27 million incident cases of TB in 2007. This
is an increase from 9.24 million cases in 2006; 8.3 million
cases in 2000 and 6.6 million cases in 1990. Most of the
estimated number of cases in 2007 were in Asia (55%)
and Africa (31%). The most important epidemiological
factor is the HIV status of population. These publications
have highlighted the fact that tuberculosis is less a disease
of the individual and more strikingly a disease of the
family and of the community. This is even more the case
with tuberculosis in children.
A Framework for Understanding the Epidemiology of

Tuberculosis
Understanding the epidemiology, natural history and
control of tuberculosis is much easier when the disease
is considered as a series of transitions from being
susceptible to becoming ill and finally being cured,
becoming a chronic case or dying of the disease.14
This model, originally proposed in the 1960s, has been
revisited recently15 and its evidence base outlined.16-35
Key transitions relevant to tuberculosis in children are
the transitions from being susceptible to becoming
infected (by way of being exposed)36-37 and transitions
from having disease to being diagnosed with the disease
(by way of accessing health services, being recognized
as showing clinical features suggestive of the disease, to
being confirmed, or at least confidently diagnosed, as a
case of tuberculosis).38
Epidemiological Methods for Measuring

Tuberculosis
A variety of methods have been applied and standardized
for the measurement of tuber-culosis in epidemiological
investigations, including mortality studies,39 studies of
routine notifications,40-43 data from routine reporting and
recording practices, prevalence surveys of disease44 and
of infection45-48 and cohort studies of risk factors of
disease.49,50 Studies have employed clinical and/or radiological examination,51-55 bacteriological techniques56-60 and
molecular techniques.61-67 Identification and isolation of
the microorganism using routine bacteriological
techniques has been considered the gold standard in
identifying a case of tuberculosis. However, this has been
reported to be insensitive in children from whom it is
exceedingly difficult to isolate Mycobacterium tuberculosis
in the majority of cases.1 Because it is so difficult to isolate
the microorganism, defining a case for study purposes is
a great challenge. For this reason, tuberculous meningitis
in children was often used as an indicator of disease as
well as of recent infection.
The tuberculin skin test, the gold standard for
indicating the presence of infection with Mycobacterium
tuberculosis has been used extensively, 68 and even
predominantly, in children. This test identifies
individuals who have been infected with Mycobacterium
species and does not indicate the presence of disease.
Distribution of Tuberculosis in Children

The distribution of a disease in a population is classically
presented by characteristics of person, place and time.
Person
Several recent reviews69,70 have evaluated a series of
studies from the prechemotherapy era that describe the
clinical course of tuberculosis in children. The variation
in distribution of tuberculosis by age71,72 is particularly
significant in tuberculosis in children. The incidence of
infection rises steadily from birth to the age of 9 years,
rises more slowly from ages 10 to 14 and then rises
steeply. The probability of developing clinically
20
significant disease following infection also varies with
age. It is highest in children under one year of age
(occurring in an estimated 12%), declines to reach its
lowest level from ages 4 to 9 years and then rises steadily
until adulthood. This trend in risk of developing disease
is accompanied by a substantially greater risk of
developing severe disease leading to death in the
youngest age group, under one year of age. The same
age distribution is seen in communities with very little
tuberculosis73 and in those with a very high prevalence
of disease.74 The pattern of infection and disease by age
identifies two distinct groups of patients, those under
10 years of age (and particularly the youngest group) and
those 10 years and older.75 Among those who will become
infected for the first time at some point in their lives, most
will acquire the infection during childhood, at least in
countries where tuberculosis is steadily declining. The
greatest risk of progressing from infection to disease occurs
in children who are infected for the first time under the
age of 2 years or during the adolescent period.
The site in the body where the disease appears also
varies with age. A study of children admitted to
sanatorium in the period prior to the advent of
chemotherapy76 showed that, among older children
(5 years of age or older), the tuberculosis manifested itself
most frequently as pleurisy (one-quarter to one-third of
cases). This was not the case for the younger children
(under 5). The frequent manifestation of tuberculosis as
pleurisy, is also observed among adults newly infected
in the course of their work,77 and raises the question of
whether this phenomenon is due to age, or due to time
elapsed since infection. Frost,6 in demonstrating mortality
rates in birth cohorts for 1880 to 1910, showed that
mortality was equal for boys and girls under 5 years of
age but was greater for girls than for boys in children
aged 5 to 9 years (relative risk 1.72) and aged 10 to 19
years (relative risk 1.67). The occurrence of complications
(including fatality) following primary tuberculosis in
children did not differ between girls and boys.74 Females
are slightly (approximately 20%) more likely to be
infected than males.78 However, among the very young
(under 5 years), this ratio is the inverse with females being
less likely (about 30%) than males to be infected.
Tuberculosis has traditionally been considered a
disease of poverty, the reason for the association being
the increased risk of exposure to Mycobacterium
tuberculosis due to crowding. However, even in a
homogeneously poor community, tuberculosis is
demonstrably associated with socioeconomic factors
indicating relative disadvantage.79
The importance of an intact immune system in
controlling Mycobacterium tuberculosis in people already
infected has been incontrovertibly shown.80 Its precise
impact on tuberculosis in children has been less clearly

investigated. Some studies have suggested a role of
genetic susceptibility.81-83 In many low income countries
there is a high prevalence of infection with both
Mycobacterium tuberculosis and HIV. This will invariably
lead to an increase in childhood TB cases, but even more
worrying also to an increase in infectious cases of TB in
adolescents and young adults, who are the very people
having young children and will transmit these infections
to their children.
Place
Striking differences in tuberculosis notification rates
among various countries have been shown to reflect
differences in probability of exposure in those locations
during the early years of life.84 Moreover, when children
born in low-burden communities of parents from highburden communities visit the latter communities, they
increase their probability of becoming infected and
developing disease.85 This fact confirms much earlier
studies of uninfected, mobile populations86-87 showing
their increasing risk of infection, disease and death as
they move into areas where their risk of exposure is
increased. In locations with a high burden of tuberculosis,
a high proportion of all existing cases are children
because they are at a high risk of becoming infected (and
rapidly developing disease), although they are frequently
undetected due to limited access to and quality of health
services.
Time
The change in age-specific incidence/mortality of
pulmonary tuberculosis has been examined in a variety
of locations. These investigations have shown an
unchanging profile of age-specific occurrence of the
disease over time. The principal change is in the level of
the disease, and not in its essential age-specific curve. A
similar study in the trend in prevalence of infection has
been shown in the Netherlands,1 where systematic
tuberculin tests have been carried out on military recruits.
This investigation shows an unvarying shape of the agespecific curve; the variation with time is only in the level
of the prevalence. These unchanging patterns have been
termed a cohort phenomenon; that is to say, each
succeeding birth cohort has a similar pattern, although
varying level, of tuberculosis. Tuberculosis in children
has a seasonal variation88 with a peak in late winter/
early spring. This might be attributed to the increased
exposure due to being indoors for a greater extent during
the seasons of inclement weather, or due to the fact that
in winter children cough from a variety of causes and
Chapter 3 Interaction of Epidemiological Factors

this cough, often from other causes, may urge the parents
to seek health care for the child-tuberculosis which might
otherwise have been undetected, is then diagnosed.
The occurrence of tuberculosis is affected by social
and political changes. This has been clearly demonstrated
for the impact of war.89,90 The impact of HIV infection on
the burden of tuberculosis in communities is dramatic.91
Other forms of socioeconomic change are associated with
a change in tuberculosis, such as a drastic reduction in
economies92 or of services.93 These effects have been
reflected promptly in the occurrence of disease in
children.94 The impact of socioeconomic conditions on
tuberculosis is substantial and sufficient to lead some
scientists to suggest that these conditions have equal or
greater impact than medical measures.95
DETERMINANTS OF TUBERCULOSIS IN CHILDREN

Exposure
If a person never encounters the Mycobacterium
tuberculosis, that person will never become infected and,
therefore, can never develop the disease. While,
exposure has been measured directly, using live guinea
pigs,96 this technique is impractical for most studies.
Indirect estimations of exposure have been developed
in contact studies. From these studies, the concentration
of bacteria in the environment, as indicated by the
concentration of bacteria in expectorated sputum of
tuberculosis cases,97 and the intensity of the interaction
between the susceptible person and the person with the
contagious disease have been identified as key
predictors of becoming infected. The scenario outlined
in these studies identifies the household as the location
where infection is most likely to occur and the
transmission is from parent to child. In a study of
tuberculous infection in a number of African countries
in the 1960s, Roelsgaard reported tuberculous infection
to be substantially more likely if there was a history of
contact with a case of tuberculosis.78 The risk ratio was
substantially higher in younger children (risk ratios of
10.1 for 0 to 4-year-old, 3.9 for 5 to 9-year-old and 1.9
for 10 to 14-year-old). The diminution in risk ratios with
age were related to a higher prevalence of infection in
older age groups (6-fold higher in 5 to 9-year-old,
compared with 0-4 year-olds and 2.2 times higher in 10
to 14-year-old compared with 5 to 9-year-old). In a
report from India it was observed that the prevalence
of tuberculosis infection and clinical disease among
children in household contact with adult patients is
higher than in the general population, and risk is
significantly increased by contact with sputum positive
adults.98 An additional factor increasing the probability
21
of becoming infected is the duration of exposure,

increased by delay in diagnosis in adult patients
carrying bacteria susceptible to antibiotics. Where the
disease is essentially untreatable (multidrug resistant),
the potential for prolonged exposure increases the
probability of transmission of the infection with these
multidrug resistant bacteria.99,100
Time Since Infection

Tuberculosis disease is most likely to appear during the
time immediately following infection.20,21 One-fifth of the
risk of subsequently developing disease occurs in the first
year following infection, if preventive chemotherapy is
not given.
The type of disease following infection also varies
with the time that has elapsed since infection. In a study
of children admitted to hospital after exposure to their
parents who had tuberculosis, Wallgren19 identified that
sites of disease such as the peripheral lymph nodes and
the pleura were affected when the disease occurred soon
after infection while genitourinary disease occurred only
many years following infection.
Host Immunity
The observation that only a minority of people develop
disease after becoming infected with Mycobacterium
tuberculosis is explained by the effective functioning
of cell-mediated immunity. The impact on tuberculosis
of reducing immune function has been dramatically
illustrated by the epidemic of human immune
deficiency virus (HIV).101 The reason for the unusual
clinical features of some tuberculosis cases associated
with HIV in industrialized countries has been studied
in Los Angeles.22 This study showed clearly that the
variation in clinical appearance associated with HIV
infection was related to the level of cell-mediated
immune function. This may explain both the difference
in clinical features of tuberculosis in small children as
compared with adults (primary tuberculosis) and the
higher rate of occurrence of tuberculosis in small
children that cannot likely be explained by an
increased risk of exposure.
EVALUATION OF INTERVENTIONS
WITH REFERENCE TO CHILDREN
Objectives of Intervention
Many have claimed that the current case management
strategy for tuberculosis (directly-observed treatment
short-course, DOTS)102 does not take sufficient notice of
the needs of children. This is, at one and the same time,
true and false. Because of its emphasis on the smear-
22
positive pulmonary patient as the priority in the strategy
and, as has been previously noted, children with
tuberculosis are under represented among cases reported
as only a minority of children has sputum smear-positive
tuberculosis. While the DOTS strategy focuses primarily
on adults (smear-positive cases), its ultimate objective is
the prevention of infection in children. The goal is to
create a generation of children free of infection. Many
industrialized countries have come close to achieving this
but many have suggested that this had already occurred
before the introduction of effective therapeutic
interventions. The evidence that a generation of children
free of infection can be achieved in high-burden or lowincome communities, through the introduction of
interventions, is comparatively rare. A substantial
reduction in prevalence of infection following promptly
on introduction of chemotherapy in aboriginal
communities in Alberta, Canada has been shown.43 A
similar impact in Beijing municipality on the reduction
of tuberculous meningitis and the prevalence of
tuberculous infection has been shown after introduction
of modern tuberculosis control policies into a community
with virtually no coherent policy of management prior
to 1978.103,104
Aims of a Program
The aims of programs for the management of tuberculosis
are two-fold: to provide a high standard of clinical
practice to the greatest proportion of tuberculosis patients
and to find and render no longer infectious (through cure)
the most potent sources of transmission (the sputum
smear-positive cases).105
Case Management Priorities

The DOTS strategy focuses on cure of adults with newly
detected tuberculosis patients as the highest priority. This
was a shift from previous policy that stressed case-finding
as the highest priority because it was shown that
treatment whose results were unsatisfactory was actually
worse from an epidemiological point of view than no
treatment at all,106,107 an observation that had been made
early after the introduction of chemotherapy but that had
been ignored until highlighted by Grzybowski.107 The
DOTS strategy has resulted in improvement of treatment
outcome, reducing the prevalence of tuberculosis patients
by curing them, and has also enhanced case-finding by
providing quality services close to the residence of the
patients, enhancing accessibility.
Case management in children is hampered by the
difficulty in case detection and diagnosis. In addition,
although childhood cases are often recorded as smearnegative cases in the TB register, there is usually no
routine reporting of smear-negative cases by age, and

thus the burden of childhood TB cases is not easily
measurable. As with the DOTS strategy, where the focus
has been on the most potent sources of transmission,
policies aimed at efficient management of tuberculosis
in children must focus on priorities. Tuberculosis in
children is a disease as much of setting as of agent;
children need to be managed as part of their community
setting. Case-finding needs to focus on investigation of
children in contact with known cases of tuberculosis.108
Moreover, a comprehensive approach is required in the
management of such children, stressing not only the
management of existing cases but the prevention of
future cases through the use of comprehensive
preventive chemotherapy. Unfortunately, the feasibility
and efficiency of comprehensively applying this
recommendation has not been demonstrated in highburden communities. There is an urgent need to
undertake an evaluation and revision of the
recommendations regarding preventive chemotherapy
in this setting.
ERADICATION OF TUBERCULOSIS
Will this strategy take us to the ultimate goal, a generation
free of tuberculous infection, with the consequent
eradication of this disease? There are reasons to suspect
that, in areas not heavily impacted by the HIV epidemic,
it should be possible to make important strides in this
direction, even with the rather inadequate tools we have
currently available.109 Clearly, to achieve the final push
against tuberculosis, it will be necessary to reverse the HIV
epidemic. The role of drug resistance in maintaining the
epidemic is controversial110 and the priority, for the
present, without question, is on effective management of
the drug-susceptible cases. What is clear is the need to
maintain political commitment for the duration of the fight
against tuberculosis, a challenge that may be difficult to
meet.
HIGHLIGHTS
Tuberculosis is less a disease of the individual and
more strikingly a disease of the family and of the
community. This is even more the case with
tuberculosis in children
Because it is so difficult to isolate the microorganism,
defining a case for study purposes is a great
challenge. For this reason, tuberculous meningitis
in children has often been used as an indicator of
disease as well as of recent infection
The variation in distribution of tuberculosis by age
is particularly significant in tuberculosis in children
The household is the location where infection is most
likely to occur and the transmission is from parent
to child

While the DOTS strategy focuses primarily on adults
(smear-positive cases), its ultimate objective is the
prevention of infection in children. The goal is to
create a generation of children free of infection
Case finding needs to focus on investigation of
children in contact with known cases of tuberculosis
A comprehensive approach is required in the
management of such children, stressing not only the
management of existing cases but the prevention of
future cases through the use of comprehensive
preventive chemotherapy.
REFERENCES
1. Styblo K. Epidemiology of Tuberculosis. KNCV Selected
Papers 1991;24:1-36.
2. Rieder HL. The Epidemiological basis of Tuberculosis
Control. Paris: International Union Against Tuberculosis
and Lung Disease 1999; 162.
3. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis
incidence and mortality during 1990-2000. Bull Wld
Health Org 1994; 72: 213-20.
4. Andvord KF. Der Verlauf der Tuberculose durch
Generationen, Beitr Klin Tuberk 1930; 75: 552-63.
5. Heimbeck J. Tuberculosis in hospital nurses. Tubercle
1936;18:97-9.
6. Frost WH. The age selection of mortality from tuberculosis in successive decades. Am J Hyg 1939;30:91-6.
7. Terris M. Relation of economic status to tuber-culosis
mortality by age and sex. Am J Pub Health 1948;38:1061-70.
8. Horwitz O, Palmer CE. Epidemiological basis of tuberculosis eradication. Dynamics of tuberculosis morbidity
and mortality. Bull Wld Health Org 1964;30:609-21.
9. Grzybowski S, Allen EA. The challenge of tuberculosis
in decline. Am Rev Respir Dis 1964; 90:707-20.
10. Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle
bacilli: The effects of chemotherapy. Tubercle 1976;57:27599.
11. Comstock GW. Epidemiology of tuberculosis. Am Rev
Respir Dis 1982;125:8-15.
12. Snider DE. Research towards global control and
prevention of tuberculosis with an emphasis on vaccine
development. Rev Infect Dis 1989;11 (suppl 2):S336-8.
13. Global Tuberculosis Control Report 2009. Available from:
URL http://www.who.int/tb/publications/global/
2009/pdf/fullreport.pdf. Accessed April 4, 2009.
14. Waaler HT, Piot MA. The use of an epidemiological model
for estimating the effectiveness of tuberculosis control
measures. Sensitivity of the effectiveness of tuberculosis
control measures to the coverage of the population. Bull
Wld Health Org 1969;41:75-93.
15. Enarson DA, At-Khaled N. Tuberculosis. In AnnesiMaesano I, Gulsvik A, Viegi G, (Eds): Respiratory
Epidemiology in Europe, Hudders-field: The
Charlesworth Group, 2000:67-91.
16. Rieder HL. Opportunity for exposure and risk of infection:
The fuel for the tuberculosis pandemic. Infection
1995;23:5-8.
23
17. Nissen Meyer S, Dahlstrom G. Tuberculosis in BCG

vaccinated and non vaccinated young adults. Acta Tuberc
Scand 1953;32(suppl).
18. Daniels M, Ridehalgh F, Springett VH, et al. Tuberculosis
in young adults. London: Lewis. 1948.
19. Wallgren A. The time table of tuberculosis. Tubercle
1948;29:245-51.
20. Ferebee SH, Mount FW. Tuberculosis morbidity in a
controlled trial of the prophylactic use of isoniazid among
household contacts. Am Rev Respir Dis 1962;85:490-510.
21. DArcy Hart P, Sutherland I. Final report of the Medical
Research Council by its Tuberculosis Vaccines Clinical
Trials Committee. BCG and vole bacillus vaccines in the
prevention of tuberculosis in adolescence and early adult
life. Br Med J 1977; ii:293-5.
22. Jones BE, Ryu R, Yang Z, et al. Chest radiographic studies
in patients with tuberculosis with recent or remote
infection. Am J Resp Crit Care Med 1997; 156:1270-3.
23. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study
of the risk of tuberculosis among intravenous drug users
with human immuno-deficiency virus infection. N Engl
J Med 1989;320: 345-50.
24. Springett VH. Ten-year results during the intro-duction
of chemotherapy for tuberculosis. Tubercle 1971;52:73-87.
25. Rutledge CJA, Crouch JB. The ultimate results in 1,694
cases of tuberculosis treated at the Modern Woodmen of
America Sanatorium. Am Rev Tuberc 1919;2:755-63.
26. National Tuberculosis Institute. Tuberculosis in a rural
population of South India: A five-year epidemiological
study. Bull Wld Health Org 1974;54: 473-88.
27. Stephens MG. Follow-up of 1,041 tuberculous patients.
Am Rev Tuberc 1941;44:451-62.
28. Xie HJ, Enarson DA, Chao CW, et al. Deaths in
tuberculosis patients in British Columbia 1980-1984.
Tuber Lung Dis 1992;73:77-82.
29. van den Broek J, Mfinanga S, Moshiro C, et al. Impact of
human immunodeficiency virus infection on the outcome
of treatment and survival of tuberculosis patients in
Mwanza, Tanzania. Int J Tuberc Lung Dis 1998;2:547-52.
30. Grzybowski S. Epidemiology of tuberculosis and the role
of BCG. Clin Chest Med 1980;1:175-87.
31. Nakielna EM, Cragg R, Grzybowski S. Lifelong followup of inactive tuberculosis: Its value and limitations. Am
Rev Respir Dis 1975;112:765-72.
32. Krebs A. The IUAT trial on isoniazid preventive treatment
in persons with fibrotic lung lesions. Bull Int Union
Tuberc 1976;51:193.
33. Alland D, Kalkut GE, Moss AR, et al. Transmission of
tuberculosis in New York City: an analysis by DNA
fingerprinting and conventional epidemiologic methods.
N Engl J Med 1994;330:1710-6.
34. Warren R, Hauman J, Beyers N, et al. Unexpectedly high
strain diversity of Mycobacterium tuberculosis in a highincidence community. S Afr Med J 1996;86:45-9.
35. Small PM, Hopewell PC, Singh SP, et al. The
epidemiology of tuberculosis in San Francisco: A
population based study using conventional and
molecular methods. N Engl J Med 1994;330: 1703-9.
36. Shaw JB, Wynn-Williams N. Infectivity of pulmonary
tuberculosis in relation to sputum status. Am Rev Tuberc
1954;69:724-32.
24
37. Grzybowski S, Barnett GD, Styblo K. Contacts of cases
of active pulmonary tuberculosis. Bull Int Un Tuberc
1975;50:90-106.
38. Beyers N, Gie RP, Schaaf HS, et al. Delay in diagnosis,
notification and initiation of treatment and compliance
in children with tuberculosis. Tubercle and Lung Disease,
1994;75:260-5.
39. Grigg ERN. The arcana of tuberculosis: with a brief
epidemiologic history of the disease in USA. Am Rev
Tuberc 1958;78:151-72.
40. Sheldon CD, King K, Cock H, et al. Notification of
tuberculosis: how many cases are never reported? Thorax
1992;47:1015-8.
41. Styblo K, Rouillon A. Estimated global incidence of smearpositive pulmonary tuberculosis. Unreliability of officially
reported figures on tuberculosis. Bull Int Union Tuberc
1981;56:118-26.
42. World Health Organization. Tuberculosis surveillance
and monitoring. WHO/TB/91.163:1-18.
43. Enarson DA. Tuberculosis in Aboriginals in Canada. Int
J Tuberc Lung Dis 1998;2:S16-22.
44. Styblo K, Dankova D, Drapela J, et al. Epidemiological
and clinical study of tuberculosis in the district of Kolin,
Czechoslovakia. Report for the first 4 years of the study
(1961-1964). Bull Wld Health Org 1967;37:819-74.
45. International Union Against Tuberculosis and Lung
Disease. Guidelines for conducting tuberculin skin test
surveys in high-prevalence countries. Tuber Lung Dis
1996;77(suppl 1):1-20.
46. Rieder HL. Methodological issues in the estimation of
the tuberculosis problem from tuberculin surveys. Tuber
Lung Dis 1995;76:114-21.
47. Rust P, Thomas J. A method of estimating the prevalence
of tuberculous infection. Am J Epidemiol 1975;101:311-22.
48. Snider DE. Bacille Calmette-Guerin vaccinations and
tuberculin skin tests. JAMA 1985;253:3438-9.
49. Comstock GW, Edwards LB, Livesay VT. Tuberculosis
morbidity in the US Navy: Its distribution and decline.
Am Rev Respir Dis 1974;110:572-8.
50. Pnnighaus JM, Fine PEM, Sterne JAC, et al. Efficacy of
BCG vaccine against leprosy and tuberculosis in northern
Malawi. Lancet 1992;339: 636-9.
51. Yerushalmy J, Harkness JT, Cope JH, et al. The role of
dual reading in mass radiography. Am Rev Tuberc
1950;61:443-64.
52. Newell RR, Chamberlain WE, Rigler L. Descriptive
classification of pulmonary shadows: a revelation of
unreliability in the roentgenographic diagnosis of
tuberculosis. Am Rev Tuberc 1954;69:566-84.
53. Springett VH. Results of the study on x-ray readings of
the ad hoc Committee for the Study of Classification and
Terminology in Tuberculosis. Bull Int Union Tuberc
1968;41:107-09;125-9.
54. Gordin FM, Slutkin G, Schecter G, et al. Presumptive
diagnosis and treatment of pulmonary tuberculosis based
on radiographic findings. Am Rev Respir Dis
1989;139:1090-3.
55. Samb B, Henzel D, Daley CL, et al. Methods of diagnosing
tuberculosis among in-patients in Eastern Africa whose
sputum smears are negative. Int J Tuberc Lung Dis
1997;1:25-30.
56. Kent PT, Kubica GP. Public Health Mycobacteriology: A

guide for the Level III Laboratory. Atlanta: US
Department of Health and Human Services, Centers for
Disease Control 1985.
Disease. Technical guide for examinations for tuberculosis
by direct microscopy. Paris 1977.
58. David HL. Bacteriology of mycobacterioses. Atlanta:US
Dept Health Education and Welfare, Public Health
Service, Communicable Disease Center 1976.
59. Chaisson RE, Moore RD, Richman DD, et al. Incidence
and natural history of Mycobacterium avium-complex
infections in patients with acquired immunodeficiency
virus disease treated with zidovudine. Am Rev Respir
Dis 1992;146:285-9.
60. Chan W, Chia M, Lee LK, et al. Bacteriological methods for
the detection of cases of pulmonary tuberculosis. Bull Wld
Health Org 1971; 45: 551-8.
61. Small PM, McClenny N, Singh SP, et al. Molecular strain
typing of Mycobacterium tuberculosis to confirm crosscontamination in the mycobacteriology laboratory and
modification of procedures to minimize occurrence of
false-positive cultures. J Clin Microbiol 1993;31:1677-82.
62. van Duin JM, Pijnenburg JEM, van Rijswoud CM, et al.
Investigation of cross contamination in a Mycobacterium
tuberculosis laboratory using IS6110 DNA fingerprinting.
Int J Tuberc Lung Dis 1998;1:425-9.
63. Small PM, van Embden JDA. Molecular epidemiology of
tuberculosis. In Bloom BR, (Ed): Tuberculosis:
Pathogenesis, protection and control. Washington:
American Society for Microbiology 1994;569-82.
64. Godfrey-Faussett P, Stoker NG. Aspects of tuberculosis
in Africa. 3. Genetic fingerprinting for clues to the
pathogenesis of tuberculosis. Trans Roy Soc Trop Med
1992;86:472-5.
65. Small PM, Schafer RW, Hopewell PC, et al. Exogenous
reinfection with mutidrug resistant M. tuberculosis in
patients with advanced HIV infection. N Engl J Med
1993;328:1137-44.
66. Das S, Chan SL, Allen BW, et al. Application of DNA
fingerprinting with IS986 to sequential mycobacterial
isolates obtained from pulmonary tuberculosis patients
in Hong Kong before, during and after short-course
chemotherapy. Tuber Lung Dis 1993;74:47-51.
67. Barnett GD, Styblo K. Bacteriological and X-ray status of
tuberculosis following primary infection acquired during
adolescence or later. Bull Int Union Tuberc 1977;52:5-16.
68. Alland D, Kalkut GE, Moss AR, et al. Transmission of
tuberculosis in New York City: an analysis by DNA
fingerprinting and conventional epidemiologic methods.
N Engl J Med 1994;330:1710-6.
69. Marais BJ, Gie RP, Schaaf HS, et al. The clinical
epidemiology of childhood pulmonary tuberculosis: A
critical review of literature from the pre-chemotherapy
era. Int J Tuberc Lung Dis 2004; 8:278-85.
70. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of
childhood intrathoracic tuberculosis: a critical review of
literature from the pre-chemotherapy era. Int J Tuberc
Lung Dis 2004;8:392-402.
71. Galtung Hansen O. Tuberculosis mortality and morbidity
and tuberculin sensitivity in Norway. WHO 1955;EURO84/15.

72. Amrane R, Djillali A, LHadj M, et al. La morbidit
tuberculeuse de 1982 a 1990 en Algrie. Tuber Lung Dis
1993;74:106-12.
73. Nobert E, Chernick V. Tuberculosis: 5. Pediatric disease.
Can Med Assoc J 1999;160:1479-82.
74. Fourie PB, Donald PR. The epidemiology and control of
tuberculosis. In Donald PR, Fourie PB, Grange JM (Eds):
Tuberculosis in Childhood. Pretoria: JL van Schalk
1999;49.
75. Styblo K. Recent advances in epidemiological research
in tuberculosis. Adv Tuberc Res 1980;20: 1-63.
76. Galbraith JD, Grzybowski S, Law CL, et al. Tuberculosis
in Indian Children. Primary Pulmonary Tuberculosis. Can
Med Assoc J 1969;11:497-502.
77. Burrill D, Enarson DA, Allen EA, et al. Tuberculosis in
female nurses in British Columbia: implications for
control programs. Canadian Medical Association Journal
1985;132:137-40.
78. Roelsgaard E, Iversen E, Blocher C. Tuberculosis in
tropical Africa. Bull Wld Hlth Org 1964;30:500-18.
79. van Rie A, Beyers N, Gie RP, et al. Childhood tuberculosis
in an urban population in South Africa: burden and risk
factor. Arch Dis Child 1999; 80:433-7.
80. De Cock KM, Soro B, Coulibaly IM, et al. Tuberculosis
and HIV-infection in sub Saharan Africa. JAMA
1992;268:1581-7.
81. Bedall AC, Hill FGH, George RH. Haemophilia and
tuberculosis. Lancet 1983;1:1226.
82. Comstock GW. Tuberculosis in twins: A re-analysis of
the Prophit survey. Am Rev Respir Dis 1978; 117:621-4.
83. Sorenson TIA, Nielsen GG, Andersen PK, et al. Genetic
and environmental influences on pre-mature death in
adult adoptees. N Engl J Med 1988;318:727-32.
84. Enarson DA, Sjgren I, Grzybowski S. Incidence of
tuberculosis among Scandinavian immigrants to Canada.
Eur J Respir Dis 1980;61:139-42.
85. McCarthy OR. Asian immigrant tuberculosisthe effect
of visiting Asia. Br J Dis Chest 1984;78:248-53.
86. Cummins SL. Tuberculosis in primitive tribes and its
bearing on tuberculosis of civilized communities. Int J
Pub Health 1920;1:10-171.
87. Schaaf HS, Nel ED, Beyers N, et al. A decade of experience
with Mycobacterium tuberculosis culture from children: a
seasonal influence on incidence of childhood tuberculosis.
88. Redeker F. Epidemiologie und Statisik der Tuberkulose.
In Hein J (Ed): Handbuch der Tuberkulose. Stuttgart:
Thieme Verlag 1958; 1:407-98.
89. Barr RG, Menzies R. The effect of war on tuber-culosis.
90. Schulzer M, Fitzgerald JM, Enarson DA, et al. An estimate
of the future size of the tuberculosis problem in subSaharan Africa resulting from HIV infection. Tuber Lung
Dis 1992;73:52-8.
91. Raviglione MC, Rieder HL, Styblo K, et al. Tuberculosis
trends in Eastern Europe and the former USSR. Tuber
Lung Dis 1994;75:400-16.
92. Brudney K, Dobkin J. A tale of two cities: Tuberculosis
control in Nicaragua and New York City. Sem Resp Inf
1991;6:261-72.
25
93. Starke JR, Jacobs RF, Jereb J. Resurgence of tuberculosis

in children. J Pediatr 1992;120:389-405.
94. Collins JJ. The contribution of medical measures to the
decline of mortality from respiratory tuberculosis: an
age-period-cohort model. Demography 1982;19:409-27.
95. Riley RL, Wills WF, Mill CM, et al. Air hygiene in
tuberculosis: Quantitative studies of infectivity and
control in a pilot ward. Am Rev Tub Pulm Dis
1957;75:420-31.
96. Liippo KK, Kulmala K, Tala EO. Focusing tuberculosis
contact tracing by smear grading of index cases. Am Rev
Respir Dis 1993;148:235-6.
97. Aoki M, Mori T, Shimao T. Studies on factors influencing
patients, doctors delay of tuberculosis case detection in
Japan. Bull Int Union Tuberc 1985;60:128-30.
98. Singh M, Mynak MI, Kumar L, et al. Prevalence and risk
factors for transmission of infection among children in
household contact with adults having pulmonary
tuberculosis. Arch Dis Child 2005; 90: 624-8.
99. Hopewell PC. Impact of human immunodeficiency virus
infection on the epidemiology, clinical features,
management and control of tuberculosis. Clin Inf Dis
1992;15:540-7.
100. Aissa K, Madhi F, Ronsin N, et al. For the CG 94 study
group, evaluation of a model for efficient screening of
tuberculosis contact subjects. AM J Respir Crit Care Med
2008; 177: 1041-7.
101. Enarson DA. Principles of IUATLD Collaborative
Tuberculosis Programs. Bulletin of the International
Union Against Tuberculosis and Lung Disease
1991;66:195-200.
102. Zhang L-X, Tu D-H, Enarson DA. The impact of directlyobserved treatment on the epide-miology of tuberculosis
in Beijing. Int J Tuberc Lung Dis 2000;4:904-10.
103. Zhang L-X, Tu D-H, He G-X, et al. Risk of Tuberculosis
Infection and Tuberculous Meningitis after
Discontinuation of Bacillus Calmette-Guerin in Beijing.
Am J Respir Crit Care Med 2000;162:1314-7.
104. Enarson D, Rieder HL, Arnadottir T. Tuberculosis guide
for low-income countries, 4th edn. Frankfurt am Main:
pmi-Verlagesgruppe GmbH 1996:1-65.
105. Frimodt-Mller J. Changes in tuberculosis prevalence in
a south Indian rural community following a tuberculosis
control programme over a seven years period. Ind J
Tuberc 1962;9:187-91.
106. Crofton J. The contribution of treatment to the prevention
of tuberculosis. Bull Int Union Tuberc 1962;32:643-53.
107. Grzybowski S, Enarson DA. The fate of cases of
pulmonary tuberculosis under various treatment
programmes. Bull Int Union Tuberc 1978;53:70-5.
108. Beyers N, Gie RP, Schaaf HS, et al. A prospective
evaluation of children under the age of 5 years living in
the same household as adults with recently diagnosed
pulmonary tuberculosis. Int J Tuberc Lung Dis 1997;1:
38-43.
109. Grange JM. Drug resistance and tuberculosis elimination.
Bull Int Union Tuberc Lung Dis 1990; 65:57-79.
110. Reichman LB. The U shaped curve of concern. Am Rev
Respir Dis 1991; 144: 741-2.
Epidemiology:
Special Reference to Children
INTRODUCTION
Group II
Tuberculosis as a disease is of great public health

importance in the developing countries. Childhood
tuberculosis is a reflection of ongoing transmission of
Mycobacterium tuberculosis in a community. It has been
described as the continuing scourge of India.1 Donald2
has defined tuberculosis in children as a hidden epidemic
in developing countries and has quoted several Indian
studies.3,4 Its clinical profile is different in developing
countries in comparison to countries of Europe and North
America. Global estimates of tuberculosis (TB) per year
among children have been described elsewhere. The
extent of tuberculosis in children is a reflection of
Tuberculosis Control Program in a particular area.
Epidemiological data regarding the extent of problem in
children is lacking globally as well as in India. The reason
in India being that in the National sample survey done
in 1955 to 1958, children less than five years were
excluded.3 It is due to difficulty in diagnosis. The two
common parameters, tuberculin test and X-ray chest with
history of contact, symptomatology are difficult to
perform at operational level. Further, the pressing
problem which was emphasized at that time was to pick
up infectious adults and their treatment. In India very
few studies are available regarding the extent of problem
of tuberculosis in children. The available data are on the
basis of hospital studies.5
Udani5 has described tuberculosis in children as a
pyramid as follows:
Majority of patients in this group have non-specific

symptoms, some may have characteristic symptoms.
They are either undiagnosed, untreated or inadequately
treated.
PYRAMID OF CHILDHOOD TUBERCULOSIS

Pediatric patients with tuberculosis can be placed in three
categories:
Group I
These patients are admitted in the hospital and constitute
6 to 10 percent of total pediatric admissions, majority of
them have serious disease like meningitis, miliary disease
or severe pulmonary involvement. They constitute the
apex of the pyramid.
Group III
It constitutes the base of the pyramid. These children are
either asymptomatic or have non-specific symptoms,
hence are usually undiagnosed and untreated. They
constitute the reservoir of primary infection from which
various post primary complication (Gr I and II) develop.
These are also forerunners of a large percentage of (i) adult
type of TB disease among adolescent children and (ii)
chronic pulmonary tuberculosis in adults.
Children are usually infected with tuberculosis by an
adult4a or an older child with sputum smear-positive
pulmonary tuberculosis, often a family member. They are
less likely to be infected with a smear-negative contact.
The best way to prevent tuberculosis in children has been
thought to be the proper identification and treatment of
infectious patients. Case notification of tuberculosis in
children usually has been 6 to 20 percent of all registered
TB cases with the National Tuberculosis Program (NTP).
In India, the prevalence of primary tubercular infection
in pediatric population is alarming. The annual risk of
tubercular infection is 1.5 in the country, and 40 percent
of children by 16 years acquire infection. Nearly 10
percent of infected eventually develop disease. Five
percent of these are expected to develop tuberculosis in
the first two years of life. This large pool of infected
children, means that TB will continue to be a major
problem in the foreseable future. Data on the burden of
all forms of TB amongst children in India are not available.
Most surveys conducted have focused on pulmonary TB
and no significant population based studies on extrapulmonary TB are available. Pulmonary TB is primarily
an adult disease and it has been estimated that 0 to 19
years old population con-tain only 7 percent of total
prevalent cases.6,7
The risk of infection in children depends on the extent
of exposure to infectious droplet nuclei. If a mother has
27
Chapter 4 Epidemiology: Special Reference to Children

sputum smear-positive pulmonary TB, her infant is more
at risk of developing the disease because of the chance of
inhaling a large number of infectious droplets. There is a
high prevalence of infection among children in household
contact with adult cases of tuberculosis. The risk is higher
for contacts of sputum-positive patients, but is also
significant for contacts of sputum-negative patients.
Severe malnutrition, younger age, and absence of BCG
vaccination are significant risk factors for the transmission
of infection. Exposure to environmental tobacco smoke
independently increases the risk of acquiring infection8.
The majority of infected children do not develop TB
disease in childhood. The only evidence of infection may
be a positive tuberculin skin test. The likelihood of
developing disease is greatest shortly after infection. This
declines steadily with time. Infants and young children
under 5 years are at particular risk of developing disease.
The majority of children will present with symptoms with
in one year of infection. For infants particularly, the timespan between the infection and disease maybe as little as
6 to 8 weeks. Various immunosuppressive illnesses
facilitate the progression of infection to disease such as
HIV-infection,8a measles, whooping cough and proteincalorie malnutrition.
In the study by National Tuberculosis Institute,
Bengaluru,9 the prevalence of tuber culosis in children in
the 0 to 4 years of age was found to be one percent. These
had not received BCG and were contacts of sputum
smear-positive cases. The problem and its extent in the
age group of 0 to 4 years can be easily estimated. The
population of India by 2000 AD had reached
one billion mark. Applying the one percent prevalence,
it could be computed that by 2009 AD, about more than
one and a quarter million children in this age group
would have already got infected. In the various programs
of WHO for control of tuberculosis, children have not
received due importance except in the latest directly
observed treatment short course therapy (DOTS). The
reasons for neglect of children in the National
Tuberculosis Control Program in India and the world
over has been due to difficulty in its diagnosis. The latter
because gold standard of diagnosis is isolation of
Mycobacterium tuberculosis either by smear or culture.
Thus, a survey conducted in South India between 1984
and 1986 and its comparison with old surveys shows a
23-year trend9 (Tables 4.1 and 4.2).
Annual incidence of primary infection described by
studies of National Institute of Tuberculosis (NIT),
Bengaluru was 0.8 percent in children under 5 year, giving
an estimate of 1.9 million getting infected every year.
Annual incidence and prevalence of tuberculosis in NTP
data is given in Table 4.3.10
The recent epidemic of HIV has slowed down the
declining trend in the incidence of tuberculosis. This has
further been aggravated because of large number of
tuberculosis-infected migrants in these countries

particularly in USA.11
Reviewing the situation in 90s, an update in Bulletin
of WHO,12 it was reported that approximately one-third
of the worlds population (1700 million) is infected with
M. tuberculosis. The majority of cases belong to Asia with
an increasing number of HIV infected individuals.
Though the overall prevalence of tuberculosis infection
is similar in both parts of the world, i.e. Sub-Saharan
Africa and Europe (34% and 28% respectively), there is a
big difference in the age distribution. In Africa, the
majority of infected individuals are below 50 years of age
(80%). In the African, South-east Asian and Western
Pacific regions more than 50 percent of the adult
population aged >15 years is infected (54%, 52% and 62%
respectively). 12 The emergence of HIV infection in
association with tuberculosis has resulted in dual
infection of 3 million individuals. Majority of them (78%)
are in Africa.
Based on data among children and adults generated
by Tuberculosis Research Centre (TRC), Chennai, among
children by National Tuberculosis Institute (NTI),
Bengaluru, and the annual risk of tuberculosis infection
Table 4.1: Prevalence rate (%) of infection in
South India 23-year period
Age
I
1962
II
1963
Survey
III
1965
0-4
5-9
10-14
0-14
2.1
7.9
16.5
8.6
1.8
7.6
16.9
8.6
1.3
7.0
16.1
7.7
IV
1967
V
1977
VI
1985
1.0
6.4
15.4
7.1
1.5
6.0
12.1
4.7
1.2
5.3
9.2
4.8
Table 4.2: Annual risk rates among 0 to 14 years over

23 years in South India
Annual risk rate (%)
Survey
I
II
III
IV
V
VI
On observed
prevalence rate
On standardized
rate
1.12
1.12
0.92
0.86
0.55
0.55
1.12
1.12
0.99
0.92
0.80
0.61
Table 4.3: Annual incidence and prevalence of

tuberculosis (NTP Data)10
Age (years)
<5
5-9
10-14
All ages
Annual incidence
of infection (%)
Prevalence of
infection (%)
0.8
1.1
1.3
1.6
2.8
13.4
38.0
28
(ARTI) estimates from the nation-wide sample survey by
NTI and TRC the estimated number of bacillary cases
was 3.8 million (95% CI: 2.8-4.7). The number of abacillary
cases was estimated to be 3.9 million and that for
extrapulmonary cases was 0.8 million giving a total
burden of 8.5 million (95% CI: 6.3-10.4) for 2000.13
Using data from district tuberculosis registry it was
observed that diagnoses of tuberculosis peaked in
northern part of India between April and June, and
reached a nadir between October and December, whereas
no seasonality was reported in the south. Overall, rates
of new smear-positive tuberculosis cases were 57 per 100
000 population in peak seasons versus 46 per 100 000 in
trough seasons. This was after ruling out general healthseeking behavior artifact. Seasonality was highest
in pediatric cases, suggesting variation in recent
transmission14
Prevalence and Annual Risk of Tuberculosis Infection

in Children in India
Multiple surveys were carried out over last 10 years in
different part of country. It suggests that the prevalence
varies from region to region. It was minimal in Kerala
and maximum in western and north India. It was more
in tribals and people living in slums, more in urban as
compared to rural area. Nutritional status did not change
prevalence estimated by tuberculin test. In some studies
children who had received BCG had lesser prevalence of
TB infection but it was insignificant. The computed ARTI
in children from different survey has been given in
Table 4.4.
A nationwide survey to estimate acute respiratory
tract infection (ARTI) in children 1-9 years of age in
selected clusters of 26 districts in four defined zones of
India using tuberculin testing with ITU PPD RT23 with
Tween 80 was carried out. Prevalence of infection was
estimated using the cut-off point method (Method I) and
the mirror-image technique (Method II) among children
without BCG scar. The ARTI computed from estimated
prevalence was found to be lowest in the southern zone
(Method I: 1.1%, Method II: 1.0%). It was higher in the
eastern zone (1.3% by both methods) and highest in the
western (Method I: 1.8%, Method II: 1.6%) and northern
zones (1.9% by both methods). The proportion of infected
children was found to be significantly higher in urban
than in rural areas in all zones.15
The overall estimates of average annual risk of
infection in children 1-9 years of age in the country was
computed as 1.5%. It was higher in urban areas, at 2.2%,
than in rural areas, at 1.3%.16 There are not many surveys
done in same setting with similar methods to judge trends
in TB infection in children. A survey done in same
population after 8.3 years in Bengaluru suggest a decline
in ARTI about 4 %.17 In another survey done to see effect

of DOTS on tuberculosis infection revealed ARTI
estimates in the three tuberculin surveys as 1.6%, 1.4%
and 1.2%, respectively. There was a significant decline in
the trend of TB infection. The annual decline estimated
from the first to the third survey was 6%.18
DISEASE BURDEN IN CHILDREN

Estimating the burden of TB in children is challenging
for several reasons. No standard case definition exists that
may be applied easily to childhood TB. In many countries,
limited resources prohibit establishing a confirmed
diagnosis. Childhood TB is given a lower public health
priority as compared to adult disease. Although many
countries collect and report TB surveillance data, these
data are not always readily available, consistent, or
reported using standard age criteria.
In India, tuberculosis in children has been regarded
as a major health hazard.26 The ICMR Survey, the only
National survey, did not include children below 6 years
of age. The methodology did not include tuberculin skin
tests and hence neither the prevalence of infection in
children nor the annual risk of infection could be
measured at that time.27 The data gathered in the National
Sample Survey 1955-58, was an eye opener. The
prevalence was reported to range from 2 to 8 cases per
1000 population. The disease was distributed equally in
rural and urban areas. The infectious cases were mainly
in adults and not in school children. Hence, there is no
National data on prevalence in children < 5 years of age.
There are studies in localized areas reporting prevalence
of infection based on Tuberculin testing. Ukit and
Benjamin28 reported that prevalence of infection was agedependent. The incidence of infection in the groups
treated with placebo in the Chingleput study, was 1.75,
2.4 and 4.03 percent in the age groups of 1-4, 5-9 and 10
to 14 years respectively.29 Results of a longitudinal survey
conducted by National Institute of Tuberculosis,
Bengaluru reported an annual risk of infection to be 3.2
percent,30 whereas studies in Chingleput have not shown
any evidence of decline in annual risk of infection over a
period of 15 years. Their results were 1.7 percent in 1969,
1.93 percent in 1979 and 1.73 percent in 1989.31
In 1989, the WHO estimated that each year 1.3 million
new cases of childhood TB occur and 450,000 children
die from disease32 In 1994, there were estimated 7,500,000
total TB cases, of which 650,000 (9%) occurred in
children.33 These estimates are based on the assumption
that childhood TB parallels adult trends and accounts for
a predictable proportion of total disease. Although
childhood TB usually represents less than 5 percent of
disease in industrialized countries, the burden of disease
borne by children in less developed, resource-poor
countries maybe as high as 39 percent.34 At a global level,
29

Table 4.4: Summary of tuberculosis surveys in different parts of India
Authors
Population surveyed
Methods used
Prevalence
Remarks
2009
4821, children 5-9

years in Kerala
Tuberculin test using

1 TU PPD RT23 with
Tween 80
reactions > 10 mm: 5%

reactions > 12 mm: 3%:
reactions > 14 mm: 2%
Rao et al 20 2008
5314 children 1-9

years of age in
Jabalpur
Tuberculin test using

1 TU of PPD RT 23
with tween 80
Overall prevalence 7.1%
Low proportion of
reactors indicated a
low level of
transmission of
infection in Kerala.
Overall ARTI 1.3%
1.3% (1.0-1.7%)
7098 children
aged 1-9 years in
Chennai
Tuberculin test
using 1 TU of PPD
RT 23 with Tween 80
1341 children
aged 1-9 years of
Saharia community
in MP
Tuberculin testing
with 1 TU of PPD
RT 23 with Tween
80
Chadha et al.23
2007
3636 children
5-9 years of age in
Andhra Pradesh
Pulickal et al24
2007
418 school children

aged 5-9 years in
Palakkad District,
Kerala
Tuberculin tested
using 1 TU PPD
RT23 with Tween
80
Tuberculin skin test
using 1 TU PPD RT
23 with Tween 80
Kumar S
19
Gopi et al 21
2008
Rao etal 22 2008
Chadha et al16
2005
Kolappan et al24a
2004
Shashidharan
et al25 2004
8637 children
Khammam tribal
district between
1-9 years
17,811 children
1-9 years from
south zone of India
without a BCG scar
10, 191 children 1-9
years from 8
districts of Orissa
Tuberculin testing
using ITU PPD RT
23 with Tween 80
tuberculin testing
using ITU PPD
RT23 with Tween 80
tuberculin testers
administered 0.1 ml
(1 TU) of PPD RT 23
with Tween 80
(95% CI: 5.58.8%)

Prevalence without
BCG scar: 6.8% (95%
CI: 4.88.9%)
Prevalence with BCG
scar: 7.6% (95% CI:
4.410.9%)
Overall prevalence: 10.5 %
No difference in
relation to BCG scar
Overall prevalence:
20.4% (95% CI: 18.222.5%)
ARTI in children
without BCG scar
1.3% (0.91.7%)
ARTI in children
with BCG scar:
1.4% (95%CI 0.82.0%);
(ARTI of 2.0%)
Prevalence slightly
higher in slums
(11.1%; ARTI 2.1%)
as compared to
non slum area
(8.9%; ARTI 1.7%);
ARTI was 3.9%
(95% CI 3.5- 4.3%).
BCG scar negative:

21.1% (95% CI: 18.323.8%)
BCG scar positive:
19.0% (95% CI 15.422.5%)
Prevalence: 9.6%
(95% CI: 8.0-11.2.)
ARTI in BCG scar

negative: 3.9%
(95% CI: 3.4-4.5%)
ARTI among BCG
scar positive 4.0%
(95% CI: 3.2-4.8%)
ARTI: 1.4% (95%
CI: 1.1-1.6)
Prevalence 15.5%
No relation with
nutritional status
BCG unvaccinated
children (24%)
BCG vaccinated (9.7%)
11.8% among children
without BCG scar and
10.6% among children
with BCG scar
5.9% (95% CI 4.0-7.7%);
6.9%
Children without
BCG Scar 1.6 %,
with BCG scar 1.5%
ARTI was 1.0%
(95% CI 0.7-1.4%)
ARTI 1.7-1.8%.
More in urban as
compared to
rural area
30
the WHO currently reports only smear-positive cases by
age. The International Union against TB and Lung Disease
(IUATLD) currently recommends stratifying the
reporting of smear-positive cases into two age categories:
younger than 15 years of age and 15 years of age and
older.35 Reporting of smear-positive cases is considered
a practical strategy that complements the Directly
Observed Therapy (DOTS) strategy. Nonetheless, an
estimated 1.2 cases of smear-negative TB occur for every
smear-positive case of TB.36 Furthermore, approximately
95 percent of cases in children younger than 12 years of
age are smear-negative.37 Thus, the WHO policy of
reporting only smear-positive cases by age causes a gross
underestimation of the burden of TB in children. Corbett
and colleagues have generated age-specific estimates
describing the global distribution of TB.38 These countryspecific estimates were based on the number of smearpositive cases reported in 2000 and published estimates
of the proportion of cases expected to be smear-positive
by age group. This analysis estimated that 8.3 million new
cases of TB occurred in 2000, of which 884,019 (10.7%)
were in children. Of the total, 659,379 (75%) occurred in
22 high-burden countries (Table 4.5). Case rates estimated
through this analytic approach for India for all age group
is 179 per 100,000 population and for 0 to 14 years age
group is 53 per 100,000 children. The proportion of TB
occurring in children in India is estimated around 10.2

percent. These figures are available only upto 2002. In
the latest report of WHO there is no data separately
tabulated for children even in sputum-positive cases.
In 2007, the countries with the highest prevalence were
India (with 2.0 million cases), China (1.3 million),
Indonesia (530,000), Nigeria (460,000), and South Africa
(460,000); of the estimated 1.37 million cases in HIVpositive persons, 79% were in Africa and 11% in Southeast
Asia.39
DETERMINANTS OF INFECTION AND DISEASE

Tuberculosis differs from various other infectious
diseases as it has a particular social and geographic
distribution.
Determinants of Infection
Tuberculosis has two stages: First is the stage of infection
and this may then progress to the second stage of disease.
Both the stages have different risk factors. The
determinants of these two stages need to be considered
separately.
Bacilli are transmitted from one infected person to the
other as an aerosol. In some cases contaminated milk may
also be responsible. In Indian children, most often the
Table 4.5: Estimated burden of childhood tuberculosis in the 22 highest-burden countries

Countries
No. of children
with TB
TB occurring in
children (%)
Childhood TB
case rates
TB case rate
(All ages)
Afghanistan
Bangladesh
Brazil
Cambodia
China
Democratic Republic of Congo
Ethiopia
India
Indonesia
Kenya
Mozambique
Myanmar
Nigeria
Pakistan
Philippines
Russian Federation
South Africa
Thailand
Uganda
United Republic of Tanzania
Vietnam
Zimbabwe
17,540
33,166
23,520
3,966
86,978
24,052
28,675
185,233
15,691
22,124
7,703
8,007
32,310
61,905
12,167
7,778
35,449
2,317
12,099
18,890
7,559
12,267
25.3
10.2
20.7
5.3
5.3
16.1
16.1
10.2
2.7
16.1
16.1
10.2
12.4
25.3
5.3
4.2
16.1
2.7
16.1
16.1
5.3
16.1
189
61
47
70
27
106
95
53
23
167
98
51
63
103
43
30
237
15
103
118
29
221
324
236
66
571
129
306
272
179
263
450
268
165
228
172
304
126
501
141
320
337
183
603
Total: 22 highest-burden countries
659,397
9.6
Corbett EL et al. Arch Intern Med 2003; 163: 1009-21.
31

primary infection is human in origin and pulmonary,
though involvement of other sites has also been
reported.40 The sharing of the space with an infectious person
puts the other person at a higher risk. It will also depend
upon the nature of disease in the source case. If cough or
sneezing produces infectious aerosols, the risk becomes
higher. The source which is producing acid fast bacilli,
on direct microscopic examination, has been shown to
contain very small number of tubercle bacilli (>104 bacilli
per ml). The undiagnosed and untreated status of these
patients makes them more dangerous as regards the spread
of the disease.
The other important determinant is the exposure and
degree of ventilation of the ambient environment. This explains
higher risk to family members of source person than to
casual controls and also higher recurrence in people
belonging to low socioeconomic status which forces them
to reside in overcrowded and ill-ventilated houses.
Whether the inhalation of bacilli will cause infection
in the uninfected person or not is determined by innate
defense mechanism of the individual. Recent observations
suggest a role for genetic factors in the resistance to
infection.41 Further evidence is available that human
immunodeficiency virus (HIV) impairs the innate
resistance and favors the development of tuberculosis
infection.42
still posed an appreciable, although greatly reduced, risk.

The majority of older children who were infected did not
have a household source identified. Infants and
adolescent were the groups at highest risk for
development of disease and death following primary
infection. Children with primary infection at 5 to 10 year
of age had the lowest risk development of disease and
death.
Infection with tubercle bacilli does not result in disease
in all the infected persons. Nearly 90 percent people may
not develop disease at all. In rest of the 10 percent, only
half will progress to the disease in first five years. Rest of
them develop disease much later in life and this delayed
disease is defined as reactivation of latent or remotely
acquired tuberculosis infection.43 This occurrence of
disease in early years has the following determinants.
Determinants of Developing Tuberculosis Disease
Tuberculosis is very severe in malnourished children.45

An improved diet with protein, energy and vitamins A,
D and C reduce the incidence of progressive disease. As
the disease may be acute or chronic in children, it may
lead to deterioration of the nutritional status of the child.
It may present as Kwashiorkor or severe Marasmus. Most
of the pediatricians today will like to rule out tuberculosis
in malnourished children.
Epidemiological concepts in childhood tuber-culosis has

been clarified by review of literature in the
prechemotherapy era. Reports describe the major
transition in tuberculosis, from exposure to infection and
from infection to disease. Children with household
exposure to a sputum smear-positive source case had the
greatest risk of becoming infected and developing
disease, particularly in a child less than two years of age.
This age was also more vulnerable to develop disease
from infection even when exposed to sputum smearnegative household source case. Nonhousehold exposure
Recent versus Old Infection

Results of several classic studies have been employed to
develop a model estimating risk of acquiring TB among
persons with recent infection and persons with
preexisting infec-tion. 44 This modeling clearly
demonstrates that children 0 to 5 years of age with recent
infection have significant annual risk of developing
disease (Table 4.6).44
Nutrition
Intercurrent Infection
The recurrent infection or intercurrent infection can lead
to decreased host resistance.40 Activation of tuberculosis
Table 4.6: Annual risk of reactivation TB

Tuberculin skin test induration in mm
Persons with existing infection

5-9
10-14
> 15
Persons with recent infection
5-9
10-14
> 15
0-5
6-15
Age in years
16-35
36-55
> 56
0.06
0.19
0.24
0.04
0.08
0.14
0.12
0.15
0.19
0.07
0.10
0.12
0.07
0.10
0.12
0.29
0.37
0.54
0.06
0.12
0.12
0.30
0.37
0.56
0.23
0.28
0.42
0.12
0.15
0.17
Horsburgh CR Jr. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004; 350:
2060-7.
32
with measles infection is a well documented
phenomenon. Some experts feel that even pertussis can
lead to activation of tuberculosis in a young child.
Length of Time after Acquiring Infection

It is one of the most important determinants of the risk of
developing the disease. Unless manifested immediately
after acquiring infection, the risk appears to decline with
passing years.
Age at Infection
The natural evolution of TB is dependent on host and
pathogen factors. In immune-competent children, the risk
of developing TB and the clinical presentation are highly
age dependent, with younger children being at greatest risk
for developing TB and severe manifestations.46 Table 4.7
shows average age specific risk for disease development
after untreated primary infection in children. After reaching
the age of 10 years, children are much more likely to manifest
adult-type disease that is primarily pulmonary in focus.47
Host Resistance
The immunocompetence is another important
determinant of the disease. This may be genetically
determined.
Distribution of TB Infection and Disease

Today the industrialized world has very low prevalence
of tuberculosis. According to Grzybowski, Britain and
Western Europe had peak of tuberculosis in first half of
the 19th century and is now declining naturally at the
Table 4.7: Average age-specific risk for disease
development after untreated primary infection*
Age at
primary infection
(years)
<1
1-2
2-5
5-10
> 10
Manifestations
of disease
No disease
Pulmonary disease
TBM or miliary disease
No disease
Pulmonary disease
No disease
Pulmonary disease
No disease
Pulmonary disease
No disease
Pulmonary disease
*Tubercular meningitis (TBM).46
Risk of
disease (%)
50
30-40
10-20
70-80
10-20
2-5
95
5
0.5
98
2
<0.5
80-90
10-20
<0.5
rate of 2 percent per annum. Referring to situation in

India, he states that the epidemic in India started in the
mid-19th century when it was in the peak in Eastern
Europe.48
The ICMR survey has shown that in India the
prevalence of disease is more or less universally
distributed throughout the country. Its prevalence was
found to be equal both in rural and urban populations.27
Social factors are responsible for an uneven
distribution in various classes of population. Poverty is
one of the important companions of tuberculosis.49 The
social cost by using DALYs (Disability Adjusted Life
Years) has been reported to be highest in Asia where it
was 5.1 percent, in India it was 3.7 percent whereas it is
only 0.2 percent in industrialized countries.
Secular Trends
Due to lack of good reporting system in developing
countries, it is difficult to assess the trend in tuberculosis
infection and disease in children. There were enough
reasons to believe that there was a naturally occurring
decline in tuberculosis in various countries of the world.
But this decline became stationary in 1980s and the last
decade has witnessed an increase in various countries
now. The available data indicate towards a real increase
in the incidence of disease and it is feared that this increase
may continue in future.50,51 With increase in number of
diseased adults and spread of HIV infection, the infection
rates in children are likely to increase.
Determinants of Outcome of Treatment of Tuberculosis

There are not many studies in literature documenting
outcome of treatment of different type of tuberculosis in
children. In a retrospective study including 541 children
receiving treatment of tuberculosis revealed that the
major factor associated with treatment failure was nonreceipt of BCG vaccination during infancy and extrapulmonary disease.52
DRUG RESISTANT TUBERCULOSIS

Resistance to commonly used drugs in the treatment has
been observed and hence an increase in number of cases
is obvious. The exact burden of drug resistant TB in
children is not known. Pattern of drug resistance among
children with TB tends to reflect that found among adults
in the same population. A 4-yr prospective study in the
Western Cape province of South Africa evaluated 149
child contacts of 80 adult multidrug resistant (MDR)
pulmonary TB cases.53 Most of the childhood contacts of
adults with MDR-TB were likely to be infected by these
MDR source cases despite their exposure to other drugsusceptible adults with TB in some instances.

In 2007, there were an estimated 500,000 cases of
multidrug-resistant (MDR) tuberculosis globally
(including 289,000 new cases); of these, 131,000 were in
India, 112,000 in China, 43,000 in Russia, 16,000 in South
Africa, and 15,000 in Bangladesh; 55 countries had
reported cases of extensively drug resistant (XDR)
tuberculosis by the end of 2008. These last figures are
reason for considerable concern and highlight a potential
threat to our ability to treat tuberculosis, both in
individual patients and in the context of a treatment
program.39
In India (Delhi region), the prevalence of resistance
to any drug was 32.4 percent, while that of multidrug
resistance was 13.3 percent during 1994 to 1997.54
Data on drug resistance in children from India is
scarce. At AIIMS out of 1579 children registered in TB
clinic over 8 years, 21 (1.32%) were diagnosed as MDR
tuberculosis and one was XDR TB.
TRENDS IN TUBERCULAR DISEASE

Mycobacterium tuberculosis enter body through lungs and
it spreads to other parts including lymph nodes, tissues
surrounding the brain and, osteoarticular and urogenital
system. Pulmonary involvement is the most common.
Among the 0 to 14-year-old tribal children of Carnicobar, the best estimate of all forms of tuberculosis was
found to be 6 per thousand (n = 6125).55 The incidence of
all forms of tuberculosis disease was found to be 2.8 per
thousand among the 1 to 4-year-old children in Chennai
(observed over a four-year period of follow-up).56 Almost
33
all of the tuberculosis patients diagnosed in these two

surveys were those of tuberculous lymphadenopathy,
either cervical or mediastinal. There were only a few
patients of tuberculosis spine and sputum positive
pulmonary tuberculosis among those diagnosed.
Widespread coverage with BCG vaccine has possibly
led to modification in the pattern of clinical manifestations.
It has been suggested that BCG vaccination is responsible
for decrease in the occurrence of disseminated and severe
disease. Localized forms of illness, e.g. intrathoracic
lymphadenopathy, and localized CNS disease have been
reported to occur with greater frequency.57,58 However,
this observation needs confirmation from epidemiological
studies.
A recent study from Spain reported an increase in
number of children with single hilar adenopathy (32%
for the period 1978-1987 to 43.4% for the period 19881997) in comparison with those with parenchymal
involvement or a mixed pattern (62% vs 45%).51 The
authors also reported a non-significant trend towards a
lower rate of tubercular meningitis in the last decade.59
At a referral hospital in India60 an increase in the
proportion of cases of extrapulmonary tuberculosis has
been observed over last four and a half decades (Fig. 4.1).
The increase was predominantly due to increase in
lymphnode tuberculosis (Fig. 4.2). The severe form of
tubercular meningitis decreased over last four decades
(Table 4.8).
The data are not a reflection of either prevalence or
incidence of the type of tuberculosis which presents in
medical colleges. In those still the predominant
presentation indoors is of tubercular meningitis, severe
Fig. 4.1: Proportion of pulmonary and extrapulmonary tuberculosis in TB clinic of AIIMS,

New Delhi, India over last 4 decades
34
Fig. 4.2: Types of extrapulmonary tuberculosis in TB clinic of AIIMS, New Delhi, India over last 4 decades
form of pulmonary disease such as miliary in younger

infants and pleural effusion in older children. The same
will be reflected in the outdoor TB clinics. In TB hospitals
such as LRS Institute of Respiratory Disease and Allied
Sciences, Delhi, most of the children will have adults type
of sputum-positive or even multidrug resistant
pulmonary tuberculosis, disseminated disease. However,
at All India Institute of Medical Sciences New Delhi, India
being a superspeciality tertiary care center, the patients
of TBM get admitted are usually in the stage III and often
present after having been treated for sufficient length of
time in other hospitals with no or poor response and
neurological sequlae.
In the outdoor of AIIMS in Pediatric TB clinic the
children who are treated are mostly non-infectious
pulmonary tuberculosis, symptomatic pulmonary
primary complex and tubercular lymphadenitis who are
referred from Pediatric Surgery Department after FNAC
confirmed diagnosis. This is because at AIIMS Pediatric
TB clinic gets a limited amount of TB drugs from a NGO
and there is constraint of personnel. The other forms of
extrapulmonary tuberculosis such as osteoarticular,
genitourinary are treated in orthopedic department and
pediatric surgery department respectively. Hence, this
data is not representative of a medical college in India.
HIV AND TUBERCULOSIS

It has been reported that HIV infection is probably one
of the most important factors for the resurgence of TB in
adults as well as in children. In the year 1990, 4.2 percent
of tuberculosis cases worldwide occurred in HIV-infected
individuals and estimates for the year 2000 were around
14 percent.61 Adults with HIV infection are more likely
to develop tuberculosis from latent infection, and those
who encounter M. tuberculosis after HIV related immune
suppression have a more rapid progression to disease.62
The impact of the HIV epidemic on pediatric TB has been

reported in several studies. A prospective cohort study
of children with TB diagnosed in Addis Ababa from
December 1995 to January 1997 in which HIV-positive
children were compared with HIV-negative children,
reported that HIV-positive children were younger, more
underweight and had a 6-fold higher mortality than HIVnegative children.63 There are not many studies from
India on proportion of children co-infected with HIV and
TB. In a small study from Mumbai, 64 18 percent of
children with disseminated tuberculosis (N = 50) were
HIV seropositive. Reported co-infection of HIV and TB
in various Indian studies varies from 16 to 68 percent.6567
Since follow up data of HIV infected children are not
available, it is very difficult to estimate annual infection
rate of tuberculosis in HIV-positive patients.
MOLECULAR EPIDEMIOLOGY
The continuous presence of tuberculosis pandemic
despite the introduction of curative anti-tuberculosis
drugs for the last 50 years has stimulated research efforts
into the molecular epidemiology of tuberculosis. Burgos
and Pym 68 has highlighted the need of research in
molecular epidemiology because the coexistence of HIV
and tuberculosis is a great threat to the population in Asia
and Africa. This new discipline of molecular
epidemiology began with the identification of IS6110, a
noval mycobacterial insertion sequence. This method is
firmly established, but is still expensive, labor-intensive
and only applicable on viable culture material.
IS6110 restriction fragment length polymorphism
(RELP) is exclusively present in M. tuberculosis complex
species, although strains of M. tuberculosis lacking this
element have also been described. IS6110-based typing
is the most widely applied genotyping method in the
molecular epidemiology of M. tuberculosis and is the gold
standard to which other methods are compared.
1
100
1
147
99
146
1966-70
N
%
1
374
373
100
99
1971-75
N
%
2
2
5
250
245
40
40
20
2
100
98
1976-80
N
%
83
71
39
35
65
110 17
666 100
556
1981-85
N %
80
152
7
7
90
5
5
146 20
752 100
606
1986-90
N %
*All India Institute of Medical Sciences, New Delhi, India.

** The figures in number and percentages are out of the total of extrapulmonary cases
*Pulmonary
*Extrapulmonary
Total
**Extrapulmonary
- TBL
- Disseminated
- TBM
- Osteoarticular
- Others
Type of TB
81
167
5
97
3
172 19
923 100
751
1991-95
N %
69
225
27
17
8
81
10
6
3
277 31
892 100
615
1996-00
N %
59
256 66
46 11
8 2
24 7
50 12
384 41
918 100
534
2000-04
N %
46
204
100
18
83
78
42
21
04
17
16
46 54
898 100
415
2005-08
N %
Table 4.8: Changing spectrum of tuberculosis over last four and a half decades in pediatric TB clinic of a tertiary care referral hospitalAIIMS*
73
1056
185
61
118
128
68
13
04
07
08
1579 27
5820 100
4241
1966-2008
N %
35
36
The application of molecular epidemiology can be
used usefully to study the following:
Dynamics of transmission with in population
Epidemiological impact of subpopulation on
tuberculosis transmission
Improving disease control by demonstrating the
exclusive potential for tuberculosis to progress to
disease and spread amongst HIV-infected persons
Determining the potential for spread of drug-resistant
strains among hospitalized patients
Quantification of the level of infectiousness among
smear-negative patients
Development and transmission of MDR-TB, defined
as resistance to at least isoniazid and rifampicin.
the grassroot level. This can be achieved by laying more

emphasis on the participation of community leaders who
can influence the grassroot workers to have high index
of suspicion for diagnosis in cases with chronic cough.
Uptil now the case finding through Maternity and Child
Health Services has been disappointing. At the same time
the children, i.e. the contacts of both sputum smearpositive and sputum smear-negative must be screened.
To begin with the vulnerable age group of 1 to 6 years
must be thoroughly investigated. Age group of 5 to 9
years need to be kept under surveillance. Again 10 to 15
years age group needs greater attention as they are likely
to develop adult type of disease.
HIGHLIGHTS
Tuberculosis Mortality
Mortality due to tuberculosis in children has been shown
to have a strong correlation with socioeconomic status of
population and disease severity. Tuberculosis has been
estimated to be responsible for 5 to 50 percent of crude
death rate in 1 to 4 year old in different parts of country.
ACTIONS BEING TAKEN IN INDIA

Uptil now the tuberculosis has been diagnosed, treated
entirely differently by pediatricians and TB specialists.
Tuberculosis Chapter of Indian Academy of Pediatrics
has defined two consensus statements, one on diagnosis69
and the other on treatment.70 Now under the Revised
National Tuberculosis Control Program (RNTCP) using
strategy of DOTS, due attention is being attempted with
the concurrence of joint committee of members of Indian
Academy of Pediatrics, Program managers and TB
experts.71 The latest Consensus Statement on Childhood
Tuberculosis Working Group on Tuberculosis of Indian
Academy of Pediatrics (IAP) has been published in 2010
(discussed elsewhere).
As mentioned earlier, out of the various precipitating
factors like measles, whooping cough, chronic diarrhea
and severe malnutrition, for tuberculosis HIV-infection
and disease is the recent addition. Measles and whooping
cough are covered in the National Program of
Immunization in India. There is never 100 percent
coverage, hence there is a need to strengthen this
program. For malnutrition there is a coordinated program
between the Ministry of Health and Family Welfare and
Ministry of Social Welfare named as Integrated Child
Development Services Scheme (ICDS). This also needs a
better cover-age of the vulnerable (1-5 years) age group.
Mitchison72 has very wisely summarized that inspite
of all the advances in understanding of immunopathogenesis, availability of high tech diagnostic
techniques, the most important aspect which would
determine the impact of all these is diagnosis in adults at
Epidemiology with special reference to children in

Indian and global context has been discussed.
The major reason for lack of data in epidemiology is
due to difficulty in diagnosis in children particularly
less than 5 years
Operational difficulty of carrying out tuberculin test
and X-ray chest in the National Program settings
Factors responsible for different presentation in
children are detailed
Government of India is making efforts to include
children in the National Program of DOTS.
Three consensus statements have been made on
diagnosis and treatment by Indian Academy of
Pediatrics and one by joint effort of TB division of
Ministry of Health Government of India with experts
in TB and renowned members of Indian Academy
of Pediatrics.
WHO office at New Delhi has included certain
features innumerated in the above consensus in the
implementation of diagnosis and treating
Child friendly weight for use wise boxes of anti TB
drugs have been made for inclusion in the program.
The draw back is that these are not available for
children weighing sixteen kilograms and less. This
conveniently excludes children below two years of age.
Certain research studies have been designed by
active participation of few members of Indian
Academy of Pediatrics to come to certain practical
solutions for the problems encountered in the
implementation of DOTS for children.
Guidelines have been prepared for uniformity in the
implementation of DOTS for Diagnosis and
Treatment.
Institutes like AIIMS have started treating resistant
TB on ambulatory basis after initial stabilization.
Preliminary data shows the commonest
manifestation of resistant TB in children is
extrapulmonary in the form of cervical adenitis.
REFERENCES
1. Prabhakar R. Tuberculosis: the continuing scourge of
India. Indian J Med Res 1976;65:19-25.
2. Donald PR. Childhood tuberculosis: the hidden epidemic.
3. Tuberculosis Research centre, Chingleput, Chennai, India.
Trends in the prevalence and incidence of tuberculosis
in South India. Int J Tuberc Lung Dis 2001;5:142-57.
4. Seth V. Tuberculosis in children: epidemiology, diagnosis
and treatment. In Seth V, Puri RK, Suchdeva HPS (Eds):
Tuberculosis in Children: New Delhi, India. Indian
Pediatr 1991;1-7.
4a. Passi GR. TB-we have lost our way. Indian Pediatr
2008;45:426.
5. Udani PM. Tuberculosis in children in India. Pediatr Clin
India 1983; 25: 125-31.
6. Chakraborty AK. Prevalence and incidence of
tuberculosis infection and disease in India: a
comprehensive review. World Health Organization,
Geneva, Switzerland 1997; WHO/TB/97/23.
7. Chakraborty AK. Tuberculosis in India. Pediatrics Today
1999; 2: 47-53.
8. Singh M, Mynak ML, Kumar L, et al. Prevalence and risk
factors for transmission of infection among children in
household contacts with adults having pulmonary
8a Cotton MF, Schaaf HS, Lottering G, et al. Tuberculosis
exposure in HIV-exposed infants in a high prevalence
setting. Int J Tuberc Lung 2008;12:225-7.
9. Chakraborty AK. Tuberculosis infection in a rural
population of South India 23 year trend. Tubercle Lung
Dis 1997;73:213-8.
10. Director General of Health Services. Department of
Tuberculosis: Now and for ever strengthen NTP. DGHS.
Ministry of Health and Family Welfare. New Delhi 1987.
11. Sunderam G, Medound RJ, Menietio T. Tuberculosis as a
manifestation of the acquired immunodeficiency
syndrome (AIDS) and pre-AIDS. Am Rev Respir Dis
1985;191:390-6.
12. Sudre P, Ten Dam G, Kochi A. Tuberculosis, a global
overview of the situation today. Bull WHO 1982;70:
149-59.
13. Gopi PG, Subramani R, Santha T, et al. Estimation of
burden of tuberculosis in India for the year 2000. Indian J
Med Res 2005;122:243-8.
14. Thorpe LE, Frieden TR, Laserson KF, et al. Seasonality of
tuberculosis in India: is it real and what does it tell us?
Lancet. 2004;364(9445):1613-4.
15. Chadha VK, Agarwal SP, Chauhan LS, et al. Annual risk
of tuberculous infection in four defined zones of India: a
comparative picture. Int J Tuberc Lung Dis. 2005;9:
569-75.
16. Chadha VK, Kumar P, Jagannatha PS, et al. Average
annual risk of tuberculous infection in India. Int J Tuberc
Lung Dis. 2005;9:116-8.
17. Chadha VK, Jithendra R, Kumar P, et al. Change in the
risk of tuberculous infection over an 8-year period among
school children in Bangalore city. Int J Tuberc Lung Dis
2008;12:1116-21.
37
18. Gopi PG, Subramani R, Narayanan PR. Trend in the

prevalence of TB infection and ARTI after implementation
of a DOTS programme in South India. Int J Tuberc Lung
Dis 2006;10:346-8.
19. Kumar S, Radhakrishna, Chadha VK, et al. Prevalence of
tuberculosis infection among school children in Kerala,
Indian J Tuberc 2009; 56:10-6.
20. Rao VG, Gopi PG, Yadav R, et al. Annual risk of
tuberculosis infection among tribal population of Central
India. Trop Med Int Health 2008; 13: 1372-7.
21. Gopi PG, Prasad VV, Vasantha M, et al. Annual risk of
tuberculosis infection in Chennai city. Indian J Tuberc
2008;55:157-61
22. Rao VG, Gopi PG, Yadav R, et al. Tuberculous infection
in Saharia, a primitive tribal community of Central India.
Trans R Soc Trop Med Hyg 2008;102:898-904.
23. Chadha VK, Kumar P, Satyanarayana AV, et al. Annual
risk of tuberculosis infection in Andhra Pradesh, India.
Indian J Tuberc 2007;54:177-83.
24. Pulickal AS, Fernandes GV. Comparison of the prevalence
of tuberculosis infection in BCG vaccinated versus
nonvaccinated school age children. Indian Pediatr
2007;44:344-7.
24a. Kalappan C, Gopi PG, Subrami R, et al. Estimation of
annual risk of tuberculosis infection (ARTI) among
children aged 1-9 years in the South Zone of India. Int J
Tuberc Lung Dis 2004;8:418-23.
25. Shashidharan AN, Chadha VK, Jagannath PS, et al. The
annual risk of tuberculosis infection in Orissa State, India.
Int J Tuber Lung Dis 2004; 8:545-51.
26. Udani PM, Bhat US, Bhave SK, et al. Problem of
tuberculosis in children in India. Epidemiology,
morbidity and mortality and Control Program. Indian
Pediatr 1976;13:881-90.
27. Indian Council of Medical Research: Tuberculosis in
India. A Sample Survey Special reprint series, 1959;
No. 34.
28. Ukit and Benjamin. Indian J Med Res. (quoted in
reference 1).
29. Tuberculosis prevention trial, Madras, trial of BCG
Vaccine in South India for tuberculosis prevention. Indian
J Med Res 1980; 72: 1-74.
30. National Tuberculosis Institute. Annual risk of infection
with tuberculosis. Tubercle Lung Dis 1992; 73: 213-8.
31. Myurnath S, Vallishayee RS, Radhamani MP,
et al. Prevalence study of tuberculosis infection over
fifteen years in a rural population in Chingleput district
(South India). Tuberculosis Research Centre, Chennai.
India J Med Res 1991; 93:70-80.
32. WHO. Childhood tuberculosis and BCG vaccine: EPI
update supplement. Geneva, Switzerland: WHO; 1989.
33. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis
incidence and mortality during 1990-2000. Bull World
Health Organisation1994; 72: 213-20.
34. Beyers N, Gie RP, Zietsman HL, et al. The use of a
geographical information system (GIS) to evaluate the
distribution of tuberculosis in a high-incidence
community. S Afr Med J 1996; 86: 40-1.
35. Enarson DA, Reider HL, Amadortir T, et al. Management
of tuberculosis: a guide for low-income countries. Paris,
38
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
France: International Union Against Tuberculosis and

Lung Disease; 2000 (monograph).
Migliori GB, Raviglione MC. Population surveil-lance and
prevention strategies for tuberculosis. Annals Nestle 1997;
55:24-34.
Jereb JA, Kelly GD, Porterfield DS. The epidemiology of
tuberculosis in children. Semin Pediatr Infect Dis
1993;4:220-31.
Corbett EL, Watt CJ, Walker N, et al. The growing burden
of tuberculosis: global trends and interactions with the
HIV epidemic. Arch Intern Med 2003;163:1009-21.
Donald PR, Van Helden PD. The global burden of
tuberculosis combating drug resistance in difficult times.
N Eng J Med 2009;360:2393-5.
Miller FJW, Slar REM, Jayntor MD. In Miller FJW (Ed):
Tuberculosis in Children, 1st edn. New Delhi; BI Churchill
Livingston Pvt Ltd 1982; 16-24.
Stend WW. Genetics and resistance to tuberculosis. Could
resistance be enhanced by genetic engineering? Ann
Intern Med 1992; 116: 937-41.
Nunn P, et al. The effect of human immunodeficiency
virus type-1 on the infections of tuberculosis. Tubercle
Lung Dis 1994;75:25-32.
Enarson DA, Chirag CY, Murray JF. Global epidemiology
of tuberculosis. In Rom WN, Garay SM, (Eds):
Tuberculosis. 2nd edn. Boston, Little Brown and
Company Inc, 2004;13-30.
Horsburgh CR Jr. Priorities for the treatment of latent
tuberculosis infection in the United States. N Engl J Med
2004;350:2060-7.
Scrimshaw NS, Gordon JE, Taylor C. The interaction of
nutrition and infection, Geneva, WHO Monograph Series
1968; No. 57.
Marais BJ, Gie RP, Schaaf HS, et al. The natural history of
childhood intrathoracic tuberculosis: a critical review of
Lung Dis 2004; 8:392-402.
Mandalakas AM, Starke JR. Current concepts of
childhood tuberculosis. Semin Pediatr Infect Dis 2005;
16:93-104.
Grzybowski S. Epidemiology of tuberculosis with particular reference to India. Indian J Tuberc 1995;42:195-200.
Terris M. Relation of economic status to tuberculosis
mortality by age and sex. Am J Pub Health 1948;38:1061-70.
World Health Organization. Tuberculosis notifi-cation
update. WHO/TB 1992;169.
Datin PJ, Ravigloone MC, Kochi A. Global tuberculosis
incidence and mortality during 1990-2000. Bull WHO
1994; 72:213-20.
Sivanandan S, Walia M, Lodha R, et al. Factors associated
with treatment failure in childhood tuberculosis. Indian
Pediatrics 2008; 45:769-771.
Schaaf HS, Van Rie A, Gie RP, et al. Transmission of
multidrug-resistant tuberculosis. Pediatr Infect Dis J
2000;19:695-99.
Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global
surveillance for antituberculosis drug resistance 19941997. N Engl J Med 1998;338: 1641-9.
55. Narmada R, Raj Narain, Raju VB, et al. Incidence of

tuberculosis among infected and non-infected children.
Indians J Med Res 1977;65:171-83.
56. Motiram G, Chakraborty AK. Prevalence of childhood
tuberculosis and problems in its diagnosis in a community
NTI Newsletter, 1990; 26:8-17.
57. Udani PM. BCG Vaccination in India and tuberculosis in
children. Indian J Pediatr 1994;61:451-62.
58. Udani PM. BCG Vaccination and Child Neurology
from modern perspectives of Child Neurology. In
proceedings of the joint convention of the 5th
International Congress and 3rd Asian Oceania Congress
of Child Neurology. Tokyo No. 4-9, 1990, Jap Pediatr Neurol
Soc 1991; 14:103-30.
59. Sanchez-Albisua I, Baguaero-Artigao F, Castillo FD,
et al. Twenty years of pulmonary tuberculosis in
children: what has changed. Pediatr Infect Dis J
2002;21:49-53
what has changed in last 20 years? Indian J Pediatr
2002;69:S5-10.
61. Raviglione MC, Snider DE Jr, Kochi A. Global
epidemiology of tuberculosis. morbidity and mortality
of a worldwide epidemic. JAMA 1995; 273:220-6.
62. Antouucci G, Girardi E, Raviglione MC, et al. For the
Gruppo Italiano di Studio Tubercoloise AIDS (GISTA).
Risk factors for tuberculosis in HIV-infected persons: A
prospective cohort study. JAMA 1995;274:143-8.
63. Palme IB, Gudetta B, Bruchfeld J, et al. Impact of human
immunodeficiency virus-1 infection on clinical
presentation, treatment outcome and survival in a cohort
of Ethiopian children with tuberculosis. Pediatr Infect Dis
J 2002;21:1053-61.
64. Merchant RH, Shroff RC. HIV seroprevalence in
disseminated tuberculosis and chronic diarrhea. Indian
Pediatr 1998;35:883-7.
65. Merchant RH, Oswal JS, Bhagwat RV, et al. Clinical
profile of HIV infection. Indian Pediatr 2001; 38: 239-46.
66. Lodha R, SinghalT, Jain Y, et al. Pediatric HIV infection
in a tertiary care center in North India: early impressions.
Indian Pediatr 2000;37:982-6.
67. Dhurat R, Manglani M, Sharma M, et al. Clinical spectrum
of HIV infection. Indian Pediatr 2000; 37:831-6.
68. Burgos MV, Pym AS. Molecular epidemiology of
tuberculosis. Eur Respir J 2002;20:54S-65S.
69. Diagnosis of childhood tuberculosis: consensus statment
of Indian Academy of Pediatric Working Group-Status
Report. Indian Pediatr 2004;41:146-55.
70. Treatment of childhood tuberculosis consensus statement:
Recommendations of Indian Academy of Pediatrics. Indian
Pediatr 1997; 34: 1093-6.
71. Management of Pediatric Tuberculosis under the Revised
National Tuberculosis Control Program (RNTCP), A joint
statement of central TB Division, Ministry of Health and
Family Welfare and experts from Indian Academy of
Pediatrics. Indian Pediatr 2004; 41: 901-5.
72. Mitchison DA. The control of tuberculosis: progress and
prospects. Indian J Med Res 2005; 121: 137-9.
SECTION 3
MICROBIOLOGY AND
IMMUNOPATHOGENESIS
Mycobacterium Tuberculosis
Nontuberculous Mycobacteria
Immunology of Tuberculosis: Basic Aspects and

Relevance for Immunodiagnostic Tests
Clinicoimmunological Profile
Mycobacterium Tuberculosis
Sarman Singh, K Gopinath, Ruchi Sood, Ashok Rattan
INTRODUCTION
The genus Mycobacteria includes species of bacteria
responsible for tuberculosis and leprosy, diseases of
antiquity which still affect millions. Tuberculosis remains
one of the deadliest diseases in the world. Tuberculosis
(TB) is diagnosed in 9.2 million people every year, of
which 1.7 million died in 2006. India tops the list by
having highest burden of infected people.1 The main
driving force is the Human Immunodeficiency Virus
(HIV) pandemic, which has allowed TB to reemerge so
dramatically.1,2 Of the total notified TB cases (0.7 million),
0.2 million deaths occurred in HIV-TB coinfected cases,1
with a 100-fold higher risk of developing disease within
one year of infection than those infected with
M. tuberculosis alone.2 Robert Koch, a physician from
Wolstein, Germany demonstrated that tuberculosis is
caused by a prokaryote. He was able to isolate pure
culture of tubercle bacilli and inoculated them into
healthy mice and guinea pigs which eventually became
diseased with the pathogen. Table 5.1 gives the Kochs
postulates. Thus, a far reaching discovery emerged after
centuries of ignorance. Koch published his findings on
10th April 1882 after presenting these on 24th of March
1882.3
The bacterium was named Mycobacterium (Greek,
Mykes, Fungus; bacterium; small rods) in 1896 by
Lehmann and Neumann in reference to the mould-like
pellicles formed by the bacteria on liquid medium. At
that time the genus contained only two species,
Mycobacterium tuberculosis and Mycobacterium leprae.
M. tuberculosis is clinically the most important
member of the M. tuberculosis complex which includes
M. tuberculosis, M. bovis and its BCG (bacille CalmetteGuerin) variant, M. africanum and M. microti. The
members of this complex are closely related as seen by
DNA homology.4 Each one of them, however, does
possess signature sequences which can be differentiated
by sequencing after PCR amplification of specific
hypervariable regions in the gene coding for the 16S
rRNA.5,6 But for all practical purposes, the degree of
homology between the species of the complex suggests
that the members of this complex might be more properly
considered serovars or pathovars of the same species
rather than five different species. Disease caused by
M. bovis and M. africanum is clinically indistinguishable

from classical tuberculosis and treatment is the same for
all the infections. M. microti causes a tuberculosis like
disease in voles, but is not considered pathogenic for
humans while BCG is essentially nonpathogenic for
humans.
TAXONOMY
Mycobacterium is the only genus in the family
Mycobacteriaceae. The high Guanine + Cytosine [GC] ratio
in the DNA of Mycobacteria (62-70%) is similar to that of
other mycolic acid producing bacteriaNocardia (60-69%),
Rhodococcus (59-69%) and Corynebacterium (51-59%). This
similarity may support the consolidation of these genera
into a single family.7 The genus Mycobacterium is responsible
for more suffering world-wide than all other bacterial
genera combined. Currently, there are over 100 recognized
species of Mycobacteria. This genus contains obligate
pathogenic, opportunistic and saprophytic species.
According to Bergeys manual of determinative
bacteriology, mycobacteria are classified in the category II
(Gram-positive bacteria having cell wall) with the following
classification:
Division:
- Prokaryote
Subdivision - Protophyta
Class:
- Shizomycetes
Order:
- Actinomycetales
Family:
- Mycobacteriaceae
Genus:
- Mycobacterium
Mycobacteria have been classified into fast and slow
growing species by the seemingly arbitrary criteria of
whether or not they produce visible growth on subculture
Table 5.1: Kochs postulates
The bacterium should be constantly associated with the
lesion of the disease
It should be possible to isolate the bacterium in pure
culture from the lesion
Inoculation of such pure culture into suitable laboratory
animals should reproduce the lesions of the disease
It should be possible to reisolate the bacterium in pure
culture from the lesions produced in the experimental
animals.
42
Section 3 Microbiology and Immunopathogenesis

in 7 days. Recently, however, this criterion was shown
to be remarkably valid taxonomically: all slow growing
species have only one operon whereas all fast growing
species have two. A phylogenetic analysis based on the
16S rRNA sequences placed the fast and slow growing
species into two clear and separate branches of the
evolutionary tree8 (Table 5.2).
DESCRIPTION OF THE GENUS

The Mycobacteria are nonmotile, nonspore forming,
slightly curved or straight bacilli, 0.2 to 0.6 by 1 to 10 m
in size, sometimes with branching. Filamentous or
mycelium like growth may occur, but it is easily
fragmented into rods or coccoid elements (Fig. 5.1A).
Mycobacteria have a unique cell wall responsible for
its virulence, diagnostic staining and treatment. The cell
wall has high (>60%) lipid content that includes a waxy
coat made of three major components: mycolic acids, cord
factor, wax D, and sulfatids. The mycolic acids of
Mycobacteria are unique alpha branched chains of
hydroxyl-fatty acids. These are strong hydrophobic and
significant determinants of virulence, as they prevent
attack on Mycobacteria by cationic proteins, lysozymes
and oxygen radicals in the phagocytic cells.
They also protect the extracellular organisms from
complement attack. The waxes make up 50% of the dry
weight of the cell envelope. The cord factor is another

constituent responsible for serpentine growth of the
organism. It is toxic to mammalian cells and is also
inhibitor of polymorphonuclear cell migration. The cord
factor is most abundant in virulent strain of
M. tuberculosis. The robust cell wall also provides
resistance to killing by acidic and alkaline compounds,
osmotic lysis via complement and resistance to common
antibiotics.
Staining Reaction
The high lipid content of the cell wall provides unusual
impermeability to aniline dyes and stains. Mycobacteria,
therefore, are not readily stained by the Gram-stain.
Special staining procedures are applied to promote the
uptake of a strong dye but once the Mycobacteria have
taken the stain, they are not easily decolorized even with
acid-alcohol. This resistance to decolorization is called
acid fastness. The property of acid fastness is not absolute
and may be partly or completely lost at some stage of
growth by some proportion of the cells of some species
of Mycobacteria. Cells of the fast growing Mycobacteria
may be less than 10% acid fast.
Koch (1882) stained the tubercle bacilli with hot
alkaline methylene blue as the primary stain and vesuvin
Table 5.2: Classification on the basis of growth rate (Also see Figs 5.1A to E)
Slow growing
mycobacteria
Rapid growing
mycobacteria
Species that do not have special

nutritional requirements
Species with special

growth requirements
M. tuberculosis complex
M. fortuitum complex
M. fortuitum
M. chelonei subsp. chelonei
M. chelonei subsp. abscessus
M. marinum
M. ulcerans
M. malmoense
M. paratuberculosis
M. haemophilum
M. lepraemurium
M. leprae
M. tuberculosis
M. bovis
M. africanum
M. microti
M. avium complex
M. avium
M. intracellulare
M. xenopi
M. scrofulaceum complex
M. scrofulaceum
M. simiae
M. gordonae complex
M. gordonae
M. szulgai
M. asiaticum
M. kansasii complex
M. kansasii
M. gastri
M. terrae complex
M. terrae
M. nonchronogenium
M. triviale
Nonphotochromogenic
M. agri
M. chitae
M. smegmatis
M. parafortuitum complex
M. parafortuitum
M. aurum
M. diernhoferi
M. vaccae
M. neoaurum
Thermotolerant strains
M. flavescens
M. phlei
M. thermoresistible
Bovine farcy
M. farcinogens
M. senegalense
Chapter 5 Mycobacterium Tuberculosis

as the decolorizer and counter stain.3 Ehrlich (1882)
discovered 3% acid fast property of the bacteria and
stained the bacilli with hot fuchsin in the presence of
aniline oil as a mordant and destaining with a dilute
mineral oil. Ziehl (1883) changed the mordant to phenol
and Neelsen (1884) combined the dye and mordant to
form carbol fuchsin. Thus, the acid fast staining
technique, although, pioneered by Ehrlich, is now known
as the Ziehl-Neelsen (ZN) method and has remained
essentially unchanged since 1884 (Figs 5.1B to D).
43
Decolorization with alcohol and cold staining techniques

as well as the use of fluorescent dyes (e.g. Auramin-O)
to visualize the Mycobacteria have also been developed.
(Fig. 5.1E) It is not possible to differentiate M. tuberculosis
from other acid fast atypical Mycobacteria. The property
of acid fastness, however, is not unique to Mycobacteria.
It is shared with Nocardia, volutin granules of
Corynebacteria, Legionella micadadi, bacterial and fungal
spores and cysts of the protozoan Cryptosporidium species,
if only 1% acid is used to decolorize.
Figs 5.1A to E: A. Scanning Electron Microscopical

observation of M.tuberculosis. B. Ziehl-Neelsen stained
M. tuberculosis cells, C. Typical serpentine growth (cord
factor) of M. tuberculosis culture grown in egg-based media
(Lowenstein-Jensen Medium), D. ZN stained cells
harvested from liquid culture (Middlebrook 7H9 broth), E.
Auramine Rhodamine (AR) stained M. tuberculosis cells.
The fluorescent staining method has higher sensitivity over
ZN method (For color version see Plate 1)
44
Mycobacterial Species
The primary mycobacteriosis throughout the world is
tuberculosis. Its prevalence and severity prompted the
studies of Robert Koch and others on its etiology that
culminated in the discovery of the tubercle bacilli in 1882.
Before the end of the century the bovine, avian, reptilian,
piscine and saprophytic varieties of Mycobacteria had
also been described. Despite sporadic reports of isolation
of many varieties of nontuberculous mycobacteria from
clinical specimens only M. tuberculosis and M. bovis were
taken seriously as a cause of human disease,9 while these
isolates were given dismissive epithets such as atypical
pseudotubercular and tuberculoid bacilli. Also, as
their classification was in chaos, they were dubbed
anonymous mycobacteria. Interest in their role as
pathogens of man commenced in earnest in the 1950s
with the description of two distinct diseases, namely
swimming pool granuloma and Buruli ulcer caused by
M. marinum and M. ulcerans, respectively. And also the
demonstration of their etiological role in the tuberculosislike pulmonary disease.10
The atypical mycobacteria isolated from clinical
material have been called by many namesparatubercle,
pseudotubercle, anony-mous, atypical, nontuberculous
(NTM), environmental, opportunistic, tuberculoid and
mycobacteria other than tubercle (MOTT) bacilli. The
diseases associated with them have been termed
pseudotuberculosis, mycobacteriosis, nontuberculous,
mycobacterial infection and tuberculosis due to one of
the specific mycobacterium by species name.
None of the proposed names is without criticism but
the most appropriate and least offensive, is nontubercular
mycobacteria (NTM).9 Certainly, atypical, anonymous
and unclassified are no longer acceptable as each of the
species is typical, for the genus Mycobacteria, when analyzed microbiologically and since species specific names
have been designated, opportunistic is also not entirely
appropriate, 10,11 but usually referred to describe such
infections in immunocompromised persons.12 It is also
MIC
GC
not right to call the disease tuberculosis because of the

pronounced differences between the two infections in
pathogenesis, epidemiology, prognosis and response to
treatment. The drug susceptibility of NTM, as measured
by tetrazolium microplate assay, showed that the pattern
of drug susceptibility is grossly different in NTM from
M. tuberculosis (Fig. 5.2). Runyon13 provided early
leadership in the classification of these mycobacteria and
on the basis of type of colony, rate of growth, pigment
production and simple biochemical reactions divided
them into four groups. Subsequent workers have
suggested different biochemical tests and High
Performance Liquid Chromatography (HPLC) analysis
of speciesspecific mycolic acids in order to improve
the identification of isolates but the basic format has
remained unchanged. From the clinical point of view,
however, these mycobacteria are divisible into three
groups:
The obligate human pathogens
Species that have been definitely shown to cause human
disease under certain circumstances, and
Those that rarely, if ever, do so.
Opportunistic infections due to MOTT or NTM have
been on the increase, mainly as a consequence of the AIDS
epidemic.14-16 Among the mycobacterial species often
implicated in NTM infections are M. avium, M. intracellulare complex, M. fortuitum, M. chelonae, M. abscesses,
M. kansasii , M. celatum, and M. xenopi.12,14,16,17
Habitat
Mycobacteria are not members of the normal bacterial
flora of man, but M. smegmatis and M. gastri can sometime
be isolated from the smegma and gastric contents,
respectively.18
M. tuberculosis is clearly not typical of the mycobacteria since, the majority of these species are essentially
environmental saprophytes and do not cause disease or
rarely do so. Thus, M. tuberculosis has been described as
being the Wayward Son of Honorable Parents. The impli-
MIC
GC
Fig. 5.2: Antimycobacterial drug susceptibility by tetrazolium microplate assay. This method is rapid, quantitative but
feasible only in center with biocontainment facility (For color version see Plate 1)

cation is that M. tuberculosis probably evolved from an
environmental organism to become the most successful
bacterial pathogen of all time utilizing successful
strategies to invade and persist within macrophages with
phases of dormancy.
Mycobacteria are most widely known as the cause of
dreadful diseases. Less well known is their role as
thriving members of environmental ecosystems. In fact,
a large variety of complex organic synthetic and
degradative processes have been described recently for
free living soil mycobacteria. Mycobacteria synthesize a
variety of steroid hormones from cholesterol.19 Various
simple and complex hydrocarbons and other organics
can be degraded and these activities could be useful in
pollution control.20
Cultural Characteristics
The Mycobacteria are aerobic nonencapsulated, nonspore
forming, nonmotile bacilli. The M. tuberculosis is one of
the slowest growing (generation time in animal tissues
~24 hours) Mycobacteria. Colony morphology varies
among the species, M. tuberculosis forms rough colonies
with bacilli compacted into curving strands (serpentine
cords). In contrast, M. avium complex usually forms
smooth transparent colonies with the bacilli arranged in
no definite pattern. Robert Koch isolated the organism
on heat coagulated sheep serum culture medium devised
by John Tyndall. Nocard later introduced glycerol-beef
broth which Koch used for his studies on tuberculin.
Mycobacteria are strictly aerobic and grow more
slowly than most bacterial pathogens. The generation
time of the mycobacteria is more than 12 hours.
M. tuberculosis has the longest replication time of 20 to
22 hours. The growth of M. tuberculosis is enhanced by
an atmosphere of CO2 between 5 and 10% for the first
few weeks of incubation. Mycobacterium requires a pH
between 6.5 and 6.8 for the growth medium and grows
better at higher humidity.
Isolation of mycobacterium poses a special problem
for the laboratory. Mycobacteria require a prolonged
time for replication [approximately 15 to 22 hours],
whereas the generation time of other bacteria present in
the specimen may be as short as 20 to 30 minutes. This
disproportionate rate of growth between mycobacteria
and other bacteria may result in rapid accumulation of
metabolic acids that liquefy the culture medium, making
it unsatisfactory for the recovery of mycobacteria.
Therefore, the successful isolation of mycobacteria
depends upon the selective suppression of contaminating
bacteria.
Egg-based solid media like Lowenstein-Jensen or
American Tradeau Society medium are very rich and
contain phospholipids, and proteins that tend to bind
and/or neutralize toxic products in clinical specimens.
45
They have been used for primary isolation of

M. tuberculosis from the clinical samples and they also
tend to yield a higher percentage of positive results in
comparison to agar based isolation media. Because of its
luxuriant growth on egg media, M. tuberculosis has been
termed eugonic.
Agar based media are prepared from semi synthetic
basal medium and are enriched with defined
supplement. Since, the medium is transparent, it permits
early microscopic detection of the colonies. Growth of
M. tuberculosis on agar based medium like Middlebrook
7H10 is enhanced by the presence of 5 to 10% of CO2 in
the incubation atmosphere. (Fig. 5.3A). The medium
should be made selective by incorporation of various
antibiotics. For the best results both an agar and egg based
media should be used for primary isolation of
mycobacteria. Most strains of mycobacteria causing
human disease can be isolated using media of two
different basal composition. Diffusible pigment is seldom
present, but colonies of some species are regularly,
variably yellow or orange. Some species require light to
form pigments (photochomogens) and other form
pigment in either the light or dark (scotochromogens)
(Fig. 5.3B).
It is true that M. tuberculosis is best isolated from
clinical specimens on rich and fairly complex media like
Middlebrook 7H9, BACTEC- MGIT960 and MB-act-240,
(Figs 5.4A to C) but the apparent fastidiousness of some
such isolates may be consequence of their injury by
conditions in host tissue or by the treatment employed
for processing the clinical specimen. Once isolated, M.
tuberculosis is capable of adapting to grow on extremely
simple medium, i.e. one containing, a simple source of
carbon and nitrogen plus some buffer salts and trace
elements. A visible mass multiplication can be seen in
Middlebrook 7H9 broth (Fig. 5.4C).
Mycobacterial Envelope
The cell envelope essentially distinguishes species of
mycobacterial genus from other prokaryotes.
Mycobacteria in general give a weakly positive response
to the Gram-stain but are phylogenetically more closely
related to Gram-positive bacteria. Based on the recent
developments in the knowledge of the ultrastructure and
chemistry of mycobacteria, the mycobacterial cell
envelop possesses 3 structural components: (1) Capsule
(2) Cell wall and (3) Plasma membrane.21 This skeleton
provides osmotic protection from outside environment
and also helps transportation of ions and molecules
beside the mechanical support and shape to the bacteria.
Mycobacterial Capsule
The outermost compartment of the cell envelop consists
of a mixture of polysaccharides, proteins and lipids, and
46
Figs 5.3A and B: A. Mycobacterium smegmatis cultured in Middlebrook7H10 agar and incubated at 37C for 5 days,
B. Mycobacterial colony and phenotypic appearance on Lowenstein-Jensen (L-J) Medium incubated at 30-37C in the
presence or absence of light (For color version see Plate 2)
Figs 5.4A to C: Middelbrook 7H9 broth containing OADC (Oleic Acid, Dextrose, Catalase) with antibiotic mixture (PANTA
Polymyxin, Amphotericin, Nalidixic Acid, Trimethoprim and Azlocillin) to prevent other contaminants is being used in
automated culture system with higher sensitivity. The growth rate of M. tuberculosis is faster (12-17 days) than the solid
(22-30 days), egg based L-J (27-45 days) culture methods. (A) BACTEC MGIT-960 (Mycobacterial growth Indicator
Tube, Becton Dickinson, USA) growth detection based on fluorescence (B) MB-BacT-240 (Biomeurieux, France) growth
detection based on colorimetry (C) Laboratory mass multiplication of M. tuberculosis in Middlebrook7H9 broth (For color
version see Plate 2).
is called capsule. The earliest mention of mycobacterial

capsules was by Chapman in 1959, who called the space
between the phagosomal membrane of the infected cell
and the wall of the enclosed Mycobacterium a capsular
space or halo. Chemically, a clear distinction between
the wall associated compounds and capsular constituents
has not been possible so far and many substances are

found in more than one envelop compartments.
However, electron microscopic studies have proved
existence of capsule in mycobacteria. It is also established
now that most part of the capsule is lost from the
mycobacteria during the conventional processing of the

samples for microscopy. Most of the species of
mycobacteria are known to possess the capsule, but the
thickness varies from species to species. The ratio of
protein to polysaccharides varies, according to the
species. For example, the major constituent in M.
tuberculosis, M. kansasii, and M. gastri are polysaccharides
while M. phlei and M. smegmatis consist mainly of
proteins.21
The major polysaccharides of mycobacterial capsule
consists of mainly the glucan (an arabino-mannan) and
a mannan. Small amounts of other oligo- and
polysaccharides are also found, which are still not
characterized. The capsular proteins are complex
mixture of polypeptides. These include superoxide
dismutase, alanine dehydrogenase, glutamine
synthetase, alcohol dehydrogenase and thioredoxine.
Even though traditionally the mycobacteria have been
considered to be surrounded by thick waxy coat but
the recent findings are that the capsule indeed consists
of mainly carbohydrates and proteins and the lipid
constituents are only 2 to 5%. The mycobacterial
lipopolysaccharide, LAM, a major bioactive constituent
of mycobacterial cell wall is not detectable from the
capsule. Various phospholipids and some species specific
lipids (e.g. Dimycocerosate of phthiocerol) and type
specific lipids of M. tuberculosis, such as PGL and
lipooligosaccharides are present on its surface, others like
trehalose dimycolates occur in the inner compartments
of the capsule.21
The role of mycobacterial capsule in pathogenesis is
important at least for the first steps of internalization of
bacteria, though not absolute. The capsule plays
important role in adhesion and penetration into the host
cell through various cell receptors, binding proteins and
adhesion molecules.
Cell Wall Core

The cell wall core is defined as the insoluble matrix of
the mycobacterial cell wall after the removal of all soluble
proteins, lipids and carbohydrates. It is composed of three
covalently attached macromolecules. The outermost, the
mycolic acids, are 70- to 90-carbon-containing, branched
fatty acids which form an outer lipid layer in some ways
similar to the classical outer membrane of gram-negative
bacteria. The mycolic acids are esterified to the middle
component, arabinogalactan (AG), a polymer composed
primarily of D-galactofuranosyl and D-arabinofuranosyl
residues. AG is connected via a linker disaccharide, a-Lrhamnosy l- (1 3)--D-N-acetyl-glucosaminosyl-1phosphate, to the 6 position of a muramic acid residue in
the peptidoglycan. The peptidoglycan is the innermost
of the three cell wall core macromolecules.21
Peptidoglycan: It is the innermost layer adjacent to plasma
membrane and is analogous to other bacteria such as
47
Escherichia coli. It is composed of glycan to which the

tetrapeptide is attached which in turn is crosslinked.
Linker disaccharide: Carbon 6 of about 10% of muramic
acid residues provide the point of attachment of
peptidoglycan to polysaccharide, arabinogalactan via a
linker disaccharide phosphate. This structure is unique
to Mycobact- eria and Nocardia.
Arabinogalactan: Attached to simple linker dis-accharide
unit is a complex polysaccharide, called arabinogalactan.
Mycolic acids are attached to the 5 position of the terminal
arabinogalactan.
Plasma Membrane
In ultrathin sections, plasma membrane occur as classical
bilayers with two electron dense layers separated by
transparent layer.21 This appearance, coupled with their
known chemical composition22 indicates that these are
normal biological membranes. Mycobacterial membranes do,
however, have some distinctive components, notably the
lipopolysaccharides lipoarabinomannan (LAM), lipomannan and phosphatidylinositol. The appearance of
mycobacterial plasma membrane is not symmetrical, the
outer, electron dense layer is thicker than the inner layer.
This asymmetry is lost when cells are killed before
fixation. There is electron cytochemical evidence that the
extra thickness is associated with carbohydrate and
possible candidate molecules are phosphatidylinositol
mannosides of LAM. There appears to be space between
outer of the plasma membrane and the inner layer of cell
wall. If we hypothesize that the walls of M. tuberculosis
form permeability barriers somewhat analogous to the
outer membranes of gram negative bacteria, then the
space between the outer leaflet of the membrane and the
wall forms a compartment analogous to the periplasmic
space of the gram-negative bacteria.
Associated Molecules of the Cell Wall

Lipoarabinomannan (LAM)
Lipoarabinomannan is a phosphatidylinositol-anchored
lipoglycan composed of a manna core with oligoarabinosyl-containing side chains. It is found in all
mycobacteria including M. tuberculosis. While LAM lacks
covalent association with the cell wall core, it is
nonetheless a crucial part of cell envelope also. LAM is a
molecule of profound interest and importance with
diverse biological activities. It has properties analogous
to gram-negative O-antigenic LPS such as nonspecific
suppression of T lymphocyte activation and inhibition
of antigenic responsiveness of human peripheral blood
leucocytes and inhibits antigenic presenting cells. LAM
also inhibit interferon gamma mediated activation of
48

macrophages. Thus, it may be implicated in the
interaction of the pathogen and the host cell in the down
regulation of T cell responses of various types. It may be
a harbinger of bad immunity (i.e. immunopathogenesis).
In addition, it is a major B cell immunogen.23 Three
general classes of LAM have been described: (1)
ManLAM, from the virulent strains Erdman and H37Rv;
(2) Phosphor-myo-inositol-capped LAM (PILAM) found
in rapidly growing mycobacteria, M. smegmatis and M.
fortuitum and (3) AraLAM which was described in M.
chelonae. Although, there is significant heterogeneity
between LAM molecules with respect to glycosylation
and acylation, differences in biological activity between
the major classes of LAM have been attributed to heavy
mannose capping.
Trehalose-based Glycolipids
Trehalose is a simple disaccharide of glucose similar in
some ways to common table sugar, which is found free
and bearing various fatty acyl groups in M. tuberculosis
and other mycobacteria. These acylated trehaloses are
associated via hydrophobic interactions with the mycolic
acids of cell wall core and thus, are on outside edge of
cell envelope. The most studied amongst these is
trehalose dimycoate, commonly known as the cord factor.
Various biological activities have been described most
of them seemingly related to their ability to induce
cytokine-mediated events, such as systemic toxicity,
antitumour activity and macrophage release of
chemotactic factors.
Another important class of lipid based on trehalose
is the sulfatides. In these molecules, trehalose is sulfated
at 2 position and acylated with array of specialized fatty
acids. Its association with virulence has been demonstrated in guinea pigs. The biological activities of the
sulfatides has been proposed as an antagonist of the
fusion of the secondary lysosomes with phagosomes or
phagosome activation, thus promoting intracellular
survival of pathogen.24
Cell Envelope Proteins

Some of the proteins of mycobacteria are preferentially
associated with the cell wall and are powerful
immunogens. A 23 kiloDalton (kDA) protein appears to
be tightly, although noncovalently, associated with
peptidoglycan. A 59 kDa protein has been identified as
the porin and the 65 kDa protein is the heat shock protein
which acts as the molecular chaperon. Bioinformatic
analysis of the M. tuberculosis genome predicts >65
lipoproteins of cell envelope origin, some of which were
identified previously as secreted proteins, or enzymes
involved in cell wall biogenesis. Besides these, there are
17 conserved MmpL and MmpS proteins, and >600 other
putative membrane proteins.
Metabolic Biosynthesis
Most mycobacteria are prototropic, i.e. they are going to
grow in a media containing only inorganic salts plus a
source of carbon. Occasional fastidious strains, however,
are encountered, which could represent naturally
occurring auxotrophic mutants. Optimal growth in
synthetic medium is generally obtained with asparagine
and glutamine for nitrogen and glycerol for carbon.
Latency seen in pathogenic mycobacteria is explained
by the metabolic shut down in the mycobacteria which
is triggered and regulated by the host immune system.
Though no clear genetic basis of dormancy and
reactivation has been described, it is expected to be
genetically programmed and controlled by intracellular
signalling pathway.
Susceptibility to Physical and Chemical Agents

Mycobacteria possess the same degree of susceptibility
to heat as other nonspore forming mycobacteria and this
property is exploited for destruction of mycobacteria in
milk by pasteurization. They are however more resistant
to acid, alkalis and chemical disinfectants due to heavy
capsule, as described above. This property is also
exploited by microbiologists by decontamination of
clinical samples in their attempt to isolate mycobacteria
in pure cultures from sites, e.g. sputum, where rapidly
growing commensal bacteria are present.
Mycobacteria are destroyed by phenols, hypochlorites or glutarldehyde. Formaldehyde is suitable for
disinfection of rooms or safety cabinets, but it has low
penetration power and its effectiveness is diminished
when bacilli are embedded in sputum. Mycobacteria are
also killed by acetone, propanol and 70% alcohol, which
are used for disinfection of clinical thermometers.
Mycobacteria are resistant to drying and survive for
weeks to months on inanimate objects if protected from
sunlight. It does not appear to replicate in the
environment but it survives for several months in soil
and cow dung. Sensitivity of mycobacteria to sunlight
or ultraviolet light depends, to some extent on their
pigmentation. Scotochromogenic strains are more
resistant than nonchromogens while uninduced photochromogens are the most sensitive to all. The pigment
does not act as a filter for UV light but appears to
neutralize photo excited substances like superoxides.
Mycobacteria are more sensitive to UV light than E.coli
and this may in part be dependent upon genome size
and capacity for DNA repair.
Genetics of Mycobacteria
Ribosomal RNA sequence comparison demonstrates that
mycobacteria are member of high Guanine + Cytosine
(GC) content gram positive bacteria. GC content varies
49

from 58% for M. leprae to 69% for M. intracellulare, and
65.6% for M. tuberculosis.
Focusing on specific operons by physical methods has
revealed the organization of the rRNA locus in several
species of mycobacteria. As is the case of all the other
Eubacteria studies, the three rRNAs are organized into
an operon with 16S RNA positioned first at the 5' end,
the 23S rRNA in the middle and and the 5S rRNA at the
3' position. The slow growing mycobacteria such as M.
tuberculosis and M. leprae have only one copy of the rRNA
operon and the fast growing mycobacteria like
M. smegmatis and M. phlei having two, this is radically
different from E.coli which has 7 copies of rRNA operon
(rRNA-G).25
A truly remarkable feature of the pathogenic
Mycobacteria is their extremely slow growth. The
Mycobacteria increase their glycogen storage which is
used during the unsuitable growth conditions.
Mycobacteria have a doubling time of approximately 17
hours under optimal conditions in vitro, and ~ 24 hours
in animal models, which is by far the longest doubling
time for any free living bacterium. However, most of the
nonpathogenic soil mycobacteria have considerably
faster growth rates.
On the basis of systematic sequence analysis of

26 loci of several isolates, it is concluded that the genome
of M. tuberculosis is either unusually inert or that the
organism is relatively young in evolutionary terms. The
size of the mycobacterial genome is 2.5 109 daltons of
4.4 million base pairs (bp). M. tuberculosis has the same
re-association kinetics as E. coli K12. The past decade has
seen dramatic advances in the understanding of the
metabolic and intracellular life style of M. tuberculosis
culmination in the recent publication of the complete
genomic DNA sequence of large number of strains.26 Of
the estimated 4000 encoded proteins, about 40% have
known biochemical functions, another 44% have
sequence homology but 16% are completely unknown
(the fun genes). 59% of the genes are transcribed in the
same direction as chromosomal replication.
Mycobacterial Genome
A total of 45 different Mycobacterium species are being
sequenced as listed in the Table. 5.3.
The genomes of M. tuberculosis26 and M. bovis27 have
been fully sequenced. The M. tuberculosis has 4,411,529
base pairs, with a G + C content of 65.6%. The genome is
rich in repetitive DNA, particularly insertion sequences
Table 5.3: Genomic sequence of mycobacterial species

Name of the strain
Associated with
Size of
the genome
Mycobacterium
abscessus
Environmental bacterium
that causes lung, wound,
and skin infections
Causative agent of
mycobacterial disease in
children, the aged, and in
immunocompromised
individuals
Causative agent of
mycobacterial disease in
children, the aged, and in
immunocompromised
individuals.
Causative agent of
Johnes disease, or
paratuberculosis, a chronic
severe intestinal infection
Causative agent of bovine
tuberculosis
Brazilian vaccine strain
5 Mb
Genoscope
complete
5 Mb
TIGR
complete
McGill University,
Canada/University of
Minnesota
in progress
4 Mb
University of Minnesota
complete
4 Mb
Sanger Institute
complete
Fiocruz - FAP
in progress
The causal agent of bovine

tuberculosis
4 Mb
Mycobacterium bovis
sequencing teams
complete
M. avium 104
M. avium subsp.
avium ATCC
25291
M. avium subsp.
paratuberculosis
K-10
M. bovis
AF2122/97
M. bovis BCG
str. Moreau RDJ
M. bovis BCG
str. Pasteur
1173P2
Sequencing center
Status
Contd....
50

Contd....
Name of the strain
Associated with
M. bovis BCG
str. Tokyo 172
This strain is being

sequenced for
comparative genome
analysis
Environmental bacterium
that causes wound,
cornea, and skin infections
Capable of degrading a
variety of polycyclic
aromatic hydrocarbons
Clinical isolate
M. chelonae
M. gilvum PYRGCK
M. intracellulare
ATCC 13950
M. kansasii ATCC
12478
M. leprae Br4923
M. leprae TN
M. liflandii
128FXT
M. marinum
DL240490
M. marinum M
M. microti
M. smegmatis str.
MC2 155
Mycobacterium sp.
JLS
Mycobacterium sp.
KMS
Mycobacterium sp.
MCS
Mycobacterium sp.
Spyr1
M. tuberculosis
98-R604 INHRIF-EM
Size of
the genome
Status
Japan BCG Laboratory/

Agencourt Bioscience
Corporation
in progress
Genoscope
in progress
DOE Joint Genome

Institute
complete
McGill University,
Canada
McGill University,
Canada
Institut Pasteur/Institut
Pasteur PF1
draft assembly
Sanger Institute
complete
Monash University
in progress
Monash University
in progress
Welcome Trust Sanger

Institute
complete
Sanger Institute
in progress
7 Mb
TIGR
complete
6 Mb
DOE Joint Genome

Institute
complete
6 Mb
DOE Joint Genome

Institute
complete
5 Mb
DOE Joint Genome

Institute
complete
DOE Joint Genome

Institute
Broad Institute
in progress
5 Mb
Well-studied clinical strain

Strain isolated from a
human skin biopsy in
Brazil
Causative agent of human
leprosy
Causes a systemic disease
in frogs
Causes systemic infection
in fish and skin infections
in humans
Causes systemic infection
in fish and skin infections
in humans
Causes generalized
tuberculosis in rodent,
cattle, and humans
Generally non-pathogenic
mycobacterium capable
of causing soft tissue
lesions
A pyrene-degrading
bacterium isolated from
the Libby Montana
Groundwater Superfund
Site
A pyrene-degrading
the Libby Montana
Site
A pyrene-degrading
the Libby Montana
Site
Isolated from a creosote
contaminated site
Strain for comparative
analysis
Sequencing center
3 Mb
6 Mb
draft assembly
in progress
in progress
Contd....
51

Contd....
Name of the strain
M. tuberculosis
02_1987
M. tuberculosis
210
M. tuberculosis
94_M4241A
M. tuberculosis C
M. tuberculosis
CDC1551
M. tuberculosis
EAS054
M. tuberculosis F11
Mycobacterium
tuberculosis GM 1503
Mycobacterium
tuberculosis H37Ra
Mycobacterium
tuberculosis H37Ra
Mycobacterium
tuberculosis H37Rv
Mycobacterium
tuberculosis
KZN 1435
Mycobacterium
tuberculosis
KZN 4207
Mycobacterium
tuberculosis KZN 605
Mycobacterium
tuberculosis T17
Mycobacterium
tuberculosis T85
Mycobacterium
tuberculosis T92
Mycobacterium
tuberculosis str.
Haarlem
Mycobacterium
ulcerans 1615
Mycobacterium
ulcerans Agy99
Mycobacterium
vanbaalenii PYR-1

Associated with
Strain being sequenced for
comparative analysis
Causative agent of
tuberculosis
Isolate from China
Drugsusceptible strain
Causative agent of
tuberculosis
Sequenced for comparative
analysis
Predominant strain in
South African epidemic
Strain used for
comparative genome
analysis
An attenuated strain used
in mycobacterial virulence
research
An avirulent strain derived
from its virulent parent
strain H37 Bacteria
Causative agent of
tuberculosis
Multidrug-resistant clinical
isolate
Size of
the genome
4 Mb
4 Mb
4 Mb
4 Mb
Sequencing center
Status
Broad Institute
draft assembly
TIGR
in progress
Broad Institute
draft assembly
TIGR
draft assembly
complete
Broad Institute
draft assembly
Broad Institute
complete
Broad Institute
draft assembly
Beijing Genomics
Institute
draft assembly
Chinese National HGC,

Shanghai/Fudan
University, PR China,
Shanghai/Johns Hopkins
University, Department
of Molecular
Microbiology and
Immunology, Bloomberg
School of Public Health,
USA, Baltimore
Sanger Institute
draft assembly
complete
complete
Broad Institute
draft assembly
Drug-susceptible clinical
isolate
Broad Institute
draft assembly
Extensively drug-resistant
clinical isolate
Strain will be sequenced
for comparative genome
analysis
Susceptible strain
Broad Institute
draft assembly
Broad Institute
draft assembly
Broad Institute
draft assembly
Clinical isolate
Broad Institute
draft assembly
A drug resistant strain

found in crowded human
populations
Mycolactone-producing
strain
The causal agent of Buruli
ulcer
Capable of degrading a
variety of polycyclic
aromatic hydrocarbons
Broad Institute
draft assembly
Monash University
in progress
5 Mb
Institut Pasteur
complete
6 Mb
DOE Joint Genome

Institute
complete
Contd....
52

and in new multigene families and duplicated
housekeeping genes. The G + C content is relatively
constant throughout the genome indicating that
horizontally transformed pathogenicity islands of a
typical base composition are probably absent. This
information has also led to development of multiplex
PCR assay for simultaneous detection and differentiation
of M. tuberculosis and M. avium complex (Fig. 5.5).
The rrn operon is situated unusually 1500 kb distant
from the putative oriC (origin of replication) and may in
part explain the slow growth of M. tuberculosis. The genes
encoding tRNAs that recognize 43 to 61 possible sense
codons are distributed throughout the genome. 3,924
open reading frames (ORF) have been identified in the
Mycobacterial genome, accounting for ~ 91% of potential
coding capacity.26
Precise function could be attributed to ~40% of

predicted proteins while some information similarly
could be found for another 44%. The remaining 16%
resemble no known proteins and may account for specific
mycobacterial function. Amino acid analysis of these
problems revealed a significant preference for Ala, Gly,
Pro, Aug and Trp which are all encoded by G + C rich
codons and a comparative reduction in the use of amino
acid encoded by A + T rich codons such as Asn, Ile, Phe
and Tyr. Circular representation of M. tuberculosis H37RV
genome and M. avium subsp. paratuberculosis K-10 is
given in Figure 5.6.
A summary of the complete genome of M. paratuberculosis K-10 and the comparison with other
mycobacterium species is given in Table 5.4.
Fig. 5.5: Multiplex PCR Assay for Simultaneous Detection and Differentiation of Mycobacterium tuberculosis, M. avium Complexes, and other
mycobacterial species directly from clinical specimens: M100 bp marker (MBI, Fermentas),1,4 M. tuberculosis, 2, 5 M. avium complex,
3, 6 M. tuberculosis + M. avium complex, 7 Negative control
Table 5.4: Summary of the complete genome of M. tuberculosis and the comparison with other
Mycobacterium species (http://www.ncbi.nlm.nih.gov/sites/entrez?db)
Property
Genome size, bp
GC content, %
Protein coding, %
ORFs
Gene density, bp per gene
Average gene length, bp
tRNAs
rRNA operon
ABC transporters#
M. ap
M. av
M. tb
M. bovis
M. leprae
M. smeg
4,829,781
69.30
91.30
4,350
1,112
1,015
45
1
60
5,475,738
68.99
NA
NA
NA
NA
45
1
4,411,532
65.61
90.80
3,959
1,114
1,012
45
1
39
4,345,492
65.63
90.59
3,953
1,099
995
45
1
42
3,268,203
57.79
49.50
1,604
2,037
1,011
45
1
24
6,988,209
67.40
92.42
6,897
1,013
936
47
2
M. ap M. avium subsp. paratuberculosis, M. av M. avium subsp. avium 104, M. tb M. tuberculosis H37Rv,

M. smeg M. smegmatis
#
Gopinath K, Singh A, Singh Sarman, Unpublished data.
53
Fig 5.6: Circular Representation of M. tuberculosis H37Rv genome and M. avium subsp. paratuberculosis K-10
Comparative Mycobacterial Genomics as a Tool for Drug

Target and Antigen Discovery
There is an evergrowing need for new drugs and vaccines
to treat and prevent mycobacterial diseases and for
improved diagnostic tools to detect infection more
reliably. The desired properties of new antitubercular
agents include reduction of the duration of treatment, as
well as activity against latent TB infections and MDRTB. Several different approaches are available to
determine which genes of M. tuberculosis are essential
and thus worthy of further investigation as targets for
drug development. These include gene knockouts,
transcript analysis and definition of the proteome.
Comparative genomics is a powerful tool for
exploring microbial evolution and identifying genes that
might encode new drug targets or protective antigens.
Genomic diversity of the M. tuberculosis complex has been
studied by DNA array technology, facilitated by the fact
that all members share a >99.95 percent identity at the
DNA level. Comparative genomics of the respective
members of the M. tuberculosis complex has revealed the
existence of a gene gradient. The human tubercle bacillus,
M. tuberculosis, has more genes than M. africanum,
M. microti, and M. bovis, as these have lost genetic material
through deletion events. Gene loss occurs at a high
frequency within the species of M. tuberculosis as a result
of homologous recombination events between copies of
IS6110 that flank genes in the direct orientation.
Microarray and Affymetrix chip studies have uncovered
an additional group of 45 genes whose presence, and

possibly function, is facultative. From the combined
findings, it can be concluded that >200 genes exist that
are not essential for growth of M. tuberculosis complex
members in the host but may influence the degree of
virulence.
The diagnosis of both the active and latent TB which
relies heavily on clinical expertise and detection of acidfast bacilli in sputum smears will also benefit from
comparative genomics. Latent infection is often
diagnosed by monitoring the extent of delayed type
hypersensitivity reactions following intradermal
injection of tuberculin, an ill-defined mixture of antigens.
Tuberculin reactivity is of limited value in communities
where BCG vaccination is a component of National
Program of Immuni-sation as in India. Its interpretation
may be confounded by infections involving other
mycobacteria. The identification of 120 genes in the
tubercle bacillus, which are absent from BCG allows a
move towards the development of a more specific test
that can distinguish between infection and immunization. Microarray and proteomics will also find wide
application in monitoring biodiversity with in the
M. tuberculosis complex and help to confirm the presence
or absence of candidate diagnostic antigens. By utilizing
these cutting-edge techniques like 2D gel electrophoresis
and Matrixassisted laser desorption/ionization-Time
of Flight (MALDI-TOF), 54 proteins, which are unique
and expressed only in multidrug resistant strains have
been identified (Fig. 5.7).
54
Fig. 5.7: Comparative proteomic analysis of multidrug resistant and drug sensitive strain of M. tuberculosis. The whole cell proteins were extracted
from both sensitive and resistant M. tuberculosis strains and analyzed with two dimensional gel electrophoresis. The spots with difference on
comparison were identified by MALDI-TOF. The results showed that more than 20 proteins are expressed only in drug resistant and not in
sensitive strains (Singh A, Gopinath K, Singh Sarman. Unpublished Data)
The dilemma facing tuberculosis researchers and

funding agencies is whether to give priority to
operational research to determine the most effective ways
of using the available control measures or to focus on
basic research into new diagnostic tests, vaccines, and
treatment regimens. Effort is being devoted to both
approaches, involving a multidisciplinary approach from
diverse disciplines such as molecular biology, social
anthropology and health economics. Nucleic acid
technology will provide rapid, specific, sensitive
diagnostic tests and rapid detection of drug resistance.
Vaccine which is able to prevent the emergence of post
primary infectious tuberculosis will be one of the
principal means of controlling tuberculosis. An
immunotherapeutic agent used in conjunction with drug
treatment will lead to a much lower failure rate, even in
cases of drug resistant diseases, and new designer
drugs with specific antitubercular activity will be used
to treat resistant cases.
Metabolic Pathway
From the genome sequence, it is clear that the tubercle
bacilli has the potential to synthesize all the essential
amino acids, vitamins and enzyme co-factors.
M. tuberculosis can metabolize a variety of carbohydrates,
hydrocarbons, alcohol, ketones and carboxylic acids.
Approximately, 13 sigma factors govern the gene
expression at the level of transcription initiation and more
than 100 regulatory proteins are predicted.26
Mycobacteriophages consist of a head and a tail. The

viral genome is enclosed within a protein shell (capsid).
Some phages are inactivated by organic solvents because
their capsids contain structural lipids. The double
stranded genomes of mycobacteriophage TM 4 (lytic
phage), L1 (temperate phage) and L5 are approximately
50 kilobases in size, that of D29 phage is 48 kb and of 18
phage 43kb. Mycobacteriophage D29 was isolated from
soil29 and is a lytic phage which is able to infect and
replicate in the slow growing pathogenic strains such as
M. tuberculosis and M. ulcerans and fast growing
environmental strains such as M. smegmatis. Growth is
initiated when a phage particle absorbs to a specific cell
surface receptor by the tip of its tail and infects its double
stranded DNA molecule into the host. Phage infection
can result in death of the host by lysis (virulent phage) at
the end of the replicative cycle or in permanent
association between the temperate phage and the host
by integrating viral DNA into the bacterial chromosome
as prophage and establishing lysogeny.
In the past, phage typing has been used as one of the
methods of finger printing of M. tuberculosis.29,30 The
utility of D29 for testing susceptibility of Mycobacteria
to anti-tuberculosis drugs was demonstrated in 1980 by
David et al.31 Recently mycobacteriophages have been
used in the rapid identification and rifampicin drug
susceptibility testing directly from the clinical samples
with encouraging results both in pulmonary and
extrapulmonary clinical samples. Commercially, the
method is known as fast-plaque assay (Figs 5.8A to C).
Mycobacteriophages
Animal Pathogenicity
Mycobacteriophages are viruses that infect Mycobacteria.

First discovered 50 years ago, there are now over 250
known mycobacteriophages.28
Humans are the only natural reservoir for M. tuberculosis

although it can be grown in laboratory primates, guinea
pigs and mice.
55
Figs 5.8A to C: FASTPlaque-TBTM method for identification of the Mycobacterium tuberculosis. All culture plates are seeded with M. smegmatis
as substrate (sensor cells) for mycobacteriophage. A. FASTPlaque-TBTM. Negative control, showing no lysis (plaque formation) of the sensor
cells. B. FASTPlaque-TB.TM Positive control, showing more than 20 plaques (virucidal units). C. FASTPlaque-TB.TM showing heavy mycobacterial
load in the clinical samples, indicated by presence of confluent (4200) plaque formation (For color version see Plate 3)
The guinea pig is highly susceptible to experimental

infection with both M. tuberculosis and M. bovis. An acute
form of disease process is seen in guinea pigs exposed to
tuberculosis by aerosol.32 In these animals the infection
is initially contained by a granulomatous response,
but after 8 to 15 weeks the centers of certain lesions
degenerate leading either to mineralization of the lesion
or extensive caseous necrosis or cavitation, eventually
resulting in the death of the animal. This process appears
to mirror the course of events in untreated human
patients. Despite this closeness to the human condition
animals larger than mice are rarely used to evaluate
antimycobacterial therapies.
The mouse provides a versatile and flexible model of
mycobacterial infections, including M. tuberculosis. Mice
can be productively infected by a variety of routes
including subcutaneous inoculation, intravenously or by
exposure to an aerosol of bacteria.
Rabbits are much less susceptible to M. tuberculosis
while cattle, monkeys, pigs, dogs and cats may be
naturally infected with M. bovis.33
HIGHLIGHTS
Description of the M. tuberculosis

Taxonomy
Description of the genus
Staining Reactions
Mycobacterial species
Habitat
Cultural Characteristics
Cellular architecture of M. tuberculosis
Mycobacterial envelope
Mycobacterial capsule
Cell wall core
Plasma membrane
Cell wall constituents

Lipoarabidomannan
Trehalose based glycolipids
Cell envelope proteins
Metabolic biosynthesis
Genetics of Mycobacteria
Mycobacteriophages
Animal Pathogenicity
Mycobacterial Genome.
Comparative mycobacterial genomics as a tool for
drug target and antigen discovery.
REFERENCES
1. World Health Organization report. Global tuberculosis
control. Surveillance, planning, financing (2008) Geneva.
World Health Organization 2008.
2. Steinbrook R. Tuberculosis and HIV in India. N Eng J
Med 2007; 356:1198-9.
3. Taylor GM, Stewart GR, Cooke M, et al. Kochs Bacillus
a look at the first isolate of M. tuberculosis from a modern
perspective. Microbiology 2003;149,3213-20.
4. Imaeda T. Deoxyribonucleic acid relatedness among
selected strains of M. tuberculosis, M. bovis BCG, M. microti
and M. africanum. Int J Sys Bacteriol 1985,35:147-50.
5. Roagall T, Flohr T, Bottger EC. Differentiation of
Mycobacterium species by direct sequencing of amplified
DNA. J Gen Microbiol 1990,136: 1915-20.
6. Krischner P, Springer B, Vogel U, et al. Genotypic
identification of Mycobacteria by nucleic acid sequence
determination: report of a 2 years experience in a clinical
laboratory. J Clin Microbiol 1993,31:2882-9.
7. Wayne LG, Kubica GP. The Mycobacteria. In: PHA
Sneath, et al. (Eds). Bergeys Manual of Systematic
Bacteriology. Baltimore, Williams and Wilkins,
1989,1435-57.
8. Stahl DA, Urbance JW. The division between fast and
slow growing species corresponds to natural
56
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
relationships among Mycobacteria. J Bacteriol

1990,172:116-24.
Sankar MM, Gopinath K, Singla R, et al. In vitro
antimycobacterial drug susceptibility testing of
Nontuberculous Mycobacteria by Tetrazolium
Microplate Assay. Ann Clin Microbiol Antimicrob
2008;7:15.
Good RC. Opportunistic pathogens in the genus
Mycobacterium. Ann Rev Microbiol 1985;39:
347-69.
Grange JM, Yates MD. Infections caused by opportunist
Mycobacteria: A review. J R Soc Med 1986;79:226-9.
Singh S, Shahdad S, Kaur M, et al. Nontubercular
Mycobacterial infections in Indian AIDS patients
diagnosed by genus and species specific 16S rRNA and
Novel ESAT-6 Polymerase Chain Reaction primers. Jpn
J Infect Dis 2007;60:14-8.
Runyon EH. Anonymous Mycobacteria in pulmonary
disease. Med Clin North Am 1959; 43:273-90.
Ratanasuwan W, Techasathit W, Chuenarom V, et al.
Infection due to nontuberculous Mycobacterium other than
MAC in AIDS patients at Siriraj hospital during 19982000: saprophyte vs pathogen. J Med Assoc Thai
2002;85:886-93.
Inderlied CB, Kemper CA, Bermudez LE. The
Mycobacterium avium complex. Clin Microbiol Rev
1993;6:266-310.
Smith MB, Schnadig VJ, Boyars MC, et al. Clinical and
pathologic features of Mycobacterium fortuitum infections.
An emerging pathogen in patients with AIDS. Am J Clin
Pathol 2001;116:225-32.
Gopinath K, Singh S. Multiplex PCR Assay for
simultaneous detection and differentiation of
Mycobacterium tuberculosis, M. avium Complexes, and
Other Mycobacterial Species directly from clinical
specimens. J Applied Microbiol 2009; 107:425-35.
OBrien RJ, Geiter L, Snider DE. The epidemiology of
nontuberculous mycobacterial diseases in the United
States. Am Rev Respir Dis 1987;135:1007-14.
Smith M, Zahuley J, Preifer D, et al. Growth and
cholesterol oxidation by mycobacteria species in Tween
80 medium. Appl Environ Microbiol 1993; 59:1425-9.
Burback BJ, Perry JJ. Biodegradation and biotransformation of groundwater pollutant mixtures by
M. vaccae. Appl Environ Microbiol 1993;59:1025-9.

21. Daffe M, Etienne G. The capsule of M. tuberculosis and
its implications for pathogenicity. Tuberc Lung Dis
1999;79:153-69.
22. Brennan PJ, Draper P. Ultrastructure of M. tuberculosis.
In Bloom BR (Ed): Tuberculosis: Pathogenesis, Protection
and Control. ASM Press, Washington DC 1994;271-84.
23. Misaki A, Azuma I, Yamamura Y. Structural and
immunochemical studies on D-arabino-D-mannan of
M. tuberculosis and other Mycobacterial species. J Biochem
1977,82:1759-70.
24. Goren MB, Hart PD, Young MR. Prevention of
phagosome lysosome fusion in cultured macrophages
by sulfatides of M. tuberculosis. Proc Natl Acad Sci USA
1976,73:2510-4.
25. Mcfadden I. Molecular biology of the mycobacterial
North Yorkshire, Surrey University Press, 1990.
26. Cole ST, Brosch R, Parkhill J, et al. Deciphering the
biology of Mycobacterium tuberculosis from the complete
genome sequence. Nature 1998; 393:537-44.
27. Garnier T, Eiglmeier K, Camus JC, and 19 other authors.
The complete genome sequence of Mycobacterium bovis.
Proc Natl Acad Sci USA 2003; 100:7877-82.
28. McNerney R. Tuberculosis. The return of the phage. A
review of fifty years of mycobacteriophage research. Int
J Tuberc Lung Dis 1999;3: 178-84.
29. Froman S, Will SD, Bogen E. Bacteriophage active against
virulent Mycobacterium tuberculosis: isolation and activity.
Am J Public Health 1954; 44:1326-33.
30. David HL. Genetics of the Mycobacteria. In: Bacteriology
of the Mycobacterioses. Centres for Disease Control,
Washington, DC: US Dept. of Health, Education and
Welfare. DHEW publication no (CDC 76-8316) 1976;71104.
31. David HL, Clavel S, Clamentand J, et al. Effects of tuberculosis and antileprosy drugs on mycobacteriophage D29
growth. Antimicrob Agents Chemother 1980;18:357-9.
32. McMurray DN. Guinnea pig model of tuberculosis. In
Bloom BR (Eds). Tuberculosis: Pathogenesis, Protection
and Control, ASM Press, Washington, DC, 1994;135-47.
33. Laidlay M. Mycobacterium: tubercle bacilli. In Collee JG,
Duguid JP, Fraser AG, Marmion BP (Eds). Practical
Medical Microbiology, 13th edition, Edinburgh,
Churchill Livingstone. 1989; 399-416.
Nontuberculous Mycobacteria
Sarman Singh, K Gopinath, Ashok Rattan
INTRODUCTION
In 1882, Robert Koch identified Mycobacterium tuberculosis
as the cause of tuberculosis. Thus, by priority this bacillus
became the typical mycobacterium. Other mycobacteria, however, were soon observed that differed from
M. tuberculosis, and these became known as atypical
mycobacteria. In 1954, Timpe and Runyon first classified
atypical mycobacteria into four groups on the basis of
their growth characteristics. This system, known as the
Runyon classification, has undergone so many
modifications that it has been more or less abandoned.
Members of the genus Mycobacterium are diverse in
their pathogenicity, in vivo adaptation, virulence, in vitro
growth rate, pigment production and/or pathogenicity.
The isolation of M. tuberculosis in pure culture by Robert
Koch (1882) was soon followed by isolation of
M. smegmatis (1885), M. avium subsp. avium (1890), M.
avium subsp. paratuberculosis (1894) and others from
different hosts and environments. These nontuberculous
mycobacteria (NTM) have been referred as atypical,
environmental, unidentified, anonymous, opportunistic,
or mycobacteria other than tuberculosis (MOTT). These
are commonly isolated from environmental sources such
as water and soil and were considered to be either of
low virulence or commensal. However, these mycobacteria attracted attention during the AIDS epidemic.
Interestingly, most of the reports are from TB nonendemic western countries. Nontuberculous mycobacterial diseases are being increasingly reported from
HIV positive individuals from both TB non-endemic and
TB endemic countries like India, Brazil, and other
countries.1,2
TAXONOMY
All Mycobacteria belong to Kingdom Bacteria, Phylum
Actinobacteria, Order Actinomycetales, Suborder
Corynebacterineae and Family and Genus Mycobacterium
(Lehman and Neumann 1896). The minimal standards
for including a species in the genus Mycobacterium are (i)
acid-alcohol fastness, (ii) the presence of mycolic acids
containing 6090 carbon atoms which are cleaved to C22
to C26 fatty acid methyl esters by pyrolysis, and (iii) a
guanine + cytosine content of the DNA of 61 to 71 mol%.
The Genus Mycobacterium consists of more than 121

species of which some species are conventionally
responsible for causing tuberculosis in humans or higher
animals (M. tuberculosis. M. bovis, M. africanum) are
grouped in the Mycobacterium tuberculosis complex and
leprosy in humans (M. leprae), while M. microti causes
tuberculosis like condition in voles. While rest of the
species are known as Nontuberculous Mycobacteria
(NTM) and are further subdivided into slow and rapid
growers. Rapid growers require < 7 days to produce a
visible colony in solid culture media on subculture, while
colonies of slow growers appear only after more than 7
days of incubation and may require up to 8 weeks of
incubation. The cell walls of mycobacterium have high
lipid content with characteristic mycolic acids with long
branched chains. Nontuberculous Mycobacteria also
resist decolorization by acid-alcohol like typical
Mycobacteria, hence the term acid-fast bacteria (AFB)
applies to these also. The Table 6.1 shows the
classification based on the growth rate of NTM.3,4
CLASSIFICATION OF NTM ON THE BASIS OF PIGMENT

PRODUCTION
1. Photochromogens: They are slow growing organisms
and produce a yellow-orange pigment when exposed
to light, e.g. M. kansasii, M. marinum.
2. Scotochromogens: They are slow growing organisms
and produce a yellow-orange pigment irrespective
of exposure to light, i.e. in the light or in dark, e.g. M.
scrofulaceum.
3. Nonphotochromogens: They are slow growing and
may or may not produce pigment, e.g. M. avium
intracellulare complex (MAIC).
4. Rapid growers: They are rapid growing mycobacteria
and do not produce pigment.
Geographical Distribution of NTMs

The first argument, to justify the highly variable
incidence and distribution of NTM, put forward is
global diversity in environmental and climatic
conditions. However, the literature search does not
reveal significant difference among the most common
environmental and clinically relevant mycobacterial
58

Table 6.1: Classification of nontuberculous
mycobacteria based on growth rate
S.No Slow growing NTMs
Rapidly growing NTMs
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
M. abscessus
M. aichiense
M. aurum
M. chelonae
M. chubuense
M. fortuitum
M. gadium
M. mageritense
M. mucogenicum
M. phlei
M. smegmatis
M. thermoresistible
M. vaccae
M. neoaurum
MAC
M. asiaticum
M. branderi
M. celatum
M. conspicuum
M. flavescens
M. gastri
M. genavense
M. gordonae
M. haemophilum
M. interjectum
M. kansasii
M. lentiflavum
M. malmoense
M. marinum
M. scrofulaceum
M. shimoidei
M. simiae
M. szulgai
M. terrae
M. triplex
M. ulcerans
M. xenopi
species between the TB endemic and TB non-endemic

countries, though exception of a few species do exist,
where these species are confined to certain geographical
regions or habitats.5-10 M. avium complex was most
frequently isolated species in a data gathered by
Diseases (IUATLD) from 41 laboratories of 14 countries
in five geographical areas.7 Similarly, M. avium complex
was a predominant and potential pulmonary pathogen
in China,11 India,1,2,10 and Korea.12,13 M. fortuitum was
isolated from soil and water samples collected from TB
endemic northern parts of Malawi. This population also
showed high cross reactivity in tuberculin test. 8
M. fortuitum was also found to be one of the most
frequently encountered species in the laboratories of
Belgium (2.1%), Czech Republic (17.5%), Denmark
(5.3%), Finland (6.7%), France (6.5%), Germany (12.2%),
Italy (2.5%), Portugal (16.5%), Spain (10.8%),
Switzerland (17.5%), Turkey (33.9%) and United
Kingdom (6.0%) during a multicountry study.7
The environment is main reservoir of these
mycobacteria. There is no evidence of human-to-human
or animal-to-human transmission.14 Most infections are
acquired either from water, both treated and untreated,
or from soil. M. kansasii, M. xenopi and M. simiae are
universally associated with water exposure. M. avium
complex (MAC) was isolated from the drinking
water distribution systems of Pretoria and
Pietermaritzburg and other small towns of South Africa9

and similar observation were reported from USA.14
These observations correlated the prevalence of MAC
with high rate of hypersensitivity pneumonitis like
reaction after the exposure to showers and hot tubs.
Even though, life style of using hot water tubs is not
common in tropical countries like India, the swimming
and consumption of unsafe water is quite common in
rural India. In 1981, during the famous Chingleput BCG
trial different species of NTM were isolated from the
ponds located near the trial area. 10 Based on these
findings some studies have suggested NTM infection
as occupational hazard. 15-18 Prashar et al 18a have
emphasized the importance of several environmental
mycobacteria which have been shown to be important
human pathogens linked to immunomodulation,
especially in relation to effect on vaccination. One
hundred nineteen isolates of environmental
mycobacteria were grown from 291 (116 soil and 175
water) samples. These isolates were identified by
standard biochemical tests, a simple, rapid and cost
effective in house developed gene amplification
restriction analysis targeting 16S-23S rRNA spacer and
flanking region and 16S-rRNA sequencing. Biochemical
tests could clearly identify only 68.1% (81/119) of
isolates to the species level. The in-house developed
gene amplification-restriction analysis methods could
confirm the identity of 102 of 119 (85.7%) isolates and
the remaining 17 isolates (14.3%) were confirmed by 16
SrRNA sequencing also. These 119 environmental
mycobacterial isolates, included several potentially
pathogenic species such as M. fortuitum, M. chelonae, M.
avium, M. marinum, M. manitobense, M. kansasii and
others belonged to nonpathogenic species such as M.
terrae, M. smegmatis, and M. flavescens. M. chelonae was
isolated from water samples only. Whereas M. fortuitum
was isolated from both water as well as soil samples.
Clinical Manifestations
The number of known nontuberculous mycobacteria
(NTM) has increased steadily during the last decade,
with, on an average, three new species described per year
since 1990. Recent developments in mycobacterial
taxonomy, however, are often disregarded by clinicians.
Their prevalent opinions are that NTM are rarely
clinically significant; that even when they are responsible
for disease, their identification to species level is of little
clinical relevance. It is useful only to distinguish the M.
tuberculosis complex from NTM. Tortoli et al19,20 have
elaborated on the clinical features of infections caused
by nontuberculous mycobacteria. Griffithe et al14 on
behalf of ATS/IDSA have detailed nontuberculous
mycobacterial diseases, their diagnosis, treatment and
prevention.
Chapter 6 Nontuberculous Mycobacteria
Respiratory Disease
The respiratory tract is the most frequent target of
mycobacterial pathologies.21 NTM pulmonary infection
is usually not distinguishable from tuberculosis, with
which it shares a wide spectrum of manifestations
ranging from lack of symptoms to cavitary disease.
Although not yet demonstrated for most of the newly
described species, the environment is considered the
natural reservoir of NTM. The main route of infection,
therefore, is by inhalation, although ingestion and direct
inoculation may have roles. Contaminated aerosolized
water is thought to be one of the most important sources
of mycobacteria. NTM pulmonary disease is rare in
young subjects and in patients without predisposing
conditions.
Diagnostic Criteria of Nontuberculous Mycobacterial

Lung Disease
59
and by fistula formation with prolonged drainage. No

changes in hematologic parameters are found.
Antimicrobial treatment is usually ineffective, but total
excision of the involved nodes assures definitive recovery
in almost all cases. The route of entry is usually oral,
including throat, gingivae, and lips. Tooth eruption has
been related to infection. Cases of adult infection and
involvement of other nodes, such as inguinal, femoral,
axillary, or epitrochlear, are rare.
M. bohemicum
M. bohemicum was responsible for disease in two cases,
one in an 11- year-old male and the second in a 2-yearold girl. In both cases, treatment, including
clarithromycin, was undertaken initially, and subsequent
resort to lymph node excision led to complete recovery.
M. celatum type I
A. If three sputum/bronchial wash results are available

from the previous 12 months:
1. Three positive cultures with negative acid-fast
bacillus smear results
or
2. Two positive cultures and one positive acid-fast
bacillus smear.
B. If only one bronchial wash is available:
Positive culture with a 2+, 3+, or 4+ acid-fast bacillus
smear or 2+, 3+, or 4+ growth on solid media.
C. If sputum/bronchial wash evaluations are
nondiagnostic or another disease cannot be excluded:
1. Transbronchial or lung biopsy yielding a
nontuberculous mycobacterium
or
2. Biopsy showing mycobacterial histopathologic
features (granulomatous inflammation and/or
acid-fast bacilli) and one or more sputa or bronchial
washings are positive for a nontuberculous
mycobacterium, even in low numbers.
Criteria refer to symptomatic patients with infiltrate,
nodular or cavitary disease, or a high resolution
computed tomography scan that shows multifocal
bronchiectasis and/or multiple small nodules.
M. celatum type I was isolated from pus draining from

the incised lymph node of a 15-month-old boy. Cure was
obtained by complete surgical removal of the node.
Lymphadenitis
M. interjectum
Lymphadenitis due to NTM is typically a childhood

disease that involves upper cervical lymph nodes.
Swelling, which develops in a few days, may vary from
barely perceptible to very disfiguring. Pain, if present, is
minimal. The infection remains unilateral and localized,
without signs of thoracic involvement on X-ray. The
overlying skin tends to be adherent and erythematous,
without increased warmth. The evolution of disease may
be characterized by softening of the lymph node mass
M. interjectum is one of the species most frequently

involved in childhood cervical lymphadenitis. Five cases
have been reported in three girls and two boys with ages
ranging from 18 months to 3 years. In four cases, one of
which required two surgical procedures, total excision
of the infected lymph nodes was required for full
recovery. In the fifth case, satisfactory results were
obtained with drainage of purulent material and
thorough curettage of the cavity.
M. elephantis and M. genavense

M. elephantis is the only mycobacterium species described
in the last 15 years that has been reported to be
responsible for lymphadenitis localized to a region other
than the neck. This organism was isolated from the
excised axillary lymph node of a 27-year-old male.
M. genavense was isolated from cheesy material in a
cervical lymph node removed from a 4-year-old girl with
normal immune function.
M. heidelbergense
M. heidelbergense was isolated in a more complicated case
of a 2-year-old girl with cervical lymphadenitis. Despite
removal of the nodes involved and subsequent treatment
with isoniazid, rifampicin, and pyrazinamide, a fistula
developed. Surgery was found ineffective when a new
fistula appeared. Subsequent involvement of the
contralateral lymph nodes required neck dissection with
removal of both tonsils and several lymph nodes.
60
M. lentiflavum
Five cases of infection due to M. lentiflavum have also been
reported. Four boys, with ages between 19 months and 4
years, were cured by means of lymph node excision. In a
3-year-old girl, suppurative cervical lymph nodes were
treated with clarithromycin and ethambutol, without
improvement in the subsequent 6 months.
Cutaneous and Soft Tissue Infections

Traumas and surgical wounds are frequently the source
of soft tissue mycobacterial infections. The clinical
manifestation, a nodular granulomatous lesion, develops
in the skin or subcutaneous tissue on an average within
1 month. Underlying lymph nodes may be involved, often
associated with suppuration, and dissemination of
infection is a frequent outcome. Other manifestations
include ulcer formation and cellulitis. Even though
mycobacteria are often visible in the stained smear of
clinical material, their failure to grow in culture is not
exceptional. Iredell et al21a has reported by laboratory
identification and in vitro susceptibility tests of 29 isolates
from Queensland Health Department Tuberculosis
Reference Laboratory contacting referring practitioners
to obtain clinical details of patients. It was in 29 patients,
M. marium was isolated, 12 had evidence of involvement
of deep tissues (including two cases of arthritis). Delay
between onset of symptoms and consultation with a
medical practitioner was five months (range two weeks
to two years). Cure was obtained in 22 of 23 cases.
Chemotherapy alone was adequate in 11 cases.
Surgical intervention was required in three. A combination
approach was required in eight cases. The drugs given
were trimethoprim/sulfamethoxazole which was
successful in nine case, combination of rifampicin and
ethambutol in six, tetracycline was employed as a single
agent in nine patients and effective in seven. Synovitis
was a common presenting feature of M. marium infection
in Queensland patients. Occupational or recreational
exposure to salt or fresh water was common. It is
summarized in their experience, that chemotherapy alone
is often adequate even with deep tissue involvement.
Combination of conventional antimycobacterial drugs
may be the therapy of choice specially for serious infection
although success was recorded with trimethoprim/
sulfamethoxazole combination.
Bone and Joint Infections

Mycobacterial infections of synovia, tendon sheaths,
bursae, and bone tissue almost always have a traumatic
or postsurgical origin and frequently evolve to
osteomyelitis. Tenosynovitis involves the tendon sheaths
and causes loss of function, swelling, and, at times,
fistulization. Granulomatous lesions accom-panied by

bone necrosis characterize the osteitis.
Disseminated Disease
Disseminated mycobacterial infections are limited to
patients with impaired immune systems. The most
important risk factors are HIV infection, hematologic
disorders, organ transplantation, and protracted steroid
treatment. Mycobacterial bone disease and endocarditis
may also be responsible for dissemination. Particularly
in AIDS patients, the most frequent symptoms are
longlasting, often high fever; weight loss; abdominal pain,
usually related to adenopathy; and splenomegaly.
Pulmonary manifestations are limited, and radiological
signs are lacking.
Mycobacterium Species Associated with Sepsis

Several cases of catheter-related sepsis due to newly
described mycobacteria have been reported. In three
cases, Mycobacterium immunogenum was isolated from a
bone marrow transplant patient, a subject with acute
leukemia, and a patient with pacemaker-related sepsis.
Five isolates of M. hackensackense were grown from
catheter and peripheral blood specimens from a 6-yearold girl with relapsed acute lymphocytic leukemia and a
history of multiple infections. A change of treatment from
vancomycin to amikacin for 1 week and clarithromycin
for 4 weeks produced rapid and definitive improvement.
The only strain of M. septicum isolated to date was from
three blood specimens and the tip of a central venous
catheter from a 2-year-old child with metastatic
hepatoblastoma.
Role of Ethnicity and Genetic

Susceptibility to NTM Infections
Agriculture is the major occupation of habitants of rural
South East Asian countries. In a recent study carried out
at four Thailand hospitals,16 it was found that nearly half
(46%) of the disseminated NTM infections in HIV
negative cases could be associated with farming. In these
patients, the commonest organ involved was lymph node
(89%) followed by skin and soft tissue (26%) and lungs
(19%). The major occupation in countries of this region
including India, China and Bangladesh remains manual
farming which leads to common physical injuries. These
injuries added with exposure to soil and water can result
into tissue invasion by NTMs.15 However, in spite of
having similarity in the occupation and safety norms, the
trend of high prevalence of NTMs observed in the Thai
patients is yet to be endorsed from other countries of the
region. Ethnicity seems to be the least likely reason for
this under reporting. Probably in other tropical countries,
NTMs are being missed out due to lack of awareness
about these potential yet neglected pathogens.15,22-30

Nevertheless some studies demonstrate the genetic
susceptibility to disseminated NTM infections in
children. This susceptibility has been associated with
multiple mutations in the interferon- receptor 1 gene.31,32
Huang et al31 investigated the polymorphisms in the
human natural resistance-associated macrophage protein
and interferon- receptor 1 gene. They found no
correlation with Mycobacterium avium intracellulare
(MAI) pulmonary disease. The susceptibility to MAI
disease was due to subtle immune defect and physical
phenotype of the patient may be merely a coincidental
marker.31 In addition, idiopathic disseminated infections
due to BCG or NTM are frequently observed with
parental consanguinity and familial forms. This
syndrome was designated as Mendelian susceptibility
to mycobacterial infection (Mendelian inheritance in man
number 209950). Therefore, this syndrome does not seem
to be confined to any particular ethnic group or
geographic region. On the other hand, an Australian and
two different New Zealand groups investigated the
pediatric population with mycobacterial lymphadenitis
and correlated the Caucasian ethnicity as a feature in
children with NTM lymphadenitis and non-Caucasian
as a risk factor for TB. Prior exposure to TB mounts an
adaptive immunity which protects them from least
virulent NTM infection as is the case with nonCaucasians.33-35 The prior exposure of environmental
mycobacteria leads to the poor efficacy of BCG vaccine
as was found during the Indian36 and Malawi trials.37
Nevertheless this exposure provides protection against
tuberculosis and leprosy.38 The most protective antigens
expressed by the anti-TB vaccine Mycobacterium bovis
(BCG) and M. tuberculosis are also conserved in M. avium39
and other mycobacterial species. The prior exposure of
tuberculosis in endemic countries may provide cross
and/or adaptive immunity against NTM infections.
Association of Nontuberculous
Mycobacteria with other Diseases
NTM can cause a variety of symptoms and may also
result in asymptomatic infections. The rates of
asymptomatic infections have been estimated using
antibody assays against common mycobacterial antigens
such as lipoarabino-mannan (LAM) or skin tests using
NTM specific purified protein such as PPD-B against
M. intracellulare.14 In AIDS patients, disseminated NTM
infections typically occurred only when the CD4+ T
lymphocyte count fell below 50/l, suggesting that specific
T-cell activities are required for protection against NTM
infections like M. tuberculosis.14,22-25 However, in the HIVuninfected patients disseminated NTM infection have
been associated with specific genetic syndromes such as
mutations in interferon (IFN-) and interleukin (IL-12)
synthesis and in response pathways of the signal
61
transducer and activator of transcription 1 [STAT1], and

the nuclear factor- essential modulator [NEMO]).
Association between bronchiectasis, nodular pulmonary
NTM infections and a particular body habitus,
predominantly in postmenopausal women have been
reported by Griffith et al.14 Pulmonary diseases by NTM
normally occurs in patients with structural lung disease,
such as chronic obstructive pulmonary disease (COPD),
bronchiectasis, cystic fibrosis (CF), pneumoconiosis, prior
TB, pulmonary alveolar proteinosis, and esophageal
motility disorders. NTM lung disease also occurs in
women without clearly recognized predisposing
factors.14,21,40 Bronchiectasis and NTM infection, usually
Mycobacterium avium complex (MAC), often coexist,
making causality difficult to determine. These patients
may carry multiple MAC strains.
Mycobacteria including the Mycobacterium bovis
(M. bovis) bacillus Calmette-Gurin (BCG) are considered
as strong inducers of T-helper type 1 immune responses
(Th1) and modulate the development of asthma both in
animal models and human beings. It is shown that a new
subset of lymphocytes (Th17) are triggered by BCG and
this activation induces a proinflammatory cytokine IL17 production. This cytokine, is considered to be
responsible for several autoimmune diseases including
asthma, allergic airway inflammation, diabetes mellitus,
etc. 41 Such report are mostly published from
industrialized world. However, hypersensitivity
pneumonitis associated with NTM infections has not
been reported from India.
Beneficial Effects of NTM Infection

The positive facet of NTM exposure is considered very
beneficial to humans. This includes not only increased
resistance to infections and prolonged survival of BCG
vaccinated people37-39 but also an immune regulatory
action of another NTM, the Mycobacterium vaccae.14,41
Recently another nontuberculous Mycobacterium w has
been found to be highly immunogenic against leprosy42
and pulmonary tuberculosis.43 It is reported that this
mycobacterium shares antigens with both M. leprae as
well as M. tuberculosis. The vaccine trials conducted in
India show that it provides protective immunity in both
BCG responders as well as BCG non-responders.42,43
Beside these well documented beneficial uses of NTMs
there may be several other beneficial effects of NTM
exposures.
Laboratory Facilities for Establishing the Diagnosis

Immunology of NTM Infections
Mycobacterial tuberculosis DosR regulon-encoded antigens
are highly immunogenic in M. tuberculosis infected
humans and are associated with latent tuberculosis
62

infection. Lin et al43a documented T-cell immunity (IFN responses) to M. tuberculosis DOSR regulon-encoded
antigens in individuals infected with or exposed to
nontuberculous mycobacteria (NTM), in the absence of
M. tuberculosis infection, M. tuberculosis exposure, or BCG
vaccination. These results support the hypothesis that
M. tuberculosis DOSR regulon-encoded antigen-directed
responses can be the result of exposure to or infection
with cross-reacting NTM.
Kobashi et al43b evaluated the clinical usefulness of
the quantiFERON-TB-2G (QFT-2G) test in patients with
nontuberculous mycobacterial (NTM) disease without a
previous history of tuberculosis (TB). They concluded
that QFT-2G may be a useful diagnostic method to
differentiate TB from M. avium-intracellulare complex
(MAIC) disease. However, its usefulness as a diagnostic
method for other NTM diseases such as those associated
with M. Kansaii and M. szulgai disease need further
resolution of several problems such as positive cut-off
level.
In India, every day, under the Revised National
Tuberculosis Control Program (RNTCP), more than
65,000 new and old cases are diagnosed and administered
antituberculosis therapy (ATT), which makes it humanly
impossible for the laboratories to identify and speciate
the Mycobacteria.30 With the implementation of directly
observed treatment short-course (DOTS), the diagnosis
of pulmonary tuberculosis is mainly made on the basis
of sputum microscopy. Recently, retrospective analysis
of four years data from South Korea has reported
recovery of NTM from 8.1% (50/616) of sputum smearpositive patients. The most common organism found was
Mycobacterium avium complex (MAC), followed by
M. abscessus.12,13 It was cautioned by these researchers
that a substantial proportion of patients with AFB smearpositive sputum specimens may have NTM lung disease
rather than pulmonary tuberculosis (PTB).12 Furthermore, using only microscopic method of diagnosis some
cases of NTM infection may be missed.22,25,44 Alarming
figures of 17.6% of the suspected MDR-PTB and 12.4%
of the suspected extrapulmonary tuberculosis cases were
confirmed as nontubercular diseases with the application
of molecular methods.2,44 Hatherill et al45 highlighted the
importance of isolation of nontuberculous mycobacteria
in children investigated for pulmonary tuberculosis in a
rural South African community. These children were
investigated for pulmonary tuberculosis as part of a
tuberculosis vaccine surveillance program (2001-2005).
The comparative yield of positive NTM cultures from
gastric lavage was 40% (95% Cl 31-50), compared to 67%
(95% CI 58-76) from induced sputum. Ninety-five percent
of children with NTM isolates were symptomatic. In
contrast M. tuberculosis was isolated in 187 children, a
crude yield of 11% (95% Cl 9-12). As compared to culture
proved M. tuberculosis, children with NTM isolates were
less likely to demonstrate acid-fast bacilli on direct smear

microscopy (95% 0.0-0.75). Children with NTM were
older (p < 0.001) and demonstrated constitutional
symptoms (p = 0.001) including fever (p = 0.03) and loss
of weight or failure to gain weight (p = 0.04). However,
tuberculin test is less likely to be strongly positive (p <
0.001) and radiological features consistent with
pulmonary tuberculosis (p = 0.04) were absent. NTM may
complicate the diagnosis of pulmonary TB in regions that
lack facilities for mycobacterial species identification.
Inter-estingly, a reverse trend may also be observed while
administering empirical anti-TB therapy, which is also
highly effective against M. kansasii and partially active
against MAC.22-24 This makes the NTM incidence and
prevalence data more difficult to interpret. Most of the
TB laboratories in TB endemic countries still use eggbased culture medium, which could be another limitation
to recovery of NTM (in particular fastidious NTMs). Most
of the laboratories which have reported maximum NTMs
have overcome the limitations of Runyon classification
system using more rapid culturing techniques, DNA
probes, and 16S rDNA sequencing methods. 2,46
According to the Seoul National University College of
Medicine and Korean Institute of Tuberculosis, number
of isolation of NTM increased from 448 to 1,562 during
the period 1992-2002. In comparison, the prevalence of
active TB over the same period decreased from 1.8 to
0.5%.27 This increase in NTMs was attributed to the
advances in methods of characterization.28 Similarly,
exact species diagnosis was made by identifying several
potentially pathogenic and rare NTM species with the
application of molecular methods in China.11 In referral
laboratories of TB endemic countries, single-species
specific PCR (M. tuberculosis specific) are commonly used
on clinical specimen which can miss the other infection(s)
or coinfections with more than one species. The use of
multiplex PCR seems to be highly useful in detecting the
single and/or multiple infections caused by M. avium
and M. tuberculosis.46 The recent guidelines of American
Thoracic Society 14 give useful information about
establishing the diagnosis of NTM disease.
It is important to strengthen the laboratory
infrastructure to address both species identification and
drug susceptibility testing of mycobacterial species
including the NTMs at referral laboratories.
SUMMARY
The new mycobacteria described here are only
occasionally responsible for human diseases, but
include more than 50% of the species described since
1990. The number of cases reported in the literature
exceeds 200. Regardless of whether such numbers are
important or not, the point should be kept in mind.
Many cases remain unpublished because the

mycobacterial agent has not been identified.
Interestingly, several features seem to distinguish the
infections due to recently described mycobacteria in
HIV-positive and HIV-negative patients. With few
exceptions, disseminated infections, mostly due to M.
genavense or M. celatum are reported in AIDS patients.
Furthermore, the frequency of these infections has
decreased dramatically following the introduction of
highly active antiretroviral treatment. In contrast, in
HIV-negative patients, the spectrum of mycobacterial
diseases is broad, and many species are involved.
Slow growers are primarily involved in respiratory
and lymph node infections, whereas sepsis and
infections of skin, soft tissues, bone, and joints are
frequently attributable to rapid growers.
Very little information is available about the
antimicrobial susceptibilities of nontuberculous
mycobacteria (NTM), in particular, of recently described
species. There is, however, a clear distinction
characterizing the susceptibilities of rapidly and
slowly growing mycobacteria. Generally, speaking,
isoniazid and pyrazinamide are not effective against
the slow growers, a variable degree of activity is shown
by rifamycins (rifampicin and rifabutin), quinolones
(ciprofloxacin, moxifloxacin, ofloxacin, and
sparfloxacin), macrolides (clarithromycin),
aminoglycosides (streptomycin and amikacin), and
ethambutol. The resistance of M. celatum to rifamycins
is unquestioned, and the repeatedly reported
multidrug resistance of the species genetically related
to M. simiae, such as M. lentiflavum and M. triplex,
seems reliable. For rapid growers, the spectrum of
effective antimycobacterial drugs is restricted to
ciprofloxacin, clarithromycin, tobramycin, and
amikacin, in addition to cefoxitin, doxycycline,
imipenem, and sulfamethoxazole.
The identification of new and rarely encountered
mycobacteria is out of reach of most routine clinical
laboratories. The best choice is to submit strains not
identifiable with commercial DNA probes to a
reference laboratory that uses genetic sequencing or,
at least, high-performance liquid chromato-graphic
analysis of cell wall mycolic acids.
HIGHLIGHTS
Boxes 6.1 and 6.2 highlight the factors for under
reporting of NTM from TB endemic countries and
important facts about nontuberculous mycobacteria.
REFERENCES
1. Gopinath K, Singh S. Non-tubercular Mycobacteria in
TB endemic countries: Are we neglecting the danger?
PLoS- NTD, 2010.
63
Box 6.1: Possible factors for under-reporting of

NTM from TB endemic countries
The NTM infections are not reportable
Lack of awareness in the treating physicians and
microbiology laboratories
Lack of proper laboratory infrastructure for culture and
identification of nontuberculous mycobacteria
High burden of TB and HIV, which attract major attention
of health care system and governments fiscal inputs
The lack of standardized or accepted criteria to define NTM
respiratory disease.
Box 6.2: Facts regarding nontuberculous mycobacteria

AIDS patients are significantly more vulnerable to NTM
infections due to severe T-cell immunodeficiency
Solid organ transplant patients, even though
immunocompromised, are not at high risk as their HIV
positive counterparts
Though there are some genetic and anatomical
predisposing factors but there is no proven association
amongst the geographical, occupational or ethnicity and
NTM infections
Anatomical abnormalities and other comorbidities such as
chronic obstructive pulmonary disease (COPD),
bronchiectasis, cystic fibrosis (CF), pneumoconiosis, prior
TB, pulmonary alveolar proteinosis, and esophageal
motility disorders are well established predisposing
conditions
Disseminated NTM infection have been associated with
specific genetic syndromes such as mutations in interferon
(IFN)-, interleukin (IL)-12 synthesis and in response
pathways and the nuclear factor- essential modulator
(NEMO).
Conventional methods are not sufficiently sensitive to
estimate prevalence and incidence of the NTM infections.
Multiplex PCR systems on relevant blood and urine
samples should be set up at tertiary care reference
laboratories and unidentified strains should be sent to these
for proper identification.
2. Singh S, Gopinath K, Shahdad S, et al. Nontuberculous

mycobacterial infections in Indian AIDS patients detected
by a novel set of ESAT-6 polymerase chain reaction
primers. Jpn J Infect Dis 2007;60:14-8.
3. Guidelines for the Control of Nontuberculous
Mycobacteria in the Northern Territory. Centre for
Disease Control. Casuarina NT 2002:3-20.
4. Ferreira RM, Saad MH, Silva MG, et al. Non-tubercular
mycobacteria I: One year clinical isolates identification
in Tertiary Hospital AIDS Reference Center, Rio de
Janeiro, Brazil, in pre highly active antiretroviral therapy
era. Mem Inst Oswaldo Cruz 2002;97:725-9.
64

5. Parashar D, Das R, Sharma VD, et al. Pathogenic rapidly
growing Mycobacterium manitobense in the environment
of Agra, North India. Indian J Med Res 2007;126:230-2.
6. Leite CQ, Viana BHJ, Leite RA, et al. Incidence of M.
tuberculosis and other mycobacteria in pulmonary
infections in Araraquara-SP. Rev Microbiol 1995;26:
101-5.
7. Martn-Casabona N, Bahrmand AR, Bennedsen J, et al.
Non-tubercular mycobacteria: Patterns of isolation. A
multi-country retrospective survey. Int J Tuberc Lung
Dis 2004;8:1186-93.
8. Chilima BZ, Clark IM, Floyd S, et al. Distribution of
environmental mycobacteria in Karonga District,
northern Malawi. Appl Environ Microbiol 2006;72:
2343-50.
9. September SM, Brzel VS, Venter SN. Diversity of
nontuberculoid Mycobacterium species in biofilms of
urban and semiurban drinking water distribution
systems. Appl Environ Microbiol 2004;70:7571-3.
10. Paramasivan CN, Govindan D, Prabhakar R,
et al. Species level identification of nontubercular
mycobacteria from South Indian BCG trial area during
1981. Tubercle 1985;66:9-15.
11. Weimin L, Guanglu J, Zhihui L, et al. Non-tubercular
mycobacteria in China. Scand J Infect Dis 2007;39:
138-41.
12. Jeon K, Koh WJ, Kwon OJ, et al. Recovery rate of NTM
from AFB smear-positive sputum specimens at a medical
centre in South Korea. Int J Tuberc Lung Dis 2005;9:
1046-51.
13. Koh WJ, Kwon OJ, Jeon K, et al. Clinical significance of
nontuberculous mycobacteria isolated from respiratory
specimens in Korea. Chest 2006;129:341-8.
14. Griffith DE, Aksamit T, Brown-Elliott BA, et al. On behalf
of the ATS Mycobacterial Diseases Subcommittee. An
Official ATS/IDSA Statement: Diagnosis, Treatment, and
Prevention of Nontuberculous Mycobacterial Diseases.
Am J Respir Crit Care Med 2007;175: 367-16.
15. Kumar A, Singh JK, Mohan D, et al. Farm hand tools
injuries: A case study from northern India. Safety Science
2008;46:54-65.
16. Chetchotisakd P, Kiertiburanakul S, Mootsikapun P, et
al. Disseminated nontuberculous mycobacterial infection
in patients who are not infected with HIV in Thailand.
Clin Infect Dis 2007;45:421-7.
17. Bahrmand AR, Madani H, Samar G, et al. Detection and
identification of non-tubercular mycobacterial infections
in 6,472 tuberculosis suspected patients. Scand J Infect
Dis 1996;28: 275-8.
18. Cattamanchi A, Nahid P, Marras TK, et al. Detailed
analysis of the radiographic presentation of
Mycobacterium kansasii lung disease in patients with HIV
infection. Chest 2008;133:875-80.
18a. Parashar D, Das R, Chauhan VD and Katoch VM, et al.
Identification of environmental mycobacteria isolated
from Agra, North India by conventional and molecular
approaches. Indian J Med Res 2009;129:424-31.
19. Tortoli E: Clinical features of infections caused by new
nontuberculous mycobacteria, part 1. Clin Micro News
2004;26:85-95.
20. Tortoli E. Clinical features of infections caused by new

nontuberculous mycobacteria, part 2. Clin Micro News
2004;26:97-100.
21. Glassroth J. Pulmonary Disease due to non-tuberculous
mycobacteria. Chest, 2008;133:243-51.
21a. Iredell J, Whitby M, Blacklockz Z. Mycobacterium marium
infection: epidemiology and presentation in Queensland.
Med J Aust 1992; 157;596-8.
22. Shanker SV, Jain NK, Chandrasekhar S, et al. Prevalence
of atypical mycobacteria in sputum of patients
undergoing treatment at a tuberculosis clinic. Indian J
Chest Dis Allied Sci 1989;31:9-13.
23. Menard O, Tanguy B, Desnanot J, et al. The incidence of
atypical pulmonary mycobacterium infections in
Reunion before the era of acquired immunodeficiency
syndrome (AIDS). Med Trop (Mars) 1990;50:185-9.
24. Al Jarad N, Demertzis P, Jones DJ, et al. Comparison of
characteristics of patients and treatment outcome for
pulmonary non-tubercular mycobacterial infection and
pulmonary tuberculosis. Thorax 1996;51:137-9.
25. Matos ED, Santana MA, de Santana MC, et al. Nontuberculosis Mycobacteria at a Multiresistant
Tuberculosis Reference Center in Bahia: Clinical
Epidemiological Aspects. Brazil J Infect Dis 2004;8:
296-304.
26. Purohit MR, Mustafa T, Wiker HG, et al.
Immunohistochemical diagnosis of abdominal and
lymph node tuberculosis by detecting Mycobacterium
tuberculosis complex specific antigen MPT64. Diagn
Pathol 2007;2:36.
27. Hong YP, Kim SJ, Lew WJ, et al. The seventh nationwide
tuberculosis prevalence survey in Korea, 1995. Int J
28. Yim J, Park Y, Lew WJ, et al. Mycobacterium kansasii
Pulmonary Diseases in Korea. J Korean Med Sci
2005;20:957-60.
29. Hargreaves NJ, Kadzakumanja O, Phiri S, et al. What
causes smear-negative pulmonary tuberculosis in
Malawi, an area of high HIV seroprevalence? Int J Tuberc
Lung Dis 2001;5: 113-22.
30. Singh S. Scaling up antimycobacterial drug susceptibility
testing services in India: It is high time. Indian J Med
Microbiol 2008; 26:209-11.
31. Huang JH, Oefner PJ, Adi V, et al. Analyses of the
NRAMP1 and IFN-g receptor 1 genes in women with
MAI pulmonary disease. Am J Respir Crit Care Med
1998;157:377-81.
32. Newport MJ, Huxley CM, Huston S, et al. A mutation in
the interferon-gamma-receptor gene and susceptibility
to mycobacterial infection. N Engl J Med 1996;335:
1941-9.
33. Pang SC. Mycobacterial adenitis in Western Australia.
34. Howell N, Heaton PAJ, Neutze J. The epidemiology of
non-tubercular mycobacterial lymphadenitis affecting
New Zealand children 19861995. NZ Med J 1997;
110:171-3.
35. Harrison AC, Jayasundera T. Mycobacterial cervical
adenitis in Auckland: Diagnosis by fine needle aspirate.
NZ Med J 1999;112:7-9.

36. Stanford JL, Sheikh N, Bogle G, et al. Protective effect of
BCG in Ahmednagar, India. Tubercle 1987;68:169-76.
37. Black GF, Dockrell HM, Crampin AC, et al. Patterns and
implications of naturally acquired immune responses to
environmental and tuberculous mycobacterial antigens
in northern Malawi. J Infect Dis 2001;184:322-9.
38. Fine PE, Floyd S, Stanford JL, et al. Environmental
mycobacteria in northern Malawi: implications for the
epidemiology of tuberculosis and leprosy. Epidemiol
Infect 2001; 126:379-87.
39. Demangel C, Garnier T, Rosenkrands I, et al. Differential
effects of prior exposure to environmental mycobacteria
on vaccination with Mycobacterium bovis BCG or a
recombinant BCG strain expressing RD1 antigens. Infect
Immun 2005;73:2190-6.
40. British Thoracic Society. Management of opportunist
mycobacterial infections: Joint Tuberculosis Committee
Guidelines 1999. Thorax 2000;55:210-8.
41. Zhang GS, Wang PL, Huang HQ, et al. New insights into
the effects of Mycobacterium bovis bacillus CalmetteGurin on asthma. Chin Med J (Engl). 2009;122:577-83.
42. Katoch K, Katoch VM, Natrajan M, et al. 1012 years
follow-up of highly bacillated BL/LL leprosy patients
on combined chemotherapy and immunotherapy.
Vaccine, 2004;22:3649-57.
43. Katoch K, Singh P, Adhikari T, et al. Potential of Mw as a
prophylactic vaccine against pulmonary tuberculosis.
Vaccine 2008;26:1228-34.
65
43a. Lin My, Reddy TBK, Arend SM, et al. Cross-Reactive

Immunity to M. tuberculosis DOSR regulon-encoded
antigens in individuals infected with environmental
nontuberculous mycobacteria (NTM). Infection and
Immunity 2009;77:5071-9.
43b. Kobashi Y, Mouri K, Yogi S, et al. Clinical evaluation of
the QuantiFERON -TB Gold test in patients with
nontuberculous mycobacterial disease. Int J Tuber Lung
Dis 2009;13:1422-6.
44. Sankar MM, Gopinath K, Singla R, et al. In-vitro
antimycobacterial drug susceptibility testing of nontubercular mycobacteria by tetrazolium microplate assay.
Ann Clin Microbiol Antimicrob 2008;7:15.
45. Hatherill M, Hawkridge T, Whitelaw A, et al. Isolation
of non-tuberculosis mycobacteria in children investigated
for pulmonary tuberculosis. Plos One 2006 Dec 20;1:e21.
46. Gopinath K, Singh S. Multiplex PCR assay for
simultaneous detection and differentiation of M.
tuberculosis, M. avium complexes, and other Mycobacterial
Species directly from clinical specimens. J Appl Microbiol
2009;107:425-35.
SUGGESTED READING
Katoch VM, Mohan Kumar T. Nontuberculous mycobacterial
infections. In: Sharma SK, Alladi Mohan (Eds). Tuberculosis
2nd Ed. Jaypee Brothers Medical Publishers (P) Ltd. New Delhi.
2009;665-81.
Immunology of Tuberculosis:
Basic Aspects and Relevance for
Immunodiagnostic Tests
Heidi Syre, Harleen MS Grewal
INTRODUCTION
Tuberculosis (TB) poses a serious threat to humans.
Mycobacterium tuberculosis, the causative agent of TB,
infects 9.27 million and kills approximately 1.77 million
people annually.1 M. tuberculosis is a gram positive, rodshaped bacterium with a cell wall that is able to retain
acid-fast color during staining, thereby named acid-fast.
M. tuberculosis is a member of the M. tuberculosis complex
(MTC), which consists of the following species:
M. tuberculosis, M. bovis, M. bovis BCG, M. africanum,
M. canettii, M. microti, M. caprae and M. pinnipedii. 2,3
Members of the MTC have different host preferences with
M. tuberculosis, M. africanum and M. canetti being human
pathogens.
Central to the success of M. tuberculosis as a pathogen
is the ability to persist within humans for decades in a
clinically latent state, creating a potentially large reservoir
for further transmission of the microbe by reactivation.
It is estimated that every third person in the world is
infected with M. tuberculosis and that 10 to 12% of immune
competent individuals who acquire primary infection and
are not given preventive therapy will develop active TB.4,5
The risk of active disease is highest in the first two years
following infection, when half of the cases occur. The risk
of active TB is higher in immune compromised
individuals. Immune suppression can be caused by
coexisting diseases such as HIV infection, use of immune
suppressive drugs, or by malnutrition.
Other host factors influencing the development and
severity of TB disease are age, genetic factors and BCG
immunization. Microbial factors that influence the disease
are virulence, tissue specificity and number of bacilli
inhaled. 6 Malnutrition has been associated with
increasing susceptibility to TB. Studies have shown that
TB patients suffer from wasting and micronutrient
deficiency.7
Concurrent macro- and micronutrient deficiency
compromises the immune system function which in turn
increases the risk of TB reactivation.8 Interaction between
malnutrition and TB is associated with complex
mechanisms.9 A study conducted to assess nutritional
status between TB patients and healthy controls, showed
that 66% of the TB patients were underweight as
compared to 10% of the healthy controls (P < 0.0001).10

Furthermore, the study showed that the plasma retinal
2 concentration in TB patients was lower than that for
healthy individuals.10
Vitamin A deficiency has been shown to be a risk
factor for developing TB.11
Various mechanisms like poor dietary intake due to
loss of appetite, poor absorption of nutrients from the
intestine and increased uptake of nutrients by specific
target tissue due to increased body metabolism, are
associated with nutritional deficiency in TB patients.11
Since anti-TB treatment is given to malnourished TB
patients, there is a possibility that nutritional deficiency
may impair treatment outcome. A study from Indonesia
by Karyadi et al. reported that micronutrient
supplementation resulted in an earlier elimination of
M. tuberculosis from the sputum.12 The number of patients
with sputum smear negative for M. tuberculosis was
higher in the micronutrient supplemented group
than in the placebo group (23% vs 13%).12 However, a
recent study conducted in Tanzania on the effect of
micronutrient supplementation on treatment outcome in
pulmonary TB patients showed that neither multimicronutrient nor zinc supplementation had a significant
effect on sputum culture conversion, although multimicronutrient supplementation was significantly
associated with weight gain (0.78 kg; P = 0.02).13 Body
mass index (BMI) is an indicator of nutritional status. A
study conducted in Tanzania on nutritional status and
weight gain in patients with pulmonary TB showed that
77% of males and 58% of females had a BMI below
18.5 kg/m2 at the time of admission.9 Furthermore, a
study from Malawi showed that there was a reduction of
20% in BMI (from 21.7 to 17.3) among pulmonary TB
patients as compared with matched controls.8
THE IMMUNE SYSTEM

The immune system comprises the outer defence (e.g.
skin, mucosa, sweat, proteolytic enzymes, acidic juices
of the stomach, and bacteria in the colon) and the inner
defence. The inner defence includes the innate and the
adaptive immune systems (Table 7.1). The innate immune
system provides immediate defence against potential
Chapter 7 Immunology of Tuberculosis: Basic Aspects and Relevance

Table 7.1: The inner defence of the immune system
The innate immune system, the adaptive immune system
Phagocytes: T lymphocytes (cellular immune response):
Macrophages helper T-cells (Th1, Th2, Th9 and Th17)
Monocytescytotoxic T-cells
Neutrophil granulocytes - T-cells
Dendritic cellsCD1 restricted T-cells
Natural killer cells
Treg cells
Mast cells B lymphocytes (humoral immune response)
Eosinophil granulocytes
Basophil granulocytes Molecules:
Cytokines
Molecules: antibodies
Cytokines (interleukins, perforin and serine proteases,
chemokines, interferons) (granzyme A and B)
Eicosanoids (prostaglandins and leukotrienes)
The complement system
Acute phase proteins
dangers threatening the host, including microorganisms,14,15 and comprises phagocytes (macrophages,
monocytes, neutrophil granulocytes and dendritic cells
[DCs]), mast cells, eosinophil granulocytes, basophil
granulocytes, natural killer (NK) cells, and immune
molecules (cytokines, eicosanoids, the complement
system and acute phase proteins). The innate immune
system provides a nonspecific protection unaffected by
repeated exposure to the microbe, i.e. no development of
immunological memory.14,15
The adaptive immune system provides an immune
response, including immunological memory by the
proliferation of memory cells specific to the antigen.14
Most often, antigen presentation is needed for activation,
and thus, the adaptive immune system needs time before
being fully activated. The main cells of the adaptive
immune system are T and B lymphocytes which belong
to the cellular and humoral immune responses,
respectively.14,15 Both T and B lymphocytes carry specific
receptors on their cell surfaces that recognize specific
targets. The B lymphocyte is able to recognize soluble
antigens directly, whereas the T lymphocyte requires
antigens to be presented by antigen presenting cells
(APCs), including macrophages, DCs and B
lymphocytes.15 Specific cell surface receptors enable the
lymphocytes to differentiate between self and nonself
antigens, and autoreactive T lymphocytes and B
lymphocytes are eliminated by apoptosis. One
lymphocyte can recognize only one specific antigen.14,15
The cellular immune response is induced by
intracellular microbes like viruses and certain bacteria
including mycobacteria.16 T lymphocytes and phagocytes
are the main effector cells in the cellular immune response
67
and they communicate via small signal molecules known

as cytokines. T lymphocytes include helper T-cells and
cytotoxic T-cells, as well as unconventional T-cells ( Tcells and CD-1 restricted T-cells) and regulatory T (Treg)
cells. 17,18 The humoral immune response includes
B lymphocytes and following activation, B lymphocytes
produce antibodies specific to the antigen that caused
the activation. The humoral immune response is induced
mainly by extracellular microbes, most often bacteria.15
M. tuberculosis enters the host through inhalation of
infectious droplets and crosses the mucosal surfaces of
the human lung. Macrophages and DCs are APCs that
are important in the surveillance of the mucosal surfaces
and ingest M. tuberculosis cells by binding via receptors
on their cell surface to M. tuberculosis specific antigens.19
Upon the microbe-receptor association, an inflammatory
response is normally rapidly induced. The microbe is
killed and digested inside the macrophage by the activity
of digestive enzymes or following a respiratory burst that
releases free radicals. 17,19,20 The resulting antigens are
presented at the surface of the macrophage in association
with molecules known as major histocompatibility
complex (MHC) class II antigens.19
If the immune system is not able to fully eliminate
the microbe, M. tuberculosis will remain in the host in a
dormant state, and may later reactivate. Infected
macrophages and DCs migrate to adjacent lymph nodes
where mycobacterial antigens are presented and specific
immune responses are initiated (mainly Th1 type
immune response).21 Accumulation of immune cells at
the site of infection will, in time, result in the formation
of a granuloma with central necrosis in which, the
microbe actively multiplies. Antibodies against
M. tuberculosis are generated during the course of
infection, but do not appear to be protective.22
Virulence Factors of M. tuberculosis

M. tuberculosis is an extremely well-adapted microbe
which has coexisted with humans for millennia, and has
learned to modulate protective host responses to ensure
its own survival and dispersal. 23 The microbe has
evolved to invade and survive inside the macrophages,
and affects many, if not all, processing steps inside the
professional APC.17,19 By adapting into an intracellular
microbe, the microbe is protected from attack by the
humoral immune system including antibodies.
Clinical strains of M. tuberculosis both secrete and
contain molecules on the cell surface that function as
antigens eliciting an immune response in the host.
Secreted bacterial proteins generally generate a stronger
immune response in the host than do cell surface
proteins.24 Although, the majority of these antigens seem
to not be crucial to the viability of the microbe, they may
function as virulence factors. 19 A number of
68

Table 7.2: Soluble molecules and cell wall components
of M. tuberculosis
Soluble molecules:
- Ag85
- CFP-10
- ESAT-6
Cell wall components:
Lipids:
- muramyl dipeptides
- mycolic acids
- phospholipids
- trehalose dimycolate (cord factor)
Proteins:
- 4 kDa
- 19 kDa
- 27 kDa
- 38 kDa
Polysaccharides:
- arabinogalactan
- arabinomannan
M. tuberculosis antigens have been identified and

characterized (Table 7.2). Secreted mycobacterial proteins
include the Ag 85 family of mycolyl transferases, culture
filtrate protein 10 (CFP-10), and early-secreted antigenic
target 6 kDa protein (ESAT-6). Cell wall components
comprise lipids (muramyl dipeptides, mycolic acids,
phospholipids, and trehalose dimycolate), proteins (14
kDa, 19 kDa, 27 kDa, and 38 kDa antigens) and
polysaccharides (arabinogalactan, and arabinomannan).
Some of the antigens are currently being assessed as
components in new vaccine candidates against TB, either
to replace or to boost the BCG vaccine.
It has been hypothesized that cholesterol is necessary
for M. tuberculosis to enter the macrophages.25 A
cholesterol-specific receptor, the Ck-like molecule on the
cell surface of M. tuberculosis, interacts with cholesterol
in the macrophage cell membrane leading to entry of the
microbe into the APC. Furthermore, it is suggested that
cholesterol mediates the phagosomal association of
tryptophan-aspartate containing coat (TACO) protein.25
The TACO protein is a host protein which inhibits the
fusion between the M. tuberculosis containing phagosome
and the lysosomes, and thus prevents degradation of
M. tuberculosis inside the macrophage.25,26 It has been
reported that phagosomes containing less than five
M. tuberculosis cells are unable to retain TACO, whereas
phagosomes containing more than five bacteria retain
TACO within their membrane. 27 An overview of
mechanisms that favor the infection and survival of
M. tuberculosis in macrophages are provided in Table 7.3.
M. tuberculosis is digested by the macrophage via
endocytosis and localized inside the cell in an early
phagosome. Normally, a microbe containing phagosome
will fuse with the lysosome, a complex vacuole containing
potent hydrolytic enzymes capable of degrading

macromolecules. The pH optimum of the hydrolytic
enzymes is pH 4.5 to 5.0,28 and the acidic environment is
maintained inside the lysosome by ATP dependent proton
pumps localized in the lysosome membrane. M. tuberculosis
inhibits fusion with lysosomes and arrests the acidification
of the phagosome, enabling growth and persistence inside
the macrophage.19 The exact mechanism is not clearly
understood, but it is believed that M. tuberculosis interferes
with putative transporters, iron-scavenging molecules and
lipid-synthesizing molecules to prevent normal
phagosome maturation. 19,20,23 By maintaining the
phagosome in an immature state, the phagosome-lysosome
fusion is prevented.19
Some suggest that M. tuberculosis inhibits the
maturation of the phagosome by the production of ESAT6, CFP-10 and SecA1/2 which inhibit the ATPase
activity.23 M. tuberculosis thereby limits the acidification
of the vacuole which is one of the key events in the
phagosome maturation in order to process and kill the
microbe.29,30 The process is moreover dependent, at least
to some extent, on blocking of a calmodulin-dependent
Ca2+ flux by multiple microbe derived molecules.31,32
Another study has suggested that M. tuberculosis prevents
fusion between the phagosome and lysosomes by the
production of ammonia via the urease enzyme.33 This
correlates well with the observation that ammonium
chloride, a weak base, affects the saltatory movement of
lysosomes and alkalinizes the acidic environment inside
the lysosome.33,34 Also the exclusion of Rab7, a GTPbinding protein located in late endosomes that facilitates
Table 7.3: Mechanisms that favor infection and survival
of M. tuberculosis in macrophages
Entering the macrophage:
Cholesterol
Prevention of phagosome maturation and phagosome-lysosome
fusion:
TACO protein
Inhibiting ATPase activity
Blocking calmodulin-dependent Ca2+ flux
Ammonia production
Exclusion of Rab7
Cord factor
Modulation of the immune response:
9 kDa
ESAT-6
LAM
Inhibition of APC maturation:
LAM
Mycobacterial decoy antigens distracting the immune system:
ESAT-6
Ag 85 B
TACO Tryptophan-aspartate containing coat, EAST-6 Earlysecreted antigenic target 6 kDa protein, APC: Antigen presenting
cell, LAM Lipoarabinomannan.

fusion of the endosome to lysosomes,35 may explain the
inhibition of the fusion process. In addition, the
M. tuberculosis cell wall lipid trehalose dimycolate (cord
factor) affects the membrane trafficking, inhibits
maturation of the phagosome and the expression of MHC
class II molecules and coreceptors on the cell surface of
the phagocyte. Thus, there is probably more than one
mechanism that helps the microbe to block the maturation
of the early phagosome and the fusion with lysosomes
containing enzymes for microbe degradation.
M. tuberculosis retains the access to early endosomal
vesicles, through which the microbe can gain access to
essential nutrients and cations, especially iron, which
enables the cell to replicate and export its own proteins.23
Once the microbe has entered the macrophage, longchained fatty acids of the M. tuberculosis cell wall strongly
stimulate the immune response of the host, resulting in
increased antigen presentation and activation of
T lymphocytes and NK cells to eliminate the invading
microbe.
However, mycobacterial cell wall lipoproteins are able
to modulate immune responses to influence the
elimination process. The 19 kDa lipoprotein of
M. tuberculosis interacts with toll-like receptor (TLR) 1
and 2 of the APCs.36,37 The interaction inhibits cytokine
production from the APCs by reducing the expression of
over a third of interferon (IFN)- activated genes.23
Moreover, the 19 kDa lipoprotein-TLR interaction
reduces the antigen processing and MHC class II
expression of the APCs. Also ESAT-6 acts via the TLR-2
and has a similar dampening effect on the immune
response.38 It is believed that ESAT-6 may contribute to
increase the virulence of the epidemic Beijing strain of
M. tuberculosis in humans by inducing high levels of IL-4
and IL-13.23,39,40
Lipoarabinomannan (LAM) is a highly immunogenic
lipopolysaccharide specific to mycobacteria. LAM is
associated with the mycobacterial cell wall and may
function as a virulence factor.41 The molecule associates
with DC-specific intercellular adhesion moleculegrabbing non-integrin (DC-SIGN) molecules on the
surface of APCs. The DC-SIGN molecule is important for
maturation of APCs. By binding the DC-SIGN molecule,
LAM not only inhibits the maturation process, but also
reduces the IL-12 production by the induction of IL-10
secretion by APCs.42 IL-10 suppresses the immune
response by the inhibition of the following: Antigen
presentation, expression of MHC molecules, and
expression of costimulating receptors on the cells surface.
LAM can furthermore inhibit the activation of
macrophages by blocking the IFN-g induction of
important macrophage genes,41 by scavenging, the toxic
free radicals of macrophages, and by inhibition of the
protein kinase C activity which plays a regulatory role
in macrophage activation. Lastly, it has been shown that
69
LAM can induce the production and release of TNF by

macrophages43 which may be responsible for fever,
weight loss, elevated acute phase reactants and necrosis
typically found in TB patients.
M. tuberculosis produces specific antigens early in the
infection process which dominate the immune response.
It has been suggested that these antigens function as
immunological decoys to distract the immune system
and prevent it from responding against antigens more
relevant to host protection.19,44 The decoy antigens bind
more strongly to MHC molecules than do the less
abundant but more important immunogenic antigens.
Potential decoy proteins are ESAT-6 and Ag85B.19 These
are dominantly secreted in the initial stages of the
infection and the production declines after approximately
3 weeks.19 Activated T-cells specific to the decoy antigens
would soon fail to recognize macrophages infected by
the microbe since these would contain M. tuberculosis
which no longer produce the current antigen but instead
express other antigens that the activated T-cell clones
would not recognize. 19.44 Thus, it is possible that
M. tuberculosis through evolution has developed
protective responses via decoy antigens.19,44
Immune Cells of the Body

The Macrophage
Alveolar macrophages are the main cells infected by
M. tuberculosis after the microbe has entered the alveoli.
Macrophages are relatively large cells (15 to 25 m in
diameter) and have a variable shape. Macrophages are
professional APCs specialized for uptake, proteolytic
cleavage, enzymatic processing, and intracellular
trafficking of antigens. Professional APCs activate the
naive Th0 cell (i.e. primary response).45 The processed
antigen is presented on the surface of the macrophage in
association with MHC class II molecules specific to
professional APCs. M. tuberculosis can also survive and
multiply in DCs, monocytes and neutrophils. 46
Macrophages and DCs are distributed in peripheral
tissues in an inactivated state. Following the interaction
with antigens, they undergo a maturation process,
migrate to the draining lymph nodes and present the
antigens to naive Th0 lymphocytes. Macrophages get help
to identify structures for ingestion by a process known
as opsonization. Opsonins are soluble factors of the
immune system which mark or single out structures to
be removed. The C3b fragment in the complement system
and antibodies secreted by the B lymphocytes are
examples of opsonins.47 Furthermore, under the influence
of IL-12, activated T lymphocytes secrete cytokines
(mainly IFN- and TNF-) which activate and lead the
macrophage to the site of infection, resulting in a more
efficient elimination of the microbe. Macrophages may
also be activated by 1,25-dihydroxy vitamin D3 alone or
70

in combination with IFN- and TNF-. By binding to the
vitamin D receptor of macrophages, the macrophages
inhibit or kill M. tuberculosis in humans, probably by
inducing the expression of enzymes in the reactive
intermediate pathway.48-50
The microbe-macrophage interaction starts
immediately following contact between the two cells. Cell
surface antigens or antigens secreted by M. tuberculosis
bind to pathogen associated molecular pattern (PAMP)
receptors localized on the surface of the macrophages and
other host cells.23 The microbe-PAMP receptor association
stimulates the macrophage to ingest M. tuberculosis, but
also initiates and shapes the immune system more specific
to the invading microbe. The TLR family is an example
of a PAMP receptor, and in particular, TLR-2, TLR-4 and
TLR-9 are essential in the creation of an effective immune
response against M. tuberculosis. 17 The binding of a
microbial antigen to the corresponding TLR transmits a
signal to the host cell nucleus inducing the expression of
genes coding for the synthesis of cytokines. The cytokines,
in turn, bind to cytokine receptors of the cytokine
producing cell or other immune cells for activation.23
Activated macrophages generate several effector
molecules with mycobactericidal effect. Reactive oxygen
and nitrogen intermediates are the main groups of
antimycobacterial molecules produced by macrophages
by the use of the phagocyte oxidase enzyme and nitric
oxide synthase 2 enzyme. In addition, sterilizing chloride
compounds are produced inside the cell by the enzyme
myeloperoxidase. IFN- and TNF- synergistically
stimulate the production of reactive intermediates via
induction of enzymes in the intermediate pathway.51
T-lymphocytes
The main effector cells in the adaptive immune system
are T and B lymphocytes, and their function is to
recognize and act against specific non-self antigens. The
B lymphocytes mainly survey the extracellular
compartments and the T lymphocytes control the
intracellular compartments.14 The T lymphocyte is able
to identify cancer cells and cells of the host infected by
microorganisms by the association with MHC molecules
expressed on the host cell surface. Table 7.4 gives an
overview of the existing classes of lymphocytes and their
main function.
The cells of the immune system have glyco-proteins
known as cluster of differentiation (CD) antigens on their
surface. The CD antigens promote cell-cell interactions
and adhesion, and transduce signals that lead to
activation of the lymphocyte. The CD antigens are used
as phenotypic surface markers to subcategorize the
immunocompetent cells.52 All T-cells express the CD2 and
CD3 antigens in addition to other CD antigens (Table 7.4).
There are two main groups of T lymphocytes; the
Table 7.4: Classes, phenotypic markers and main

functions of lymphocytes
Lymphocyte class Phenotypic markers Main function
Helper T-cell CD2, CD3, CD4, TCR Regulates immune
cells via cytokine secretion
Cytotoxic T-cell CD2, CD3, CD8, TCR Lysis of cells
infected by virus or bacteria, cancer cells and allografts
T-cell CD2, CD3, TCR Lysis of cells infected by virus/
bacteria/cancer cells, recognizes nonpeptide antigens
CD-1 restricted T-cell CD2, CD3, mainly TCR Recognizes
foreign lipid antigens presented by APCs, induces cytolysis
NK cell CD2, CD16, CD56 Lysis of cells infected by virus,
bacteria or cancer cells
Treg cell CD2, CD4/CD8, CD25, TCR Suppresses the
immune response, induces lysis
B cell CD19, CD21, MHC class II Antibody secretion
CD cluster of differentiation antigen, TCR- T-cell receptor,
NK cell-natural killer cell.
helper T-cell and the cytotoxic T-cell. T lymphocytes are

activated by IL-1 secreted by activated macrophages and
by interaction between the T-cell receptor (TCR) localized
on the lymphocyte surface and a foreign antigen
presented by a MHC class II molecule of an APC.19 Helper
T-cells are limited to associate with only one type of
antigen in their TCR. The TCR is coupled closely to the
CD3 antigen comprising a group of 5 transmembrane
polypeptides. By binding a MHC class II associated
antigen, the TCR/CD3 complex sends signals to the
interior of the cell to proliferate and differentiate.52 The
CD4 and CD8 coreceptors which exist each on the two
main groups of T lymphocytes; the helper T lymphocyte
and cytotoxic T lymphocyte, respectively, aid in the
T-cell activation together with the CD28 membrane
molecule.52 The ligand of CD28 is B7 localized on the cell
surface of professional APCs. Thus, the helper T-cell
requires two signals for activation; one signal from the
presented antigen through the TCR and one signal
through CD28. Without the CD28-B7 association, the
T-cell will not proliferate or develop effector mechanisms.
Polarization into different T-cell sets is mostly dictated
by cytokines, but also the microbe binding to the TCR
and the genetic composition of the host contribute in the
stimulation of appropriate effector cells providing the best
possible immune response. Specific cytokines stimulate
the development of one T-cell type and suppress the
development of another T-cell type.
Helper T-lymphocytes
Helper T-cells, also known as CD4+ T-cells, play a major
role in the immune defence against M. tuberculosis. This
is demonstrated in TB-HIV coinfected individuals who
have a considerable increased risk of progression to TB

after infection, when the number of helper T-cells is
reduced. By cytokine production and by direct contact,
the helper T-cells regulate the immune response by
directing immune cells; T helper 1 (Th1) cells regulate
the activity of macrophages and cytotoxic T-cells, and T
helper 2 (Th2) cells regulate the activity of B cells.
Helper T-cells express receptors including CD3, CD4,
CD28 and TCR on their surface.52 The TCR of the helper
T-cell recognizes antigens presented along with the MHC
class II molecules which only exist on the surface of
professional APCs (macrophages, DCs and possibly also
B lymphocytes). One specific helper T-cell recognizes only
one type of antigen and the cell is activated when (i) the
MHC class II associated antigen is coupled to the TCR
and (ii) the B7 receptors of the macrophages interact with
the T lymphocyte DC28 receptor.
Following activation, the T-cell increases in size, the
receptors on the cell surface change and they differentiate
into a helper T-cell subtype. Classically, following
activation helper T-cells differentiate into Th1 cells or Th2
cells. Recent data suggest that naive helper T-cells may
also develop upon activation into two novel T-cell lineages;
T helper 9 (Th9) cells and T helper 17 (Th17) cells. The
subtypes express different cytokine profiles and thereby
have different functions. Th1 cells secrete IFN-, IL-2, IL12, granulocyte-macrophage colony-stimulating factor
(GM-CSF), and lymphotoxin (previously known as
TNF-). Th1 cell binding to the antigen recruits cytokine
production and IL-2 induces clonal expansion of the Th1
cell by binding the IL-2 receptor (autocrine effect). Via the
secretion of cytokines, Th1 cells activate the microbicidal
function of macrophages (mainly by IFN- and TNF-),
NK cells and cytotoxic T-cells (mainly by IL-2) and are thus,
important in the cellular immunity against intracellular
microbes like virus and mycobacteria.16 Several studies
have shown that the IFN- production by Th1 cells is of
major importance for protection against TB in mice17,53,54,
and IFN- receptor deficiency on the immune cells is
associated with increased susceptibility to mycobacterial
infections.55-57 The different cytokines and their function
in response to M. tuberculosis infection is summarised in
Table 7.5.
The T-cell receptor (TCR) together with an upregulation of the CD40 ligand on the cell surfaces of
activated Th2 cells provides stimulatory signals for the
activation of B lymphocytes. The cytokines secreted by
the Th2 cells are IL-4, IL-5, IL-6, IL-10 and IL-13. Th2 cells
support the differentiation and proliferation of
B lymphocytes leading to production of antibodies, which
are important in the fight against extracellular microbes
as well as in atopic and parasitic diseases.16
Tumour growth factor (TGF)- is important in the
development of helper T-cell lineages distinct from Th1
and Th2. Under the influence of IL-6, the TGF- is
responsible for the development of the IL-17 producing
71
Table 7.5: Cytokine origins and function in response to

M. tuberculosis
Cytokine secreting cell function
IFN- Th1 cells*, NK cells, T-cells activates
macrophages, NK cells and cytotoxic T-cells
IL-1 Macrophages Activates T-cells, IL-6 production by
macrophages
IL-2 Th1 cells proliferation of helper T-cells, cytotoxic
T-cells and NK cells
IL-4 Th2 cells*, eosinophils, basophils, antagoniges the
TNF- effect, suppresses the effect of mast cells, NK cells
and some APCs the Th1 response
IL-6 Macrophages and Th2 cells mediates
hyperglobulinemia, acute phase proteins
IL-10 Macrophages, Th1 and Th2 cells Th1 and Th2
proliferation and cytokine production, inhibits antigen
presentation
IL-12 Macrophages IFN- secretion, activates
NK-cells
IL-17 M Th17 cells recruit neutrophils to infection site
TNF- Macrophages*, Th1 and Th2 cells protects against
active TB, induces apoptosis, granuloma formation
Lymphotoxin Macrophages, Th1* and Th2 cells regulate
leukocyte movement and granuloma formation
*The main secreting cell.
Th17 cells. Also IL-23 (produced by DCs and macrophages)

is required for the Th17 cells to become an established
population. Th17 cells are associated with autoimmune
diseases, but they also recruit neutrophils to the infection
sites, participate in the inflammatory responses in response
to an infectious microbe and thus, participate in the
protection against TB.58 Th17 cells probably provide a first
line of defence against the microbe and participate in the
early steps of granuloma formation.59
Recently, a second subpopulation of helper T-cells,
know as Th9 cells, has been presented. Th9 cell
subpopulation develops under the influence of IL-4 and
TGF-, typically in chronic diseases like asthma.60 Th9
cells secrete IL-9 and IL-10. IL-9 has an important role in
airway remodeling, most notably with mucus production
in the epithelium.61
Cytotoxic T-lymphocytes
The cytotoxic T-cells, also known as CD8+ T-cells, kill
cells infected by virus or bacteria, or otherwise damaged
or dysfunctional cells, by the secretion of cytotoxins. One
specific cytotoxic T-cell recognizes only one type of
antigen and the cell is activated only when the specific
antigen in association with a MHC class I molecule is
coupled to the TCR. The MHC class I molecule exists on
the surface of all human cells. Recognition of the antigenMHC complex is aided by a coreceptor named CD8,
thereby the name CD8+ T lymphocytes.52 Like the helper
T-cell, also the cytotoxic T-cells require a second signal
72

for activation, the association between CD28 localized
on the surface of the cytotoxic T-cell and the B7 molecule
of the macrophage. Activated cytotoxic T lymphocytes
express IL-2 receptors on the cell surface. IL-2 from
activated helper T lymphocytes binds the IL-2 receptor
and induces proliferation of the cytotoxic T lymphocytes.
Activated cytotoxic T lymphocytes travel in the body
searching for identical antigen-MHC complexes
presented on the cell surfaces. Upon binding, cytotoxins
including perforin are secreted. Perforin contributes to
pore formation in the plasma membrane of the infected
target cell resulting in cell lysis, thereby limiting infection
by elimination of the place where M. tuberculosis
multiplies.19 Granlysin, another cytotoxin secreted by the
cytotoxic T-cells, diffuses into the cell via the perforincreated pores and induces target cells to undergo
apoptosis. Apoptosis can also be induced by association
between the Fas receptor (also known as CD95 or the
death receptor) on the surface of an infected cell and the
Fas ligand on the cytotoxic T-cell surface.62 Fas ligand is
expressed on the surface of the cytotoxic T-cell following
activation. Thus, apoptosis of the target cell may be
induced both by soluble molecules secreted by the
cytotoxic T-cell and by direct cell-cell interaction. By
inducing cell lysis, M. tuberculosis is exposed to activated
macrophages with increased antimycobacterial activity.
In addition, cytotoxic T-cells contribute to protect against
infection by the production of IFN-. Following activation,
T memory cells specific to M. tuberculosis will develop.
A beneficial attribute of cytotoxic T-cells in
mycobacterial infection is their recognition of antigens
coupled to MHC class I molecules that are expressed by
all cells in the host, whereas the helper T-cells only
recognize antigens coupled to MHC class II molecules
limited to APCs. Thus, parenchymal cells of the lung
infected with M. tuberculosis would remain undetected
by the helper T-cells. Such infected cells would be
detected only by the cytotoxic T-cells and probably by
the
T-cells.
Unconventional T-lymphocytes
The unconventional subgroup of T lymphocytes includes
T-cells and CD-1 restricted T-cells. The membranes of
the unconventional T lymphocytes contain receptors
which are less variable than those of B and T lymphocytes,
and T-cells have an alternative TCR () as opposed to
the TCR of helper T-cells and cytotoxic T-cells (). The
unconventional T-cells do not need MHC molecules for
antigen recognition. The exact function of such cells is
not known, but it is believed that they are important in
the early stages of the immune response, before the
cytotoxic T-cells and helper T-cells have been fully
activated. The T-cells and the CD-1 restricted T-cells
undergo considerable proliferation during the initial
phase of an infection. These cells have receptors distinct

from helper T-cells and cytotoxic T-cells and they target
different molecules than the more conventional
T lymphocytes. Thus, the unconventional T lymphocytes
extend the number of epitopes the immune system is able
to act against.
CD1-restricted T-cells comprise two functional
groups: cells that produce mainly Th1 cytokines and are
often cytolytic in their function, and cells that produce
both Th1 and Th2 cytokines, particularly important in
preventing autoimmunity.63 CD-1 restricted T-cells
recognize mycobacterial glycolipids, such as LAM and
mycolic acids, presented by DC-1 molecules expressed
mainly on the cell surface of professional APCs.63
Upon binding the antigen, the CD-1 restricted T-cell
induces cytolysis of the M. tuberculosis infected APC.
T-cells respond to small nonpeptide M. tuberculosis
antigens. 64 Activated T-cells proliferate and
differentiate into cytotoxic cells and secrete cytokines
typically associated with a Th1 response. The IFN-
secretion results in increased expression of MHC and
costimulating molecules on the macrophages surface, and
increases the IL-12 and IL-18 production which again
have a positive feed-back effect on the IFN- production.
The importance of IL-12 has been demonstrated in human
genotypes with mutations in the IL-12 receptor which
are associated with an extreme susceptibility for
mycobacterial infections.
Regulatory T-Cells
Treg cells are a subset of CD4+ T-cells that suppress
immune responses by the production of IL-10 and
TGF-.18,65,66 The two cytokines reduce the inflammatory
responses by the inhibition of macrophages, DCs and
lymphocytes resulting in reduced host tissue damage.65,67
Treg cells also induce cytolysis via secretion of granlysin
and perforin. Treg and Th17 cells appear to have opposing
functions in the regulation of protective immunity in TB.
A recent study has shown that a population of purified
CD4+ T-cells from naive mice gave protection to Rag1
knock out mice (mice without B and T-cells) against TB,
whereas the protection was reduced to that seen in wild
type mice when Th and Treg cells were cotransferred into
Rag1 knock out mice.18 The results suggest that the
presence of Treg cells could reduce an otherwise effective
T-cell response against M. tuberculosis and thereby
prevent efficient clearance of the microbe.
The B-lymphocytes
The B-lymphocytes identify microbes when antibodies
localized on their cell surface bind to a specific foreign
antigen.14 The antigen-antibody complex is ingested by
the B-lymphocyte and peptides are generated through
proteolysis. The peptides are presented together with

MHC class II molecules on the surface of the
B-lymphocyte14, and attract a matching Th2 lymphocyte
via cytokine secretion (mainly IL-2, IL-4 and IL-5) or via
direct association between cell surface molecules of the B
and T lymphocytes. More specifically, the antigen binding
induces the B lymphocyte to express the B7 and CD40
molecules on their cell surface. B7 and CD40 interact with
CD28 and CD40 ligand, respectively, on the cell surface
of the activated Th2 cell. Following activation, the B-cell
starts to proliferate and evolve into antibody producing
plasma cells and memory cells responsible for
immunity.14 B lymphocytes can also be activated without
helper T-cell assistance. The T-cell independent activation
of B lymphocytes occurs most often in the presence of
carbohydrate antigens with identical repetitive antigenic
determinants or in the presence of polyclonal activators,
exemplified by lipopolysaccarides localized in the outer
membrane of gram negative bacilli. The T-cell dependent
B lymphocyte activation occurs most often in the presence
of protein antigens.
Each B-cell line expresses a unique, antigen-specific
antibody. The specific antibodies circulate in the lymph
and blood, and bind antigens identical to the original
epitope. Antigen-antibody complexes activate the
complement system, macrophages and granulocytes.
Macrophages bind the antigen-antibody complex via
the Fc receptor and engulf the microbe. Macrophages also
contain complement receptors on their cell surfaces, and
may by this receptor, engulf the complement-bound
microbes. Finally, antibodies can neutralize antigens
directly. Examples of such antigens are toxins or receptors
located on the cell surface of the microbes.
It has been generally accepted that B cells and their
antibodies play a limited role in the TB immune response,
since M. tuberculosis is an intracellular microbe and
antibodies are specialised for targeting extracellular
microbes. However, new knowledge opens for the
possibility that the humoral immune response contributes
in the defence against M. tuberculosis. The demarcation
between humoral and cellular immune responses is
probably more synergetic than previously suggested,
resulting in a mixed immune response. B cells secrete
cytokines typically associated with a Th1 response (IFN and IL-12) or cytokines associated with a Th2 response
(IL-4). B cells also secrete IL-6 which stimulates the T-cell
response and IL-10 which inhibits the activity of DCs and
macrophages. IL-10 furthermore suppresses the DC
production of IL-6 and IL-12. Antibodies secreted by the
B-lymphocytes play an essential protective role against
mycobacterial infections via their opsonin effect, as
previously mentioned. It has been shown that neutrophils
and macrophages increase the internalization and killing
of mycobacteria in the presence of antibodies68,69, and
mycobacteria coated by specific antibodies are processed
more efficiently by DCs. 70,71 Also studies in B-cell-
73
deficient and SCID mice (mice 15 with impaired ability

to make T or B lymphocytes) show that antibody
responses are essential to combat mycobacterial
infection.72,73
NK Cells
NK cells are large lymphocytes specialized to identify
and kill infected cells (e.g. cells infected with virus or
intracellular bacteria as M. tuberculosis) or cancer cells in
the body. NK cells are cytotoxic and small granula in their
cytoplasm contain proteins such as perforin and proteases
known as granzymes which induce apoptosis of the target
cell. NK cells express CD16 (which includes the Fc
receptor for IgG) and CD56 molecules on their cell
surfaces. In contrast to T lymphocytes, they do not express
CD3 or TCR. NK cells are activated in response to
cytokines and have two kinds of receptors on
the cell surface to control cytotoxic activity; activating and
inhibitory receptors. The inhibitory receptors recognize
MHC class I molecules present on all cell surfaces of the
host. If the amount of MHC class I molecules is reduced,
as by infection or by cancer cells, the NK-cells kill the cell
by inducing apoptosis. NK cells also kill cells coated by
IgG antibodies by binding the antibodies to the Fc receptor
of CD16 (antibody dependent cell mediated cytotoxicity;
ADCC).
Cytokines
Cells of the immune system communicate in part via
direct contact and in part via small soluble molecules.
Signal molecules of the immune system are usually small
polypeptides or glycoproteins (MW 15-35 kDa) and are
known as cytokines. They are produced mainly by helper
T lymphocytes, but also by B lymphocytes, macrophages
and other immune cells. Cytokines function by association
with specific receptor on the cell surface of the secreting
cell (autocrine effect) or a neighbour cell (paracrine effect).
The most important cytokines in the fight against TB are
IFN-, IL-4, IL-10, IL-12 and TNF-. IFN- protects against
TB disease (Table 7.5)74 and is produced mainly by the
helper T-cells. IFN- is probably also produced by Tcells and NK cells in the initial phase of the infection, and
by cytotoxic T-cells in later stages of the disease. The
important role of IFN- in the fight against M. tuberculosis
can be demonstrated by testing monocytes from healthy
individuals exposed to the microbe. The monocytes will
by exposure to M. tuberculosis specific antigens produce
high levels of IFN-. Monocytes from patients with
pulmonary TB and TB-HIV coinfection have reduced INF production,75 indicating that the Th1 responses are
depressed in patients with TB. Moreover, IFN- knockout
mice are highly susceptible to virulent M. tuberculosis53,76,
and individuals with defect in genes for IFN- or the IFN receptor are susceptible to M tuberculosis infection.77 INF-
74

activates macrophages, NK cells and cytotoxic
T-cells. Furthermore, IFN- stimulates the development
of T-cells towards a Th1 cell direction, and inhibits the
development of T-cells towards a Th2 cell or Th17 cell
direction.78 The Th2 cell cytokines IL-4 and IL-10 have
similar inhibiting effect on the development of Th1 cells.
Secretion of IL-4 is induced by cell wall components of
M. tuberculosis (phosphoglycolipids and 19 kDa antigen)
and tends to increase in serious phases of TB disease
(miliary and meningeal TB). It has been suggested that
progressive TB disease is due to the suppressive effect of
IL-4 on the Th1 response, and not due to the absence of a
Th1 response, since IL-4 producing T-cells and IL-4
mRNA are increased in pulmonary TB patients and
correlates with the extent of lung cavitations.79 The IL-4
hypothesis is supported by the observation that vaccine
candidates (a DNA vaccine based on heat shock protein
65 of M. leprae and a heat-killed M. vaccae vaccine
candidate) that down-regulate the IL-4 effect have an
immuno-therapeutic in murine TB models.79 It is also
suggested that IL-4 antagonizes the apoptotic stimulation
effect of TNF-.23
IL-10 is an inhibitory cytokine. IL-10 inhibits antigen
presentation, expression of MHC molecules and
costimulating receptors on the cell surfaces of APCs.
IL-10 furthermore inhibits the production and function
of IFN-, lymphocyte proliferation, cytokine production
by lymphocytes, and IL-12 production by macrophages.17
IL-10 increases in patients with active TB, whereas IL-12
induces IFN- production and thereby protects against
TB disease. Mutations in the gene encoding the IL-12
receptor make such individuals extremely susceptible to
TB infection.80
The important anti-mycobacterial effect of TNF- is
demonstrated by the high risk of reactivation of TB
infection in patients with rheumatoid arthritis treated by
TNF- receptor antagonists. However, together with high
levels of IL-4, the TNF- has an opposite effect: induces
necrosis and apoptosis, resulting in the formation of
granulomas. TNF- is furthermore responsible for the
weight loss and fever in TB patients.
No single immunological marker has so far alone
shown to give full protection against TB. Instead,
combinations of certain pattern of cytokines released are
most likely to provide protective immunity.
Cell Death
If the cell-mediated immune response fails to eliminate
the intracellular microbe, the host needs to eliminate the
infected cell to remove the microbe. This may be done by
two different processes; apoptosis and necrosis. By
apoptosis the infected cell is eliminated without major
effects on the neighboring, uninfected cells, resulting in
minimal tissue destruction.81 TNF is a potent inducer of
cell death by apoptosis. Cell death by necrosis, on the

other hand, results in lysis of the infected cell and the
release of viable M. tuberculosis into the adjacent
extracellular matrix. This in turn damages the
surrounding tissue 81 , leads to central necrosis of
unresolved granulomas, and extracellular M. tuberculosis
may spread to new hosts. M. tuberculosis has evolved to
actively promote necrosis over apoptosis82-84 and to
inhibit apoptosis, and thereby avoid the death of its host
cell.
TB Pathogenesis
M. tuberculosis is spread through the air by droplet nuclei
produced by a patient with active pulmonary TB. Droplet
nuclei are 1-5 m in diameter, contain two or three
M. tuberculosis cells, and are small enough to reach the
alveoli within the lungs.85 Alveolar macrophages survey
the mucosal surfaces of the lungs and ingest the
M. tuberculosis containing particles. Some of the infected
macrophages traffic to the draining lymph nodes and
present the microbes to naive T lymphocytes. Other
infected macrophages are trapped in the lung
parenchyma. Following antigen presentation, the
activated M. tuberculosis specific T lymphocytes
proliferate and differentiate into effector cells. Cytokines
produced by immune cells located at the site of infection
attract uninfected macrophages and leukocyte populations, including T lymphocytes. Activated antigenspecific T lymphocytes recognize M. tuberculosis-infected
macrophages and granuloma formation is induced. A
granuloma is characterized by a relatively small number
of M. tuberculosis infected phagocytes, surrounded by
activated macrophages and lymphocytes. 86 In the
granuloma, M. tuberculosis has the capacity of staying
viable for years. Whether or not the inhaled bacilli are
able to multiply inside the macrophage and establish an
infection in the lung depends on the degree of aerosol
production, the bacterial load in the inoculum, the
bacterial virulence, and the microbicidal ability of the
immune system of the host.85
In the majority (approximately 90%) of immune
competent individuals, the immune response arrests and
limits M. tuberculosis to the primary site of infection; the
lung parenchyma and the local draining lymph nodes,
resulting in the primary complex (the Ghon complex).
This stage of TB infection is known as latent TB or
persistent TB. Individuals with latent TB have no
symptoms of TB disease. The majority of primary
complexes are not visible on chest radiography and are
clinically silent.85 A positive tuberculin skin test is the
only indication of M. tuberculosis infection. Gradually, the
granulomas heal and leave small, fibrous and calcified
lesions. The lesions can be identified on chest radiography
for years. Individuals with latent TB are not infectious,

cannot transmit the microbe and can be asymptomatic
for the rest of their life-time. If the immune system of the
host is unable to control the initial TB infection or if the
infected person later in life becomes immune compromised for example due to HIV infection, malnutrition,
drugs or age, primary TB disease and post-primary
TB disease, respectively, may develop. The granulomas
may increase, become liquefied and function as a rich
medium where M. tuberculosis can multiply uncontrolled.
Primary TB is defined as TB disease that develops during
the first five years following the primary infection.5
Postprimary TB is defined as any TB diagnosed more than
5 years after primary infection. Cell death in the
granuloma leads to necrosis. If the granuloma is close to
the lung surface, tissue destruction caused by necrosis
can breach the mucosal surface and M. tuberculosis reach
the lung lumen, a process referred to as cavitation. At
this point, the patient will have the prototypic symptoms
of TB: persistent cough with hemoptysis and fever. The
person is highly infectious and spreads the microbe by
aerosols.
Viable M. tuberculosis may leave the granuloma and
infect the surrounding lung parenchyma (active
pulmonary TB) or migrate to other organs through
lymphatics and blood (miliary or extrapulmonary TB).
Certain organs and tissues are more susceptible to the
multiplication of M. tuberculosis than others. Examples of
environments that favor the growth of M. tuberculosis are
the upper lung zones, kidneys, bones and brain.
Biomarkers
Early identification of active TB is crucial to combat the
TB epidemic. Also identification of individuals with latent
TB, especially those with the highest risk of progression
to active TB, assessment of disease activity, immune
responses, responses to treatment, and early indication
of relapse would be useful. It would further more be
helpful to classify TB patients at diagnosis or early on
during therapy into risk groups and adjust the treatment
accordingly.
Studies have shown that patients responding early
on anti-TB treatment may receive a shortened course of
treatment, 87,88 thereby improving compliance and
treatment outcome. Finally, biomarkers could help to
define a surrogate end-point for vaccine efficacy in Phase
II/III vaccine clinical trials. The vaccine end-point of
today is the diagnosis of clinical TB disease which due to
a usually long incubation time is inconvenient. The
development of such tests has proven to be one of the
greatest challenges in TB research and control. A
biomarker is defined as an objectively measured
characteristic feature which is evaluated as an indicator
of a normal or a pathological process or as an indicator
of the response to an intervention.89 Biomarkers of TB
75
include in theory all tests or markers that can tell if the

person is infected with M. tuberculosis. Currently, the most
widely used biomarkers for TB infection and disease are
the chest radiography, the TST and the Ziehl-Neelsen
(ZN) staining of sputum smears. Another widely used
biomarker for TB infection is IFN- secreted by antigenspecific T-cells. Measurement of IFN-g is also used to
monitor vaccine efficacy in clinical trials.
WHO recommends performing sputum-smear
microscopy on all patients suspected to suffer from
pulmonary TB.90 Limitations of ZN smear microscopy
are low sensitivity (detection limit: 5,000-10,000 bacilli/
ml sputum, and approximately half of the estimated TB
cases worldwide are sputum smear negative) and low
specificity in areas with a high prevalence of
nontuberculosis mycobacteria since all mycobacteria are
acid fast bacilli. Moreover, in areas with high prevalence
of HIV-TB coinfection, the smear microscopy has become
less useful since the suppression of cellular immune
responses results in reduced cavity formation and thus,
greater proportion of both smear negative TB and
extrapulmonary TB.91 This has stimulated the search for
new biomarkers to replace smear microscopy.
Cultivation and drug susceptibility testing are the
gold standards of TB diagnostics, but these are limited
in many areas with a high incidence of TB due to high
costs and/or long turn around time. Numerous novel
biomarkers have been developed and evaluated, but no
test has been able to replace ZN smear microscopy. New
biomarkers of TB infection need high sensitivity and
specificity, should be easy to perform and interpret, have
low costs, provide rapid test results, and should be able
to be performed in small laboratories in resource-limited
areas. Moreover, the patient should not need to return to
the TB diagnostic centre for a test result assessment as
currently needed for TST.
TB specific and host specific biomarkers may be useful
as an adjunct to conventional tests for the diagnosis of
pulmonary TB. The promising TB specific biomarkers
malate synthase (MS) and MPT51 are most likely to be
expressed during active replication of M. tuberculosis. It
has been shown that MS and MPT51 elicit the production
of antibodies in patients at different TB stages (smear
negative TB, smear positive TB, non-cavitary TB and
cavitary TB) in both HIV positive and HIV negative
individuals.92-95 Moreover, anti-MS and anti-MPT51 have
been detected in sera from patients drawn before they
developed active TB92, but were absent in sera from
persons with negative purified protein derivative (PPD)
test, healthy PPD test positive or HIV positive, TB
negative persons, thus, demonstrating their correlation
with active TB. A recent study performed by Wanchu et
al. on 480 Indian subjects including HIV positive and HIV
negative TB patients showed that anti-MS and anti-
76

MPT51 provided high sensitivity (~80%) and specificity
(>97%) for the diagnosis of active TB, and the performance
was not compromised by concurrent HIV infection or the
site of infection.96 The antibodies were also detected in
sera from ~45% of HIV negative, smear negative TB
patients. To increase the sensitivity, the authors suggest
including one or two additional antigens together with
MS and MPT51. Thus, detection of antibodies to MS and
MPT51 may serve as biomarkers for active TB and for
incipient TB in HIV positive individuals at high risk of
developing active TB.96 Table 7.6 gives an overview of
selected TB biomarkers.
Host Specific Biomarkers

IGRAs
The diagnosis of latent TB has for many decades relied
on the TST. Limitations of the TST are as follows: Inability
to differentiate M. tuberculosis infection from BCG
vaccination or exposure to environmental mycobacteria,
low sensitivity (< 75%) particularly in immune
compromised individuals, in persons of young age and/
or with severe malnutrition97, and false negative results
that may be associated with extensive disease. 98
Moreover, the person tested has to return for test result
assessment two days after the test has been administered
which may be difficult for persons living far from TB
diagnostic centers. Efforts are being made to find a test
to replace the TST, but it is difficult without a proper
reference test for TB latency. The goal is to develop a test
for identification of persons at high risk of progression
from latency to active TB and therefore, those that would
Table 7.6: Overview of immune-based TB biomarkers
M. tuberculosis specific biomarkers-Host specific biomarkers
Antigen 85 complex (sputum)-TST
Antigen 85B RNA (sputum) IFN- release assays:
38 kDa antigen (serum) - ESAT-6
LAMCFP-10
M. tuberculosis DNA (urine) IL-4/IL-42 ratio
Malate synthaseM. tuberculosis specific antibodies:
MPT51anti-LAM
MPT64anti-38 kDa antigen
Antigen 60anti-MS
PE and PPE antigens (serum)anti-MPT51
HBHAanti-antigen 85
DosR regulonencoded M. tuberculosis antigens - antiPPE55
Volatile M. tb markers-(breath)
CFP-10Culture filtrate protein 10, ESAT-6Early-secreted
antigenic target 6 kDa protein, HBHAHeparin-binding
hemagglutinin adhesion, ILInterleukin, IFNInterferon,
LAMlipoarabinomannan, MS: Malate synthase, M. tbM.
tuberculosis, PEproline-glutamine, PPEProline-prolineglutamine, TSTTuberculin skin test.
most likely benefit from TB preventive therapy. More

precise targeting of preventive treatment is a key element
of TB control.
In 2001, Lalvani et al. developed an enzyme-linked
immunospot (ELISpot) for the detection of IFN-
producing T-cells in response to the M. tuberculosis specific
antigens ESAT-6 and CFP-10.99 ESAT-6 and CFP-10 are
encoded by the region of difference 1 (RD1), a region
of the mycobacterial genome present in all
M. tuberculosis and pathogenic M. bovis strains, but absent
in M. bovis BCG vaccine strains and most environmental
mycobacteria (with the exception of M. kansasii, M. szulgai,
M. flavescens and M. marinum).
ESAT-6 and CFP-10 elicit secretion of high IFN- levels
from T-cells pre-sensitized with M. tuberculosis100 during
early stages of TB infection. Moreover, it has been
questioned if a rise in IFN- represents bacilli replication
and thus, the IFN- level could be used as a prognostic
factor for development of active TB. Currently, two
commercially available tests for the detection of T-cell
activation by M. tuberculosis, the IFN- release assays
(IGRAs), have the potential to replace the TST; the
QuantiFERON-TB In-Tube (Cellestis Limited, Victoria,
Australia) and T-SPOT.TB (Oxford Immunotec, UK).
Meta-analysis and systematic review undertaken by
Menzies et al.101 and Pai et al.102, respectively, have shown
that IGRAs have high specificity (QuantiFERON-TB Gold:
94-100% and T-SPOT. TB: 86-100%) unaffected by previous
BCG vaccination. The specificity of TST is high in
unvaccinated persons (95-99%), but low and variable in
BCG vaccinated individuals. The sensitivities of the IGRAs
and TST were not consistent across tests and populations,
but on average the T-SPOT. TB was more sensitive than
the other tests evaluated (QuantiFERON-TB Gold 72-82%,
T-SPOT. TB 86-93% and TST 71-82%). Even though the
IGRAs show a high specificity for TB infection, they have
not proven to be able to distinguish between active and
latent TB101, and data on populations with high risk of
developing active TB, including children and immune
compromised persons, are limited. Studies have shown
that the sensitivity of IGRAs in children is reduced
compared to adults (83% vs 90%, respectively) and that
indeterminate results have been detected in patients on
immunosuppressive therapy.103 However, in a study in
South Africa where 293 children suspected to suffer from
TB were tested, it was found that the sensitivity of ELISpot
(on which T-SPOT.TB is based) was higher and less affected
by factors such as age under three years, HIV co-infection
and malnutrition, than TST.97 Other studies conclude that
the T-SPOT. TB test performs independently of HIV
associated immune suppression.104,105 The results suggest
a potential role for IGRAs in the diagnosis of M. tuberculosis
infection and disease in immune compromised individuals.
Since the IGRAs do not differentiate between latent and
active TB, the test may be useful for detection of latent TB

in contact tracing and screening of high-risk groups in lowendemic areas. The test performance will be reduced in
high-endemic areas since a large proportion of the
population is likely to be latently infected. Carrara et al.106
have used the IFN- assay (ELISpot) to monitor treatment
outcome in 18 microbiologically confirmed TB patients.
They found a fall in the T-cell responses to ESAT-6 in the
blood of all 13 active TB patients with an adequate clinical
response during anti-TB therapy (measured by the time
of diagnosis and after 3 months of anti-TB treatment), but
remained elevated in the five patients where the treatment
failed.
Similarly, studies have shown a fall in specific IFN-
production in patients recovering from TB disease.107,108
If the IGRAs correlate with mycobacterial load, the tests
could be useful biomarkers for successful anti-TB
treatment.
Nemeth et al. have recently demonstrated the ability
to distinguish latent and active TB by flowcytometric
assessment of M. tuberculosis specific IFN- producing
helper T-cells isolated from the infection focus compared
to the number of specific T-cells isolated from peripheral
blood.109 Fifteen patients diagnosed with active TB were
examined and the test showed a sensitivity of 100% and
specificity of 90%. Flowcytometric measurements can
provide the test results the same day. The study
demonstrates that the examination of T-cells from
peripheral blood alone may not be sufficient for the
detection of active TB cases. Larger prospective clinical
trials are needed to evaluate if responses assayed by IGRAs
from local infection sites have the potential to distinguish
between active and latent TB.
IL-4/IL-4
2 Ratio
It has been shown that IL-4, IL-42 and IL-13 are raised
in freshly isolated peripheral blood mononuclear cells
and in bronchoalveolar lavage cells from TB patients and
their levels correlate with the severity of disease.110,111
Wassie et al.112 have evaluated the expression of IL-4, IL42 and IFN- over time in TB patients from Ethiopia and
their contacts. They found that the IL-4/IL-42 ratio was
higher in healthy contacts than in patients, the ratio
increased after treatment, the ratio decreased in contacts
who developed symptoms, and that the ratio tended to
rise in patients with latent TB. Thus, the authors
concluded that the IL-4/IL-42 ratio was a correlate of
immunity.
77
obtain from the patient compared to induced sputum,

they are easy to perform, and test results may be available
within one day. There are three main groups of
immunological tests for the detection of pulmonary TB:
(i) detection of humoral immune responses (antibodies)
to M. tuberculosis in serum, (ii) detection of T-cell based
cellular immune responses (IFN- release assays: IGRAs)
in whole blood, and iii) detection of antigens in specimens
other than serum (e.g. lipoarabinomannan in urine).
Most tests have focused on the detection of
M. tuberculosis specific antibodies in serum, but the
specificities have been low due to the use of crude,
nonspecific antigen mixtures.113 Development of purified,
recombinant M. tuberculosis specific proteins has
increased the test proficiencies. Dozens of commercially
available serological tests for active TB are available, but
no immunological test has as yet proven accurate enough
to replace microscopy and culture.102,114,115 Recent reviews
and meta-analysis have shown that existing commercial
and in-house antibody based tests have poor accuracy
and limited clinical utility in pulmonary TB.114,115 The
Anda-TB IgG ELISA kit for the detection of antibodies to
Antigen 60 was the most frequently evaluated test in the
review and showed limited sensitivity (range, 63-85%)
and inconsistent specificity (range, 73-100%) in smear
positive TB patients.114
Commercially available antibody detection tests for
the diagnosis of extrapulmonary TB provide highly
variable estimates of sensitivity (range, 0% to 100%) and
specificity range, 59 to 100%).116 Thus, today antibody
detection tests have no role in case detection of
extrapulmonary TB116 and limited role in the detection
of pulmonary TB. Possible reasons for the low test
performances of immunological TB diagnostic tests could
be that a good TB test has to distinguish between
exposure, latency and active TB disease, as well as
distinguish between TB infection and infection caused
by NTM or by BCG vaccination. It is likely that sera from
patients in different stages of TB infection and TB disease
show antibody reactions specific to the current TB stage.
Thus, it has been recommended that panels of multiple
antigens have to be analysed to improve the test
performance.117,118 Combinations of absence or presence
of antibodies in the sera may indicate a specific infection/
disease stage.
Microbe Specific Biomarkers for TB

Antigen 85 Complex Proteins
Antigen/Antibody Based Tests

The detection of antigens, antibodies or immunecomplexes associated with M. tuberculosis is an alternative
to conventional diagnostic tests for TB. Immunological
diagnostic tests for TB are advantageous in areas with
high TB incidence, since blood and urine are easy to
The Antigen 85 (Ag85) complex proteins are major

secretory proteins produced by actively replicating
mycobacteria and include Ag85A, Ag85B, and Ag85C.
The proteins are mycolyl transferases important in the
biosynthesis of trehalose-dimycolate (cord factor) in the
final stages of the cell wall synthesis. Mycolyl-transferase
78

inhibitors inhibit the transfer and the deposition of
mycolates into the mycobacterial cell wall.119 The proteins
share high sequence homology with each other and with
Ag85 from other mycobacterial species. They induce
delayed hypersensitivity, protective immune responses,
and the production of specific antibodies in infected mice
and guinea pigs. The level of anti-Ag85 is often low in
healthy PPD-positive individuals but high in patients
with active TB.120,121 It has been shown that the median
serum Ag85 level is 50 to 150-fold higher in patients with
active TB than in healthy controls or in patients with nontuberculous pulmonary disease.122 Wallis et al. evaluated
the Ag85 complex expression in 42 patients with
pulmonary TB and found that relapse after anti-TB
treatment could be predicted by an increase in Ag85 in
sputum after two weeks of therapy.123 All subjects with
Ag85 complex values of <60 pg/ml on day 14 after the
initiation of anti-TB treatment responded rapidly to
treatment and were cured. Of those with values of > 60
pg/ml, TB persisted at or after day 90 in 33% and
treatment failed in 17%. Ag85 is not detectable in urine
since most serum Ag85 exists in complexes with plasma
fibronectin and IgG rather than in unbound form and
thus, is too big for filtration in the kidneys.
38 kDa Antigen
The 38 kDa antigen is a lipoprotein on the cell surface of
mycobacteria and functions as a phosphate transport
protein. Several kits for detection of the 38 kDa antigen
as a biomarker for M. tuberculosis infection are
commercially available. The test performance varies with
the sputum smear status of the patient, patient population
studied and disease manifes-tations.124 In sera from
patients with culture positive specimens, the sensitivity
ranged from 40 to 89% and the specificity from 44 to
100%.124 The test performance increased when the 38 kDa
antigen was combined with other antigens to detect
antibodies in TB patients. Furthermore, it has been shown
that the severity of TB disease correlates with levels of
antibodies against the 38 kDa antigen and such antibodies
are particularly found in patients with advanced TB
disease.125
Lipoarabinomannan
One of the candidate antigens for the immunological
diagnosis of TB is LAM. LAM is released from
mycobacteria into the circulation and may be detected in
serum or urine after filtration through the kidneys.
Theoretically, the titre of LAM in the urine should reflect
the bacterial load, metabolic activity and/or rate of
degradation of the bacteria, and hence permit
differentiation between individuals with active TB, latent
TB and non-infected individuals. However, there is not a
consistent relationship between the levels of LAM
detected in the urine and the bacterial load, thus, LAM

based diagnostic tests do not show a sufficient test
performance to be used as the only TB test in a field
setting.126-128 Also tests for the detection of anti-LAM
antibodies in serum have been developed, but so far no
test has shown a sufficient test performance.
Theoretically, direct antigen detection in urine would
be advantageous, especially in areas with a high incidence
of TB-HIV coinfection, because of the following: no need
for an invasive procedure for specimen collection,
independent of a well functioning immune system,
reflects more uniformly the total body bacillary burden,
and HIV infected TB patients are more often likely to have
extrapulmonary TB. The ideal test would be in a dip-stick
format where the result could be read after minutes
allowing a high sample throughput. Potential biomarkers
for the detection of TB in the urine are LAM and
mycobacterial DNA fragments. Disadvantages are low
test performance till date and the fact that the tests do
not provide information on anti-mycobacterial drug
susceptibilities.
Transrenal Mycobacterial DNA

Small extracellular DNA fragments from mycobacteria
originating in the lungs or extrapulmonary foci may be
detected in the urine collected from TB patients in the
form of 150 to 200 bp fragments.129 Metabolically active
mycobacteria promote apoptosis of the infected host cell.
Bacillary DNA released from the apoptotic cell into the
plasma is later cleared by the kidneys. Cannas et al.130
evaluated 43 pulmonary TB patients confirmed by culture
for the detection of trans-renal M. tuberculosis complex
specific fragments (IS6110 DNA) by semi-nested PCR.
M. tuberculosis complex specific sequences were found
in the urine of 34 (79%) of the 43 TB patients studied,
whereas all controls (10 patients with non-tuberculous
pulmonary diseases and 13 healthy controls) were
negative. The M. tuberculosis complex specific DNA
fragments could not be detected in the patients 2 months
after initiated anti-TB treatment. The method, although
promising, requires nested PCR and the sensitivity may
not be sufficient for M. tuberculosis strains with a low
IS6110 copy numbers.
MPT64
The secreted protein MTP64 is a 23-kDa protein which
elicits T-cell responses in individuals infected with TB.
MTP64 is specific to the members of the M. tuberculosis
complex (MTC), but absent in some strains of BCG.131 It
has been shown that MPT64 protects mice from
developing TB following M. tuberculosis H37Rv challenge
by prompting the Th1 response.132 Recently, using
immunohistochemistry, MTP64 has been used as marker
of infection with MTC in biopsies from patients suspected
with TB.133
Antigen 60
Antigen 60 (A60) is one of the most widely studied
mycobacterial antigens and is deployed in a commercially
available ELISA kit.114,124 As mentioned previously, the
sensitivity and specificity of an anti-A60 based test in
patients with pulmonary TB varies considerably.114,124 The
sensitivity is lowest in children and in patients with
extrapulmonary TB.
PE and PPE antigens

The Proline-Glutamine (PE) and Proline-ProlineGlutamine (PPE) antigens are protein families named after
the amino acid sequences located near the N-terminus in
the majority of these proteins. A protein in the PPE family,
PPE55 which is specific to the M. tuberculosis complex, is
detected in sera from guinea pigs with incipient TB after
being infected with virulent M. tuberculosis.134 In the same
study, anti-PPE55 was detected in sera from 29/30 (97%)
HIV-negative and 17/24 (71%) HIV positive TB patients.
Sera from PPD positive healthy controls were negative,
suggesting that the expression of PPE55 protein correlates
with active M. tuberculosis infection. Anti-PPE55 was
furthermore detected in sera obtained prior to
manifestation of clinical TB from 17/21 (81%) HIV positive
patients, suggesting that the protein is expressed during
incipient TB in HIV-infected persons.134
Rv3872, a PE-related protein encoded in the RD1
region (which is absent in M. bovis BCG), has shown
promising sensitivity and specificity when tested on sera
from pulmon ary (n = 240) and extra-pulmonary (n = 179)
TB patients from India and compared to healthy BCG
vaccinated controls (n = 123). The sensitivity for
pulmonary TB patients was 92.5% and for extrapulmonary TB patients 89%, the specificity was 95%.135
Further studies are required to confirm these results.
HBHA
Heparin-binding hemagglutinin adhesin (HBHA) is a
surface protein found in all MTC members and promotes
bacterial aggregation and adhesion to epithelial cells
required for the extrapulmonary spread of the microbe.71
HBHA identifies TB patients in an early stage of infection
and it has been suggested that the detection of antibody
specific to HBHA may be an alternative biomarker for
TB infection. However, a pilot study performed in Finland
showed that anti-HBHA can also be detected in healthy,
BCG vaccinated individuals.136 Thus, HBHA detection
may not discriminate TB infection from immune reactivity
caused by previous BCG vaccination.
DosR Regulon Regulated Proteins

The 48-gene dormancy survival regulon (DosR) is
believed to be associated with latency and proteins
79
encoded by this regulon are antigens with the potential

to be protective against TB. The proteins are produced
by M. tuberculosis in vitro under hypoxia and low-dose
nitric oxide exposure,137 conditions thought to mimic the
environment encountered by M. tuberculosis in vivo during
latency.138 Thus, these antigens are considered to be
characteristic of latent infection139 and have been
associated with immunity against latent M. tuberculosis
infection. Black et al.140 have tested the immunogenicity
of the DosR regulon regulated antigens, measured by
IFN-g responses of 51 DosR regulon regulated
M. tuberculosis antigens in 131 TST positive and/or ESAT6/CFP10 fusion protein positive, HIV negative healthy
household contacts of TB patients in South Africa, Gambia
and Uganda. Rv1733c was the most frequently recognized
DosR regulon regulated antigen, but also Rv1735c and
Rv1737c were frequently recognized. The results may
provide hope for the development of a rBCG vaccine with
some of the DosR regulon regulated antigens
incorporated (BCG alone fails to induce significant
responses to latency antigens) 141 that can provide
protection against progression from latency to active TB
disease.
Volatile Mycobacterial Markers in Breath

Recently, suggestions have been made to use volatile
metabolites from M. tuberculosis for the rapid diagnosis
of TB as well as for biomarkers of cure and relapse.142
The hypothesis is based on the observations that
mycobacteria and oxidative stress in patients resulting
from mycobacterial infection both produce distinctive
patterns of volatile metabolites that are liberated into the
breath. Several mycobacteria including M. tuberculosis
produce volatile metabolites that act as chemical
fingerprints, and 2 compounds specific to M. tuberculosis
and M. bovis have been identified by solid phase
microextraction and gas chromatography/mass
spectrometry:143 methyl p-anisate and methyl nicotinate.
These compounds were detectable in culture before the
visual appearance of colonies, and had characteristic
odors. Phillips et al. have studied volatile metabolites in
TB patients confirmed by culture and patients previously
suspected to be suffering from TB, but where TB had been
ruled out. The authors concluded that the volatile
biomarkers in breath were sensitive and specific for
pulmonary TB.142 Further evaluation of this approach for
TB diagnosis is underway.
New Trends in Search for Biomarkers in TB

New approaches for the identification of TB biomarkers
have been developed. The use of novel technological
platforms such as transcriptomics (analysis of gene
expression), proteomics (analysis of protein expression)
and metabolomics (analysis of small metabolites in body
80

fluids) where fishing for rather than targeted search to
identify novel biomarkers involved in TB disease,
pathogenesis and treatment response are exploited.88 The
complex nature of the immune response makes it
probable that a combination of biomarkers; a
biosignature, rather than one single biomarker will be
required for a reliable correlate of protection.88 These
biomarker studies are ongoing and show promising
results.
Vaccination and Vaccine Candidates

TB remains a major cause of morbidity and mortality
worldwide. In spite of effective anti-TB drugs and the
widespread use of BCG, TB is out of control globally. The
most effective tool for disease prevention is vaccination,
and a more effective vaccine has to be developed and
distributed before the TB epidemic can be controlled.144
BCG has been distributed to >3 billion people and is the
most commonly used vaccine in the world. By vaccination
the person is able to mount an accelerated response to
the microbe if re-exposed, by the generation of long-lived
memory T-cells. BCG provides a good protection against
miliary and severe forms of TB in infants, but the efficacy
against pulmonary TB in adults is highly variable (varies
from 0% to 80%). A meta-analysis has concluded that BCG
immunization reduces the risk of pulmonary TB in adults
by an average of 50%.145 BCG provides protection against
TB in areas with high incidence of TB for a limited time
period.146 The vaccine provides high protection against
M. tuberculosis in low-epidemic areas (For examples: UK
and North America) but reduced protection in highepidemic areas such as India and Africa.145,147,148 The
highly variable efficacy of BCG may be explained by
previous exposure to atypical mycobacteria which alters
the immune response to BCG,149 by the use of genetically
different BCG strains in different parts of the world150,
phenotypic changes in the BCG strain during passage
from original cultures and during manufacturing
processes, variability in dose, route and age at
administration, deletion of protective antigens from
BCG151, and by host variables which alter the ability of
certain population groups to respond successfully.
Immunological responses elicited by BCG vaccination
comprise a wide spectrum of T-cell phenotypes, including
unconventional T lymphocytes, since BCG contains a
number of proteins, lipids and carbohydrates. In contrast,
the response following subunit vaccination comprises
mainly helper T-cells and cytotoxic T-cells that respond
to protein antigens.
Studies have shown that BCG is ineffective in
individuals pre-exposed to atypical mycobacteria.152,153
A possible explanation is that the pre-existing
mycobacterial immune responses may cross-react with
BCG and neutralize the BCG immune responses. This may
explain why BCG fails to increase the immune response
of a previous BCG vaccination, making BCG inapplicable

as a booster vaccine.23 The variable efficacy of BCG may
indicate that vaccines derived from M. tuberculosis strains
may provide better protection than BCG154, or that more
than one vaccine may be needed to provide protection
worldwide. Also strategies for combining BCG with a
new vaccine to improve the efficacy are attractive.
Around 90% of HIV-negative individuals infected by
M. tuberculosis control the infection and will never
develop active TB. Thus, the immune system of the host
has mechanisms to control the microbe although, the host
rarely achieve eradication of M. tuberculosis. By studying
the naturally induced host responses, it maybe possible
to find potential biomarkers that indicate a protection
against TB. These biomarkers could serve as a guideline
for monitoring vaccine-induced immunity against TB,
and could provide valuable information about vaccine
efficacy prior to the clinical end-point of TB disease.
New vaccines candidates include recombinant BCG
(rBCG) or other live vaccine vectors expressing immune
dominant mycobacterial antigens, attenuated strains of
M. tuberculosis, DNA vaccines and subunit vaccines
(protein, peptide or non-peptide vaccines in adjuvants).
Table 7.7 provides an overview of some of the vaccine
candidates being evaluated in clinical trials. Currently,
at least 16 new TB vaccine candidates are under
development and the candidates are first extensively
tested in animal models before they can be tested in
humans. Factors that influence the protective efficacy in
animal models are: the species of test animals used, the
route of vaccination (respiratory, intranasal and oral), the
interval between vaccination and challenge, the route and
dose of challenge, and the interval between challenge
and termination of testing in the animal model.155 Prior
to Phase I clinical trials, preclinical evaluation of the
vaccine candidate including safety and efficacy testing
in mouse and guinea pig models, and if possible
Table 7.7: Overview of the vaccine candidates currently
being evaluated
Vaccine candidate
rBCG:
rBCGUreC:Hly+
rBCG-pfo
rBCG30
Attenuated M. tb:
lysA panCD mutant
RD1 panCD mutant
Sub-unit vaccines:
Mtb72F
Hybrid-1
Viral-vectored vaccine:
MVA expressing Ag85A
UreUrease, HlyListeriolysin, pfoPerfringolysin, lysLysine,
panpantothenic acid, MVAModified Vaccinia Ankara virus

evaluation of safety in non-human primates is required.
In animal models the vaccinated test animals are
challenged by a virulent strain of M. tuberculosis to
evaluate the degree of post-vaccine induced resistance.
Both bacteriological and immunological tests are
performed: by autopsy bacterial loads and
histopathological changes in the organs are assessed, and
immunological signs of protection are looked for, i.e.
increased IFN-, TNF-a and IL-2 production by activated
T-cells. IFN- is not the perfect biomarker to identify
protective vaccines, since IFN- alone is insufficient
for the prevention of TB disease. However, IFN- is till
date the best biomarker for protection against
M. tuberculosis. Another approach for the measurement
of the immune protection level is to assess the increased
numbers of activated helper T-cells and cytotoxic T-cells
in the lungs. If the vaccine candidate shows equal or
superior protection compared to the conventional BCG,
it may be evaluated in clinical Phase I, II, III and IV trials.
In Phase I clinical trials, the vaccine candidate is for
the first time tested in a small group (usually 10 to 25
individuals) of healthy adults volunteers, and safety and
side effects are measured. Phase II evaluates the effect of
increasing dose of the vaccine candidate on safety and
immunogenicity. Phase III evaluates the efficacy of the
vaccine, and Phase IV clinical trials are normally the large
scale surveillance of individuals who have received the
vaccine with registration of adverse effects that occur with
a low frequency. Optimal design for a Phase III efficacy
trial is a double blind, randomized, placebo controlled
trial. However, ethical norms prevent the withdrawal of
BCG vaccination in a randomized control trial of a new
TB vaccine in a TB endemic area since BCG has shown to
protect against serious childhood forms of TB. A
randomized placebo controlled trial of a vaccine
candidate to boost a previous BCG vaccination is possible
without the withdrawal of BCG.
Most TB vaccines candidates under development
today attempt to induce cellular immune responses
dominated by the IFN- secreting helper T-cells, essential
for control and elimination of intracellular microbes.
However, also IFN- secreting cytotoxic T-cells provide
protective immunity against TB especially important in
the absence of helper T-cells as in HIV infected
individuals156, and cytotoxic T-cells are important in the
control of latent TB.157 Recent studies have shown that
M. tuberculosis elicits a mixed immune response involving
both humoral and cellular immunity. 124 Vaccine
candidates consisting of a combination of subunits stimulating both humoral and cell-mediated parts of the
immune system elicit a stronger immune response than
either of the subunits alone124,158 and are probably the
best candidates. There are two potential vaccine strategies
against TB: before (pre-exposure, prophylactic) or after
(postexposure, therapeutic) exposure to the microbe.
81
Novel TB Vaccine Candidates

Live Attenuated Vaccines
(modified BCG and M. tuberculosis)
BCG was generated in the early 20th century by continual
passage of virulent M. bovis, the causative agent of bovine
TB. Live attenuated vaccines are safe, efficacious,
stimulate both humoral and cell-mediated immune
responses, and are generally more potent than nonliving
vaccines in stimulating cell-mediated immune responses.
The difficulty in live attenuated vaccines is safety; to
achieve a satisfactory level of attenuation without
severely compromising immunogenicity. The strength of
the immune response is a function of the amount of
antigens expressed. The goal is to develop an attenuated
strain able to perform a limited replication in vivo, yet
safe with the potential to induce a robust and prolonged
memory T-cell response. With the availability of the
complete genome sequence of BCG and M. tuberculosis,
it is possible to develop mutants with improved
immunogenicity.
Recombinant BCG (rBCG) expressing listeriolysin
(rBCGUreC:Hly+) is a recombinant vaccine under
development. rBCG with listeriolysin uses BCG as vector
to improve the activation of cytotoxic T-cells. Listeriolysin
is a cytolysin derived from Listeria monocytogenes that
forms pores in the membrane of the early phagosome in
macrophages.151 By secretion of listeriolysin, the early
endosomes are destroyed and BCG may leak into the
cytosol of the infected host cell. Since listeriolysin is most
active in an acidic environment and urease blocks the
acidification of early endosomes, the urease gene of BCG
(ureC) is deleted in the vaccine candidate. The presence
of BCG in the cytoplasm increases the MHC presentation
of BCG antigens to cytotoxic T-cells and induces a
cytotoxic immune response. Apoptosis releases BCG
derived antigens into the extracellular environment and
induces cellular immunity. A mouse model has shown
that the rBCGUreC:Hly+ provided better protection and
was safer than BCG in immune compromised SCID
mice.159 Phase I trials for this vaccine started in 2006. An
equivalent rBCG vaccine has been constructed to escape
from the endosome using the pH-independent
perfringolysin (rBCGpfo), instead of listeriolysine. The
vaccine candidate overexpresses immunodominant
antigens, including Ag85A, Ag85B and TB10.4, thereby
combining two ways of immune activation.
Another rBCG vaccine candidate is the rBCG30 with
the overexpression of Ag85B. Ag85B is a highly
immunogenic protein secreted by M. tuberculosis and BCG
with mycolyl-transferase activity required for
mycobacterial cell-wall synthesis. Studies have shown
that the vaccine candidate induces an increased level of
protection compared to its parental BCG strain160,161 and
there were no significant safety issues in the Phase I trial.
82

Problems associated with rBCG vaccines are the need to
demonstrate a better efficacy than BCG before moving
on to Phase I trials, and the possibility of inhibition by
prior sensitization by environmental mycobacteria.162
Live, attenuated M. tuberculosis strains are attractive,
novel vaccine candidates. They have the ability to persist
in the host for a limited time, may have a greater
protective efficacy than that of the BCG and have an
improved safety profile. An absolute criterion for
knockout mutants of M. tuberculosis as vaccine candidates
is to eliminate the possibility to mutate back to the
parental wild type genotype and thereby cause disease.
At a minimum, live attenuated M. tuberculosis vaccine
candidates used in humans should have two independent
and unlinked genomic deletions (double knockouts) as
well as proven safety in immune compromised persons.
This is particularly important in TB vaccines since TB
epidemic areas also have a high prevalence of HIV
infection. A way to evaluate safety is to test the vaccine
candidate in SCID mice.
Current multiple knock-out mutants of M. tuberculosis
include the DlysA DpanCD mutant (known as mc26020)
and the DRD1 DpanCD mutant (known as mc26030). The
panC and panD genes are involved in the pantothenic acid
synthesis and both mutants have been shown to be highly
stable and conferring significant protection in mice or
guinea pigs following aerosol challenge with virulent
M. tuberculosis equivalent to that provided by BCG
vaccination. The DlysA DpanCD mutant was completely
cleared from the organs of SCID mice within the first 5
weeks163 and > 50% of SCID mice vaccinated by the DRD1
DpanCD mutant survived for over 350 days.163 Larsen et
al. have shown that both mutants were safe and well
tolerated in monkeys, but the vaccine candidates did not
provide an efficacy superior to that of BCG164 following
a high-dose intrabronchial challenge with virulent
M. tuberculosis. Moreover, Waters et al have shown that
the DRD1 DpanCD mutant given in two weeks old calves
failed to protect them against low dose, aerosol M. bovis
challenge at 2.5 months of age. 165 In contrast, BCG
vaccinated calves had reduced TB associated pathology
as compared to nonvaccinated calves and calves
vaccinated with the mutant.165
Sub-unit Vaccines
To eliminate the risk of reactivation of attenuated whole
cell vaccines, sub-unit vaccines, consisting of one or two
defined protein antigens or recombinant protein
components delivered with powerful adjuvants, have
been developed. Most of the M. tuberculosis specific
antigens tested have been derived from bacilli culture
filtrates containing approximately 200 different proteins
produced during different stages of incubation (early
versus mid-log phase). Antigens under evaluation are the
Ag85 family, MPT32, MPT53, MPT63, MPT64, GroES,

ESAT-6, CFP-10, the19-kDa lipoprotein, Rv3407, Mtb32
and Mtb39. Single proteins have so far not shown to elicit
high enough protection, but hybrid protein vaccines,
consisting of two or more strongly immune stimulating
proteins, have shown promising results. The recombinant
fusion protein constructs Mtb72F (consists of Mtb32 and
Mtb39) and Hybrid-1 (constitute Ag85B and ESAT-6)
have shown to be protective in mice and guinea pig
models against TB.166-169 The protective effect of Hybrid1 has been shown not to be affected by previous
sensitization with environmental mycobacteria162, and
moreover, boosts the immune response provided by BCG,
with a resulting survival time doubled to over two years
in guinea pigs.166 Mtb72F and Hybrid-1 are currently being
evaluated in Phase I clinical trials.
Prime-boost vaccine strategy is a new approach in the
development of more effective TB vaccines. By boosting
the BCG effect with another antigen, the TB specific preexisting memory T-cells against antigenic epitopes shared
by both the priming and booster vaccines expands. The
booster includes viral vectors such as recombinant
adenovirus or poxvirus engineered to express
immunogenic and protective mycobacterial candidate
antigens (for example, Ag85A, Ag85B and TB10.4) or
recombinant proteins (for example, HyVac-4, Hybrid-1
and Mtb72F) delivered with adjuvants (such as AS02A,
AS01B, IC31 and LipoVac). The prime-boost approach is
of high interest since BCG has been distributed to > 3
billion people worldwide.
Viral-vectored Vaccines
Vaccines elicit the best immune responses when highly
active expression vectors are used. Plasmids with a strong
viral promoter that drives the in vivo transcription and
translation of the gene of interest are good vectors. Nonreplicating, recombinant poxviruses and adenoviruses
are able to efficiently boost a previously primed T-cell
response. Recently, the AERAS-402/Crucell Ad35 vaccine
candidate using a replication-deficient adenovirus as
vector has entered Phase IIb clinical trials in South Africa
in 2008. The vaccine includes the 3 highly immunogenic
mycobacterial antigens Ag85A, Ag85B and Tb10.4, and
is designed to boost BCG or rBCG. The AERAS-402/
Crucell Ad35 vaccine induces high levels of cellular
immunity in mice.170
A leading booster vaccine is the recombinant Modified
Vaccinia Ankara virus (MVA) that expresses Ag85A from
M. tuberculosis. Goonetilleke et al. have shown that
boosting a previous BCG primed immune response with
MVA85A induced increased levels of helper T-cells and
cytotoxic T-cells and enhanced protection in mice and
guinea pigs compared with a vaccination regimen using
either BCG or MVA85A alone.171,172 The safety and

immunogenicity of boosting a BCG vaccine with
MVA85A has been evaluated in a series of Phase 1 and
Phase 2 studies conducted in the United Kingdom,
Gambia and South Africa.173-175 MVA85A has been found
to be safe, well tolerated, and highly immunogenic. The
MVA85A vaccine candidate has entered Phase IIb clinical
trials in South Africa in 2009, where the efficacy will be
evaluated in 4-month-old BCG vaccinated infants in a
randomized, placebo controlled study design. The Phase
III trial for this vaccine is anticipated in 2012.
DNA Vaccines
DNA vaccines consist of small, circular DNA fragments
known as plasmids that have been genetically engineered
to produce one or two M. tuberculosis specific proteins.
The plasmids are injected into the host cell, following
which the host cell machinery produces the bacilli
proteins. The M. tuberculosis specific proteins are foreign
to the host and trigger an immune response. DNA
vaccine candidates have received increased attention and
many of these candidates have shown protection in
mouse models. These include both DNA vaccines
encoding native proteins, but also DNA encoding active
fusion polyproteins. DNA vaccines function well in
prime-boost strategies, can be delivered in multiple ways,
and can be codelivered with genes encoding
cytokines.171,176
In the long-term, satisfactory control of the TB
epidemic will depend on an efficacious vaccine that
prevents pulmonary TB in adults and thereby the
transmission of M. tuberculosis.177 A safe and effective
prime-boost strategy which boosts the BCG primed
immune response is probably the most realistic strategy
for future TB control. Ideally the rBCG prime would
include over-expression of important antigens from
different stages of the M. tuberculosis life cycle. The
vaccine candidate needs to prove safety in immune
compromised individuals and to protect latently infected
individuals from undergoing activation to active TB.
Little is known if the vaccine candidates of today provide
protection against activation from latency, and animal
models of latency for preclinical vaccine evaluation are
under development. Although, compared to the situation
a few years ago, the number of promising novel vaccine
candidates have rapidly expanded, there is still some way
to go before the ideal vaccine is available.
HIGHLIGHTS
M. tuberculosis, the causative agent of TB, poses a
serious threat to humans by annually infecting 9.2
million and killing 2 million people. M. tuberculosis
is an extremely well-adapted microbe which has
coexisted with humans for millennia. The microbe
has developed virulence factors and learned to
83
modulate protective host responses to ensure its own

survival and dispersal.
TB specific and host specific biomarkers may be
useful as an adjunct to conventional tests (smear
microscopy and culture in solid or liquid media) for
the diagnosis of pulmonary TB. TB biomarkers are
also useful to monitor vaccine efficacy in clinical
trials. The complex nature of the immune response
from M. tuberculosis makes it probable that a
combination of biomarkers; a biosignature, rather
than one single biomarker will be required for a
reliable correlate of protection.
BCG, the current TB vaccine, provides high
protection against M. tuberculosis in low epidemic
areas, but reduced protection in high-epidemic
areas.
The most effective tool for disease prevention is
vaccination, and a more effective vaccine has to be
developed and distributed before the TB epidemic
can be controlled. Promising novel vaccine
candidates are under development.
ACKNOWLEDGMENT
The authors thank Dr Mark Doherty for helpful
suggestions and are grateful for support from the
Research Council of Norway, NUFU and the Western
Norway Regional Health Authority.
REFERENCES
1. Global Tuberculosis Control Report. 2009. Available from
URL http:// www.who.int/tb/publications/global/
2. Cousins DV, Bastida R, Cataldi A, et al. Tuberculosis in
seals caused by a novel member of the Mycobacterium
tuberculosis complex: Mycobacterium pinnipedii sp. nov. Int
J Syst Evol Microbiol 2003; 53: 1305-14.
3. Prodinger WM, Brandsttter A, Naumann L, et al.
Characterization of Mycobacterium caprae isolates from
Europe by Mycobacterial Interspersed Repetitive Unit
Genotyping. J Clin Microbiol 2005; 43: 4984-92.
4. Enarson DA, Rouillon A. The epidemiological basis of
tuberculosis control. In: Davies PDO, ed. Clinical
tuberculosis. Chapman and Hall Medical, London,
England 1998: 35-52.
5. Vynnycky E, Fine PE. Lifetime risks, incubation period,
and serial interval of tuberculosis. Am J Epidemiol 2000;
152: 247-63.
6. Seth V, Kabra SK. Immunopathogenesis: Basic aspects
and their relevance to diagnosis in children. In: Seth V,
Kabra SK, Eds. Essentials of Tuberculosis in Children.
Jaypee Brothers Medical Publishers (3rd edn) 2006:
76-94.
7. van Lettow M, Harries AD, Kumwenda JJ, et al.
Micronutrient malnutrition and wasting in adults with
pulmonary tuberculosis with and without HIV
co-infection in Malawi. BMC infectious diseases 2004; 21:
4-61.
84

8. Macallan DC. Malnutrition in tuberculosis. Diagn
Microbiol Infect Dis 1999; 34: 153-7.
9. Kennedy N, Ramsay A, Uiso L, et al. Nutritional status
and weight gain in patients with pulmonary tuberculosis
in Tanzania. Trans R Soc Trop Med Hyg 1996; 90: 162-6.
10. Karyadi E, Schultink W, Nelwan RH, et al. Poor
micronutrient status of active pulmonary tuberculosis
patients in Indonesia. J Nutr 2000; 130: 2953-8.
11. Mathur ML. Role of vitamin A supplementation in the
treatment of tuberculosis. The National Medical Journal
of India 2007; 20: 16-21.
12. Karyadi E, West CE, Schultink W, et al. A double-blind,
placebo-controlled study of vitamin A and zinc
supplementation in persons with tuberculosis in
Indonesia: effects on clinical response and nutritional
status. Am J Clin Nutr 2002; 75: 720-7.
13. Range N, Andersen AB, Magnussen P, et al. The effect of
micronutrient supplementation on treatment outcome in
patients with pulmonary tuberculosis: a randomized
controlled trial in Mwanza, Tanzania. Trop Med Int
Health 2005; 10: 826-32.
14. Abbas AK, Lichtman AH, Pillai S. Properties and
overview of immune responses. In: Abbas AK, Lichtman
AH, Pillai S. Cellular and molecular immunology, 6th
edition. Saunders Elsevier, Philadelphia, PA, USA, 2007c.
15. Parkin J, Cohen B. An overview of the immune system.
Lancet 2001; 357: 1777-89.
16. Abebe F, Bjune G. The protective role of antibody
responses during Mycobacterium tuberculosis infection.
Clin Experim Immunol 2009; 157: 235-43.
17. Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev
Immunol 2001; 19: 93-129.
18. Kursar M, Koch M, Mittrucker HW, et al. Cutting edge:
regulatory T-cells prevent efficient clearance of
Mycobacterium tuberculosis. J Immunol 2007; 178: 2661-5.
19. Baena A, Porcelli SA. Evasion and subversion of antigen
presentation by Mycobacterium tuberculosis. Tissue
Antigens 2009; 74: 189-204.
20. Ehrt S, Schnappinger D. Mycobacterial survival strategies
in the phagosome: defence against host stresses. Cell
Microbiol 2009; 11: 1170-8.
21. Cooper AM. Cell-mediated immune responses in
tuberculosis. Annu Rev Immunol 2009; 27: 393-422.
22. Kumararatne DS. Tuberculosis and immunodeficiency of
mice and men. Clin Exp Immunol 1997; 107: 11-4.
23. Dietrich J, Doherty TM. Interaction of Mycobacterium
tuberculosis with the host: consequences for vaccine
development. APMIS 2009; 117: 440-57.
24. Woodworth JS, Fortune SM, Behar SM. Bacterial protein
secretion is required for priming of CD81 T-cells specific
for the Mycobacterium tuberculosis antigen CFP10. Infect
Immun 2008; 76: 4199-205.
25. Kaul D, Anand PK, Verma I. Cholesterol-sensor initiates
M. tuberculosis entry into human macrophages. Mol Cell
Biochem 2004; 258: 219-22.
26. Ferrari G, Langen H, Naito M, et al. Coat protein on
phagosomes involved in the intracellular survival of
mycobacteria. Cell 1999; 97: 435-47.
27. Schuller S, Neefjes J, Ottenhoff T, et al. Coronin is

involved in the uptake of Mycobacterium bovis BCG in
human macrophages but not in phagosome maintenance.
Cell Microbiol 2001; 3: 785.
28. Mellman I, Fuchs R, Helenius A. Acidification of the
endocytic and exocytic pathways. Annu Rev Biochem
1986; 55: 663-70.
29. Crowle AJ, Dahl R, Ross E, et al. Evidence that vesicle
containing living, virulent Mycobacterium tuberculosis or
Mycobacterium avium in cultured human macrophages are
not acidic. Infect Immun 1991; 59: 1823-31.
30. Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, et
al. Lack of acidification in mycobacterium phagosomes
produced by exclusion of vesicular proton-ATPase.
Science 1994; 263: 678-81.
31. Connolly SF, Kusner DJ. The regulation of dendritic cell
function by calcium-signaling and its inhibition by
microbial pathogens. Immunol Res 2007; 39: 115-27.
32. Vergne I, Chua J, Lee HH, et al. Mechanism of
phagolysosome biogenesis block by viable Mycobacterium
tuberculosis. Proc Natl Acad Sci USA 2005;102:4033-8.
33. Gordon A, DArcy Hart P, Young MR. Ammonia inhibits
phagosome-lysosome fusion in macrophages. Nature
1980; 286: 79-81.
34. DArcy Hart P, Young MR, Jordan MM, et al. Chemical
inhibitors of phagosome-lysosome fusion in cultured
macrophages also inhibit saltatory lysosomal movements.
A combined microscopic and computer study. J Exp Med
1983; 158: 477-92.
35. Via LE, Deretic DE, Ulmer RJ, et al. Arrest of
mycobacterial phagosome maturation is caused by a
block in vesicle fusion between stages controlled by rab5
and rab7. J Biol Chem 1997; 272: 1326-31.
36. Stenger S, Modlin RL. Control of Mycobacterium tuberculosis
through mammalian toll-likereceptors. Curr Opin Immunol
2002; 14: 452-7.
37. Takeda K, Takeuchi O, Akira S. Recognition of
lipopeptides by Toll-like receptors. J Endotoxin Res 2002;
8: 459-63.
38. Pathak SK, Basu S, Basu KK, et al. Direct extra-cellular
interaction between the early secreted antigen ESAT-6 of
Mycobacterium tuberculosis and TLR2 inhibits TLR
signalling in macrophages. Nat Immunol 2007; 8: 610-8.
39. Manca C, Reed MB, Freeman S, et al. Differential
monocyte activation underlies strainspecific
Mycobacterium tuberculosis pathogenesis. Infect Immun
2004; 72: 5511-4.
40. Reed MB, Domenech P, Manca C, et al. A glycolipid of
hypervirulent tuberculosis strains that inhibits the innate
immune response. Nature 2004; 431: 84-7.
41. Chan J, Fan X, Hunter SW, et al. Lipoarabino-mannan, a
possible virulence factor involved in persistence
Mycobacterium tuberculosis within macrophages. Infect
Immun 1991; 59:1755-61.
42. Briken V, Porcelli SA, Besra GS, et al. Mycobacterial
lipoarabinomannan and related lipoglycans: from
biogenesis to modulation of the immune response. Mol
Microbiol 2004;53:391-403.

43. Moreno C, Taverne J, Mehlert A, et al. Lipoarabinomannan
from Mycobacterium tuberculosis induces the production of
tumor necrosis factor from human and murine
macrophages. Clin Exp Immunol 1989;76:240-5.
44. Winslow GM, Cooper A, Reiley W, et al. Early T-cell
responses in tuberculosis immunity. Immunol Rev
2008;225:284-99.
45. Cooper AM, Khader SA. The role of cytokines in the
initiation, expansion, and control of cellular immunity to
tuberculosis. Immunolog Reviews 2008;226:191-204.
46. Wolf AJ, Linas B, Trevejo-Nunez GJ, et al. Mycobacterium
tuberculosis infects dendritic cells with high frequency and
impairs their function in vivo. J Immunol 2007;179:250919.
47. Anderson JM, Miller KM. Biomaterial biocompatibility
and the macrophages. Biomaterials 1985;5:5-10.
48. Crowle A, Ross EJ, May MH. Inhibition by 1,25(OH)2vitamin D3 of the multiplication of virulent tubercle bacilli
in cultured human macrophages. Infect Immun
1987;55:2945-50.
49. Rockett K, Brookes R, Udalova I, et al. 1,25Dihydroxyvitamin D3 induces nitric oxide synthase and
suppresses growth of Mycob-acterium tuberculosis in a
human macrophage-like cell line. Infect Immun
1998;66:5314-21.
50. Rook GAW. The role of vitamin D in tuber-culosis. Am
Rev Respir Dis 1988;138:768-70.
51. Ding AH, Nathan C, Stuehr D. Release of reactive nitrogen
intermediates and reactive oxygen intermediates from
mouse peritoneal macrophages. J Immunol 1988;141:240712.
52. Abbas AK, Lichtman AH, Pillai S. Cells and tissues of
the adaptive immune system. In: Abbas AK, Lichtman
AH, Pillai S. Cellular and molecular immunology, 6th
edition. Saunders Elsevier, Philadelphia, PA, USA, 2007a.
53. Cooper AM, Dalton DK, Stewart TA, et al. Disseminated
tuberculosis in interferon- genedisrupted mice. J Exp Med
1993;178:2243-7.
54. Schroder K, Hertzog PJ, Ravasi T, et al. Interferon-gamma:
an overview of signals, mechanisms and functions. J
Leukoc Biol 2004;75:163-89.
55. Dorman SE, Picard C, Lammas D, et al. Clinical features
of dominant and recessive interferon gamma receptor 1
deficiencies. Lancet 2004;364:2113-21.
56. Fernando SL, Britton WJ. Genetic susceptibility to
mycobacterial disease in humans. Immunol Cell Biol
2006:84:125-37.
57. Newport MJ, Huxley CM, Huston S, et al. Mutation in
the interferon-gamma-receptor gene and susceptibility to
mycobacterial infection. N Engl J Med 1996;335:1941-9.
58. Khader SA, Bell GK, Pearl JE, et al. IL-23 and IL-17 in the
establishment of protective pulmonary CD4+ T-cell
responses after vaccination and during Mycobacterium
tuberculosis challenge. Nature Immunol 2007;8:369-77.
59. Ouyang W, Kolls JK, Zheng Y. The biological functions
of T helper 17 cell effector cytokines in inflammation.
Immunity 2008;28:454-67.
60. Soroosh P, Doherty TA. Th9 and allergic disease.
Immunology 2009;127:450-8.
85
61. Longphre M, Li D, Gallup M, et al. Allergen-induced IL9 directly stimulates mucin transcription in respiratory
epithelial cells. J Clin Invest 1999;104:1375-82.
62. Kagi D, Vignaux F, Ledermann B, et al. Fas and perforin
pathways as major mechanisms of T-cell-mediated
cytotoxicity. Science 1994;265:528.
63. Vincent MS, Gumperz JE, Brenner MB. Understanding
the function of CD1-restricted T-cells. Nature Immunol
2003;4:517-23.
64. Kaufmann SH. How can immunology contribute to the
control of tuberculosis? Nat Rev Immunol 2001;1:20-30.
65. Abbas AK, Lichtman AH, Pillai S. Immunological
tolerance. In: Abbas AK, Lichtman AH, Pillai S. Cellular
and molecular immunology, 6th edition. Saunders
Elsevier, Philadelphia, PA, USA, 2007b.
66. van Crevel R, Ottenhoff THM, van der Meer JWM. Innate
immunity to Mycobacterium tuberculosis. Clin Microbiol
Reviews 2002;15:294-309.
67. OGarra A, Vieira PL, Vieira P, et al. IL-10-producing and
naturally occurring CD4+ Tregs: limiting collateral
damage. J Clin Invest 2004;114:1372-8.
68. Brown RM, Cruz O, Brennan M, et al. Lipoarabinomannanreactive human secretory immunoglobulin response
induced by mucosal bacilli CalmetteGuerin vaccination.
J Infect Dis 2003;187:513-7.
69. de Valliere S, Abate G, Blazevic A, et al. Enhancement of
cell-mediated immunity by antimycobacterial antibodies.
Infect Immun 2005;73:6711-20.
70. Chambers MA, Gavier-Widen D, Hewinson RG.
Antibody bound to the surface antigen MPB83 of
Mycobacterium bovis enhances survival against high dose
and low dose challenge. FEMS Immunol Med Microbiol
2004; 41:93-100.
71. Pethe K, Alonso S, Biet F, et al. The heparin-binding
hemagglutinin of M. tuberculosis is required for
extrapulmonary dissemination. Nature 2001;412:190-4.
72. Guirado E, Amat I, Gil O, et al. Passive serum therapy with
polyclonal antibodies against Mycobacterium tuberculosis
protects against post-chemotherapy relapse of tuberculosis
infection in SCID mice. Microbes Infect 2006;8:1252-9.
73. Voldermeier HM, Venkataprasad N, Harris DP, et al.
Increase in tuberculous infection in organs of B-celldeficient mice. Clin Exp Immunol 1996;106:312-6.
74. Dorman SE, Holland SM. Interferon-gamma and
interleukin 12 pathway defects and human disease.
Cytokine Growth Factor Rev 2000;11:321-33.
75. Hirsch CS, Toossi Z, Othieno C, et al. Depressed T-cell
interferon-gamma responses in pulmonary tuberculosis:
analysis of underlying mechanisms and modulation with
therapy. J Infect Dis 1999;180:2069-73.
76. Flynn JL, Chan J, Triebold KJ, et al. An essential role for
interferon- in resistance to Mycobacterium tuberculosis
infection. J Exp Med 1993;178:2249-54.
77. Ottenhof TH, Kumararatne D, Casanova JL. Novel human
immunodeficiencies reveal the essential role of type-1
cytokines in immunity to intracellular bacteria. Immunol
Today 1998;19:491-4.
78. Cruz A. Khader SA, Torrado E, et al. IFN- regulates the
induction and expansion of IL-17-producing CD4 T-cells
86
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
during mycobacterial infection1. J Immunol 2006;177:

1416-20.
Rook GAW, Hernandez-Pando R, Dheda K, et al. IL-4 in
tuberculosis: implications for vaccine design. Trends
Immunol 2004;25:483-8.
de Jong R, Altare F, Haagen IA, et al. Severe mycobacterial
and Salmonella infections in interleukin-12 receptordeficient patients. Science 1998;280:1435-8.
Bocchino M, Galati D, Sanduzzi A, et al. Role of
mycobacteria-induced monocyte/macrophage apoptosis
in the pathogenesis of human tuberculosis. Int J Tuberc Lung
Dis 2005;9:375-83.
Budak F, Uzaslan EK, Cangur S, et al. Increased pleural
soluble Fas ligand (sFasL) levels in tuberculosis pleurisy
and its relation with T-helper type 1 cytokines. Lung
2008;186:337-43.
Gan H, Lee J, Ren F, et al. Mycobacterium tuberculosis blocks
crosslinking of annexin-1 and apoptotic envelope
formation on infected macrophages to maintain virulence.
Nat Immunol 2008;9:1189-97.
Mustafa T, Mogga SJ, Mfinanga SG, et al. Significance of
Fas and Fas ligand in tuberculous lymphadenitis.
Immunology 2005;114:255-62.
Dunlap NE, Bass J, Fujiwara P, et al. Diagnostic standards
and classification of tuberculosis in adults and children.
Am J Respir Crit Care Med 2000;161:1376-95.
Gonzalez-Juarrero M, Turner OC, Turner J, et al. Temporal
and spatial arrangement of lymphocytes within lung
granulomas induced by aerosol infection with
Mycobacterium tuberculosis. Infect Immun 2001;69:1722-8.
Balasubramanian R, Sivasubramanian S, Vijayan VK, et
al. Five year results of a 3-month and two 5-month
regimens for the treatment of sputum-positive pulmonary
tuberculosis in south India. Tubercle 1990; 71:253-8.
World Health Organization 2008b. Joint TDR/EC expert
consultation on biomarkers in tuberculosis, Geneva: WHO
2008.
Atkinson AJ, Atkinosn AJ, DeGruttola WA, et al.
Biomarkers and surrogate endpoints: preferred
definitions and conceptual framework. Clin Pharmacol
Ther 2001;69: 89-95.
World Health Organization 2003. Treatment of TB:
guidelines for national programmes. 3rd ed. Geneva: WHO
2003.
Perkins MD, Cunningham J. Facing the crisis: improving
the diagnosis of tuberculosis in the HIV era. J Infect Dis
2007;196:S15-S27.
Achkar JM, Dong Y, Holzman RS, et al. Mycobacterium
tuberculosis malate synthase- and MPT51-based
serodiagnostic assay as an adjunct to rapid identification
of pulmonary tuberculosis. Clin Vaccine Immunol
2006;13:1291-3.
Samanich K, Belisle JT, Laal S. Homogeneity of antibody
responses in tuberculosis patients. Infect Immun
2001;69:4600-09.
Singh KK, Dong Y, Hinds L, et al. Combined use of serum
and urinary antibody for diagnosis of tuberculosis. J Infect
Dis 2003;188:371-7.
Singh KK, Dong Y, Belisle JT, et al. Antigens of
Mycobacterium tuberculosis recognized by antibodies
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
during incipient, subclinical tuberculosis. Clin Diagn Lab

Immunol 2005a;12:354-8.
Wanchu A, Dong Y, Sethi S, et al. Biomarkers for clinical
and incipient tuberculosis: performance in a TB-endemic
country. PLoS One 2008;3:e2071.
Liebeschuetz S, Bamber S, Ewer K, et al. Diagnosis of
tuberculosis in South African children with a T-cell-based
assay: a prospective cohort study. Lancet 2004;364:
2196-03.
Huebner RE, Schein MF, Bass Jr LB. The tuberculin skin
test. Clin Infect Dis 1993;17:968-75.
Lalvani A, Pathan AA, McShane H, et al. Rapid detection
of Mycobacterium tuberculosis infection by enumeration
of antigen-specific T-cells. Am J Respir Crit Care Med
2001b;163:824-8.
Andersen P, Andersen AB, Sorensen AL, et al. Recall of
long-lived immunity to Mycobacterium tuberculosis
infection in mice. J Immunol 1995;154:3359-72.
Menzies D, Pai M, Comstock G. Meta-analysis: new tests
for the diagnosis of latent tuberculosis infection: areas of
uncertainty and recomm-endations for research. Ann
Intern Med 2007;146:340-54.
Pai M, Zwerling A, Menzies D. Systemic review: T-cellbased assay for the diagnosis of latent tuberculosis
infection: an update. Ann Intern Med 2008;149:177-84.
Ferrara G, Losi M, Meacci M, et al. Routine hospital use
of a new commercial whole blood interferon- assay for
the diagnosis of tuberculosis infection. Am J Respir Crit
Care Med 2005;172:631-5.
Dheda K, Lalvani A, Miller RF, et al. Performance of a Tcell-based diagnostic test for tuberculosis infection in
HIV-infected individuals is independent of CD4 cell
count. AIDS 2005;19:2038-41.
Lawn SD, Bangani N, Vogt M, et al. Utility of interferongamma ELISPOT assay responses in highly tuberculosisexposed patients with advanced HIV infection in South
Africa. BMC Infect Dis 2007;7:99.
Carrara S, Vincenti D, Petrosillo N, et al. Use of a T-cellbased assay for monitoring efficacy of anti-tuberculosis
therapy. Clin Infect Dis 2004;38:754-6.
Lalvani A, Nagvenkar P, Udwadia Z, et al. Enumeration
of T-cells specific for RD1-encoded antigens suggests a
high prevalence of latent Mycobacterium tuberculosis
infection in healthy urban Indians. J Infect Dis
2001a;183:469-77.
Pathan AA, Wilkinson KA, Klenerman P, et al. Direct ex
vivo analysis of antigen-specific IFN-gsecreting CD4 Tcells in Mycobacterium tuberculosisinfected individuals:
association with clinical disease state and effect of
treatment. J Immunol 2001;167:5217-25.
Nemeth J, Winkler HM, Zwick RH, et al. Recruitment of
Mycobacterium tuberculosis specific CD4+T-cells to the site
of infection for diagnosis of active tuberculosis. J Intern
Med 2009;265:163-8.
Fletcher HA, Owiafe P, Jeffries D, et al. Increased
expression of mRNA encoding interleukin (IL)-4 and its
splice variant IL-4delta2 in cells from contacts of
Mycobacterium tuberculosis, in the absence of in vitro
stimulation. Immunology 2004;112:669-73.

111. Seah GT, Scott GM, Rook GA. Type 2 cytokine gene
activation and its relationship to extent of disease in
patients with tuberculosis. J Infect Dis 2000;181:385-9.
112. Wassie L, Demissie A, Aseffa A, et al. Ex vivo cytokine
mRNA levels correlate with changing clinical status of
ethiopian TB patients and their contacts over time. PLoS
ONE 2008;3:e1522.
113. Pai M, Kalantri S, Dheda K. New tools and emerging
technologies for the diagnosis of tuberculosis: Part II.
Active tuberculosis and drug resistance. Expert Rev Mol
Diagn 2006;6:423-32.
114. Steingart KR, Henry M, Laal S, et al. Commercial
serological antibody detection tests for the diagnosis of
pulmonary tuberculosis. PLoS Med 2007b;4:e202.
115. Steingart KR, Dendukuri N, Henry M, et al. Performance
of purified antigens for serodiagnosis of pulmonary
tuberculosis: a metaanalysis. Clin Vaccine Immunol 2009;
16:260-76.
116. Steingart KR, Henry M, Laal S, et al. A systematic review
of commercial serological antibody detection tests for the
diagnosis of extrapulmonary tuberculosis. Postgrad Med
J 2007a;83:705-12.
117. Davidow A, Kanaujia GV, Shi L, et al. Antibody profiles
characteristic of Mycobacterium tuberculosis infection state.
Infect Immun 2005;73:6846-51.
118. Gennaro ML. Serologic tests for TB: is there hope? Int J
Tuberc Lung Dis 2005;9:18.
119. Belisle JT, Vissa VD, Sievert T, et al. Role of the major
antigen of Mycobacterium tuberculosis in cell wall
biogenesis. Science 1997;276:1420-2.
120. Havlir DV, Wallis RS, Boom WH, et al. Human immune
response to Mycobacterium tuberculosis antigens. Infect
Immun 1991;59:665-70.
121. Turneer M, Van Vooren JP, De Bruyn J, et al. Humoral
immune response in human tuberculosis: immunoglobulins
G, A, and M directed against the purified P32 protein antigen
of Mycobacterium bovis bacillus Calmette-Gurin. J Clin
Microbiol 1988;26:1714-9.
122. Bentley-Hibbert SI, Quan X, Newman T, et al.
Pathophysiology of antigen 85 in patients with active
tuberculosis: antigen 85 circulates as complexes with
fibronectin and immu-noglobulin. G Infect Immun
1999;67:581-8.
123. Wallis RS, Perkins M, Phillips M, et al. Induction of the
antigen 85 complex of M. tuberculosis in sputum: a
determinant of outcome in pulmonary tuberculosis. J
Infect Dis 1998, 178:1115-21.
124. Abebe F, Holm-Hansen C, Wiker HG, et al. Progress in
serodiagnosis of Mycobacterium tuberculosis infection.
Scand J Immunol 2007;66:176-91.
125. Sartain MJ, Slayden RA, Singh KK, et al. Disease state
differentiation and identification of tuberculosis
biomarkers via native antigen profiling. Mol Cel
Proteomics 2006;5:2102-13.
126. Boehme C, Molokova E, Minja F, et al. Detection of
mycobacterial lipoarabinomannan with an antigencapture ELISA in unprocessed urine of Tanzanian patients
with suspected tuber-culosis. Trans R Soc Trop Med Hyg
2005;99: 893-900.
87
127. Tessema TA, Hamasur B, Bjune G, et al. Diagnostic

evaluation of urinary lipoarabin-omannan at an Ethiopian
tuberculosis centre. Scand J Infect Dis 2001;33:279-84.
128. Tessema TA, Bjune G, Assefa G, et al. Clinical and
radiological features in relation to urinary excretion of
lipoarabinomannan in Ethiopian tuberculosis patients.
Scand J Infect Dis 2002;34:167-71.
129. Umansky SR, Tomei LD. Transrenal DNA testing:
progress and perspectives. Expert Rev Mol Diagn
2006;6:153-63.
130. Cannas A, Goletti D, Girardi E, et al. Mycobacterium
tuberculosis DNA detection in soluble fraction of urine
from pulmonary tuberculosis patients. Int J Tuberc Lung
Dis 2008;12:146-51.
131. Harboe M, Nagai S, Patarroyo E, et al. Properties of
proteins MPB64, MPB70, and MPB80 of Mycobacterium
bovis BCG. Infect Immun 1986;52:293-302.
132. Luo XD, Zhu DY, Chen Q, et al. A study of the protective
effect of the DNA vaccine encoding tubercle antigen 85B
with MPT64 in mice challenged with Mycobacterium
tuberculosis. Chin J Tuberc Respir Dis 2004;27:611-6.
133. Mustafa T, Wiker HG, Mfinanga SG, et al. Immunohistochemistry using a Mycobacterium tuberculosis complex
specific antibody for improved diagnosis of tuberculous
lymph-adenitis. Mod Pathol 2006;19:1606-14.
134. Singh KK, Dong Y, Patibandla SA, et al. Immunogenicity
of the Mycobacterium tuberculosisPPE55 (Rv3347c) protein
during incipient and clinical tuberculosis. Infect Immun
2005b;73:5004-14.
135. Mukherjee P, Dutta M, Datta P, et al. The RD1-encoded
antigen Rv3872 of Mycobacterium tuberculosis as a potential
candidate for serodiagnosis of tuberculosis. Clin
Microbiol Infect 2007;13:146-52.
136. Savolainen L, Pusa L, Kim HJ, et al. Pilot study of
diagnostic potential of the Mycobacterium tuberculosis
recombinant HBHA protein in a vaccinated population
in Finland. PLoS ONE 2008;3(9):e3272.
137. Voskuil MI, Schnappinger D, Visconti KC, et al. Inhibition
of respiration by nitric oxide induces a Mycobacterium
tuberculosis dormancy program. J Exp Med 2003;198:
705-13.
138. Shi L, Jung YJ, Tyagi S, et al. Expression of Th1-mediated
immunity in mouse lungs induces a Mycobacterium
tuberculosis transcription pattern characteristic of
nonreplicating persistence. Proc Natl Acad Sci USA
2003;100:241-6.
139. Boshoff HI, Barry CE. Tuberculosis - metabolism and
respiration in the absence of growth. Nat Rev Microbiol
2005;3:70-80.
140. Black GF, Thiel BA, Ota MA, et al. Immunogenicity of
novel DosR regulon-encoded candidate antigens of
Mycobacterium tuberculosis in three high-burden
populations in Africa. Clin Vaccine Immunol
2009;16:1203-12.
141. Lin MY, Geluk A, Smith SG, et al. Lack of immune
responses to Mycobacterium tuberculosis DosR regulon
proteins following Mycobacterium bovis BCG vaccination.
Infect Immun 2007;75:3523-30.
88

142. Phillips M, Cataneo R, Condos R, et al. Volatile
biomarkers of pulmonary tuberculosis in the breath.
Tubercul 2007;87:44-52.
143. Syhre M, Chambers ST. The scent of Mycobacterium
tuberculosis. Tuberculosis 2008; 88:317-23.
144. Bishai DM, Mercer D. Modelling the economic benefits
of better TB vaccines. Int J Tuberc Lung Dis 2001;
5:984-93.
145. Brewer TF. Preventing tuberculosis with bacillus
CalmetteGuerin vaccine: a meta-analysis of the
literature. Clin Infect Dis 2000;31:64-7.
146. Andersen P, Doherty TM. The success and failure of BCG:
implications for a novel tuberculosis vaccine. Nat Rev
Microbiol 2005;3:656-62.
147. Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG
vaccine in the prevention of tuberculosis. JAMA 1994;
271:698702.
148. Roche PW, Triccas JA, Winter N. BCG vaccination against
tuberculosis: past disappointments and future hopes.
Trends Microbiol 1995;3:397-401.
149. Smith D, Wiegeshaus E, Balasubramanian V. An analysis
of some hypotheses related to the Chingelput bacille
Calmette-Guerin trial. Clin Infect Dis 2000;31:77-80.
150. Behr MA. Correlation between BCG genomics and
protective efficacy. Tuberculosis 2001; 81:165-8.
151. Skeiky YA, Sadoff JC. Advances in tuberculosis vaccine
strategies. Nat Rev Microbiol 2006;4:469-76.
152. Leung CC, Tam CM, Chan SL, et al. Efficacy of the BCG
revaccination programme in a cohort given BCG
vaccination at birth in Hong Kong. Int J Tuberc Lung Dis
2001;5:717-23.
153. Rodrigues LC, Pereira SM, Cunha SS, et al. Effect of BCG
revaccination on incidence of tuberculosis in school-aged
children in Brazil: the BCG-REVAC cluster-randomised
trial. Lancet 2005;366:1290-5.
154. Sambandamurthy VK, Jacobs Jr WR. Live attenuated
mutants of Mycobacterium tuberculosis as candidate
vaccines against tuberculosis, Microbes Infect 2005b; 7:
95561.
155. Orme IM. Current progress in tuberculosis vaccine
development. Vaccine 2005;23:21058.
156. Derrick SC, Repique C, Snoy P, et al. Immunization with
a DNA vaccine cocktail protects mice lacking CD4 cells
against an aerogenic infection with Mycobacterium
tuberculosis. Infect Immun 2004;72:1685-92.
157. van Pinxteren LAH, Cassidy JP, Smedegaard BHC, et al.
Control of latent Mycobacterium tuberculosis infection is
dependent on CD8 T-cells. Eur J Immunol 2000;30:368998.
158. Garg SK, Tiwari RP, Tiwari D, et al. Diagnosis of
tuberculosis: available technologies, limitations, and
possibilities. J Clin Lab Anal 2003;17:155-63.
159. Grode L, Seiler P, Baumann S, et al. Increased vaccine
efficacy against tuberculosis of recombinant
Mycobacterium bovis bacille Calmette-Gurin mutants that
secrete listeriolysin. J Clin Invest 2005;115:2472-9.
160. Horwitz MA, Harth G, Dillon BJ, et al. Recombinant
bacillus Calmette-Gurin (BCG) vaccines expressing the
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
Mycobacterium tuberculosis 30-kDa major secretory

protein induce greater protective immunity against
tuberculosis than conventional BCG vaccines in a highly
susceptible animal model. Proc Natl Acad Sci USA
2000;97:13853-8.
Horwitz MA, Harth G. A new vaccine against
tuberculosis affords greater survival after challenge than
the current vaccine in the guinea pig model of pulmonary
Brandt L, Cunha JF, Olsen AW, et al. Failure of the
Mycobacterium bovis BCG vaccine: some species of
environmental mycobacteria block multiplication of BCG
and induction of protective immunity to tuberculosis.
Infect Immun 2002;70:672-8.
Sambandamurthy VK, Derrick SC, Jalapathy KV, et al.
Long-term protection against tuberculosis following
vaccination with a severely attenuated double lysine and
pantothenate auxotroph of Mycobacterium tuberculosis.
Infect Immun 2005a;73:1196-1203.
Larsen MH, Biermann K, Chen B, et al. Efficacy and safety
of live attenuated persistent and rapidly cleared
Mycobacterium tuberculosis vaccine candidates in nonhuman primates. Vaccine 2009;27:4709-17.
Waters WR, Palmer MV, Nonnecke BJ, et al. Failure of a
Mycobacterium tuberculosis RD1 panCD double
deletion mutant in a neonatal calf aerosol M. bovis
challenge model: comparisons to responses elicited by
M. bovis bacille Calmette-Gurin. Vaccine 2007;25:
7832-40.
Brandt L, Skeiky YAW, Alderson MR, et al. The protective
effect of the Mycobacterium bovis BCG vaccine is increased
by co-administration with the Mycobacterium tuberculosis 72kilodalton fusion polyprotein Mtb72F in M. tuberculosisinfected guinea pigs. Infect Immun 2004;72:6622-32.
Olsen AW, Hansen PR, Holm A, et al. Efficient protection
against Mycobacterium tuberculosis by vaccination with a
single subdominant epitope from the ESAT-6 antigen. Eur
J Immunol 2000;30:1724-32.
Olsen AW, Williams A, Okkels LM, et al. Protective effect
of a tuberculosis subunit vaccine based on a fusion of
antigen 85B and ESAT-6 in the aerosol guinea pig model.
Infect Immun 2004;72:6148-50.
Skeiky YA, Alderson MR, Ovendale PJ, et al. Differential
immune responses and protective efficacy induced by
components of a tuberculosis polyprotein vaccine,
Mtb72F, delivered as naked DNA or recombinant protein.
J Immunol 2004;172:7618-28.
Radosevic K, Wieland CW, Rodriguez A, et al. Protective
immune responses to a recombinant adenovirus type 35
tuberculosis vaccine in two mouse strains: CD4 and CD8
Tcell epitope mapping and role of gamma interferon.
Infect Immun 2007;75:4105-15.
Goonetilleke NP, McShane H, Hannan CM, et al.
Enhanced immunogenicity and protective efficacy against
Mycobacterium tuberculosis of bacille Calmette-Guerin
vaccine using mucosal administration and boosting with
a recombinant modified vaccinia virus Ankara. J Immunol
2003;171:1602-9.

172. Williams A, Goonetilleke NP, McShane H, et al. Boosting
with poxviruses enhances Mycobacterium bovis BCG efficacy
against tuberculosis in guinea pigs. Infect Immun
2005;73:3814-6.
173. Hawkridge T, Scriba TJ, Gelderbloem S, et al. Safety and
immunogenicity of a new tuberculosis vaccine, MVA85A,
in healthy adults in South Africa. J Infect Dis 2008;198:
544-52.
174. Ibanga HB, Brookes RH, Hill PC, et al. Early clinical trials
with a new tuberculosis vaccine, MVA85A, in
tuberculosis-endemic ountries: issues in study design.
Lancet Infect Dis 2006;6:522-8.
89
175. McShane H, Pathan AA, Sander CR, et al. Boosting BCG

with VA85A: the first candidate subunit vaccine for
tuberculosis in linical trials. Tuberculosis 2005;85: 47-52.
176. Kamath AT, Hanke T, Briscoe H, et al. Co-immunization
with DNA accines expressing granulocyte-macrophage
colony-stimulating actor and mycobacterial secreted
proteins enhances T-cell immunity, but not protective
efficacy against Mycobacterium tuberculosis. Immunology
1999;96:5116.
177. Kaufmann SHE, Parida SK. Tuberculosis in Africa:
learning from pathogenesis for biomarker identification.
Cell Host Microbe 2008;4:219-28.
Clinicoimmunological Profile
Vimlesh Seth
INTRODUCTION
Clinical, morphological and immunological studies of
human tuberculosis have demonstrated the existence
of a spectrum of immune response in tuberculosis. At
one extreme, the infection is subclinical and merely
leads to tuberculin hypersensitivity and at the other
extreme is a progressive disseminated disease of the
nature of miliary and meningeal tuberculosis. The
presence of an immune spectrum in tuberculosis was
first suggested by Skinsness in 1968.1
An immune spectrum with two polar forms, reactive
and unreactive tuberculosis (RR and UU) was described
by Lenzini way back in 1977.2 The reactive form (RR) is
characterized by localized lesions with lymphocytes and
epitheloid cells and by a marked early response to
antituberculosis drugs. Immunologically, this form
shows evidence of active cell mediated immunity with
little or no antibody response. In particular, the reaction
of PPD-tuberculin is that of a typical delayed
hypersensitivity response and is also reflected in the
positive cellular response in vitro. The unreactive form
(UU) is characterized by rapid dissemination of the
lesions within the chest and to other organs and a
poor response to treatment. This group shows
immunologically a very poor or an absent cell mediated
immune response, resulting in both tuberculin test and
leukocyte migration inhibition test (LMIT) being
negative with abundant antibody response. In between
these two polar forms is an intermediate reactive group
(IR) showing characteristics of the two extreme polar
groups RR and UU.
Clinical Profile
A number of studies were carried out by Seth
et al3-5 to study the immunological spectrum of tuberculosis
in children. The following profile has emerged using the
above criteria.
i. Tuberculin positive, asymptomatic with no manifest
tuberculous lesion: the asymptomatic Mantoux
positive (ASMP) group.
ii. Tuberculin positive with symptoms of tuberculosis
but without any manifest tuberculous lesion: the
symptomatic positive (SMP) group.
iii. Pulmonary primary complex (PPC) which is of three
iv.
v.
vi.
vii.
types: (a) nodal, (b) parenchymal and (c) parenchymal plus nodal.
Tuberculous lymphadenitis (TBL) with or without
pulmonary lesion of the nature of nodal,
parenchymal or nodal plus parenchymal lesion.
Progressive primary disease (PPD).
Miliary tuberculosis (MTB).
Meningeal tuberculosis (TBM).
Interaction between Immune

Status and Clinical Manifestation
Immune status of patients can be tested by indirect
indicators such as tuberculin test, leukocyte migration
inhibition test (LMIT), T cell counts, and immunoglobulin
profile.
Tuberculin Test
Tuberculin test is an indirect indicator of T cell function.
It is also used for diagnosis of tuberculosis in children.
Table 8.1 shows results of tuberculin test in children
diagnosed to have SMP, PPC and TBL.
An induration of >10 mm to PPD-tuberculin has been
taken as a positive tuberculin reaction and leukocyte
migration inhibition test (LMIT) was considered as
positive if the index was less than 0.8.6,7 Analysis of the
immunological aspects of the data from studies by Seth
et al3-7 have been presented.
Table 8.1: Degree of positive tuberculin reaction in
various manifestations of tuberculosis
TB group
10-14
a. SMP N = 25
b. PPC N = 70
c. TBL N = 25
P value a b
bc
ac
Size of tuberculin reaction (mm)

15-19
> 20
3 (12)
8 (11.4)
5 (20)
11 (44)
20 (28.5)
4 (16)
11(44)
23 (32.8)
11(44)
NS
NS
<0.01
NS
NS
<0.01
NS
NS
NS
Figures in parentheses indicate percentages.

SMP = Symptomatic Mantoux positive, PPC Pulmonary
primary complex, TBL Tuberculous lymphadenitis,
NS Not significant.
91
Chapter 8 Clinicoimmunological Profile

Table 8.2: Tuberculin reaction positivity and leukocyte
migration inhibition test (LMIT) positivity in various
manifestations of tuberculosis
TB group
Positive tuberculin
reaction
Positive
LMIT
a. SMP N = 25
b. PPC N = 70
c. TBL N = 25
25 (100)
51 (72.8)
20 (80)
16 (64)
30 (42.8)
11 (44)
P value
ab
a c, b c
<0.01
NS
NS
NS
Figures in parentheses indicate percentages.
Tuberculin reaction positivity was highest in TBL

group after SMP. Distribution of cases according to the
size of tuberculin reaction was comparable in SMP and
TBL groups. A larger proportion (44%) of children in the
TBL group had induration more than 15 mm.5,6
Leukocyte Migration Inhibition Test (LMIT)

LMIT was positive only in 64% of tuber-culin positive
children with no obvious tuberculous lesion (SMP). In
PPC group, 72.8% were tuberculin positive and 42.8%
LMIT positive. In TBL group, the immune profile was
somewhat similar to PPC showing 80% tuberculin
positive and 44% LMIT positive children (Table 8.2).
The extent of inhibition in LMIT positive cases in the
three groups was also similar (Table 8.3). Percentage of
T cells was significantly lower in TBL group in
comparison to PPC and SMP groups. However, the total
lymphocyte and absolute T cell counts were comparable
in the three groups. In miliary and meningeal tuberculosis groups reported earlier,5 only 13.3% of children
were tuberculin positive as against 93.3% LMIT positive
children, the difference was highly significant (P < 0.001).
It is quite baffling that no correlation was found
between the tuberculin and LMIT positivity in the three
clinical presentations of SMP, PPC and TBL in childhood
tuberculosis. Skvor and Trinka8 observed that in active
tuberculosis there is, on an average, a decreased

proportion of lymphocytes, competence for cellular
immunity and the more extensive the tuberculous
process, the greater the decrease in T cell counts. In the
study at AIIMS, total lymphocyte counts, absolute Tlymphocyte counts and LMI index were comparable in
SMP, PPC and TBL. However, there was slight variation
in the percentage of T cells. It indicates that immune
competence in these types of TB manifestations is
comparable (Table 8.3).
In severe cases of pulmonary tuberculosis in adults,
the T cell unresponsiveness has been attributed to antigen
load. Lenzini2 demonstrated that in the intermediate
forms of tuberculosis, the LMIT positivity could be
induced with a larger dose of antigen in the in vitro
system. In the present study, the dose of antigen used
was 15 g/ml standardized in a tuberculin positive child
who had not received BCG vaccination and had no
evidence of active disease radiologically or
bacteriologically. It is possible that PPC and TBL groups
are some what similar to the intermediate category of
immune spectrum of tuberculosis described by Lenzini.2
These may be requiring a large dose of antigen to have
an optimum amount of secretion of specific migratory
inhibition factor (MIF) lymphokine necessary for LMIT
positivity. It is possible that in PPC and TBL groups, the
lesion gets localized mostly by the formation of
nonimmune response. The direct activation of
macrophages by bacterial cell wall prevents early
dissemination of bacilli. This type of macrophage
activation of granuloma formation is induced by peptidoglycan layer of the bacterial cell wall and also by its
synthetic derivative muramyl dipeptide. This probably
is the mechanism by which the local host response
generated is sufficient to fight the infection (locally) in
the lungs. The specific cell mediated immune response
induced by thymus dependent lymphocytes activates the
macrophages for their antibacterial action through a
lymphokine called macrophage activating factor (MAF).
It is possible that in PPC and TBL groups this amount of
specific immune response by its action through
macrophage activation factor (MAF) is sufficient to
Table 8.3: T cell percentage and LMI index (meanSD) in various manifestations of tuberculosis
TB group
T cell %
Total lymphocyte count
Absolute T-lymphocyte count
LMI index
a. SMP N = 25
62.06
7.08
58.93
9.06
48.76
10.42
2719.28
1053.09
4030.07
2103.29
3709.92
1838.24
2462.48
1796.51
2086.54
1178.34
1864.92
912.37
0.65
0.13
0.64
0.12
0.70
0.08
NS
p < 0.001
NS
NS
NS
b. PPC N = 70
c. TBL N = 25
P value a b
ac,bc
92

localize the infection at the local site. The other
lymphokine MIF which is necessary for the LMIT
positivity is probably secreted in lesser quantities as there
may be lesser number of a subset of immune competent
T cells due to a low antigen load in well-localized lesions
of PPC and TBL. In SMP the host defense mechanisms
attempt to localize the infection by preventing the
migration of leukocytes by secreting differentially a larger
amount of MIF. Probably different stimuli or signals
induce secretion of different lymphokines by different
subpopulations of T cells 9 . Gatner et al, 10 have
demonstrated that the amount of leukocyte migratoryinhibitor factor (LMIF) secreted in adults with pulmonary
tuberculosis is comparable to the value among nontuberculous subjects. It substantiates our hypothesis that
there is differential secretion of various lymphokines by
different immune competent T cells and probably MAF
has an upper hand in localizing the infection. Hence, in
addition to the detailed studies of subpopulation of T
cells, assay of different lymphokines in vitro is needed to
unravel the mechanisms of tubercular immunity in
children.
Kramer et al11 demonstrated in animals that the T cells
from malnourished guinea pigs secrete a larger amount
of MIF to low doses of antigen in comparison to the T
cells of well-nourished animals. Keeping this in view, the
nutritional status was also assessed in our studies. It is
clear from Table 8.4 that the percentage of children having
grade III malnutrition was very low in SMP, PPC and
TBL in comparison to miliary and meningeal tuberculosis.
This maybe responsible for lower response in LMIT
positivity in these three clinical situations. In an earlier
study by Seth et al12 where CMIR was measured by
tuberculin reaction and LMIT after BCG in relation to the
nutritional status, it was demonstrated that LMIT
positivity had a direct relationship with the degree of
malnutrition. The more severe the malnutrition, the
higher the positivity of LMIT (Table 8.5).
Khumenku et al13 demonstrated lesser extent of
inhibition in LMIT in pulmonary tuberculosis in adults
Table 8.4: Nutritional status in various manifestations
of tuberculosis
TB group
SMP N = 25
PPC N = 70
TBL N = 25
Miliary and
TBM N = 15
Nutritional status
Normal
Under-nutrition
kutrition
Grade I and II
Severe
PEM
12 (48)
30 (42.9)
6 (24)
12 (48)
36 (51.4)
17 (68)
1 (4)
4 (5.7)
2 (8)
2 (13.3)
8 (53.4)
5 (33.3)
Figures in parentheses indicate percentages, PEM = protein

energy malnutrition
Table 8.5: Cell mediated immune response after BCG

vaccination in preschool children in relation to nutritional
status
Nutritional status
Tuberculin
+ve No.
LMIT
+ ve No.
a. Normal N = 61
b. Undernourished
N = 69
c. Severe PEM N =24
42 (68.8)
43 (62.3)
34 (55.7)
51 (73.9)
9 (37.5)
20 (83.3)
NS
<0.05
<0.02
<0.05
NS
<0.01
P value
ab
bc
ac
Figures in parentheses indicate percentages
after three months treatment. In our study most of the

children had not received any antituberculosis drugs. A
few had received chemotherapy upto 2 weeks. It is
possible that mere presence of the drug in vivo
differentially activates the macrophage system much
more, both directly and through MAF and there is less
secretion of MIF.
In conclusion, the comparison of immune
mechanisms in some of the clinically encountered types
of tuberculosis in children has raised many queries. There
is an urgent need for carrying out prospective studies on
immunology of tuberculosis in children as per WHO
recom-mendations to provide some guidelines regarding management of tuberculosis in children. Research in
the areas of (i) determination of phenotype and function
of T cells, (suppressor or helper), lymphokine production,
assessment of macrophage function, monocyte/
macrophage activation for killing of M. tuberculosis and
chemotaxis would be of immense help in the
understanding of a very wide clinical spectrum of
tuberculosis in children. It is the interaction between
tubercle bacilli and the immune system of the body which
determines the outcome of primary infection. The
relationship is shown in Figure 8.1.
It is mostly the cell mediated immunity which
determines the outcome of primary infection though
changes in the humoral immunity also occur. Seth et al5
investigated the cell mediated immune response (CMIR)
to assess the delayed cutaneous hypersensitivity (DTH)
in children with tuberculosis under five years of age. The
clinical profile is shown in Table 8.6. A large proportion
(86.7%) of children were malnourished with severe
malnutrition in 30% of them. Quantitatively there was
no significant difference in the value of T cells in the
children with tuberculosis in comparison to the controls
(Table 8.7). Leukocyte migration inhibition test was
positive in 63.3% of cases; LMIT positivity was
significantly higher (p < 0.001) in cases investigated
before initiation of therapy as compared to the group
93

Table 8.8: LMIT in relation to therapy and correlation
with positive tuberculin test (5TU)
LMI index
Before
therapy
(N = 15)
During
therapy
(N = 15)
LMI index +ve

Tuberculin +ve (5 TU)
Tuberculin ve (LMI +ve)
Both tub and LMI ve
Both tub and LMI +ve
15 (100)*
8 (53)
7 (47)
0
7 (47)
7 (46)*
5 (33)
2 (13)
8 (53)
5 (33)
*P < 0.001. Tub Tuberculin, Figures in parentheses are

percentages
tested during therapy (Table 8.8). The value of leukocyte

migration inhibition index was much lower which was
statistically significant in before therapy group as
compared to the controls and during therapy group
(Table 8.8).
In the spectrum of tuberculosis it has been
demonstrated by Seth et al14 that in pulmonary primary
complex, the most common manifestation of tuberculosis
in children was an absolute T cell count which was more
in the nodal and nodal plus parenchymal groups in
comparison to the group with parenchymal lesion alone.
CMIR judged by Mantoux test and LMIT was comparable
in the three groups who were normally nourished. But
in children who were malnourished CMIR was better in
the nodal and nodal plus parenchymal groups.
Fig. 8.1: Clinical profile of tuberculosis
Table 8.6: Clinical profile of tuberculosis

Types of TB
No.
Tuberculous meningitis
Miliary
Spinal
Constrictive pericarditis with mediastinitis
Peritoneal (with ascites)
Cervical lymphadenitis
Pulmonary tuberculosis:
Primary complex (PPC)
Collapse, consolidation (PPD)
14
1
2
1
3
1
Total
30
6
2
Table 8.7: LMI index and T cells (mean SD) in childhood

tuberculosis
CMIR
Patients
(N = 30)
Controls
(N = 12)
LMI index :
Before therapy
During therapy
Total
15
15
30
0.62 0.16*
0.87 50
0.74 0.38**
1.06 0.22
T cells:
Percentage
Absolute count
16
16
56 9.29
2222 12
57.6 11.2
2193 99
*P < 0.001
**P = 0.05
Immunology of Tuberculous Lymphadenitis

The immunology of tuberculous lymphadenitis, the next
common manifestation of the tuberculous disease in the
outpatient department was investigated in children below
12 years by Seth et al. 15 Both cellular and humoral
components were studied. The three groups investigated
were histologically proved tuberculous lymphadenitis,
reactive lymphadenitis group and controls. The status of
severe malnutrition, and Mantoux test positivity was
highest (93.3%) in the histopathologically proved with
definitive diagnosis of TBL group (Table 8.9). Routine
hemogram was comparable in the three groups (Table
8.10).
CMIR estimated quantitatively by T cell estimation
and qualitatively by LMIT (Tables 8.11 and 8.12)
demonstrated that absolute T cell counts were It is mostly
the cell mediated immunity which determines the
outcome of primary infection though changes in the
humoral immunity also occur. Seth et al5 investigated the
cell mediated immune response (CMIR) to assess the
delayed cutaneous hypersensitivity (DTH) in children
with tuberculosis under five years of age. The clinical
profile is shown in Table 8.6. A large proportion (86.7%)
of children were malnourished with severe malnutrition
in 30% of them. Quantitatively there was no significant
94

Table 8.9: Status of nutrition, BCG vaccination and Mantoux test in tuberculous lymphadenitis
Nutritional status
Group
a. Control (N = 20)
b. Reactive (N = 27)
c. TBL
(N = 18)
P value*
Normal nutrition
Under PEM
(I and II)
Severe PEM
(III and IV)
9 (45)
14 (51.8)
4 (22.2)
10 (50)
11 (40.7)
12 (66.7)
1 (5)
2 ( 7.4)
2 (11.1)
ab
ac
bc
BCG
vaccination
Mantoux test
positivity
8/24 (33.3)
4/16 (25 )
2 (10)
4/27 (14.8)
14/15 (93.3)
NS
NS
NS
NS
< 0.001
NS < 0.001
Figures in parentheses are percentages, * Chi square test,

NS Not significant,
TBL Tuberculosis lymphadenitis
Table 8.10: Hemogram (mean SD) in chronic cervical lymphadenitis

Group
a. Control
(N = 20)
b. Reactive
(N = 20)
c. TBL
(N = 15)
P value* a b,
a c, b c
Hemoglobin
(g/dl)
TLC
(per cumm)
DLC
(1)
(2)
P
(3)
L
(4)
E
(5)
B
(6)
10.96 1.68
9246 3790.33
57 18.09
36.68 18.07
1.32 2.54
2.64 2.49
10.64 1.11
10462 4311.60
51.55 9.76
41.95 10.37
1.95 1.47
3.70 3.18
10.17 1.51
10562.3 4304.19
54.07 8.96
39.60 11.51
2.27 2.12
4.47 4.31
NS**
NS
NS
* For variables 1, 3 and 4 One way analysis of variance test

**For variables 2, 5 and 6 Wilcoxons nonparametric test
Table 8.11: T cells (I and 24 hours) in chronic cervical lymphadenitis

T cells
Absolute count
(2)
Percentage
(3)
Absolute count
(4)
39
6.8
36.8
5.9
(N= 20)
33.2
5.5
1712.95
748.6
1658.6
645.5
54.44
10.50
48.89
7.45
1493
652.5
44.95
6.63
1840.50
1039.37
2268.9
916.99
(N = 20)
1951.62
836.69
NS
<0.05
NS
NS
NS
NS
<0.05
<0.01
NS
NS
NS
NS
Group
Percentage
(1)
a. Control (N = 20)
b. Reactive (N =27)
c. TBL (N = 18)
P value*
ab
ac
bc
*For variables 1 and 3 one way analysis of variance followed by, Norman-Keuls multiple range test,
For variables 2 and 4 Wilcoxons nonparametric tests were applied
95

Table 8.12: Leukocyte migration inhibition test (LMIT) in chronic cervical lymphadenitis
Group
LMIT positivity
Value of LMIT (mean % SD)
P value*
Control (N=20)
Reactive (N=15)
TBL (N=10)
0
7 (46.6)
6 ( 60 )
0.98 0.47
0.83 0.25
0.77 0.24
<0.01
<0.01
*For variable (1) - Chi square test. For variable (2) one way analysis of variance test, P value between the reactive and TBL
groups were applied
Table 8.13: B cells and serum immunoglobulins (mean + SD) in chronic cervical lymphadenitis
Data are mean SD
B cells
Immunoglobulin levels (IU)
Group
Percentage
Absolute count
IgG
IgM
IgA
a. Control (N = 20)
19.84
4.71
14.48
4.05
13.94
2.71
662.71
346.71
634.94
293.97
465.08
179.41
147.26
53.18
274.93
330.25
191.83
37.88
220.02
108.10
288.14
296.90
255.67
67.82
107.37
44.49
128.14
55.74
156.50
32.42
< 0.001
< 0.001
NS
NS
<0.05
<0.05
0.001
<0.05
<0.001
NS
NS
NS
NS
<001
NS
c. TBL (N=18)
P value*
ab
ac
bc
*Wilcoxons nonparametric test
difference in the value of T cells in the children with

tuberculosis in comparison to the controls (Table 8.7).
Leukocyte migration inhibition test was positive in 63.3%
of cases; LMIT positivity was significantly higher
(p < 0.001) in cases investigated before initiation of
therapy as compared to the group tested comparable in
all the groups. LMI index value was significantly low (i.e.
more positivity) in the TBL group.
Humoral immunity estimated by B cell counts and
levels of IgG, IgM and IgA indicated that absolute B cell
counts were significantly low in TBL group. Levels of IgG
were significantly higher in this group (Table 8.13). The
level of albumin was decreased in TBL with a corresponding increase in the level of globulins (Table 8.14).
Immunology of Tuberculous Meningitis

CMIR as well as humoral immune response (HIR) was
investigated by Seth et al16 in this most serious form of
tuberculosis in children. Absolute T cell counts were
significantly increased though T cell percentages were
comparable with the control group, LMIT positivity was
very high (93%) (Tables 8.15 and 8.16). In humoral
response, there was no quantitative but qualitatively all
the three types of immunoglobulins IgG, IgM and IgA
were statistically significantly low (Table 8.17).
Hence investigation of both CMIR and HIR (humoral
immune response) indicated that there was an increase
in the absolute T cell counts, maximum being in TBM
and minimum in PPC. Mantoux test, an in vivo measures
Table 8.14: Total and differential serum proteins (mean

SD) in chronic cervical lymphadenitis
Serum proteins (g/dl)
Group
Total
Albumin
Globulin
a. Control (N = 20)
7.40
1.31
7.02
3.31
7.29
0.60
4.07
0.78
3.31
0.38
3.49
0.48
3.11
0.84
3.71
0.46
3.82
0.28
NS
NS
NS
<0.001
<0.05
NS
<0.01
<0.01
NS
c. TBL (N = 15)
P value*
ab
ac
bc
*One way analysis of variance test followed by Norman-Keuls

multiple range test were applied
Table 8.15: T and B cell profile (mean SD) in tubercular

meningitis (TBM)
T-cell
B-cell
Group
Percentage
Absolute
count
Percentage
Absolute
count
TBM
(N = 30)
Control
(N = 20)
59.80
8.44
54.44
10.50
3126
1632
1840
1039
18.95
5.13
19.84
4.71
679
312
662
342
P value
NS
<0.01
NS
NS
96

Table 8.16: Leukocyte migration inhibition test (LMIT), Mantoux test positivity, and LMI index in
tubercular meningitis (TBM)
Group
Positive No.
Mantoux
(%)
LMIT
LMI index
(mean SD)
TBM
Before therapy (N = 15)
During therapy (N = 28)
Control (N = 20)
8 (53.3)
15(53.5)
14 (93.3)
16 (57.1)
0.62 0.16
0.77 0.23
1.20 0.41
P value
NS
< 0.05
< 0.001*
*Level of significance in comparison to before therapy and during therapy groups
Table 8.17: Serum immunoglobulin (mean SD) and

complement profile in tubercular meningitis (TBM)
Group of
cases
Immunoglobulin
levels (IU)
Complement
levels
IgA
IgG
IgM
(mg/ml)
TBM
(N = 30)
Control
(N = 20)
79.48
33.78
109.63
43.22
115.01
32.56
149.75
52.13
148.50
51.88
208.35
107.81
0.651
0.27
0.537
0.27
P value
<0.01
<0.01
<0.05
NS
of CMIR indicated that there was maximum positivity in

PPC followed by PPD disease group and least in the TBM.
However, leukocyte migration inhibition test positivity
was maximum in TBM followed by PPD and PPC
especially in the malnourished group. Quantitative
measures of B-cell indicated an increase in the absolute
counts, maximum was in PPC, followed by PPD, it was
least in TBM. Serum IgG levels were significantly
increased in PPC and PPD but decreased in TBM. IgM
levels were decreased in all the three, but were
comparatively higher in TBM. IgA levels were decreased
only in TBM. The rise in complement was also more in
PPC and PPD in comparison to TBM. The results indicate
that there is gradient of both humoral and cellular
immunity, the best immunocompetence being in PPC,
followed by PPD and the least in TBM. Humoral
immunity is of significance as it indicates an attempt of
using these antibodies to coat the antigen before
processing by macrophages. The high positivity of LMIT
in patients, specially the malnourished, indicates that
there is an increased secretion of migratory inhibition
factor, a lymphokine attempting to produce CMIR which
is the main protective immune mechanism in
tuberculosis.
Seth et al17,18 have reviewed the subject of tuberculosis
in its complete immunological perspective and can be
referred to for details.
IMMUNE RECONSTITUTION DISEASE ASSOCIATED

WITH MYCOBACTERIAL INFECTIONS
Tuberculosis (TB) occurs commonly in HIV-infected
children especially in the absence of antiretroviral therapy
(ART).19 Clinical deterioration of TB can occur despite
appropriate anti-TB chemotherapy on start of ART.
Occurrence of this deterioration is called paradoxical
immune reconstitution inflammatory syndrome (IRIS).
The paradoxical reactions are due to inflammatory
phenomena. 20 Paradoxical IRIS due to TB is well
recognized in adults but there are few clinical descriptions
in children. The immune reconstitution inflammatory
syndrome (IRIS) has emerged as a new clinical entity in
HIV infected children with tuberculosis associated with
use of antiretroviral therapy.21 Immunereconstitution
disease associated with a range of mycobacteria including
BCG constitutes a challenge to delivery of antiretroviral
treatment worldwide. Data concerning the pathogenesis
and management of all forms of mycobacterial immune
reconstitution disease are lacking.20,22 It was more
commonly seen with advanced HIV infection and
malnutrition.23,24 The clinical manifestations include
worsening of clinical features (fever, distress) and
radiological features after starting ART.25 Enlargement
and suppuration of regional lymphnodes in BCG
vaccinated children may occur following ART. 26
Lymphnode enlargement, chylothorax and chylous ascites
have been reported as IRIS in a child with HIV and TB.27
REFERENCES
1. Skinsness OK. Comparative pathogenesis of mycobacterioses. Ann N Y Acad Sci 1968;154: 19.
2. Lenzini L, Rottali P, Rottali L. The spectrum of human
tuberculosis. Clin Exp Immunol l 1977; 27: 230.
3. Seth V, Nath N, Singh U. Immunological spectrum in
tuberculous children. Indian J Tuberc 1985;32:29-39.
4. Seth V, Seth SD. Cell mediated immune response in
childhood tuberculosis. Proceedings of the International
Meeting of the Commonwealth Foundation 1984.

5. Seth V, Malaviya AN, Sahai V, et al. Cell mediated
immune response in childhood tuberculosis. Indian J Med
Res 1981;73:68-73.
6. Seth V, Kukreja N, Sundaram KR, et al. Leucocyte
migration inhibition test as an in vitro measure of cell
mediated immune response after BCG in preschool
children in relation to their nutritional status. Indian J
Med Res 1981;74: 554-8.
7. Seth V, Kukreja N, Sundaram KR, et al. Delayed
hypersensitivity after BCG in preschool children in relation
to their nutritional status. Indian J Med Res 1981; 74: 392-8.
8. Skvor J, Trinka L. Immunological profile studies in
patients with pulmonary tuberculosis. Correlation of
pretherapy cellular tests with characteristics of the
disease. Scand J Respir1979; 60: 161-8.
9. Grange JM. Some aspects of immunology relevant to
pediatric tuberculosis. Pediatr Clin India 1983; 18:50-60.
10. Gatner EMS, Anderson R. An in vitro assessment of
cellular and humoral immune function in pulmonary
tuberculosis. Correction of defective neutrophil mobility
by ascorbate, levamisole, metoprolol and propranolol.
Clin Exp Immunol 1980; 40: 327-40.
11. Kramer TR. Ability of protein malnourished guinea pigs
to produce MIF to low doses of antigen. Fed Proc 1976;
35: 588-94.
12. Seth V, Kukreja N, Seth SD, et al. In vivo and in vitro
correlation of cell mediated immune response in
preschool children after BCG in relation to their
nutritional status. Indian J Med Res 1982; 75: 360.
13. Khumenku AG, Auerbach MM. Chemotherapy and
antituberculous immunity. Bull Int Union Tubercle 1983;
58: 1236-42.
14. Seth V, Singh U. Immune basis or symptomatic
pulmonary primary complex. Indian Pediatr 1986; 23: 830.
15. Seth V, Rohatagi M, Bhuyan UN et al. Tuberculous
cervical lymphadenitis in children as a relatively immune
competent state. Indian J Med Res 1985; 81:364-71.
16. Seth V, Kabra SK, Beotra A, et al. Tuberculous meningitis
in children manifestation of an immune compromised
state. Indian Pediatr 1993; 30: 1181-6.
97
17. Seth V, Singh U. Immunopathogenesis in tuberculosis.

Part I. Cellular mechanisms of resistance. Indian J Pediatr
1987; 54: 311-19.
18. Seth V, Singh U. Immunopathogenesis in tuberculosis,
Part II. Humoral mechanisms of resistance. Indian J
Pediatr 1987;54:830-40.
19. Walters E, Cotton MF, Rabie H, et al. Clinical presentation
and outcome of tuberculosis in human immunodeficiency
virus infected children on antiretroviral therapy. BMC
Pediatrics 2008; 8: 1.
20. Boulware DR, Callens S, Pahwa S. Pediatric HIV immune
reconstitution inflammatory syndrome. Curr Opin HIV
AIDS 2008; 3: 461-7.
21. Zar HJ. Global paediatric pulmonology: Out of Africa.
Paediatr Respir Rev 2006; 7 Suppl 1: S226-8.
22. Lawn SD, Lipman MC, Easterbrook PJ. Immune
reconstitution disease associated with mycobacterial
infections. Curr Opin HIV AIDS 2008;3: 425-31.
23. Wang ME, Castillo ME, Montano SM, et al. Immune
reconstitution inflammatory syndrome in human
immunodeficiency virus-infected children in Peru.
Pediatr Infect Dis J 2009; 28: 900-3.
24. Smith K, Kuhn L, Coovadia A, et al. Immune
reconstitution inflammatory syndrome among HIVinfected South African infants initiating antiretroviral
therapy. AIDS 2009; 23: 1097-107.
25. Narendran G, Swaminathan S, Sathish S, et al. Immune
reconstitution syndrome in a child with TB and HIV.
Indian J Pediatr 2006; 73: 627-9.
26. Puthanakit T, Oberdorfer P, Punjaisee S, et al. Immune
reconstitution syndrome due to Bacillus CalmetteGurin after initiation of antiretroviral therapy in
children with HIV infection. Clin Infect Dis 2005; 41:
1049-52.
27. Rabie H, Lomp A, Goussard P, et al. Paradoxical
tuberculosis associated immune reconstitution
inflammatory syndrome presenting with chylous ascites
and chylothorax in a HIV-1 Infected Child. J Trop Pediatr
2010 Jan 25. [Epub ahead of print].
SECTION 4
CLINICAL SPECTRUM
Tuberculous Lymphadenitis
Abdominal Tuberculosis
Neurotuberculosis
Pathology and Pathogenesis
Clinical Manifestations, Diagnosis and
Management
Case Studies
Osteoarticular Tuberculosis
Genitourinary Tuberculosis
Tuberculosis and the HIV Infection

TB in HIV Infected Children
Tuberculosis and Childhood Malignancy
Unusual Manifestation of Tuberculosis
Cutaneous Tuberculosis
Adolescent Tuberculosis: Prelude to Future Infertility
Endocrine Manifestations of Tuberculosis
Congenital Tuberculosis
INTRODUCTION
Lungs are the portal of entry of Mycobacterium tuberculosis
in the body. Majority of infections due to Mycobacterium
tuberculosis remain unrecog-nized and recover
spontaneously without treatment. Lungs are the
commonest site for tuberculous disease. The disease in
lungs varies from a small parenchymal lesion to disseminated disease. The clinical manifestations depend on the
underlying pulmonary lesions. This chapter deals with
natural history of tuberculous infection, clinical
manifestations of various lesions and diagnosis of
pulmonary tuberculosis.
TRANSMISSION
Transmission of M. tuberculosis generally is from personto-person and occurs via inhalation of mucous droplets
that become airborne when an individual with
pulmonary or laryngeal TB coughs, sneezes, speaks,
laughs, or sings. After drying, the droplet nuclei can
remain suspended in the air for hours. Only small
droplets (<10 microns in diameter) can reach alveoli.
Droplet nuclei also can be produced by aerosol treatments, by sputum induction, and through manipulation
of lesions.
Numerous factors are associated with the risk of
acquiring M. tuberculosis infection.1 The risk of acquiring
infection has been associated consistently with the
extent of contact with the index case, the burden of
organisms in the sputum, and the frequency of cough in
the index case. Patients with smear-positive pulmonary
TB are more likely to transmit infection. Markers of close
contact such as urban living, overcrowding, and lower
socioeconomic status all are correlated with the acquisition of infection. An increased risk of developing infection has been demonstrated in multiple institutional settings, including nursing homes, correctional institutions,
and homeless shelters. The risk of acquiring infection
increases with age from infancy to early adult-hood, likely
attributable to increasing contact with other persons.
In a recent report from Laos increased latent
tuberculosis infection was found in children below 15
years of age living with sputum positive adults (OR: 3.3,
95% CI: 1.4 -7.7), patients highly positive sputum prior
to treatment (AFB >2+; OR: 4.7, 95% CI: 1.7-12.3), and

living in ethnic minorities (OR: 5.4, 95% CI: 2.2-13.6).2
A study from Paris reported a total of eight
independent risk factors that determine the risk of latent
TB infection: age, with three subgroups: 6-14 years (3.6;
1.6-8.0); 15-29 years (3.7; 1.8-7.7); > or > 30 years (4.1; 2.08.5); cavitation on the index cases chest radiograph (1.6;
1.1-2.2); an index case sputum smear with 100 or more
acid-fast bacilli per field (1.8; 1.2-2.8); household contact
at night (2.1; 1.3-3.2); first-degree family relationship with
the index case (2.1; 1.3-3.3); active smoking by the contact
(1.6; 1.1-2.4); free health care (2.0; 1.2-3.2); and birth in a
country with TB incidence rate higher than 25 of 100,000
(2.2; 1.5-3.2).3
PATHOPHYSIOLOGY
Primary infection with M. tuberculosis in children usually
occurs following inhalation of viable microorganisms.
The usual sites of primary tuberculous implantation in
lungs are the lower segments of middle lobe (lingula) and
upper segments of the lower lobe. Initially, there is
polymorphonuclear response; this is later replaced
by macrophage/mononuclear cell response. In a
previously nonexposed child, the mycobacteria multiply
intracellularly after being phagocytosed by the
macrophages. Cell mediated immune response develops
in about 2 to 4 weeks time. In the absence of cell-mediated
immunity the tissue damage is minimal and the
symptoms and signs are absent. Once cell mediated
immunity develops, lesions undergo caseous necrosis in
their centers and bacillary multiplication decreases. The
area of necrosis is surrounded by macrophages,
lymphocytes, giant cells and collagenous fibersforming
a granuloma, called tubercle. Some tubercle bacilli
traverse into the regional lymph nodes via the lymphatic
vessels and cause an inflammatory response there. The
primary focus, the draining lymphatics and the involved
regional lymph node are collectively called the primary
complex. About 80% of the primary infections are initiated
by one focus.4,5 These are more commonly present in the
mid zone of the lungs as the ventilation is maximum here.
Lesions in right lung are more common than in the left
because of greater volume and the fact that the right
102
Section 4 Clinical Spectrum
bronchus is more vertical, short and wide. Some authors,

however, suggest that all parts of the lungs are apparently
at equal risk of being seeded.6 Sluggish air current in the
peripheral parts of the lung allow the bacilli to stay there
longer; this explains the predominant occurrence of
primary focus in the subpleural region. Ghon noted that
at least 70% of primary pulmonary foci are subpleural.4
A hallmark of primary tuberculosis infection is the
relatively large size and importance of the adenitis,
compared with the relatively insignificant size of the
initial focus in the lung.
The lymphatic drainage of lungs predomi-nantly
occurs from left to right.7 This explains the frequent
involvement of right paratracheal nodes, the
parenchymal lesion is left sided even when cervical nodes
may be affected as they have communications with
paratracheal lymph node chains and also they drain the
apical pleura.
RISK OF INFECTION TO DISEASE IN INFANTS AND

YOUNG CHILDREN
Risk of developing tuberculosis disease is more in young
children, specifically infants. This is contributed by
multiple factors including: decreased monocyte
recruitment at site of infection, reduced microbial killing,
less effective major antigen presenting cells (APC) and
poor response of nave T cells.8-10
NATURAL HISTORY OF TUBERCULAR INFECTIONS

Time Table of Clinical Disease After Pulmonary Infection
in Childhood
Time table of clinical disease after pulmonary infection
in childhood has been described by Marais et al11 as
follows:
Phase 1: It occurs 3 to 8 weeks after primary infection.
The initial incubation period is usually asymptomatic but
at times may have initial fever, erythema nodosum, a
positive tuberculin skin test response due to
hypersensitivity reaction. On chest radiograph there is
formation of primary complex.
Phase 2: It occurs 1 to 3 months after primary infection.
This period follows the occult hematogenous spread
occurring during incubation period. It represents the
period of highest risk for development of tuberculous
meningitis and miliary tuberculosis in young children.
Phase 3: It occurs 3 to 7 months after primary infection.
This is the period of pleural effusions in children over 5
years and bronchial disease in those below 5 years.
Phase 4: It lasts 1 to 3 years after primary infection and
continues until the primary complex is calcified. This is
the period of development of osteoarticular tuberculosis
in children under 5 years. However, adult-type disease

with delayed clinical onset can occur even after
calcification.
Phase 5: It occurs more than 3 years after primary
infection. This represents the period in which late
manifestations of TB including pulmonary reactivation
disease develops.
Marais et al 11 pointed out that this time table describes
common clinical patterns of disease and does not
represent dogmatic rules regarding the course of
tuberculosis in children. The vast majority of disease
manifestations occur in the first 6 to 12 months following
primary infection.
There are varying immune mechanisms underlying
the different intrathoracic manifestations of tuberculosis
in childhood. The maturation of host immunity is an
important variable that influences the ultimate TB disease
manifestations in childhood. Dynamic host-pathogen
balance is affected by variation in both the pheno- and
genotypic pathogenicity of the organism. Pabst way back
in 198012 emphasized the ontogeny of the host immune
response towards infection with M. tuberculosis. Seth13
described immune basis of clinicoradiological
presentation of pulmonary tuberculosis and tuberculosis
in its entire spectrum. Childhood covers the age range
from birth to 15 years of age. In this age period due to
profound changes occurring in the immune system
development the natural response to infection is variable.
It is a period of dynamic growth and maturation. Marais
et al14 described the diverse and changing spectrum of
pathology seen in childhood tuberculosis, and also
described the diversity of disease in childhood pulmonary
tuberculosis. They have proposed radiological
classification of childhood intrathoracic tuberculosis
which highlights the changing spectrum of pathology
seen in childhood tuberculosis.15 On this depends, the
treatment and prognosis. Hence, the knowledge of age
dependent differences in the immune response to
M. tuberculosis infection is crucial for not only directing
future research but helps in improved case management.
PRINCIPLES OF DISEASE
Dynamic Balance
Balance between the pathogenicity of the organism and
hosts immune competence determines the clinical
manifestations of an infectious disease. Persistence of
dormant bacilli inside sequestered foci (latent infection)
provides an ever present risk of reactivation whenever
there is a shift of the balance in favor of the organism. In
addition to the risk of reactivation of a primary focus,
high level of transmission implies a high-risk of
reinfection in high burden settings.
Chapter 9 Pulmonary Tuberculosis
Pathogen
The number of organisms inhaled (size of the infecting
inoculum), the virulence of the organisms and their ability
to resist eradication (persistence) are various variables
related to pathogen which determine the spectrum of
disease presentation. Variation in the dose of infecting
organism Mycobacterium tuberculosis seems negligible.
Only the tiniest aerosol droplets containing <5 bacilli are
likely to reach the terminal airways and establish a
pulmonary focus of infection. Larger droplets of
organisms do not remain suspended in the air and are
deposited in the proximal airways where the infection is
effectively resisted.
The intensity of exposure influences the risk of both
infection and disease.16,17 Duration of exposure and
number of infectious particles in the ambient air influence
the risk of infection. In humans, multiple infections or
increased virulence of the infecting organisms rather than
the variation in the infecting dose are responsible for
increased tendency of infection progressing to disease.
High intensity exposure is to a sputum smear-positive
case in the household. Primary infection is usually
visualized as a single parenchymal (Ghon) focus.
Exposure to multiple infecting doses increases the
likelihood of establishing infection and/or disease. The
phenotypic virulence might differ according to the
sputum smear-status of the source case. Exposure to
ultraviolet irradiation or drying determine the influence
of these environmental factors depending upon the
proximity of the source case.
Genetic variation in the organism does not explain
the consistent epidemiological finding that household
contacts of sputum smear-positive source case are
more likely to progress to disease following infection.
Several mechanisms that enable M. tuberculosis to persist
both intracellularly (inside macrophages) and
extracellularly (inside the caseous centers of granulomas)
have been demonstated.18,19 Unless there are favorable
circumstances, the reactivation of dormant bacilli does
not occur. One of the important factor is compromization
of immune response which is responsible for activation
of the disease.
Host Immunity
Local pulmonary defenses along with innate and acquired
immune responses comprise host immunity. Decreased
mucosal immunity, compromised clearance of the microorganisms, and a favorable microenvironment at the
point of deposition of organism, all contribute to an
increased risk of infection and disease.
The protection provided by the innate immune
response seems limited because bacilli grow unrestrained
in the nave macrophages and occult hematological
103
dissemination occurs frequently during 1st 4 to 6 weeks

after primary infection. For prevention of uncontrolled
disease progression and containment of organism,
acquired cellular immune response is of crucial
importance. There is striking age-related risk of
developing tuberculosis following primary infection and
the age related difference in the disease manifestations.
Immature immune response in very young children (2 to
3 years of age) are at high risk of developing progressive
disease while children (3 to 10 years) are the least likely
to progress to disease after primary infection. In India
even 3 to 5 years age is considered vulnerable but less as
compared to less than three years. After this golden
period there is a sudden increase in the risk of progressing
to disease following primary infection during
adolescence. This is what leads to so called Adult type of
disease, i.e. development of adult type pulmonary
cavitation.20 In early childhood, disease is mostly limited
to regional lymphadenopathy. The time since infection
is another important variable that influences particular
disease manifestations by the time table of tuberculosis
in children.
The course of the infection depends on the immune
response of the host. If the host resistance is good, the
inflammatory exudate around the primary focus is
absorbed and the caseous area inspissated. Healing
occurs by fibrosis and calcification. When the cell
mediated immune response is weak, the bacilli continue
to multiply and the inflammatory process extends to the
contiguous areas. Progressive primary disease (PPD) is
a serious complication of the primary pulmonary complex
(PPC) in which the PPC, instead of resolving/calcifying,
enlarges steadily and develops large caseous center. The
center then liquifies; this may empty into an adjacent
bronchus leading to formation of a cavity. This is
associated with large numbers of tubercle bacilli.11 From
this stage, the bacilli may spread to other parts of the
lobe or the entire lung. This may lead to consolidation of
area of lung or bronchopneumonia. Cavitary disease is
uncommon in children before adolescence. It may be
difficult to differentiate PPD from a simple tuberculous
focus with superimposed acute bacterial pneumonia.
Appearance of a segmental lesion is fan shaped on a
roentgeno-gram, representing mainly atelectasis and
almost always involves that very segment occupied by
the primary pulmonary focus21,22 (Figs 9.1 and 9.2).
Some of the events may occur because of involvement
of lymph nodes.4,23,24 The enlarged lymph nodes may
compress the neighboring airway.25-27 Ball-valve effect
due to incomplete obstruction may lead to trapping of
air distal to obstruction (emphysema).28 Enlarged paratracheal nodes may cause stridor and respiratory distress.
Subcarinal nodes may impinge on the esophagus and may
104
Complicated Ghons Focus and/or Disseminated Disease

(RIsk group: Children <2 to 3 years of age/all immune
compromised children)
Immune compromised children with suboptimal cellular
immune responses which results in poor disease
containment. They are usually very young (<2 to 3 years
of age). Eventual cavitation of the Ghons focus due to
unrestrained multiplication of bacilli at the point of
Fig. 9.1: Natural history of tubercular infections
Figs 9.2A to D: Pulmonary tuberculosis
cause dysphagia. If the obstruction of bronchus is

complete, atelectasis occurs.
Description of Specific Disease Entities

Uncomplicated Ghons Focus and/or Lymph Node
Disease (Risk group: Children <5 years of age)
A localized pneumonic process develops at the site of
organism deposition with primary pulmonary infection.
Bacilli drain via local lymphatics to the regional lymph
nodes from this Ghons focus. Together these constitute
the primary complex. It is often subclinical and is only
detected if there is active surveillance after recent
infection. It is considered a proof of recent primary
infection but not necessarily disease when there are no
clinical symptoms of disease or presence of radiological
complications.
deposition of organisms will cause progressive

parenchymal damage. Tuberculous meningitis can result
due to poor containment of bacilli with in the regional
lymph nodes. Disseminated disease rarely occurs in older
immune competent children.
Complicated lymph node disease
(Risk group children < 5 years of age)
A spectrum of air way complications are referred as
lymphoproliferative tuberculosis due to lymph node
disease. This is due to the exuberant lymph node
enlargement following primary infection along with
the anatomical characteristics of small size of their
airway which leads to lymphoproliferative disease in
children < 5 years of age. Marais14 has emphasized
that extraluminal com-pression results when an
airway is compressed by large lymph nodes and
the associated inflammatory edema. Polyps,
granulomatous tissue or caseous material within the
airway, partial airway obstruction can cause

intraluminal obstruction. Ball-valve effect with distal
hyperinflammation and total obstruction can lead to
distal atelectasis.
Intrabronchial spread can occur due to aspiration
of caseous material from a diseased lymph node that
has herniated into the bronchial airway. Destructive
caseous pneumonia can be a severe complication
depending on the dose and virulence of the aspirated
bacilli, the degree of airway obstruction and immune
competence of the host.
Pleural effusion
(Risk group: Children > 5 years of age)
A peripheral Ghons focus may have a limited pleural
reaction which is considered as a part of primary
complex but large effusions are less common. It occurs
mainly in children > 5 years of age and indicates recent
primary infection. It occurs when a few organisms
from a subpleural focus spread to pleural cavity,
bilateral pleural effusions indicate either bilateral
pulmonary foci or hematogenous dissemination.
Accumulation of straw-colored fluid containing very
few bacilli is due to the hypersensitivity response.
Caseous tuberculous empyema can result rarely if the
bacilli are very virulent and immune competence of
the host is limited.
Adult type disease
(Risk group: Children > 10 years of age)
Cavitation occurring in the lung apices is the disease
characteristic in this category and appears around
puberty. Posterior segments of the upper lobes and
the superior segments of the lower lobes are also
frequently involved. The natural history of the disease
indicates that this type might rapidly follow (within
6 to 12 months) the primary infection. There is
associated positivity of tuberculin skin test (TST). This
is due to poor containment of a recent primary
infection rather than reactivation of an old, well
contained infection. Preferential organism deposition
and their growth explains the typical anatomical
distribution.
Preferential deposition: Air flow is directed towards
the dependent lung zones on inhalation which favours
deposition of the organisms in the lung bases.
Coughing can cause airdropping and the organisms
get deposited in the apices or simon focus can occur
due to preferential hematogenous spread. However,
radiologically in Ghons focus, dependent zones of
the right lung (middle and lower lobes) are most
frequently involved.
Preferential growth: The occurrence of adult type of
disease around puberty is due to the changes that
occur in the immune response around puberty rather
due to the preferential growth of M. tuberculosis.
Although immune maturation occurs throughout
105
childhood, major changes relating to the effective

containment of primary M. tuberculosis infection seems
to occur around 2 years and around puberty (>10
years of age) when hormonal changes might be an
important factor in the altered pathogenesis. Immune
response during adolescence is essential for disease
containment and excessive tissue necrosis aids in the
development of parenhymal cavities. This distinctive
immune response allows the organisms to take full
advantage of a favorable microenvironment. Oxygen
tension is highest in the lung apices owing to high
ventilation/perfusion (V/Q) ratios29 which allows
vigorous growth and multiplication of M. tuberculosis
in these areas. A more favorable microenvironment
results due to progressive parenchymal damage
which raises the V/Q ratio and oxygen tension. Poor
blood flow and decreased lymph node formation also
is responsible for the vulnerability of lung apices.29
These changes explain the occurrence of adult type
of TB at adolescence and its anatomical location.
Pathology based disease classification of pulmonary
tuberculosis in children described by Marais11 et al is as
follows:
Pulmonary Infection
Tuberculosis infection uncomplicated by clinical
symptoms (there is only self-limiting viral like illness) or
radiological abnormalities (other than primary complex).
Primary complex includes the Ghons focus with
associated tuberculous lymphangitis and affected
regional lymph nodes. When there is successful
containment of the organism, there is no progression of
pulmonary infection to disease.
Pulmonary Disease
It is associated with marked clinical symptoms and
radiological abnormalities apart form primary complex.
There are separate disease entities:
Ghons focus with or without cavitation: There is poor
containment of organism leading to progressive
parenchymal caseation surrounding Ghon focus. Cavity
formation can result due to discharge of caseous material
into the bronchus with endobronchial spread.
Lymph node disease: The presence of marked clinical
symptoms due to enlargement of regional lymph nodes
differentiate lymph node disease from primary infection.
Bronchial disease: Affected regional lymph nodes attach
to the bronchus associated with primary infection. It can
be accompanied with (i) airway obstruction (ii) collapse/
hyperinflation. There can be allergic consolidation,
bronchopneumonic consolidation, or caseating
consolidation.
106
Pleural disease: It can be due to pleural involvement after

direct spread of caseous material from a subpleural
parenchymal or lymph node focus or from hematogenous
spread. The degree of pathology depends upon the dose
and virulence of bacilli entering the pleural space together
with the immune status of the host. It can be associated
with effusion, empyema or adult-type disease.
Hematogenous Spread
This is a condition of infinite gradation depending upon
the frequency, dose and virulence of the bacilli as well as
host immunity. During the occult spread bacilli are
seeded into susceptible organisms and the child remains
asymptomatic. When it is associated with invasion of the
bloodstream, tuberculous bacilli lodge in small capillaries,
where they may progress to form tubercles. These are
visible as typical, even sized miliary lesions on chest
radiograph usually less than 2 mm.
Outcome of Bronchial Obstruction

i. Complete expansion and resolution of chest X-ray
findings.
ii. Disappearance of the segmental lesions.
iii. Scarring and progressive compression of the lobe
or segment leading to bronchiectasis.
A caseated lymph node may erode through the wall
of the bronchus, leading to tuberculous bronchitis/
endobronchial tuberculosis. Fibrosis and bronchiectatic
changes may supervene. Discharge of M. tuberculosis into
the lumen may lead to bronchial dissemination of
infection.
Hematogenous dissemination of M. tuberculosis occurs

early in the course of the disease; this results when the
bacilli find their way into bloodstream through lymph
nodes. This may result in foci of infection in various
organs. If the host immune system is good, then these
foci are contained and disease does not occur. Seeding of
apex of lungs leads to development of Simons focus.
Lowering of host immunity may lead to activation of
these metastatic foci and development of disease. This is
especially seen in young infants, severely malnourished
children, and children with immunodeficiency (including
HIV infection). Massive seeding of bloodstream with M.
tuberculosis leads to miliary tuberculosis, where all lesions
are of similar size. This usually occurs within 3 to 6
months after initial infection.
Pulmonary tuberculosis resulting from endogenous
reactivation of foci of infection is uncommon in children;
but may be seen in adolescents. The commonest site for
this type of disease is the apex of the lung (Puhls lesion),
because the blood flow is sluggish at apex. Regional
lymph nodes are usually not involved in this type of
tuberculosis. A summary of the pathological progression
of disease without chemotherapy is given in Figure 9.3.
In summary pulmonary tuberculosis in childhood is
often considered a benign condition with little risk to the
child and no contribution to the transmission of disease
with in the community. Marais 11 emphasizes that
although this is true for the majority of infected children,
specific high-risk groups exist where disease poses a highrisk to fatality for the individual and or a high-risk of
transmission to the community. It has been further
described by him that major determinant of risk for
Fig. 9.3: Progression of pathology in intrathoracic TB following primary pulmonary infection in childhoodMarais et al15

disease development after primary infection is the host
immunity. Infants with immature immune systems are
at highest risk for development of pulmonary disease (30
to 40%). Tuberculous meningitis or miliary disease can
occur in 10 to 20%. The risk decreased in the second year
reaching its lowest in the 5 to 10 years age group. It was
highlighted by Marais20 that primary infection during
adolescence was associated with a high risk of developing
adult-type disease.
CLINICAL FEATURES
Childhood TB can be divided into two broad
classifications: intra and extrathoracic TB. Most children
with TB will develop pulmonary TB. Nonetheless, the
recognition of extrathoracic TB is equally important
because of its great potential for causing morbidity. There
is a trend that extrathoracic tuberculosis is increasing in
children and constitutes up to half of total cases.30
Intrathoracic Tuberculosis
Diagnosis of tuberculosis in a child is often difficult
because of absence of typical symptoms; signs and
microbiologic evidence in the majority of children with
pulmonary tuberculosis. The onset of symptoms is
generally insidious, but may be relatively acute in miliary
tuberculosis.
Primary infection usually passes off unrecognized.
Asymptomatic infection is defined as infection associated
with tuberculin hypersensitivity and a positive tuberculin
test but with no striking clinical or radiologic
manifestations. Most symptoms in children with primary
complex are constitutional in the form of mild fever,
anorexia, weight loss, decreased activity.31 Cough is an
inconsistent symptom and may be absent even in
advanced disease. Irritating dry cough can be a symptom
of bronchial and tracheal compression due to enlarged
lymph nodes. In some children, the lymph nodes continue
to enlarge even after resolutions of parechymal infiltrate.
This may lead to compression of neighboring regional
bronchus. Pulmonary primary complex is the most
commonly encountered presentation in the outpatient
setting. In a community setting, often primary infection
occurs without sufficient constitutional symptoms to
warrant medical advice. The PPC may be picked up
accidentally during evaluation of intercurrent
infections.31
Progressive primary disease (PPD) is the result of
progression of primary disease. Children with PPD may
present with moderate to high grade fever and cough.
Expectoration of sputum and hemoptysis are usually
associated with advanced disease and development of
cavity or ulceration of the bronchus. Physical findings of
consolidation or cavitation depend on the extent of the
disease. Abnormal chest signs consist mainly of dullness,
107
decreased air entry, and crepitations. Cavitating

pulmonary tuberculosis though uncommon is well
documented in children.32,33 Cavities are better seen on
computerized tomographic scan than X-ray film of
chest.34
Marais et al20 reported eight children (10 to 14 years
of age) who developed adult-type cavitating disease
which could be diagnosed by sputum smear microscopy
in contrast to younger children for whom smear
microscopy has very little diagnostic value. This
emphasizes the importance of correct disease
classification in childhood tuberculosis both for prognosis
and estimation of the transmission risk. It is well known
that adolescent girls are at higher risk to develop
tuberculosis after primary infection than boys.
Children with endobronchial tuberculosis may
present with fever, troublesome cough (with or without
expectoration). Dyspnea, wheezing and cyanosis may be
present. Occasionally, the child may be misdiagnosed as
asthma. In a wheezing child less than 2 years of age,
possibility of endobronchial tuberculosis should always
be considered, especially if there is poor response to antiasthma medications. Partial compression of the airway
can lead to emphy-sema. Features of collapse may be
present if a large airway is completely compressed.
Miliary tuberculosis is an illness characterized by
heavy hematogenous spread and progressive
development of innumerable small foci throughout the
body. The disease is most common in infants and young
children. The onset of illness is often sudden. The clinical
manifestations depend on the numbers of disseminated
organisms and the involved organs. The child may have
high grade fever, which is quite unlike other forms of
tuberculosis. The child may also have dyspnea and
cyanosis. There are hardly any pulmonary findings but
fine crepitations and rhonchi may be present. These
findings may occasionally be confused with other acute
respiratory infections of childhood. The illness may be
severe, with the child having high fever, rigors and
alteration of sensorium. In addition, these children may
have lymphadenopathy and hepatosplenomegaly. The
other presentation of miliary tuberculosis may be
insidious with the child appearing unwell, febrile and
losing weight. Choroid tubercles may be seen in about
13 to 87% children. 35 Meningitis may occur due to
bacillemia involving meninges and brain.36
The pleura may also be infected by hematogenous
spread from the primary focus. The effusion usually
occurs because of hypersensitivity to tuberculoproteins.
If the sensitivity is high, there is significant pleural
effusion along with fever and chest pain on affected side.
Minor effusions associated with the rupture of primary
foci are usually not detected. Tuberculous effusion is
uncommon in children younger than 5 years of age, is
more common in boys, and is rarely associated with
108
segmental lesion and miliary tuberculosis. The onset may

be insidious or acute with rise in temperature, cough,
dyspnea and pleuritic pain on the affected side. There is
usually no expectoration. Pain in chest may disappear
once the fluid separates the inflamed pleural surfaces;
this may be replaced by some discomfort. Increase in
effusion may make breathing shallow and difficult. The
clinical findings depend on the amount of fluid in the
pleural sac. In early stages, a pleural rub may be present.
Early signs include decreased chest wall movement,
impairment of percussion note and diminished air entry
on the affected side. As the fluid collection increases, the
signs of pleural effusion become more definite. 37
In some instances, acute secondary bacterial infection
occurs, presenting with high fever, cough and
crepitations. The symptoms and signs respond to
antibiotics, but the chest X-ray findings persist due to
underlying tuberculosis. Calcification of the primary
complex results from caseation. This occurs more
commonly in children.
Extrathoracic Tuberculosis
A complete description of extrathoracic TB is beyond the
scope of this chapter, but clinicians must consider this
possibility when evaluating children with a history of
persistent fever. The most common forms of extrathoracic
disease in children include TB of the superficial lymph
nodes (scrofula) and the central nervous system. Other
rare forms of extrathoracic disease in children include
osteoarticular, abdominal, gastrointestinal, genitourinary,
cutaneous, and pericardial disease.
DIAGNOSIS
Diagnosis of tuberculosis in children is usually based on
clinical signs and symptoms, chest roentgenogram,
tuberculin testing and history of contact with adult
patients. Clinical features may be nonspecific and chest
radiograph and Mantoux test are difficult to interpret. In
addition these do not give conclusive evidence of the
disease. Though demonstration of mycobacte-rium in
various clinical specimens remains gold standard, this is
often not possible in children due to the paucibacillary
nature of the illness.
Over last few decades many advances in
microbiologic methods, molecular techniques and
immunological investigation have taken place. Benefits
of these advances are not available to people in
developing countries due to cost, technical problems and
limited resources. Even with availability of these tests in
developed countries they are not very useful in children
suffering from tuberculosis due to paucibacillary nature
of illness.
CLINICAL FEATURES/SCORING SYSTEMS

It is important to make early diagnosis of tuberculosis in
children. Early intervention with antituberculosis drugs
in children may prevent dissemination of illness. Early
diagnosis of tuberculosis in children based on clinical
features is difficult. The common clinical features such
as-fever, cough, loss of appetite, weight loss or poor
weight gain may be present in other common childhood
illnesses.
To overcome the problem of diagnosis in children;
combination of clinical features, history of exposure to
an adult patient with tuberculosis, result of tuberculin
test and radiological finding have been evaluated by
various workers. In these scoring system38,39 more
weightage is given to laboratory test, i.e. acid-fast bacilli,
tubercles in biopsy, suggestive radiology and tuberculin
test >10 mm induration. Various scoring systems have
been developed after giving different weightage to these
variables (Table 9.1). Migliori et al40 proposed certain
criteria for diagnosis of pulmonary tuberculosis in
children for countries where culture for AFB are not
available (Table 9.2). These scoring systems need
validation in individual countries. To reduce the problem
of under/over diagnosis Osborne has provided
guidelines for suspecting TB in children (Table 9.3).41
Laboratory Tests
The diagnostic tests for pulmonary tuberculosis can be
broadly divided into 2 categories:
a. Demonstration/isolation of Mycobacterium tuberculosis
or one of its components.
b. Demonstration of hosts response to exposure to
M. tuberculosis, are described here with:
Table 9.1: Scoring systems for diagnosis of tuberculosis

Parameters
Acid-fast bacilli
Tubercle in biopsy
Tuberculin test >10 mm
Suggestive radiology
Compatible physical
examination
Contact with tuberculosis
in the family
Stengen
et al38
Nair
et al39
Seth*
+3
+3
+3
+2
+5
+5
+3
+3
+5
+5
+3
+3
+1
+3
+2
+2
+2
+3
Scores 1-2 TB unlikely; 3-4 tuberculosis possible; 5-6

tuberculosis probably; > 7 tuberculosis unequivocal,
* Unpublished data
109
Table 9.2: Diagnostic criteria for pulmonary tuberculosis40
Gastric Lavage
Gastric washes positive for AFB

or
Two or more of the following criteria:
History of contact with a tuberculosis adult
Suggestive symptoms of PTB (cough for more than 2 weeks)
2 TU PPD reaction positive
>10 mm in unvaccinated BCG patients
>15 mm in vaccinated BCG patients
Radiological findings compatible with PTB
Response to treatment (body weight increase > 10% after
2 months of treatment, plus clinical improvement).
The best specimen for demonstration of M. tuberculosis

in children is the early morning gastric aspirate (GA)
obtained by using a nasogastric tube before the child
wakes up and peristalsis empties the stomach of the
respiratory secretions swallowed overnight.44 The yield
of M. tuberculosis on ZN stain is less than 20% and
depends on extent of pulmonary disease and number of
specimen tested. 45 For better results 3 consecutive
specimen of gastric aspiration are recommended.46 If a
delay in the processing of specimen is expected the GA
should be neutralized with sodium bicarbonate for higher
yield.47
Table 9.3: Guidelines for the diagnosis of tuberculosis

Suspected tuberculosis
Any child with history of contact with confirmed case of
pulmonary TB
Is not gaining normal health after measles, pertussis
Has loss of weight, cough and wheeze not responding to
antibiotic therapy for respiratory disease
Has painless swelling in superficial group of lymph nodes.
Probable tuberculosis
A suspected case and any of the following:
Positive mantoux test (induration > 10 mm)
Suggestive radiological finding
Suggestive histological appearance of biopsy
Favorable response to antituberculosis therapy
Confirmed tuberculosis
Detection of tubercle bacilli by microscopy or culture
Identification of tubercle bacilli as mycobacterium by
culture characteristics.
Demonstration of M. tuberculosis or its Components

Specimens for demonstration of M. tuberculosis: The
specimens used for demonstration of M. tuberculosis in
pulmonary tuberculosis include: sputum, gastric lavage,
bronchoscopic lavage fluid, or pleural fluid.
Sputum: Sputum is conventionally used for diagnosis of
tuberculosis in adult patients. However, it is difficult to
collect sputum in young children. Therefore, gastric
aspirate is used for demonstration of M. tuberculosis in
children with suspected pulmonary tuberculosis. Recent
reports suggest good results of isolation of M. tuberculosis
from induced sputum in young children.42,43
For sputum induction child is pretreated with 200 g
salbutamol given via metered dose inhaler with attached
spacer or nebulizer to prevent the occurrence of
bronchoconstriction. A jet nebuliser attached to oxygen
at a flow rate of 5 liter/min or compressor can be used to
deliver 5 ml of 3% sterile saline for 15 minutes. Sputum
is obtained either by expectoration (in children able to
cooperate) or by suctioning through the nasopharynx or
oropharynx using a sterile, mucus extractor of catheter
size 6. Specimens should be transported directly to the
laboratory for processing.
Bronchoscopy and Bronchoalveolar Lavage

It has been documented that gastric aspirate (GA) is
superior to bronchoalveolar lavage (BAL) fluid for the
yield of AFB in childhood tuberculosis.44,48 A recent study
on 58 children comparing GA and BAL showed that in
10 (17.2%) children M. tuberculosis was grown from gastric
lavage whereas 12 children had their BAL positive for
this bacteria. Overall, mycobacterial isolation was
possible in 20 patients (34.4%) as two children had grown
M. tuberculosis in GA as well as BAL.49 Addition of BAL
to the diagnostic workup increased the mycobacteriological yield from 17.2% with gastric lavage alone to 34.4%
when BAL was also performed. Results of this study
suggest that there is no difference in mycobacterial
isolation rates from gastric lavage and BAL when studied
in isolation. However, when both GA and BAL are used,
these procedures complement each other to increase the
diagnostic yield. Gastric lavage for isolation of M.
tuberculosis is a well-accepted method. It is suggested that
one should try to obtain gastric aspirate for diagnosis of
tuberculosis in children as far as possible. Bronchoscopy
may be considered when diagnosis is doubtful or a
possibility of resistant tuberculosis is considered.
Methods for Identification of M. tuberculosis

A. Smear
i. Ziehl-Neelsen (ZN) staining: ZN stain is positive if the
number of M. tuberculosis is more than 104 /ml of
specimen. 50 It can be used on all the specimen
including sputum, induced sputum, gastric aspirate
and bronchoalveolar lavage. The yield of M.
tuberculosis on ZN stain is less than 20% and depends
on extent of pulmonary disease and number of
specimens tested.45
ii. Special staining for AFB: Fluorochrome stained smears
can be viewed more efficiently as they are viewed
under high dry magnification rather than oil
immersion. The organisms are easier to detect
against dark background and significantly larger
110

area of the smear can be screened per unit of time.45
These smears have a greater sensitivity than those
of ZN stain51 Staining at 37 C enhances detection of
mycobacterium by fluorochrome staining.52 More
recently immunomagnetic separation have been
used to improve the detection of mycobacterium.53
In a recent study, the sensitivity of ZN stain on
GA in pulmonary primary complex (PPC) and
progressive primary disease (PPD) was 1.1% and
31.8% respectively; it improved to 9.4 percent
and 50% respectively with auramine-O staining.54
Though auramine-O staining increases the yield of
identification of M. tuberculosis, need for fluorescence
microscopy limits its role in the diagnostic work up.
B. Culture: A variety of media are in use for cultivation

of M. tuberculosis. These include Lowenstein Jensen (LJ),
Middlebrook 7H10 and 7H11 media.
LJ medium is most widely used. In this characteristic
features of colony morphology, growth rate and pigment
production can be seen. Using culture technique it is
possible to isolate mycobacteria from specimen
containing more than 10 mycobacteria/ml. Though the
culture technique is simple, 7 to 10 weeks of incubation
may be necessary for detection of organisms. Microscopic
examination of thin layer culture plate may lead to
detection of microcolonies of M. tuberculosis as early as
7 days.55 However, recovery of M. tuberculosis from this
is less efficient and labor intensive. The yield of culture
varies from 30 to 50%. Higher yield up to 70% have been
reported in infants with extensive disease.46
Excessively long period required for isolation of
M. tuberculosis by LJ medium has led to development of
other techniques for culture: BACTEC Radiometric Assay,
Septi-check AFB system and Mycobacterial growth indicator
tube system (MGIT).
The BACTEC system improves the yield of positive
cultures from clinical specimen and lessens the time taken
to detect M. tuberculosis.56 The average time required for
detection of M. tuberculosis by BACTEC is 9 to 14 days.
Venkatraman et al56 reported 87% of the positive cultures
by day 7 and 96% by day 14. The capability of performing
rapid mycobacterial drug sensitivity is an additional
advantage of the BACTEC system.57
The limitation of BACTEC system include high cost
of instruments, inability to observe colony morphology
and detect mixed cultures, overgrown by contaminants,
need for disposal of radioactive and extensive use of
needles.
The available studies have used sputum in BACTEC
system. The experience with other body fluids including
gastric lavage is limited. In a recent study using gastric
aspirate in BACTEC, there was not even a single case
positive of Pulmonary Primary Complex (PPC).54
Septi-check AFB system requires about 3 weeks

incubation. Various studies carried out in adults have
suggested that Septi-check system is more sensitive than
LJ Media/7H11 and BACTEC in percentage age of
isolates recovered.58 Though, pediatric studies are not
available, this system may be useful in children as well.
Mycobacterial Growth Indicator Tube System (MGIT): It
uses a fluorescent compound embedded in silicone on
the bottom of the tube containing modified 7H11 broth
with antibiotic mixture and growth supplements for
mycobacteria. As this fluorescent compound is sensitive
to oxygen, depletion of the latter by growth of
mycobacteria, unmasks the fluorescence, which can be
detected by observing the tube under long wave
ultraviolet light. Available literature suggests that this
method is as sensitive as the BACTEC system.59 Nutrient
broth growth supplementation of standard MGITs
improved the mycobacterial yield and significantly
reduced the time to detection of mycobacteria in pediatric
samples. 60
C. Polymerase chain reaction (PCR): Polymerase chain
reaction is the most commonly used technique of nucleic
acid amplification, used for diagnosis of tuberculosis. The
PCR may be used to:
i. Diagnose tuberculosis rapidly by identifying DNA
from M. tuberculosis in clinical samples that are
negative by microscopic examination.
ii. Determine rapidly whether acid-fast organisms
identified by microscopic examination in clinical
specimens are M. tuberculosis or atypical
mycobacteria.
iii. Identify the presence of genetic modifications known
to be associated with resistance of some
antimycobacterial agents.
The results of the studies on utility of PCR in diagnosis
of childhood tuberculosis has been summarized in
Table 9.4. In children, the results of PCR have been
compared with clinical diagnosis and not culture. The
most commonly used target for detection of M.
tuberculosis is the insertion sequence IS6110. The
sensitivity ranges from 4 to 80% and the specificity 80 to
100%.54,61-65 These results are not very promising.
A blinded study comparing results obtained on
specially prepared standardized samples by 7 different
laboratories, demonstrated significant differences in the
results obtained.66 This demonstrates the variability in
the pickup rates in different laboratories. In addition, the
clinical laboratories may not obtain results similar to those
in research laboratories.
It appears that PCR has a limited role in evaluating
children for tuberculosis. A negative PCR never
eliminates possibility of tuberculosis, and a positive result
111

Table 9.4: Utility of PCR in diagnosis of tuberculosis in children (in gastric aspirate)
Authors
Subjects
Test/ Fragment
Standard
Sensitivity
Specificity
Delacourt
et al,61
1995
53 suspected TB,
(24 active disease
11 Exposure and
Mantoux +ve,
11 Suspected TB;
7 Exposure ve
Mantoux +ve)
15 Controls
35 Pulmonary TB
PCR/ IS6110
Clinical
diagnosis
Active disease 83.3,

Infection without
disease 38.9
100
PCR/ IS6110
40
100
PPC 38.6
PPD 44
4.1 (There was
discordance
between culture
and PCR results)
100 with CSF,
20 with gastric
aspirate, 100
pleural fluid
samples
90 in culture
positive cases
100 for smear
positive,
77 for smear
negative
80
Smith et al62
1996
Ninan SA54
1997
Neu et al63
1999
40 (31- PPC,
9-PPD)
27 Suspected TB
PCR/ IS6110
PCR
(Amplicor)
Clinical
diagnosis
Clinicoradiologic diagnosis
Clinicoradiologic diagnosis
Jatana et al64
2000
80 children,
41 probable TB,
39 controls
IS6110 as target
for DNA
Clinical
criteria
Montenegro
et al65 2003
392 specimen
from 222 children
Heminested
IS6110 PCR
Clinical
diagnosis and
culture
93
94
PPD Progressive primary disease
is not always confirmatory. In addition, the results of this

expensive technique may be less promising in routine
clinical laboratories. The PCR may be useful in evaluating children with significant pulmonary disease when
diagnosis is not readily established by other means, and
in evaluating immunocom promised children (HIV
infection) with pulmonary disease.67-69
D. Gas liquid chromatography (GLC) or High
performance liquid chromatography (HPLC): These
methods have been used to aid in characterization of
mycobacteria by analysis of cellular long chain fatty acids.
The fatty acid pattern is species specific. Though this
method is reliable, economical, it requires considerable
expertise.70
Demonstration of Host Response on Exposure to

M. tuberculosis
The host response to infection with M. tuberculosis may
be cell mediated or humoral. Humoral immune response
may be assessed by measuring the immunoglobulins to
various antigens (serodiagnosis). The cell-mediated
response can be demonstrated by skin tests (Mantoux test)
In vivo and by Leukocyte Migration Inhibition Test (LMIT)

and lymphoblast transformation in-vitro.
Serodiagnosis
In absence of good diagnostic method for tuberculosis, a
lot of interest has been generated in serodiagnosis. ELISA
has been used to detect antibodies to various purified or
complex antigens of M. tuberculosis in children. Despite a
large number of studies71-76 published over the past
several years (Table 9.5), serology has found little place
in the routine diagnosis of tuberculosis in children, even
though it is rapid and does not require specimen from
the site of disease. Sensitivity and specificity depend on
the antigen used, gold standard for the diagnosis of
tuberculosis and the type of tubercular infection. Though
most of these tests have high specificity, their sensitivity
is poor.71-76 In addition, these tests may be influenced
by factors such as age, prior BCG vaccination and
exposure to environ-mental mycobacteria. At present,
serodiagnosis does not have any role in diagnosis of
childhood pulmonary tuberculosis. Most of the available
tests lack acceptable sensitivity and specificity.
112

Table 9.5: Utility of serodiagnosis in diagnosis of childhood TB
Authors
Subjects
Antigen used
Antibody
Sensitivity (%)
Specificity (%)
Delacourt
et al,71 (1993)
14 culture positive
17 probable TB
16 infected but
healthy
198 healthy controls
A 60
IgG
71 in culture positive TB
65 in probable TB
98
Gupta et al72
pulmonary TB
58 definite
A 60
IgA,
IgG,
IgG 32.7
IgM
IgM 55.2
IgG 95.7
IgA 36.2
IgM+ IgA 72.4
IgM 92.6 (1997)
OT 40.3
PPD 50
30 kD 36.1
OT 96.3
PPD 96.8
30 kD 97.3
161 controls
Zheng et al73
(1994)
122 children with

clinical diagnosis
of TB
187 controls
Polymerized
old tuberculin
(OT)
PPD 30 kD
antigen
IgG
Turneer et al74
(1994)
35 asymptomatic
primary TB (ATB)
29 symptomatic
TB (STB)
23 post TB
81 controls
35 pulmonary TB,
7 TB lymphaadenitis and 22
healthy control
A 60
IgG, IgM
Swaminathan
et al75 (1999)
Imaz et al76
IgA
(2001)
3
ATB
STB
Post
TB
A 60
38 kDa
antigen
IgG
6
14
26
IgG, IgM
IgG
74 active TB,
16-kDa
IgG, IgM
49 healthy contact
antigen
and IgA
Pulm TB
TBL
Culture +
Pulm TB
TBL
Culture +
ATB
IgM
23
17
35
IgA 96.3
IgM+A 92
IgG or IgM
26
31
48
IgM IgG
74
17
57
86
80
30
37
86
50
IgG
95
IgM
95
IgG and IgM
99
IgM
IgG
50
86
IgG
73
IgG
IgM
34
19
149 nonmycobacterial infection

TBL TB lymphadenitis, PPD Purified protein derivative
PCR Based Cytokine Detection in Tuberculosis

Cytokine expression has not been studied in detail in
children with TB. The relative amounts of the various
cytokines released at the site of infection may be
important determinants of TB disease development and
pathology. Aubert-Pivert et al77 determined cytokine
transcripts (IFN- gamma, IL-12, TNF- alpha, IL-10, IL-4,
TGF- beta 1) in bronchoalveolar cells (BACs) recovered
from 9 children presenting with TB and from 9 children
with pulmonary diseases other than TB. Expression of
mRNA encoding TGF-beta, TNF-alpha and IFN-gamma
was statistically significantly higher in BACs from
children with TB than in BACs from children with other
pulmonary diseases; whereas the levels of mRNA

transcription for TGF- beta was high, the levels of mRNA
transcription for IFN-gamma and TNF-alpha remain low.
All children had low levels of mRNA for IL-12. IL-4 was
barely detectable in all cases. Children with miliary TB
had high levels of IL-10 transcripts and low levels of
mRNA encoding TGF-beta. The immunosuppressive
cytokines TGF-beta and IL-10 are overproduced in
children with non-miliary TB and miliary TB respectively
and are probably involved in the progression of the
disease. Further studies are required to confirm these
findings. Such information may lead to development of
tests to help differentiate tuberculosis from other
respiratory conditions.
113
Circulating Immune Complex

Simonney et al78 performed ELISAs using the three
glycolipids LOS, DAT and PGLTb1 in whole serum and
immune complexes from 20 children with tuberculous
disease or infection, in seven child contacts, and in 26
children with nontuberculous disease. The contribution
of complexed IgG antibody to the diagnostic values was
established for each group. The antibody levels in free
serum were higher (P < 0.01) in children with tuberculous
disease or infection and in contacts than in controls. By
contrast, except for PGLTb1, the IgG antibody levels were
higher (P < 0.02) in children with tuberculous disease than
in the other groups. The detection of immune complexes
and IgG antibodies against the three glycolipid antigens
is useful as a complementary technique for the
serodiagnosis of children with a high probability of
pulmonary tuberculosis. As of now, this test does not
seem to have significant contribution in diagnosis of
tuberculosis in children. Srivastava et al79 measured
antigen and antibody in circulating immune complexes
(CIC) in 52 children with pulmonary and extrapulmonary
TB. CIC antigen was present in 92.3% and CIC antibody
in 88.96% of children. Out of these 52 patients, 20 were
proved cases and CIC antigen and antibody were present
in all 20 cases. More experience is required for use of CIC
in diagnosis of TB in children.
consensus regarding the most common site of

involvement.80-83 In Tuberculosis clinic of AIIMS, New
Delhi, India 35% of children had only parenchymal lesion,
nodal component in 36%, whereas 29% had both
parenchymal as well as nodal lesions (Table 9.6).
Consolidation in progressive primary disease (PPD)
is usually heterogeneous, poorly marginated with
predilection of involvement of apical or posterior
segments of upper lobe or superior segment of
lower lobe84 (Fig. 9.5). There may be features of collapse
Skin Test as a Measure of Cell Mediated

Immune Response
Table 9.6: Distribution of parenchymal (P), nodal (N) and

parenchymal plus nodal (P+N) lesions of pulmonary
primary complex (PPC)
Tuberculin skin test is useful in evaluation of children

suspected of having tuberculosis in as much that a
significant reaction supports the diagnosis, while absence
of the same does not rule out tuberculosis. The test should
be performed using 1 TU PPD with RT23 and tween 80;
as the cutoff values for induration are available for this
strength for Indian children. An induration of more than
10 mm in presence of clinical setting suggest active
tuberculosis. Isolated positive tuberculin test indicates
infection with M. tuberculosis. An induration of between
5 to 10 mm with a clinical setting in children with
immunocompromized state suggest presence of
tuberculosis disease.
Fig. 9.4: X-ray film of PPC showing left hilar adenopathy with ill
defined parenchymal lesion
Type of lesion
PPC (P)
PPC (N)
PPC (P + N)
567
585
444
35
36
29
1596
100
Total
Radiology
Chest radiograph has an important role in diagnosis of
childhood tuberculosis, especially pulmonary
tuberculosis. In extrapulmonary tuberculosis, presence
of lesions on chest radiograph supports diagnosis.
The typical chest X-ray appearance of a pulmonary
primary complex is that of an airspace consolidation of
variable size, usually unifocal, homogeneous (Fig. 9.4).
Enlarged lymph nodes are usually seen in the hila, right
paratracheal region. Adenopathy alone may be the sole
manifestation of primary tuberculosis. There is no
Fig. 9.5: PPD showing consolidation
114
as well (Fig.9.6). Bronchiectasis may occur in PPD because

of (i) destruction and fibrosis of lung parenchyma
resulting in retraction and irreversible bronchial
dilatation, and (ii) cicatricial bronchostenosis secondary
to localized endobronchial infection resulting in
obstructive pneumonitis and distal bronchiectasis. In
children, cavitary disease is uncommon (Fig. 9.7).
Pleural effusion may occur with or without lung lesion
(Fig. 9.8).
In miliary tuberculosis, there are multiple lesions of
size 2 to 5 mm (Fig. 9.9). Associated lymphadenopathy is
seen in more than 90% children.85 Occasionally, the chest
radiograph may be normal and lymphadenopathy may
be detected on computed tomography (CT), which is not
evident radiographically.86 In addition, CT features such
as low attenuation lymph nodes with peripheral
enhancement, lymph node calcification, branching
centrilobular nodules and miliary nodules are helpful in
Fig. 9.8: Massive pleural effusion on left side
Fig.9.6: Collapse consolidation of right upper lobe
Fig. 9.9: Miliary shadows with right paratracheal adenopathy
Fig. 9.7: Cavity
suggesting the diagnosis in cases where the radiograph

is normal or equivocal. Other features such as segmental
or lobar consolidation and atelectasis are nonspecific.87
In a study by Kim et al,87 CT including high resolution
CT (HRCT) revealed lymphadenopathy, which was not
demonstrated in 21% of radiographs, and parenchymal
abnormalities, not seen on 35% of radiographs. HRCT is
more sensitive than chest radiography for the detection
of miliary TB. The HRCT findings are widespread
multiple small (< 2 mm diameter) nodules.88 The nodules
may be so numerous that they coalesce to form larger
nodules greater than 2 mm in diameter or even
consolidation with air bronchograms. Thickening of the
interlobular septa may also be a feature. Mediastinal and
hilar lymphadenopathy may also be present. Cavitation
is reported to be rare on chest radiography in children
with TB. However, children with both HIV and TB may
have atypical radiographic features and cavitation has
115
been reported89,90 CT may show areas of cavitation that

are not apparent on chest radiography, which may raise
the possibility of a previously unsuspected underlying
immune disorder.91 HRCT can differentiate old fibrotic
lesions from newly active tuberculous lesions. CT scan
may help in CT guided aspirations for diagnosis and
drainage of cold abscess.92 Role of high-resolution and
color Doppler ultrasonography (US) in diagnosis of
cervical lymphadenopathy has been reported. Central
irregular hyperechogenic areas, blurred margins and
central necrosis were most frequent in bacterial,
tuberculous and cat scratch disease.93
most often made by combination of a positive tuberculin

skin test, chest radiograph, physical examination and
history of contact with adult patient often in the family
with tuberculosis. Newer diagnostic methods such
as PCR, chromatography have not given encouraging
results. Same is the case with serodiagnosis. Newer
staining and culture methods have found their place in
the better and early laboratory diagnosis. There is an
urgent need to develop better techniques for diagnosis
of tuberculosis disease in children. The suggested
algorithm for diagnosis of pulmonary TB in children is
METHODS TO DIAGNOSE LATENT TUBERCULOSIS

INFECTION
Treatment
Till date, tuberculin skin test (TST) was the only method
to diagnose latent tuberculosis infection. Recently, new
in vitro diagnostic aids that measure a component of cellmediated immune reactivity to M. tuberculosis, and is
based on the quantification of interferon-gamma (IFNgamma) released from sensitized lymphocytes in whole
blood incubated overnight with different antigens from
M. tuberculosis. Initially the interferon gamma release
assays (IGRA) used purified protein derivatives (PPD)
as stimulating antigens. Now PPD is replaced with more
specific antigens like, Early Secreted Antigenic Target-6
(ESAT-6), Culture Filtrate Protein 10 (CFP 10), TB 7.7
(Rv2654). Antigens; ESAT-6 and CFP 10 are not shared
with BCG and other species of atypical mycobacterium,
making these tests more specific for infection with
mycobacterium tuberculosis. There are two sets of
commercially available tests based on interferon-gamma
(IFN- gamma) estimation (Quanti FERON-TB(R) Gold InTube (QFT-IT) and T-SPOT.TB). Studies comparing
performance of both tests suggest variable results.94
However, on reviewing all the studies it can be concluded
that the sensitivity and specificity of IGRA methods
compares well with the TST. However, IGRA methods
are associated with single visit and as it is an in vitro test
there are no chances of complications associated with TST,
including exaggerated delayed type hypersensitivity
reactions causing necrosis and vesiculations. At present
the major limiting factor to replace TST with these tests
is their cost. In future when the cost is less they may be
used to replace TST.95
The sensitivity of IGRA based tests may be less in
younger age as compared to tuberculin skin test.96
The principles of therapy have been dealt with elsewhere.

One of the important biologic determinants of success of
therapy is the size of the bacillary population in the child.
Most of children with pulmonary tuberculosis have
paucibacillary disease. The approximate numbers of
bacilli in different types of lesions are as follows: cavity
109, asymptomatic Mantoux positive 103 to 104, primary
complex 104 to 105. To some extent, the load can be judged
on a chest X-ray. Lack of cavitary lesions implies a lower
bacillary load. A child with positive Mantoux and a
normal chest X-ray has some bacilli in his macrophages,
the bacillary load is less. It increases in primary complex
and progressive primary disease.
Drug Regimens
During the last few years, dramatic changes have
occurred in the therapeutic approaches to childhood TB
DIAGNOSTIC ALGORITHM FOR PULMONARY

TUBERCULOSIS
The diagnosis of tuberculosis disease in children
continues to be extremely challenging throughout the
world. Even in the advanced nations, the diagnosis is
Fig. 9.10: Proposed diagnostic algorithm for pediatric PTB
116
as a result of large number of treatment trials for children

and increased concern about the development of
resistance to antituberculosis drugs. Short-course chemotherapy, with the treatment duration as short as 6 months,
has become the standard practice. Thrice weekly
intermittent regimens have been documented to be as
effective as daily regimen in the adult population.97
However, there are few studies comparing twice a week
intermittent regimen in childhood tuberculosis.98-101 A
meta- analysis of all these studies revealed that daily
regimen is superior to twice a week intermittent
regimen.102
Directly observed therapy short-course (DOTS) has
been successfully used in children.103 The major problem
in inclusion of children in DOTS is difficulty in
demonstration of AFB and classification of different
clinical manifestations according to categories described
for adults. There have been efforts to develop
classification of different types of childhood TB into three
categories similar to those for adults. A classification was
developed and evaluated in the tuberculosis clinic of a
tertiary care hospital.104 In this study on 459 children with
TB, 365 (80%) children completed the treatment. Of these,
302 (82.7%) were cured with the primary regimen
assigned to them in the beginning, 54 (14.8%) required
extension of treatment for 3 months and 9 (2.5%) patients
required change in the treatment regimen. The authors
concluded that it is feasible to classify and manage various
types of tuberculosis in children in different categories
similar to WHO guidelines for adult tuber-culosis.105
Recently a consensus statement jointly prepared by
Indian Academy of Pediatrics and Revised National

Tuberculosis Control Program (RNTCP) has also
proposed a classification of different types of tuberculosis
in children into three categories.105
Drug Regimens for Pulmonary Tuberculosis

Table 9.7 gives standardized clinical categories given by
WHO. For all type of pulmonary tuberculosis except PPC
and minimal pleural effusion the recommended
treatment regimen is 2H3R3Z3E3 4 H3R3 if treated under
DOTS and otherwise it may be a daily regimen of 2HRZE
4 HR at home. For PPC and minimal pleural effusion
under DOTS it may be 2 H3R3Z3, 4 H3R3 and otherwise a
daily regimen of 2 HRZ 4 HR is recommended. Here
minimal pleural effusion is defined as unilateral blunting
of costophrenic angle but lung fields are visible and an
underlying lung parenchymal lesion has been ruled out.
Children who have received antituberculosis drugs in
past for more than 4 weeks should receive 2 S3H3R3Z3
E3/1 H3R3Z3E3/5 H3 R3 E3 under DOTS otherwise a daily
regimen of 2 SHRZE 1 HRZE 5 HRE should be given to
them.
Though DOT short-course chemotherapy regimens
have been found to be very effective in adults, it is not
possible to have the kind of infrastructure needed under
DOTS for all children across board. Hence along with
DOTS, the regimens suggested in Table 9.7 by the authors
should be evaluated further.
In HIV infected children with pulmonary tuberculosis,
these regimens can be used, but the duration of therapy
is increased to 9 months.
Table 9.7: Standardized (clinical categories, clinical conditions and suggested drug
regimens by the authors in children)
Categories
As suggested by
WHO for adults
Suggested conditions
in children
Suggested drug
regimens
Category I
New sputum positive

Pulmonary TB
PPD, TBL
Pleural effusion
Abdominal TB or
Osteoarticular TB
Genitourinary TB*
CNS TB
2 HRZE
4 HR
2 SHRZ
4 HR
Category II
Relapse
Treatment failure
Return after adult default
(Interrupted treatment)
Relapse
Treatment failure
Interrupted treatment
2 SHRZE
1 HRZE
7 HRE
Category III
Sputum-negative pulmonary
with limited parenchymal
involvement
Extrapulmonary TB
(less severe forms)
Single lymphnode
Small effusion
Skin TB
PPC
2 HRZ
4 HR
PPC Pulmonary Primary Complex , PPDProgressive Primary Disease, TBL Tubercular Lymphadenitis, CNS TB
Central Nervous System Tuberculosis
*In genitourinary tuberculosis, dose to be adjusted as per creatinine clearance.
Interrupted Treatment
Whenever the treatment is interrupted for more than
2 weeks, the child should be reassessed clinically and
radiologically. Wherever possible bacteriological
examination should be perfor-med. A suggested
guideline for treatment after interruption of therapy is
given in Table 9.8.
Corticosteroids
Corticosteroids, in addition to antitubercular drugs, are
useful in treatment of children with CNS tuberculosis and
some children with pulmonary tuberculosis. These are
mainly useful in settings where the host inflammatory
reaction contributes significantly to tissue damage. Shortcourses of corticosteroids are indicated in children with
endobronchial tuberculosis that causes localized
emphysema, segmental pulmonary lesions or respiratory
distress. Some children with severe miliary tuberculosis
may show dramatic improvement with cortico-steroids
if alveolo-capillary block is present. Significant
improvement in symptoms can occur in children with
tuberculous pleural effusion with use of corticosteroids.
The most commonly used medication is prednisolone, in
dose of 1 to 2 mg/kg/day for 4 to 6 weeks.
Monitoring of Therapy
Response to treatment can be judged by using the
following criteria: clinical, radiological, bacteriological,
and laboratory test.106
Clinical Criteria
Clinical improvement in a child on ATT is the mainstay
of judging response to therapy. The child should be seen
every 2 to 4 weeks initially, then every 4 to 8 weeks. On
each visit, improve-ment in fever, cough, appetite and
Table 9.8: Treatment after interruption
Duration
Duration of Decision
therapy
interruption
Up to 4 weeks
< 2 weeks
> 2 weeks
4-7 weeks
< 2 weeks Resume original regimen

> 2-8 weeks Extend intensive phase by
1 month, Category II regimen
> 8 weeks Reassess and start appropriate
regimen
> 8 weeks
< 2 weeks
> 2 weeks
Resume original regimen

Reassess and start appropriate
regimen
Resume the original regimen

Resume therapy Category II
117
subjective well-being is assessed. The child is examined

for weight gain and improvement in chest findings.
Compliance is assessed by talking to parents and checking
medications on each visit. Majority of children show
improvement in symptoms within a few weeks.
In the presence of poor response or worsening of
symptoms or signs, the initial basis of diagnosis is
reviewed, especially, if there are no problems with
compliance. Assessment for possibility of drug resistant
tuberculosis should be made. After the treatment is over,
follow-up every 3 to 6 months for next 2 years is desirable.
Radiological Criteria
Clinical improvement precedes radiological clearance of
lesion on chest X-ray films. The optimal frequency of
radiological monitoring in children with pulmonary
tuberculosis is unclear. One protocol suggests obtaining
X-ray films of the chest after 4 to 8 weeks of therapy. If it
shows improvement in combination with clinical
response, 2nd X-ray should be done at the end of
therapy.107
In our opinion, the first chest X-ray during therapy
should be done after 8 weeks, i.e. at the end of intensive
phase. In patients who show increase or little change in
radiological features coupled with delayed clinical
response, prolongation of intensive phase by a month is
recommended. Further films are taken after 4 weeks. If
the child is better, should be shifted to continuation phase;
else the child is investigated for failure of treatment and
drug resistance. The degree of radiological clearance can
be graded as (1) Complete clearance, (2) Moderate to
significant clearance(1/2-2/3 clearance), (3) Mild
clearance (1/3 decrease in size) or (4) No clearance or
appearance of new lesion.108
One should not attempt to treat till complete
radiological clearance, improvement in the X-ray may
continue to occur even after stoppage of therapy.109
Microbiological Criteria
Most of the childhood pulmonary tuberculosis is
paucibacillary. In children, where isolation of
M. tuberculosis was possible at the time of diagnosis, every
effort should be made to document disappearance of
bacilli during therapy.
Nonspecific Test for Monitoring

Although an elevated erythrocyte sedimentation rate
(ESR) may be expected in children with tuberculosis, a
recent study found that one-third of children with TB had
a normal ESR at the time of diagnosis, suggesting little
value in using ESR as a diagnostic and monitoring test
for childhood tuberculosis.110
118
Determinants of Outcome of Treatment of

Childhood Tuberculosis
Majority of patients respond very well to ATT with good
compliance. Factors such as extensive disease, young age,
poor adherence, underlying immune deficiency and drug
resistant TB can be associated with poor outcome. A
recent study reported that AFB positivity at time of
diagnosis, nonreceipt of BCG vaccination during infancy
and extrapulmonary tuberculosis were associated with
treatment failure.111
HIGHLIGHTS
Natural history of clinical expression of infection due
to M. tuberculosis depends upon the age of infection
and host immune status.
Children infected prior to age 4 have a very high
rate of developing immediate clinical or
radiographic manifestations or both. This group is
less likely to develop reactivation disease in
adulthood.
Children infected in preadolescents or adolescence
are more prone to develop severe adult type
pulmonary tuberculosis soon after infection or in
adulthood.
Serodiagnosis does not have any role in the diagnosis
of pulmonary tuberculosis in children.
Both in industrialized or developing countries, the
triad of a positive tuberculin skin test, radiographic
and/or consistent clinical manifestations along with
establishment of recent contact to a known infectious
case of tuberculosis in the home or immediate
surrounding is the gold standard for diagnosis.
Though some prevention of childhood tuberculosis
can be achieved by the use of BCG, use of
chemotherapy to treat latent tuberculosis discovered
via contact tracing is of paramount importance even
when BCG is given.
REFERENCES
1. Comstock G. Epidemiology of tuberculosis. In: Reichman
LB, Hersh- field E (Eds). Tuberculosis: A Comprehensive
International Approach. New York: Marcel Dekker, Inc.
2000;129-48.
2. Nguyen TH, Odermatt P, Slesak G, et al. Risk of latent
tuberculosis infection in children living in households
with tuberculosis patients: A cross-sectional survey in
remote northern Lao Peoples Democratic Republic. BMC
Infect Dis 2009;9:96.
3. Aissa K, Madhi F, Ronsin N, et al. CG94 Study Group.
Evaluation of a model for efficient screening of
tuberculosis contact subjects. Am J Respir Crit Care Med
2008;177:1041-7.
4. Ghon A. The primary lung focus of tuberculosis in
children. London, JA Churchill, 1916.
5. Sweany HC. Studies on the pathogenesis of primary

tuberculous infection. Am Rev Tuber 1933;27:559-88.
6. Medlar EM. Behaviour of pulmonary tuberculous lesions:
A pathological study. Am Rev Tuberc 1955;71:31.
7. Courtice FC, Simmonds WJ. Physiological significance
of lymph drainage of serous cavities and lungs. Physiol
Rev 1954;34:419-42.
8. Upham JW, Rate A, Rowe J, et al. Dendritic cell
immaturity during infancy restricts the capacity to
express vaccine-specific T-cell memory. Infect Immun
2006;74:1106-12.
9. Holt PG. Postnatal maturation of immune competence
during infancy and childhood. Pediatr Allergy Immunol
1995;6:59-70.
10. Newton SM, Brent AJ, Anderson S, et al. Paediatric
Tuberculosis. Lancet Infect Dis 2008; 8:498-510.
11. Marais BJ, Gie RP, Schaff HS, et al. The natural history of
childhood intrathoracic tuberculosis: A critical review of
Lung Dis 2004; 8:392-402.
12. Pabst HF. Ontogeny of the immune response as a basis
of childhood disease. J Pediatr 1980;97: 519-34.
13. Seth, Vimlesh, Kabra SK, Rachna Seth. Clinicoimmunological profile. Indian scenario in; Essentials of
tuberculosis in children. Seth, Vimlesh, Kabra SK, (Eds),
Jaypee Brothers Medical Publisher (P) Ltd. New Delhi
2006;95-108.
14. Marais BJ, Donald PR, Gie RP, et al. Diversity of disease
in childhood pulmonary tuberculosis. Annals of Tropical
Paediatrics 2005;25:79-86.
15. Marais BJ, Gie RP, Schaaf HS, et al. A proposed radiologic
classification of childhood intra-thoracic tuberculosis.
Pediatr Radiol 2004;33: 886-94.
16. Converse PJ, Dannenberg AM, Estep JE, et al. Cavitary
tuberculosis in rabbits by aerosolized virulent tubercle
bacilli. Infect Immune 1996;64: 4776-87.
17. Marais BJ, Gie RP, Schaaf HS, et al. The clinical
epidemiology of childhood pulmonary tuberculosis: A
critical review of literature from the prechemotherapy
era. Int J Tuberc Lung Dis 2004;8:278-85.
18. Zahrt TC. Molecular mechanisms regulating persistent
Mycobacterium tuberculosis infection. Microbes Infect
2003;5:159-67.
19. Boom WH, Canaday DH, Fulton SA, et al. Human
immunity to M. tuberculosis. T cell subsets and antigen
processing. Tuberculosis 2003;83:98-106.
20. Marais BJ, Gie RP, Hesseling AH, et al. Adult-type
pulmonary tuberculosis in children 10-14 years of age.
The Pediatric Infectious Disease Journal. 2005;24:743-4.
21. Lamont A, Cremin B, Pettenet B. Radiologic patterns of
pulmonary tuberculosis in the pediatric age group.
Pediatr Radiol 1986; 16:2-7.
22. Morrison JB, Natural history of segmental lesions in
primary pulmonary tuberculosis. Arch Dis Child
1973;48:90-8.
23. Lincoln EM, Harris LC, Bovornkitti S, et al. Endobronchial tuberculosis in children. Am Rev Tuberc Pulm
Dis 1958;77:39-61.
24. Seal RME, Thomas SME. Endobronchial tuber-culosis in
children. Lancet 1956;2:995-6.

25. Schwartz P. Lymph node tuberculosis: A decisive factor
in pulmonary pathology. Arch Pediatr 1957;74:159-77.
26. Stansberry SD. Tuberculosis is infants and children. J
Thorac Imag 1990;5:17-27.
27. Daly JF, Brown DS, Lincoln EM, et al. Endobronchial
tuberculosis in children. Dis Chest 1952; 22:380-98.
28. Matsaniotis N, Kattanis C, Economou-Mavron C, et al.
Bullous emphysema in childhood tuberculosis. J Pediatr
1967;71:703-8.
29. Murray JF. Bill Dock and the localization of pulmonary
tuberculosis: how bed rest might have helped
consumption. Am J Respir Crit Care Med 2003;168:102933.
what has changed in last 20 years. Indian J Pediatr. 2002;69
Suppl 1:S5-10.
31. Seth V, Singhal PK, Semwal OP, et al. Childhood
tuberculosis in a referral centre: clinical profile and risk
factors Indian Pediatr. 1993;30:479-85.
32. Dannenberg AM, Sugimoto M. Liquefaction of caseous
foci in tuberculosis. Am Rev Respir Dis 1976;113:257-9.
33. Maniar BM. Cavitating pulmonary tuberculosis below
age of 2 years. Indian Pediatr 1994:31:181- 90.
34. Al-Tawfiq JA, Saadeh BM. Radiographic manifestations
of culture-positive pulmonary tuberculosis: Cavitary or
noncavitary? Int J Tuberc Lung Dis 2009;13:367-70.
35. Locham KK, Singh J. Choroid tubercles. Indian Pediatr
2004;41:1167.
36. Donald PR, Schaaf HS, Schoeman JF. Tuberculous
meningitis and miliary tuber-culosis: the Rich focus
revisited J Infect 2005; 50:193-5.
37. Chiu CY, Wu JH, Wong KS. Clinical spectrum of
tuberculous pleural effusion in children. Pediatr Int
2007;49:359-62.
38. Stengen G, Kenneth J, Kaplas P. Criteria for guidance in
the diagnosis of tuberculosis. Pediatrics 1969;43:260-3.
39. Nair PM, Philip T. A scoring system for diagnosis of
tuberculosis in children. Indian Pediatrics 1981;18;299303.
40. Migliori GB, Borghesi A, Rossanigo P, et al. Proposal of
an improved score method for the diagnosis of pulmonary
tuberculosis in childhood in developing countries. Tuber
Lung Dis 1992;72:145-9.
41. Osborne CM. The challenge of diagnosing childhood
tuberculosis in a developing country. Arch Dis Child
1995;72:369-74.
42. Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus
gastric lavage for microbiological confirmation of
pulmonary tuberculosis in infants and young children:
A prospective study. Lancet 2005;365:130-4.
43. Zar HJ, Tannenbaum E, Apolles P, et al. Sputum induction
for the diagnosis of pulmonary tuberculosis in infants
and young children in an urban setting in South Africa.
Arch Dis Child 2000;82:305-8.
44. Abadco DL, Steiner P. Gastric lavage is better than
bronchoalveolar lavage for isolation of Mycobacterium
tuberculosis in childhood pulmonary tuberculosis. Pediatr
Infect Dis J 1992;11:735-8.
45. Strumpf IJ, Tsang AY, Sayre JW. Reevaluation of sputum
staining for the diagnosis of pulmonary tuberculosis. Am
Rev Respir Dis 1979;119:599-602.
119
46. Vallejo J, Ong LT, Starke JR. Clinical features, diagnosis

and treatment of tuberculosis in infants. Pediatrics
1994;94:1-7.
47. Hall GS. Primary processing of specimens and isolation
and cultivation of mycobacteria. Clin Lab Med
1996;16:551-67.
48. Somu N, Swaminathan S, Paramasivan CN, et al. Value
of bronchoalveolar lavage and gastric lavage in the
diagnosis of pulmonary tuberculosis in children. Tuberc
Lung Dis 1995; 76:295-9.
49. Singh M, Moosa NV, Kumar L, et al. Role of gastric lavage
and bronchoalveolar lavage in the bacteriological
diagnosis of childhood pulmonary tuberculosis. Indian
Pediatr 2000;37: 947-51.
50. Allen BW, Mitchison DA. Counts of viable tubercle bacilli
in sputum related to smear and culture gradings. Med
Lab Sci 1992;49:94-8.
51. Bates JH. Diagnosis of tuberculosis. Chest 1979; 76(S):75763.
52. McCarter YS, Robinson A. Detection of acid-fast bacilli
in concentrated primary specimen smears stained with
rhodamine-auramine at room temperature and at 37C.
J Clin Microbiol 1994; 2:2487-9.
53. Murtagh JJ, Mathukutty J, Kimani AP, et al. Detection
and separation of mycobacteria by immunomagnetic and
bioluminescent techniques. Am J Respir Crit Care Med
1995;151: 148.
54. Ninan SA. Comparitive study of different methods of
identification of Mycobacterium tuberculosis in gastric
aspirate of children suffering from pulmonary
tuberculosis. MD thesis. AIIMS, June 1997.
55. Idigoras P, Peres-Trallero E, Alcorta M, et al. Rapid
detection of tuberculous and nontuber-culous mycobacteria
by microscopic observation of growth on
Middlebrook7H11 agar. Eur J Clin Microbiol Infect Dis
1995;14:6-10.
56. Venkatraman P, Herbert D, Paramasivan CR, et al.
Evaluation of the BACTEC radiometric method in the
early diagnosis of tuberculosis. Ind J Med Res
1998;108:120-7.
57. Roberts GD, Goodman NL, Heiffels L, et al. Evaluation
of the BACTEC radiometric method for recovery of
mycobacteria and drug susceptibility testing of
Mycobacterium tuberculosis from acid-fast smear-positive
specimens. J Clin Microbiol 1983;18:689-96.
58. Sewell DL, Rashad AL, Rourke WJ, et al. Comparision of
the Septi-Chek AFB and BACTEC systems and
conventional culture for recovery of mycobacteria. J Clin
Microbiol 1993; 31:2689-91.
59. Zuhre-Badak F, Kiska DL, Setterquist S, et al.
Comparision of mycobacteria growth indicator tube with
BACTEC 460 for detection and recovery of mycobacteria
from clinical specimens. J Clin Microbiol 1996;34:2236-9.
60. Brittle W, Marais BJ, Hesseling AC, et al. Improvement
in mycobacterial yield and reduced time to detection in
pediatric samples by use of a nutrient broth growth
supplement J Clin Microbiol 2009;47:1287-9.
61. Delacourt C, Doveda JD. Use of polymerase chain reaction
for improved diagnosis of tuberculosis in children.
J Pediatr 1995;126:703-9.
120

62. Smith KC, Starke JR, Eisenach K, et al. Detection of
Mycobacterium tuberculosis in clinical specimens from
children using a polymerase chain reaction. Pediatrics
1996;97:155-60.
63. Neu N, Saiman L, SanGabriel P, et al. Diagnosis of
pediatric tuberculosis in modern era. Pediatr Infect Dis J
1999;18:122-6.
64. Jatana SK, Nair MN, Lahiri KK, et al. Polymerase chain
reaction in the diagnosis of tuberculosis. Indian Pediatr
2000;37:375-82.
65. Montenegro SH, Gilman RH, Sheen P. Improved
detection of Mycobacterium tuberculosis in Peruvian
children by use of a heminested IS6110 polymerase chain
reaction assay. Clin Infect Dis 2003;36:16-23.
66. Noordhoek GT, Kolk AH, Bjune G, et al. Sensitivity and
specificity of PCR for detection of Mycobacterium
tuberculosis: A blind comparision study among seven
laboratories. J Clin Microbiol 1994;32:277-84.
67. Lodha R, Kabra SK. Newer diagnostic modalities for
tuberculosis. Indian J Pediatr 2004;71:221-8.
childhood tuberculosis. Indian J Med Res 2004;120:38797.
69. Lodha R, Kabra S K, Seth V. Diagnosis of tuberculosis.
Indian J Pediatr 2000;67:S3-S8.
70. Glickman SE, Kilburn JO, Butler WR, et al. Rapid
identification of mycolic acid patterns of mycobacteria
by high performance liquid chromatography using
pattern recognition software and a mycobacterium
library. J Clin Microbiol 1994;32:740-5.
71. Delacourt C, Gobin J, Gaillard JL, et al. Value of ELISA
using antigen 60 for the diagnosis of tuberculosis in
children. Chest 1993;104:393-8.
72. Gupta S, Bhatia R, Datta KK. Serological diagnosis of
childhood tuberculosis by estimation of mycobacterial
antigen-60 specific immunoglobulin in the serum.
Tubercle Lung Dis 1997;78:21-7.
73. Zheng YJ, Wang RH, Lin YZ, et al. Clinical evaluation of
the diagnostic value of measuring IgG antibody to 3
mycobacterial antigen- preparations in the capillary blood
of children with tuberculosis and control subjects. Tuber
Lung Dis 1994;75:366-70.
74. Turneer M, Nerom ZV, Nyabenda J, et al. Determination
of humoral immunoglobulins M and G directed against
mycobacterial antigen 60 failed to diagnose primary
tuberculosis and mycobacterial adenitis in children. Am
J Respir Crit Care Med 1994;150:1508-12.
75. Swaminathan S, Umadevi P, Shantha S, et al. diagnosis
of tuberculosis in children using two ELISA kits. Indian J
Pediatr 1999;66:837-42.
76. Imaz MS, Comini MA, Zerbini E, et al. Evaluation of the
diagnostic value of measuring IgG, IgM and IgA
antibodies to the recombinant 16-kilodalton antigen of
Mycobacterium tuberculosis in childhood tuberculosis. Int
77. Aubert-Pivert EM, Chedevergne FM, Lopez-Ramirez GM,
et al. Cytokine transcripts in pediatric tuberculosis: A
study with bronchoalveolar cells. Tuber Lung Dis
2000;80:249-58.
78. Simonney N, Bourrillon A, Lagrange PH. Circulating

immune complex analysis of circulating immune
complexes (CICs) in childhood tuberculosis: Levels of
specific antibodies to glycolipid antigens and relationship
with serum antibodies. Int J Tuberc Lung Dis 2000;4:15260.
79. Srivastava L, Srivastava VK. Detection of mycobacterial
antigen in circulating immune complexes in patients with
childhood tuberculosis. Indian J Pathol Microbiol 1999;42:
405-9.
80. Leung AN, Muller NL, Pineda PR, et al. Primary
tuberculosis in children. Radiographic manifestation
1992;182:87-91.
81. Woodering JW, Vandiviere HM, Fried AM, et al. Update:
The radiographic features of pulmonary tuberculosis. Am
J Roentgenol 1986; 148:496-506.
82. Starke JR, Taylor Watts KT. Tuberculosis is the pediatric
population in Houston, Texas. Pediatrics 1989;84:28-35.
83. McAdams HP, Erasmus J, Winter JA. Radiologic
manisfestations of pulmonary tuberculosis. Radiol Clin
North Am 1995;33:655-78.
84. Palmar PES. Pulmonary tuberculosis: Usual and unusual
radiographic presentations. Semin Roentgenol
1979;14:204-42.
85. Khun JP. Primary pulmonary tuberculosis. In: Caffey J
(Eds). Pediatric X-ray Diagnosis, Vol. 2, (8th edn).
Chicago, Year Book Publishers Inc, 1985;1210-27.
86. Copley SJ. Application of computed tomography in
childhood respiratory infections. Br Med Bull 2002;61:26379.
87. Kim WS, Moon WK, Kim IO, et al. Pulmonary
tuberculosis in children: Evaluation with CT. Am J
Roentgenol 1997;168:1005-9.
88. Jamieson DH, Cremin BJ. High resolution CT of the lungs
in acute disseminated tuberculosis and a pediatric
radiology perspective of the term miliary. Pediatr Radiol
1993;23:380-3.
89. Haller JO, Ginsburg KJ. Tuberculosis in children with
acquired immunodeficiency syndrome. Pediatr Radiol
1997;27:186-8.
90. Kornreich L, Goshen Y, Horev G, et al. Mycobacterial
respiratory infection in leukemic children. Eur J Radiol
1995;21:44-6.
91. Bosch-Marcet J, Scrrescreixams X, Zuasnabar-cotro A, et
al. Comparison of ultrasound with plain radiography and
CT for the detection of mediastinal lymphadenopathy in
children with Tuberculosis Pediatr Radial 2004;34:895900.
92. Papakonstantinou O, Bakantaki A, Passpalaki P, et al.
High-resolution and colour Doppler ultrasonography of
cervical lymphadenopathy in children. Acta Radiol
2001;42:470-6.
93. Biddulph J. Short-course chemotherapy for childhood
tuberculosis. Pediatr Infect Dis J 1990;9:794-801.
94. Pai M, Zwerling A, Menzies D. Systematic review: T-cellbased assays for the diagnosis of latent tuberculosis
infection: An update. Ann Intern Med 2008;149:177-84.
95. Tavast E, Salo E, Seppl I, et al. IGRA tests perform
similarly to TST but cause no adverse reactions: Pediatric
experience in Finland BMC Res Notes 2009;15;2-9.

96. Nicol MP, Davies MA, Wood K, et al. Comparison of TSPOT.TB assay and tuberculin skin test for the evaluation
of young children at high risk for tuberculosis in a
community setting. Pediatrics 2009;123:38-43.
97. Mwandumba HC, Squire SB. Fully intermittent dosing
with drugs for treating tuberculosis in adults. Cochrane
Database of Systematic Reviews 2001, Issue 4. Art. No.
CD000970.
98. Ramachandran P, Kripasankar AS, Duraipandian M.
Short course chemotherapy for pulmonary tuberculosis
in children. Indian J Tuberc 1998;45:83-7.
99. Kansoy S, Kurta N, A it S, et al. Superiority of intermittent
short-course chemotherapy in childhood pulmonary
tuberculosis. Turkish J Med Sci 1996;26:41-3.
100. Kumar L, Dhand R, Singhi PD, et al. A randomised trial
of fully intermittent and daily followed by intermittent
short-course chemo-therapy for childhood tuberculosis.
101. Te Water Naude JM, Donald PR, Hussey GD, et al. Twiceweekly vs daily chemotherapy for childhood TB. Pediatr
Infect Dis J 2000;19:405-10.
102. Menon P R, Lodha R, Sivanandan S, et al. Intermittent or
daily short-course chemotherapy for tuberculosis in
children: A systematic review and meta-analysis of
randomized controlled trials. Indian Pediatr 2010;47:
67-73.
103. Sharma S, Sarin R, Khalid UK, et al. The DOTS strategy
for treatment of pediatric pulmonary tuberculosis in
104.
105.
106.
107.
108.
109.
110.
111.
121
South Delhi, India. Int J Tuberc Lung Dis 2008;12:

74-80.
Kabra SK, Lodha R, Seth V. Category based treatment of
tuberculosis in children. Indian Pediatr 2004;41:927-37.
Chauhan LS, Arora VK. Management of pediatric
tuberculosis under the revised national tuberculosis
control program (RNTCP). Indian Pediatr 2004;41:901-6.
Kabra SK, Ratageri VH. Tuberculosis in children:
Monitoring of treatment and management of side effects.
Paediatr Today 1999;2:81-4.
Seth Vimlesh, Kabra SK, Lodha R. Management
tuberculosis in children. In: Seth V, Kabra SK (Eds).
Essentials of tuberculosis in children, (2nd edn). New
Delhi: Jaypee Brothers Medical Publishers (P) Ltd.
2001;349-54.
Mukhopadhyay S, Gupta AK. Imaging in childhood
tuberculosis. In: Seth Vimlesh, Kabra SK (Eds). Essentials
of tuberculosis in children, (2nd edn). New Delhi: Jaypee
Brothers Medical Publishers (P) Ltd. 2001;262-85.
Starke JR. Current concepts of epidemiology, diagnosis
and treatment of childhood tuberculosis in the United
States. Indian Pediatr 1991;28:335-55.
l-Marri MR, Kirkpatrick MB. Erythrocyte sedimentation
rate in childhood tuberculosis: Is it still worthwhile? Int J
Tuberc Lung Dis 2000; 4:237-9.
with treatment failure in childhood tuberculosis.Indian
Pediatr 2008;45:769-71.
10
Tuberculous Lymphadenitis
Ben J Marais, PR Donald
INTRODUCTION
Tuberculosis lymphadenitis (historically referred to as
scrofula) is the most common form of extrapulmonary
TB recorded in children from TB endemic areas, being
present in 8-10% of children diagnosed with TB in India
and South Africa. 1,2 The cervical lymph nodes are
predominantly affected. Lymph nodes become infected
with Mycobacterium tuberculosis following lymphatic
drainage from a local disease site or after hematogenous
dissemination. In highly endemic areas TB lymphadenitis
is a common cause of persistent cervical adenopathy in
children. In South Africa, 22% of children who presented
to a primary health center with persistent cervical
adenopathy (>1 1 cm, not responding to a course of
oral antibiotics) were diagnosed with TB lymphadenitis
and this increased to 64% once a visible local cause was
excluded. Figure 10.1 presents a flow diagram of all 167
children referred with persistent cervical adenopathy.
Table 10.1 demonstrates the demographics and etiology
of persistent cervical adenopathy in the 158 children who
were evaluated.
protection against disease caused by these organisms.10 A

similar protective effect provided by natural infection with
M. tuberculosis, which may also enhance the protection
provided by universal BCG vaccination, probably explains
why lymphadenitis due to M. avium complex and other
environmental mycobacteria are rare in countries with a
high-burden of TB, despite the fact that 10% of rural
children react to avian PPD-tuberculin.11
EPIDEMIOLOGY
The mycobacteria that cause cervical lymphadenitis are
highly variable depending on the setting. In areas where
the control of bovine tuberculosis is poor and milk is not
routinely pasteurized, M. bovis may be a frequent cause.3-5
In areas where TB is endemic and bovine TB is well
controlled, M. tuberculosis would be the most common
cause.3,6-7 In developed countries with low rates of TB
transmission, non-tuberculous mycobacteria (NTM),
particularly M. avium complex (MAC), are mainly
responsible.8 The etiologic agent may be determined by
different environmental conditions. For example, the
decrease in M. scrofulaceum (historically associated with
scrofula) and the concurrent increase in M. avium complex
as a cause of chronic cervical lymphadenopathy has been
attributed to the chlorination of potable water supplies.9
In the context of these shifting epidemiological
patterns, it is interesting to note that the stoppage of BCG
immunization in certain developed countries has led to a
marked increase in the incidence of lymphadenitis caused
by NTM, suggesting that BCG immunization provides
Fig. 10.1: Children who presented to primary health care facilities with
persistent cervical adenopathy in a TB endemic area
Not TBsymptom resolution in the absence of antituberculosis
chemotherapy
TBbacteriologic confirmation; isolation of M. tuberculosis from a lymph
node, or microscopically visible acid-fast or autofluorescent bacilli
associated with caseating necrosis on cytology, or clinical diagnosis;
significant therapeutic response (lymph node size decreased from 2
2 cm to <1 x 1 cm after 3 months of standard antituberculosis treatment)
Not evaluateddid not return to the clinic for evaluation by the
investigator
Rx responsesignificant therapeutic response as for clinical diagnosis
#
One chronic inflammatory process diagnosed after excision biopsy,
one nonacute bacterial abscess diagnosed after incision and drainage
Adapted from Marais BJ et altuberculous lymphadenitis as a cause
of persistent cervical lymphadenopathy in children from a tuberculosisendemic area3
Chapter 10 Tuberculous Lymphadenitis

Table 10.1: Demographics and etiology of persistent
cervical adenopathy in children presenting to primary
health facilities in a TB endemic area (n = 158)
Demographics
Gender
Male
Female
Age groups
<5 years
5-9 years
>10 years
Number (%)
69 (43.7)
89 (56.3)
93 (58.9)
51 (32.2)
14 (8.9)
Etiology
Visible local cause
105 (66.5)
Bacterial infection (crusted impetigo)
26 (16.5)
Tinea capitis (with secondary infection) 34 (21.5)
Traction folliculitis
44 (27.8)
Otitis externa
1 ( 0.6)
No visible local cause
53 (33.5)
Tuberculous lymphadenitis
35 (22.2)
Reactive nodes
13 ( 8.2)
Nonspecific inflammation
4 ( 2.5)
Nonacute bacterial abscess
1 ( 0.6)
Malignancy
0
Reactive nodescervical mass <2 2 cm, tuberculin skin test negative
and natural symptom resolution
Adapted from Marais BJ et altuberculous lymphadenitis as a cause
of persistent cervical lymphadenopathy in children from a tuberculosisendemic area.3
BCG itself may cause regional lymphadenitis and

even disseminated disease in severely immune
compromised children. The simultaneous change of the
M. bovis BCG strain (from Japanese to Danish) and the
application route (from transcutaneous to intradermal)
used for neonatal BCG vaccination in South Africa
resulted in a marked increase in the number of infants
who developed right sided axillary lymphadenitis.12 This
sudden increase in regional BCG-related complications
was partly explained by previous inadequate delivery
methods and initial unfamiliarity with the new
intradermal technique.12 However, of particular concern
was a number of HIV-infected infants who developed
both regional, defined as axillary lymphadenitis on the
side of the BCG vaccination scar, and/or disseminated
BCG disease following neonatal vaccination.13 Axillary
BCG lymph adenitis may also be a manifestation of the
immune reconstitution inflammatory syndrome (IRIS),
mostly seen in severely immunocompromised
HIV-infected children within the first 3 months of starting
anti-retroviral therapy (ART).13 In a Thai study, IRIS was
documented in 19% of children with low CD4
percentages (<15%) newly started on ART; the majority
of cases (9) were caused by MOTTs, 3 by M. tuberculosis
and 2 by M. bovis BCG.14
123
PATHOGENESIS
In the vast majority of cases, TB lymphadenitis represents
the glandular component of a primary complex, which
consists of the Ghons focus (or site of primary infection)
and the regional lymph nodes. This was concluded from
clinical experience during the prechemotherapy era.
Peripheral lymphadenitis frequently occurred in
complete isolation, but in a substantial number of cases
traces of a primary focus could be found after careful
scrutiny.15 These cases suggested that the lymph nodes
involved also reflect the most likely site of the Ghons
focus. The submandibular group of nodes was most
frequently affected and was associated with visible
calcification of the intrathoracic lymph nodes, suggesting
a primary focus in the lung. Similarly, involvement of
the supraclavicular nodes was associated with a primary
focus in the apex of the lung.15 However, in a minority
of cases cervical lymph node involvement may originate
from a Ghons focus in the tonsils, oropharynx or tissues
of the head and neck.15 TB lymphadenitis involving
axillary or inguinal nodes is uncommon but if present, it
is usually associated with a local Ghons focus and a
diligent search may be rewarded by finding a tuberculous
skin lesion at some distal point.15-17 TB lymphadenitis
usually develops within the first 6-12 months after
primary infection with M. tuberculosis. In rare cases,
generalized TB lymphadenitis may be associated with
hematogenous dissemination and this may occur in the
absence of overt miliary disease.18
Disease pathology within the lymph node is similar to
that seen in other organs, with initial tubercle formation
and lymphoid hyperplasia that may progress to caseation
and necrosis. Isolated involvement of a single node is rare
and nodes are usually matted due to considerable
periadenitis, although one node is frequently more
prominent than others within a matted group of nodes.19
A cold abscess results when the caseous material liquefies
and this is signified by a soft fluctuant node with
violaceous discoloration of the overlying skin;
spontaneous drainage and sinus formation may follow.16
Untreated, the natural course of TB lymphadenitis in an
immune competent host follows a prolonged and
relapsing course often interrupted by transient lymph
node enlargement, fluctuation and/or sinus formation
before ultimately healing with associated scarring and/
or calcification.16
CLINICAL FINDINGS AND DIAGNOSIS

The various conditions that should be considered in the
differential diagnosis of a child with chronic cervical
adenopathy are listed in Table 10.2. The clinical findings
in 35 children with confirmed TB cervical lymphadenitis
124

Table 10.2: Differential diagnosis of peripheral lymphadenitis
Infections
Acute suppurative
Bacterial
Chronic granulomatous
Mycobacteria
Fungi
Other
Reactive hyperplasia
Viral
Malignancy
Congenital malformations
Unknown
Gram-positive organismsStaphylococcus aureus, Group A streptococci and

peptostreptococci Gram-negative organisms
M. tuberculosis, M. bovis, M. bovis BCG, nontuberculous mycobacteria (NTM), especially M.
avium complex (MAC)
Histoplasmosis, Coccidioidomycosis, Actinomycosis
Brucellosis, Tuleraemia, Toxoplasmosis, Cat scratch disease, Sarcoidosis
Infectious mononucleosis (EBV), Human Immuno-deficiency Virus (HIV), Mumps,
Cytomegalovirus (CMV)
Non-Hodgkins lymphomata, particularly Burkitts lymphoma
Hodgkins disease, Neuroblastoma, Rhabdomyosarcoma, Histiocytosis X
Branchial, Thyroglossal and/or Dermoid cysts
Deep cavernous hemangioma
Reactive hyperplasia of undetermined etiology
when they presented to the primary health care facility

are described in Table 10.3. A history of close contact
with an adult index case remains important and is
documented in approximately 50% of children with TB
lymphadenitis.3,19 The condition seems to occur with
equal frequency in all age groups, except infancy where
it is rarely seen.3 TB lymphadenitis is characteristically
painless and not tender to palpation; nodes are large
(>2 2 cm) and frequently matted.3,19 The lymph nodes
are initially firm but may become fluctuant and sinus
formation may be present.19,20 If secondary infection
complicates the picture the affected nodes become red,
warm and painful. Superficial lesions on the scalp such
as infected tinea capitis may cause persistent cervical
adenopathy that disappears only when the local lesions
are adequately treated.
The most important clinical clues that may assist the
diagnosis of TB lymphadenitis are summarized in Table
10.4. A strongly positive tuberculin skin test (TST) and/
or radiographic signs suggestive of TB support a
diagnosis of TB lymphadenitis. 3,21 In non-endemic
settings, a positive TST is more indicative of NTM disease
and provides a fairly accurate diagnosis in the absence
of known TB exposure and/or BCG vaccination. 8
Radiographic signs of TB are present in less than 50% of
children with TB lymphadenitis and few report
pulmonary symptoms.3,20,22
Culture from a discharging sinus may provide
bacteriological confirmation. If there is no sinus, fine
needle aspiration (FNA) is the diagnostic procedure of
choice. FNA provides an excellent bacteriologic yield and
is a minimally invasive procedure,3,23-26 especially when
a fine 22G needle is used. In some cases, an excision
biopsy may be considered and this a treatment option as
well, particularly in NTM disease where the therapeutic
response to chemotherapy is frequently suboptimal.8

Incision biopsy should be discouraged at all times as this
may result in sinus formation, a complication not seen
with FNA.3,26 Material obtained should be submitted for
histology and/or cytology (rapid cytological diagnosis
reduces diagnostic delay); performing a mycobacterial
culture is also advised as it increases the diagnostic
accuracy, allows identification of mycobacterial species
and drug susceptibility testing if required.
HIV infection complicates the diagnosis of TB
lymphadenitis because the TST is more likely to be
negative than in HIV-uninfected children, 27 which
increases the importance of establishing a bacteriological
diagnosis. Studies in Zambia indicate that TB lymphadenitis is less common in HIV-infected (3%) children
compared to HIV-uninfected children (5%).28 In contrast,
axillary M. bovis BCG adenitis is more common in HIVinfected children and usually develops within
3-6 months after BCG immunization, or as a manifestation
of IRIS when it presents within 3-6 months of ART
initiation.13,14
Tubercular LymphadenitisIndian Experience

Tubercular lymphadenitis is the commonest form of
extrapulmonary tuberculosis in India, may be at a
practitioners clinic, children surgical and medical
outpatient departments (Pediatric tuberculosis clinic at
a tertiary care center) like All India Institute of Medical
Sciences. The reasons are many, in reality the incidence
of peripheral lymphadenitis has increased depending
upon the center, e.g. in a TB hospital like Lala Ram Sarup
Institute of Tuberculosis and Allied Sciences, the major
presentation in the Pediatric ward is pulmonary
tuberculosis of the adult type because their criteria for
125

Table 10.3: Clinical characteristics of children diagnosed with TB lymphadenitis in a TB endemic area (n = 35)
Lymph node characteristics
Number (%)
Persistence (present for >4 weeks, no response to antibiotics)

Size
< 2 2 cm
(2-4) (2-4) cm
> 4 4 cm
Character
Single
Multiple
- discreet
- matted
Solid
Fluctuant
- without secondary bacterial infection
- with secondary bacterial infection (red and warm)
Associated findings
0 mm
1-9 mm
>10 mm
>15 mm
Mean response 19.1 mm (standard deviation 2.9 mm)
Constitutional symptoms
Any symptom
Fever
Cough
Night sweats
Fatigue
Failure to thrive
Chest radiograph
Suggestive of tuberculosis
Lymph node disease
- uncomplicated
- with airway compression
- with parenchymal consolidation
35 (100)
4 (11.4)
25 (71.5)
6 (17.1)
5 (14.3)
14 (40.0)
16 (45.7)
28 (80.0)
5 (14.3)
2 ( 5.7)
2 ( 5.7)
0
33 (94.3)
32 (91.4)
21 (60.0)
7 (20.0)
9 (25.7)
8 (22.8)
19 (54.3)
10 (28.6)
13 (37.1)
8 (22.8)
1 (2.9)
4. (11.4)
Sizetransverse diameter of the largest cervical mass

Fatigueless playful and active since the mass was first noted
Failure to thrivecrossing at least one centile line in the preceding 3 months or having lost more than 10% of bodyweight (minimum 1 kg) over
any time interval
Adapted from Marais BJ et altuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosisendemic area3
Table 10.4: Clues to the diagnosis of TB lymphadenitis

History
Lymph node characteristics
Location
Size and character
Duration
Reactive tuberculin skin test (TST)
Chest radiograph
Contact with an adult index case with pulmonary tuberculosis

Cervical, rarely inguinal or axillary
(If axillary nodes ipsilateral to the site of BCG vaccination, consider
BCG adenitis)
Visible, >2 2 cm
Non-tender and/or matted
Usually solid, but may be fluctuant (may also be secondarily infected)
Persistent for > 1 month
Despite excluding/treating potential local causes
>10 mm in all children, >5 mm if HIV-infected children
Suggestive of TB
Fine needle aspiration (FNA) offers a relatively easy noninvasive means of establishing a definitive tissue and/or
bacteriological diagnosis
126
treating tuberculosis is like adults based on primarily

sputum examination. The other major chunk is tubercular
lymphadenitis with a chronic discharging sinus not
responded to usual category three treatment. The reason
is partial treatment with antituberculosis drugs before
the patient presents to the TB Hospital or children
surgical outpatient department. The diagnosis is often
made by aspiration cytology which usually shows
reactive hyperplasia due to partial treatment and poor
adherence to treatment. In the TB Hospital, usually
excision biopsy is done which is examined for
histopathology by detailed microscopic examination
and specimen is processed for all microbiological
investigations.
Same is the routine at a tertiary care center like All
India Institute of Medical Sciences (AIIMS). In addition
at AIIMS, specimen is also examined for drug sensitivity
testing to rule out resistant tuberculosis. In such cases,
family history of TB is often positive.
Mantoux Test
In a project on the complete clinical, histopatholegical,
microbiological and immunological studies done by
Rohatgi and Seth29 revealed the following interesting
finding:
1. Clinical: Cervical nodes were the most commonly
involved site. Size was bigger than 1 cm. The glands
were often matted due to perilymphadenitis.
2. Histopathology: This was changed if the patient has
been put on antituberculosis therapy. It showed
reactive adenitis and not typical granulomatous
lymphadenitis.
3. Mantoux test: The positivity of Mantoux test was
highest in comparison to any other type of
4. Immunological: Cell-mediated immune response as
measured quantitatively by absolute T-cell counts and
qualitatively by lymphoblast transformation and
leukocyte migration inhibition test was better
preserved as compared to the TB of other organs such
as pulmonary, neurotuberculosis.
5. Resistant TB: Case reports.
TREATMENT
Randomized controlled trials have demonstrated
convincingly that TB lymphadenitis can be treated with
short-course chemotherapy. In adults the results of 9
months treatment with rifampicin (RMP) and isoniazid
(INH) accompanied by ethambutol for the initial 2
months did not differ significantly from those receiving
prolonged therapy for 18 months.30 Equally good results
were achieved by using a regimen of INH and RMP for
6 months supplemented by pyrazinamide (PZA) during
the initial 2 months.31 Short-course chemotherapy with

intermittent drug administration during the consolidation phase gave satisfactory results in 110 children
with TB lymphadenitis in Papua New Guinea.32 These
children received 2 months of daily INH, RMP, PZA and
streptomycin followed by 4 months of twice weekly INH
and RMP, but there is no convincing reason to add
streptomycin during the intensive phase. Good results
have been reported in smaller groups of children
receiving the same standard TB treatment regimen as
used in children with uncomplicated intrathoracic
disease.3,33,34 In fact, the organism load in children with
isolated peripheral TB lymphadenitis is low and an even
shorter courses of chemotherapy may suffice in
uncomplicated cases, but no randomized studies have
been performed to support this. Despite successful
treatment, nodal enlargement during or following
treatment may occur in a minority of patients, which
probably represents an immune reaction as cultures from
such lesions are usually negative. Surgery is advised only
for exceptionally tense fluctuant nodes or in the presence
of severe discomfort. Full excision is advised and not
incision and drainage.
The treatment of M. bovis and M. bovis BCG adenitis
is more problematic. Isolated axillary adenitis in an
immune competent child may warrant a conservative
approach, with surgical excision only if no spontaneous
resolution occurs or in the presence of severe discomfort.
In HIV-infected children, there is a real risk of developing
disseminated BCG disease,13 and local excision is often
impossible due to poor anatomical localization and
infiltration of the tissues surrounding the lymph node.
M. bovis is inherently resistant to PZA and in addition
M. bovis BCG may show intermediate resistance to INH.35
Thus, treatment with ordinary anti-tuberculosis therapy
seems inadequate and should include INH in a dose of at
least 10-15 mg/kg together with a third and probably
even fourth drug to replace PZA. No guidelines exist
currently, but it seems prudent to medically treat HIVinfected or immune compromised children with M. bovis
BCG adenitis in order to prevent disseminated disease.13
Lymphadenitis caused by NTM is more resistant to
chemotherapy. Apart from rifampicin, ethambutol the
newer macrolides have shown some efficacy, but surgical
excision is frequently required.8,36
REFERENCES
1. Reddy MP, Moorchung N, Chaudrey A. Clinicopathological profile of paediatric lymphadenopathy. Indian J
Pediatr 2002;69:1047-1-51.
2. Marais BJ, Gie RP, Schaaf HS, et. al. The spectrum of
disease in children treated for tuberculosis in a highly
endemic area. Int J Tuberc Lung Dis 2006;10:732-8.
3. Marais BJ, Wright CA, Schaaf HS, et.al. Tuberculous
lymphadenitis as a cause of persistent cervical
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
lymphadenopathy in children from a tuberculosisendemic area. Ped Infect Dis J 2006;25:142-6.

Grzybowski S, Allen EA. History and importance of
scrofula. Lancet 1995;346:1472-4.
Wilson GS, Blacklock JNS, Riley RW. Non-pulmonary
tuberculosis of bovine origin in Great Britain and
Northern Ireland. London: National Association for
Prevention of Tuberculosis, 1952.
Krishnaswami H, Koshi G, Kulkarni KG, et al.
Tuberculous lymphadenitis in South India A
histopathological and bacteriological study. Tubercle
1972;53:215-20.
Lai KK, Stottmaier KD, Sherman IH, et al. Mycobacterial
cervical adenopathy. JAMA 1984;251:1286-9.
Lindeboom JA, Kuijper EJ, Prins JM, et.al. Tuberculin skin
testing is useful in the screening for nontuberculous
mycobacterial cervicofacial lymphadenitis in children.
Primm TP, Lucero CA, Falkinham JO. Health impacts of
environmental mycobacteria. Clin Microbiol Rev 2004;
17:98-106.
Romanus V. Tuberculosis in BCG immunized and
unimmunized children in Sweden: A ten-year evaluation
following the cessation of BCG immunization of the
newborn in 1975. Pediatr Infect Dis J 1987;6:272-80.
Kleeberg HH. Epidemiology of mycobacteria other than
tubercle bacilli in South Africa. Rev Infect Dis 1981;3:100812.
Jeena PM, Chagan MK, Topley J, et al. Safety of intradermal Copenhagen 1331 BCG vaccine in neonates in
Durban, South Africa. Bull Wld Hlth Org 2001;79:33743.
Hesseling AC, Rabie H, Marais BJ et.al. Bacille CalmetteGuerin vaccine-induced disease in HIV-infected and
HIV-uninfected children. Clin Infect Dis 2006;42:548-58.
Puthanakit T, Oberdorfer PM, Akaratum N, et al.
Immune reconstitution syndrome after highly active
antiretroviral therapy in human immunodeficiency virusinfected Thai children. Ped Infect Dis J 2006;25:53-8.
Miller FLW, Cashman JM. Origin of peripheral
tuberculous lymphadenitis in childhood. Lancet
1958;1:286-9.
Miller FKW, Cashman JM. The natural history of
peripheral tuberculous lymphadenitis associated with a
visible primary focus. Lancet 1955;1:1286-9.
Lincoln EM, Sewell EM. Tuberculosis in children. New
York, NY: Mc Graw-Hill Book Company Inc, 1963:
207-15.
Harris LC. Generalized tuberculous adenitis in Bantu
children in South Africa. Pediatrics 1959;23:935-44.
Narang P, Narang R, Narang R, et al. Prevalence of
tuberculosis lymphadenitis in children in Wardha
district, Maharashtra state, India. Int J Tuberc Lung Dis
2005;9:188-94.
McMaster P, Ezeilo N, Freisen H, et al. Ten-year
experience with paediatric lymph node tuberculosis in
Port Moresby. J Trop Pediatr 2001;47:160-4.
127
21. Seth V, Kabra SK, Semwal OP, et al. Tubercular

lymphadenitis: Clinical manifestations. Indian J Pediatr
1995;62:565-70.
22. Belin RP, Richardson JD, Richardson DL, et al. Diagnosis
and management of scrofula in children. J Pediatr Surg
1974;9:103-7.
23. Handa U, Palta A, Mohan H, et al. Fine needle aspiration
diagnosis of tuberculous lymphadenitis. Trop Doct
2002;32:147-9.
24. Rameshkumar K. Tuberculous lymphadenitis in
childrenrole of fine needle aspiration cytology. J Assoc
Physicians India 1999;47:976-9.
25. Lau S, Ignace W, Kwan S, et al. Combined use of fine
needle aspiration cytologic examination and tuberculin
skin test in the diagnosis of cervical tuberculous
lymphadenitis. Arch Otolaryngol Head Neck Surg
1991;117:87-90.
26. Thomas J, Adeyi AO, Olu-eddo AO, et al. Fine needle
aspiration cytology in the management of childhood
palpable masses: Ibadan experience. J Trop Pediatr
1999;45:378.
27. Madhi S, Gray G, Huebner RE, et. al. Correlation between
CD4+ lymphocyte counts, concurrent antigen skin
test and tuberculin skin test reactivity in human
immunodeficiency virus type 1infected and uninfected
children with tuberculosis. Pediatr Infect Dis J
1999;18:800-5.
28. Chintu C, Bhat G, Luo C, et. al. Seroprevalence of human
immunodeficiency virus Type 1 infection in Zambian
children with tuberculosis. Pediatr Infect Dis J
1993;12:499-504.
29. Rohatgi M, Seth Vimlesh. Clinico-immunohistopathologic and microbiological correlation of
peripheral lymphadenopathy in children. (unpublished
data).
30. Campbell IA. The treatment of superficial tuberculous
lymphadenitis. Tubercle 1990;71:1-3.
31. Campbell IA, Ormerod LP, Friend JAR, et al. Six-months
versus nine-months chemotherapy for tuberculosis of
lymph nodes: preliminary results. Resp Med 1992;86:15-9.
tuberculosis. Pediatr Infect Dis J 1990;9:794-801.
33. Kumar L, Dhand R, Singhi PD, et al. A randomised trial
of fully intermittent vs. daily followed by intermittent
short course chemotherapy for childhood tuberculosis.
34. Jawahar MS, Sivasubramanian S, Viajayan VK, et al.
Short-course chemotherapy for tuberculous lymphadenitis in children. Br Med J 1990;301:359-61.
35. Hesseling AC, Schaaf HS, Victor T, et al. Resistant M.
bovis disease; implications for management of BCGdisease in HIV infected children. Pediatr Infect Dis J
2004;23:476-9.
36. Hazra R, Robson CD, Perez-Atayde AR, et al.
Lymphadenitis due to nontuberculous mycobacteria in
children: presentation and response to therapy. Clin
Infect Dis 1999;28:123-9.
11
BR Thapa, Pawan Rawal, Ravi Angara
Tuberculosis (TB) is still a rampant disease in children

with varying presentation in developing countries. Recent
upsurge has been noted in developed countries also. Main
organs affected with tuberculosis are lungs, central
nervous system and lymph nodes whereas abdominal
involvement is less common. There is paucity of literature
from medical centers regarding gastrointestinal
tuberculosis in the pediatric age group1,2 and it is mostly
reported from pediatric surgical centers.3-6 Pediatricians
might be missing tuberculosis of gastrointestinal tract
(GIT) due to unawareness and lack of facilities to confirm
the diagnosis. However, abdominal tuberculosis of adult
population has been well published with large series and
reviews.7-12
Abdominal TB is defined as TB infection of abdomen
including gastrointestinal tract, peritoneum, omentum,
mesentery, lymph nodes and other solid organs like liver,
spleen and pancreas. Abdominal tuberculosis (ATB) may
be isolated or associated with extra intestinal tuberculosis
lesion. 1,13 Abdominal TB complicates untreated
pulmonary disease in 6 to 38% of cases.14 M. tuberculosis
is the principle causative agent and rarely M. bovis and
nontuberculous Mycobacterium are encountered.
TB and most cases are constituted by immigrant

population. In contrast in low and middle income
countries, childhood TB constitutes about 15 to 40% of
all TB, and risk factors being poverty, crowding and
malnutrition.17 Furthermore, susceptibility to TB is
enhanced by HIV infection. Studies have suggested that
HIV-infected children are more likely than HIVuninfected children to be exposed to parents with smear
positive TB.18 The increased risk of TB among HIVpositive children is attributable to immunosuppression
which makes the HIV-infected children more likely to
be exposed to TB within their families. Other factors that
are associated with an excess risk of TB infection in
children include malignancy, peritoneal dialysis and
passive smoking.19 BCG plays an important but narrow
role in the prevention of TB, particularly childhood TB.
Efficacy of BCG has varied from 0 to 80% in the
prevention of adult pulmonary TB. A meta-analysis
estimated that the overall protective effect of BCG was
50%.20 Its protective effect is in the serious forms of TB
as TB meningitis, miliary, disseminated or abdominal TB.
Hospital data shows that abdominal TB forms 0.8 to
3.6% of total admissions and intestinal TB contributes to
15% of all intestinal obstructions and 5 to 7% of all
gastrointestinal perforations.
Epidemiology
Causative Organisms
Exact epidemiology of abdominal tuberculosis is not

known. Majority of patients with TB live in the most
populous countries of Asia: Bangladesh, China, India,
Indonesia and Pakistan and account for half (48%) of the
new cases that arise every year.15 Incidence of disease
and the prevalence and death rates are almost stable in
majority of regions of world with exception being parts
of Africa.16 Present and past transmission and incidence
rates and peak age have varied in different parts of world.
Incidence rate is highest among young adults, and most
cases are due to recent infection in Africa and South East
Asia. By contrast, in Western Europe and North America,
which now have low incidence rates, the most cases have
shifted to older adults, and a higher proportion of cases
are attributable to a reactivation of latent infection.
Similarly the risk factors and disease vary between
developed and developing countries. In developed
countries, childhood TB constitutes about 2 to 7% of all
In the early 19th century, TB was recognized as a disease

believed to be caused by an infectious organism. In 1882,
Koch, identified M. tuberculosis as the causative
microorganism. Despite routine use of BCG vaccine in
most parts of world, TB has not been fully controlled by
vaccination. M. tuberculosis has been the predominant
mycobacterial infection in most developed countries. M.
tuberculosis has unusual tenacity and viability. It has the
ability to infect humans and then persist in a dormant
state in the host in lymphoid tissue especially in GIT for
many years. Four closely related mycobacteria are there:
M. tuberculosis, M. bovis, M. africanum, and M. microti. M.
microti does not cause disease in humans.21 Mycobacteria
other than those in the TB complex are referred to as
nontuberculous mycobacteria. These other mycobacteria
can cause localized disease, such as regional
lymphadenitis, in healthy individuals or disseminated
disease in immunocompromised patients.
INTRODUCTION
129
Chapter 11 Abdominal Tuberculosis

Recognition of cattle as a potential reservoir of bovine
TB lead to testing and destruction of infected animals,
universal pasteurization and the practice of boiling of
milk. This markedly reduced the spread of the disease.
Infected cattle remain a source of the disease in
developing countries. The major route of transmission
of M. bovis is the ingestion of infected milk or milk
products, and the intestinal tract and associated lymph
nodes become the primary complex. Overall most bacilli
isolated in patients with abdominal tuberculosis are M.
tuberculosis and not M. bovis though reports from San
Diego, California have shown that Mycobacterium bovis
is a significant cause of tuberculosis in children residing
along the United StatesMexico border in the Baja
California Region. In earlier reports from India, TB due
to M. bovis infection constituted 5% but these days it is
very rare.
Nontuberculous mycobacteria usually do not cause
disease but can affect immunocompromised hosts as in
HIV, immunosuppression treatment and malignancies.
The important nontuberculous mycobacteria include
M. intracellulare and M. avium. High index of suspicion
and no response to routine antitubercular treatment
should give clue to the presence of these nontuberculous
mycobacteria.
Pathogenesis
The major route for transmission of TB is respiratory.
Most of the children become infected after contact with
an adult living in their household. An adult with active
cavitary/bronchiectatic pulmonary TB with a productive
cough is the classic source of infection. The abdominal
tuberculosis may involve the gastrointestinal tract (GIT),
peritoneum, lymph nodes or solid viscera. Tuberculous
involvement of abdomen can be due to primary
involvement of the intestines and other abdominal
viscera; however, this is very rare nowadays. In prechemotherapeutic era it was calculated to be about 5%.22
Boiling of milk, pasteurization, eradication of infected
cattle and lack of infected material may be responsible
for this. Ingestion of tubercle bacilli along with the
sputum can also lead to intestinal tuberculosis as evident
from well established association with pulmonary
tuberculosis. Involvement of intestine might be related
to number of bacilli ingested, virulence of organism,
nutritional status and immunological state of the child.
The site of involvement also varies. Factors that lead to
development of intestinal TB are given in (Table 11.1).
The post primary complex elsewhere in the body may
spread via hematogenous route. Mostly, it is intermittent
silent bacteremia occurring at low rate and leads to the
disseminated TB involving intra-abdominal organs. But
there can be rupture of infected focus into the blood vessel
and this can lead to miliary tuberculosis involving GIT.
The order of involvement of various sites is ileum,
Table 11.1: Predisposing factors for intestinal TB

Rich in lymphoid tissue: Peyers patches and lymph
nodes
AFB affinity for lymphoid tissue
Number of bacilli ingested
Virulence of bacilli
Nutritional and immunological status
Alkaline pH in small and large intestine
Stasis in ileocecal area (Ileal break)
More of water absorption and no digestive activity
Table 11.2: Site of involvement in abdominal

tuberculosis (n = 78)
Site
Intestinal
Duodenum
Jejunum
Ileum
Ileocecal
Colon and rectum
Peritoneal
Nodal
Hepatic
Number
Percent
52
2
3
34
5
8
21
3
2
67
2.5
3.8
43.6
6.5
10.2
27.0
3.8
2.5
ileocecal region, colon, jejunum, rectum, duodenum,

stomach and esophagus.23 The frequency of involvement
of various abdominal organs as seen by Thapa et al24 is
shown in (Table 11.2). In another study of gastrointestinal
tuberculosis, which included large number of pediatric
patients also, most common site of involvement was
ileocecal region followed by small bowel and colonic
tuberculosis.25 7.3% of patients had evidence of perforation and fistulae which included esophagocutaneous,
rectovesical, choledochoduodenal, rectoileal, jejunojejunal, rectoileouterine, ileoileal, rectouterine,
enterocutaneous and coloduodenal. Secondary
reactivation of old healed focus, common in adults, may
occur in older children and adolescents. Contiguous
extension from adjacent organs is commonly reported
in adolescent girls with tuberculous salpingitis and
tuberculosis of the spine.22 The pathogenesis of ATB is
summarized in (Fig. 11.1).
Immunopathogenesis
Macrophage cells found in the follicle-associated
epithelium of intestinal Peyers patches of gut-associated
lymphoid tissue, provide a route of entry for pathogens
into the mucosa and can phagocytose tubercle bacilli.
Cytokines have been implicated in the protective
immunity, pathophysiology and development of tuberculosis. Most people who become infected with M.
tuberculosis mount an effective protective immune
response, but 5-10% develop disease. Patients with active
disease show depressed interferon gamma responses to
130
Fig. 11.1: Pathogenesis of abdominal tuberculosis in children
mycobacterial antigens in vitro, a state dened as anergy.

Systemic features are due to cell mediated immune
response. Fever develops due to IL-1 and hyperglobinemia due to IL-6. Interleukins-12 and -18 might
play an important role in the initial host responses to
infection. The proinflammatory cytokine, TNF-, may
play a critical immunomodulatory role in the defense
mechanisms of the disease, maintaining a balance
between protective immunity and pathophysiology.
Positive Mantoux test develops because of delayed
hypersensitivity. Development of endarteritis leads to
deep ulceration and hemorrhage.
Pathology
The ileocecal region is the most common site of
involvement in older children and adults, although ATB
can have a focus at any site in the gastrointestinal tract,
associated lymph nodes and/or peritoneum. Intestinal
Tuberculosis (ITB) usually has one of the three forms:
ulcerative, hypertrophic or ulcerohypertrophic, or
fibrous. Tuberculous granulomas initially form in the
mucosa or Peyers patches, whereas ulcers are relatively
superficial, with a different appearance from those in
Crohns disease. Intestinal TB progresses slowly and
presents late with complications, especially acute or
subacute obstruction due to the mass (tuberculoma),
stricture formation in the ileocecal region or perforation
leading to peritonitis. Peritoneal TB (PTB) is rare in the
absence of any other debilitating disease. In PTB, the
peritoneum is studded with multiple yellowwhite
tubercles.
Types of abdominal tuberculosis in children
Tuberculosis of the intestine
Ulcerative
Hypertrophic
Ulcerohypertrophic
Stricture formation
Fistula
Miliary (granular)
Peritoneal TB
Peritonitis
- Ascitic
a. Generalized
b. Localized
Dry plastic type
- Adhesions interloop
- Fibroplastic
Miliary TB peritoneum
Granular peritoneal surface
Omental TB
Rolled up
Miliary
TB of lymph nodes
Tabes mesenterica
Retroperitoneal
Peripancreatic
Porta hepatis
Other organ TBhepatobiliary, splenic, pancreas.
In majority of children the tuberculosis of intestine
presents pathologically in two major forms.
Ulcerative Type
Patients with ulcerative type have induration and edema
of diseased segment with ulcers which can be solitary or
multiple. Ulcers are usually transverse to the long axis
of the bowel Girdle ulcers. Areas of normal mucosa
may be found amidst diseased segments and are called
as skip lesions. Depth of the ulcers varies from
submucosa to muscularis propria or even serosa. Healing
and fibrosis lead to napkin ring strictures causing
obstructive symptoms. Adhesions between bowel loops
prevent free perforation but promote fistula formation.
Related mesenteric lymph nodes may caseate to form
mesenteric abscesses.
Stricturous/Hypertrophic type
In contrast to the ulcerative form, stricturous/
hypertrophic form may occur in young well nourished
patients. Cecum is the commonest site affected. Usually
the clinical setting is of low volume infection by less
virulent organisms in a relatively healthy host. Extensive
inflammation and fibrosis occurs in this form causing
adhesion of bowel, mesentery and lymph nodes into a
mass. Caseation is common in mesenteric lymph nodes.
Clinical Features
Abdominal tuberculosis has protean manifestations and
most of symptoms are nonspecific. In children, the
peritoneal and nodal form of tuberculosis is much more
common than intestinal tuberculosis. The clinical
presentation of abdominal tuberculosis can be acute,
chronic or acute on chronic. Clinical presentation
131

Table 11.3: Clinical profile of abdominal TB
Symptoms
No.
Percent
Pain abdomen
Anorexia
Fever
Weight loss
Chronic diarrhea
Vomiting
Diarrhea
63
60
53
66
50
24
14
81
77
68
84
64
31
18
Constipation
Cough
4
29
5
37
depends upon the site of disease and the type of

pathological involvement. Analysis of symptoms and
signs of patients of abdominal tuberculosis by Thapa et
al have been shown in (Table 11.3).24
Presentation According to Site of Involvement

Peritoneal Tuberculosis
Tuberculous peritonitis often exhibits female
predominance. Individuals with HIV infection, cirrhosis,
diabetes, malignancy, and those receiving continuous
ambulatory peritoneal dialysis are at high risk for
tuberculous peritonitis. 26,27 This type presents as
abdominal distention and ascites or as soft cystic lump
secondary to loculated ascites. Constitutional symptoms
of fever and night sweats may be present. Diffuse
abdominal tenderness, doughy abdomen, hepatomegaly,
and ascites may be noted on physical examination.
Mesenteric lymph nodes may present as vague
abdominal pain. There may be associated systemic
manifestations seen in up to 33% of cases like low grade
fever, malaise, night sweats, anemia or weight loss. The
extra-abdominal tuberculous lesion may give additional
clues towards the diagnosis of abdominal tuberculosis
especially when associated with GI symptoms.
Conversely, there may not be any evidence of tuberculosis elsewhere in the presence of abdominal tuberculosis. Concomitant positive radiologic evidence of
pulmonary tuberculosis has been seen in variable
percentages. It was 20% in a study by Narasimharao
et al.28 Thapa et al reported 68.2% of patients having
pulmonary lesions.24
In GIT, all parts from the esophagus to the rectum
may be involved in isolation or in combination.
Esophagus: Esophagus is very rarely involved because of
its tubular structure. Involvement occurs mainly by
extension of disease from adjacent lymph nodes in
mediastinum. The patient usually presents with low
grade fever, dysphagia, odynophagia and an ulcer.29
Most commonly it involves mid or upper esophagus.
Tracheoesophageal fistula and rarely, aorto esophageal
Signs
No.
Percent
Distention
Visible peristalsis
Lump abdomen
Doughy abdomen
Ascites
Hepatomegaly
Splenomegaly
Enterocutaneous Fistula
Peripheral lymphadenopathy
Lung signs
54
21
15
30
12
41
16
3
26
13
69
27
19
39
15
52
21
4
33
17
fistula causing massive hematemesis are rare

complications. Endoscopy, fine needle aspiration
cytology (FNAC) and biopsy are mandatory for
confirmation of the diagnosis.
Gastric: Involvement of stomach is rare due to paucity of
lymphoid tissue and presence of acid in stomach.
Ulcerative form is the commonest form seen in stomach
in 80% with ulcers usually on the lesser curvature.30
Symptoms are nonspecific and include abdominal pain,
nausea, vomiting, GI bleed, fever and weight loss.
Sometimes patients may present with features of gastric
outlet obstruction. Antrum is more often involved and
simulates Crohns disease, lymphoma or carcinoma.
Duodenal: This is also a rare site of tuberculosis.
Symptoms include non specific dyspeptic symptoms,
fever and weight loss. Patients can present with
obstruction which is more common due to extrinsic
compression than luminal obstruction.31 Strictures and
duodeno- colic fistula also have been reported.
Small intestinal and ileocecal: The involvement of ileocecal
area is more commonly encountered in older children
and adults. It can present as ulcerative, hypertrophic or
both.7-11
Ulcerative Type
Ulcerative form has been found more often in
malnourished children. This type presents with chronic
diarrhea and features of malabsorption. This has been
reported in 16-30% of patients.24 The cause of malabsorption in intestinal tuberculosis is thought to be
bacterial overgrowth in a stagnant loop, bile salt
deconjugation, decreased absorptive surface due to
ulceration, and involvement of lymphatics and lymph
nodes. Rarely hemorrhage can be the manifestation of
this form of tuberculosis.
Stricturous/Hypertrophic Type
Stricturous/hypertrophic type presents with features of
subacute intestinal obstruction in the form of
132
constipation, obstipation, vomiting, diarrhea, abdominal

distention and colicky abdominal pain. Subacute
intestinal obstruction is characterized by attacks of
incomplete obstruction that resolve spontaneously. This
may be associated with gurgling, feeling of ball of wind
moving in the abdomen and visible intestinal loops. It
may also present as enterocutaneous or enteroenteric
fistula, which may be single or multiple. In fact the
intestinal tuberculosis has been a great mimicker of
Crohns disease and resembles it in many ways.
Colorectal: It can present with nonspecific symptom or
with weight loss, anemia and lower GI bleed. There can
be diffuse or segmental colitis.32-35 This can simulate
Crohns colitis and ulcerative colitis.
Anal tuberculosis: Anal tuberculosis is also uncommon
and has a distinct clinical presentation in form of anal
discharge, perianal swelling, pain or fistulae. Tubercular
fistulae are usually multiple, hence should be
differentiated from Crohns disease.36-37
Hepatobiliary tuberculosis: Hepatobiliary tuberculosis may
occur as primary hepatic tuberculosis or as part of
disseminated or miliary tuberculosis. Tuberculoma if
found can be single or multiple. Other findings can be
tubercular abscess, involvement of biliary tract, fatty
change, amyloidosis and granulomatous hepatitis.
Presentation can be in the form of pain (usually localized
to right hypochondrium), fever, jaundice, hepatomegaly,
tenderness, splenomegaly, anemia or ascites.
Pancreatic tuberculosis: Pancreatic tuberculosis occurs in
2 to 4% in miliary tuberculosis. Focal tuberculosis of
pancreas is very uncommon. It may result in common
bile duct (CBD) obstruction. Untreated cases may develop
changes of chronic pancreatitis.38 More often peripancreatic
lymph nodes are involved and lead to the mass formation
engulfing pancreas.
Splenic tuberculosis: Spleen usually gets enlarged as a
part of disseminated tuberculosis. Occasionally there can
be massive splenomegaly also. Spleen can show multiple
hypodense discrete or conglomerate granulomas of
variable size. There may be formation of abscesses also.
Sometimes the clinical and radiological picture may
mimic lymphoma.
Investigative Approach to Abdominal Tuberculosis

Abdominal tuberculosis is a paucibacillary disease. It is
not possible always to obtain microbiological proof. A
high degree of suspicion in endemic areas should guide
the investigative approach. Diagnosis of ATB is based
on any of the following positive criteria in the presence
of strong clinical suspicion:
1. Demonstration of acid fast bacillus (AFB) in the lesion
or ascitic fluid.
2. Growth of M. tuberculosis on culture of tissue or ascitic
fluid.
3. Histological evidence of caseating granuloma.

4. Operative evidence of ATB.
5. Good therapeutic response to chemotherapy, which
there is no evidence of any other disease.
Granulomas have been reported in only 40% of ATB
patients and may be present only in lymph nodes. They
are absent in enteric lesions. In a host with good defense
response or low virulence of the organism noncaseating
granulomas may be seen. Caseation is a histological
marker for ATB and helps in differentiating it from
Crohns disease.39-41 ATB is a paucibacillary disease;
therefore the working diagnosis is mainly based on
history, clinical findings and histology. Most of the times
the demonstration of AFB in tissue or culture is not possible
in children.
Techniques for Definitive Diagnosis

Demonstration of AFB
Demonstration of bacilli can be done by direct staining
or culture of tissue or various body fluids which can be
obtained by various techniques described below.
Demonstration can be done by direct staining of the
material or cultured by various methods. Zeihl-Neelsen
staining, Cold staining methods like Kinyoun, Gabett
methods and fluorescence microscopy with auramine,
rhodamine are the various staining method used.
Conventional culture with LJ medium takes 6 to 8 weeks
for the result. Rapid culture methods like BACTEC, MGIT
(Mycobacterial growth indicator tube), Septicheck and
micobacteriophage based assays can be used to get early
results within 2 to 4 weeks.
1. Fine needle aspiration cytology (FNAC): FNAC from
intra-abdominal mass is a well established mode of
quick diagnosis. This is less invasive if a mass is
palpable. A mass could be due to lymph nodes, rolledup omentum, and hypertrophied lesion of intestine.
Aspiration can be guided by ultrasound or CT if a
mass is deep seated or directly from enlarged lymph
nodes. US/CT guided FNAC is possible from
retroperitoneal, peripancreatic, mesenteric, and porta
lymphnodes. Endoscopic (upper and lower GI)
guided FNAC can be done from submucosal lesions.
FNAC can pick up a background necrotic tissue. A
recently published Indian study reported 92 cases
diagnosed by FNAC from 1996 to 2006. It is a simple,
fast accurate and inexpensive diagnostic procedure.42
2. Ascitic fluid for AFB and culture: The yield of
organisms from ascitic fluid either by AFB staining
or by culture is very low. AFB can be demonstrated
from the ascitic fluid in < 3% cases and tubercle bacilli
can be cultured in < 20% cases. The yield of culture
can increase upto 80 to 83% if at least one liter of ascitic
fluid is concentrated by centrifugation.43
3. AFB in the biopsy tissue: Demonstration of AFB in
the biopsy material obtained by endoscopy confirms
133
the diagnosis. M. tuberculosis can also be cultured

from biopsied tissue/material or the specimen
obtained and can be subjected to PCR for detection.
In various studies sensitivity of endoscopic biopsy is
reported; varying from 30 to 80%, but 8 to 10 biopsies
for histology from same site by dug well technique
and 3 to 4 specimens for culture should be obtained
for better yield. The crushed smear made out of biopsy
can demonstrate necrotic tissue, epitheloid cells, giant
cells and AFB.44
Histopathology of the Tissue

Various ways to obtain biopsy material are:
1. Upper GI endoscopy: In children, pediatric size
endoscope can be used to have direct visual
impression of lesions in esophagus, stomach and
duodenum (Fig. 11.2, see color verions, Plate 00). With
the help of flexible endoscopic biopsy forceps, biopsy
can be obtained. At the same time FNAC can be
obtained. Other endoscopic techniques like
enteroscopy, double balloon enteroscopy and capsule
endoscopy can be used to visualize the bowel to
greater extent and help in diagnosis.
2. Lower GI endoscopy: Pediatric size sigmoidoscope or
colonoscope is used to see the colon for any lesion
and the material can be directly obtained for
confirmation of diagnosis. Granulomas have been
reported in 8 to 48% patients and 33 to 38% of positive
cases showed caseation.34 In a study of 8 patients by
Thapa et al45 with colonic symptoms, biopsy material
revealed submucosal granuloma in all. Endoscopic
FNAC can be used for quick diagnosis. Ulcers ranging
from few mm to 2 cm long and nodular friable mucosa
are the most common findings at colonoscopy. Cecum
is the most commonly affected site. Ascending and
transverse colon are more commonly involved than
sigmoid colon. Endoscopic appearances in
tuberculosis include hyperemic nodular friable
mucosa, pseudopolyps, edematous folds and
deformed, edematous or hypertrophied and gaping
of ileocecal valve (Figs 11.3 and 11.4, see color verions,
Plate 00). Usually lesions are circumferential in
contrast to Crohns disease (Figs 11.5A and B, see color
verions, Plate 00). Areas of strictures with nodular or
ulcerated mucosa also may be seen and are usually
but not invariably <3 cm in size. Endoscopic biopsy
may not reveal granulomas in all cases as the lesions
are submucosal and deeper and segmental. At least 8
to 10 biopsies are taken from the edge of the ulcer
and deep biopsies from hypertrophied lesions are to
be taken. Entire colon may be involved in 4% cases10 and
segmental involvement of the disease up to 26% cases.46
Colonoscopic biopsies yielded 40% culture positivity and
combination of histopathology and cultures could
establish diagnosis in upto 60% cases. Demonstration of
Fig. 11.2: Tubercular ulcer in duodenum (For color version see Plate 3)
Fig. 11.3: Ulceration, nodularity and gaping of ileocecal valve

(For color version see Plate 3)
Fig. 11.4: Girdle shape ulcers with exudates in transverse colon

134
Figs 11.5A and B: (A) Transverse ulcers of tuberculosis in colon, (B) compared to longitudinal ulcers in Crohns disease
Fig. 11.6: Histopathology (For color version see Plate 4)
typical tuberculous granulomas with caseating necrosis

and AFB confirms the diagnosis (Fig. 11.6, see color
verions, Plate 00).
3. Peritoneal biopsy: Peritoneal biopsy can be done with
Vim-Silverman needle and Cope needle. It should be
carried out when enough ascitic fluid is there. Pick
up rate varies from 30 to 50%, more so reported in
adult literature.
4. Laparoscopy/peritoneoscopy: These are very helpful to
diagnose peritoneal and omental tuberculosis as
tissue can be obtained for AFB detection,
histopathology and culture under direct vision which

gives pick up rate of about 85%.45,46 The role of
laparoscopy can be further extended to therapeutic
purposes, i.e. stricturoplasty/adhesiolysis.
5. Laparotomy: Rarely laparotomy may be needed when
other parameters are not contributory and diagnosis
of tuberculosis is strongly considered. Two patients
were diagnosed on laparotomy only by Thapa et al.24
6. Liver biopsy: Liver biopsy reveals varied changes such
as granulomatous hepatitis, miliary tubercles,
conglomerate tubercles and nonspecific hepatitis,
135
Figs 11.7A and B: Plain X-ray abdomen showing (A) Multiple dilated small bowel loops with air fluid levels,
(B) Calcified tubercular lymph nodes
fatty infiltration, inflammatory cell infiltrate portal

inflam-mation, portal fibrosis, Kupffer cell hyperplasia, tuberculomas, abscesses and cholangitis in
abdominal tuberculosis.47 The yield is <30% on liver
biopsy, but on postmortem this goes upto 70%.
7. Splenic aspirate: FNAC is very useful to pick up TB
lesions in the spleen in case of conglomerate
hypodense area on ultrasonography/computerized
tomography (USG/CT).
Investigations to Support ATB

Mantoux Test
Mantoux positivity in ATB has been reported from18 to
66% in different case series.48 In Indian children it ranged
from 33 to 58%.49-52 Because of low sensitivity and specificity, its positivity alone is not reliable for diagnosis.
Negative Mantoux test does not exclude tuberculosis.
Utility of this test is doubtful especially in areas where
TB is highly endemic as positive test does not differentiate
between active or inactive disease. However if the
Mantoux test is positive >15 mm usually indicates active
TB in the child.
Radiology
a. X-ray chest: Incidence of pulmonary tuberculosis
varies from 19 to 58% in abdominal tuberculosis.13
Abnormal chest X-ray is seen in 50 to 75% cases of
tuberculous peritonitis.48 12 to 63% patients also had
concomitant pleural effusion as reported by Dinler

et al.48 Hilar adenopathy was seen in 32% and hilar
adenopathy with parenchymal lesions were present
in 37% patients.24 In contrast to adults, cavitary lesions
and bronchiectasis ware rarely encountered in
children.24,51 Signs of old tuberculosis was present in
20% of patients, like obliterated costophrenic angle,
calcified lymphnodes or a fibrocalcific parenchymal
lesion by Kapoor et al.53 Chest X-rays are more likely
to be abnormal in patients who present with acute
complications.
b. Family screening: A definite history of contact is not
always present but various case series reported
had a positive family history in 37 to 66% cases of
ATB.24, 48, 50 X-ray chest of all family members and
Mantoux test of preschool age children should be
done when there is history of contact.
c. Plain X-ray abdomen: A mottled calcification in the
mesenteric lymph nodes or calcified granulomas in
retroperitoneal lymph nodes and liver are well
defined on plain X-ray abdomen. Otherwise, the
plain film is invaluable in acute presentations like
acute/subacute obstructive features which show
dilated jejunal and ileal loops with multiple air fluid
levels (Fig. 11.7A) and relative paucity of gas in the
colon, perforation and intussusception. Multiple
fluid levels are seen in 13 to 20.5% suggesting
subacute intestinal obstruction (SAIO) and intraabdominal mesenteric calcification 2.6 to 2.8% as in
(Fig. 11.7 B).24,50
136
d. Barium studies: Sharp and Goldman reported Barium

meal follow through (BMFT) examination as the best
diagnostic test demonstrating bowel lesions, their
extent and site in upto 84% of cases.54
Barium swallow and meal: Barium examination can show
lesions in esophagus, stomach and duodenum (Fig. 11.8).
Barium meal follow-through

The features seen in a small bowel are, accelerated
intestinal transit, hypersegmentation of the barium
column (chicken intestine), precipitation, flocculation
and dilution of the contrast material, stiffened and
thickened folds; luminal stenosis with smooth but stiff
contours (hour glass stenosis), ulcerations, fistulae,
multiple strictures with segmental dilatation of bowel
loops and fixity and matting of bowel loops (Figs 11.9
and 11.10). Double contrast study can be used in which
barium and air form the contrast for study of small
bowel and colon. In contrast to conventional barium
study, this gives better delineation of the lesion and
pick up rate is very good.55,56 Enteroclysis (small bowel
enema) is preferred when subacute intestinal
obstruction or stricture is suspected. It delineates the
single or multiple strictures in the jejunum and ileum
clearly (Fig. 11.11). Even bowel wall thickening and
ulceration can be picked-up. Similarly double contrast
can pick colonic and cecal lesions.
Barium enema
Barium enema is indicated when colonic/ileocecal lesion
is suspected. Barium enema helps to find out ulcerated
and hypertrophic lesions causing obstruction in the colon
(Fig. 11.12). This can also pick-up fistulous communications.55,56
The following features53 are very classical to suggest
tuberculous pathology. These radiological signs develop
following burnt-out fibrosed lesions due to long standing
tuberculosis of the intestine.
i. Early involvement of the ileocecal region can
manifest as spasm and edema of the ileocecal valve.
Thickening of the lips of the ileocecal valve and/or
wide gaping of the valve with narrowing of the
terminal ileum (Fleischner or inverted umbrella
sign) are characteristic.
ii. Thickened folds and irregular contour of the
terminal ileum, better appreciated on double
contrast study as compared to conventional barium
enema.
iii. Conical cecum: Cecum is shrunken in size and pulled
out of the iliac fossa due to contraction and fibrosis
of the mesocolon (Fig. 11.10D). The hepatic flexure
may also be pulled down.
Fig. 11.8: Barium swallow study showing extrinsic impression

(By mediastinal lymph nodes) in mid esophagus
iv. Loss of normal ileocecal angle and dilated terminal

ileum, appearing suspended from a retracted,
fibrosed cecum (Goose neck deformity) (Fig. 11.13).
v. Purse string stenosis: Localized stenosis opposite the
ileocecal valve with a rounded off smooth cecum
and a dilated terminal ileum.
vi. Stierlins sign is a manifestation of acute
inflammation superimposed on a chronically
involved segment and is characterized by lack of
barium retention in the inflammed segments of the
ileum, cecum and variable length of the ascending
colon, with a normal configured column of barium
on either side. It appears as a narrowing of the
terminal ileum with rapid emptying into a
shortened, rigid or obliterated cecum.
vii. String sign: There is persistant narrow stream of
barium indicating stenosis. Both Stierlin and String
signs can also be seen in Crohns disease and hence,
are not specific for tuberculosis. Enteroclysis
followed by a barium enema may be the best
protocol for evaluation of intestinal tuberculosis.
Percutaneous fistulogram
Contrast can be injected through the fistulous tract to
delineate the enteric communication as shown in Figure
11.14.
Double-contrast barium examination shows typically
linear or stellate shallow ulcers with characteristic
elevated margins. The ulcers in tuberculosis tend to be
larger than those in Crohns disease and oval rather than
round, and produces greater thickening of the bowel
wall. Fistulae and sinus tracts are rare. Characteristic
137
Figs 11.9A to D: Barium meal follow through (BMFT) study showing (A) Ulceration in terminal ileum with narrowing, (B) Multiple adhesive and
stricturous small bowel loops, (C) Multiple strictures, ulcers and ileocolic fistula and (D) Multiple strictures with segmental dilatation of bowel
deformities in advanced disease include symmetric

annular napkin ring stenosis and obstruction,
shortening, retraction, and pouch formation and
amputated cecum. Amputation of the cecum may be seen
in amebiasis, but this disease rarely involves the small
intestine to the same degree as in tuberculosis.
The signs suggestive of ATB are:
i. Ulceration or filling defects in the cecum which may
be contracted or pulled up making the ileocecal
angle obtuse and resulting in a gaping or stenotic
ileocecal valve.
ii. Strictures or ulcers in the small bowel.
iii. Motility disturbances (increased/decreased transit

time).
iv. Hypersegmentation or thickened mucosal folds.
Abdominal Ultrasound
Characteristic sonographic features of early ATB are
mesenteric thickness of 15 mm or more, increased
mesenteric echogenicity due to fat deposition and
lymphatic obstruction and mesenteric lymphadenopathy.57
Portal hypertension and lymphomas are the other two
conditions which can present with mesenteric thickening.
Intra-abdominal fluid can be seen which may be free or
138
Figs 11.10A to D: Barium meal follow through (BMFT) study showing, (A) Clumped small bowel with peritoneal involvement, (B) Clumped
bowel loops with free perforation, (C) Terminal ileal strictures with enteroliths and (D) Pulled up, conical and contracted cecum
loculated and clear or complex with debris and septae.

USG is superior to CT in detecting ascites. Local
exudation from the inflammed bowel forms interloop
ascites lead to localized fluid between radially oriented
bowel loops (Club sandwich or sliced bread sign).
Presence of other sonographic findings like ascites,
dilated small bowel loops, matted fixed bowel loops,
omental inflammation and thickening of bowel wall
further substantiate the diagnosis.58 Tuberculosis has a
predilection of involvement of periportal, peripancreatic
and mesenteric lymphnodes more commonly as
compared to retroperitoneal adenopathy. This is because
mesenteric lymphnodes drain from small bowel and
other intra-abdominal viscera drain into thoracic duct
directly via cysterna chili. This feature can help ATB to

be differentiated from lymphomas. Lymph nodes in
lymphoma have uniform echogenicity whereas in TB
different lymphnodes have different echogenecities.
Regression of these changes can also be noted on followup after therapy. Lymphadenopathy regresses early and
mesenteric thickening and echogenicity are last abnormalities to regress completely. These features can be
followed up in patients who do not have other objective
evidence of disease like abnormal barium studies or
colonoscopic evidence.58 Malik and Saxena59 evaluated
the role of ultrasound and ultrasound guided biopsy. By
ultrasound, findings can be evaluated with regard to the
involvement of lymphnodes, intestines, peritoneum,
139
Figs 11.11A to D: Barium enteroclysis showing (A) Enteroenteric fistula, (B) Small segment stricture with proximal dilatation which was missed
on BMFT, (C) Multiple small segment strictures in jejunum and (D) Terminal ileal stricture with ulceration
solid viscera and abdominal abscess. Peritonitis of the

wet ascitic type is the most common. Ultrasound
guided FNAC can be directly taken from masses,
lymphnodes or hypertrophied bowel. Ultrasonography
can pick-up lesions in form of large conglomerate granulomas and abscesses in liver and spleen. The classical
sonographic findings in mesenteric lymph nodes and
peritoneal tuberculosis (clumped loops and ascites) are
shown in (Fig. 11.15).
CT Abdomen
CT demonstrates lymphadenopathy, organ lesions,
conglomerate masses and omental cakes (Fig. 11.16).
Hyperplastic ileocecal tuberculosis is usually well
evaluated on CT. In earlier stages symmetric circumferential thickening of cecum and terminal ileum is seen
(Fig. 11.17A). In later stages asymmetric thickening of
the ileocecal valve and adjacent medial wall of the cecum
is seen. In more advanced disease gross wall thickening,
adherent loops, large regional nodes and mesenteric
thickening together form a soft tissue mass centered
around the ileocecal junction.60 Ulceration or nodularity
of the terminal ileum, narrowing and proximal dilatation
can be picked up on CT scan. Circumferential wall
thickening, narrowing of the lumen and ulceration are
the features of bowel involvement. Involvement of the
ascending colon is common. Complications like
perforation, abscess, and obstruction are also seen on CT
scan. Typically lymphadenopathy is in the porta hepatis
140
Figs 11.12A to D: Barium enema showing (A) Segmental colonic TB in transverse and descending colon,
(B) Multiple ulcers in large bowel seen as diffuse colitis, (C) Colonic perforation (D) Stricture and ulceration in rectum
and in the para-aortic region, but can also involve the

mesenteric nodes with typical fanning out of the vessels
and marginalization of the bowel loops.61 The nodes are
usually matted together with hypodense centers which
probably are due to caseation and many occasionally
contain calcification.60,62
Lymph nodes may be calcified or show calcification
over the time, but the most characteristic appearance is
that of ring-enhancing nodes with low-density centers.
Central necrosis with rim enhancement, though not
pathognomonic, is a useful sign and readily seen in the
current generation CT scanners.63
Unlike USG the complex nature of the ascites is
difficult to demonstrate by CT, however CT is useful in
determining the density of the ascitic fluid which is

reported to be having high attenuation (25 to 45 HU);
presumably due to the complex nature of the fluid. The
high density nature of the fluid is reported by some
authors64,65 as specific for TB whereas others66 suggest
that it is not a reliable factor and can overlap with
peritoneal carcinomatosis.63
Mesenteric disease on CT scan is seen as a patchy or
diffuse increase in density, strands within the mesentery,
and a stellate appearance. Lymph nodes may be
interspersed. Omental thickening is well seen often as
an omental cake with stranding. A fibrous wall can cover
the omentum, developing from long standing
inflammation and is called omental line.67 Lesions in solid
Fig. 11.13: Goose neck deformity with stricture

in colon
141
Fig. 11.14: Fistulogram showing enterocutaneous fistula
Figs 11.15A and B: High frequency ultrasound abdomen showing (A) Multiple lymph nodes with hypoechoic centers and
(B) Multiple clumped small bowel loops with free fluid in abdomen
organs are seen as low-density multifocal areas, most

commonly in the liver and spleen, and rarely in the
pancreas. Over time these lesions may show calcification.
Inflammatory masses composed of bowel loops with
adherent omentum and lymphadenopathy are best
demonstrated on CT, as are omental cakes, seen
immediately deep to the abdominal wall. A combination
of the above CT features, especially when lymphadenopathy is rim enhancing or calcified, is highly
suggestive of the disease. CT scan can help in
differentiating intra-abdominal M. tuberculosis infections
from M. intracellulare infections in patients with AIDS.68
Andronikous et al evaluated the CT of 22 children
who had ATB. Commonest CT findings were
lymphadenopathy (N = 17) followed by solid organ

involvement (Fig. 11.17B) (N = 12) ascites (N = 5), bowel
wall thickening (N = 5) inflammatory masses (N = 2),
and omental thickening in one.61
Ascitic Fluid Analysis

The peritoneal fluid if present in ATB is either straw colored
or clear and is exudative in nature with proteins more than
3 g/dl, cells more than 1000/cumm (mostly lymphocytes),
ascitic/ blood glucose ratio less than 0.96 and serum
albumin ascitic gradient (SAAG) level less than 1.1 g/dl.
Adenosine deaminase (ADA) in ascitic fluid has been
considered to be a useful screening test in children with
142
Figs 11.16A and B: Computed tomography (CT) abdomen showing (A) and (B) Formation of omental cake
Figs 11.17A and B: Computed tomography (CT) abdomen showing (A) Thickened bowel loops with multiple enlarged lymph nodes with
hypodense necrotic centers and (B) Multiple hypodense lesions in spleen (Splenic tuberculosis)
ATB. A level of more than 33U/L has a sensitivity and

specificity of 93% and 96% respectively with positive
predictive value of 93%.69
Malabsorption Studies
Abnormal malabsorption tests seen in these children are
not diagnostic. Abnormal parameters were seen in 30.8%
of cases in pediatric series.24 It has been 17 to 33.7% in
different series in adults.4,23 Malabsorption is due to
decreased small intestinal mucosal surface, lymphatic
obstruction, fistula formation between the small and large
intestine, deconjugation of bile salts secondary to
bacterial overgrowth and decreased bile salt pool because
of impaired active absorption in the terminal ileum.
Histopathology of Peripheral Lymph Node

In presence of abdominal symptoms, lymph node biopsy,
FNAC is helpful in diagnosis. Presence of caseating
granuloma is the histological marker of tuberculosis.
Hematological and Biochemical Tests

They may indicate the extent of dysfunction of GIT but
are not specific for diagnosis of abdominal tuberculosis.
Anemia, hypoalbuminemia and raised ESR are the usual
findings. TLC is raised with predominantly lymphocytosis in upto 50% cases.24
Newer Modalities
Virtual CT Enteroclysis and virtual CT Colonoscopy
Demonstration of AFB
AFB can be demonstrated in gastric aspirate, stool,
sputum, urine and secretions from the fistulous tract.
However, their presence does not confirm abdominal
tuberculosis.
This is performed to define the site of hypertrophic and

stricturous lesions non invasively and in cases where the
routine endoscopy is not possible. This is done after good
preparation of the bowel and images are reconstructed
to define the nature and exact location of pathology. The

limitation of this technique is that the biopsy specimen
is not possible.
Sonoenteroclysis
Sonoenteroclysis is another modality with which bowel
can be examined for mural thickening and intra mural
pathologies.
Ascitic Fluid Adenosine Deaminase

Adenosine deaminase (ADA) is an aminohydrolase
involved in the catabolism of purine bases that converts
adenosine to inosine. T lymphocytes have more activity
of ADA than B-lymphocytes. ADA activity depends
upon the degree of T-cell activation. Because of
stimulation of T-cells by mycobacterial antigens ADA
levels are increased in tuberculous ascitic fluid. ADA in
ascitic fluid has been considered to be a useful screening
test in children with ATB. A level of more than 33U/L
has a sensitivity and specificity of 93% and 96%
respectively with positive predictive value of 93%.69
Serodiagnosis of Tuberculosis
i. Antibodies: There are various serological methods to
detect antibodies such as complement fixation,
hemagglutination precipitation and gel diffusion,
soluble antigen fluorescent antibody (SAFA), radioimmunoassay (RIA), enzyme linked immunosorbent
assay (ELISA), circulating immune complex and
agglutination tests such as Kaolin Agglutination Test
(KAT). ELISA and SAFA have been reported to be
more sensitive and specific.70-72 KAT in a recent study
was positive in 94.1% of abdominal tuberculosis.73
Various authors have shown rise of IgG and IgE
classes of antibodies but out of these IgG (IgG2) has a
better correlation.70 In a study comparing efficacy of
ELISA for IgG anti-bodies against specific glycolipid
antigen(PGL Tb1, Study I) and AST 6 antigen of M.
tuberculosis (Study II) with ZN staining and culture
on LJ media, ELISA tests showed a significantly
higher sensitivity (49% study I; 53%, study II) as
compared with LJ medium culture method (15.4%,
study I; 28.9% study II) and ZN staining (27.7%, study
I; 20.5%, study II) in all patients (p < 0.05). The results
were comparable with PCR (40%, study I; 42.2% study
II). Specificity of ELISA test was 100% in all the
patients.74
ii. Monoclonal antibodies: Monoclonal antibodies have
been developed against M. tuberculosis. Monoclonal
antibodies (IgG type) also called TB 72, are raised in
74% of pulmonary tuberculosis but very high titres
have been reported in patients with peritoneal,
pleural, pericardial and bone tuberculosis. In the same
way, synthetic peptides have been developed to
detect M. tuberculosis antibodies.70
143
iii. Antigens: To detect the presence of mycobacterial

antigen in the blood, very sensitive methods like RIA
and ELISA have been used. ELISA is highly sensitive
for detection of antigen in CSF.75 A simple dot-ELISA
for detection of M. tuberculosis in sputum samples has
been developed. The sensitivity of antigen detection
was 61 % in AFB positive compared to 40% in AFB
negative samples.76
iv. Polymerase chain reaction (PCR): Nowadays PCR is
used to diagnose tuberculosis rapidly by identifying
DNA of M tuberculosis in clinical samples. Most
commonly used target is insertion sequence IS6110
which is present in 60% of specimens.77 Even though
studies showed high sensitivity and specificity of PCR
in pulmonary TB whereas in ATB it has low sensitivity
and specificity. This is attributed to large size of
specimens and uneven distribution of disease. But
some studies showed that M. tuberculosis strains
originating from India do not contain IS6110. An
Indian study of PCR in ATB using 340 bp nucleotide
sequence located within 38 kDa protein gene of M.
tuberculosis showed 77% sensitivity and 66%
specificity.78 PCR amplification of IS6110 in fecal
samples of intestinal tuberculosis showed high
sensitivity (88.8%) and specificity (100%).79
v. Interferon gamma release assays (IGRA): Recently
IFN-gamma responses to M. tuberculosis specific
antigens (ESAT-6, CFP-10, TB 7.7) are being used
in the in vitro diagnostic tests for tuberculosis.
Commercial version of these tests includes
QuantiFERON-TB Gold (QFT-G), QuantiFERON-TB
Gold in Tube (QFT-GIT) and ELISPOT. These tests
have high specificity of 97.7% and 92.2% for QFT and
Elispot respectively.80
vi. Other newer serological markers: Most recently
chemokine IP-10 (CXCL 10) has been introduced as a
specific diagnostic marker for infection with M.
tuberculosis.81 Thakur et al has proposed high serum
CA-125 as a pointer towards tuberculous infection.82
Purohit et al in their recent study concluded that
immunohistochemistry using anti-MPT64 is simple
and sensitive technique for establishing an early
diagnosis of M. tuberculosis with sensitivity and
specificity of 92% and 97% respectively.83
Various criteria have been suggested for the diagnosis
of abdominal tuberculosis and are given in (Table 11.4).13
Any one of these criteria has to be positive to label the
diagnosis of abdominal tuberculosis.
Differentiating ATB from Inflammatory Bowel Disease

(IBD)
Intestinal tuberculosis and inflammatory bowel disease
are great mimickers. Both intestinal tuberculosis and
Crohns disease are chronic inflammatory disorders of
144

Table 11.4: Criteria for diagnosis of abdominal
tuberculosis
Table 11.5: Difference between intestinal

TB and Crohns disease
Definitive
Intestinal TB
Crohns disease
Histological evidence of tubercles with caseation necrosis

A good typical gross description of operative findings with
biopsy of mesenteric nodes showing histologic evidence
of tuberculosis
Animal inoculation or culture of suspected tissue resulting
in growth of M. tuberculosis
Histological demonstration of acid fast bacilli in a lesion.
Fever ++
Circumferential/
transverse and patulous
IC valve
Hypertrophic lesions/
Nodularity/
Pseudopolyps
Caseating conglomerate
granulomas, AFB +ve
Anorectal lesions and
fistula less often
Excellent response
to ATT
Fever +
Deep linear ulcers and
normal IC valve
Modified
Histological evidence of caseating granulomas or AFB
Presence of M. tuberculosis in sputum or tissue or ascitic
fluid
Clinical/radiological/operative evidence of proven
tuberculosis elsewhere with good therapeutic response
Good therapeutic response to antituberculosis
chemotherapy
bowel that pose difficulties in differentiating from one

another. Distinguishing intestinal tuberculosis from
Crohns disease may be extremely difficult, even when
the results of endoscopy, surgical, and histologic
evaluation are available.84 Although both have similar
clinical manifestations, their ultimate course and
treatment are quite different. Intestinal tuberculosis can
be completely cured if diagnosed early and treated
appropriately. In contrast, Crohns disease is not curable
and treatment modalities are completely different.
Steroids and other immunosuppressive agents are useful
in the treatment of Crohns disease but, can be deleterious
if used in intestinal tuberculosis. The differentiation of
intestinal tuberculosis from Crohns disease is therefore
very important (Table 11.5).
It has been reported that 40 to 65% of patients with
Crohns disease either received a trial of ATT or were
misdiagnosed as having intestinal tuberculosis before
they were finally diagnosed as Crohns disease.85,86
Confluent granulomas are strongly suggestive of
tuberculosis and in Crohns granulomas are not confluent
even though two or three may lie in close proximity.87 In
Crohns granulomas are typically comprised of closely
packed aggregates of epitheloid cells and macrophages
and multinucleated giant cells are usually more abundant
in tuberculosis.39 The presence of central caseation is a
hallmark of granulomas caused by tuberculosis, but small
areas of central necrosis can occasionally be seen in a
granuloma caused by Crohns disease.39 The granulomas
of tuberculosis are always surrounded by inflammatory
cells, whereas those of Crohns disease can occur in an
otherwise normal biopsy, particularly in the rectum.88
The ulcers of tuberculosis almost always show a
granulomatous response whereas in Crohns disease the
ulcers and fissures may not always show granulomas.39
In tuberculosis the inflammatory infiltrate is usually seen
Cobblestone appearance
and Aphthous ulcers
Noncaseating compact
granulomas AFB ve
More often
No response to ATT,
require immunosuppression therapy
in the lamina propria in Crohns colitis shows variation

in the density of the infiltrate in different parts of the
biopsy. 80 AFB positivity establishes diagnosis of
tuberculosis.
Colitis type of lesions in tuberculosis is very difficult
to differentiate from ulcerative colitis. The differentiating
features are given in Table 11.5. No single endoscopic
finding is absolutely specific to either disease. Combining
endoscopic findings can predict the correct diagnosis in
nearly 90% of cases.84
Anorectal lesions, longitudinal ulcers, aphthous
ulcers, and cobblestone appearance were significantly
more common in patients with Crohns disease.
Involvement of fewer than four segments, a patulous
ileocecal valve, transverse ulcers, and scars or pseudopolyps were observed more frequently in patients with
intestinal tuberculosis. The direction of ulcers is
longitudinal in patients with Crohns disease and
transverse in those with intestinal tuberculosis.84
Presence of extraintestinal manifestations such as
uveitis, arthritis and fistulae strongly suggests Crohns
disease. The correct diagnosis of either disease can be
made in most patients, if the results of clinical, endoscopic
(both conventional and capsule), pathologic, bacteriologic, and PCR evaluations are combined.
Colorectal tuberculosis can mimic ulcerative colitis
when it presents in the form of colitis. The colitis in
tuberculosis is usually segmental though it can be diffuse
at times, whereas ulcerative colitis usually involves
rectum and left colon and may present as pancolitis. The
differentiating points between TB colitis and ulcerative
colitis are given in (Table 11.6).
Complications
The most common complication of ATB that requires
surgical intervention is intestinal obstruction. Obstruction
can be due to adhesions, enlarged lymphnodes causing

Table 11.6: Difference between colorectal TB and
ulcerative colitis
Colorectal TB
Ulcerative colitis
Segmental lesions
Rectal disease uncommon
Diffuse colitis rare
Disease could be
elsewhere in small bowel
TB granuloma, AFB+
Left colon disease often

Commonly involved
Common in children
Response to ATT
Backwash ileitis at times

No granuloma, Chronic
colitis No AFB
Response to 5-ASA and
steroids
extrinsic compression or due to stricture formation.

Intestinal obstruction was the indication for explorative
laparotomy in 40 to 65% cases in various surgical series.52,89
Fistula formation and confined perforation with abscess
are also common. The most important fistulae are enteroenteric, entero-cutaneous and perineal which could be
single or multiple. Free perforations are rare because of
thickened peritoneum and adhesions with adjacent tissues.
Incidence of free perforation ranged from 0 to 11% in
different studies and terminal ileum is most common
site. Multiple perforations are reported in 10 to 40%
cases.90,91 Hemorrhage, enterolithiasis, cocoon formation,
traction diverticula and malabsorption are uncommon
consequences.
Intestinal hemorrhage due to enteric tuberculosis is
uncommon and usually is mild. It is usually due to
bleeding from ulcers. Massive GI bleed due to
tuberculosis is very rare. In case of massive GI bleed most
common site is terminal ileum followed by large bowel.92
Intraperitoneal hemorrhage can also occur and it can be
massive rarely due to erosion of major vessels. Ulceration
with thinned bowel wall, and adhesions can lead to
traction diverticulae. Malabsorption is also an uncommon
complication. This can be due to strictures causing stasis,
bacterial overgrowth and deconjugation of bile acids.
Mesenteric adenopathy at times may cause lymphatic
obstruction and can cause fatty acid malabsorption.
Enteroliths also can occur in intestinal TB, stricture and
stasis being the predisposing factors. Subacute intestinal
obstruction is causative factor rather than a consequence
of enteroliths. They occur mostly in small intestine. They
can be radiolucent or radio-opaque and can occur in
various shapes. Radiolucent center with dense rim is the
characteristic radiographic feature. Usually in duodenum
and jejunum with acidic pH enteroliths are radiolucent
and in ileum with alkaline pH due to precipitation of
calcium they are radio-opaque.93
Abdominal cocoon, also known as sclerosing
encapsulating peritonitis (SEP), which is a rare condition
that is characterized by the encasement of the small bowel
by a fibrocollagenic cocoon like sac that causes intestinal
145
obstruction.94 Abdominal cocoon is described primarily

in adolescent girls and tuberculosis is also described as
infrequent cause of cocoon leading intestinal obstruction.
Rare case of cocoon due to tuberculosis is described in
children also.95,96
Although few nonspecific radiological signs on plain
X-ray, barium series and computerized tomogram scan
are described but diagnosis is usually made at
laparotomy, which shows the encasement of the small
bowel within the sac-like cocoon. Although the disease
primarily involves small bowel, it can also involve other
organs like the large intestine, liver and stomach. The
treatment is by lysis of this covering membrane, and
rarely, further procedure such as resection, is required.97
Treatment
Antituberculous chemotherapy is the mainstay in the
management of abdominal tuberculosis. Surgical options
are reserved for tissue diagnosis or treatment of
complications. Chemotherapy consists of 4 drugs and for
duration of 6 months. Short-course chemotherapy is well
studied in adults. Even though initial responses are good,
it is associated with frequent relapses. So many physicians
tend to extend therapy upto 12 months. Short-course
chemotherapy and role of pyrazinamide have not been
evaluated in children with abdominal tuberculosis. There
is a report of short-term chemotherapy in adults with
3 drug regimen of INH, rifampicin and pyrazinamide for
2 months followed by INH and rifampicin for 4 months.
Favorable response was seen in 97% in short-course
therapy versus 92% in standard treatment group. However
toxicity was 26% in short-course group and 13% in the
standard therapy group.98 Short-course chemotherapy
regimen consists of INH (4-6 mg/kg per day), rifampicin
(10 mg/kg/day), ethambutol (15 mg/kg/day) and
pyrazinamide (25 mg/kg/day) for initial 2 months. After
2 months ethambutol and pyrazinamide are stopped but
INH and rifampicin in same dose are continued for 7
months. If the nodal tuberculosis is dominating then
antituberculosis therapy (ATT) is continued for 9 to 12
months. In ATB nodal tuberculosis is always there,
therefore consensus is to continue ATT for 9 months to
avoid relapse. If M. bovis is isolated pyrazinamide can be
discontinued because of its innate resistance to the drug.
But it usually takes 2 to 3 months to make this
differentiation. Ninety percent patients with enteric
tuberculosis and even higher percentage of patients with
peritoneal tuberculosis will respond to medical therapy
alone if it is started early enough.99-101
Hepatic transaminases are monitored periodically till
completion of therapy. When hepatotoxicity is present,
both the drugs INH and rifampicin are stopped and
alternate therapy is given till the time there is recovery
of hepatic injury.
146
It is believed that ATT reduces fibrosis along with

healing and also causes some regression in fibrosis
thereby reducing predisposition to adhesions and
stricture formation. The role of corticosteroids in the
management of ATB to decrease the formation of
adhesions and stricture is not proven.101,102 Two large
studies did not show any beneficial effect with use of
steroids in ATB. 103,104 Clinical and radiological resolution
of tuberculous strictures may occur with treatment with
ATT even in patients presenting with features of subacute
intestinal obstruction.101 Therapy can also increase the
incidence of perforation. Drugs are usually well tolerated
in children and adverse reactions occur in only 1.1%
cases, all of which are reversible.105 Compliance however,
still remains a significant hurdle, is seen in only 62%.
Prolongation of treatment and motivation is needed in
such cases. The second cause of failure is the development
of drug resistance. Culture sensitivity studies and appropriate modification of the regimen is required.
In peritoneal tuberculosis, effective anti-tuberculosis
therapy is the mainstay of treatment. In enteric
tuberculosis which is commonly associated with
complications, surgery may be required. Antituberculosis
therapy should be given preferably for 6 to 8 weeks prior
to surgery and continued for at least 6 to 9 months after
surgery.
dissection and thus reduces chances of injury to the

duodenum and ureter.101,110,111 Bypass procedures like
ileotransverse anastomosis are avoided and limited right
hemicolectomy with a 5 cm margin from grossly
abnormal bowel is the procedure of choice in ileocecal
TB.112
In cases of perforation, resection rather than simple
closure is safer.113,114 Freshening of the bowel edges and
transverse closure is an option if the bowel is healthy.
All patients of perforation and peritonitis should have
peritoneal toilet and drainage as well. Simple strictures
are best treated with stricturoplasty, which involves a
longitudinal enterotomy along the anti-mesenteric
border which is then sutured transversely. 25, 52,101
Resection is advocated for multiple strictures or if there
is significant edema of the bowel wall. Recurrent
adhesive obstruction may require intestinal stenting.
Fistulizing disease like enteroenteric and enterocutaneous fistulae are initially treated with ATT for 3
to 4 months then can be taken up for surgical correction
in case of persistence.
Surgery in ATB is hazardous, requires great care and
restrains to minimize bowel handling and dissection.
Enterocutaneous fistula formation is not uncommon after
surgery. These high output fistulas require aggressive
management, which entails adequate drainage, TPN,
antibiotics and ATT.
Role of Surgery in Abdominal Tuberculosis

The role of surgery is now largely limited to tissue
diagnosis in case of peritoneal and lymphnodal ATB and
for the management of complications which include
obstruction, perforation, fistula formation or rarely
significant bleeding.2,101,106,107 The indications for surgical
treatment are:
Diagnostic
Minilaparotomy and biopsy
Laparoscopic biopsy in ascitic type
Extra-abdominal lymph node biopsy.
Exploratory laparotomy in acute abdomen
Management of complications like strictures,
adhesive obstruction, fistulae or bleeding.
Before the advent of effective antituberculous drugs,
surgical management consisted of bypassing the stenosed
segment with enterostomy and ileo transverse colostomy
procedures, because any resectional surgery is hazardous
in presence of active disease. These led to the
complications like short gut and blind loop syndrome,
fistulae and recurrent obstructions in the remaining
segments. However, with the realization that tuberculous
pathology heals well with ATT, conservative surgical
resection and stricturoplasty became popular.42,108-110 For
ileocecal lesions, limited resection of the ileocecal area
rather than a formal right hemicolectomy, involves lesser
HIGHLIGHTS
Abdominal TB is the uncommon form of
tuberculosis in pediatric age group.
The diagnosis is made on high index of suspicion
with detailed clinical history and examination of the
patient.
Often the disease is either missed or over diagnosed
due to lack of investigative tools in the peripheral
centers.
Definitive diagnosis is made by demonstration of
caseating granulomas with AFB positivity in the
tissue, however majority of times this is not possible.
Endoscopic descriptions of lesions, FNAC,
histopathology of biopsy specimen, crush smears
for cytology, culture and PCR from the tissue give
the definite diagnosis in majority of cases of
intestinal TB.
Barium studies, USG and CT scan are the other
modalities which have specific signs and add to the
diagnostic armamentarium.
In case of peritoneal, wet type of TB, estimation of
ADA is very sensitive and specific method.
The diagnosis of nodal tuberculosis is made by
ultrasound, CT and FNAC of lymph nodes.

Surgical treatment is only required in cases of
complications otherwise ATT is very effective to
ameliorate the symptomatology and to cure the
disease.
The treatment has to be well controlled and
monitored and to be given for 9 months to avoid
relapse. The outcome is excellent with adequate
ATT.
REFERENCES
1. Miller FJW. Oral and alimentary tuberculosis. In:
Tuberculosis in Children, 1st edn. New Delhi, Churchill
Livingstone 1982;137-43.
2. Udani PM. Tuberculous hepatic and splenic lesion and
hepatosplenomegaly. Indian J Child Health 1962;11:37287.
3. Madhok P, Kaur VK. Abdominal tuberculosis in children.
Prog Pediatr Surg 1982;15:173-80.
4. Diwedi BD. Abdominal tuberculosis in children. Prog
Pediatr Surg 1982;15:169-71.
5. Mitra SK, Yadav K, Mehta S, et al. Abdominal
tuberculosis in children. Indian J Surg 1978;40: 96-100.
6. zbey H, Tireli GA, Salman T. Abdominal tuberculosis
in children. Eur J Pediatr Surg 2003;13:116-9.
7. Kapoor V K. Abdominal tuberculosis. Postgrad Med J
1998;74:459-67.
8. Tandon RK, Sarin SK, Bose SL, et al. A Clinicoradiological reappraisal of intestinal tuber-culosis
changing role/gastroenterol Jap 1986; 21:17-22.
9. Faylona JMV, Chung S CS. Abdominal tuberculosis
revisited. Ann Coll surg 1999;3:65-70.
10. Sharma MP, Bhatia V. Abdominal tuberculosis. Indian J
Med Res 2004;120:305-15.
11. Pimparkar BD. Abdominal tuberculosis. J Assoc
12. Vij JC, Malhotra V, Choudhary V, et al. A
clinicopathological study of abdominal tuberculosis.
Indian J Tuberc1992;39:213-20.
13. Paustian FF, Marshall JB. Intestinal tuberculosis, In:
Bockus Text Book of Gastroenterology. Vol 3, Ed. Berk
EJ 4 edn. Philadelphia, WB Saunders Company
1985:2018-36.
14. Andronikou S, Welman CJ, Kader E. The CT features of
abdominal tuberculosis in children. Pediatr Radiol
2002;32:75-81.
15. Dye C. Global epidemiology of tuberculosis. Lancet
2006;367:938-40.
16. Dye C, Watt CJ, Bleed DM, et al. Evolution of tuberculosis
control and prospects for reducing tuberculosis
incidence,prevalence, and deaths globally. JAMA 2005;
293:2767-75.
17. Nelson LJ,Wells CD. Global epidemiology of childhood
tuberculosis. Int J Tuberc Lung Dis 2004;8:636-47.
18. Mukadi YB, DeCock K. Special challenges of tuberculosis
in HIV infected children. Ann Nestle 1997;55:3441.
19. Datta M, Swaminathan S. Global aspects of tuberculosis
in children.Paed Respir Rev 2001; 2:91-6.
147
20. Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG
vaccine efficacy in the prevention of tuberculosis. Metaanalysis of the published literature. JAMA 1994;271:698702.
21. Centers of Disease Control and Prevention. Core
curriculum on tuberculosis: What a clinician should
know. 4th edn. Atlanta (GA): US Dept of Health and
Human Services; 2000.
22. Achar ST, Viswanathan Abdominal tuberculosis in
children. In:Textbook of Tuberculosis, 2nd edn. Rao KN,
New Delhi, Vikas Publishing House Pvt Ltd 1981;387-8.
23. Bhansali SK. Abdominal tuberculosis. Experience with
300 cases. Am J Gastroenterol 1977;67:324-37.
24. Thapa BR, Yachha SK, Mehta S. Abdominal tuberculosis.
Indian Pediatr 1991; 28:1093-1100.
25. Nagi B, Sodhi KS, Kochhar R, et al. Small bowel
tuberculosis: Enteroclysis findings. Abdom Imaging
2004;29:335-40.
26. Talwani R, Horvath JA. Tuberculous peritonitis in
patients undergoing continuous ambulatory peritoneal
dialysis: case report and review. Clin Infect Dis 2000;
31:70-5.
27. Wang HK, Hsueh PR, Hung CC, et al. Tuberculous
peritonitis: analysis of 35 cases. J Microbiol Immunol
Infect 1998; 31:113-8.
28. Narasimharao KL, Yadav K, Mitra SK, et al. Abdominal
tuberculosis in children. Ann Pediatr Surg 1984;1:22-4.
29. DiFebo G, Calabrese C, Areni A, et al. Oesophageal
tuberculosis mimicking secondary oesophageal
involvement by mediastinal neoplasm. Ital J
Gastroenterol Hepatol 1997;29: 564-8.
30. Ali W, Sikora SS, Banerjee D, et al. Gastro-duodenal
tuberculosis. Aust NZ J Surg 1993;63:466-7.
31. Gupta SK, Jain AK, Gupta JP, et al. Duodenal
tuberculosis. Clin Radiol 1988;39:159-61.
32. Chawla S, Mukherjee P, Bery K. Segmental tuberculosis
of the colon: a report of ten cases. Clin Radiol 1971;22:
104-9.
33. Arya TVS, Jain AK, Kumar M, et al. Colonic tuberculosis:
a clinical and colonoscopic profile. Indian J Gastroenterol
1994; 13 (Suppl): A 116.
34. Singh V, Kumar P, Kamal J, et al. Clinico-colonoscopic
profile of colonic tuberculosis. Am J Gastroenterol
1996;91:565- 8.
35. Chaudhary A, Gupta NM. Colorectal tuberculosis. Dis
Colon Rectum 1986; 29:738-41.
36. Dandapat MC, Mukherjee LM, Behra AN. Fistula in ano.
Indian J Surg 1990;52:265-8.
37. Wadhwa N, Agarwal S, Mishra K. Reappraisal of
abdominal tuberculosis. J Indian Med Assoc 2004;102:
31-2.
38. Brusko G, Melvin WS, Fromkes JJ, et al. Pancreatic
tuberculosis. Am Surg. 1995;61:513-5.
39. Tandon HD, Prakash A. Pathology of intestinal
tuberculosis and its differentiation from Crohns disease.
Gut 1972;13:260-9
40. Tandon H. The Pathology of intestinal tuberculosis. Trop
Gastroenterol 1981;2:77-93.
41. Kapoor VK. Kochs or Crohns. Int J Clin Pract
1997;51:246-7.
148

42. Handa U, Garg S, Mohan H. Fine needle aspiration
cytology in the diagnosis of abdominal TB: a review of
92 cases. Trop Doct 2009;39:30-32.
43. HK Ha, JI Jung, MS Lee, et al. CT differentiation of
tuberculosis peritonitis and peritoneal carcinomatosis. Am J
Roentgenol 1996;167:743-8.
44. Bhargava DK, Tandon HD, Chawala TC, et al. Diagnosis
of ileocecal and colonic tuberculosis by colonoscopy.
Gastrointest
Endosc1985;31:
68-70.
45. Thapa BR, Nagi B, Malik AK, et al. Colorectal tuberculosis
in children. Indian Pediatr 1988, 25: 1044-9.
46. Shah S, Thomas V, Mathan M, Chacko, et al.
Colonoscopic study of 50 patients with colonic
tuberculosis. Gut 1992;33:347-51
47. Essop AR, Poscn JA, Hodgkinson JH, et al. Tuberculous
hepatitis. A clinical review of 96 cases. Quart J Med
1984;63:465-77.
48. Dinler G, Sensoy G, Helek D, et al. Tuberculous
peritonitis in children: Report of nine patients and review
of the literature. World J Gastro-enterol 2008;14:7235-9.
49. Vijayasekaran D, Arvind Kumar R, Gowrishankar NC, et
al. Mantoux and contact positivity in tuberculosis. Indian
J Pediatr 2006;73:989-93.
50. Basu S, Ganguly S, Chandra P K. Clinical profile and
outcome of abdominal tuberculosis in Indian children.
Singapore Med J 2007;48:900-5.
51. Thapa BR, Gupta V. Abdominal tuberculosis in children.
Indian J Pediatr 2008; Supplement.
52. Veeragandham RS, Lynch FP, Canty TG, et al. Abdominal
tuberculosis in children: Review of 26 cases. J Pediatr
Surg 1996;31:170-5.
53. Kapoor VK, Chatterjee TK, Sharma LK. Radiology of
abdominal tuberculosis. Aust Radiol 1988;32:365-7.
54. Sharp JF, Goldman M. Abdominal tuberculosis in East
Birmingham: A 16 year study. Postgrad Med J
1987;63:539-42.
55. Bhargava DK, Tandon HD, Chawala TC, et al. Diagnosis
of ileocecal and colonic tuberculosis by colonoscopy.
Gastrointest
Endosc1985;31:
68-70.
56. Duggal RK. Roentgenologic spectrum of gastrointestinal
tuberculosis in pediatric age group (0-12 years). Thesis
submitted for MD Radiodiagnosis, PGIMER,
Chandigarh, 1987.
57. Jain R, Sawhney S, Bhargava DK, et al. Diagnosis of
abdominal tuberculosis, sonographic findings in patients
with early disease. Am J Radiol 1995; 165:1391-5.
abdominal tuberculosis: Sonographic findings in patients
with early disease. Am J Roentgenol 1995;165:1391-5.
59. Malik A, Saxena NC. Ultrasound in abdominal
tuberculosis. Abdom Imaging 2003;28:574-9.
60. Gulati MS, Sarma D, Paul SB. CT appearances in
abdominal tuberculosis. A pictorial assay. Clin Imaging
1999;23:51-9.
61. Andronikou S, Wieselthaler N. Modern imaging of
tuberculosis in children: Thoracic, central nervous system
and abdominal tuberculosis. Pediatr Radiol 2004;34:86175.
62. Epstein BM, Mann JH. CT of abdominal tuberculosis. AJR

Am J Roentgenol 1982, 139:861-6.
63. Sinan T, Sheikh M, Ramadan S, et al. CT features in
abdominal tuberculosis: 20 years experience. BMC
Medical Imaging 2002; 2: 3.
64. Sheikh M, Mossa I, Hussein FMY, Qurttom,
et al: Ultrasonographic diagnosis in abdominal
tuberculosis. Ustralasian Radiology 1999; 43:175-9.
65. Seshul MB, Coulam CM. Pseudomyxoma peritonei.
Computed tomography and sonography. Am J
Roentgenol 1981;136:803-6.
66. Bankier AA, Fleischman D, Wiesmayr MN,
et al. Update: Abdominal tuberculosisunusual findings
on CT. Clin Radiol 1995;50:223-8.
67. HK Ha, JI Jung, MS Lee, et al. CT differentiation of
tuberculosis peritonitis and peritoneal carcino-matosis.
Am J Roentgenol 1996;167:743-8.
68. Radin DR. Intra-abdominal M. tuberculosis vs M.
intracellulare infections in patients with AIDS.
Distinction based on CT findings. Br J Surg 1988; 75:2-3.
69. Sathar MA, Simjee AE, Coovadia YM. Ascitic fluid
gamma interferon concentration and adenosine
deaminase activity in tuberculous peritonitis. Gut
1995;36:419-21.
70. Agarwal A, Moudgil KD. Immunodiagnosis of
tuberculosis. Problems,progress and future projections.
Indian J Tub 1989;36:1-14.
71. Grange JM, Gibson J, Batty A, et al. The specificity of
humoral immune response in tuberculosis. Tubercle
1980;61:145-52.
72. Srinivas, Raj M, Kiran U, et al. Correlation of different
classes of immunoglobulins in tuberculosis with SAFA
test. Indian J Med Microbiol 1985;3:33-8.
73. Sarnaik RM. An evaluation of kaolin agglutination test
as serodiagnostic test for tuberculosis. Indian J Tub
1989;36:81-93.
74. Dayal R, Sirohi G, Singh K, et al. Diagnostic value of
ELISA serological tests in childhood tuberculosis. J Trop
Pediatr 2006;52:433-7.
75. Sada E, Quiz-Palacious GM, Zopex Vidal Y, et al.
Detection of mycobacterial antigens in meningitis by
enzyme linked immunosorbent assay. Lancet 1983;2:651.
76. Kameswaran M, Kadival GV, Samuel AM, et al. A simple
dot- Blood ELISA for the detection of Mycobacterium
tuberculosis antigen in sputum samples. Indian J Tub
1989;36:103-6.
77. MoatterT, Mirza S, Siddiqui MS, et al. Detection of
Mycobacterium tuberculosis in paraffin embedded
intestinal tissue specimen by polymerase chain reaction:
characterization of IS6110 element negative strains. J Pak
Med Assoc 1998;48:174-8.
78. Kulkarni S, Vyas S, Supe S, et al. Use of polymerase chain
reaction in the diagnosis of abdominal tuberculosis.
Journal of Gastro-enterology and Hepatology
2006;21:819-23.
79. Balamurugan R, Venkataraman S, John KR, et al. PCR
amplification of the IS6110 insertion element of
Mycobacterium tuberculosis in fecal samples from
patients with intestinal tuberculosis. J Clin Microbiol
2006;44:1884-6.

80. Menzies D, Pal M, Cornstock G. Meta-analysis: New tests
for the diagnosis of latent tuberculosis infection. Area of
uncertainty and recomm-endation for research. Ann
Intern Med 2007;146: 340-354.
81. Ruhwald M, Bjerregaard-Anderson M, Rabna P, et al.
Introducing IP-10 as a specific diagnostic marker for
infection with M. Tuberculosis. Microbes Infect
2007;9:806-12.
82. Thakur V, Mukherjee U, Kumar K. Elevated serum cancer
antigen 125levels in advanced abdominal tuberculosis.
Med Oncol 2001;18:289-91.
83. Purohit MR, Mustafa T, Wiker HG, et al. Immunohistochemical diagnosis of abdominal and lymph node
tuberculosis by detecting Myco-bacterium tuberculosis
complex specific antigen MPT64. Diagn Pathol 2007;2:36.
84. Ghosh P. Tuberculosis of the gastrointestinal tract. In:
Allan RN, Rhodes JM, Hanauer SB (Eds). Inflammatory
bowel diseases. 3rd edn. New York: Churchill
Livingstone, 1997:391-8.
85. Yang SK. Current status and clinical characteristics of
inflammatory bowel disease in Korea. Korean J
86. Tonghua L, Guozong P, Minzhang C. Crohns disease:
Clinicopathologic manifestations and differential
diagnosis from enterocolonic tuberculosis. Chinese Med
J 1981;94:431-40.
87. Talbot IC, Price AB. Crohn disease. In: Biopsy pathology
in colorectal disease. London. Chapman and Hall
1987:135-48.
88. Surawicz CM, Meisel JL, Ylvisaker T, et al. Rectal biopsy
in the diagnosis of Crohns disease: value of multiple
biopsies and serial sectioning. Gastroenterology
1981;81:66-71.
89. zbey H, Tireli GA, Salman T. Abdominal tuberculosis
in children. Eur J Pediatr Surg 2003; 13:116-9
90. Wig JD, Malik AK, Chaudhary A, et al. Free perforation
of tuberculous ulcers of the small bowel Ind J
Gastroenterol 1985;4:259- 61.
91. Bhansali SK, Desai AN, Dhaboowala CB. Tuberculous
to antituberculous treatment. Gut 1988;29:62-9.
92. Kel M, Agrawal A, Sharma R, et al. Clinical and
Experimental Gastroenterology 2009;2: 129-31.
93. Mishra D, Singh S, Juneja M. Indian J Pediatr
2009;76:1049-50.
94. Foo KT, Ng KC, Rauff A, et al. Unusual small intestinal
obstruction in adolescent girls the abdominal cocoon. Br
J Surg 1978;65:427-30.
95. Sahoo SP, Gangopadhyay AN, Gupta DK, et al.
Abdominal cocoon in children. A report of four cases. J
Pediatr Surg 1996;31:987-8.
149
96. Hamaloglu E, Altun H, Ozdemir A, et al. The abdominal

cocoon. A case report. Dig Surg 2002;19:422-4.
97. Deeb LS, Mourad FH, El-Zein YR, et al. Abdominal
cocoon in a man. Preoperative diagnosis and literature
review. J Clin Gastro-enterol 1998.
98. Balasubramanium R, Ramachandran R, Joseph P, et al.
Interim results of a controlled clinical study of abdominal
tuberculosis. Indian J Tub 1989;36:117-21.
99. Andronikous S, Welman CJ, Keder E. The CT features of
abdominal tuberculosis in children. Pediatr Radiol
2002;32:75-81.
100. Tandon RK, Sarin SK, Bose SL, et al. A clinico radiological
reappraisal of intestinal tuberculosis. Gastroenterol Jpn
1986;21:17-22.
101. Millar AJW, Cywes S. Abdominal tuberculosis in
children-surgical management. A review of 95 cases.
Pediatr Surg Int 1990;5:392-6.
102. Sabah-AL I-I, Walia HS, Al-sayer HM. Abdominal
tuberculosis. Cand J Surg 1990;33: 233-7.
103. Anand BS, Nanda R, Sachdev GK. Response of tuberculous stricture to antituberculous treatment. Gut
1988;29:62-9.
104. Dutt AK, Moers D, Stead WW. Short course chemotherapy for extrapulmonary tuberculosis. Nine years
experience. Ann Intern Med 1986; 104:7-12.
105. Kapoor S, Aggarwal S, Mittal SK. Abdominal tuberculosis in children. Pediatr Today 2000;3:133-8.
106. Aston NO. Abdominal tuberculosis. World J Surg
1997;21:492-9.
107. Ahmed ME, Hassan MA. Abdominal tuberculosis. Am R
Coll Surg Engl 1994;76:75-9.
108. Desmond NM, Kingdom E, Beale TJ, et al. Tuberculous
pancreatic abscess. An unusual manifestation of HIV
infection. J R Soc Med 1995; 88:109-10.
109. Narasimhamurty NK, Veciatm AJ. Tuberculous abscess
of the spleen (a case report). Indian J Surg 1992;54:333-4.
110. Marks IN. Abdominal tuberculosis. In: Watters DAK,
(Ed). Baillieres clinical, tropical and communicable
diseases, London; Bailliere 1998; 329-48.
111. Wig JD, Nair PM, Srinath BS, et al. Stenotic lesion of the
bowel. Indian Surg 1979;41: 322-30.
112. Manohar A, Simjee AE, Haffagee AA, et al. Symptoms
and investigative findings in 145 patients with
tuberculosis peritonitis diagnosed by peritoneoscopy and
biopsy over a five year period. Gut 1990;31:1130-2.
113. Shukla HS, Gupta SC, Singh G, et al. Tuberculosis fistula
in ano. Br J Surg 1988;75: 38-9.
114. Kakkar A, Aranya RC, Nair SK. Acute perforation of the
small intestine due to tuberculosis. Aust NZ Surg
1983;53:381-3.
12
Neurotuberculosis
12.1 PATHOLOGY AND PATHOGENESIS

PM Udani
MAGNITUDE, CHANGING CLINICAL PATTERNS AND

SYNDROMES SPECIALLY IN BCG-VACCINATED CHILDREN
Tuberculosis in children is a major health hazard and
neurotuberculosis especially tuberculous meningitis
(TBM) is the main cause of death amongst the various
complications of primary infection. TBM has varied
pathological changes in the nervous system. Various
brain damaging mechanisms have been described and
some illustrated by neuropathological findings seen in
children at autopsy. The classification of tuberculosis of
the nervous system has been described more than two decades
ago, but newer clinical pictures and syndromes have emerged
mainly over the last two decades because of extensive coverage
of children with BCG vaccination. Misuse of powerful
antituberculous drugs has been in practice in recent years
and these drugs are abused or inadequately used in many
types of pediatric tuberculosis resulting in poor control
of primary infection or disease. As a result, newer clinical
pictures of neurotuberculosis are emerging.
BCG vaccination imparts partial immunity. It
prevents the hematogenous spread of infection.
However, it cannot prevent the lodgment of tubercle
bacilli in the lung and thus development of primary
infection and its local complications. Similarly partial or
inadequate antituberculous drug therapy improves the
T lymphocyte functions in the child so that neurological
complications of primary infections have emerged with protean
clinical manifestations.
The localized form of neurotuberculosis involving
brain and meninges are being commonly seen now. The
various neurological signs which develop during the
treatment of TBM like convulsions due to tuberculoma,
are being seen under these situations and they have been
described with cliniconeuropathological correlation.
Thus, neurotuberculosis presentations pose a diagnostic
challenge, though awareness of clinical features and the
availability of CT scan and Magnetic Resonance Imaging
(MRI) have helped not only to suspect the disease but
also to understand its pathogenesis. Here early diagnosis

and adequate management is of vital importance.
In early 50s the mortality was high with low rate of
recovery. With improvement in treatment the recovery
rate has improved with an increase in serious sequelae
as the diagnosis and treatment are often delayed. Hence,
the most important aspect is prevention of serious
complications of primary infection by the use of three
drug combinations in the intensive phase followed by
two drugs in the continuation phase as labeled category
III under DOTS in Revised National Tuberculosis Control
Program (RNTCP) of the Government of India. This is
particularly important in high risk cases.
As long as tuberculosis in adults remains a major
problem, the same will be reflected in children and
various changing manifestations of neurotuberculosis
will continue to challenge the diagnostic and therapeutic
ability of the pediatricians.
Neurotuberculosis is one of the serious complications
of primary tuberculous infection. TBM is the main cause
of death and disability in children with tubercular
disease. In a study by Dhariwal and Udani,1 of the 246
children who died at the Institute of Child Health,
Bombay, 16.5% died of tuberculosis. In another series by
them over a period of 2 years (1981-83) tuberculosis was
responsible for 9.6% of admissions and 10% of the
mortality.2 In an autopsy series of cases in adults and
children under 15 years of age studied over a period of
10 years from 1976 to 1987, deaths due to tuberculosis
were 11.6% in 7676 adults and 10.8% in 4080 children.3
CNS tuberculosis accounted for 65.5% of the total deaths,
i.e. neurotuberculosis was responsible for two-third of
the deaths. This data represent the picture about two
decades ago. In the current scenario due to vigorous
attempts of Government of India to cover adults and to
some extent children with DOTS under RNTCP picture
might have changed. However, even in the present
scenario of availability of imaging technology (CT and
MRI), the high index of clinical suspicion is very
Chapter 12 Neurotuberculosis
151
important. (Some of these pathological changes can be

correlated with CT and MRI findings as illustrated in the
chapters 12.3 of clinical case studies and 26 on imaging
in children).
PATHOLOGICAL ASPECTS
General Considerations
The nervous system is damaged by a number of
pathological mechanisms in neurotuberculosis4-6 (Figs
12.1.1 to 12.1.10). The following description of
pathological aspects found on classical autopsy studies
need correlation with CT and MRI findings. Some of these
have been described in the imaging chapter.
Meningeal Exudate
These occur mainly at the base of the brain. Exudate per
se can involve a number of structures at the base of the
brain with resultant clinical manifestations (Figs 12.1.1
to 12.1.6).
Obstruction of CSF Pathway

Hydrocephalus is mostly due to obstruction of the CSF
pathway of the basal cisterns but can occur at the level of
interventricular foramina, aqueduct of Sylvius or
foramina of Lushka and Magendie. At times the
obstruction occurs at multiple levels. Hydrocephalus is
one of the most common mechanisms of brain damage
by causing myelin depletion, axonal degeneration and
neuronal fall out initially in cerebral white matter and
later in the cortex (Figs 12.1.5 and 12.1.7).
Fig. 12.1.1: Coronal slice through cerebral hemisphere showing large

tuberculoma in the right thalamic and subthalamic region, asymmetrical
dilatation of the lateral ventricles, virtual absence of left basal ganglia
(due to infarction) with a small remaining scar (curved arrow) basal
exudate enveloping and causing narrowing of left middle cerebral artery
(short thin arrow), marked narrowing (almost like a slit) of the third
ventricle (split arrow), which is displaced to the left by the tuberculoma
on the right. In the cerebral hemispheres bulkiness of white matter due
to edema and thinning of the gray matter can be seen (Dastur and
Udani 1983)4
Fig. 12.1.2: Histological section study of narrowed third ventricle (see

Fig. 12.1.1) by medial border of the right thalamic tuberculoma (curved
arrows). On the left, there is basal exudate with a number of blood
vessels in it including a large artery (long arrow) showing marked
narrowing of the lumen by subintimal fibrosis and exudate lining the
ependyma of the third ventricle, and periependymal congestion (paraffin
section, hematoxylin and eosin X 15). Multiple brain damaging
mechanisms in the region of the thalamus and hypothalamus can be
appreciated, viz. tuberculoma, basal exudate, ependymitis and its paraventricular extension to the brain structures, (see Fig. 12.1.3) partial
arterial occlusion with ischemic brain damage, etc. (Dastur and Udani,
1983)4
Fig. 12.1.3: A microscopic view of the ependymal exudate seen in Figure

12.1.1, showing mass of small mononuclear cells on the ventricular
side of the destroyed ependyma, with some border-zone encephalitis
(in the form of perivascular inflammation) and edematous white matter
at the lower border of the picture (hematoxylin and eosin X 110) (Dastur
and Udani, 1983) 4
Large Vessels
Varying degrees of involvement and occlusion of large
vessels in the Circle of Willis and that of middle cerebral
artery in the sylvian fissure by the exudate leads to
152
Fig. 12.1.4: Microscopic view showing choroid plexitis. Histology of the

third ventricle (Fig. 12.1.2) showing predominantly small mononuclear
cell reaction amidst thickened and obliterated papillae of choroid plexus
(Dastur and Udani, 1983)4
Fig. 12.1.5: Coronal section of the brain in a child who died of advanced
TBM (Udani and Dastur, 1971).21 Figure shows destruction of the
subthalamic and subputaminar areas by the basal exudate which has
penetrated the region of the nucleus subthalamicus on both sides,
especially the right. Also note the hydrocephalus of both the lateral
ventricles caused by obstruction (gluing) of the basal cisterns. Edematous
bulky matter can also be seen on both sides. Such dense exudate at the
base of the brain can produce: (i) brain damage (infarction) by the occlusion of vessels, (ii) damage to the nerves which are engulfed in the
exudate, and (iii) direct damage by the exudate by tracking up to the
basal ganglia, and (iv) obstructive hydrocephalus due to gluing of the
basal cisterns
ischemic foci in the brain. With complete occlusion of

the artery, there is infarction with severe brain edema
around it (Fig. 12.1.6).
Small Arteries
Small arteries particularly lenticulostriate vessels have
small areas of infarction in the region supplied by them.
These small lesions lead to focal lacunar infarcts with
edema around them which clinically may present with
localized encephalopathy (Figs 12.1.9 and 12.1.10) and
Fig. 12.1.6: Coronal slice of the brain in an advanced case of TBM

(Dastur and Udani, 1983).4 It shows proliferative type of basal exudate
surrounding the two optic nerves adhering to the base of the brain and
extending into the sylvian fissures especially on the right where the
middle cerebral artery is compressed and the upper lip of the fissure is
softened. Such dense basal exudate surrounding the two optic nerves
can produce: (i) optic neuritis per se, (ii) and/or direct compression of
the optic nerve by the exudate with primary optic atrophy, (iii) damage
to the small arteries, (iv) compression of the middle cerebral artery on
right side with infarction in its territory, (v) necrosis and softening of
upper lip of the sylvian fissure, and (vi) hydrocephalus
Fig. 12.1.7: Coronal slice through highly edematous right frontal lobe
(Dastur and Udani, 1983).4 Note pale bulky white matter due to myelin
loss and consequent thinning of the gray matter especially of the frontal
lobe constituting an edematous encephalopathy, the patient presenting
with drowsiness progressing to coma
can be detected in CT scan as hypodense areas. They are

better appreciated in MRI of the brain.
Nerves
Engulfment and/or destruction of the cranial nerves,
particularly II, III, IV, VI, VII result in multiple cranial
nerve palsies.
Fig. 12.1.8: Histology of the edematous frontal lobe with pale bulky
white matter (Fig. 12.1.7), that part of the edematous frontal white matter
showing marked pallor (due to loss of myelin) and a relatively darker gray
matter of the gyri included especially at the top left, outside which is some
vascular reaction in the leptomeninges. The white subcortical line
represents actual spongy degeneration (Heidenhains myelin stain, X
15)
Other Structures
153
Fig. 12.1.9: Histological section of the brain with perivascular and

paravascular cellular reaction as well as diapedesis of red blood cells
into the brain. There are three small arterioles seen in the picture. Such
a peri-or paravascular microscopic hemorrhage is one of the
characteristic features of tuberculous encephalopathy. Though such
lesions are seen in diffuse tuberculous encephalopathy localized
lesions/cerebral edema leading to cerebral damage might develop in
children who are vaccinated. Severe edema may lead to necrosis of
the brain
Extension of the basal meningeal exudate into the brain

with damage to various structures, for example
involvement of nucleus subthalamicus and its pathways
results in ballismic movements (Fig. 12.1.5). Less
commonly damage to hypothalamic nuclei in the floor
of the third ventricle results in leukotomy or frontal lobe
syndrome.
Border-zone Encephalitis
This may coexist with meningitis.
Ventriculitis
This may occur with subpial or subependymal necrosis.
Choroid Plexitis
Large and small tuberculomas with varying degrees of
brain edema.
Generalized Edema due to Microangiopathy

Generalized edema can produce severe damage to the
brain without any infarction, tuberculoma or other naked
eye lesions. Edema and microscopic hemorrhages due
to capillary damage are the most important mechanisms
in tuberculous encephalopathy (Figs 12.1.9 and 12.1.10).
Fig. 12.1.10: A case of hemorrhagic encephalopathy. Coronal slice of

one hemisphere shows confluent and discrete hemorrhages in the white
matter of the cerebrum and cerebellum. Such gross hemorrhages in
the cerebrum and cerebellum are rare, though microscopic
hemorrhages along with exudation of edema fluid due to damage to
capillaries (microangiopathy) are characteristic features of tuberculous
encephalopathy. This girl took adequate treatment. Six months later
she presented with high fever, meningeal signs and pin-point pupils. A
posterior fossa tuberculoma was suspected. However, before the operation could be done she died. Autopsy revealed gross hemorrhages in
the cerebrum and cerebellum
BCG-vaccinated Children
Those who have some immunity may get localized lesions
due to focal microangiopathy with clinical features
depending upon the area involved. Such localized
edematous area can be detected in CT scan and MRI of the
brain. When the edema is severe, it causes necrosis of the
brain tissue.
Venous Involvement
Less commonly, involvement of the veins with
hemorrhagic infarction and rarely thrombosis of superior
longitudinal sinus are seen.
Extension of TBM to brainstem and around the spinal
cord constitute spinal TBM.
154
Fig. 12.1.11: Clinical classification of neurotuberculosis6,20 (does not include various neurological and other related syndromes)
HYD-Hydrocephalus, ENC-Encephalopathy, MULT.CR.N-Multiple cranial nerve
Damage to the Motor Roots

By exudates or immunological mechanism which leads
to polyneuritis or localized motor neuropathy.
Peripheral Nerve Damage

By immunological mechanism.
Figure 12.1.11 gives the various types of
neurotuberculosis encountered in day-to-day practice.
SPECIFIC CONDITINS
Pathogenesis of Neurotuberculosis and its Implication
on the Detection of AFB in CSF and Highlighting the
Clinical Spectrum of the Disease
It is now well recognized that hypersensitivity plays a great
role in the pathogenesis of neurotuberculosis in children.
Various studies have revealed that symptoms of TBM
can be produced by injection of tuberculoprotein
intrathecally or intracisternally in sensitized experimental
animals while none can be seen in control animals.7
Moreover, the symptoms and pathology are dose related.
A large dose (with evidence of basal exudate) will
produce convulsions, coma and death in animals. Studies
by Tandon et al8 in Indian monkeys have confirmed the
production of localized meningitis or localized
encephalomalacia in BCG-vaccinated or drug protected
animals and meningitis with edematous and
hemorrhagic encephalopathy in animals who were
hypersensitized by tuberculoprotein and Freuds
adjuvant. When live bacilli were injected in nonsensitized
or tuberculin negative animals, they developed
generalized meningitis and died. A similar pathogenesis
was postulated in children with varying types and
severity of clinical features on meningeal involvement.
Wisniewski and Bloom9 studied the pathogenesis of
myelin loss not only in TBM, but also in tuberculous
neuropathy, and established that it is due to direct

destruction by immunocompetent T cells which migrate
from blood of the neural tissues and produce myelin
damage. The same findings have been seen both in their
human as well as animals studies.
Brain Edema and Hemorrhage

These are due to severe damage to the capillaries. Normally, intact capillaries provide a strong blood-brain
barrier. With damage to the capillaries (usually immunomediated) there is greater migration of fluid into the brain
tissue, mainly in the white matter. Severe edema leads
to myelin loss, while capillary damage may produce
small microscopic hemorrhages in brain which are perivascular and rarely, gross petechial hemorrhages.10-12
Immunological Study
The immunological study of CSF by ELISA in children of
subacute meningitis, Chandramukhi and Nayak13 found
that tubercle bacilli were not found in CSF of 105 children
with tuberculous meningitis, while Tandon in an
exhaustive study of tuberculous meningitis in adults
isolated bacilli only in 2.5% of cases.14 The maximum
incidence of finding tubercle bacilli was 20% in children
by Joishy and Sant.15 This shows that the yield of tubercle
bacilli is very low in CSF in spite of repeated cultures even
at the advanced and sophisticated centers in India.
However, researchers in National Institute of Mental
Health and Neurosciences (NIMHANS), Bengaluru found
that there was a high yield of TB antigen particularly LAM
(Lipoarabinomannan) antigen in 81.7% of cases and fairly
high yield of specifically delineated epitopes 14, 19, 38 and
50 kilodalton (kD) with defined levels of monoclonal
antibodies. Also, there was fairly high yield of TB
monoclonal antibody to the epitopes mentioned above;
though per se the yield is not high (35.41%) and is poor
under the age of two years.
155
Immune complex was found in a fair number of TBM
patients indicating that antigen antibody reaction or
hypersensitivity plays a very important role in the
causation of various symptoms. This has been the reason
why bacillary yield from CSF is very low as opposed to
the findings of workers in developed countries like UK.
It appears that depending upon whether tubercle bacilli,
TB antigen, antibody, or immune complex are present in
a patient and from time-to-time, there will be failure of
detection of tubercle bacilli in CSF in children, as
hypersensitivity plays a predominant role in the
pathogenesis of TBM in them.7-9,12,15,16
In this connection, the spectrum of tuberculous
disease can be compared to leprosy where in a case of
lepromatous leprosy there are huge number of bacilli, in
tuberculoid leprosy there are fewer number of bacilli
while in intermediate cases bacilli would be variable.
Hence, in children in India who are vaccinated and those
who have received prior drug therapy the yield of
tubercle bacilli is very poor.
Atypical or Modified Clinical

Pictures in BCG-vaccinated Children
A large number of atypical clinical pictures have been
described by Udani et al17-20 in vaccinated children.
Following are some of the localized lesions in the
meninges or different parts of the brain.
Meningeal Tuberculoma
Serous tuberculous meningitisIt is at the base of the brain
which may result in mild hydrocephalus and hemiparesis
on one side with or without cranial nerve palsies.19,20
Localized meningitis on the

superiolateral surface of the brain
Localized meningitis in the posterior fossamentioned in the
classification with unilateral or bilateral cerebellar
hemispheric signs or signs of involvement of vermis with
disturbance of equilibrium.
Isolated Spinal Tuberculous Meningitis

Localized Lesions
Localized lesions in various parts of the brain which may
be isolated or present with different combinations of
pathological and clinical features are:
Internal capsule.5
Thalamic nuclei with or without involvement of
adjacent structures.
Basal ganglia, viz caudate nucleus, putamen and
globus pallidus.
Subthalamic nucleus with development of
hemiballismic movements on the contralateral side
often with associated hemiplegia on the opposite
side.21
Involvement of optic nerve by the exudate or
tuberculoma causing primary or secondary optic
atrophy. The latter may require urgent surgical
decompression.22
Localized involvement of aqueduct with dilatation
of third and lateral ventricles.6
Localized involvement of geniculate bodies and/or
superior and inferior colliculi with impairment of
hearing and vision, particularly with involvement of
eye movements like upward gaze.
Localized involvement of brainstem with
development of locked-in syndrome (Table 12.1.1).
Localized involvement of midbrain with upper
cranial nerve palsy, III, IV, VI and red nucleus and
other areas in the midbrain (Table 12.1.2).5
Localized involvement of lower part of pons and
medulla with involvement of VII to XII nerve nuclei
or nerves.5
Some of the above mentioned clinical entities either
isolated or with various complications are examples
of clinical manifestations of neurotuberculosis.
Table 12.1.1 gives the various brainstem syndromes
described by Rowland 23 some of which have been
recorded by Udani et al.17,18,21 Table 12.1.2 provides the
Table 12.1.1: Various brainstem syndromes likely to occur in localized TBM with involvement of vessels
Syndrome
Medial syndromes
medulla
Inferior pons
Artery
affected
Paramedian branches
Paramedian branches
Anterior inferior cerebellar

Superior pons
Paramedian branches
Structure
involved
Emerging fibers of the
XII nerve
Pontine gaze center, near or
in the nucleus of
the VI nerve
Emerging fibers of the
VII nerve
Medial longitudinal
fasciculus
Manifestation
Ipsilateral
hemiparalysis
Paralysis of gaze
to side of lesion
Ipsilateral facial
paralysis
Internuclear
ophthalmoplegia
156

Table 12.1.2: Clinicopathological correlation of extrapyramidal neurological syndromes in
tuberculous meningitis (Udani, 1965unpublished data)
Clinical features
Unilateral plastic rigidity

with static tremor (Parkinsons syndrome)
Unilateral hemiballismus
Frequency
Principal location of
morbid anatomy
Rare
Contralateral substantia
nigra plus(?) other structures
Contralateral subthalamic nucleus
of Luys, prerubral areas and
Forels fields
Caudate nucleus and putamen
Contralateral striatum and connections with thalamus
Homolateral cerebellar hemisphere
or middle and inferior cerebellar
peduncles, superior brachium
conjunctivum (ipsilateral if below
the decussation, contralateral if above)
Usually bilateral in tegmentum,
involving upper brainstem particularly red nucleus or structures
between red and vestibular nuclei
Contralateral dentate nucleus or
superior cerebellar peduncle or
ipsilateral central tegmental tract
(dentato-olivary pathway)
Neuronal degeneration, usually
diffuse or predominating in cerebral
cortex and dentate nuclei
Very
common
Choreic movements
Athetosis and dystonia
Rare
Common
Cerebellar incoordination,
intention tremor and hypotonia
Not common
Decerebrate rigidity
Usually present in
advanced stage
Facial myoclonus
(rhythmic)
Rare
Diffuse myoclonus
Very rare
clinicopathological correlations of extrapyramidal

neurological syndromes.
With improvement and recovery in children with
various types of neurotuberculosis especially TBM, there
have been a number of new clinical features and
syndromes emerging either at the onset but more
commonly during the course of the disease and some
even months and years after the child has recovered from
meningitis. Some of the syndromes have been described
by Udani et al.10,1719,21,24,25 The various syndromes which
were seen are detailed in the Tables 12.1.1 and 12.1.2.
However, after this description of the syndromes in 1974
Udani et al saw many more syndromes with increasing
recovery rate of TBM. They opined that the varieties of
clinical features are likely to be encountered in children
with TBM at various stages.21,24,25
PATHOLOGICAL BASIS OF
VARIOUS SYNDROMES21,26-28
The structures at the base of the brain and around the
lateral and third ventricles particularly the latter, are
commonly affected and hence their damage is expressed
with development of different syndromes. Peri-
ventricular structures are likely to be affected because of

ventriculitis affecting the adjacent grey matter of
thalamus. The hypothalamus is much more likely to be
affected because of the basal exudate which is often dense
at the base of the brain in the middle cranial fossa.
Exudate itself can spread to the adjacent areas of hypothalamus or the dilated third ventricle may compress
upon various parts of the hypothalamus and hypothalamic pituitary axis and rarely the red nucleus.
The thalamus and hypothalamus, especially the latter,
can also be damaged by ischemia produced by the exudate
compressing the various branches of the circle of Willis
particularly their small branches. The various syndromes
can present as isolated manifestation of a focal lesion. If
there are multiple focal lesions, the clinical presentation
may change but when there is generalized meningitis and
involvement of brain, the syndromes are masked. However,
they may manifest during or after improvement of TBM
with treatment and at times at the onset from a focal
lesion.
Tables 12.1.3 to 12.1.5 mention some of the clinical
syndromes observed in the past21,24,25 but are being seen
in recent years particularly because of the detection of
the lesions in the neuro CT scan and MRI with better
157
Table 12.1.3: Classification and incidence of various
syndromes at onset
Syndrome
No.
Paralyses
Hemiplegia
Quadriplegia
Monoplegia
Paraplegia (cerebral)
Abnormal movements
Hemiballismus
Tremors: Generalized
Parkinsonian
Myoclonic jerks
Posterior fossa meningitis with
midline cerebellar syndrome
Therapeutic paradox
Spinal leptomeningitis
Total
%
98
96
13
3
31.5
30.9
4.2
0.9
57
32
1
1
2
18.3
10.4
0.3
0.4
0.6
6
2
1.8
0.6
311
100.0
understanding of probable pathogenetic mechanisms.

These can be classified as:
Syndromes at onset (Table 12.1.3)
After the disease is well established (Table 12.1.4)
Those occurring during the recovery phase (Table
12.1.5).
At the onset of the disease almost one-third of the
cases develop either hemiplegia or quadriplegia. When
the disease is well established 58.2% of the cases develop
paralysis of motor nerves. The rare syndromes occurring
after the recovery from the disease.
Korsakoffs Syndrome
Udani et al saw this syndrome in a child when he was
recovering from TBM. The likely lesion is damage to the
mammillary body and Ammons horns of the
hippocampus.

syndromes after the disease is well-established
Syndrome
No.
Cranial nerve palsies

Optic nerve
71
Motor nerves
226
Motor
Decorticate spasm/rigidity
16
Decerebrate spasm/rigidity
63
Flexor spasm
2
Acute increase of intracranial pressure
5
Cerebellar hemispheric syndrome
5
Involvement of brainstem and
locked-in syndrome*
Reappearance of neonatal reflexes*
Total
18.3
58.2
4.2
16.2
0.5
1.3
1.3
388
100.0
*These syndromes have been described in literature, but not

documented in our series by Udani et al10,17-19,21,24,25

syndromes during the recovery
Syndrome
Hypothalamic-pituitary syndromes
Cushings disease
Obesity*
Diabetes insipidus*
Excessive sleeping (somnolence)
Syndrome of SIADH
Clinical pictures like Barter's syndrome*
Syndrome of persistent pyrexia*
Recurrent attacks of serous meningitis*
Postmeningitic encephalopathy*
Postlumbar puncture (postmeningitic)
spinal epidermoid
No.
6
1
1
* These syndromes have been described in literature, but not

documented in our series
Fever, Psychiatric Aberrations and Diabetes Insipidus21
Unilateral Contralateral Hemiballismus
This is due to damage of supraoptic nuclei of the

hypothalamus and damage may be transient or long
lasting.
This is commonly seen in children with TBM when they

have hemiplegia on one side and hemiballismus on the
opposite side. With the improvement in hemiplegia often
the ballismic movements become bilateral. This is due to
damage to the subthalamic nucleus by the exudate
tracking up from the base of the brain.
Precocious Puberty
Udani et al21 described precocious puberty in 1971. This
is probably due to involvement or damage to the pineal
gland, which has inhibiting influence on sexual
maturity. The destruction of the parenchyma of the
pineal gland abolishes this influence. It is also possible
that irritation of the tuber cinereum of hypothalamus
by the enlarging third ventricle provides the stimulus
for early sexual development.5,21,27,28
Syndrome of Inappropriate Secretion of

Antidiuretic Hormone (SIADH)
The supraoptic nucleus of the hypothalamus probably
produces antidiuretic hormone (ADH) which stimulates
absorption of water from distal portion of renal tubules
independent of solids. Neurons of supraoptic nucleus have
158
osmoreceptors, which are very sensitive to changes in the

osmolality of the surrounding tissues and regulate the water
metabolism of the body. Damage to these nuclei causes
diabetes insipidus and patient develops polyuria and
polydypsia. Polyuria occurs only if cortisol is present.
Operative removal of neurohypophysis does not prevent
diabetes insipidus because ADH producing nuclei promote
the hormone to enter the circulating blood directly. SIADH
is common in TBM and some authors have found its
incidence to be as high as 67%. However, unless it is severe
it can be easily missed.29
Persistent Pyrexia
Often children with TBM improve with treatment but
later start getting persistent high fever. This is probably
due to damage to the rostral hypothalamus particularly
preoptic area which regulates body temperature. Such
cases were seen in whom temperature is lowered with steroid
therapy. However, prognosis is poor in such cases.5
Obesity/Emaciation
Table 12.1.6: Hypothalamic and other syndromes

described in neurotuberculosis24
Syndrome
Massive hematemesis (acute gastric ulcers)
Acute intestinal colic simulating acute
abdomen (appendix removed)
Abdominal pain and hyperperistalsis
(common in advanced TBM)*
No.
3
2
* Described in literature, but not documented in the series by

Udani et al.24
increased parasympathomimetic activity which may

result in increased intestinal peristalsis. Udani et al24 have
described severe abdominal pain simulating appendicitis. Laparotomy was done in these children and the
appendix was found to be normal. However, soon they
developed the characteristic picture of TBM and died
(Table 12.1.6).
Acute Gastrointestinal Bleeding
Hypothalamus also controls the regulation of food intake.

The lateral area of tubercinerium acts as a center for
hunger or appetite, while the ventromedial nucleus of
the thalamus is concerned with satiety. Damage to the
latter affects satiety with the result that child develops
voracious appetite and obesity. This is seen long after
the stoppage of steroid therapy is omitted in a child with
TBM and may appear even after months. On the other
hand, lesions in the lateral nucleus of the hypothalamus
produce total loss of appetite leading to emaciation.
Three children presented with massive hematemesis.

However, within one week of the bleeding episode the
children had characteristic evolution of signs and
symptoms of TBM and died. Autopsy revealed acute
gastric ulcers. Such stress ulcers with bleeding from
gastrointestinal tract are probably due to stomatostatin
depletion. Wright described acute gastric ulcers in
experimental animals caused by damage to the
hypothalamus.30
Abnormal Sexual Development
Four cases of cushing disease during the course of TBM

have been described by Udani et al.24 These children had
hypertension, flushed facies, tachycardia, tachypnea and
striae-symptoms which are due to increased sympathomimetic activity caused by stimulation of caudal
hypothalamus particularly the posterior nucleus and area
lateralis. Usually, the syndrome is caused by pituitary
tumor (basophilic adenoma). However, hypothalamic
neurons being surrounded by dense capillary network,
control neural as well as neurosecretory and humoral
mechanisms.26 It also occurs due to involvement of cells
of neurohypophysis.21
Both hypogenitalism as well as precocious puberty with

involvement of hypothalamus have been described by
Udani et al.24 If the child recovers there will be an effect
on the sexual behavior in future. The gonadotrophic
center is located in the infundibular or ventromedial
nucleus which releases gonadotrophic pituitary
hormone. Sexual behavior inhibitory center is located
rostral to the ventromedial nucleus. As mentioned earlier,
precocious puberty has been observed in children in
whom tuberculous granulomatous reaction with
vasculitis has produced damage to the hypothalamus
rostral to the infundibulum and ventromedial nucleus.
Loss of inhibitory center is considered as the cause of
precocious puberty.
Serious Autonomic Nervous System Dysfunction

Acute Abdomen
This usually occurs at the onset of the disease. The
hypothalamus represents the cerebral center for all
autonomic functions of the body. Stimulation of the rostral
hypothalamus particularly the supraoptic area produces
Cushing Disease
Hyperglycemia
Hyperglycemia and a picture of diabetes mellitus can be
seen rarely in a child during the course of disease.24 It
responds to insulin, is often transient, and is due to
damage to the caudal hypothalamus.
Behavior
There are various types of behavioral changes in children
during or after recovery. Irritability can occur at the onset
159
of meningitis but is often seen during course of the

disease or after recovery. A child may also develop
aggressive, destructive behavior which is due to damage
to the ventromedial portion of the hypothalamus.
be caused by damage to the caudal portion of

hypothalamus and increased sympathomimetic activity
which may also produce hypertension, increase blood
sugar, etc.
Leukotomy or Frontal Lobe Syndrome
Focal Cerebral Lesions
This is due to involvement of the medial nucleus of the

thalamus which sends fibers to the associated areas of
the prefrontal lobe. These children, who are usually
obese, develop personality changes like those seen after
leukotomy. The visceral impulses coming from hypothalamus probably influence mood, leading to feeling of
happiness or of depression.26
Focal cerebral lesions with focal neurological deficits

resembling transient ischemic attacks which may or may
not progress to TBM can also occur.
Psychomotor Seizures
When hippocampus particularly cells of Ammons
horns are irritated by inflammation or by the adjacent
tuberculous process, either an exudate, scar or a large
third ventricle it may produce seizure like conditions
referred to as psychomotor attacks or twilight states.
EEG shows synchronized discharges. Ammons horn
is the most epileptogenic part of the entire brain.
Bilateral Loss
Bilateral loss of Ammons horns as well as damage to the
mammillary bodies produce Korsakoffs syndrome
described earlier, in which the child has disorientation of
time and space. Child is conscious, replies well but has lost
ability to memorize and has no idea of time and space.
Hessler27 considered the activity of Ammons horns to be a
mechanism for the chronological registration and marking
of perceptions and experiences.
Amnestic Syndrome
Bilateral inhibition of fornix can produce acute amnestic
syndrome in which there is loss of memory of recent
events. In amnestic syndrome old memories are retained
but there is loss of recent memory caused by damage to
mammillary bodies and Ammons horns (which can also
produce Korsakoffs syndrome). However, severe
cerebral edema which can occur in a child with tuberculous encephalopathy with or without meningitis can
produce transient compression of the arteries supplying
Ammons horns and may lead to amnestic syndrome.
Abdominal Symptoms
Abdominal colicky pain simulating appendicular pain
has been described earlier. Usually children with TBM
have scaphoid abdomen. However, cases with abdominal
distention simulating paralytic ileus and severe
constipation have been reported. Such a condition can
Episodes of Sensory Disturbances

Like numbness and weakness rarely the patients may
present with recurrent and reversible neurological
deficits resembling transient ischemic attacks and
without progression to fixed neurologic deficits. The
pathogenesis of these episodes is unclear. Tuberculous
vasculitis is a strong possibility and tuberculoma with
edema is less likely. CT scan shows hypodense lesions
which are due to ischemia secondary to a vascular lesion
or may show frank tuberculoma. Diagnosis is evident if
the patient progresses to frank TBM.26 A young adult
had focal sensory signs on the right side and CT scan
showed hypodense area in the sensory area of the left
cerebral cortex. Later he developed right hemiparesis and
characteristic picture of TBM.
Alternating Hemiplegia
This finding has been described during the course of
TBM. Probable pathogenesis was suspected to be focal
vasculitis with spasm.19
Loss of Vision
Loss of vision occurring during treatment of TBM is well
documented. 24 A child of 8 years who was under
treatment for TBM developed blindness within a period
of 4 days. CT scan revealed moderate hydrocephalus.
Child was otherwise conscious and alert. However, after
shunt surgery and with three bactericidal drugs and
steroids, he recovered fully in 4 months. Rapid deterioration of vision in a case was described by Teoh et al.31 A
cranial CT scan revealed visual failure due to tuberculoma compressing both optic nerves and chiasma.
Although continued antituberculous chemotherapy is the
treatment of choice in intracranial tuberculoma, rapid
deterioration in vision in this case necessitated immediate
surgical decompression with resultant complete recovery
of vision. In children with TBM and optic atrophy caused
by optochiasmatic arachnoiditis, scraping of the exudates
vision improved in 2 out of 6 cases.32,33 However, with
better chemotherapeutic drugs and massive use of
steroids and hylase, surgical intervention is usually not
indicated particularly in children in stage II of TBM.
160
Appearance of Tuberculoma during Treatment of TBM

Udani and Dastur5 have described five cases of multiple
tuberculomas appearing during treatment of TBM as seen
in serial CT scans. Depending upon the site of development of tuberculoma, the child develops. Newer clinical
signs, which should be kept in mind during the course
of disease when antituberculous therapy is being
continued. Though paradoxical enlargement of
intracranial tuberculoma is well recognized, its
pathogenesis is not clear.31,3436 Perhaps the most likely
explanation is a complex host-organism interaction.
Chemotherapy of any tuberculous focus causes destruction of acid fast bacilli and liberation of tuberculoprotein.
This probably invokes the inflammatory response with
resulting edema and swelling of the focus. It is well
recognized that new cervical nodes may appear and
enlarge during treatment of tuberculous lymphadenitis.
This is reported to occur in up to 25% of patients and has
been attributed to trapping of the antigen-reactive
lymphocytes within the lymph node.37
Vertical Gaze Palsy

Vertical gaze palsy in a 14 years old boy with TBM has
been reported by Udani et al24 and Schlernitzauer et al.32
It appears to be due to a lesion in the region of the dorsal
midbrain. The syndrome occurred some years after
recovery from TBM and the child recovered with steroids,
antituberculous drugs and shunt revision.
Horizontal Gaze Palsy

It is rare but occurs due to a lesion in the contralateral
frontal or ipsilateral pontine gaze center. An irritative
lesion in the pontine gaze center causes the eye to deviate
in a direction opposite to the side of lesion. Deviation of
head and eyes to one side like in epileptic seizure, is often
seen in TBM particularly when the child has seizures.38,39
Syringomyelia following Tuberculous Meningitis

Patients recovering from TBM may develop intraspinal
cavities as a late complication. Chronic arachnoiditis at
the foramen magnum probably leads to cavity formation
by interfering with CSF outflow from the 4th ventricle
provided the central canal is patent. Circumstantial
evidence pointing to postmeningeal syringomyelia as
being of communicating type came when contrast
material injected intraventricularly was seen filling the
intraspinal cavity. In 3 out of 4 cases studied by Mateo et
al39 by MRI of the brain and spinal cord, the cavity
extended through multiple segments of the spinal cord,
usually in coexistence with marked arachnoidal
adhesions. Some of these patients who had paraplegia

at the onset of TBM, deteriorated neurologically for years
after the complication of syringomyelia. One patient
developed paraplegia 8 months after treatment of TBM
was started. The authors suggest that syringomyelia
following TBM is not communicating in type
and postulate that stagnation of perimedullary fluid and
subarachnoid blockage is a crucial pathogenetic mechanism in the causation of syringomyelia following TBM.
Internuclear Ophthalmoplegia (INO)

It is not easy to diagnose this condition in infancy and
early childhood but if kept in mind it can be detected in
older children and adolescents particularly when the
child presents or develops focal signs during apparent
improvement with treatment. In internuclear ophthalmoplegia the patient cannot adduct the eye on the side of
lesion, while there is nystagmus in the abducting eye.
Internuclear ophthalmoplegia is caused by dysfunction
of the medial longitudinal bundle in the brainstem
(Table 12.1.1). When signs are present in horizontal gaze
in both directions it is bilateral internuclear
ophthalmoplegia and is usually seen in adults with
multiple sclerosis. Unilateral ophthalmoplegia is usually
vascular in origin40 but has also been reported in TBM
by Teoh et al.40 As occlusive vascular disease causes INO,
it is usually due to tuberculous vasculitis causing intrinsic
ischemic brainstem damage and hence indicates poor
prognosis as it can damage vital centers in the brainstem.
If INO presents at the onset or is detected early, aggressive treatment with massive steroid therapy for vasculitis
alongwith bactericidal drugs may help the child.
However, two adult patients of Teoh et al40 were not
benefitted by steroids because of aggressive vasculitis.
This has happened in some of the cases of encephalopathy probably because of hypersensitized T cell
reactivity.
Subacute or Chronic Encephalopathy following

Sudden Withdrawal of Steroids in TBM5
Udani et al6 have described a child of 1-year-age who
developed this complication had intrathoracic
tuberculosis with parenchymal lesions, mediastinal
nodes, positive tuberculin test, history of contact within
the family. He developed TBM with characteristic CSF
picture. CT scan showed small ventricles. The child was
kept for 6 weeks in hospital with improvement in clinical
condition. Parents were advised to continue treatment
with three bactericidal antitubercular drugs.
Steroid therapy was tapered slowly over 6 weeks. In
such a case if a second CT scan alone is seen diagnosis of
161
Alexanders disease; could have been made, but because
of overall data there was no doubt about the diagnosis
of TBM. It appears that sudden withdrawal of steroid
therapy leads to severe hypersensitivity of T lymphocytes
which particularly affects the white matter as per the
second CT scan picture resembling leucodystrophy,
Alexanders disease and other white matter disease. This
shows that massive dosage of steroids could control brain
damage by immune mechanism as sudden withdrawal
of steroids showed a marked edema of the white matter.
It indicated that there was probably vasogenic edema
which later did not respond to steroids, glycerol and
mannitol. Wisnieski and Bloom9 have demonstrated the
mechanism of myelin damage both in experimental
animals and humans which could be due to direct
destruction of myelin by immune competent sensitized
lymphocytes and secondly by macrophages activated by
T lymphocytes.
Bobble-head Doll Syndrome

It is due to trapped 4th ventricle and aqueduct. Children
with bobble-head doll syndrome have head tremors
resembling movements of head suspension dolls.41 These
movements disappear in supine position and during
sleep. Usually enlargement of third ventricle due to
arachnoiditis or aqueductal stenosis has been found in
these cases. With surgical decompression of the ventricle
the tremors usually disappear. The syndrome is caused
by compression of the dorsal median nucleus of the thalamus by the third ventricle. However, the same syndrome
has been described even with trapped and dilated fourth
ventricle. It is postulated that dilated third ventricle and/
or aqueductal dilatation compress the red nucleus which
extends from the caudal margin of superior colliculus in
the central diencephalon. It is known that the lesions of
red nucleus can produce postural tremors.
12.2 CLINICAL MANIFESTATIONS, DIAGNOSIS AND MANAGEMENT

S Aneja, Vimlesh Seth, A Maheshwari
INTRODUCTION
Central Nervous System (CNS) disease caused by
Mycobacterium tuberculosis is a devastating manifestation
of tuberculosis. CNS tuberculosis accounts for
approximately 1% of all cases of tuberculosis, carries a
high mortality and neurological morbidity, and
disproportionately afflicts children. It is the most
common type of chronic CNS infection in developing
countries. Due to the protean nature of the clinical
manifestations, tuberculosis of the CNS remains a
formidable diagnostic challenge. Because the burden of
CNS tuberculosis lies largely in resource-poor regions
of the world, additional challenges in implementing
practical and usable methods to diagnose and treat this
disease remain largely unmet. Increase in cases of multidrug resistant TB and co-infection with HIV have added
to the challenge especially in pediatric age group.
Neurological tuberculosis may be classified as shown in
Table 12.2.1.
Epidemiology
Tubercular Meningitis (TBM) is the commonest type of
CNS tuberculosis encountered in children of our country.
The frequency of TB meningitis is closely related with
the incidence of primary infection with tubercle bacilli.
Table 12.2.1: Classification of Neurological Tuberculosis

Intracranial TBM1
Tubercular Meningitis
Space occupying lesions (tuberculomas, tubercular
abscess)
Tubercular encephalopathy
Tubercular vasculopathy
Spinal TB1
Potts spine and paraplegia
Tubercular arachnoiditis
Nonosseous spinal tuberculoma
Spinal meningitis
Incidence of TBM varies from 1-4% of total inpatient

admissions in different parts of India. The developing
world has 1.3 million cases of TB and 40,000 TB-related
deaths annually among children younger than 15 years.1
The rate of incidence of TB in developed world is stable
at around 11 cases per 100,000 population since 1997. The
proportion of tuberculous meningitis (TBM), the most
severe form of TB, reported through the French
mandatory notification system is low, at around 1.5% of
all TB cases.2 Because of diagnostic difficulty and the lack
of a standardized definition for culture-negative cases,
the surveillance of TBM and comparison of its incidence
across countries is difficult. In a high disease burden area
162
of Cape Town, the TB incidence rate in children aged 05 years was 338/100000, corresponding to a cumulative
incidence of 1.7%. The proportion of TBM cases among
TB cases aged <1 year was 35% and proportion of miliary
TB cases was 32%.3
Pathogenesis
The pathogenesis of TB meningitis is the two-step model
of CNS tuberculosis, as described by Arnold Rich and
Howard McCordock, more than 75 years ago. It remains
central to our current understanding of pathogenesis of
CNS tuberculosis. Infection usually occurs after inhalation
of the bacilli in infected respiratory secretions.
Mycobacteria, inhaled as small aerosol particles, reach the
alveoli where dendritic and macrophage cells process the
bacteria. Dendritic cells are particularly efficient at antigen
presentation due to their robust surface expression of
major histocompatibility complex molecules, which
provide costimulatory signals for T-cell activation Antigen
presentation mostly occurs in regional lymph nodes to
CD4+ T-cells. 4 In the lungs, M. tuberculosis bacteria
multiply in alveolar macrophages. Within 2 to 4 weeks,
through blood circulation, bacilli spread to
extrapulmonary sites and produce small granulomas in
the meninges and adjacent brain parenchyma. These small
granulomas are known as Rich focus. Meningitis
occurred once mycobacteria contained within these lesions
are released into the subarachnoid space, an event that
might happen months or years after the initial bacteremia.
Decreased immunity is believed to play a role in rupture
of Rich foci. Miliary tuberculosis is directly involved in
the pathogenesis of tuberculous meningitis. The bacilli
enter the central nervous system by traversing the blood
brain barrier (BBB). The bacteremia that accompanies
miliary TB increases the likelihood that a meningeal or
subcortical tuberculous focus will be formed.
The mechanism by which M. tuberculosis crosses the
BBB into the CNS is not well characterized. Some have
postulated that free bacilli traverse across the endothelial
barrier, while others suggested that bacilli enter via the
passage of infected macrophages. Using an in vitro
monolayer of human brain microvascular endothelial
cells and infecting them with several strains of
mycobacteria, Jain et al reported that extra cellular
mycobacteria are capable of traversing the endothelial
cells.5
Apoptosis of infected macrophages is an effective
hosts mechanism against tubercle bacilli. Virulent strains
of M. tuberculosis have evolved several genetic
mechanisms to escape host immune responses leading
to prolonged survival. The cell wall glycoproteins of
virulent mycobacteria manipulate the host immune
system. The two important glycolipids are lipoarabinomannans and lipomannans. Lipoarabinomannan
is involved in the inhibition of phagosome maturation,
apoptosis, interferon-gamma signaling in macrophages
and interleukin-12 cytokine secretion of dendritic cells.
The virulence of mycobacteria are dependent on their
ability to induce macrophages to secrete large amounts
of tumor necrosis factor alpha (TNF-) and interleukin10 (IL-10), but downregulate toll-like receptor-2, toll-like
receptor- 4 and major histocompatibility complex class
II expression.
Several genetic abnormalities are implicated in
increasing the hosts susceptibility to M. tuberculosis and
its severe forms particularly CNS and miliary forms. P2X7
receptor is an ATP gated calcium channel, which upon
activation leads to the induction of apoptosis and death
of infecting mycobacteria. Polymorphisms of this
receptor is associated with impaired killing of
mycobacteria, thereby increasing host vulnerability to
tubercular infection. 6 Polymorphism in interferongamma gene are also associated with increased host
susceptibility to tubercular infection.7 Single nucleotide
polymorphisms (SNP) toll-interleukin-1 receptor and
presence of toll-like receptor-2 gene polymorphisms has
been shown to increase the susceptibility of host to severe
forms of tuberculosis like miliary tuberculosis and
tuberculous meningitis. 8,9 Single nucleotide polymorphisms, located at these genes, are thought to
influence cytokine levels and regulate resistance and
susceptibility of an individual to tuberculosis.10 Recently
from an epidemiological study in Colombia, three M.
tuberculosis clinical strains were isolated from the
cerebrospinal fluid (CSF) of patients with meningeal
tuberculosis, and used to infect experimental mice
through the intratracheal route. These strains showed a
distinctive spoligotype pattern. The course of infection
in terms of strain virulence (mice survival, bacillary loads
in lungs), bacilli dissemination and extrapulmonary
infection (bacilli loads in blood, brain, liver, kidney and
spleen), and immune responses (cytokine expression
determined by real time PCR in brain and lung) were
studied and compared with that induced by the
laboratory strains of M. tuberculosis and other five clinical
strains isolated from patients with pulmonary TB. All
the clinical isolates from meningeal TB patients
disseminated extensively through the hematogenous
route infecting the brain, producing inflammation in the
cerebral parenchyma and meninges, whereas H37Rv and
clinical isolates from pulmonary TB patients showed very
limited efficacy to infect the brain. Thus, it seems that
mycobacterial strains with a distinctive genotype are able
to disseminate extensively after the respiratory infection
and infect the brain.11
Immunopathogenesis
The entry of mycobacteria in the CNS triggers host
immune responses leading to a surge in various cytokines
like TNF- that result in breech of the blood-brain barrier
with consequent cerebral edema and increased
intracranial pressure.12 Microglial cells (the resident
macrophages of the brain) are the principal cells
producing cytokines against tubercle bacilli. Several
studies have shown that microglia produce a variety of
chemokines that act to initiate or promote inflammatory
responses in the central nervous system through
facilitating the recruitment of peripheral immune cells
into the brain parenchyma.13,14 The elevated levels of
serum and cerebrospinal fluid TNF- and interferongamma have a positive correlation with the severity of
the tuberculous meningitis.15 Human immunodeficiency
virus co-infection with tuberculous meningitis attenuate
these inflammatory changes. The greater level of immune
suppression with advanced HIV disease leads to very
low level of cerebrospinal fluid interferon-gamma
concentration, which is independently associated with
death. Thus the host immune response is pivotal for
hosts immunity and survival.16
Pathology
The characteristic pathologic features of TBM are
meningeal inflammation, dense basal exudates, vasculitis
and hydrocephalus. The tubercle bacilli are lodged
principally at two sites, leptomeninges and brain
parenchyma. The miliary tubercles in the leptomeninges
are most frequently on the lateral aspect of parietal and
temporal lobes on either side of the sylvian fissure and
along the blood vessels at these sites. The parenchymatous
lesions in the brain are commonly located at superficial
part of the brain (Rich focus), base of the brain (subthalamic
and subputaminal region) and along the supero-lateral
surfaces. The exudate is usually copious, thick and
adhesive in nature. The exudate has a predilection for the
interpeduncular fossa, over the floor of 3rd ventricle,
around the optic chiasm, distal ends of the internal carotid
artery and proximal portion of the middle meningeal
artery. The middle meningeal arteries are often throttled
by the exudate. The exudate extends backwards over the
pons and cerebellum and occupies cisterna ambiens and
cisternapontis, forming a collar which compresses the
brain stem and emerging third cranial nerve, and blocks
the medullocerebellar angles where the foramina of
luschka open. Exudates may be seen surrounding the
lower part of the spinal cord and cauda equina resulting
in tuberculous radiculomyelopathy.
The brain tissue underlying the tuberculous exudates
shows varied degree of edema, perivascular cuffing, and a
microglia reaction collectively termed as border-zone
encephalitis.17 Other parenchymal changes seen are
163
infarction, diffuse edema and tuberculoma. Diffuse

tubercular encephalopathy is characterized by diffuse
edema of the brain, perivascular myelin loss and
hemorrhagic leuko-encephalopathy. The exact cause of
tuberculous encephalopathy is unclear. Hypersensitivity to
proteins liberated by lysed tubercle bacilli, isoimmunization
to host myelin proteins or cerebral microangiopathy play
variable role.
Infarction is caused by inflammation of the vessels
involved in the basal exudate. Frequently the exudate
causes external compression and occlusion of large
arteries at the base of the brain. The vessels of the circle
of Willis are more frequently involved than the vessels
of the basilar system. There is arterial narrowing with or
without total occlusion causing infarction in the zone
supplied by the artery, mostly the middle cerebral artery.
The vascular changes occur in the form of periarteritis
and endarteritis, vascular edema, necrosis and
thrombosis. The changes depend on the caliber of the
vessels involved, severity, duration, stage of the disease,
and treatment status of the patient. In cases of long
duration, subintimal fibrosis and changes in internal
elastica are seen in medium sized vessels.
Hydrocephalus is due to obstruction to the flow of
the CSF in the subarachnoid spaces by dense basal
leptomeninges and interference in the absorption of CSF
by the arachnoid granulations. Excessive production of
CSF does not occur since the ependymal lining of the
choroid plexus is damaged by the exudate.
Clinical Features
The majority of the cases (75-85 %) are below the age of
five years. The disease can occur in any age group but is
uncommon before 6 months and rare before 3 months.
The peak incidence is in 3-5 years age group. Only 2.55%
of total TBM cases were younger than 6 months.19 There
is preponderance of the disease in boys. The onset of the
disease is usually subacute or chronic, taking more than
three weeks to develop.
The clinical manifestations may be grouped into three
stages (Table 12.2.2).20 Often the symptoms in the first
stage are non specific and only when the child fails to
improve and develops convulsions, meningeal irritation
or cranial nerve palsies, is referred to a hospital.
In prodromal stage (stage 1), the symptoms are
nonspecific and diagnosis is difficult to establish. The
disease may follow any condition which lowers the
general resistance such as pertussis or measles, or any
bacterial infection.
Occasionally head injury has been observed to initiate
the disease. The prodromal stage usually spans 2 to
3 weeks and often the symptoms are nonspecific such as
low grade fever, anorexia and sleep disturbances. General
apathy, lack of interest in play, irritability, lassitude,
164

Table 12.2.2: Medical Research Council, Staging of
tuberculous meningitis (TBM)
Stage
Clinical Manifestations
Stage I
The symptoms are nonspecific with few or no

clinical signs of meningitis. The patient is fully
conscious and alert
Signs of meningitis, drowsiness or lethargy,
cranial nerve palsies
Severe clouding of consciousness, stupor or coma,
convulsions, gross paresis or paralysis
Stage II
Stage III
listlessness, altered behavior, headache and vomiting are

usually present. While the older child can complain of
headache, those under 3 years of age can not localize their
symptoms. In these children fatigue and altered behavior
are subtle signs of TBM. In infants and children less than
three years, a high index of suspicion is required to
diagnose. In these children the presentation may be acute
and simulate pyogenic meningitis. In older children with
subacute onset, there are behavioral disturbances and
they are sometimes referred to psychiatrist.
Stage 2 is characterized by appearance of signs of
meningeal irritation and definite neurological signs. The
child may present with convulsions and develop
neurological deficits involving cranial nerves such as
squint, visual disturbances, facial asymmetry, ptosis and
dilated irregular pupils. The child may develop motor
deficit such as hemiplegia or monoplegia. Extrapyramidal signs are frequent accompaniment to the other
presenting features. Meningeal signs are present along
with symptoms of raised intracranial tension. The child
develops loss of consciousness in the second stage. The
child who was apathetic, dull or drowsy in the first stage
now becomes semi comatose and can be aroused with only
painful stimuli.
In the 3rd stage, there is deep coma, and child may
have progressive neurological deficits with dilated
pupils. As the child progresses in this stage, signs of brain
stem compression with well marked neck retraction,
opisthotonic posturing, decorticate followed by
decerebrate spasms appear. Irregular breathing pattern,
Biots breathing appears in 2nd stage and continue into
the 3rd stage. In the terminal stages, pupils are dilated
and severe hyperpyrexia of central origin appears. The
advanced stages of tuberculous meningitis are marked
by deep coma, hemiplegia, decerebrate posturing,
deterioration in vital signs, and, eventually, death.
The presenting symptoms reported in various series
are fever in 80-90% cases, convulsions in 50-60%, vomiting in 40-45% and altered sensorium in 20-45%.20-23
Generalized tonic and clonic seizures are the commonest
type of seizures followed by focal seizures and tonic
spasms. In children with advanced central nervous
disease even after the age of one year there may be
reappearance of neonatal reflexes.
Hemiplegia and quadriplegia occur in about 20% of

cases of TBM, monoplegia and cerebral paraplegia are
uncommon. Paraplegia is either caused by tuberculous
radiculomyelitis or intramedullary tuberculomas.
Tuberculous radiculomyelopathy is characterized by the
subacute paraparesis. Several types of movement
disorders like chorea, hemiballismus, athetosis,
generalized tremors, myoclonic jerks and ataxia have been
described at onset or during the course of the disease.
These are more common in children than in adults.
Cranial nerve palsies are seen in approximately 25%
of cases. The sixth cranial nerve is most commonly
affected cranial nerve. Third and fourth cranial nerves
may also be involved. They are affected either because
of nerve entrapment in adhesive basal exudates or raised
intracranial tension. Vision loss is a devastating
complication of tuberculous meningitis secondary to
optic nerve involvement. The possible reasons for optic
nerve involvement are optochiasmatic arachnoiditis and
granuloma, third ventricular compression of optic
chiasma in patients with a large hydrocephalus, optic
nerve granulomas.25
Complications of Tuberculous Meningitis

Acute Complications
The acute phase of TBM is characterized by marked
features of raised intracranial tension. Seizures may be
present in the initial part of the illness. The frequency of
acute symptomatic seizure in TBM ranges from 16.3 to
31.5%.23 They may also occur due to various electrolyte
abnormalities like hyponatremia (repeated vomiting,
SIADH or cerebral salt wasting), hypernatremia
(secondary to diabetes insipidus to diffuse cerebral
damage), hypoglycemia or hypocalcemia. Hematemesis
may occur at the onset of tuberculous meningitis. Acute
gastric ulcers resulting from hypothalamic lesions have
been documented. Autonomic dysfunction like excessive
perspiration, abdominal pain and hyperperistalsis occur
occasionally.
Hydrocephalus
A recent report on a large cohort of children who had
tuberculous meningitis demonstrated hydrocephalus in
70% of cases.22 Communicating hydrocephalus is the
commonest type. Obstruction of the fourth ventricular
outlet foramina resulting in non-communicating
hydrocephalus, occurs much less commonly (about 20%
of cases). Proximal CSF obstruction (at the level of
foramen of Munro or aqueduct of Sylvius) is a rare cause
of non-communicating hydrocephalus in tuberculous
meningitis. Progressive hydrocephalus if not appropriately treated may have devastating consequences of
irreversible optic atrophy and loss of vision.
The clinical features that suggest the presence of
hydrocephalus are nonspecific. In any patient with TBM
with altered sensorium, hydrocephalus should be
suspected irrespective of the presence or absence of
papilledema. Hydrocephalus is also likely to be present
in patients who are alert and who complain of increasing
headache with or without vomiting and blurring of
vision.
Tubercular Cerbrovascular Disease

TB has a significant impact on the global stroke burden.
Eight percent of strokes in the young in India have been
attributed to TB vasculopathy. The incidence of vasculitis
in TBM is variably reported. In autopsy study on TBM,
vasculitis was reported in 41%.18 On angiographic studies
in TBM, irregular beaded narrowing in supra-clinoid
portion of internal carotid artery, widely sweeping
pericallosal artery, and thalamostriate vein and delayed
circulation of middle cerebral vein with scanty collateral
circulation were reported. Computed tomography (CT)
scan studies show infarctions in 17 to 63% of patients.22,24
In TBM, the basal ganglionic infarcts are the commonest
because of involvement of perforating vessels. In a CT scan
study, the infarctions were located at head of caudate,
anteromedial thalami, anterior limb and genu of internal
capsule due to involvement of medial striate, thalamotuberal, and thalamoperforate arteries in 75%.26 On
magnetic resonance imaging (MRI), infarctions were
reported in 10 of 20 patients with TBM and confirmed the
reported distribution of vascular involvement.27 Infarct has
been reported as a poor prognostic predictor in children
with TBM.28,29
Ocular Lesions
The common ocular lesions in order of frequency are
papillitis, optic atrophy and papilledema. Choroidal
tubercles may be associated with miliary tuberculosis.24
Choroid tubercles are rarely seen but if present are
pathognomic of CNS tuberculosis. Optic atrophy may
sometimes be the primary manifestation of TBM. It may
revert back with early institution of antitubercular
treatment. Involvement of visual area of cortex may lead
to cortical blindness.
Spinal Tuberculous Arachnoiditis

It is a rare complication of CNS tuberculosis. It is an
inflammatory condition that involves the arachnoid lining
along the spinal tract. This condition was previously termed
adhesive spinal arachnoiditis or chronic adhesive
arachnoiditis. This clinical entity is uncommon in developed
countries, but is still commonly reported in South-East Asia,
the Indian subcontinent, South America, and Africa. Three
different pathogeneses are suggested for the occurrence of
spinal tuberculous arachnoiditis i.e. a tuberculous lesion
165
primarily arising in the spinal meninges, downward

extension of intracranial tuberculous meningitis; and
extension of tuberculous spondylitis. Among these,
involvement of the spinal arachnoid lining secondary to
intracranial tuberculous meningitis is the most common
pathogenesis. The thoracic region is the most frequently
affected site, followed by the lumbar and cervical regions.
Macroscopically, exudate can be seen surrounding the
spinal cord and nerve roots. Microscopically, granulomatous inflammation, areas of caseation, tubercles, and
fibrous tissue are noted. In chronic cases, the subarachnoid
space may be irregularly obstructed, with the formation
of pockets of CSF. Spinal cord parenchymal changes
include border-zone rarefaction and vacuolization of the
cord, extensive atrophy and circumscribed central necrosis,
severe gliosis with no recognizable parenchymal tissue,
and intramedullary tuberculoma, which can result in
multicystic myelomalacia and syringomyelia.
Diagnosis of Tubercular Meningitis

Tuberculous meningitis is a serious illness which, if not
diagnosed timely and managed, leads to a high rate of
mortality and permanent disabilities. Tubercular
meningitis poses a diagnostic problem. The reason is that
it presents in a similar manner to other meningoencephalitides particularly partially treated pyogenic meningitis.
Definitive diagnosis of tuberculous meningitis can be
made by demonstration of mycobacteria in cerebrospinal
fluid (CSF), by direct staining or culture. These tests are
time consuming and seldom positive. Recognizing this
problem of diagnosis, many newer serological tests have
been developed to diagnose tuberculous meningitis and
differentiate it from pyogenic meningitis. However, none
of these have a high specificity to be of any clinical utility.
A high index of suspicion is required for early diagnosis
of TBM. Global encephalopathy with focal deficit is
hallmark of TBM. CSF must be examined in every such
case. In case of inconclusive results, it should be repeated
48-72 hours after antibiotic therapy and if it shows no
change in clinical status and CSF results, then it may favor
diagnosis of TBM. CSF glucose must be interpreted in
conjunction with simultaneous blood glucose level. CSF
smear and culture are negative in 90% of cases. CSF antibody
tests are not recommended due to poor sensitivity,
specificity and predictive value. CSF PCR is also variable.
Mantoux test is negative in 70% of patients. CECT (contrast
enhanced computed tomography) scan is useful and should
be considered if possible. Hydrocephalus and basal
exudates are seen in 80-100% patients. Normal CT scan does
not rule out TBM. Towards this end a set of criteria for the
diagnosis of TBM at admission was designed by Ahuja30 et
al and its validity was tested against polymerase chain
reaction (PCR), bacterial isolation and autopsy when
available. Modified Ahuja Criteria were used by Seth and
Sharma31 for diagnosis of TBM in children is as documented
166

Table 12.2.3: Modified Ahuja31 Criteria for diagnosis of
TBM in children
A. Mandatory features
Fever lasting for more than 14 days

Abnormal CSF findings (pleocytosis with more than
20 cells and more than 60% lymphocytes, protein >100
mg/dl, sugar <60% of corresponding blood sugar
values)
In addition to the above, any 2 of the following features

Evidence of extra neural tuberculosis
Positive family history of exposure to a case of
tuberculosis
Positive mantoux reaction (1 TU) >10 mm
Abnormal CT scan findings (2 or more of following):
Exudate in the basal cistern or in the sylvian fissure
Hydrocephalus
Infarcts
Gyral enhancement
in Table 12.2.3. In practice, treatment is generally started

on the basis of clinical features and CSF picture. Certain
clinical features like prodromal stage >7 days, optic atrophy
on fundal examination, focal deficit, abnormal movements,
and CSF leukocytes <50% polymorphs may give a clue to
the diagnosis.32
Clinicoinvestigational Features of
TBM in Children at AIIMS
Diagnosis of TBM at AIIMS, a tertiary care hospital in
India is followed as per the following criteria (Table
12.2.4).
In TBM higher strength of PPD, i.e. 5 TU is recommended for Mantoux test by Vimlesh Seth, because
Table 12.2.4: Diagnosis of TBM
Demonstration of acid fast bacilli in the CSF or fulfillment

of the following criteria:
Essential
CSF showing:
Predominant lymphocyte pleocytosis > 50/mm3
Protein > 60 mg percent
Sugar < 2/3 of blood sugar
Supportive
Along with the essential ones, two or more of the following
clinicoinvestigational criteria:
History of fever of two weeks or more

Positive family history of tuberculosis
Generalized lymphadenopathy
Mantoux test (5 TU) > 10 mm*
Positive radiological evidence of tuberculosis
elsewhere in the body
CT scan evidence of basal exudates or CNS
tuberculosis
Isolation of AFB from gastric lavage or other sites
Histologically proven tubercular lymphadenitis
delayed type of hypersensitivity is better elicited with

higher strength of PPD. Hence, Seth recommends based
on her various studies on immunology, tuberculin test
positivity elicitation is more with 5TU PPD. For details
see chapter clinicoradioimmunological profile, i.e.
Chapter 8 and tuberculin test Chapter 19.23 The profile
of patients of TBM over a period of twenty years is given
in Table 12.2.5.
Table 12.2.5: Clinicoinvestigational features in TBM (AIIMS Data), (1984-2004)

Parameter assessed
History of fever > 2 weeks

Positive family history
Positive Mantoux
Radiological evidence of pulmonary tuberculosis
Isolation of AFB from any site
CT scan
Histologically proven tubercular lymphadenitis
Generalized lymphadenopathy
1984-1986
N* = 52
1991- 2000
N = 136
2000-2004
N = 23
100
40.6**
61.5
69.2
100***
44.2
71.2
38.4
28.8
45.6
4
84
1.6
5.6
95.6
30.4
9.1
21.7
100
3.9
59.6
36.5
3.2
38.4
58.4
4.3
39.1
56.6
Stages of TBM
Stage I
Stage II
Stage III
*N= Number of patients
**N=Contacts surveyed by CXR
+ = Percent
***CT done in 45/52 patients

All figures are in percentage
Diagnostic Modalities
Evidence of extraneural TB
Chest radiography: Posteroanterior and lateral views
may reveal hilar lymphadenopathy, simple
pneumonia, infiltrate, fibronodular infiltrate/
cavitation, and/or pleural effusion/pleural scar.
Abnormal chest finding are seen in 87% of patients.
Ultrasound: abdomen revealing retroperitoneal
lymphadenopathy or matted bowel loops.
Tuberculin Skin Test (Mantoux test): In childhood
tuberculosis (TB), 10 mm (induration) cutoff is taken
as positive reaction. It is applicable to use for strengths
of PPD only up to 5TU. Efforts should be made to use
only 1 TU PPD to decrease the false positives. Negative
results from the purified protein derivative test do not
rule out TB. It is non reactive in 50- 70% of cases with
TBM.
IFN--Releasing Assays (IGRAs): A new generation
of immune-based rapid blood tests for the diagnosis
of latent tubercular infection, called IGRAs, offers
particular advantages over the conventional Mantoux
test. These tests rely on the host response to M.
tuberculosis infection by measuring the IFN-
produced by T-cell responses to M. tuberculosisspecific antigens called early secreted antigenic target
6 (ESAT-6) and culture filtrate protein 10. However,
IGRAs do not distinguish between latent and active
disease. It has been suggested that very high or rising
levels of IFN- in IGRAs may be able to predict the
asymptomatic individual with latent tuberculosis that
is at highest risk of progressing to disease 33,34 but
long-term prospective studies are needed to
investigate this interesting finding.
CSF Analysis
The CSF is under pressure and with the help of a
manometer pressure is estimated to be 30- 40 cm H2O.
It may be opaque or clear on gross examination. There
may be pellicle or cobweb formation on standing. Cell
counts are increased with predominant lymphocytic
pleocytosis. Early on in the disease there is
polymorphonuclear response. Proteins are
moderately elevated often >100 mg/dl. Glucose levels
with a simultaneous blood glucose level are less than
2/3 of blood levels.
CSF smear for AFB: Definitive diagnosis of TBM can
be made only if acid-fast bacilli are isolated. Various
techniques can be used to improve the sensitivity of
AFB staining in the CSF. These include using multiple
samples of CSF, staining the clot that forms in
standing CSF and spinning down the CSF sediment
onto a slide for microscopic examination. Tubercle
167
bacilli have been reported in up to 87% of patients

with repeated sequential CSF examination in
laboratory settings under ideal situations. But in
clinical practice the yield is not high. A recent study
established that both CSF volume and duration of the
microscopic evaluation are independently associated
with bacteriological confirmation of CNS
tuberculosis, suggesting that a minimum of 6 ml of
CSF fluid should be examined microscopically for a
period of 30 minutes. Using this simple method AFB
were demonstrated on microscopy in 58% of adults
with TBM.34
CSF culture for M. tuberculosis is not usually
positive. Rates of positivity range from 25-70%.
Isolation of M. tuberculosis on solid media often takes
3 to 6 weeks, followed by another 2 to 4 weeks for
drug susceptibility testing. Improvements in
laboratory methods now permit more rapid culture,
identification, and drug susceptibility testing of
mycobacterial by automatic radiometric methods,
such as BACTEC, in which a decontaminated,
concentrated specimen is inoculated into a bottle of
medium containing carbon 14-labeled palmitic acid
as the substrate. As mycobacteria metabolize the
labeled acid, carbon dioxide14 accumulates in the
bottle, where radioactivity can be measured. The
addition of appropriate dilutions of antituberculosis
drugs permits the evaluation of drug susceptibility.
The time for isolation and drug susceptibility testing
of mycobacteria can be reduced to 1 to 3 weeks if the
radiometric system is used. The use of high-pressure
liquid chromatography allows for rapid identification
of isolated organisms, usually within 24 hours.
Polymerase chain reaction (PCR): Amplification of
the mycobacterium tuberculosis-specific DNA
sequences by polymerase chain reaction (PCR) or
(nucleic acid amplification) (NAA) has been
evaluated as a means of rapid diagnosis of TBM. One
step amplification used in conventional methods has
a low sensitivity which is attributed to the low copy
numbers of DNA template that could be extracted
from CSF of patients with TBM. In comparison twostep nested amplification can improve the sensitivity.
Using this technique, Liu et al detected the
M. tuberculosis genome in 90.5% of patients with
clinically suspected TBM.35
The PCR has the advantage of being the only
technique besides AFB smear which can confirm the
diagnosis within 24 hours. Kox et al observed a
sensitivity of 48% for PCR compared to 9% by
microscopy in their patients with TBM.36 PCR can be
applied to CSF even after initiation of antitubercular
treatment. It is not affected by presence of other
infecting
bacteria
as
may
occur
in
immunocompromised patients.
168
False negative PCR results are attributed to several

factors like treatment effect on CSF, presence of PCR
inhibitory factors in CSF, extremely low bacterial
numbers, small amount of CSF tested and the method
of extraction of DNA. Even with PCR positive cases,
culture must be done for drug susceptibility testing
especially for emergence of MDR strains.
Nucleic acid amplification (NAA) tests are
categorized as commercial and in-house (homebrew). Most laboratories use commercial kits such
as the Amplicor M. tuberculosis tests (Roche Molecular
Systems, Branchburg, NJ, USA), and the Amplified
M. tuberculosis Direct Test (MTD; Gen-Probe Inc, San
Diego, CA, USA).37 Overall sensitivity of PCR for the
diagnosis of TBM ranges from 33 to 90.5%, with
specificities ranging from 88.2 to 100%.38 An inhouse (home brew) PCR technique has been
developed for the detection of M. tuberculosis DNA,
which targets a 340 bp nucleotide sequence located
within the 38 kDa protein gene, for amplification.
This was developed in Mumbai, India. This test can
detect as small an amount of DNA as 10 fg, which
is equivalent to two to three organisms, and is
highly specific. The sensitivity of this PCR was 90%
and specificity, 100%.39 In the 35 studies with inhouse tests, the summary accuracy could not be
established with confidence because of wide
variability in test accuracy.38,39 Though the in-house
PCR testing may be cheaper but they have
unreliable sensitivities. A systematic review and
meta-analysis of 49 studies was performed to
establish the accuracy of nucleic acid amplification
(NAA) tests for tuberculous meningitis. It estimated
that in 14 studies with commercial NAA tests, the
sensitivity and specificity range were 0-56% and 098% respectively.40 The use of PCR to monitor
successful treatment in TBM is not yet defined. PCR
can detect M. tuberculosis up to 6 weeks after starting
treatment. Thus to conclude negative PCR does not
rule out the possibility of TBM. The commercial NAA
tests show a potential role in confirming tuberculous
meningitis diagnosis, although their overall low
sensitivity and comparative high cost precludes the
use of these tests in routine practice in resource poor
settings.
CSF adenosine deaminase (ADA) levels: Adenosine
deaminase is produced by lymphocytes and
monocytes. The adenosine deaminase (ADA) activity
test is a rapid test that has been used for the diagnosis
of the pleural, peritoneal and pericardial forms of
tuberculosis. However, the usefulness of ADA in TBM
is uncertain. Recently a systematic review was
conducted to evaluate ADA as a diagnostic test for
TBM. Of 380 patients with TBM included in the
analysis the sensitivity and specificity and diagnostic

odds ratios (DOR) were calculated based on arbitrary
ADA cut-off values from 1 to 10 U/l. The cut-off values
of 8 U/l (sensitivity 59% and specificity 96%)
improved the diagnosis of TBM (p <0.001).41 However
ADA is also increased in pyogenic meningitis and it
cannot be used to discriminate between TBM and
bacterial meningitis. The increased levels of ADA can
be used as an adjunct to improve TBM diagnosis,
particularly after bacterial meningitis has been ruled
out.41
Tuberculostearic acid: Tuberculostearic acid is a fatty
acid component of the M. tuberculosis cell wall, which
has been detected in CSF of patients with TBM via
various forms of gas chromatography.42-44 Although
this method has good sensitivity (89-95%) and
specificity (91-99%) in limited studies, the
requirement for expensive equipment and
considerable expertise has limited the clinical use of
this technique. The biomarkers for the diagnosis of
TBM are summarized in Table 12.2.6.
Serological Testing in CSF

During an infection of CNS with M. tuberculosis many
secretory or degradative products of the bacilli are
present in the CSF. Since the manifestations of TBM are
due to immunologically directed inflammatory reaction
to M. tuberculosis, it is logical to look for specific antigen,
antibody and immune complexes in the CSF. The use of
serological tests as a diagnostic tool appears attractive
but caution must be exercised in interpreting the results
in relation to the stage of the disease. LAM antigen,
17KDa antigen and antigen85 complex of M. tuberculosis
are strong candidate antigens useful in TBM.45 It must
be recognized that presence of concurrent immunecomplexes, and specific antigen selected affect the
sensitivity of these tests. The antigen based tests would
be helpful early in the disease process. As the disease
progresses, increasing levels of antibodies form immune
complexes which result in a phase where the detection
of both antigen and antibody becomes difficult.
Subsequently the levels of antibody increases. The
changes in relation to temporal phase of the disease make
interpretation difficult and limit the applicability of these
tests in clinical practice.
Antibody detection: Antibodies against glycolipids and
proteins isolated from M. tuberculosis, BCG, PPD, antigen
5 and lipoarabinomannan in the CSF have all been used
as rapid test to diagnose TBM. ELISA, radioimmunoassay
and immunoblot techniques have been used to detect
these antibodies. Various authors have reported
sensitivity ranging from 61-90% and specificity of 58100%.46-48
169
Table 12.2.6: Performance of various diagnostic tests for TBM
Test
Sensitivity
(%)
Specificity
(%)
Remarks
Commercially available NAA assays

Roche Amplicor MTB38
Modified Gen-Probe MTD51
Meta-analysis 14 studies with
commercial NAA assays40
In house PCR (Indian)39
60
83
56
100
100
98
Positive PCR is specific for diagnosis;

but negative PCR does not rule out
TBM
31-98
88-100
Adenosine deaminase (ADA levels)41
59
96
Tuberculostearic acid assays

Gas chromatography and mass
Spectrometry42
Gas-liquid chromatography43
Antibody assays
89
99
95
91
In-house (so-called home-brew) PCR

produce highly inconsistent results
compared with commercial NAATs
( 8 IU/L cut off) cannot differentiate
reliably between pyogenic meningitis
and TBM
Requirement for expensive equipment
and considerable expertise has limited
the clinical use of this technique
ELISA50
ELISA53
ELISA (immunoglobulin G complexes)54
ELISA and Western blotting57
Passive hemagglutination assay and
Western blotting58
Antigen assays
72
61
64
93
81
92
100
91
96
93
role in clinical care of pediatric cases
Reverse passive hemagglutination59

Radioimmunoassay56
Dot immunobinding assay60
88
79
63
95
100
100
Not relevant for routine management

and diagnosis of tuberculosis
Commercial antibody testing has no
While the detection of antibodies in the CSF to

diagnose TBM is rapid, earlier studies evaluating the
utility of measuring M. tuberculosis-specific antibodies
in the CSF have shown that these techniques are limited
by the inability to differentiate acute infection from
previous infection and problems with cross-reactivity49,50 in addition to variable and often poor sensitivity and specificity.51-53 An example of a more recent
study shows that measuring antibodies against a 30 kDa
protein that is a specific antigen of M. tuberculosis 54
yielded a more promising sensitivity of 92%.55 In a study
of patients with a clinical diagnosis of TBM that
compared the utility of detecting anti-M. bovis BCG
antibody-secreting cells in the CSF by enzyme-linked
immunospot (ELISPOT) assay, PCR to detect an
insertion sequence (IS6110) specific for M. tuberculosis
in the CSF, and an enzyme-linked immunosorbent assay
(ELISA) to detect anti-BCG antibodies, the ELISPOT
method was more sensitive (84% versus 75% and 52.3%,
respectively) and as specific as (91.8% versus 93.7% and
91.6%, respectively) the other methods tested.56 Those
authors also emphasized that the sensitivity of the
ELISPOT method was better earlier in the clinical course
of TBM and that the sensitivity improved to 100%
among those tested within 4 weeks of onset of TBM
symptoms.56
Antigen detection: In addition to measuring M.

tuberculosis-specific antibodies or antibody-secreting cells,
assays to measure M. tuberculosis-specific antigens
directly in the CSF have also been evaluated.57-59 A
theoretical advantage of antigen detection over antibody
detection would be that they indicate active infection . In
a study among patients with a clinical diagnosis of TBM
that compared a dot immunobinding assay for an M.
tuberculosis-specific 14-kDa protein antigen with PCR to
detect IS6110, specific for M. tuberculosis in the CSF, the
immunobinding assay was more sensitive than the PCR
method (75% versus 40.5%, respectively).60
Despite the obvious advantage of low cost and ease
of performing these antigen antibody tests as compared
to complicated and costly PCR based methods the utility
of these tests in clinical situation is uncertain and are
therefore not recommended in routine practice.
Currently these tests also have limited utility in
clinical practice.
Neuroimaging
CT (Computed Tomography)
Neuroimaging studies can be useful for the diagnosis of
TBM. The characteristic computed tomographic (CT)
170
changes include basal enhancement, presence of

exudates, hydrocephalus and periventricular infarcts. CT
shows obliteration by iso-attenuating to marginally
hyperattenuating exudate at the basal cistern and plaque
like dural thickening. On intravenous contrast, there is
enhancement of basal cisterns which may extend to the
convexities, ventricles and sylvian fissure. A review of
computed tomographic findings of 289 patients revealed
that in 35 patients computed tomography was normal.
Remaining 254 patients had some abnormality. Common
abnormalities were hydrocephalus (80.3%), parenchymal
enhancement (24.4%), contrast enhancement of basal
cisterns (19.2%), cerebral infarct and focal or diffuse brain
edema (15.3%), and tuberculoma (5.5%).61 Presence of
hydrocephalus was shown to be associated with a higher
risk of stroke and poor prognosis.62,63 Follow-up imaging
may be valuable as it may demonstrate some new feature
that is not initially present (like hydrocephalus and
infarcts).62 The degree of hydrocephalus correlates with
the duration of the disease.
Magnetic Resonance Imaging (MRI)

Nonenhanced MRI may be normal in the early stages of
TBM. However gadolinium enhanced MRI is superior
to conventional CECT for detection of basal meningeal
enhancement and small Tuberculomas. Advantages of
contrast MRI are summarized in Table 12.2.7. Post-gad
MRI has been shown to be superior to computed
tomography in demonstrating ischemia in TBM,
especially of the brainstem.64 It is also superior to detect
diffuse or focal meningeal granulomatous change and
delineate focal infarcts of basal ganglia and diencephalon.
Cranial nerves may appear thickened on both T1 and T2
weighted images and may show hyperintensity on T2
weighted images. Proximal part of the cranial nerve may
show enhancement with gadolinium. MRI when
combined with MRS (magnetic resonance spectroscopy)
is useful in differentiating tuberculomas from other
infective lesions such as brain abscess or neurocysticercosis
and neoplastic lesions as it demonstrates the biochemical
fingerprints of the tubercle bacilli in a granuloma.65,66
For neuroimaging refer to chapter on imaging
Treatment of TBM
The primary aim of treatment of TBM is to ensure the
recovery of the child without neurological deficit and
cognitive disabilities. In addition, it should prevent
transmission and halt the evolution of resistant strains.
In cases of doubt as to whether the patient has partially
treated meningitis or TBM (a very important differential
diagnosis in our setting), it is prudent to start dual
therapy with antibiotics and antitubercular therapy and
reassess the patient in 7-10 days.
Table 12.2.7: Advantages of Godolinium enhanced MRI

vs CECT for diagnosis of TBM
Detection of basal meningeal enhancement and small
tuberculomas
Detect diffuse or focal meningeal granulomatous change
Delineate focal infarcts of basal ganglia and diencephalons
Can reveal hemorrhagic nature of infarcts?
Table 12.2.8: The recommended doses of antitubercular

drugs by Indian Academy of Pediatrics67
Drug *
Isoniazid **
Rifampicin
Pyrazinamide
Ethambutol
Strepyomycin
Daily dose
(mg/kg)
Intermittent
dose (mg/kg)
5-10
10
30-35
20
15-20
15
15
35
30
20
* All the drugs should be administered in a single daily dose

on an empty stomach.
** Vitamin B6 is not necessary in children taking INH.
Hepatotoxicity may be seen in vulnerable patients,
(malnutrition/disseminated disease)
Antitubercular treatment: It is the cornerstone of effective

treatment of TBM. The main objectives of anti-TB treatment
are to: cure the patient; prevent death from active TB or
its late effects; prevent relapse of TB (by eliminating the
dormant bacilli); prevent the development of drug
resistance (by using a combination of drugs) and decrease
TB transmission to others. In TBM the drug should be able
to penetrate the blood brain barrier (BBB) and achieve
effective concentration in CNS. The Consensus Statement
of IAP (Indian Academy of Pediatrics) recommends the
doses of antitubercular drugs as listed in Table 12.2.8.67
The drug regimens used are summarized in Table 12.2.9.
In 1993, RNTCP (Revised National Tuberculosis Control
Program) incorporating the internationally recommended
DOTS strategy, was developed. The RNTCP recommends
intermittent short-course chemotherapy (ISSC) under
Directly Observed Treatment-Short-course (DOTS)
strategy and the Indian Academy of Pediatrics endorses
the same for all forms of childhood tuberculosis.68
Antitubercular therapy (ATT) regimens are divided
in two, an initial intensive phase and a continuation
phase. In intensive phase, a regimen of INH, rifampicin,
pyrazinamide along with streptomycin/ethambutol is
recommended. In continuation phase, two drug regimens
is given for four months or longer or optimal length
therapy is not yet established but most experts give ATT
for at least 9 months.
Due to different degrees of drug penetration into the
central nervous system, some experts recommend
171
Table 12.2.9: Drug regimens used in TBM
Protocol
Intensive phase**
Continuation phase**
Total duration (months)
IAP consensus
2 HRZE
10 HRE
12
DOTS, RNTCP*
2H3R3Z3E3
7H3R3
Cat I of DOTS; 9 months
* intermittent therapy
** H (INH), R (Rifampicin), Z (Pyrazinamide), E (Ethambutol)
modifying the standard anti-TB treatment regimen for

children. As ethambutol and streptomycin have poor
penetration in CSF, some experts recommend
ethionamide as the fourth drug because it crosses both
healthy and inflamed meninges. Furthermore, because
rifampicin does not penetrate uninflamed meninges well
and pyrazinamide dose, some experts recommend
continuing pyrazinamide for the full 6-months
treatment.69 While optimal duration of therapy is not well
established, it is prudent to use the upper end of the doses
range and longer continuation phase (up to 7 months) in
treatment of TBM.
Efficacy of ISSC (Intermittent Short-Course Chemotherapy) in children with pulmonary tuberculosis (PTB)
and other non-serious forms is well established.68-74 There
is limited published data on its efficacy of ISSC in serious
extra pulmonary tuberculosis (EPTB) particularly TBM.7577
Regarding the efficacy of ISSC in tubercular meningitis
(TBM), the published evidence is almost nonexistent in
children, and scarce in adults.78 WHO Guidelines for
management of tuberculosis in children recommends the
treatment regimens for TBM as described in Table
12.2.10.69 There are no randomized controlled trials
(RCTs) available to definitely conclude the optimum
duration of treatment to prevent relapses and long term
sequel. Multiple reports have confirmed the efficacy of
shorter courses of drugs with similar cure rates and better
compliance with fewer drop out rates.79-84
Daily versus intermittent?

Ideally daily DOTS would be desirable pending RCTs to
unequivocally establish the efficacy of intermittent
therapy in pediatric tuberculosis especially severe
extrapulmonary TB. Under the umbrella of RNTCP, fully
intermittent thrice weekly therapy is being used. The
overall response rate for treatment of pediatric TB is 95%,
which is comparable to 90-100% response reported with
daily therapy.68,71,72 The cure rates in neurotuberculosis
is 86%.79 The thrice weekly regimens under RNTCP has
good patient compliance, fewer dropouts in addition to
being cost effective and preventing emergence of resistant
strains.
Relatively few studies have evaluated the
effectiveness of fully intermittent chemotherapy for
childhood tuberculosis or its effect on adherence to
treatment. A randomized control trial done by Te Water

et al73 concluded that fully intermittent twice weekly
chemotherapy is an acceptable treatment option for the
management of uncomplicated pulmonary childhood
tuberculosis. There are no RCTs to conclude whether this
is applicable to cases of CNS tuberculosis. In fact a metaanalysis was done to compare the effectiveness of
intermittent with daily chemotherapy (both containing
rifampicin) in childhood tuberculosis (age < 16 years) to
achieve cure or significant improvement. Four
randomized controlled trials comparing twice weekly
and daily therapy included 466 children (pulmonary 439;
extrapulmonary 27). It was concluded that twice weekly
intermittent short-course therapy is less likely to cure
tuberculosis in children as compared to daily therapy.80
The studies included, however, did not have CNS
tuberculosis. Hence, for neurotuberculosis it is safer to
use daily regimen.
Corticosteroids
Corticosteroids are routinely recommended in TBM. The
evidence of its utility to significantly reduce death and
disabling residual neurological deficit amongst patient
has recently been confirmed by Cochrane review.85 A
study from Vietnam showed that patients who received
dexamethasone, on follow-up had significantly improved survival. However, treatment with corticosteroids
did not alter the combined outcome of death and severe
disability. However, subgroup analysis revealed that
for the patients in stage-I there was a slight statistically
significant benefit for the combined outcome. This
observation suggested that early treatment is
important.86 The mechanism by which corticosteroids
Table 12.2.10: Selected regimens for treatment of TB
meningitis in children69
Intensive phase
Continuation phase
2HRZE
4HR
2HRZ(S or Eth)
6HRZEth
7-10HR
(regimen for 6 months
in total)
Eth, ethionamide; H, isoniazid; R, rifampicin; S,

streptomycin; Z, pyrazinamide.
172
exert survival benefit is currently unclear. Two broad

mechanisms have been proposed: (i) the immune
modulating effect of dexamethasone in the CNS and
(ii) the ability of steroids to prevent hydrocephalus.
Besides, steroids reduce the spinal block, decrease CSF
protein and pleocytosis besides depressing the
tuberculin hypersensitivity.
Corticosteroids should be added to the therapeutic
regimen in patients of tuberculous meningitis. The
treatment of cerebral edema has improved survival and
thus administration of corticosteroids in high dosage is
clearly indicated in the management of cerebral edema.
Oral prednisolone (2 mg/kg/day for 3 weeks then
tapered over next 3 weeks) can be used. Alternatively
dexamethasone (0.4 mg/kg/day) followed by oral
prednisolone can be used. The total duration of steroids
is 6-8 weeks.
Antiepileptic Drugs
In acute phase of TBM, seizures may occur due to
electrolyte imbalance such as hyponatremia, raised
intracranial pressure. They mainly require the treatment
of underlying cause. Seizures occurring later than the
first week or associated with tuberculoma and infarct
require initiation of antiepileptic drugs (AED). Seizure
in TBM are mainly acute symptomatic and may not
necessitate the use of long term AED. In the absence of
detailed investigatory work up for finding out the cause
of convulsions, clinical presentation of seizures like focal
seizures and cases with generalized tonic clonic seizures
(GTCS) and tonic seizures which are recurrent and those
manifesting after first week may be reasonable
indications for starting long-term AED.87
Phenobarbitone should not be used for treatment as
it has cerebral depressant effect and induces hepatic
microsomal enzymes which lead to production of
acetylating agents of INH which causes increased
hepatotoxicity.
Medical Management of Cerebral Edema

Mannitol: Mannitol is most frequently used in the
emergency treatment of cerebral edema. The dose of
mannitol (20 %) is 5 ml/kg stat followed by 2 ml/kg 6
hourly for 8 doses. Repeated administration of the
mannitol may cause fluid and electrolyte imbalance with
a secondary increase in intracranial pressure (the rebound
phenomenon). Hence, these drugs should be used for
the first 48-72 hours of therapy only. Besides mannitol,
glycerol and acetazolamide can be used for treatment of
chronic raised intracranial pressure (ICP).
Paradoxical Response to Antitubercular Treatment

A paradoxical deterioration during antitubercular
therapy is defined as a transient worsening of disease, at
a pre-existing site, or the development of new tuberculous lesions in a patient who initially improved on antitubercular therapy. This phenomenon is more commonly
associated with extra pulmonary tuberculosis. It most
frequently occurs in the first 2 weeks after starting treatment, but may occur anytime even up to 1 year during
chemotherapy despite a regular standard antitubercular
treatment. New granuloma(s) or abscess(es) may appear
in children receiving chemotherapy for TBM during the
follow-up. Hydrocephalus may also appear despite a
regular chemotherapy in treated TBM cases. Immature
faintly enhancing tuberculomas have a more likely
chance of resolution with antituberculous chemotherapy
and glucocorticoids, while a well-formed and probably
large sized (>3 cm) granulomas may have a risk of
paradoxical enlargement.88 Paradoxical reaction are more
common in HIV positive patient. It is as high as 30% in
HIV positive patients as compared to 10% in immunocompetent patients.
Surgical Management of Hydrocephalus

Modern imaging techniques, such as CT and MRI, have
clearly shown that hydrocephalus is very common and
plays an important role in increasing the raised ICT with
subsequent brain damage.
There is no consensus in the literature regarding the
most appropriate treatment for tuberculous
hydrocephalus, mainly because of lack of well-designed,
prospective controlled trials. There are 2 options for
treatment of hydrocephalusventriculoperitoneal shunt
(VP shunt) and endoscopic third ventriculostomy (ETV).
Palur staging is mainly used for determining the
severity of the disease.89 Tuberculous meningitis with
hydrocephalus was graded as follows: grade 1, normal
sensorium and no neurologic deficit; grade 2, normal
sensorium with neurologic deficit; grade 3, altered
sensorium with/without dense neurologic deficit; and
grade 4, deeply comatose with/without decerebrate or
decorticate posturing.
The usual approach to the management of acute
hydrocephalus and raised ICP in tuberculous meningitis
is that of selective shunting. Noncommunicating hydrocephalus, which carries the risk of herniation, is treated
by immediate ventriculoperitoneal shunt, whereas
communicating hydrocephalus, which carries no
immediate risk, is first given a trial of medical treatment.
Medical and surgical treatment was compared in
children who had stage 2 and 3 tuberculous meningitis
by means of a controlled clinical trial. The medical and
surgical treatment groups did not differ in clinical
outcome or resolution of hydrocephalus (ventricular
size on CT) after completing 6 months of antituberculosis therapy.85 A large follow-up study recently
confirmed that approximately 70% of cases of communicating hydrocephalus will respond to medical therapy
(antitubercular treatment and diuretics), which reduces
the need for shunt surgery significantly.89 The benefits
of this, especially in resource limited countries where
tuberculous meningitis occurs most commonly, are
many. The risk of shunt dysfunction (obstruction or
infection) in tuberculous meningitis has been reported
to be as high as 30%. 90 This percentage has been
attributed to the high CSF protein content and also the
high incidence of shunt infection. Late shunt
dysfunction in a patient who has become shuntdependent may have serious consequences if left
undiagnosed or untreated because of unavailability of
neurosurgical services.
Some studies report good outcome after surgical
intervention by VP Shunt.91 The potential for better
outcome needs to be weighed against the risk of
complications of VP Shunt.
Endoscopic third ventriculostomy (ETV) is another
surgical option. It creates a communication between third
ventricle and subarachnoid space bypassing cerebral
aqueduct. It is now considered as a safe and long-lasting
treatment option for hydrocephalus in patient with
tuberculous meningitis. This procedure was most
frequently reserved for patients who experienced multiple
episodes of shunt dysfunction. Endoscopic third
ventriculostomy is likely to fail in the presence of advanced
clinical grade, dense adhesions in prepontine cisterns and
an unidentifiable third ventricular floor anatomy.91
Though various authors have had a success rate of 6568% for treatment of tubercular hydrocephalus, failure
rates have been quite high in acute cases due to thickening
of the floor of third ventricle and distorted anatomy.
However, success rate is higher in chronic and burnt out
cases.
To conclude the type of surgical management, and
time of intervention depend upon the type of
hydrocephalus and the grading of the patient. Initially,
medical management should be tried for a week or so in
patients in grades I and II. The patient should be
monitored closely during this period to detect any
worsening or lack of improvement and a shunt should
be promptly offered in case of failure of medical
management. Prolonging medical therapy in patients in
good grades could be harmful and may lead to
irreversible brain damage.92
As children with grade IV disease usually have poor
outcome, aggressive surgical management will have little
effect on outcome. Such children should have external
ventricular drainage, followed by shunting only if
improvement is seen.
As expertise with ETV increases across various
centers its role in acute and subacute cases of TBM with
hydrocephalus may increase93,94 (Table 12.2.11).
173
Table 12.2.11: Indications of surgical intervention in

hydrocephalus
Noncommunicating hydrocephalus
Communicating hydrocephalus not responding to medical
treatment.
Grade II and III hydrocephalus
Prognosis
The mortality rate associated with treated TBM is 20 to
50% in several series.85,95-98 In a large series from Egypt,
the initial stage of disease at presentation was reported
to be a major prognostic indicator for mortality.95 In their
series, the mortality rate was 18% for stage I TBM, 34%
for stage II, and 72% for stage III. The importance of the
stage of disease in predicting outcome has been well
documented in other series as well.99-101 Even the large
dexamethasone trial by Thwaites et al had 31.8%
mortality in the steroid-treated arm, with mortality rates
diverging depending on the presenting stage of disease
(stage I, 16.7%; stage II, 31.1%; stage III, 54.8%).85 Among
the survivors of TBM, some form of neurological
impairment afflicts approximately 20 to 30%. These
impairments range from cranial nerve palsies,
ophthalmoplegia, seizures, psychiatric disorders, and
ataxia to hemiparesis, blindness, deafness, and mental
retardation.
Researchers seeking additional predictors of poor
outcome in CNS tuberculosis, specifically in children,
identified advanced stage of the disease at
presentation,100,101 age, and the presence of any infarction
other than a purely hemispheric infarction as important
predictors. Studies that included primarily adults
identified the stage of disease, HIV coinfection, the
combination of isoniazid and rifampicin resistance and
CSF parameters such as high CSF lactate, CSF leucopenia,
and low CSF glucose as being poor prognostic
indicators.102 Misra et al studied both children and adults
and identified stage, age, focal weakness, cranial nerve
palsies, and hydrocephalus as predictors of mortality at
3 months.103 Interestingly, features such as presenting
intracranial pressure, cytokines in the CSF,104 isoniazid
or streptomycin resistance, 105 and M. tuberculosis
genotype106 have been shown not to be predictive of a
poor outcome. Presence of brain stem lesion, as visualized
on MRI, also portends poorer outcome. Prompt diagnosis
and timely initiation of antitubercular treatment and
corticosteroids is a major determinant to favorable
outcome.85,100-102
174
Mortality and Sequelae
SPECIAL SCENARIOS
Motor disability and intellectual handicap are common

long-term complications in survivors. Adverse sequelae
occur in 10 to 85% of cases. 95-98 These are mental
retardation, epilepsy, neurological deficit in the form of
hemiplegia, quadriplegia, cranial nerve palsy (commonly
7th, 3rd and 6th cranial nerves), blindness, deafness,
behavioral problems, hydrocephalus, hypothalamic
disturbances in the form of precocious puberty and
diabetes insipidus. Behavioral abnormalities have also
been reported in patients with TBM. These children have
disruptive behavior, attention problems, hyperactivity,
aggressive behavior, rule-breaking behavior. There is
high incidence of ADHD or conduct disorder amongst
stage III TBM patients.107
In a prospective study at AIIMS (2000-2004) by Seth
et al,100 90 patients with TBM were followed for 2 to 11
months with a mean duration of follow-up of 6.5 months.
The neurological outcome was assessed as follows:
When to Suspect MDR-TB
Classification of Neurological Outcomes

Attention deficit
WellChild appears well, minor physical
abnormality not interfering with normal routine.
Minor disabilityMild mental retardation, epilepsy,
deafness, hyperactivity, behavioral problems
Major disabilitySevere mental retardation with
physical abnormalities such as hemiparesis or
blindness.
The neurological outcome depended upon the stage
of presentation (Table 12.2.12).
In Stage I and II, the percentage of children who were
well, ranged from 86-67% and there was no death. In
comparison in the children who presented in stage III,
61% had major disability and 27% died.
Relationship with BCG

Children with TBM who are vaccinated with BCG appear
to maintain better mentation and have a superior
outcome. This may in part be explained by the better
immune response to infection as reflected in the higher
CSF cell counts.101
The multidrug-resistant (MDR) TB has, increasingly been

recognized in children commensurate with the rising
number of adults with HIV/AIDS. Tuberculosis is the
most common opportunistic infection noted in these
adults, many of whom may be MDR. Close proximity to
adult patients with multidrug-resistant TB makes
children prone to developing primary multidrug- resistant TB, a vulnerability documented in a South African
study.108
Tubercular Meningitis in HIV Infected Children

Confection with human immunodeficiency virus (HIV)
and Mycobacterium tuberculosis poses major diagnostic
and management challenges. HIV-infected children are
more likely to develop disseminated forms of TB and
may develop immune reconstitution phenomena and
complex drug interactions.
The clinical picture of TBM in children is often
insidious, resulting in delayed diagnosis. HIV infected
children with TBM may manifest signs of HIV disease,
such as generalized lymphadenopathy, splenomegaly,
hepatomegaly, and clubbing, but are frequently
tuberculin skin test negative. Cerebrospinal fluid (CSF)
findings are comparable in HIV-infected and HIVuninfected patients with TBM.108,109
In the absence of a definitive microbiological diagnosis, computed tomography (CT) can provide
diagnostic certainty in most HIV-uninfected children.
However, HIV-infected children are less likely to display
the classic signs associated with TBM on CT: obstructive
hydrocephalus (72% vs 98%), basilar enhancement (38%
vs 71%), and parenchymal granulomas (0% vs 15%).109
The optimal time to begin antiretroviral (ARV)
therapy in the ARV-naive, HIV-infected child with TBM
is unclear because of the risk of immune reconstitution
inflammatory syndrome (IRIS). IRIS represents the
paradoxical worsening of symptoms after an initial
period (2 weeks to 3 months) of improvement. IRIS is
generally a self-limiting phenomenon and should not be
mistaken for ATT treatment failure. Most management
Table 12.2.12: Clinical outcomes of TBM in relation to stage of presentation.
Clinical outcome
Clinical stage
No. of cases
Well
Minor disability
Major disability
Mortality
I
II
III
7
43
44
6(86)*
29(67)
3(7)
1(14)
9(2)
2(5)
0
5(12)
27(61)
0
0
12(27)
* Figures in parentheses are percentages.
175
guidelines suggest delaying ARV therapy for 4 or more

weeks after ATT initiation.
For children diagnosed with TBM while on ARV
therapy, the specific ARV drug regimen may need to be
altered to minimize interactions with the ATT
medications.110 Coadministration of antitubercular and
antiretroviral therapy is common in high-burden
countries where tuberculosis is the commonest
opportunistic infection. Concomitant use of rifampicin
and many antiretroviral drugs is complicated by druginteractions caused by the potent induction by rifampicin
of genes involved in drug metabolism and transport,
which could result in subtherapeutic antiretroviral drug
concentrations. The major interactions involve
antiretrovirals used in resource-limited settings: the nonnucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz or nevirapine, and ritonavir-boosted protease
inhibitors. The reduction of nevirapine concentrations
with concomitant rifampicin is greater than with
efavirenz, particularly during the lead-in dose period
when subtherapeutic concentrations occur in the majority
of patients. There is reassuring data on the effectiveness
of standard doses of efavirenz with concomitant
rifampicin, but the largest cohort study found a higher
risk of virological failure with nevirapine. The drug-drug
interaction between rifampicin and ritonavir-boosted
protease inhibitors is more marked than with the
NNRTIs, and therapeutic concentrations have only been
achieved with adjusted doses of lopinavir/ritonavir or
with saquinavir/ritonavir. The major barrier to using
adjusted dose protease inhibitors with rifampicin is the
high rates of hepatotoxicity seen in healthy volunteers.
The alternative strategy that can be followed in resourcerich settings is to replace rifampicin with rifabutin, but
even if the price of rifabutin were to be dramatically
reduced it would be difficult to implement in highburden countries where standardized antitubercular
regimens with fixed-dose combinations are used.111
epithelioid cells derived from altered mononuclear

phagocytes and surrounded by lymphocytes. Tubercles
originate during initial bacteremia which is known to occur
in chronic tuberculous infections. The extent and rate of
local progression of these initial foci into tuberculomas is
extremely variable and depend upon complex and
incompletely understood mechanisms. Often,
polymorphonuclear leukocytes may infiltrate into these
lesions. The center of the tuberculoma becomes necrotic,
forming caseous debris, while the periphery tends to
encapsulate with fibrous tissue. There may be liquefaction
of the caseous material, resulting in a tuberculous abscess
in extreme cases. Apparently this is due to the presence of
polymorphonuclear leukocytes.4 The size of cerebral
tuberculomas is quite variable. In most cases, their
diameter ranges from a few millimeters to 3 or 4
centimeters in size.
Intracranial tuberculomas in patients under the age
of 20 years are usually infratentorial, but supratentorial
lesions predominate in adults.114 Most frequent site of
involvement in children was considered to be the
cerebellum. However, with the advent of neuroimaging,
supratentorial lesions are increasingly being recognized
in children. In spite of hematogenous origin of
tuberculomas due to initial bacillemia, solitary
tuberculomas are more frequently seen than multiple
lesions.114
On gross examination, a cerebral tuberculoma is
usually found to be hard, nodular, comparatively
avascular and easy to shell out. There may be a
connection to the adjacent dura and occasionally there
may be a gross resemblance to meningioma. Edema
forms the integral feature of tuberculoma. Indeed it is
occasionally so extensive and out of proportion to the
size of the tuberculoma itself that it has been considered
to constitute a tuberculous edematous encephalopathy.
In addition, there are many atypical forms of tuberculoma
including cysts and abscesses.
TUBERCULOMA OF BRAIN
Clinical Features
Tuberculoma is a manifestation of tuberculosis which occurs

in solid organs. A tuberculoma usually begins in an area of
TB cerebritis as a cluster of microgranulomas, which
coalesce into a mature noncaseating granuloma. The relative
frequency of CNS tuberculomas varies from country to
country. The proportion of tuberculomas of the brain among
the space occupying lesions ranges from 1.4-15.9%.112,113 Its
incidence is higher in the developing countries as compared
to the developed world.111 With the availability of effective
antitubercular treatment, a correct diagnosis and early
institution of specific treatment is warranted.
Clinical features of intracranial tuberculoma are

dependent on size and site of the lesion as well as
presence of concurrent meningitis. Intracranial
tuberculomas usually present with seizures without
associated meningeal signs or evidence of tuberculosis
elsewhere in the body. Neurological symptoms
consequent to the mass effect of a tuberculoma may
occasionally precipitate symptoms of raised intracranial
tension. Depending on the location of the lesion, various
cerebellar or brain stem syndromes occur. Infratentorial
tuberculoma may present with raised ICT. In a British
tertiary care set-up, a retrospective case survey revealed
38 children with CNS tuberculosis. TB meningitis was
apparent in 23 children and 10 cases had TBM with
associated tuberculomas and five had tuberculomas
Pathogenesis
A tuberculoma is a conglomerate mass of tissue made up
of small tubercles which consist of a central core of
176
alone. In five patients with TBM, new tuberculoma

developed during treatment as a result of paradoxical
response to ATT.109
Diagnosis
The diagnosis of intracranial tuberculoma often rests on
clinical assessment, imaging findings and response to
therapy. Bacteriological diagnosis is hardly ever made
and surgical biopsy to confirm the diagnosis of TB is
risky. A high clinical index of suspicion is required for
timely diagnosis. Evidence of extra cranial TB and a close
family contact with active TB are common pointers to
the diagnosis in pediatric age group. When the signs and
symptoms of concomitant TBM are present, the diagnosis
is relatively easy. The differential diagnoses that need to
be considered are neurocysticercosis (NCC), brain
abscess, fungal infection and malignancy.
The advent of modern imaging techniques has
revolutionized the diagnosis of intracranial granulomas.
Contrast enhanced computed tomography (CECT) is
utilized as initial imaging modality. Focal parenchymal
tuberculomas measure 5-30 mm but are occasionally
larger, up to 60 mm and 15-20% present with multiple,
separate lesions although grape-like clusters of
granulomas occur.112 Tuberculomas may occur anywhere
in the parenchyma. A typical symptomatic tuberculoma
has surrounding vasogenic edema and central necrosis.
The increased interstitial space fluid of vasogenic edema
is hypodense on CT and T2 hyperintense on MRI with
no contrast enhancement. The granuloma is iso- to
hyperdense on CT and on MRI is slightly T1 hyperintense
with marked T2 hypointensity. Small granulomas, up to
10 mm, will enhance diffusely following IV contrast on
CT and on T1 post-gadolinium images. This is consistent
with the vasogenic component of the inflammatory
process and the absence of (macroscopic) necrosis.
Necrosis, usually central, is associated with loss of
enhancement and results in ring-enhancing lesions. MRI
changes are summarized in Table 12.2.13.
The imaging features of caseating granulomas or

granulomatous abscess are not specific for TB and are
not distinguishable from cysticercus granuloma or, when
large, from fungal and pyogenic lesions. In areas where
both TB and cysticercosis are prevalent (as in India), a
single ring-enhancing lesion detected on CT in a patient
investigated for a focal or generalized seizure remains a
diagnostic dilemma. The morphological characterization
of intracranial mass lesions using conventional MRI
alone, even after contrast administration may sometimes
be difficult without the histopathological examination of
the suspected tissue. Hence, other noninvasive
techniques are utilized to overcome this shortcoming and
provide more diagnostic specificity.109 Proton Magnetic
Resonance Spectroscopy (1H-MRS) is helpful in differential diagnosis of untreated intracranial space-occupying lesions (SOLs).115,116 MRS provides a detailed biochemical analysis (metabolites) of the tissue, 117,118
allowing direct insight into in vivo human brain
metabolism.118 Magnetic resonance spectroscopy of brain
tuberculomas commonly detects a peak of lipids
attributable to the large lipid fraction in the tuberculous
bacillus.119,120 The MRS reveals increased choline/creatine ratio in tuberculoma which is the result of damage
to the brain tissue and is minimal in NCC. MRS analyzing
viable cyst contents (cystic fluid) find other amino acid
peaks, including lactate, alanine, and succinate.121-125
Rajshekhar et al made an attempt to differentiate
between these two entities on the basis of clinical and
CT features of histologically confirmed tuberculoma and
NCC.126 They noted that cysticerci are usually round or
oval with smooth margins, 20 mm or less in size with
ring enhancement or visible scolex, and cerebral edema
severe enough to produce midline shift or focal
neurological deficit is not seen.126
Another technique to differentiate two common
etiologies of ring lesions, tuberculomas and cysticercal
Table 12.2.13: MRI changes in tuberculoma

Stage of tubercoloma
MRI (Magnetic Resonance Imaging)
Non- caseating granulomas
Hypointense compared to the brain tissue on T1 weighted images and are seen
hypointense on T2 weighted and fluid-attenuated inversion recovery (FLAIR)
images. They generally exhibit homogeneous nodular contrast enhancement and
a peripheral hypointensity.
Either hypointense or isointense on T1 weighted images with ring enhancement
on contrast administration.
Variable degree of perilesional edema is present. Most tuberculomas are further
outlined by a collar of high signal intensity due to edema.
Central hypointensity on T1 and hyperintensity on T2 weighted images with a
peripheral hypointense ring which represents the capsule of tuberculoma.
Caseating granulomas with solid center
Caseating granulomas with liquid center
177
Table 12.2.14: Differences between neurocysticercosis and tuberculoma

Tuberculoma
Neurocysticercosis
May present at any age

Present with progressive neurological deficit
Rare before the age of 3 years

Generally no neurological deficit may have postictal
focal deficits of varying severity, and all deficits
resolve within a matter of days to weeks
Usually smaller, regular rounded outline with less
cerebral edema
Usually supratentorial
Midline shift usually not seen
No lipid peak
T2 relaxation time is longer
On size > 20 mm, irregular outline with marked

cerebral edema
May be supratentorial or infratentorial
Likely to cause midline shift
MRS has lipid peak
Relaxation time on T2 relaxometry images to be
shorter than NCC (above)
cysts, is to use T2 relaxometry. It is a simple, reliable and

valuable non-invasive magnetic resonance imaging
(MRI) technique to differentiate between intracranial
cysticercal cysts and tuberculomas, and may be
incorporated in routine diagnostic protocols. The mean
T2 relaxation times of cysticercal cysts is 617 ms (range
305-1365 ms; SD 272.2) and that of tuberculomas is 161
ms (range 83-290 ms; SD 60.3; 95% confidence). 127
Differences between NCC and tuberculoma are
summarized in Table 12.2.14.
Dynamic contrast-enhanced (DCE) MRI is a technique
that derives perfusion indices with immunohistochemically obtained vascular endothelial growth
factor (VEGF) and matrix metalloproteinase-9 (MMP-9)
in a cellular fraction of brain tuberculomas. Perfusion
indices include (cerebral blood volume [CBV], transfer
coefficient and leakage) and thereby maps are generated
for the quantitative analysis. Using this technique, it is
possible to assess therapeutic response to ATT by
evaluating the changes in k(trans) and edema volume
even when there is a paradoxical increase in the lesion
volume.124
Stereotactic biopsy is the last resort if diagnosis is
uncertain. Previously published series have shown the
efficacy of stereotactic biopsies using smear techniques
for pathology to be 28%. 128 In the rest, a chronic
inflammation with gliosis was the histopathological
picture which was inconclusive. Invasive diagnostic
procedures are reserved for few atypical cases and
sometimes required for aspiration of TB abscess.129
Treatment
The treatment protocol for intracranial tuberculomas
includes antitubercular treatment as described in section
with TBM. It is essential that in addition to antitubercular
treatment, adequate measures should be instituted for
symptomatic management of raised intracranial tension
and seizures. Steroids should also be instituted to take
care of cerebral edema. A repeat scan should be done to

look for changes in radiological picture.
The majority of tuberculomas respond to
antituberculosis drugs, showing a radiological response
in 6 to 8 weeks. Paradoxical increase in tuberculomas,
although uncommon, can occasionally occur and requires
continued ATT and may at times need surgical decompression. Surgical decompression or excision is rarely
required in large masses which cause significant
increased intracranial pressure or impending loss of
vision. A CSF diversion procedure may be performed in
cases of obstructive hydrocephalus caused by
tuberculomas.
Outcome
Tuberculomas usually resolve over 3-6 months on TB
treatment, however, larger lesions may take considerably
longer. Occasionally paradoxical appearance of
granulomas and increase in size of granulomas may occur
in patients on anti-TB therapy. Occasionally calcification
is noted and rarely a tuberculoma will resolve to a small
calcified focus.
SPINAL TUBERCULOSIS IN CHILDREN

Tuberculosis of the vertebral column (Potts spine)
Introduction
Spinal TB can involve the bones of vertebral column (Potts
disease), the cord (myelitis, abscess, or granuloma), and
its dura (arachnoiditis or extradural abscess). Potts disease
is the most common form of skeletal involvement by
tuberculosis (about half the cases of skeletal
tuberculosis).130 It is estimated that spinal involvement
occurs in less than 1% of patients with TB, but it still remains
a leading cause of paraplegia in developing nations.130-132
The other forms of spinal involvement like intramedullary
tuberculomas, epidural abscess and spinal arachnoiditis are
rare in pediatric age group.
178
Clinical Features
Presentation depends upon the stage of the disease, site
of the disease (bone or spinal cord), and presence of
complications. Constitutional symptoms such as
weakness, loss of appetite and weight, evening rise of
temperature and night sweats generally occur before the
symptoms related to the spine manifest. There may be
evidences of associated extraskeletal tuberculosis like
cough, expectoration, lymphadenopathy, diarrhea, and
abdominal distension. Back pain (spinal or radicular) is
the earliest and most common symptom. This pain may
worsen with activity. Relaxation of muscles during sleep
permits movements which are very painful and wakeup the patient. As the infection progresses, pain increases,
and paraspinal muscle spasm occurs. Muscle spasm
obliterates the normal spinal curves, and all spinal
movements become restricted and painful.
Physical examination of the spine reveals localized
tenderness and paravertebral muscle spasm. A kyphotic
deformity due to prominence of spinous process may be
evident due to collapse and anterior wedging of vertebral
bodies. Tuberculous necrotic material from the
dorsolumbar spine may lead to cold abscess in the rectus
sheath and lower abdominal wall along the intercostal,
ilioinguinal, and iliohypogastric nerves; in the thigh
along the psoas sheath; in the back along the posterior
spinal nerves; in the buttock along the superior gluteal
nerve; in the Petits triangle along the flat muscles of
abdominal wall, or, in the ischiorectal fossa along the
internal pudendal nerve. Upper cervical spine
involvement though less common, can cause dangerous
and rapidly progressive symptoms. In the case of
retropharyngeal abscesses, the abscess may track down
the mediastinum to enter trachea, esophagus, or pleura;
may spread to sternomastoid muscle. Segmental signs
depending on the level of lesion and upper motor neuron
signs may be present on examination giving a clue to
underlying compressive myelopathy.
Imaging Modalities for Diagnosis of Spinal Tuberculosis

Plain radiographs
Plain radiographs are the first line of investigations in our
country. Earliest radiological features are narrowing of the
joint space and indistinct paradiscal margin of vertebral
bodies. Gradually, the disk space narrows due to either
atrophy or prolapse into the vertebral body of the disc
tissue. The collection of tubercular granulation tissue and
necrotic material leads to formation of paravertebral
abscess. In the region of thoracic spine it is visible on plain
radiographs as a fusiform or globular radiodense shadow
called the bird nest appearance. Long standing abscesses
may produce concave erosions around the anterior
margins of the vertebral bodies producing a scalloped
appearance called the aneurysmal phenomenon. Wedging

of vertebral bodies leads to a kyphotic deformity. Less
common radiological presentations of spinal tuberculosis
are central type, anterior type, and appendiceal type.
Central disease presents as destruction, ballooning of
vertebral bodies, and concentric collapse. Anterior type is
more common in the pediatric dorsal spine and appears
as erosion of anterior margin of vertebral bodies. CT scan
and MRI are increasingly being used to diagnose various
types of bony and soft tissue involvement and presence
of associated abscess and granulation tissue.
CT scanning and MRI

For a radiolucent lesion to be seen on a plain radiograph,
30% of mineral loss must be there. CT and MRI detect
lesions at an earlier stage. CT scanning provides much
better bony detail of irregular lytic lesions, sclerosis, disc
collapse, and disruption of bone circumference. Lowcontrast resolution provides a better soft tissue
assessment, particularly in epidural and paraspinal areas.
CT is more effective for defining the shape and
calcification of soft tissue abscesses. CT is useful in
assessing bone destruction, but is less accurate in defining
the epidural extension of the disease. MRI is the gold
standard for evaluating disc space infection and
osteomyelitis of the spine, and is most effective for
demonstrating the extension of disease into soft tissues
and the spread of tuberculous debris under the anterior
and posterior longitudinal ligaments. MRI is most
effective for demonstrating neural compression. MRI
with contrast is helpful in differentiating TB from
noninfectious causes and delineating the extent of
disease. Serial MRI can be used to assess the response to
treatment and regression of the disease. MRI is the
imaging modality of choice for spinal arachnoiditis,
intramedullary tuberculoma and epidural abscesses.
Bone scan with Tc-99m

Bone scan with Tc-99m is considered to be highly
sensitive, but nonspecific. It may only aid to localize the
site of active disease and to detect multilevel
involvement. Patients with active disease have an
increased uptake. Bone scan however is not diagnostic
of tubercular involvement because it shows increased
uptake in any inflammatory process.
Intramedullary Tuberculoma
Intramedullary tuberculomas may present like any other
intraspinal mass with segmental signs and paraparesis distal
to the lesions. Intramedullary spinal tuberculomas are
extremely rare lesions, even in areas where TB is endemic.133
Reviewing 74 cases of TB paraplegia without bony
involvement, Dastur134 found intramedullary lesions in 8%
of the patients. MacDonnell et al135 reviewed the literature
and found a total of 43 cases (mean age, 28 years) reported
between 1960 and 1990. The lesions most commonly
occurred in the thoracic cord.135 These patients mostly
present with progressive weakness, paresthesias, and loss
of bladder and bowel control.136
MRI is the imaging modality of choice for spinal
involvement and can localize the tuberculoma in the
extradural, intradural extramedullary, and intramedullary
compartments.137 The lesions have hypo- to low intensity
on T1-weighted images, low intensity with or without
central hyperintensity (depending on the amount of
caseous necrosis) on T2-weighted images, and ring
enhancement with a hypointense center on post-contrast
images.
TB Extradural/Epidural Abscess
Spinal epidural abscess is seen mostly in patients over
30 years of age and are rare in children. MRI demonstrates
a sensitivity of 91% for the diagnosis of spinal epidural
abscess,138 thus, being the investigation of choice.139
Epidural TB lesions are usually iso-intense to the spinal
cord on T1 weighted images. Mixed signal intensity is
seen on T2 weighted images, with peripheral
enhancement post-gadolinium in TB epidural abscess.140
Spinal Tuberculous Arachnoiditis

Spinal tuberculous arachnoiditis is a rare complication
of CNS tuberculosis. It is an inflammatory condition that
involves the arachnoid lining along the spinal tract. This
condition was previously termed adhesive spinal
arachnoiditis or chronic adhesive arachnoiditis. This
clinical entity is uncommon in developed countries, but
is still commonly reported in South-East Asia, the Indian
subcontinent, South America and Africa. Three different
pathogeneses are suggested for the occurrence of spinal
tuberculous arachnoiditis, i.e. a tuberculous lesion
primarily arising in the spinal meninges, downward
extension of intracranial tuberculous meningitis; and
extension of tuberculous spondylitis. Among these,
involvement of the spinal arachnoid lining secondary to
intracranial tuberculous meningitis is the most common
pathogenesis. The thoracic region is the most frequently
affected site, followed by the lumbar and cervical regions.
Macroscopically, exudate can be seen surrounding the
spinal cord and nerve roots. Microscopically,
granulomatous inflammation, areas of caseation,
tubercles, and fibrous tissue are noted. In chronic cases,
the subarachnoid space may be irregularly obstructed,
with the formation of pockets of CSF. Spinal cord
parenchymal changes include border-zone rarefaction
and vacuolization of the cord, extensive atrophy and
179
circumscribed central necrosis, severe gliosis and

intramedullary tuberculoma, resulting in multicystic
myelomalacia and syringomyelia.
Complications of Spinal Tuberculosis

Due to the destruction of the anterior part of vertebral
body, the cartilage plates that are responsible for the
growth are destroyed. The growth of the vertebral
column in the child is thereby stopped and leads to major
growth discrepancy and progressive spinal deformity.
The posterior part of the vertebral bodies is usually
unaffected and continues to grow. With the passage of
time this can produce a significant kyphotic deformity.
The degree of damage to the anterior vertebra determines
the extent of growth alteration. Moreover, younger the
child, greater is the final growth discrepancy. This can
lead to serious neurological complications.
The neurological problems can arise due to physical
compression of the neural tissues like spinal cord and
nerves, inflammation of these structures and their
coverings by the disease (meningitis/arachnoiditis/neuritis),
edema and vascular thrombosis. The functional deficit can
be as insignificant as tingling numbness and mild
weakness (paraparesis, quadriparesis) or as catastrophic as
complete loss of sensations, power and bladder-bowel
(paraplegia, quadriplegia) control.
Treatment for Spinal Tuberculosis

In addition to institution of antitubercular treatment
(with steroids) surgery may be required if features of
spinal cord compression are present. Usual indications
for surgical decompression are:
Neurological complications that worsen after a fair
trial of conservative therapy (ATT + spinal
immobilization) for 3-4 weeks
Patients with Potts spine in whom neurological deficits
develop during conservative treatment
Recurrence of neurological complications
Prevertebral cervical abscesses, neurological signs,
and difficulty in deglutition and respiration
Advanced cases of neurological involvement such as
marked sensory or sphincter disturbances or flaccid
paralysis.
Prognosis
Prognosis depends on many factors. The site and stage of
disease are important variables that affect the ultimate
outcome. Severe malnutrition, delay in starting ATT,
degree of compression and neurological deficit also
determines the prognosis. Prognosis is poor if cord
involvement is complete, if there is longer duration of
neural complications, late onset cord involvement, neural
complications that developed rapidly.
180
HIGHLIGHTS
The incidence of CNS tuberculosis is directly
proportional to the prevalence of tuberculous
infection in general.
Neurotuberculosis is represented by different and
possibly concomitant forms:
Intracranial TBM, TBM with miliary tuberculosis
Space occupying lesions (Tuberculoma, multiple
small tuberculomas with miliary tuberculosis,
tuberculous abscess)
Tuberculous encephalopathy, tuberculous
vasculopathy.
SpinalPotts spine and Potts paraplegia,
tuberculous arachnoiditis (myeloradiculopathy)
nonosseous spinal tuberculoma, spinal meningitis.
The most frequent are tuberculous meningitis
(TBM) and tuberculoma.
In great majority of patients with neurotuberculosis,
the diagnosis is based on characteristic clinical,
cerebrospinal (CSF) and imaging findings.
Because of partial immunity achieved by BCG, there
are a large number of localized lesions in different
parts of brain and/or meninges with protean clinical
manifestations depending upon the site of the
lesions (see for details Chapter 12.3 of case studies).
There is increased incidence of tuberculosis with
HIV. Of concern is the reported development of new
clinico-radiological findings of TBM despite therapy
and the emergence of drug resistant strains in HIV

positive patients.
On analyzing our data, there was no difference in
the clinical spectrum of neurotuberculosis when
analyzed year-wise from 1991 to 2004 (p = 0.82)
though the severity of the disease was lesser in later
years.
Various immunoassays are available such as
hemagglutination, enzyme linked immunosorbant
assay (ELISA), immunofluorescent assay (IFA),
radioimmunoassay (RIA), immunoblot assays and
T cell-based gamma interferon release assay. The
variations in sensitivity and specificity of many
immunoassays have resulted in lack of faith among
clinicians in the use of immunodiagnostics of
neurotuberculosis.
Differentiating cysticercus granuloma from
tuberculoma is of paramount importance, both of
which are common in our country and have different
treatment.
Early diagnosis and prompt treatment with all
regimens is recommended.
Clinical response with antituberculosis therapy in
all forms of neurotuberculosis is excellent if the
diagnosis is made early before irreversible
neurological deficit is established. As the emergence
of neurological deficit has been seen in some of these
studies, a minimum of 9-12 months of treatment
would be worth while.
12.3 CASE STUDIES

PM Udani, S Gulati, Rachna Seth, V Kalra, Vimlesh Seth
PROFILE OF TBM IN CHILDREN MODIFIED BY BCG

DR PM UDANIS EXPERIENCE
Case 1
Advanced TBM with hydrocephalus, multiple cranial
nerve palsies, hemiplegia on right side and
hemiballismus on the left but the child had complete
recovery on treatment
A one-year-old boy, had history of fever for a period
of one month. The child had convulsions after 22 days
which became more severe by the next day. The initial
CSF showed turbid fluid with 950 mg/dl of protein, 140
cells with 80% polymorphs. This child was given BCG at
5 months of age and had BCG adenopathy. However,
the initial tuberculin test was negative. A repeat CSF
examination showed findings suggestive of suspicious

pyogenic meningitis. He was treated as a case of probably
mixed meningitis of both pyogenic and tubercular
etiology. A second tuberculin test done after two months
of treatment was strongly positive. He was rehospitalized
three months after tuberculin test and had well marked
meningeal signs, evidence of increased intracranial
pressure, right sided hemiplegia, hemiballismus on left
side, multiple cranial nerve palsies, strongly positive
tuberculin and BCG tests. A lymph node biopsy revealed
tubercular lymphadenitis. The first CT scan (not shown
here) done after three months showed massive
hydrocephalus and evidence of basal exudates along the
vessels. An urgent shunt operation was done. Second CT
scan was done after shunt operation (Fig. 12.3.1A) which
181
Figs 12.3.1A and B: Advanced TBM with hydrocephalus, multiple cranial nerve palsies,
hemiplegia on right side and hemiballismus on the left but the child had complete recovery on treatment
shows that the hydrocephalus had become smaller. Child

also had exudate in the posterior fossa. He improved with
chemotherapy, steroids and ventriculoperitoneal shunt
(V-P shunt) and was completely normal clinically and
developmentally when seen at the age of two years. A
third CT scan (Fig. 12.3.1B) done at the age of two years
showed the basal exudates present around the vessels
as well as in the posterior fossa. There was a dense
shadow in the sylvian fissure which was probably due
to thick exudate around the middle cerebral artery. A
follow-up fourth CT scan (Fig. 12.3.1C) done at the age
of three years revealed the ventricular system to be
normal and exudate completely disappeared.
Comments
This case had many interesting points. (i) Initially it could
not be made out whether the child had mixed meningitis
(both pyogenic and tuberculous types) or TBM with
multiple complications. He made complete recovery
clinically as well as CT imagingwise. (ii) The basal
exudate along the vessels as seen in CT scan after shunt
operation (Fig. 12.3.1A) appeared to be denser in the third
CT, 8 months after treatment, showing that often the
exudate persists for a long time. With this dense exudate
child also had moderate hydrocephalus. However, the
fourth CT done at the age of three years (Fig. 12.3.1B),
showed complete disappearance of exudate and
ventricles became normal in size. This is an example of a
child who had advanced TBM with complications, but
recovered completely with therapy with four bactericidal
drugs and steroids.
Case 2
CT scan showing localized basal TBM with
hydrocephalus in a BCG-vaccinated child (conscious
type of TBM)
Child aged three years was brought with a history of
fever, vomiting off and on for three months. Child had
no convulsions or any disturbance in sensorium. He was

conscious and alert but had well marked meningeal signs
with cracked pot sound, hyperreflexia in both lower
limbs and extensor plantar response. However, he could
not sit up, walk or talk (Fig. 12.3.2A). BCG had been given
but scar was faint. CSF showed increased proteins, 182
mg/dl, glucose 31 mg/dl, chlorides 626 mg/dl and 96
cells/cubic ml with 90% lymphocytes. Chest X-ray
showed intrathoracic lymph node enlargement. The first
CT scan (Fig. 12.3.2B) showed dense basal exudate and
moderate hydrocephalus. Child was treated with
antituberculosis drugs and steroids. He improved
remarkably in two weeks and could walk and talk, and
looked almost normal. However, he still had well marked
meningeal signs. A second CT scan (Fig. 12.3.2C) done
after two weeks showed dense basal exudate but
hydrocephalus had improved. Hence surgery was not
necessary. Child was seen again after one week and CT
scan (not shown here) showed remarkable reduction in
the size of the ventricles. The ventricles appeared only
slightly dilated. Basal exudate was still present, but less.
There was also minimal vascularity (fine exudate in
between the cortical gyri).
Comments
This case is a modified clinical picture of TBM in a
vaccinated child.
Case 3
CT scan of a child who had TBM with localized basal
meningitis, hydrocephalus and blindness
This female child of 18 months was first seen with
irregular fever for 16 days, vomiting and failure to talk.
She also had uprolling of eyeballs and mild weakness of
the right side of the body. Examination revealed a fairly
built and nourished child with a weight of 9 kg, a head
circumference of 46 cm and chest circumference of 41
cm. Macewans sign was positive. She had well marked
182
Figs 12.3.2 A to C: (A) Conscious child with TBM, (B) CT head showing dense basal exudates,
(C) CT head showing basal exudates with improvement in hydrocephalus
Figs 12.3.3A to C: (A) CT scan head showing basal exudates extending into sylvian fissure. (B) CT scan head after VP shunt, no improvement
in hydrocephalus. (C) CT scan head showing increasing hydrocephalus with infarction in right parietooccipital region
meningeal signs, dilated and fixed pupils, dazed look and

could not sit up by herself. BCG had been given two
months ago and there was a scab at the site. She was
diagnosed as a case of TBM with hydrocephalus,
blindness and left sided weakness. CSF examination
showed proteins 160 mg/dl, gulcose 20 mg/dl, chlorides
520 mg/dl and 20 cells/mm, 3 predominantly
lymphocytes. A first CT scan (Fig. 12.3.3A) done on three
days after admission showed basal exudates extending
into the sylvian fissure. She was kept on four bactericidal
drugs and massive doses of dexamethasone and mannitol
for 7 days and then a V-P shunt was placed. Within 10
days of treatment the child improved and could sit up,
stand with support, play with objects and identify familiar
voices but was still completely blind. As the child still
had evidence of increased intracranial pressure, a second
CT scan (Figs 12.3.3B) was done after three weeks. It
revealed that the extent of hydrocephalus remained
almost the same and also the basal exudate. Within a

week of the second CT scan child started getting high
irregular fever. Urinary infection was detected and
treated but improvement was not satisfactory. She also
developed peritoneal infection as evidenced by severe
abdominal distention and tenderness at the site of V-P
shunt. The childs condition became worse, she became
dull and developed hemiparesis on the left side. A third
CT scan (Fig. 12.3.3C) done after another three week
showed a slight increase in hydrocephalus with a
massive infarct in the right parieto-occipital region. She
suddenly died after one week probably due to coning
of the medulla.
Comments
This child developed TBM with hydrocephalus and
blindness, probably because the child already had
183
Figs 12.3.4A to C: CT scan in a child with serous TBM, hemiplegia and infarction in the internal capsule
infection when BCG was given. Hence protection was

either absent or limited. Initially, child improved remarkably except for the blindness, but in spite of V-P shunt
the changes in the CT scan did not regress significantly
and the third CT scan revealed worsening, with increase
of hydrocephalus and development of massive infarct. It
is possible that the urinary infection, and localized
peritonitis at the abdominal site of the shunt also led to
the worsening of TBM. This was attributable to
Shwartzmans phenomenon in which nontuberculous
bacterial infection leads to worsening of the local tuberculous lesion, viz. the brain in this child. It is also possible
that the large hypodense area is a result of progressive
vasculitis in spite of treatment. However, Shwartz mans
phenomenon may also explain the progress of the lesion.
Case 4
CT scan in a child with serous TBM, hemiplegia and
infarction in the internal capsule
A three year male child, had a strongly positive
tuberculin test, history of contact with an adult case of
tuberculosis, and had mediastinal lymph node
tuberculosis. He was vaccinated at three months of age.
Because of the strongly positive tuberculin test and
intrathoracic tuberculosis, he was given two drugs
isoniazid and rifampicin. He had a fall from the bed
following which he developed hemiplegia on the left side
within a few hours. When seen after three weeks he had
meningeal signs and spastic hemiplegia on the left side
with greater involvement of lower limb, normal CSF
cytology and biochemistry. First CT scan (Fig. 12.3.4A)
of head showed hypodense area due to infarction in the
right internal capsule. Child improved over a period of
three weeks and recovered with mild weakness of the
left foot. A second CT Scan (Fig. 12.3.4B) done after three
weeks revealed that the hypodense area was smaller and
better defined because of reduction of edema around the
infarct in the internal capsule. With antituberculosis
drugs and steroids he maintained his improvement and
a third CT scan (Fig. 12.3.4C) after 15 weeks revealed a
very well defined and smaller area of infarction. The CT
scan shows basal exudate almost uniformly dense not

tapering like cerebral arteries. The exudate is around the
middle cerebral arteries.
Comments
This is an unusual clinical picture with posttraumatic
serous TBM and hemiplegia due to infarction in the
internal capsule. The EEG showed abnormal spike and
slow wave discharges on both sides.
Case 5
CT scan of a child with chronic tuberculous
encephalopathy (modified clinical and CT scan pictures
due to BCG) aggravated later with sudden withdrawal
of steroid therapy
A 1 years old girl, was admitted with history of fever
off and on, vomiting and difficulty in sitting and standing
up for two months duration. There was no history of
convulsions. Child was healthy at birth and milestones
in infancy were normal. She was given BCG at three
months of age and a good scar was seen. There was
suspicious contact with a case of tuberculosis. Initially
the child developed intrathoracic tuberculosis with a
segmental lesion in the right upper zone and enlarged
paratracheal nodes. CSF examination revealed increased
proteins, mildly diminished sugar and pleocytosis
predominantly lymphocytic. When seen five months later
the child had well marked meningeal signs with neck
retraction, positive Macewans sign, mild spastic
quadriparesis, mild involvement of upper limbs but
severe spastic paralysis of lower limbs. The child was
mentally alert, conscious and could talk. Tuberculin test
was strongly positive. Skull X-ray showed separation of
sutures. The child had received treatment for five months
with only two drugs, isoniazid and ethambutol. A
diagnosis of localized TBM, conscious type with spastic
quadriparesis was made. CT scan (Fig. 12.3.5) diagnosis
of leucodystrophy was made. However, clinical and
radiological data and CSF report supported the diagnosis
of localized basal meningitis with quadriparesis and the
184

the diagnosis. In the absence of evidence of clinical,
biochemical and pathological data, other diagnoses
considered were Canavans and Alexanders disease.
Case 6
Fig. 12.3.5: Head CT scan of 1 year old child, showing hypodensity

of white matter mimicking leukodystrophy. Brain biopsy in this child
showed characteristic findings of tubercular encephalopathy
child was put on four antituberculosis drugs and steroids.

The child improved remarkably and in about four weeks
time she could sit with support, eat biscuits without help
and speak 5 to 6 words. The child was discharged but
unfortunately only antituberculosis chemotherapy was
given and parenteral steroids were discontinued. As a
result the child relapsed after two weeks and had well
marked neck retraction, decerebrate fits and complete
blindness. Fundi showed optic atrophy. Second CT scan
done after one month had small ventricles. A brain biopsy
revealed characteristic pathological findings of
tuberculous encephalopathy. This child failed to improve
with three weeks treatment and was discharged on
request.
Comments
A female child of 1 years was given BCG at three months.
The child had intrathoracic tuberculosis with enlarged
nodes for which the child was treated for a period of five
months with two antituberculosis drugsisoniazid and
ethambutol. The child developed meningitis and spastic
quadriparesis, with greater involvement of lower limbs. The
clinical picture was modified because of BCG vaccination.
CT scan of brain changes showing bulky white matter was
suggestive of tuberculous encephalopathy. The diagnosis
was confirmed by pathological findings of myelin loss and
minimal inflammatory reaction by way of perivascular
cuffing of cells (because of massive steroid therapy). This
child improved with treatment and relapse occurred
because of sudden withdrawal of steroid therapy. Probably
steroid therapy helped to reverse the immunological
damage to the brain, and during second admission
increased white matter bulkiness seen in CT scan did not
respond to edema-reducing drugs. Such a clinical and CT
scan picture appeared to be due to an unusual progressive
immune reaction of the white matter. Had the child not
had evidence of intrathoracic tuberculosis, TBM and initial
improvement with steroids and chemotherapy, the
diagnosis would have been difficult. Moreover,
characteristic findings in brain biopsy helped to confirm
Tuberculous encephalopathy in a BCG- vaccinated

child
A boy of 11 years was referred with a history of fever for
two months, headache, vomiting and right hemiparesis.
Child was vaccinated in the first three months of life.
When seen by a pediatric colleague he had miliary
tuberculosis and TBM of conscious type. A chest X-ray
showed characteristic picture of miliary tuberculosis and
enlarged hilar and paratracheal nodes. CSF showed
increased proteins, cells and reduced sugar and chlorides.
When seen by us he was fairly built and nourished,
conscious, alert with well marked meningeal signs and
spastic hemiparesis on the right. Child was given four
drugsstreptomycin, isoniazid, rifampicin and
pyrazinamide. He was transferred to Bombay Hospital
and three oral bactericidal drugs were continued
alongwith dexamethasone injections. He improved
remarkably and within a period of three weeks, the chest
X-ray was almost clear. Figure 12.3.6A shows the child
with remarkable improvement, barring slight internal
squint, right facial weakness and ptosis of the right eyelid.
Till two months after admission to hospital the child
appeared to be almost normal and was conscious, alert,
smiling, standing and walking. CT scan done on
admission to hospital (not shown here) showed a well
marked hydrocephalus for which a shunt operation was
done. As he developed hepatotoxicity to rifampicin it was
stopped and replaced with ethambutol. A repeat CT scan
done (Fig. 12.3.6B) showed no hydrocephalus but a cyst,
probably a lacunar infarct in the middle temporal region,
with a hyperdense area in the right frontoparietal region
due to localized surface meningitis (Fig. 12.3.6C). MRI
done showed mild hydrocephalus and the cystic lesion.
After 2 to 3 weeks of apparent improvement he started
showing mental and neurological deterioration. He
stopped smiling, talking, was dazed and started passing
urine in bed. It was realized that the child was
progressing to edematous encephalopathy probably
because of aggressive microangiopathy. A CT scan done
(Fig. 12.3.6D) showed a large cyst in the region of
thalamus and multiple lacunar infarcts; MRI confirmed
the three cysts. Even though the child had miliary
tuberculosis initially and classical TBM with
characteristic CSF and CT scan showing hydrocephalus,
because of the cystic lesions, albendazole was given
empirically for neurocysticercosis. Antituberculosis
chemotherapy was continued with increase in the dose
of steroids. His hemiparesis improved, but his condition
again deteriorated. A digital subtraction angiography
(DSA) was done. There was no significant abnormality
185
Figs 12.3.6A to D: (A) Child with TBM having right facial weakness and ptosis of right eyelid.(B) Head CT scan of child, showing lacunar infarct
in middle temporal region with hyperdense area in right frontoparietal region due to localized meningitis. (D) Head CT scan after 1 years
showing large cyst in region of thalamus and multiple lacunar infarct
in the large cerebral vessels and their branches. The

patient died after a few days. Autopsy could not be done.
Comments
This 11-year-old vaccinated child with a history of contact
of tuberculosis developed miliary tuberculosis, TBM with
hydrocephalus, multiple cranial nerve palsies which
improved remarkably with the administration of four
antituberculosis bactericidal drugs and large dose of
steroids within 3 to 4 weeks and became almost normal.
However, 2 to 3 weeks later he showed mental and neurological regression and died of edematous encephalopathy
probably due to aggressive massive microangiopathy
(microvasculitis). Usually BCG vaccine helps to localize
the disease and prevents diffuse damage to the brain. It
appears that in some of these BCG vaccinated children
particularly the older ones, there is a hyperimmune

response of the T lymphocytes which strip the myelin
and continue to produce arteriolar and venous damage
with progressive edema. This is a dangerous but
fortunately rare complication in a vaccinated child as
acute and fulminating cases are likely to die.
PROFILE OF TBM: AIIMS EXPERIENCE

None of the children had received BCG.
Case 7
Tubercular meningitis with suspected secondary
resistance
A six-years-old boy presented to AIIMS with fever and
frontal headache for three months along with inability
186
to move the right side of the body for two months and
right focal seizures. At admission he was irritable and
had slurred speech, choreoathetoid movements, right
hemiparesis and right upper motor neuron facial palsy.
CSF examination revealed 450 cells/mm3 (240 lymphocytes, 110 polymorphs), sugar CSF/ blood: 46/114 mg/
dl and proteins 162 mg/dl. Mantoux test was 15 mm and
CT scan of head showed enhancing basal exudates with
mild dilatation of lateral, third and fourth ventricles. He
also had central diabetes insipi-dus. He was started on
four drug antituber-culosis treatment (INH, rifampicin,
ethambutol and pyrazina mide), dexamethasone,
mannitol, acetazola mide, glycerol, phenytoin and
chlorpromazine. Pyrazinamide was stopped after two
months and rest of antituberculosis drugs (ATT) were
stopped by parents on their own after 11 months. The
child had improved with ATT but four months after
discontinuing ATT, he developed fever, vomitings,
altered sensorium, seizures and aphasia. He was
readmitted and on examination had meningeal signs,
right hemiparesis, right facial nerve palsy upper motor
neuron type with flexion deformity of right wrist, elbow
and foot along with optic atrophy of the right eye.
Investigations revealed CSF 200 cells/mm 3 (90%
lymphocytes) sugar CSF/blood 120/171 mg/dl, proteins
333 mg/dl, CT Scan head-basal exudates with right
parietal granuloma, moderate hydrocephalus with
periventricular ooze. Besides supportive care, ATT (INH,
rifampicin, ethambutol, pyrazinamide, ofloxacin and
amikacin) was started. He developed dystonia of right
upper limb and lower limb. Amikacin and pyrazinamide
were stopped after two months and the rest continued
for one and half years. At present the child is afebrile,
has right hemiparesis and dystonia (Figs 12.3.7A and B)
which are improving and he is on trihexyphenidyl and
carbamazepine. His CT scan (Fig. 12.3.7C) shows a
lacunar infarct in the right caudate head with
postischemic sequelae (L) basal ganglia and adjacent
temporoparietal cortex.
Case 8
Child with tuberculoma in midbrain
A six-year-old boy presented to AIIMS with history
of intermittent fever for four months with ataxia and
other cerebellar signs for 3 months. He was given
steroids by a private practitioner following which he
developed improvement in cerebellar signs. He
developed abnormal behavior for two weeks prior to
admission. At admission, examination findings
revealed bilateral sixth nerve palsy, scanning speech
and other cerebellar signs, brisk reflexes with ill
sustained ankle clonus. Investigations revealed high
Figs 12.3.7A and B: Child with TBM with right hemiparesis and
dystonia on follow-up
Fig. 12.3.7C: CT head of a child with TBM showing lacunar infarct in

the right caudate with postischemic sequelae (L) basal ganglia and
adjacent temporoparietal cortex
CSF proteins (175 mg/dl) with mononuclear cells,

Mantoux test 20 mm, fundus examination showedblurring of superior margins of optic nerve bilaterally.
MRI showed inflammatory granuloma of upper pons
and lower midbrain on right side causing indentation
upon aqueduct with mild prominence of supratentorial ventricular system consistent with tuberculoma (Fig. 12.3.8A). He was started on ATT (INH,
rifampicin, ethambutol, pyrazinamide), prednisolone,
acetazolamide and glycerol. He became afebrile and
cerebellar signs showed marked improvement.
Steroids were stopped after six weeks, ethambutol
187
Fig. 12.3.8A: T1 weighted MR images of brain showing tuberculoma

of upper pons and lower midbrain
Fig. 12.3.8B: T1 weighted MRI brain images after six months of ATT
showing resolution of tuberculoma
stopped after three months, pyrazinamide after four

months. He improved steadily and repeat MRI after
six months of ATT showed small discoid
enhancement on administration of contrast with no
dilatation of ventricles (Fig. 12.3.8B). After completing
12 months of INH and rifampicin, CT head revealed
hyperdense lesion right midbrain (Figs 12.3.8C and
D). INH and rifampicin given for total 21 months. At
present he is better and has some cerebellar signs
persisting. Follow-up CT head is totally normal but
follow-up MRI is showing gliosis in cerebellum
explaining his symptoms.
Case 9
Child with tuberculoma differentiated from
neurocysticerosis by magnetic resonance spectroscopy
(MRS)
A five-year-old female child with normal
development presented with sudden onset of multiple
Figs 12.3.8C and D: Head CT scan after 12 months of ATT showing

hyperdense lesion right midbrain
episodes of right sided complex partial seizures. There

was associated headache but no history of fever,
vomiting, weight loss, altered sensorium or visual
complaints. History of contact with tuberculosis was
positive.
On examination, the child was well built with stable
vitals. The systemic and neurological examination was
within normal limits. Chest X-ray was normal and
Mantoux test was not reactive. Serology (IgG) for
neurocysticercosis (NCC) was positive. CT scan revealed
presence of three ring enhancing lesions (9.6-13 mm in
size) with enhancing eccentric foci in left frontal and both
parietal regions with mild to moderate perilesional
edema. There was no evidence of midline shift. The CT
diagnosis was multiple inflammatory granulomas more
likely to be neurocysticercosis There was no evidence of
papilledema/intraocular cysticercosis on ophthalmological examination. The child was given conventional
188
Figs 12.3.9A and B: The arrow denotes the lipid peak identified in the spectrum obtained during MRS suggestive of
tubercular etiology of the lesion. Similar lipid peaks were seen in all the lesions
antiepileptics and first course of cysticidals (albendazole

for 28 days and steroids for 2 months).
On follow-up, there was no clinical improvement and
the child continued to have multiple seizures per day
despite increasing the dose of antiepileptic drug therapy
(AED) and trial with second line AEDs. The child
developed right lower limb paresis and papilledema
while on cysticidal therapy and steroids.
A repeat CT done weeks after the first cysticidal
course showed persistence of the three ring enhancing
lesions as in previous CT with increased perilesional
edema around the right parietal and left frontal lobe
lesion as compared to previous CT.
A repeat course of cysticidal was given with
praziquantel and steroids three months after the first
course of cysticidal drugs. Seizures persisted even after
the second course of cysticidal drugs. A repeat CT
showed no radiologic improvement with persistence of
perilesional edema. Magnetic resonance spectroscopy
(MRS), a noninvasive procedure utilizing the principle
of magnetic resonance, was planned. Proton MRS
spectroscopy using 1.5 Tesla, Sonata, Siemens was
performed which identified a lipid peak in all the lesions
(Figs 12.3.9A and B); thus, the diagnosis of tuberculoma
was considered.
The patient was subsequently started on four-drug
antituberculosis drug therapy (ATT) comprising of
isoniazid, rifampicin, pyrazinamide and ethambutol with
steroids (2 hrze 10 hr) in the first eight weeks (full dose
and tapered over two weeks). The child has been on ATT
for the past six months and is showing clinical
improvement. The child is seizure free for the past five
months. The headache, monoparesis and papilledema
have also resolved. CT done six months after starting
ATT showed the left parietal lesion calcification. A disc
enhancing lesion is seen in the left frontal region. The
lesion in right parietal region shows gliosis with
reduction of perilesional edema. Perilesional edema
around the left sided lesions (frontal and parietal) had
resolved.
This shows that misdiagnosis of inflammatory
granulomas can occur using conventional methods of
investigation. MRS could be a useful diagnostic aid to

differentiate the two most common forms of
inflammatory granulomas (neurocysticercosis and
tuberculoma). There is absence of lipid peak in NCC.
Discussion
The diagnostic dilemma of inflammatory granulomas is
highlighted from the case history discussed. Common
causes of inflammatory granuloma include NCC
(common) followed by tuberculosis, toxoplasmosis,
cerebral abscess and fungal lesions. This child presented
with seizures, showed a positive serological response
towards NCC and CT findings were compatible with
NCC (< 20 mm, regular outline with no midline shift).
Yet the child was suffering from tuberculous
granulomatous lesions which were expected to be larger
(> 20 mg) with an irregular outline and midline shifts.
The patient was given two courses of cysticidals with no
clinical/ radiological improvement which prompted the
authors to review the diagnosis.
*MR spectroscopy identified lipid peaks in the lesions
and raised the suspicion of tuberculoma. A high peak of
lipids, more choline and less N-acetylaspartate and
creatinine. The choline/creatinine ratio was greater than
one in all tuberculomas but in none of the cysticerci.
*Ref. Seth R, Kalra V, Sharma U and Jagannathan N.
Magnetic resonance spectroscopy in ring enhancing
lesion. Indian Pediatr 2010;47:803-4.
Case 10
Child with stage III TBM showing marked decerebrate
rigidity 11 months old male child presented to AIIMS
in 1992 in stage III of advanced TBM with decerebrate
rigidity.
Comments
This eleven months old male child presented in the third
stage of TBM with marked decerebrate rigidity in an
unconscious stage. He had convulsions and mild signs
of raised intracranial pressure. He was put on SHRZE
1 HRZE and 8 HRE along with anticonvulsants,
mannitol and oral glycerol in the initial week to reduce
raised intracranial pressure. He was on nasogastric feed,
IV line was maintained for giving anticonvulsants. Oral
glycerol and acetazolamide was being given through
the nasogastric tube. This child did not require shunt,
improved to some extent in the first four weeks but was
left with marked sequelae in the form of convulsions,
mental subnormality. For increased tone, physiotherapy
was started in the ward and followed in the outpatient
department. It is important to diagnose a child in stage
189
I, outcome is best in stage I and not so good in stage II

and worst in stage III. This child had not received BCG.
Figures 10.3.10A to K show the picture at presentation
and during the course of treatment.
Case 11
A female child, one-year-old presented with stage III of
TBM with marked rigidity, convulsions and in a
semicomatosed stage. She was put on anticonvulsants
along with oral glycerol and IV mannitol for medical
decompression. Antituberculosis regimen started was
SHRZE 1 HRZE 8-10 HRE. (Figs 12.3.11A to D).
Figs 12.3.10A to E: (A) Stage III TBM with decerebrate rigidity involving all the four limbs, (B) Advanced decerebrate rigidity involving all the four
limbs and the child is unconscious, (C) Advanced stage III of TBM showing scissoring of the lower extremities due to marked degree of decerebrate
rigidity and note opisthotonus, (D) Same child, note fisting of the upper extremities with closed wrists showing grasp reflex like in a newborn child.
He is still unconscious and showing marked decerebrate rigidity. Child is being fed with a nasogastric tube as he is still semicomatozed, (E) Same
child showing grade III of protein energy malnutrition with marked wasting of abdominal and intercostals muscles showing prominent intercostal
depression
190
Figs 12.3.10F to K: (F) Same child is still comatosed with dececrebrate rigidity. Baby on nasogastric feeds and IV therapy with anticonvulsant
drugs. There is a life line kept for intravenous medication during convulsions and mannitol for reducing raised intracranial tension, (G) Sensorium
slightly better but needs intragastric feeding. Right wrist showing fisting due to advanced decerebrate rigidity, (H) Same child showing fisting, note
the fisted right hand. The position of the hand is like grasp reflex of a newborn, (I) Same child showing fisting, i.e. grasp replex due to decorticate
rigidity, (J) Same child after one month of therapy with five antituberculosis drugs, steroids, anticonvulsants, IV mannitol, glycerol through the
nasogastric tube. Slight improvement in sensorium but still needs intragastric feed, (K) Same child still on intensive phase of antituberculosis
drugs with HRZE, streptomycin was stopped after 15 days. He is still on anticonvulsants and steroids. He is not on any medication for raised
intracranial pressure. Left upper arm still showing marked rigidity. Child though conscious but very irritable
191
Figs 12.3.11A to D: (A) The child in stage III of TBM with encephalopathy and severe malnutrition. Absolutely flaccid paralysis is obvious. Life line
for anticonvulsants and for medical decompression with mannitol is being maintained, (B) Child in comatozed stage III of TBM with marked flaccid
paralysis of both lower limbs. Hypertonicity in the left upper limb. Life line is being maintained for giving anticonvulsants and IV dexamethazone,
(C) The child showing similar features as described in Fig. 10.3.10A, except slightly better in the consciousness status, associated severe
malnutrition is evident with wasting of intercostal and muscles of the extremities, (D) Child is still semicomatozed and is showing severe degree
of malnutrition with wasting of muscles of the extremities and a scaphoid abdomen
Figs 12.3.12A to D: (A) Semiconscious child with marked decerebrate

rigidity, involving all four limbs, fisting, i.e. reappearance of grasp reflex,
(B) Again showing decerebrate posture, appearance of grasp reflex,
marked decerebrate rigidity and hypertonicity, upturning of the eye balls
making sclera visible indicative of raised intracranial pressure,
(C) Another picture of the same child with practically same findings,
(D) Another picture of same child, notice the upturning of the eye balls
with appearance of sclera, indication of raised intracranial pressure
192
Figs 12.3.12E to K: (E) Close up of face of the child, fully unconscious,

and still requires intragastric feed, (F) Whole body showing the features
of TBM encephalopathy, marked rigidity, appearance of grasp reflex,
(G) Notice marked degree of right sided foot drop and marked fisting in
an unconscious child, appearance of sclera, sign of raised intracranial
pressure, (H) Marked flexion of left hand with fisting, again due to
increased rigidity, (I) Same findings in the right hand, (J) No significant
improvement in consciousness, child still comatozed, being fed with
intragastric tube and medications are being given through the
nasogastric tube, (K) Same child showing right wrist fisting due to
increased rigidity Grasp reflex reappearance
193
Figs 12.3.13A to D: (A) Ten months old stuperous child again showing feature of encephalopathy, decerebrate rigidity. This child did not have
raised intracranial pressure, (B) Different view but almost same clinical features, (C) Child with TBM, stage III with encephalopathy, dececrebrate
rigidity, with associated severe malnutrition, (D) Almost similar typical feature of encephalopathy slightly better as the child had received
antituberculosis drugs for 15 days while she was in the hospital. Slight improvement in the consciousness
Comments
The child presented with TBM and encephalopathy.
These picture were taken in the 1st two week of intensive
therapy when the child was getting antituberculosis
drugs, along with medical decompression. The child had
not received BCG. Mother had active pulmonary
tuberculosis.
Case 12
Ten months old male child presented with stage III of
TBM with encephalopathy, marked decerebrate rigidity,
semiconscious. For medication both life line and
intragastric tube feeding had to be maintained. Again
this child was put on SHRZE 1 HRZE 8-10 HRE along
with anticonvulsants, medicines to decrease intracranial
pressure.
The various Figures (12.3.12A to K) were taken in the
Ist week of hospital admission. After 4 weeks of intensive
therapy the child was still semiconscious, had to be fed
by nasogastric tube on discharge as there were lots of

sequelae. The child had lots of sequelae on follow-up.
Case 13
Ten months old female child presented with clinical
picture of stage III of TBM with encephalopathy figures
12.3.13A to D. She had marked respiratory distress, Xray showed miliary tuberculosis. On asking for family
history, the mother was suffering from active tuberculosis
and getting therapy form one of the TB centers. She had
not received BCG.
HIGHLIGHTS
PM Udani Case Studies:TBM presentations in
children who had received BCG
Cases of TBM presented by Dr PM Udani from
Mumbai had shown comparatively better outcome,
probably the pick up was at an earlier stage and
children were of older age. All had received BCG.
194

Aggressive use of neuroimaging, timely institution
of antituberculosis drugs along with symptomatic
relief for medical decompression, and institution of
V-P shunt when indicated for raised ICT, resulted
in some what better outcome.
AIIMS, New Delhi Experiences:
Most of the children were in the younger age group.
Though aggressive therapy was given, in few V-P
shut was also put in, but still the over all outcome
was much less rewarding. None of children had
received BCG and presented in stage III of TBM with
lots of neurological deficits.
Neuroimaging and astute clinical judgment are
important factors for making early diagnosis.
Outcome of this group except case no. 7 and 8 who
were older survived but with neurological
morbidity. Case no. 9 was interesting from the point
of differential diagnosis in which, magnetic
resonance spectroscopy (MRS) had to be used to
diagnose tuberculoma. Child improved when put
on antituberculosis drugs. Before this CT and MRI
were indicative of neurocysticercosis and the child
did not respond to drugs for that.
REFERENCES
1. Dhariwal N, Udani PM. Principal causes of deaths in
children under 12 years of age with special reference to
contributory factors. Institute of Child Health, JJ Group
Hospitals and Grant Medical College, Bombay 1977 data.
2. Udani PM. Pediatrics tuberculosis pyramid and its fate
with and without chemotherapy/chemoprophylaxis.
Indian J Pediatr 1990;57:627-37.
3. Udani PM. Tuberculosis in children in India, a major
health hazard. Pediatr Clin India 1983;18:11-42.
4. Dastur DK, Udani PM. Severe brain damaging
mechanisms in tuberculous meningitis illustrated by one
autopsied case. Pediatr Clin India 1983;18:116-25.
5. Udani PM, Dastur DK. CNS tuberculosis. In: Udani PM
(Ed): Textbook of Pediatrics with Special References to
Problems of Child Dealth in Developing Countries.
Jaypee Brothers, Medical Publisher Pvt. Ltd. New Delhi
1990;1237-332.
6. Udani PM. Tuberculosis in children with special reference
to neurotuberculosis. Ann Natl Acad Med Sci
1980;16:121-61.
7. Burn CG, Finlay KH. The role of hypersensitivity in the
production of experimental meningitis. J Exp Med
1932;56:203-21.
8. Tandon PN, Singh B, Mohapatra LN, et al. Experimental
tuberculosis of the central nervous system. Neurol India
1970;18:81.
9. Wisniewski HM, Bloom BR. Primary demyelination as a
nonspecific consequence of a cell- mediated immune
reaction. J Exp Med 1975;141:346-59.
10. Udani PM. Tuberculous encephalopathy with and
without meningitis. Proceedings of the first Asian
Pediatric Congress, India Dec-Jan 1958-9.
11. Dastur DK, Udani PM. Tuberculous encephalo-pathy

with and without meningitis. Pathology, pathogenesis
and clinical correlation. Proceedings of the Xth
International Congress of Neuropathology, 1965.
12. Dastur DK, Udani PM. Pathology and patho-genesis of
tuberculous encephalopathy. Acta Neuropathologica
1966;6:311-26.
13. Chandramukhi A, Nayak P. Subacute and chronic
meningitis in childrenAn immuno-logical study of
cerebrospinal
fluid.
Indian
J Pediatr 1990;57:685-91.
14. Tandon PN, Bhatia R, Bhargava S. Tuberculous
meningitis. In:Harris AA (Ed), Handbook of Neurology
Microbial Diseases Vol. 8, Elseivers Science Publisher.
1988;195-226.
15. Joishy KN, Sant MV. Experience with the laboratory
diagnosis of tuberculous meningitis in children.
In:Kapila CC, Dastur DK, Singh B, Tandon PN (Eds).
Tuberculosis of Nervous System. Monograph on the
Proceedings of the Symposium, Bombay, India Feb 25,
1974;117-9.
16. Mohanakuma T, Mohapatra LN, Tandon PN.
Experimental tuberculosis of the central nervous system
in monkeys and guinea pigs, Bacterio-logical aspects.
In:Kapila CC, Dastur DK, Singh B, Tandon PN (Eds).
Tuberculosis of Nervous System. Monograph on the
Proceedings of the Symposium, Bombay, India Feb. 2-5,
1974;167-72.
17. Udani PM, Dastur DK. Tuberculous encephalo-pathy
with and without meningitis. Clinical features and
pathological correlations. J Neurol Sci 1970;10:541-61.
18. Udani PM, Bhave SY, Tilak AM, et al. CNS tuberculosis
with clinical picture modified by BCG vaccination and/
or drug therapy. Bulletin of JJ Group of Hospital and
Grant Medical College 1979;24:3-10.
19. Udani PM. Serous tuberculous meningitis. Indian J Child
Health 1955;4:566-75.
20. Udani PM, Parekh UC, Dastur DK. Tuberculosis of the
central nervous system, incidence and classification.
21. Udani PM, Parekh UC, Dastur DK. Neurological and
related syndromes of CNS tuberculosis, clinical features
and pathogenesis. J Neurol 1971;14:341-57.
22. Teoh R. Rapid diagnostic tests in tuberculous meningitis
(TBM). Abstracts of XIVth World Congress of Neurology.
Neurol India 1989;37: 121.
23. Rowland LP. Various brainstem syndromes likely to occur
in localized TBM with involvement of vessels. In:Kandel
ER, Schwartz JH (Eds). Principles of Neural Sciences. New
York, Elsevier-North Publishers, Holland, 1981;419-30.
24. Udani PM, Parekh UC, Dastur DK. Neurological and
related syndromes in neurotuberculosis in children:
Further observations. In:Kapila CC, Dastur DK, Singh B,
Tandon PN (Eds). Tuber-culosis of the nervous System.
Monograph on the Proceedings of the Symposium.
Bombay, India, Feb. 25, 1974;37-49.
25. Udani PM, Parekh UC, Dastur DK. Some neurological
syndromes in CNS Tuberculosis. Neurol India
1972;(suppl) 63-9.
26. Duus P. Tropical diagnosis in neurology. Stuttgart, Pub
Georg Thieme Verlaz, 1983;247-96.
27. Hassler R. The fucntional Anatomy of limbic systems.
Nervenarzt 1964;35:386-96.
28. Chari CR, Rao Chitra NS. Transient neurological deficit
as a presentation of tuberculosis of the central nervous
system. Neurology 1987;37:188-45.
29. Menon RK, Sharma V, Siddique MH, et al. Study of
syndromes of inappropriate antidiuretic hormone
secretion (SIADH) in meningo-encephalitis using a
highly sensitive ADH assay. Abstract of 18th National
Conference of Indian Academy of Pediatrics, Hyderabad,
Jan 31-Feb 2, 1981. Abstract book 1981;111.
30. Wright S. Applied physiology. London, Oxford
University Press 1942;190, 606.
31. Teoh R, Poon W, Humphries MJ, et al. Suprasellar
tuberculoma developing during treatment of tuberculous
meningitis requiring urgent surgical decompression. J
Neurol 1988;235:32-12.
32. Schlernitzauer DA, Hodges FJ, Bazan M. Tuberculoma
of the left optic nerve and chiasm. Arch Ophthalmol
1971;85:75-8.
33. Scott RM, Sonntag VK, Wilcox LM, et al. Visual loss from
optochiasmatic arachnoiditis after tuberculous
meningitis. J Neurosurg 1977;46: 524-6.
34. Lees AJ, Macleod AF, Marshall J. Cerebral tuber-culomas
developing during treatment of tuberculous meningitis.
Lancet 1980;1:1208-11.
35. Lebas J, Malkin JE, Coquin Y, et al. Cerebral tuberculomas
developing during treatment of tuberculous meningitis.
Lancet 1980;2:84.
36. Chambers ST, Hendrickse WA, Record C, et al.
Paradoxical expansion of intracranial tubercu-lomas
during chemotherapy. Lancet 1984;2:181-3.
37. Iles PB, Emerson PA. Tuberculous lymph-adenitis. BMJ
1974;1:143-5.
38. Fenichel GM. A signs and symptoms approach.
In:Clinical pediatric neurology, Philadelphia: WB
Saunders Co. 1988;314-5.
39. Mateo AR, Antiguedad C, De Andres M, et al. Magnetic
resonance in syringomyelia following tuberculous
meningitis. Abstracts of XIVth World Congress of
Neurology. Neurol India 1989;37:118.
40. Teoh R, Humphries J, Chan JCN, et al. Inter-nuclear
ophthalmoplegia in tuberculous meningitis. Tubercle
1989;70:61-4.
41. Cocker SB. Bobble-head Doll Syndrome. Pediatr Neurol
1986;2:115-7.
Clinical Manifestations, Diagnosis

and Management
1. Newton SM, Brent AJ, Andersen S, et al. Pediatric
tuberculosis. Lancet Infect Dis 2008;8:498-510.
2. Cailhol J, Che D, Jarlier V, et al. Incidence of tuberculous
meningitis in France, 2000:a capture-recapture analysis.
195
3. Moyo S, Verver S, Mahomed H, et al. Age-related

tuberculosis incidence and severity in children under 5
years of age in Cape Town, South Africa. Int J Tuberc
Lung Dis 2010;14:149-54.
4. Smith S, Jacobs RF, Wilson CB. Immunobiology of
childhood tuberculosis:a window on the ontogeny of
cellular immunity. J Pediatr 1997;131;16-26.
5. Jain SK, Paul-Satyaseela M, Lamichhane G, et al.
Mycobacterium tuberculosis invasion and traversal across
an in vitro human blood-brain barrier as a pathogenic
mechanism for central nervous system tuberculosis. J
Infect Dis 2006;193:1287-95.
6. Britton WJ, Fernando SL, Saunders BM, et al. The genetic
control of susceptibility to M. tuberculosis. Novartis Found
Symp 2007;281:79-89.
7. Sallakci N, Coskun M, Berber Z, et al. Interferon-gamma
gene+874TA polymorphism is asso-ciated with
tuberculosis and gamma interferon response.
Tuberculosis (Edinb) 2007;87:225-30.
8. Hawn TR, Dunstan SJ, Thwaites GE, et al. A
polymorphism in Toll-interleukin 1 receptor domain
containing adaptor protein is associated with
susceptibility to meningeal tuberculosis. J Infect Dis
2006;194:1127-34.
9. Thuong NT, Hawn TR, Thwaites GE, et al. A
polymorphism in human TLR2 is associated with
increased susceptibility to tuberculous meningitis. Genes
Immun 2007;8:422-8.
10. Caws M, Thwaites G, Dunstan S, et al. The influence of
host and bacterial genotype on the development of
disseminated disease with M. tuberculosis. PLoS Pathog
2008;4:e1000034.
11. Hernandez Pando R, Aguilar D, Cohen I, et al. Specific
bacterial genotypes of M. tuberculosis cause extensive
dissemination and brain infection in an experimental
model. Tuberculosis (Edinb) 2010 Jun 25 [Epub ahead of
print].
12. Tsenova L, Bergtold A, Freedman VH, et al. Tumor
necrosis factor alpha is a determinant of pathogenesis
and disease progression in mycobacterial infection in the
central nervous system. Proc Natl Acad Sci 1999;96:565762.
13. Rock RB, Hu S, Gekker G, et al. M. tuberculosis-induced
cytokine and chemokine expression by human microglia
and astrocytes:effects of dexamethasone. J Infect Dis
2005;192:2054-8.
14. Rock RB, Olin M, Baker CA, et al. Central nervous system
tuberculosis:pathogenesis and clinical aspects. Clin
Microbiol Rev 2008;21:243-61.
15. Nagesh Babu G, Kumar A, Kalita J, et al. Proinflammatory
cytokine levels in the serum and cerebrospinal fluid of
tuberculous meningitis patients. Neurosci Lett 2008;436:4851.
16. Simmons CP, Thwaites GE, Quyen NT, et al.
Pretreatment intracerebral and peripheral blood immune
responses in Vietnamese adults with tuberculous
meningitis: Diagnostic value and relationship to disease
severity and outcome. J Immunol 2006;176:2007-14.
196

17. Garg RK. Tuberculous meningitis. Acta Neurol Scand
2010;122:75-90.
18. Dastur DK, Lalitha VS, Udani PM, et al. The brain and
meninges in tuberculous meningitis-gross pathology in
100 cases and pathogenesis. Neurol India 1970;8:86-100.
19. Singh SK, Chandra J, Patwari AK, et al. Tuberculous
meningitis in early infancy. Indian Pediatr 1998;35:88790.
20. Streptomycin in tuberculosis trials committee, Medical
Research Council. Streptomycin treatment of tuberculous
meningitis. Lancet 1948;1:582.
21. Benakappa DG, Chandrasekhar SK, Chandra-sekhar P,
et al. Tuberculous meningitis: Review of 50 cases. Indian
Pediatr 1975;12:1161-7.
22. Van-Well GT, Paes BF, Terwee CB, et al. Twenty years of
pediatric tuberculous meningitis: A retrospective cohort
study in the Western Cape of South Africa Pediatrics
2009;123:e1-e8.
23. Aneja S, Basu S. Neurotuberculosis. Pediatrics Today
2000;3:107-14.
24. Bullock MR, Welchman JM. Diagnostic and prognostic
features of tuberculous meningitis on CT scanning. J
Neurol Neurosurg Psychiatry 1982;45:1098-101.
25. Sinha MK, Garg RK, Anuradha HK, et al. Vision impairment in tuberculous meningitis: Predictors and prognosis.
J Neurol Sci 2010;290:27-32.
26. Kingsley DP, HendrickseWA, Kendall BE, et al.
Tuberculous meningitis:Role of CT in management and
prognosis. J Neurol Neurosurg Psychiatry 1987;50:30-6.
27. Hsieh FY, Chia LG, Shen WC. Locations of cerebral infarctions in tuberculous meningitis. Neuroradiology
1992;34:197-9.
28. Gupta RK, Gupta S, Singh D, et al. MR imaging and
angiography in tuberculous meningitis. Neuroradiology
1994;36:87-92.
29. Andronikou S, Wilmshurst J, Hatherill M, et al. Distribution of brain infarction in children with tuberculous
meningitis and correlation with outcome score at 6
months. Pediatr Radiol 2006;39:1289-94.
30. Ahuja GK, Mohan KK, Prasad K. Diagnostic criteria for
diagnosis of TBM and its validation. Tubercle and Lung
Dis 1994;75:149-52.
31. Seth R, Sharma U. Diagnostic criteria for tubercular
meningitis. Indian J Pediatr 2002;69:299-303.
32. Kumar R, Singh SN, Kohli N. A diagnostic rule for
tuberculous meningitis. Arch Dis Child 1999;81:221-4.
33. Diel R, Loddenkemper R, Meywald-Walter K, et al. A
Predictive value of a whole blood IFN-gamma assay for
the development of active tuberculosis disease after
recent infection with M. tuberculosis. Am J Respir Crit
Care Med 2008;177:1164-70.
34. Thwaites, GE, Chau TT, Farrar JJ. Improving the
bacteriological diagnosis of tuberculous meningitis. J Clin
Microbiol 2004. 42:378-9.
35. Liu P, Shi ZY, Lau YJ, et al. Rapid diagnosis of TBM by
simplified nested amplification protocol. Neurology
1994;44:1161-4.
36. Kox LFF, Kuijper S, Kolk AHJ. Early diagnosis of TBM

by PCR. Neurology 1995;45:2228-32.
37. Centers for Disease Control and Prevention.
Update:nucleic acid amplification tests for tuberculosis.
MMWR Morb Mortal Wkly Rep 2000;593-4.
38. Bonington A, Strang GJ, Klapper PE, et al. Use of Roche
AMPLICOR M. tuberculosis PCR in early diagnosis of
tuberculous meningitis. J Clin Microbiol 1998;36:1251-4.
39. Kulkarni SP, Jaleel MA, Kadival GV. Evaluation of an
in-house-developed PCR for the diagnosis of tuberculous
meningitis in Indian children. J Med Microbiol
2005;54:369-73.
40. Pai M, Flores LL, Pai N, et al. Diagnostic accuracy of
nucleic acid amplification tests for tuberculous meningitis:
A systematic review and meta-analysis. Lancet Infect Dis
2003;3:633-43.
41. Tuon FF, Higashino HR, Lopes MI, et al. Adenosine
deaminase and tuberculous meningitis-a systematic
review with meta-analysis. Scand J Infect Dis 2010;42:198207.
42. Brooks JB, Daneshvar MI, Haberberger RL, et al. Rapid
diagnosis of tuberculous meningitis by frequency-pulsed
electroncapture gas-liquid chromatography detection of
carboxylic acids in cerebrospinal fluid. J. Clin. Microbiol
1990;28:989-99.
43. French GL, Teoh R, Chan CY, et al. Diagnosis of
tuberculous meningitis by detection of tuberculostearic
acid in cerebrospinal fluid. Lancet 1987;18:117-9.
44. Mardh PA, Larsson L, Hoiby N, et al. Tuberculostearic
acid as a diagnostic marker in tuberculous meningitis.
Lancet 1983;12:367.
45. Chandrmukhi A, Bothamley GH, Brennen PJ, et al. Levels
of antibody to defined antigen of M. tuberculosis in
tubercular meningitis. J Clin Microbiol 1989;27:821-5.
46. Mathai A, RadhakrishnanVV, Thomas M. Rapid
diagnosis of TBM with dot enzyme immunoassay to
detect antibody in CSF. Eur J Clin Microbiol Infect Dis
1991;10:440-3.
47. SrivastavA L, Prasanna S, Srivastava VK. Diagnosis of
TBM with ELISA test. Indian J Med Res 1994;99:8-12.
48. Behari M, Raj M, Ahuja GK, et al. Soluble antigen
fluorescent antibody test in serodiagnosis of TBM. J Assos
49. Katti MK. Assessment of antibody responses to antigens
of M. tuberculosis and Cysticercus cellulosae in
cerebrospinal fluid of chronic meningitis patients for
definitive diagnosis as TBM/NCC by passive
hemagglutination and immunoblot assays. FEMS
Immunol. Med. Microbiol 2002;33:57-61.
50. Katti MK, Achar MT. Immunodiagnosis of tuberculous
meningitis:detection of antibody reactivity to antigens
cerebrospinal fluid tuberculous meningitis patients by
ELISA. J Immunoassay Immunochem 2001;22:401-6.
51. Lang AM, Feris-Iglesias J, Pena C, et al. Clinical
evaluation of the Gen-Probe Amplified Direct Test for
detection of M. tuberculosis complex organisms in
cerebrospinal fluid. J Clin Microbio l998;36:2191-4.
52. Prabhakar S, Oommen A. ELISA using myco-bacterial
antigens as a diagnostic aid for tuber-culous meningitis.
J Neurol Sci 1987;78:203-11.
53. Chandramuki A, Bothamley GH, Brennan PJ, et al. Levels
of antibody to defined antigens of M. tuberculosis in
tuberculous meningitis. J Clin Microbiol 1989;27:821-5.
54. Kashyap RS, Kainthla RP, Satpute RM, et al. Differential
diagnosis of tuberculous meningitis from partiallytreated pyogenic meningitis by cell ELISA. BMC Neurol
2004;4:16.
55. Kashyap RS, Kainthla RP, Satpute RM, et al.
Demonstration of IgG antibodies to 30 Kd protein antigen
in CSF for diagnosis of tuberculous meningitis by
antibody-capturing ELISA. Neurol India 2004;52:359-62.
56. Quan C, Lu CZ, Qiao J, et al. Comparative evaluation of
early diagnosis of tuberculous meningitis by different
assays. J. Clin. Microbiol 2006;44:3160-6
57. Patil SA, Gourie-Devi M, Chaudhuri JR, et al.
Identification of antibody responses to M. tuberculosis
antigens in the CSF of tuberculous meningitis patients
by Western blotting. Clin Immunol Immunopathol
1996;81:35-40.
58. Katti MK. Assessment of antibody responses to antigens
cerebrospinal fluid of chronic meningitis patients for
definitive diagnosis as TBM/NCC by passive
hemagglutination and immunoblot assays. FEMS
Immunol Med Microbiol 2002;33:57-61.
59. Chandramuki A, Allen PR, Keen M, et al. Detection of
mycobacterial antigen and antibodies in the cerebrospinal
fluid of patients with tuberculous meningitis. J Med
Microbiol 1985;20:239-47.
60. Sumi MG, Mathai A, Reuben S, et al. A comparative
evaluation of dot immunobinding assay (Dot-Iba) and
polymerase chain reaction (PCR) for the laboratory
diagnosis of tuberculous meningitis. Diagn Microbiol
Infect Dis 2002;42:35-8.
61. Ozates M, Kemaloglu S, Gurkan F, et al. CT of the brain
in tuberculous meningitis. A review of 289 patients. Acta
Radiol 2000;41:13-7.
62. Chan KH, Cheung RT, Fong CY, et al. Clinical relevance
of hydrocephalus as a presenting feature of tuberculous
meningitis. QJM 2003;96:643-8.
63. Andronikou S, Wieselthaler N, Smith B, et al. Value of
early follow-up CT in pediatric tuberculous meningitis.
Pediatr Radiol 2005;35:1092-9.
64. Kalita J, Misra UK, Nair PP. Predictors of stroke and its
significance in the outcome of tuberculous meningitis. J
Stroke Cerebrovasc Dis 2009;18:251-8.
65. Jinkins JR, Gupta R, Chang KH, et al. MR imaging of
central nervous system tuberculosis. Radiol Clin N Am
1995;33:771-86.
66. Burtscher IM, Holtas S. Proton MR spectroscopy in
clinical routine. J Magn Res Imaging 2001;13:560-7.
67. Consensus statement on childhood tuberculosis. Indian
Pediatr 2010;47:41-55.
68. Chauhan LS, Arora VK. Management of pediatric
tuberculosis under the Revised National Tuberculosis
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
197
Control Program (RNTCP) - The consensus statement.

Guidance for national tuberculosis programs on the
management of tuberculosis in children. WHO/HTM/
TB/2006.371.
Kumar L, Dhand R, Singhi PD, et al. A randomized trial
of fully intermittent vs daily followed by intermittent
short course chemotherapy for childhood tuberculosis.
Hong Kong Chest Service, British Medical Research
Council. Controlled trial of four thrice weekly regimens
and daily regimen all given for six months for pulmonary
tuberculosis. Lancet 1981;8213:171-4.
Varudkar BL. Short-course chemotherapy for
tuberculosis in children. Indian J Pediatr 1985;52:593-7.
Te Water Naude JM, Donald PR, Hussey GD, et al. Twice
weekly vs daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis 2000;19:405-410.
Gocmen A, Ozcelic U, Kiper N, et al. Short-course
intermittent chemotherapy in childhood tuberculosis.
Infection 1993;21:324-7.
Jawahar MS, Rajaram K, Sivasubramanian S, et al.
Treatment of lymph node tuberculosis- a randomized
clinical trial of two 6-month regimens. Trop Med Int Health
2005;10:1090-8.
Arora VK, Gupta R. Directly observed treatment for tuberculosis. Indian J Pediatr 2003;70:885-9.
Anadol D, Kiper N, Gocmen A, et al. Intermittent
chemotherapy for miliary tuberculosis in children. Turk
J Pediatr 1999; 41:53-9.
Rajeswari R, Sivasubramanian S, Balambal R, et al. A
controlled clinical trial of short-course chemotherapy for
tuberculoma of the brain. Tuber Lung Dis 1995;76:311-7.
Venugopal K. Therapeutic efficacy of fully intermittent
regimen for neuro TB-A field study in South India.
Pulmon 2006;8;89-92.
Indumati CK, Prasanna KK, Dinakar C, et al. Intermittent
short course therapy for pediatric tuberculosis. Indian
Pediatr 2010;47:93-6.
Menon PR, Lodha R, Sivanandan S, et al. Intermittent or
daily short course chemotherapy for tuberculosis in
children:Meta-analysis of randomized controlled trials.
Indian pediatr 2010;47:67-73.
Abernathy RS, Dutt AK, Stead WW, et al. Short-course
chemotherapy for tuberculosis in children. Pediatrics
1983;72:801-6.
Iseman MD, Cohn DL, Sbarbaro JA. Directly observed
treatment of tuberculosis - we cant afford not to try it.
N Engl J Med 1993;328: 576-8.
Jacobs RF, Sunakorn P, Chotpitayasunonah T, et al. Intensive short-course chemotherapy for tuberculous
meningitis. Pediatr Infect Dis J 1992;11:194-8.
Prasad K, Singh MB. Corticosteroids for managing
tuberculous meningitis. Cochrane Database Syst Rev
2008, Art. No. CD002244. DOI:10.1002/14651858.
CD002244.pub3.
Thwaites GE, Nguyen DB, Nguyen HD, et al.
Dexamethasone for the treatment of tuberculous
meningitis in adolescents and adults. N Engl J Med
2004;351:1741-51.
198
87. Patwari AK, Aneja S, Chandra D, et al. Long-term

anticonvulsant therapy in tuberculous meningitisa
four-year follow-up. J Trop Pediatr 1996;42:98103.PMID:8984222.
88. Kumar R, Prakash M, Jha S. Paradoxical response to
chemotherapy in neurotuberculosis. Pediatr Neurosurg
2006;42:214-22.
89. Palur R, Rajshekhar V, Chandy MJ, et al. Shunt surgery
for hydrocephalus in tuberculous meningitis:a long-term
follow-up study. J Neurosurg 1991;74:64-9.
90. Mathew JM, Rajshekhar V, Chandy MJ. Shunt surgery
in poor grade patients with tuberculous meningitis and
hydrocephalus:effects of response to external ventricular
drainage and other variables on long term outcome. J
Neurol Neurosurg Psychiatr 1998;65:115-8.
91. Agrawal D, Gupta A, Mehta VS. Role of shunt surgery
in pediatric tubercular meningitis with hydrocephalus.
Indian Pediatr. 2005;42:245-50.
92. Rajshekhar V. Management of hydrocephalus in patients
with tuberculous meningitis. Neurol India 2009;57:36874
93. Bhagwati S, Mehta N, Shah S. Use of endoscopic third
ventriculostomy in hydrocephalus of tubercular origin.
Childs Nerv Syst. 2010 May 28. [Epub ahead of print].
94. Chugh A, Husain M, Gupta RK, et al. Surgical outcome
of tuberculous meningitis hydro-cephalus treated by
endoscopic third ventri-culostomy:prognostic factors and
postoperative neuroimaging for functional assessment
of ventriculostomy. J Neurosurg Pediatr 2009; 3:371-7.
95. Girgis NI, Sultan Y, Farid Z, et al. Tuberculosis
meningitis, Abbassia Fever Hospital-Naval Medical
Research Unit No. 3-Cairo, Egypt, from 1976 to 1996. Am.
J Trop Med Hyg 1998;58:28-34.
96. Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA
1979;241:264-28.
97. Kent SJ, Crowe SM, Yung A, et al. Tuberculous
meningitis:a 30-year review. Clin Infect Dis 1993;17:98794.
98. Ogawa SK, Smith MA, Brennessel DJ, et al. Tuberculous
meningitis in an urban medical center. Medicine
(Baltimore) 1987;66:317-26.
99. Mahadevan B, Mahadevan S, Serane VT. Prognostic
factors in childhood tuberculous meningitis. J Trop
Pediatr 2002;48:362-5.
100. Seth V, Gulati S. Clinical manifestations, diagnosis and
treatment. Neurotuberculosis II In:Essentials of
Tuberculosis in children. Seth Vimlesh, Kabra SK. (Eds),
Jaypee Brothers Medical Publisher Pvt. Ltd. New Delhi.
2006;157-210.
100a. Kumar R, Dwivedi A, Kumar P, et al. Tuberculous
meningitis in BCG vaccinated and unvaccinated
children. J Neurol Neurosurg Psychiatry 2005;76:1550-4.
101. Karande S, Gupta V, Kulkarni M, et al. Prognostic clinical
variables in childhood tuberculous meningitis:an
experience from Mumbai, India. Neurol India
2005;53:191-5.
102. Thwaites GE, Simmons CP, Quyen NTH, et al.
Pathophysiology and prognosis in Vietnamese adults
with tuberculous meningitis. J Infect Dis 2003;188:110515.
103. Misra UK, Kalita J, Srivastava M, et al. Prognosis of

tuberculous meningitis: A multivariate analysis. J Neurol
Sci 1996;137:57-61.
104. Simmons CP, Thwaites GE, Quyen NT, et al.
Pretreatment intracerebral and peripheral blood immune
responses in Vietnamese adults with tuberculous
meningitis:diagnostic value and relationship to disease
severity and outcome. J. Immunol 2006;176:2007-14.
105. Thwaites GE, Chau TT, Caws M, et al. Isoniazid
resistance, mycobacterial genotype and outcome in
Vietnamese adults with tuberculous meningitis. Int J
Tuberc Lung Dis 2002;6:865-71
106. Maree F, Hesseling AC, Schaaf HS, et al. Absence of an
association between M. tuberculosis genotype and clinical
features in children with tuberculous meningitis. Pediatr
Infect Dis J 2007;26:13-8.
107. Wait J, Stanton L, Schoeman JF. Tuberculosis meningitis
and attention deficit hyperactivity disorder in children. J
Trop Pediatr 2002;48:294-9.
108. Schaaf HS, Gie RP, Kennedy M, et al. Evaluation of young
children in contact with adult multidrug- resistant
pulmonary tuberculosis: A 30-month follow-up.
Pediatrics 2002;109:765-71.
109. Van der Weert EM, Hartgers NM, Simon H, et al.
Comparison of diagnostic criteria of tuberculous
meningitis in human immuno-deficiency virus-infected
and uninfected children. Pediatr Infectious Dis J
2006;25:65.
110. Rowe JS, Shah SS, Marais BJ, et al. Diagnosis and
management of tuberculous meningitis in HIV-infected
pediatric patients. Pediatr Infectious Dis J 2009;28:147-8.
111. Maartens G, Decloedt E, Cohen K. Effectiveness and
safety of antiretrovirals with rifampicin: crucial issues
for high-burden countries. Antivir Ther 2009;14:1039-43.
112. Lalitha VS, Dastur DK. Tuberculosis of the central
nervous system. Neurol India 1980;28: 202-5.
113. Reddy DB, Kameshwararao V. Tuberculoma of the brain.
Indian J tubercul 2004;51:92-8.
114. Farinha NJ, Razali KA, Holzel H, et al. Tuberculosis of
the central nervous system in children:a 20-year survey. J
Infect 2000;41:61-8.
115. Preul MC, Caramanos Z, Collins DL, et al. Accurate, non
invasive diagnosis of human brain tumors by using
proton magnetic resonance spectroscopy. Nature Med
1996;2:323-5.
116. Tzika AA, Zarifi MK, Goumnerova L, et al.
Neuroimaging in Pediatric Brain Tumors:Gd-DTPAenhanced, Hemodynamic, and Diffusion MR Imaging
Compared with MR Spectroscopic Imaging. Am J
Neuroradiol 2002;23:322-33.
117. Burtscher IM, Holtas S. Proton MR spectroscopy in
clinical routine. J Magn Res Imaging 2001;13: 560-7.
118. Luyten PR, Marien AJH, Heindel W, et al. Metabolic
imaging of patients with intracranial tumors:H-1 MR
spectroscopic imaging and PET. Radiology 1990;176:7919.
119. Bruhn H, Frahm J, Gyngell ML, et al. Non- invasive
differentiation of tumors with use of localized H-1 MR
spectroscopy in vivo: initial experience in patients with
cerebral tumors. Radiology 1989;172:541-8.
120. Jayasundar R, Singh VP, Raghunathan P, et al.
Inflammatory granulomas:evaluation with proton MRS.
NMR Biomed 1999;12:139-44.
121. Gupta RK, Pandey R, Khan EM, et al. Intracranial
tuberculomas:MRI signal intensity correlation with
histopathology and localised proton spectroscopy. Magn
Reson Imaging. 1993;11:443-9.
122. Tripathi RP, Gupta A, Gupta S, et al. Co-existence of dual
intracranial pathology clinical relevance of proton MRS.
Neurol India 2000;48:365-9.
123. Pandit S, Lin A, Gahbauer H, et al. MR spectro-scopy in
neurocysticercosis. J Comput Assist Tomogr 2001;25:9502.
124. Haris M, Gupta RK, Husain M, et al. Assessment of
therapeutic response in brain tuberculomas using serial
dynamic contrast-enhanced MRI. Clin Radiol
2008;63:562-74.
125. Rajshekhar V, Haran RP, Prakash GS, et al. Differentiating
solitary small cysticercus granuloma and tuberculoma
in patients with epilepsy. Clinical and computerized
tomographic criteria. J Neurosurg 1993;78:402-7.
126. Rajshekhar V, Chandy MJ. Validation of diagnostic
criteria for solitary cysticercus granuloma in patients
presenting with seizures. Acta Neurol Scand 1997;96:7681.
127. Jayakumar PN, Srikanth SG, Chandrashekar HS, et al. T2
relaxometry of ring lesions of the brain. Clin Radiol
2007;62:370-5. Epub 2007 Feb 21.
128. Rajsekhar V, Chandy MJ. CT-guided stereotactic surgery
in the management of intracranial tuberculomas. Br J
Neurosurg 1993;7:665-71.
199
129. Mohanty A, Santosh V, Anandh B, et al. Diagnostic efficacy

of stereotactic biopsies in intracranial tuberculomas. Surg
Neurol 1999; 52:252-8.
130. Garg RK. Tuberculosis of the central nervous system.
Postgrad Med J 1999;75:133-40.
131. Pande KC, Babhulkar SS. Atypical spinal tuber-culosis.
Clin Orthop Relat Res 2002;398:67 74.
132. Tuli SM. Tuberculosis of the skeletal system. 2nd ed. New
Delhi:Jaypee Brothers 1997;177-8.
133. Devi BI, Chandra S, Mongia S, et al. Spinal intramedullary
tuberculoma and abscess: A rare cause of paraparesis.
Neurol India 2002; 50:494-6.
134. Dastur HM. Diagnosis and neurosurgical treatment of
tuberculous disease of the CNS. Neurosurg Rev
1983;6:111-7.
135. MacDonnell AH, Baird RW, Bronze MS. Intramedullary
tuberculomas of the spinal cord:a case report and review.
Rev Infect Dis 1990;12:432-9.
136. Bansal D, Singhi PD, Ray M, et al. Cervical intramedullary tuberculoma:acute presentation and rapid response to medical therapy. J Trop Pediatr 2002;48:55-7.
137. Kayaoglu CR, Tuzun Y, Boga Z, et al. Intramedullary
spinal tuberculoma:a case report. Spine 2000;25:2265-8.
138. Hlavin ML, Kaminski HJ, Ross JS, et al. Spinal epidural
abscess: A ten-year perspective. Neurosurgery
1990;27:177-84.
139. Teman AJ. Spinal epidural abscess. Early detection with
gadolinium magnetic resonance imaging. Arch Neurol
1992;49:743-6.
140. Jinkins JR, Gupta R, Chang KH, et al. MR imaging of
central nervous system tuberculosis. Radiol Clin North
Am 1995;33:77.
13
Osteoarticular Tuberculosis
PP Kotwal, PK Dave, BN Upendra
The disease tuberculosis is old and existed even in the

early ages. Descriptions of this disease can be found in the
Rig Veda, Atharva Veda (3500-1800 BC) and also in Charak
Samhita (1000-600 BC).
The incidence of tuberculosis had a dramatic fall in
the Western world. However, it still continues to be a
problem in the developing countries. According to a
WHO report it is still one of the chief causes of death and
crippling in many countries of the world.1 The disease
still remains a serious health problem and is increasing.
It is estimated that 1 to 6% of children with primary
infection may develop bone and joint tuberculosis in 1 to
3 years if left untreated.2,3 For purposes of description
osteoarticular tuberculosis can be discussed under
following heads:
Tuberculosis of joints
Bone tuberculosis
Spinal tuberculosis
Infection of a joint or bone with Mycobacterium
tuberculosis is almost always secondary to a primary focus,
in the lymphatic glands or lungs or mesentery, from where
it disseminates by hematogenous route. Malnutrition,
debilitating disease, poor sanitation, lack of sunshine and
fresh air increase the incidence of the disease. Patients
with immunodeficiency disease or HIV infection are more
prone to develop tuberculosis.
Tuberculous lesions can involve any bone or joint in
the body. The lesion in the joint can be:
i. Extra-articular
ii. Intraarticular
It can originate in the bone (osseous lesion) or in the
synovium (synovial disease).
Osteoarticular tuberculosis can involve any bone or
joint in the body, but vertebral involvement is the most
common and is nearly equal to tuberculosis of all other
regions put together.4-9
There may be a history of trauma, under the effect of
which a small hematoma may form resulting in vascular
stasis in that area. The hematoma may become a nidus for
the tubercle bacilli to settle down and form a tuberculous
follicle with caseation, epitheloid cells, giant cells and
fibrosis at the periphery. The original follicles enlarge and
may coalesce to form a tubercle, which may become visible
to the naked eye.
The lesion in the bone is essentially a lytic lesion which

is evident radiologically, unlike in pyogenic infection
which is characterized by intense sclerotic activity. As the
tuberculous lesions heal, sclerosis takes place. At certain
sites like the short long bones and in hand and feet or the
clavicle, there is intense sclerotic activity by layer of
subperiosteal bone and is characteristic of a tuberculous
lesion. The tuberculous pus formed in the medullary canal
may travel distally or laterally thus, lifting the periosteum,
may form an abscess and even burst giving rise to a
tuberculous sinus. Multifocal tuberculosis is occasionally
seen in children involving multiple bones/joints.
The response to a tuberculous lesion is often exudative
and may form a cold abscess, which is nothing but a
collection of necrotic material, caseous tissue and the
exudative reaction. These cold abscesses then track through
the fascial planes or the neurovascular bundles and present
at a distant site. Since this abscess is away from the area of
inflammatory activity, it has no signs of inflammation in
the skin overlying the abscess. These abscesses are, therefore,
termed as cold abscesses. A superficial abscess may burst
and result into a sinus or an ulcer.
Granulation tissue is almost always present in the
tuberculous lesion. Ischemic necrosis of bone due to
endarteritis and thromboembolic phenomenon in bone
leads to formation of sequestra, which in osseous
tuberculosis hap-pens to be small. Isolated large sequestrae
in osteoarticular tuberculosis are rare.
JOINT INVOLVEMENT
The tuberculosis of the joints is relatively less common. It
mainly involves big joints (Tubercular arthritis). The
common differential diagnosis includes pauciarticular
juvenile chronic arthritis and septic arthritis. The
involvement of joint may be osseous or synovial but if not
treated, one would infect the other. Tuberculous synovitis
leads to effusion in the joint and synovial membrane
becomes edematous. At this stage the joint would look
swollen and movements may be present or limited due to
muscle spasm. The radiological picture may show an
increased joint space.
The cartilage is resistant to tuberculous infection
because it contains a plasmin inhibitor and the bacilli do
not possess the plasminogen activator unlike the pyogenic
Chapter 13 Osteoarticular Tuberculosis

bacteria. The articular cartilage is thus not attacked by
plasmin and remains intact.10 Later on the granulation
tissue may extend from the periphery on to the articular
cartilage or in the subchondral region in the form of a
pannus thus eroding it. Once the articular cartilage is
eroded there is tremendous muscle spasm and all
movements are restricted. Because of the destruction of the
articular cartilage the joint space on X-ray looks
diminished.
When the lesion is osseous, it involves the subchondral
bone which also leads to erosion of the cartilage. The lesion
may start from the epiphysis in children or may be
metaphyseal in origin. When the disease begins to heal,
fibrosis occurs across the joint leading to a fibrous
ankylosis. At this stage the movements of the joint are
restricted and may be painful. There is considerable muscle
spasm which may produce a deformity at the joint.
Prolonged muscle spasm may lead to subluxation or
dislocation of the joint causing further deformity and
shortening. If sinus has formed, secondary infection may
be superimposed on the tuberculous infection. Fibrous
ankylosis may be converted into bony ankylosis either due
to complete healing or new bone formation due to
superadded pyogenic infection. There are no movements
in the joint after bony ankylosis and it is also painless.
Radiologically, in bony ankylosis the trabeculae are seen
to be crossing the joint line.
Clinical Features
Osteoarticular tuberculosis mostly occurs during
childhood, however, it is seen at any age and in all
socioeconomic groups. It is characteristically insidious
in onset, and starts as monoarticular or monoosseous
involvement. The child complains of pain in the joint,
aggravated by movement, and often wakes up at night
because muscle spasm gets reduced and causes pain. It
is classically called night cries. Low-grade fever, loss
of weight and appetite are some of the symptoms of
generalized toxemia usually seen. Joint movements are
painful and elicit muscle spasm on attempted movement.
In later stages when the cartilage gets eroded, all
movements get restricted. Muscle atrophy around the joint
is a predominant feature and occurs early. Sometimes an
abscess forms which bursts to form a sinus. It may get
secondarily infected and may alter the radiological
picture. It has been seen that material scrapped from the
lining or the abscess is more likely to be positive for gramnegative bacilli than from the center of the lesion.
Investigations
Blood
A low hemoglobin, relative lymphocytosis and raised
erythrocyte sedimentation rate (ESR) are often found in
201
the active stage of the disease. The ESR is often used as a

guide in monitoring the progress of the disease during
treatment, however, it is not a reliable parameter.
Mantoux Test
A positive Mantoux test is seen in patients infected with
M. tuberculosis which may be an active or a dormant
lesion. In children under two years of age, a positive
tuberculin reaction indicates an active tuberculous lesion.
A nega-tive test may be seen in severe or disseminated
disease or in an immunocompromised patient.
Synovial Fluid
Examination of the synovial fluid may occasionally help
in diagnosis in the early cases of tuberculosis. It may show
leukocytosis (with predominently polymorphs), decreased
glucose content and raised protein content.
Serology
ELISA (Enzyme-linked Immunoabsorbent Assay) test
was described by Engvall and Perlmann11 for antibody
to mycobacterial antigen-6, in the serological diagnosis
of osteoarticular tuberculosis. Although they reported a
sensitivity of 94% in the diagnosis of tuberculosis, it is
not considered a very reliable test in clinical practice as
the%age of false-negative and false-positive are very
high.
Radiology
It can be diagnostic in view of the typical radio-logical
appearance of the tuberculous lesions. In early stage of
the joint disease, capsular markings may become
prominent. The earliest sign is widespread osteoporosis
around a joint. Lytic lesion and periosteal reaction are
seen, although latter is much more prominent in pyogenic
infection.
In case of joints, small bone erosions occur near the
capsular reflection. Joint space decreases due to cartilage
erosion and lytic lesions are seen in the epiphyseal area.
The radiological signs of a healing lesion are absence of
rarefaction and bony ankylosis.
Smear and Culture

Tuberculous pus, joint aspirate, granulation tissue,
sputum, etc. may be examined by smear and culture for
tubercle bacilli. These can be processed by various
techniques (described elsewhere).
The culture and sensitivity tests for various
antituberculosis drugs also helpful in giving appropriate
chemotherapy in resistant cases or cases of multidrug
resistant tuberculosis; which are seen quite frequently in
todays clinical practice.
202
Isotope Scintigraphy
Most cases of osteoarticular disease can be diagnosed by
clinicoradiographic correlation. However, there would still
remain a number of cases where diagnosis may become
difficult and doubtful. In such situations, radionuclide
scanning using technetium-99 m can be useful particularly
in differentiating soft tissue infection from osteomyelitis.
Three phase bone scan and SPECT (single photone
emission tomography) are also useful in the follow-up for
evaluating the response to treatment.
in bone or from synovium is more likely to be positive.14,15

Biopsy can be done as an open biopsy or a needle biopsy
(CT guided).
Investigations should also be done to find out the
primary focus of the disease. An X-ray of the chest should
always be done. Some other investi-gations may include:
sputum smear examination and culture, routine urine
examination for isolation of tubercle bacilli and an
intravenous pyelogram for ruling out pulmonary and
genitourinary lesions, respectively.
Management
Ultrasonography
Ultrasonography can demonstrate soft tissue abscesses. It
can also be used to judge the effect of treatment on the size
of these abscesses at periodic intervals.
CT Scan
CT scan is helpful in detecting small lytic/destroyed areas
in the bone. The destruction of bone due to the disease
process and also the soft tissue swellings or abscesses can
be seen on CT scan better and much earlier. It also helps in
evaluating difficult areas in spine such as cervico-dorsal
junctions, which cannot be seen properly on plain X-rays.
MRI Scan
MRI scan is a far better diagnostic tool, than CT scan or
plain X-rays. It can demonstrate not only the bony lesions
(destruction) but also the soft tissue abscess, changes in
the spinal cord, etc. It can also pick up changes in the
bones much earlier than the plain X-rays.
Fine Needle Aspiration Cytology (FNAC)

Occasionally, even the most modern methods of imaging
may not help the clinician to reach a final diagnosis, and
therefore, FNAC or biopsy may be undertaken to obtain
tissue diagnosis. FNAC is now available for the cytological
diagnosis of vertebral tuberculosis. Mondal et al 12
recommend that fine needle aspiration biopsy is a safe
and a quick diagnostic procedure with high accuracy in
the hands of trained cytopathologists. He recommends
that it should be practised in all diagnostic centers of our
country, even for suspected vertebral tuberculosis.
Confirmation by FNAC has also been recommended by
Arora and Seth.13
Biopsy
Biopsy may have to be done in cases where there is doubt
about the diagnosis, particularly in the early stages of the
disease. Biopsy from the bone or synovium can provide an
early diagnosis for timely starting the treatment and
preventing damage to the joint. Biopsy from a cystic lesion
The patients response to treatment is variable as anywhere

else in the body and is dependent upon the host resistance,
severity of infection, and the stage of the disease when the
diagnosis is first made and treatment started. Eradication
of the disease and preservation of function are important
both in osseous and joint diseases. In case of joints, joint
mobility and stability are also the early goals to be achieved.
It is possible only if treatment is started early, i.e. when the
disease is limited only to synovium. In case the articular
cartilage is eroded the joint becomes unsalva-geable in
terms of function, mobility and stability. In such a situation
the aim of treatment is to achieve a sound bony ankylosis
which is painless and gives stability, although the patient
will not have movements at that joint.
General Measures
Good nutrition consisting of a high calorie and protein
diet is essential to build up the resistance. General rest
and local rest to the specific bone and joint are essential
parts of the treatment. Local rest can be provided by means
of splints or plaster casts. However, in cases where the
articular surface is not involved a judicious blend of rest
and mobilization exercises have to be resorted for
restoration of function.
Hospitalization may be required for cases with
complications and also for cases having deformities. The
deformities may need treatment by traction.
Chemotherapy
In bone and joint tuberculosis it is customary to give at
least four antituberculous drugs to start with. Seth et al16
have recommended the use of 4 to 5 drugs in the intensive
phase. (described elsewhere). Combined drug therapy also
prevents the emergence of drug resistant strains.
There is enough evidence that 85% of osteo-articular
lesions would respond to anituber-culous drugs17,18
particularly if the therapy is started early in the vascular
stage of the disease.
It was earlier thought that the antituber-culosis drugs
do not penetrate into the diseased area in effective
concentrations since the lesion was considered avascular.

However, various studies have shown that the
antituberculosis drugs do reach the lesion in effective
concen-trations.19-23 Further, in case of persistently
draining sinuses which are secondarily infected, suitable
broad spectrum antibiotics have to be given. About 15% of
patients do not respond to chemotherapy alone if the lesion
contains much caseation and sequestra. In such situations
excision of the diseased focus not only removes the diseased
toxic material but also increases vascularity and allows
the anti-tuberculosis drugs to reach the site of the lesion.
A standard drug regimen is given which includes
rifampicin, pyrazinamide, ethambutol, isoniazid, and
in some cases even streptomycin. The latter is useful
because it kills the rapidly multiplying extracellular
tubercle bacilli in the lungs for the initial two months.19
After two months if the lesion shows signs of healing
clinically and radiologically, pyrazinamide is stopped
and isoniazid, rifampicin and etham-butol are
continued for one year. Since the recom-mendation of
the use of four to five drugs in the intensive phase, shortcourse chemotherapy can be used as in neurotuberculosis for a total period of 6 to 9 or at best 12
months if there is no surgical debridement. This has
been emphasized by Hazara, and Laha24A very recently.
It has been shown in the review of literature by them
justifying the use of short-course chemotherapy for 6 to
9 months. If there is suspicion of multidrug resistant
tuberculosis, the duration has to be prolonged may be
up to 18 months. So is the case where there is association
between HIV and tuberculosis. (described elsewhere)
In some cases therapy may be required for longer period
for complete healing of the lesion. In case the infection is
suspected to be with multidrug resistant organisms, other
drugs such as ethionamide, ofloxacin, capreomycin,
kanamy-cin, etc. may have to be given (described
elsewhere).
Spinal tuberculosis with paraplegia:

If paraplegia has occurred during chemotherapy,
If paraplegia is worsening in spite of ade-quate
chemotherapy,
Radiological increase in the size of the abscess, and
If the paraplegia is of sudden onset.
The surgical procedures generally performed in children

are:
Drainage of an abscess
Excision of a focus
Curettage of the lesion
Synovectomy
Costotransversectomy
Anterolateral decompression
The general principle of surgery in tuber-culosis
demands that the abscess should be completely evacuated.
In case of an osseous lesion, all sequestra, granulation
tissue and caseous material should be removed till new
bleeding bone is encountered, so that the drugs may reach
the site of lesion better. The cavities so produced should be
packed with autogenous bone grafts. Avoid dead spaces
to prevent hematoma formation and close the wound
primarily with or without suction.
Tuberculosis can involve any bone or joint of the body
but in children it has a special predilec-tion for the hip
and knee joints commonly, ankle and elbow joints are
rarely involved. Tuberculosis of spine with or without
paraplegia is extremely common. Long bones are rarely
involved but the short long bone involvement is somewhat
common. Diagnostic algorithm for osteoarticular
tuberculosis is given in Figure 13.1.
Surgical Treatment
Surgical treatment is an adjunct to the anti-tuberculosis
drug therapy. It cannot be a substitute for the prolonged
course of the drug therapy. Surgical treatment has become
safe with the advent of powerful antituberculosis drugs
and one is no longer scared of a flare up of the lesion.
However, a trial of conservative treatment must be given
before surgical treatment is undertaken. The indications
for surgery are specific and are as follows:
Doubtful diagnosis requiring excision of the focus or
curettage of the lesion.
An abscess or a lesion increasing in spite of adequate
chemotherapy.
Synovitis not involving the articular carti-lage;
synovectomy should be done to prevent the latter from
getting eroded.
Curettage of a lesion in proximity of the articular
cartilage to prevent the latter from getting involved.
203
Fig. 13.1: Diagnostic algorithm for osteoarticular tuberculosis
204
Fig. 13.2B: Stages of the tubercular arthritis of the hip
abduction and external rotation. Movements are painful

and limited in the terminal degrees. Radiographs may
show only soft tissue swellingthe capsular markings
appear distended due to effusion. There may or may not
be rarefaction of the bones of the hip joint (Fig. 13.2B).
Fig. 13.2A: Common sites of tuberculous involvement
around the hip joint
TUBERCULOSIS OF THE HIP JOINT

Tuberculosis of the hip is not uncommon and is seen
after 3 to 4 years of age. The natural history of tuberculosis
of the hip joint depends upon the site of the lesion, its
duration and the treatment given. The lesion is seen in
the superior part of the head of femur or contiguous area
in the acetabulum, the neck of femur, Babcocks triangle
or the greater trochanter24 (Fig. 13.2A). Tuberculosis of
the greater trochanter may involve the bursa overlying it
and is known as trochanteric bursitis.
Clinical Profile
The earliest complaint is pain in the hip joint often referred
to the knee. The child walks with a painful antalgic gait
and suffers from night cries, i.e. pain due to eroded joint
surfaces rubbing against each other resulting from relief
of muscle spasm during sleep.
There may be constitutional symptoms like low grade
fever, particularly in the evening, loss of appetite,
irritability, etc. On examination, in the initial stages of the
disease, there will be only tenderness over the hip
anteriorly (at the base of the femoral triangle) or over the
trochanter. In association, there will also be spasm in the
lower abdominal muscles and in the adductor muscles of
the hip. In an untreated case the disease follows through
the following stages:
Stage I
This is the stage of tuberculous synovitis. In this stage,
effusion in the hip joint causes a deformity of flexion,
Stage II
With the progression of the disease, there occurs
destruction/damage to the articular cartilage. At the hip
joint, flexion, adduction and internal rotation deformity
develops due to muscle spasm and capsular thickening.
There is appreciable muscle wasting and mild shortening
of the limb. All movements are limited. X-ray shows areas
of destruction, diminution of joint space and marked
osteoporosis (Fig. 13.2B).
Stage III
Destruction of the femoral head and acetabulum, and true
shortening are also added to the deformity as in stage II
(Fig. 13.2B). Movements are grossly restricted. X-ray shows
marked erosion of the articular cartilage and areas of
destruction in the head and neck of femur and acetabulum.
As the destruction of the acetabulum or the head of
femur increases further, it is likely to find a wandering
acetabulum or a frank dislocation of the hip. In some cases
the floor of the acetabulum is considerably weakened so
as to cause protrusio acetabuli.
It is rare to see patients during the synovitis stage. Most
often they present when the tuberculous disease has
already established. There is flexion, adduction and
internal rotation deformity of the hip with shortening. Not
uncommonly one comes across an unusual deformity, i.e.
flexion, adduction and external rotation of the hip even in
arthritis stage. This is usually seen in patients treated by
traction, or spica or in the unlikely event of destruction of
the iliofemoral ligament.
Figure 13.3 shows the AP radiograph of the tuberculosis
hip showing destruction of the head and acetabulum and
irregular joint space reduction on the right side.
Fig. 13.3: AP radiography of the tuberculosis of right hip showing

destruction of the head and acetabulum and irregular joint space
reduction with abduction deformity
Although this is the usual clinicoradiological picture,

one is often confronted with no cor-relation between the
clinical signs and the X-ray picture.21 Shanmugasundaram,25
therefore, evolved a clinicoradiological classification with
distinct radiological pattern which not only helps in
formulating an appropriate treatment plan but also in
predicting the end result.
Can we predict the final outcome of the disease in children at its
initial presentation?
Tuberculosis of the hip in children often ended in fibrous
ankylosis before the introduction of chemotherapy. With
the induction of chemo-therapy, more favorable results
were seen with good range of motion and without pain on
completion of chemotherapy. However, the outcomes were
quite often poor even with effective chemotherapy.
Shanmugasundaram25 (1985) showed that the radiological
appearance of the hip at presentation accurately predicts
the final outcome.
Shanmugasundaram reported 7 types of radiological
features at initial presentation:
1. Normal type,
2. Traveling acetabulum type ,
3. Dislocating type,
4. Perthes type,
5. Protrusioacetabuli type
6. Atrophic type, and
7. Mortar and pestle type.
He demonstrated that hips of normal type, Perthes
type and dislocating type with a normal joint space after
reduction will have a good result. A narrow joint space
after reduction (< 3 mm) predicted a poor result. Hips of
atrophic, traveling-acetabulum. Protrusioacetabuli and
mortar and pestle types have a poor result. In a normal
hip, the disease is mainly localised to the synovium.
205
Pannus does not proliferate over the area of joint cartilage.

Protective immunity is related to granuloma formation
and is seen in the normal, synovial type of tuberculous
hip disease. In the atrophic, traveling-acetabulum,
protrusioacetabuli and mortar-and-pestle types of
disease, irreversible damage has occurred before
presentation. It seems possible that tissue-destroying
hypersensitivity, causing subchondral erosion, may be
responsible for the atrophic hip , traveling-acetabulum,
protrusio-acetabuli, and mortar and pestle types. In the
normal type of disease chemotherapy almost invariably
gives a good or excellent result. Also Shanmugasundaram 25 reported that the mean duration of
symptoms in normal, Perthes, dislocating and atrophic
types varied from 4 to 7 months, and for the traveling
acetabulum, protrusio acetabuli and mortar and pestle
types, for 10 to 14 months.
The functional outcome of tuberculosis in other joints
also usually follows the amount of joint space preservation
on presentation. The lesser the joint space the worse is the
prognosis and vice versa.
Management
Antituberculosis Drugs
A three or four drug regime is started initially and then
maintained on two drugs for a total period of about 12 to
18 months. People now recommend therapy in the
maintenance stage for 9 to 12 months only.
Immobilization
The joint is immobilized temporarily for a period of 2 to 4
weeks for relief of pain and to overcome muscle spasm
or deformity. This may be done by traction or plaster cast/
slab.
Aim of Treatment
The primary aim of treatment is to provide painless
functional range of movement without deformity.
However, this may not be possible in all cases. Since
osseous lesions are more common than the synovial ones,
many cases may present with destruction or damage to
the articular cartilage. Therefore, based on the clinical and
radiological profile of a case, one must decide whether the
outcome of the treatment should be a mobile joint or a
fixed joint.
Mobile Joint
One can achieve a mobile joint when (i) the disease is
entirely synovial and the articular cartilage is not involved,
and (ii) the subchondral bone may be involved in an
osseous lesion but the articular surfaces are intact.
206
Fixed Joint
A fixed or an ankylosed joint is usually the out-come when
the articular cartilage is destroyed due to the disease
process. Any attempted movements in such a case can be
painful and at times impossible.
Treatment Directed to Achieve a Mobile Joint

In the early stage of the disease where there is an osseous
lesion without involving the articular cartilage, bilateral
skin traction is given to prevent spasm and deformity along
with anti-tuberculosis drugs. Intermittent gentle exercises
are recommended in individual cases. After 12 to 16 weeks
the traction is discontinued and non-weight bearing crutch
walking is instituted, which is followed by the weightbearing one once the disease is under effective control.
Careful monitoring of these patients is absolutely necessary
otherwise these patients may develop unwanted
deformities.
In acute tuberculous arthritis arthrotomy of the joint is
urgently required to relieve tension and to preserve the
articular cartilage. Postoperatively, the patient has to be
kept on traction; the subsequent management is identical.
The concept of early surgery aiming at mobility and
stability has been proposed by Vora.26 The aim, according
to him, was to carry out excisional surgery without
dislocating the hip. This included partial synovectomy of
the hip, curettage of cavities in the head and neck of femur
and acetabulum. He claimed full movement in 60% of cases
and painless functional range of movement in 33% of
cases.
Lesions in the roof of the acetabulum without involving
the hip joint require curettage of the lesion from outside
without entering the joint.
Treatment Directed to Achieve a Fixed Joint

The aim here is to achieve fusion (ankylosis) of the affected
joint in a functionally optimum position.
If the patient already has involvement of the articular
cartilage and the movements are res-tricted, the joint as a
functional entity is finished. In such a situation a hip spica
should be applied in the functional position so as to get a
sound ankylosis.
Arthrodesis (fusion) of the affected joint may be
achieved by surgical intervention. The affec-ted joint is
excised and raw surfaces of the bones of the joint, thus
created, are opposed to each other and are compressed by
an internal or external fixation.
In case the head and neck are completely destroyed,
curettage, after dislocating the hip joint, is resorted to and
the hip is immobilized in a functional position.
in the gait. Arthrodesis (intra-articular) of hip is not only

difficult to achieve in children but is quite unacceptable in
India because of the social customs and sitting habits.
Extra-articular arthrodesis was done in the
preantituberculosis drug era so as not to attack the disease
directly for fear of disse-minating it, but it is not practised
now.
TUBERCULOSIS OF THE KNEE JOINT

Tuberculosis of the knee joint is predominantly a synovial
lesion and becomes osseous only at a later stage. In the
beginning the child complains of pain and limping; there
is minimal synovial effusion with thickening. There is
considerable wasting of the thigh muscles. Spasm of
muscles may result in flexion deformity. Later on when
the articular cartilage is involved, the joint gets destroyed
and the knee joint may get deformed due to spasm of the
hamstring muscles. This deformity is known as triple
deformity and consists of flexion at the knee joint, posterior
subluxation of the tibia and external rotation of the leg.
The movements at this stage get comp-letely restricted.
X-ray appearance in the early stage may only show a soft
tissue shadow. Subse-q-uently involvement of the articular
cartilage is shown by diminution of joint space, irregularity
of the cartilage and areas of destruction in the epiphysis
(Fig. 13.4).
As time passes, if the destruction increases, further
evidence of deformity may be seen and the joint may
undergo fibrous or bony ankylosis.
Treatment
Aim of Treatment
The aim of treatment is to achieve a fully func-tional
painless joint. The outcome of treatment will depend upon
the extent of damage to the joint. Whether to achieve a
mobile joint or a fixed joint can again be decided on the
same principles as discussed in the treatment of
Treatment of Late Sequelae

Once the disease is healed, the deformity per-sists. A
corrective osteotomy results in appre-ciable improvement
Fig. 13.4: AP radiograph of tuberculosis of right knee joint in an

adolescent showing, irregular diminution of joint space and irregular
destruction of epiphysis.

tuberculosis of the hip joint. The patient is started on
antituber-culosis drugs and in the early stage of synovial
disease the patient should be treated on skin traction so as
to keep the joint surfaces apart. This helps in preventing
deformities. After 3 to 4 weeks when the disease gets
controlled, nonweight-bearing exercises can be started and
maintained so that the chances of giving a good functional
recovery increase. In synovial disease if it is hypertrophied
and the response to antituberculosis drugs is poor,
synovectomy should be done.
In case the articular cartilage is involved the patient
should be treated by plaster cast immo-bilization and
antituberculosis drugs. In case there is a lytic area in the
epiphysis, curettage of the lesion should be carried out so
as to prevent the disease from destroying the articular
cartilage. If the joint gets destroyed there is no chance of
achieving a satisfactory functional recovery and therefore,
the joint needs arthro-desis. Charnleys compression
arthrodesis is performed using Charnleys compression
clamps. Charnley27 believed that after a sound arthrodesis
in children the epiphyseal cartilage continues to grow and
the growth is not hampered, but there is a possibility of
hampering growth due to the compression effect.
These days, arthrodesis can also be perfor-med by
using Ilizarov apparatus. It perhaps gives more stability
and allows early ambulationfull-weight-bearing with
crutches.
TUBERCULOSIS OF THE ANKLE AND ELBOW

The lesion may be osseous or synovial in the ankle and
elbow. The clinical picture is the same as elsewhere, giving
rise to pain, swelling around the joint due to synovial
thickening and effusion, and limitation of movements once
the articular cartilage is involved (Fig. 13.5).
When the lesion is near the joint, early curettage will
prevent it from getting involved. In the elbow joint once
207
Fig. 13.6: Tuberculous dactylitis involving second metatarsal head
the lesion is healed and growth is complete, arthroplasty

can be perfor-med. In the ankle joint, if the movements are
lost, ankle arthrodesis can be performed after the growth
period is complete.
TUBERCULOSIS OF THE SHORT LONG BONES

Tuberculosis commonly involves the metatarsals and
phalanges (Fig. 13.6).
The lesion starts in the diaphysis as opposed to the
metaphysis in the long bones. This is because of the blood
supply of the short long bonesthe nutrient artery which
enters the bone in the middle of its shaft. Within a short
period the finger becomes fusiform and enlarged and painful.
The skin becomes smooth and shiny and an abscess may
form. As the bone gets involved, new subperiosteal bone is
laid down giving rise to a typical enlargement of the shaft
(Figs 13.7A and B). The condition is also known as spina
ventosa. The prognosis in this condition is good. The lesions
heal completely with antituberculosis drugs alone. If the
diagnosis is in doubt or if there is a discharging sinus,
involvement of all the flatbones including ribs, mandible,
pelvic bones, patella and skull bones with tuberculosis have
been reported.28-31 The lesion should be curetted out.
TUBERCULOSIS OF THE SPINE (POTTS SPINE)
Fig. 13.5: AP and lateral radiographs of tuberculosis of the ankle joint

showing epiphyseal and metaphyseal destruction of tibia and soft
tissue swelling around the ankle
Spine is the most common bone involved in tuberculosis27

and accounts for nearly 50% of all cases of osteoarticular
tuberculosis. Like all other skeletal tuberculosis, spinal
tuberculosis is secondary to a primary focus elsewhere in
the body. Spread is hematogenous either through the
arteries or through the Batsons plexus of veins (Fig. 13.8).
Proximity of the cisterna chyli may cause lymphatic
spread of the infection from foci in the mesenteric lymph
nodes. According to a recent estimate more than two
million patients all over the world have active spinal
tuberculosis and the incidence is increasing.
208
Figs 13.7A and B: Spina ventosa of 4th metacarpals: note the destruction, thickening and soft tissue swelling
with discharging wound over dorsum of 4th metacarpals (For color version see Plate 5)
The tuberculous infection in the vertebra starts at any

of the following sites:
Central
In this variety the central part of the body of the vertebra
undergoes destruction and eventually may collapse under
the body weight resulting into a wedge shaped vertebra.
Metaphyseal
Fig. 13.8: Blood supply of vertebrae
Tuberculosis of the spine commonly affects the

thoracolumbar spine, however, it is also seen in the other
regions of the spine. The thoracolumbar spine is
commonly affected because of the excessive stresses and
strains it is subjected to, due to excessive mobility in this
region.
The disease is more severe in children less than 10
years of age. The average vertebral involvement and
vertebral destruction is more in children leading to more
severe deformity and disability.32-35 Atypical spinal
tuberculosis mani-festing as an involvement of single
vertebral extradural extraosseous involvement
presenting as abscess, and isolated infections of the
neural arch and spinal tuberculosis in newborn have
been reported.30,31
This is the most common type in which the disease starts

under the end plate of the vertebra (close to the
intervertebral disc) either at its superior or inferior end.
The adjacent parts of two vertebrae are generally affected
because the intercostal artery supplies the two adjacent
vertebrae. The vertebral end plates are destroyed and the
nutrition of the intervertebral disc suffers which gets
reduced in size. The radiographic finding of destruction
of a vertebra along with diminution of the intervertebral
disc space is considered to be pathognomonic of a tuberculous lesion of the spine.
Anterior
This is a rare type where the disease starts in the vertebra
under the anterior longitudinal ligament.
A lesion under the posterior longitudinal ligament is
extremely rare and is also termed as spinal tumor
syndrome.
Appendiceal
Vertebral appendages such as lamina, spinous process,
etc. are rarely involved in children.
209
Clinical Picture
A few patients may present with constitutional symptoms
such as fever, cough, loss of appetite and weight, but
generally pain is the predomi-nant symptom.
The child generally complains of pain in back, more at
night time. The pain is localized over the affected area of
the spine. Occasionally, the patient may feel referred pain
(called as girdle pains) along the intercostal nerves, in
tuberculosis of the dorsal spine. Tenderness at the local
site and spasm of the paraspinal muscles are also evident.
Any part of the spine can be affected but it most commonly
involves the lower dorsal and dorsolumbar regions.36,37
Cold Abscess
Tuberculous infection causes destruction, casea-tion and
necrosis of the vertebra. Pus forms and may come out of
the vertebra and present as an abscess. The abscess may
remain close to the vertebra and present, on the
radiography, as prevertebral or paravertebral abscess; or
may present clinically as a cold abscess.
Cold abscesses in tuberculosis spread along the fascial
planes or along the neurovascular bundles. In the cervical
spine it collects behind the prevertebral fascia and many
present as a retropharyngeal abscess. It may also spread
to posterior or anterior triangle in the neck. It can also
track in the mediastinum. In the thoracic region, it may
present as a paravertebral abscess or may track along the
intercostal vessels on the chest wall. In the lumbar spine it
tracks in the psoas sheath and may present as a psoas
abscess or may present in the lumbar triangle at the back.
The abscess may also present on the medial side of the
upper thigh and may simulate as femoral hernia. Lesions
from the lumbosacral junction may present as a pelvic
abscess and through the greater sciatic notch may find a
place in the gluteal region.
Paralysis
Compression of the spinal cord can result into paralysis,
the extent of which depends upon the level and area of the
cord involved. The para-lysis may be incomplete or
complete with bladder and bowel involvement.
When the infection is in the cervical region, quadriplegia
may develop; the upper limbs are involved before the lower
limbs.
Deformity
The disease causes collapse of the vertebra and a slight
kyphosis may develop. As the disease progresses more,
vertebrae collapse and a more severe kyphosis results
(Fig. 13.9) which causes development of secondary lordotic
curves below and above the kyphotic curve. The collapse
of vertebrae in children is more marked because a large
Fig. 13.9: Kyphosis due to collapse of vertebrae
amount of cartilage is present. Influence of growth during

childhood is a significant factor in the causation of
deformity. When the metaphyseal region is destroyed the
posterior elements continue to grow; this differential
growth increases the deformity even though the disease
may become quiescent. The deformity itself may give rise
to two dreaded complications, i.e. paraplegia and
cardiopulmonary complications, although it must be
mentioned here that deformity is not a common cause of
paraplegia.
Since tuberculosis is more common in the dorsal or
dorsolumbar spine, paraplegia is more common. In fact,
paraplegia is quite often the presenting feature in
tuberculosis of the spine. Its incidence varies from 16 to
35%.38-40 Paraplegia in tuberculosis has crippling complications. Earlier, the paraplegia was differentiated into (i)
paraplegia of early onset, and (ii) paraplegia of late onset;
but it is pragmatic to differentiate it betweenparaplegia
with or without active disease. Paraplegia associated with
active disease may be early or late.
The causes of paralysis in tuberculosis of the spine
are:
Pressure on the cord due to abscess, granula-tion tissue
or edema.
Mechanical pressure on the cord by sequestra, pus,
and granulation tissue.
Angular deformity of the spine with sub-luxation.
Thrombosis of the anterior spinal artery.
Tuberculoma or diffuse extradural granu-loma of the
cord.
It must be appreciated that in a given patient, there
may be more than one cause for paraplegia.
210
Unsteady gait (due to spasticity) is the earliest symptom

and clonus is the most prominent early sign of paraplegia
(Potts paraplegia).
Paralysis may increase with varying rapidity through
the following stagesgirdle pain, muscle weakness,
spasticity, incoordination, paraplegia in extension, and
the pressure increases to paraplegia in flexion. Bowel and
bladder control are lost and in the most severe form the
paralysis becomes flaccid. Sensory involvement is
uncommon and occurs usually late.
Investigations
Investigations are the same as for any other type of
tuberculosis.
Radiology
Plain X-ray
The anteroposterior and lateral views is often sufficient
for the diagnosis. The lateral view is particularly important
as it gives more information than the anterior posterior
(AP) veiw. The earliest features on lateral view are
diminution of the intervertebral disc space (Fig. 13.10A).
Later on one may also see destruction and collapse of the
vertebra. Anteroposterior view may show destruction of
the pedicle and a paravertebral shadow, cast by an abscess
in that area (Fig. 13.10B). Even with resolution of the acute
infectious process the kyphosis may continue and cause
compression of the cord and late neurological sequelae.
Generally, speaking the following radio-graphic

changes are seen:
Diminution of the intervertebral disc space.
Lytic lesion in the vertebra leading to collapse.
Generalized osteoporosis of spine.
Presence of a paravertebral abscess which may be
fusiform or more globular in nature.
In early stages there is a central vertebral lesion without
diminution of the intervertebral disc space.
Subsequently the disc also gets involved.
In a large number of cases skip lesions at different levels
are also encountered.
Bone scintigraphy with technetium-99 m will often show
a hot spot.
Magnetic resonance imaging (MRI) provides an early
diagnosis since it can pick up changes like destruction
of the vertebra and soft tissue abscesses much before
they become evident on plain X-rays. Therefore, MRI is
very useful in doubtful cases (Fig. 13.10C). Common
MRI findings in tubercular spondylitis are
hypointensity of the involved tissue on T1 weighted
images, hyperintensity on T2 weighted images (Fig.
13.10C) destruction of 2 or more adjacent vertebral bodies
with involvement of the intervening disc and epidural and
paraspinal extension and or abscess.
Children have a higher deformity at presentation, a
greater tendency for collapse during the active phase of
the disease, and continued and variable progression even
after the disease is cured, due to variable destruction of the
vertebral growth plates. Tuli et al42 observed that children
Figs 13.10A to C: Tuberculosis of the spine. A. Lateral view; B. AP view showing

destruction of D4-5 vertebrae; C. MRI Showing destruction and prevertebral and
epidural abscess (T2weighted)

< 10 years of age with more than 3 adjacent vertebral
involvement had a higher spinal deformity on follow-up.
In children, the changes during the period of growth are
more important than changes during the active period of
the disease which usually determines the progress of
deformity. Children prone for such late progressive
collapse can be identified during the early stages by the
presence of spine at risk radiologic signs. Four radiologic
signs have been described by Rajasekaran43 to indicate
the presence of spinal instability in active stage (Fig. 13.11).
a. Facet joint separation (Subluxation),
b. Posterior body retropulsion,
c. Lateral translation and
d. Tilt or toppling.
Each of these sign is given a score of one with a
maximum score of four. A spinal instability score of more
than two is associated with a significantly higher chances
of progression of kyphotic deformity.
These signs are useful clinically because they occur
early in the course of the disease and preventive surgery
for progressive collapse can be advocated. Late progression
and surgical correction of an established deformity is
associated with a high rate of morbidity and can be avoided.
Presence of these Spine at Risk signs should alert the
pediatrician/family physician to refer the patient to a
specialist dealing with spinal deformities for early surgical
intervention to avoid late onset paraplegia with
progression of kyphosis.
211
Myelography
Although myelography has largely been replaced now
by other imaging modalities, but in some unusual cases
of Potts paraplegia where the neurological picture does
not correspond to the osseous lesion, or when multiple
skip lesions are present, myelography may be useful in
determining the level of obstruction (Fig. 13.10.C).
Needle Biopsy
A needle biopsy of the vertebra done by using an image
intensifier or CT guided, may be necessary in an unusual
situation to clinch the diagnosis.
Treatment
Chemotherapy
These children need the same general treatment, i.e. good
nutrition, rest and antituberculosis drugs. Drug therapy
used to be given for a total period of 18 months. Minimal
duration of therapy should be six months. In a systematic
review41 of chemotherapeutic treatment for spinal TB, it
was concluded that six months of therapy is probably
sufficient for the majority of cases. Both six and nine months
treatment regimens give acceptable rate of recovery.
The United States Centers for Disease Control
recommend that for infants and children with miliary TB
or bone and joint TB, treatment should last at least
Fig.13.11: Spine at risk radiologic signs
212
12 months. Treatment would probably be needed to be

prolonged in immuno-compromised subject such as HIV
or malignancies. In children the response of conservative
management is generally good. The spine of these
children has to be protected from collapsing, which can
be achieved by providing a plaster jacket for about three
months. A plaster jacket in the initial stages of treatment
can restrict the degree of kyphotic deformity of the spine.
The progress of the disease can be monitored by clinical
and radiological methods. Even in case of Potts
paraplegia the response to treatment is good. Most
authors believe that the results of conservative treatment
in children are satis-factory.44 However, in some cases
the abscess or the paraplegia may increase despite
adequate conservative treatment and may require surgical
intervention.
Indications for Surgery (Middle path regimen)42

i. Neurological deficit not improving with adequate trial
of chemotherapy (3 to 4 wks)
ii. Neurological deficit developing during antitubercular
chemotherapy
iii. Neurological deficit worsening during antitubercular
chemotherapy
iv. Recurrence of neurological complication
v. Difficulty in deglutition/respiration with cervical
abscess
vi. Advanced acute neurological deficit with flaccid/
flexor spasms and bladder involvement.
In case of paraplegia associated with a tense bird
nest type of paravertebral abscess, costotransversectomy may suffice. If on removing the rib and
transversed process, pus is not encountered one may
proceed to do an anterolateral decompression. In case
of a healed vertebral body lesion (Fig. 13.9) resulting in
an increasing defor-mity due to differential growth,
posterior spinal fusion must be done as a preventive
measure.
HIGHLIGHTS
Tuberculosis of the bones and joints is still common
in children in India.
It has been discussed under the following three hands:
Bone tuberculosis
Tuberculosis of the joints
Spinal tuberculosis.
Joint involvement is relatively less common. Mostly
big joints such as hip and knee are involved.
Spinal tuberculosis is most common.
Newer modalities in radiology, MRI are available for
diagnosis in difficult cases and those whose response
to conservative therapy is not satisfactory.

Mainstay of management is:
Short-course chemotherapeutic regimens lasting
for 6-9-12 months depending upon the response
of the patients along with general measures of rest
and good nutrition.
Indications of surgical intervention have been
clearly defined depending upon the site of
involvement.
REFERENCES
1. Duthie RB, Bentley G. Skeletal tuberculosis. In: Mercers
(Ed). Orthopedic Surgery, 9th edn. London: Arnold
publications 1996;596.
2. Starke JR, Smith MHD. Tuberculosis. In: Feigin RD, Cherry
TD (Eds): Textbook of Pediatric Infectious Diseases, 4th
edn. London: WB Saunders company 1998;1196-1239.
3. Luckheie M. Tuberculosis of cervical spine. South Afr Med
J 1996;86:553-6.
4. Wilkinson MC. Observations on the pathogenesis and
treatment of skeletal tuberculosis. Ann R Coll Surgery
Engl 1949;4:168-71.
5. Girdlestone GR, Somerville EW. Tuberculosis of bone
and joint. 2nd edn. London: Oxford University Press; 1952.
6. Mukhopadhyaya B. The role of excisional surgery in the
treatment of bone and joint tuberculosis. Ann R Coll Surg
Engl 1956;18:288-313.
7. Grewal KS, Singh M. Tuberculosis of spine. Indian J Surg
1956;18:394-405.
8. Mukhopadhyaya B, Mishra NK. Tuberculosis of the
Spine. Ind J Surg 1957;19:59-81.
9. Tuli SM, Srivastava TP, Verma BP, et al. Tuberculosis of Spine.
Acta Orthop Scand 1967;38:445 58.
10. Lack CH. Chondrolysis in arthritis. J Bone Joint Surg
1959;41-B:384.
11. Engvall E, Perlmann P. Enzyme-linked Immunoabsorbent Assay (ELISA) Test. Immunochemistry
1971;8:871.
12. Mondal A, Mitra S, Mitra D, et al. Role of fine needle
aspiration biopsy in cytological diagnosis of vertebral
tuberculosis. Indian J Tuberc 1996; 43:15-8.
13. Arora S, Seth S. Isolated tubercular tenosynovitis in
children. J Pediatr Orthopedics 1994;14:752-4.
14. Versefeld GA, Solomon A. A diagnostic approach to
tuberculosis of bones and joints. J Bone Joint Surg 1982;64B:446.
15. Jacobs JC, Lis C, Ruzal-Sharpino C, et al. Tuberculous
arthritis in children, diagnosis by needle biopsy of the
synovium. Clin Pediatr 1994; 33:344-8.
16. Seth Vimlesh. Management of tuberculosis. In: Seth
Vimlesh and Kabra SK (Ed): Essentials of Tuberculosis in
Children. 1st edn. New Delhi: Jaypee Brothers Medical
Publishers Pvt. Ltd. 2006; 530-8.
17. Medical Research Council Working Party on Tuberculosis
of Spine. A controlled trial of ambulant outpatient
18.
19.
20.
21.
22.
23.
24.
24a.
25.
26.
27.
28.
treatment and inpatient rest in bed in the management

of tuberculosis of spine in young Korean patients on
standard chemotherapy. J Bone Joint Surg 1973;55-B:678.
Medical Research Council Working Party on Tuberculosis
of Spine. A five year assessment of controlled trials of
inpatient and outpatient treatment with plaster of Paris
jackets for tuberculosis of spine in children on standard
chemotherapy. J Bone Joint Surg 1976;58-B: 399.
Fellander M, Hirtonn T, Wallmark G. Studies on the
concentration of streptomycin in the treatment of bone
and joint tuberculosis. Acta Tuber Scand 1952;27:176-89.
Barclay WR, Elbert RH, Le Roy. Distribution and excretion
of radioactive isoniazid in tuberculous patients. J Am Med
Assoc 1953;151:1384-8.
Haungren A. Studies on the distribution and fate of C 14
and T-labelled p-aminosalicylic acid (PAS) in the body.
Acta Radiol (Suppl)1959;175.
Friedmman B, Kapur VN. Newer knowledge of
chemotherapy in the treatment of tuberuclosis of bones
and joints. Clin Orthop 1977;97:5-15.
Tuli SM, Brighton CT, Morton HE, et al. Experi-mental
induction of localized skeletal tuberculous lesions and
accessibility of such lessions to antituberculous drugs. J
Bone Joint Surg 1974; 56-B:551-9.
Somerville EW, Wilkinson MC. In: Girdlestone (Ed). Tuberculosis of bone and joints. London. Oxford University
Press 1965;43.
Hazara A, Laha Baisakhi. Chemotherapy of osteoarticular
tuberculosis. Indian J Pharmacol 2005;37:5-12.
Shanmugasundaram TK. Current concepts in bone and
joint tuberculosis. Chennai, Documentation Center,
International Bone and Joint Club, 1985.
Vora PH. Role of early surgery in the management of
tuberculosis of the hip: In: Shanmugasundaram TK (Ed).
Current concepts in bone and joint tuberculosis. Chennai:
Documentation Centre, International Bone and Joint Club,
1985.
Charnley J. Compression arthodesis. London: E and S.
Livingstone Ltd. 1953.
Change JH, Kim SK, Lee WY. Diagnostic issues in
tuberculosis of ribs with a review of 12 surgically proven
cases. Respirology 1999;4:244-53.
213
29. Unuwar E, Oghuz F, Sadikooglu B, et al. Calvarial

tuberculosis. J Pediatr Child Health 1999;35:221-2.
30. Erasmus JH, Thompson JO, Vanerwesthinzen AJ.
Tuberculous osteomyelitis of mandible report of a case. J
Oral Maxiflofac Surg 1998;56:1355-8.
31. Dillon MS, Rao SS, Sandhu MS, et al. Tuberculosis of
patella. Skeletal Radiology 1998; 27: 40-2.
32. Rajasekaran S, Shanmugasundaram TK, Prabhakar R, et
al. Tuberculous lesion of the lumbosacral region. A 15
years follow-up of patients treated by ambulatory
chemotherapy. Spine 1998;23:1163-7.
33. Tuli SM. Severe kyphotic deformity in tuberculosis of the
spine. Int Orthop 1995;19:327-31.
34. Beekarun DD, Govender S, Rasool MN. Atypical spinal
tuberculosis in children. J Pediatr Orthop 1995;15:
148-51.
35. Gupta DK, Gopal, Sharma SP, et al. Neonatal tuberculosis
of the spine. Trop Doctor 1998;28: 119.
36. Paus B. Treatment for tuberculosis of spine. Acta Orthop
Scand (suppl): 1964;72.
37. Hodgson AR, Yau ACMC. Anterior surgical approaches
to the spinal column. In: Apley AG (Ed). Recent
Advances in Orthopaedics. London: J and A. Churchill,
1969; 289-323.
38. Hodgson AR, Stock FE. Anterior spinal fusion for
tuberculosis of spine. J Bone Joint Surg 1960;42-A:295.
39. Martin NS. Tuberculosis of the spine. J Bone Joint Surg
1970;52-B:613.
40. Tuli SM. Results of treatment of spinal tuberculosis by
middle path regime. J Bone Joint Surg 1975; 57-B:13.
41. Van Loenhout-Rooyackers JH, Verbeek AL, et al.
Chemotherapeutic treatment for spinal tuber-culosis. Int
42. Tuli, S.: Tuberculosis of the Skeletal System, New Delhi,
Jaypee Brothers Medical Publishers Pvt Ltd 1997;
241.
43. Rajasekaran S. The problem of deformity in spinal
tuberculosis. Clinical Orthopaedics and Related Research
2002; 398: 85-92.
44. Moon MS, Kim I, Woo YK, et al. Conservative treatment
of tuberculosis of the thoracic and lumbar spine in adults
and children. Int Orthopaedics 1987;11:314-22.
14
Arvind Bagga
Genitourinary tuberculosis is a common form of extrapulmonary tuberculosis, and is secondary to a

symptomatic or asymptomatic pulmonary lesion.1 Renal
involvement may occur secondary to miliary tuberculosis.
Approximately 10% of patients with pulmonary
tuberculosis are at risk of developing this complication.2
The kidney is usually the primary organ involved and
other organs are involved by direct extension.3 The onset
and course of the disease is insidious, hence diagnosis
and treatment are delayed, resulting in high rate of
urogenital organ destruction and renal failure. In children
the disease typically presents in late adolescence, chiefly
due to the time lag between primary infection and
urogenital involvement.
PATHOGENESIS
Once inhaled, the bacilli multiply in the pulmonary alveoli
with primary granuloma formation; the infection is
clinically silent and self-limited. The multiplying M.
tuberculosis organisms might be implanted in other organs,
including the renal and prostate parenchyma. The patient
then enters a latent phase, with likelihood of disease
reactivation in the following 4 to 5 years. In most cases,
latent foci are reactivated following reduction in immunity,
secondary to malnutrition, measles or pertussis infection,
use of corti-costeroids and/or immunosuppressive agents
and immunodeficiency.4
The mean latent period between pulmonary infection
and clinical features of urogenital tuberculosis is 22 years.5
After reactivation, infection progresses from a single
focus, affecting one kidney and sparing the other. This
accounts for the greater frequency of unilateral renal
tuberculosis. The renal infection is progressive,
asymptomatic, and highly destructive. 6 Kidney
destruction may be due to progression of the focal lesion,
with caseous granuloma formation, fibrosis and renal
cavitation, and obstruction of the urinary collecting
system. The spread to renal pelvis causes pyonephrosis
like lesions, the cement or putty kidney.7 Multiple
stenoses may develop throughout the ureter, resulting
in the beaded or cockscrew ureter. The site commonly
affected is the ureterovesical junction. In bladder
tuberculosis, the earliest forms of infection start around
ureteral orifice followed by an acute inflammatory
process, ulceration, and tubercle formation in the vicinity

of the ureteral meatus, with subsequent fibrosis of the
bladder wall.
Tuberculosis affects the whole male genital tract, with
lesions in the prostate, seminal vesicles, vas deferens,
epididymis and testis. Genital tuberculosis in males most
commonly involves the epididymis followed by the
prostate. Tuberculous epididymitis is a result of bloodborne infection, since it is often an isolated finding
without urinary tract involvement. The disease usually
starts in the globus minor, because it has a greater blood
supply than other parts of the epididymis.
CLINICAL PRESENTATION
Classic symptomatic renal tuberculosis is late and
uncommon complication in children, rarely occurring
less than 4 to 5 years after the primary infection.
Therefore, the condition is most commonly diagnosed
after adolescence. Adult studies have shown that 26 to
75% of renal tuberculosis coexists with active pulmonary
tuberculosis and 6 to 10% of patients with sputumpositive pulmonary tuberculosis have renal involvement.
Most children with the disease are asymptomatic.
They may present with symptoms related to the organ
involved or may have long standing unexplained
urological problems. The common features at
presentation are: (i) recurrent or resistant urinary tract
infection (UTI), sterile pyuria with or without hematuria;
(ii) irritative voiding symptoms, e.g. urgency, frequency,
dysuria; (iii) renal or epididymal mass; and (iv) impaired
renal functions. Occasionally the diagnosis of renal
tuberculosis is made incidentally in a patient with known
The patient may not manifest overt symptoms, but
has persistent leukocyturia. Microscopic hematuria is
present in 50% cases. Undiagnosed and untreated renal
tuberculosis may have a wide spectrum of clinical features,
which mimic other conditions including pyelonephritis,
renal colic, stones, sepsis and renal failure. Tuberculosis
can cause renal failure by two mechanisms that involve
intrinsic infection within the renal parenchyma or
obstructive uropathy. Patients with tuberculosis and AIDS
may show kidney and prostate abscesses.8
Chapter 14 Genitourinary Tuberculosis

Involvement of bladder is usually secondary to renal
infection and is found in one-third of patients. The chronic
inflammation and decrease in bladder capacity cause
symptoms of urinary frequency and urgency. Patients
with thimble bladder (due to mural fibrosis) present
with urinary incontinence. Chronic inflammation at
vesicoureteric junction leads to golf hole ureter.
Involvement of the prostate gland, urethra and male
genitalia is rare in children. Tuberculous epididymitis
may be the first and only presenting symptom of
genitourinary tuberculosis.
215
Imaging
The tuberculin test is a standard screening tool for detection

of tuberculosis exposure. Patients with end-stage renal
disease have a compromised immune status that may mute
skin test response. QuantiFERON gold test and Elispot
may offer a better method for detecting tuberculosis
infection in patients with end-stage renal disease.
Definitive diagnosis of genitourinary tuberculosis involves
demonstration of M. tuberculosis by micro-biological,
cytopathological and histopathological methods.
Plain Radiographs: Plain X-ray films may show

calcification in the renal areas and in the lower
genitourinary tract. Renal calcification may not
represent inactive process.
Ultrasonography, Computed Tomography: Ultrasound
examination may reveal renal calyceal dilation and
overt evidence of obstruction. Increased echogenicity
of the renal pelvis is a feature of advanced disease as a
result of fibrosis and scarring. Computed tomography,
which can identify calyceal abnormalities, renal
parenchymal destruction and hydronephrosis, has
replaced intravenous urography as the imaging
modality of choice.11
Intravenous Urography: Intravenous urography may
show changes in a single calyx with evidence of
parenchymal necrosis. In more advanced disease,
urography will show calyceal distortion, ureteric
strictures and bladder fibrosis.
Cystoscopy, Bladder Biopsy: Cystoscopy is rarely
indicated for diagnostic purposes. Bladder biopsy
should be avoided in the presence of acute
tuberculous cystitis to prevent dissemination of the
disease, but may be done after 4 to 6 weeks of therapy.
Urine Examination
Radioisotope Studies
Sterile pyuria is the classic finding on urinalysis and

culture. Detection of acid-fast bacilli from urine samples
by microscopy (Ziehl-Neelsen acid fast stain) is not
reliable, because of the possible presence of M. smegmatis,
which are acid-fast bacilli too. At least three, but
preferably five, consecutive early morning specimens of
urine should be cultured. Urine cultures require 6-8 weeks
in Lowenstein-Jensen medium and the sensitivity ranges
between 80 to 97%.9
They are used to determine split renal function and for

evidence of obstruction in advanced disease.
Radioisotope imaging with diethylene triamine
pentacetic acid (DTPA) provides information on
differential renal function and mercaptotriacylglycine
(MAG3) provides information on whether the collecting
system is obstructed.12
DIAGNOSIS
Screening Tests
Rapid Identification of Mycobacterium

Radiometric liquid systems, i.e. BACTEC give rapid
results and are highly sensitive. These methods have the
limitations of requiring the need of radioactive materials
and expensive apparatus. In the mycobacteria growth
indicator tube (MGIT), growth of the organism is detected
by a nonradioactive detection system. This system helps
in early detection (7-12 days) of bacterial growth and is
useful for drug susceptibility testing.
Polymerase Chain Reaction

Polymerase chain reaction for M. tuberculosis is a useful
diagnostic tool since it provides results in 24 to 48 hours
and allows diagnosis even when there are few bacilli. The
investigation is highly (95.6%) sensitive and specific
(98.1%).10
THERAPY
Genitourinary tuberculosis is a severe form of disease,
and the bacterial load is similar to cavitatory pulmonary
tuberculosis. If not treated aggressively, infection might
lead to irreversible structural lesions. Yearly urine
assessment is advocated for all patients with history of
pulmonary tuberculosis, especially in those who are
immunocompromised.13
Short-course anti-tuberculous therapy for 6 months
is an effective mode of therapy. Therapy includes an initial
2 months intensive phase with administration of 3 to 4
medications daily [rifampicin, isoniazid, pyrazinamide and
ethambutol (or streptomycin)] followed by 4 months
continuation phase with two drugs (rifampicin, isoniazid).
In the latter phase, the drug may be given twice or thrice
weekly. In complicated cases (recurrence of tuberculosis,
immunosuppression and HIV), longer duration (9-12
months) of therapy is necessary. In HIV-patients, the
216
antiretroviral therapy interacts adversely with rifampicin.

When rifabutin is used instead, therapy must be extended
to 9 to 12 months.
Short-term (4-9 months) treatment is justified because of
good renal vascularity, high urinary concentration of drugs,
low bacillary load in urine and similar efficacy compared to
longer duration regimens.14 Most investigators recommend a
10 years follow-up after pharmacologic treatment because of
the risks of late relapse. There is no evidence to support the
routine use of corticosteroids for preventing ureteric strictures
in patients with renal tuberculosis.15
Dose Modification in Renal Failure

Special considerations apply to the treatment of
tuberculosis in patients with impaired renal function.
Rifampicin, isoniazid, pyrazinamide and ethionamide may
be given in normal dosage. They are eliminated in the bile
or broken down to metabolites that are not excreted by
the kidney. Care is required in the use of streptomycin
and ethambutol. These are wholly excreted via kidney.
Surgical Treatment
Surgery might be required in the following instances: (i)
drainage of hydronephrosis (ureteric stenting or
percutaneous nephrostomy); (ii) drainage of abscesses and
collections; (iii) partial nephrectomy; (iv) reconstruction of
the upper urinary tract; (v) bladder augmentation; and (vi)
reconstruction of the urethra.16
In most cases, patients should receive at least 4 weeks
of intensive chemotherapy before surgery. Early ureteral
stenting or a percutaneous nephrostomy may be useful in
patients with tubercular ureteral strictures, and enable the
possibility of later reconstructive surgery and decrease the
likelihood of renal loss. Every effort must be made to
preserve functioning renal tissue. In cases of a unilateral
nonfunctioning kidney, most experts recommend
nephrectomy to avoid relapse, eliminate storage
symptoms, treat hypertension and avoid abscess
formation. Relapse is likely if a nonfunctional kidney is
not removed, since pharmacological treatment might not
sterilize all tuberculous foci.17,18
HIGHLIGHTS
Genitourinary tuberculosis is rare in childhood.
Given the long latent period between onset of
pulmonary and urogenital tuberculosis, the latter
diagnosis is usually made during adolescence.
Kidneys are the chief organ affected; disease involving
the ureters and urinary bladder is often secondary.
The diagnosis of genitourinary tuberculosis is based
on multiple urine cultures.
Polymerase chain reaction for M. tuberculosis

identification in the urine is a useful diagnostic tool
since it gives results in 24 to 48 hours and allows for
diagnosis to be made even when there are few bacilli.
Appropriate imaging studies are highly sensitive for
detecting urogenital tuberculosis.
Medical treatment for 6 months is the first line
therapy for genitourinary tuberculosis. Patients with
recurrences of tuberculosis, immunosuppression
and in the setting of HIV infection/AIDS require
therapy for 9 to 12 months.
Surgery may be ablative, with removal of the
nonfunctional kidney or epididymis, or
reconstructive for unblocking the collecting system
or augmentation of the contracted bladder.
REFERENCES
1. Chattopadhyay A, Bhatnagar V, Agarwala V, et al.
Genitourinary tuberculosis in pediatric surgical practices.
J Pediatr Surg 1997;32:1283-6.
2. Ferrie BG, Rundle JS. Genitourinary tuberculosis in
Glasgow 1970 to 1979: a review of 230 patients. Scott Med
J 1985; 30: 30-4.
3. Leite OHM. Tuberculosis. Problems Gen Surg 2001;18:
69-78.
4. Christensen WI. Genitourinary tuberculosis. Review of
102 cases. Medicine (Baltimore) 1974; 53: 377-90.
5. Narayana AS. Overview of renal tuberculosis. Urology
1982;19:231-37.
6. Eastwood JB, Corbishley CM, Granje J. Tuberculosis and
the kidney. J Am Soc Nephrol 2001;12:1307-14.
7. Clinman AC. Genitourinary Tuberculosis. Urology
1982;20:353-8.
8. Trauzzi SJ, Kay CJ, Kaufman DG, et al. Management of
prostatic absess in patients with human
immunodeficiency syndrome. Urology 1994; 43: 629-33.
9. Katoch VM. Newer diagnostic methods for tuberculosis.
Indian J Med Res 2004;120:418-28.
10. Negi SS, Khan S F, Gupta S, et al. Comparison of the
conventional diagnostic modalities, BACTEC culture and
polymerase chain reaction test for diagnosis of
tuberculosis. Indian J Med Microbiol 2005; 23: 29-33.
11. Wang LJ, Wu CF, Wong YC, et al. Imaging findings of
urinary tuberculosis on excretory urography and
computerized tomography. J Urol 2003, 169:524-8.
12. Warren D, Johnson JR, Johnson CW, et al. Lowe:
Genitourinary Tuberculosis, Campbells Urology, 8th edn.
Philadelphia. Saunders 2002; pp 744-63.
13. Caminero JA. Treatment of tuberculosis In: Caminero JA,
(Ed). A tuberculosis guide for specialist physicians. Paris:
Disease 2004; 8: 162-200.
14. Weinberg AC, Boyd SD. Short-course chemo-therapy and
role of surgery in adult and pediatric genitourinary
tuberculosis. Urology 1988;31: 95-102.
15. Cek M, Lenk S, Naber KG, et al. Members of the Urinary
Tract Infection (UTI) Working Group of the European
Association of Urology (EAU) Guidelines Office. EAU
Chapter 14 Genitourinary Tuberculosis

guidelines for the management of genitourinary
tuberculosis. Eur Urol 2005; 48: 353-62.
16. Global Tuberculosis Program, Treatment of Tuberculosis:
Guidelines for National Control Program 3rd edition,
Geneva. World Health Organization, 2003 (WHO/CDS/
TB/2003.313).
217
17. Lee KS, Kim HH, Byun SS, et al. Laparoscopic

nephrectomy for tuberculous non-functioning kidney:
comparison with laparoscopic simple nephrectomy for
other diseases. Urology 2002; 60:411-4.
18. Wong SH and Lau WY The surgical management of nonfunctioning tuberculous kidneys. J Urol 1980; 124: 187-91.
15
15.1 TB IN HIV-INFECTED CHILDREN

BJ Marais, PR Donald
EPIDEMIOLOGY
Exposure
Globally, the tuberculosis (TB) epidemic remains rampant

in areas affected by poverty,1 war,2 and in particular by
human immunodeficiency virus (HIV) infection.3-5 The HIV
epidemic and especially its impact on children, is also
greatly influenced by conditions of poverty.6 Children in
these areas carry a disproportionately large TB disease
burden that is frequently not appreciated.7,8 In an attempt
to improve collection of the most relevant data, recent World
Health Organization (WHO) guidelines recommend that
National TB Programs should report 1) the HIV status of all
TB cases9 and 2) the number of child TB cases; in two age
bands, less than 5 and 5-15 years of age.10 Hopefully this
will raise awareness and improve data collection to better
quantify the extent of the child TB epidemic and the impact
of HIV. However, the data on children in the latest WHO
report 10a is not available.
Initial evidence relating HIV infection and childhood
TB appeared conflicting, as autopsy studies indicated that
TB was an uncommon cause of death in HIV-infected
children11 although clinical studies documented high HIV
prevalence rates among children diagnosed with TB.12,13
However, more recent autopsy and clinical studies confirm
the high TB-related morbidity and mortality suffered by
HIV-infected children,14-16 with an estimated 20 fold
increase in TB incidence compared to HIV-uninfected
children.17 In a hospital-based study from South Africa, M.
tuberculosis was one of the most common organisms isolated
from children with community acquired pneumonia that
failed to respond to first line antibiotics; being present in
18% and 29% of HIV-infected and uninfected infants
respectively (of those in whom an organism was identified),
versus 39% and 57% of those older than 1 year of age.18
Another prospective study documented 23.4 cases of active
TB per 100 HIV-infected children per year.19 These high
disease rates may be explained by 1) an increased risk of TB
exposure/infection and/or 2) an increased risk of
progression to active disease following TB infection.
The HIV epidemic has caused a marked increase in the

incidence of TB. In the case of pulmonary TB this is true
of both sputum smear-positive and smear-negative
disease. In addition, there has been a pronounced age
and gender shift with a lowering in the peak ageprevalence, the highest incidence of TB now occurs
among young adults (20-35 years),20-21 and an increase
in the proportion of women. The high prevalence of both
TB and HIV among adults in their reproductive years
increases the risk of TB exposure and infection at a very
young and vulnerable age.3 In high prevalence areas,
routine HIV-testing and active TB case-finding among
HIV-infected pregnant women should be implemented
to decrease the perinatal risks for mother and baby.
Managing a baby born to a mother who is co-infected
with TB and HIV is difficult; ensure that the mother is
optimally treated and regard the baby as being at risk for
TB, HIV and other congenital infections. Counseling and
preventive measures to reduce the risk of HIV transmission
to the baby is needed together with appropriate HIV-related
care. The possibility of active TB in the baby needs to be
considered and treated. If the baby does not have active
TB, then isoniazid preventive therapy (IPT) is indicated if
the mother remains symptomatic or has been on TB
treatment for less than 2 months. During screening for
enrollment into a prospective IPT trial, TB exposure/
infection was documented in 77 (10.1%) of 766 HIVexposed infants, demonstrating the high risk of TB
exposure in HIV-affected families/households in TB
endemic areas.22
The overall effect of HIV on TB transmission within
communities has been debated, as HIV-infected adults
with pulmonary TB are more likely to be sputum smearnegative TB and/or present quicker for care, reducing
their transmission risk. However, reports from Tanzania
and Botswana indicate that most HIV-infected patients
are sputum smear-positive and/or are only diagnosed
Chapter 15 Tuberculosis and the HIV Infection

after a considerable period of symptomatic disease, and
so may make a significant contribution to TB transmission
in endemic areas.23,24
Disease
The most important factors that influence a childs risk of
developing TB following infection are age, with the highest
risk occurring in immune immature children (<3 years of
age), and the immune status of the child.25 In an HIVinfected child this is determined by the degree of immune
compromise and/or the severity of HIV-disease. In a
prospective study from Cte dIvoire, the risk of TB was 4
times higher in children with CD4% below 15% than in
those with a higher CD4%, and 3 times higher with a
baseline plasma HIV RNA above 5 10log10.26 A study
from South Africa demonstrated a markedly elevated risk
amongst HIV-infected children to develop TB (OR 16.6,
95% Confidence Interval 12.5-22.4) in the 9 months prior
to the institution of highly active anti-retroviral therapy
(HAART) compared to the period thereafter.27
DIAGNOSIS
The diagnosis of childhood TB presents a major challenge
as bacteriologic confirmation is achieved in only a minority
of children.28 In the absence of bacteriologic confirmation,
the diagnosis of childhood TB is often based upon the
triad of 1) close contact with an index case; 2) positive
tuberculin skin test (TST); and 3) suggestive signs on the
chest radiograph (CXR). This triad is less helpful in
endemic areas where exposure to M. tuberculosis is common
and often undocumented.28 In these settings, the diagnosis
of childhood TB depends mainly on clinical features and
the subjective interpretation of the CXR.
The diagnostic problems are more pronounced in HIVinfected children and all current diagnostic algorithms
perform poorly in this group.3,29 Factors contributing to these
additional diagnostic difficulties include:
Children from HIV-affected households are more likely
to be exposed to an adult index case at home, although
the index case may be sputum smear-negative and the
transmission risk not fully appreciated.
The TST an extremely insensitive marker of TB infection
in HIV-infected children.30
Chronic pulmonary symptoms due to other HIV-related
conditions such as gastro-esophageal reflux or
bronchiectasis frequently coexist.
Weight loss or failure to thrive are typical features of
both TB and HIV.
Rapid TB disease progression may occur in severely
immune compromised children, which reduces the
sensitivity of diagnostic approaches that focus on
chronic symptoms
219
CXR interpretation is frequently complicated by HIVrelated comorbidity such as bacterial pneumonia,

lymphocytic interstitial pneumonitis (LIP),
bronchiectasis, pulmonary Kaposi sarcoma (KS) and
the atypical presentation of TB in immune compromised
children.
Following TB exposure, the TST is generally used to
indicate M. tuberculosis infection, but it has important
limitations:
Conversion may be delayed for up to 3 months
following infection.
Inability to indicate when primary infection occurred
or to register a reinfection event.
Poor sensitivity in immunocompromised children.
Reduced specificity due to environmental mycobacteria
and cross-reaction with BCG, although this is less of a
confounder in TB endemic countries where BCG is
given during the neonatal period.
The poor sensitivity of the TST is the main limitation in
HIV-infected children; only a minority of HIV-infected
children with bacteriologically confirmed TB record
a positive TST, despite using a reduced induration size
cut-off of 5mm. 30 Novel T-cell-assays, utilizing
M. tuberculosis specific antigens (ESAT-6 and CFP-10), seem
to offer higher sensitivity and specificity, but results remain
unconvincing and conflicting.31 As for the TST, novel Tcell-based assays do not differentiate M. tuberculosis
infection from active disease. Identifying the correct
application of these novel T-cell-based assays in TB
endemic areas remains a priority for future research.
HIV-infected children seem prone to develop
disseminated and other forms of TB that reflect poor
organism containment, but in general the clinical disease
presentation is similar to that seen in HIV-uninfected
children.3,32 From a diagnostic perspective it is essential
to know a childs HIV status as this guides clinical
management; effective interventions such as trimethoprimsulphamethoxazole (TS) prophylaxis and HAART have
become more readily available.
TREATMENT
Preventive Chemotherapy
WHO guidelines advise that all children under 5 years of
age in close contact with a sputum smear-positive index
case should be actively traced, screened for TB, and
provided preventive chemotherapy once active TB has been
excluded.10 It acknowledges that in settings where a TST
and CXR are not readily available, symptom-based
screening improves access to preventive chemotherapy for
asymptomatic high-risk contacts.
Isoniazid preventive therapy (IPT) has proven efficacy
to prevent active disease after documented TB exposure
and/or infection, but under standard programmatic
220
conditions adherence is often very poor.33 Restricting the

focus to the groups at highest risk and identifying
alternative short-course preventive therapy regimens
remain important areas for future research. The diagnosis
of latent TB infection (LTBI) is important in HIV-infected
children due to the high risk of disease progression and
the well-documented benefits of IPT in adults with LTBI.
IPT eradicates existing TB bacilli but does not protect
against future re-infection, which explains the waning of
its beneficial effect after 2-3 years in endemic areas with a
high infection pressure. Due to the reduced sensitivity of
the TST in HIV-infected children, IPT seems warranted
(and is recommended by WHO) for any HIV-infected child
with documented exposure to an adult with pulmonary
TB irrespective of the childs age or TST result, once active
TB has been excluded.10
The effect of providing blanket IPT to all HIV-infected
infants in a TB endemic area was recently explored in a
randomized controlled trial.19 The placebo arm of the study
was discontinued after interim analysis of the first 263 HIVinfected children of whom 132 (50.2%) had been assigned
to isoniazid. The mortality rate was significantly lower in
the isoniazid group (8.3%) compared to the placebo group
(16%) as well as the incidence of confirmed or probable TB
(isoniazid 4.5% vs placebo 9.2%), however, this did not
explain the difference in mortality.19 It remains uncertain
whether blanket IPT is more effective than conscientious
post-exposure IPT; a second randomized controlled trial is
currently underway to help in guiding public health policy.
There are valid concerns that IPT may promote the
development of drug resistance, especially if the presence
of active TB disease is not adequately excluded. However,
the provision of IPT to young children poses a negligible
risk, because they usually develop pauci-bacillary disease,
rarely acquire drug resistance and contribute little to disease
transmission.
Curative Treatment
The main variables that influence the success of
chemotherapy, apart from primary drug resistance, are
the bacterial load and the anatomical distribution of bacilli.
For treatment purposes the wide spectrum of pathology
observed in children with intrathoracic TB can be reduced
to three main categories:
1. Sputum smear-negative, low organism load: Success of the
standard regimen of three drugs (2RHZ) for the
intensive phase and of two drugs (4RH) for the
continuation phase is well established; the risk of
acquired drug resistance is low.
2. Sputum smear-positive, high organism load: As for adults,
four drugs (2RHZE) during the intensive phase are
warranted. This group has high risk of acquiring drug
resistance.
3. Disseminated/miliary TB: Disseminated/miliary TB
occurs predominantly in very young (immune
immature) and/or immuno-compromised children.

It is important to consider the cerebrospinal fluid (CSF)
penetration of drugs as it is frequently associated with
tuberculous meningitis (TBM).
Many studies have documented poorer response to
treatment and higher mortality in HIV-infected children
with TB compared to HIV-uninfected children.
Possible reasons for the poor outcome include:3
Higher incidence of co-infections with other pathogens.
Poorer absorption and low levels of anti-TB drugs
especially in the younger children.
Misdiagnosis of TB in children with another HIVrelated lung disease.
Underlying chronic lung disease resulting in poor
penetration of drugs.
Poor adherence to treatment because of chronic illness
or parental death.
Advanced immunosuppression and severe
malnutrition.
In adults, a large proportion of HIV/TB-related deaths
occur in the first few months after TB therapy has
commenced; the situation in children is similar.
Present recommendations are to treat HIV-infected
children with TB in a similar fashion to HIV-uninfected
children.10 Thiacetazone was discontinued in HIVendemic regions due to fatal Stevens-Johnson reactions in
HIV-infected individuals. Ethambutol was introduced in
many countries to replace thiacetazone, but concerns exist
about the toxicity of ethambutol in young children. Seth et
al33a have shown no ocular toxicity in children above three
years of age on ethambutol therapy in the dosage of 20
mg/kg by measuring visual evoked response and latency
at 3, 6 months during therapy with ethambutol. A recent
WHO report concluded that the use of ethambutol is safe
at the recommended dose of 15-25 mg/kg/day, although
serum levels may be sub-optimal.34 Achieving effective
serum antibiotic levels is particularly important in
immunocompromised children; little data exist to guide
optimal dosing and the effect of suboptimal drug levels
on disease outcome has not been adequately studied.
There is an increased risk of disease relapse in HIVinfected children3,35 and consideration may be given to
prolong the treatment duration from 6 months to 9 months,
particularly in the face of more extensive cavitating disease,
although there have been no randomized controlled trials
to substantiate this.
Drug Interactions
TB is frequently the presenting disease in children with
previously undiagnosed HIV infection who may have
advanced HIV disease requiring HAART.27 The Centers
for Diseases Control and Prevention (CDC) has
established guidelines for initiating HAART in adults
presenting with TB and for initiating TB treatment in

those already on HAART. The guidelines are regularly
revised; see the relevant CDC website for the latest
recommendations. 36 No pediatric guidelines are
provided, but issues regarding initiation of HAART,
drug interactions, overlapping side-effects and
adherence concerns are similar. Since both HIV and TB
have its highest mortality during infancy, most
clinicians caring for very young children would start
HAART as soon as possible after initiating TB treatment.
In older children, in the absence of severe immunosuppression, it seems reasonable to complete the TB
treatment first.
Significant drug interactions occur between the
rifamycins, especially rifampicin, and some of the
nonnucleoside reverse transcriptase inhibitors (NNRTIs)
and/or protease inhibitors (PIs). Rifampicin is regarded
as being compatible with all nucleoside reverse
transcriptase inhibitors (NRTIs), although it promotes
the glucoronidation and elimination of zidovudine
(AZT). Abacavir, another NRTI that has been used
in triple NRTI regimens, is also eliminated by
glucoronidation. Little pharmacokinetic information is
currently available on the interaction of these drugs in
children. Using a triple NRTI regimen is an option in
patients on TB treatment, but the regimens not performed
well in comparative efficacy studies.3 In the absence of
rifabutin (which is frequently used to replace rifampicin
in developed countries) current recommendations are to
retain a double NRTI backbone in combination with
efavirenz (NNRTI) or ritonavir (PI) as the levels of these
two drugs are least affected by rifampicin. An alternative
PI strategy would be to boost lopinavir/ritonavir with
additional ritonavir.
Other Relevant Issues

Trimethoprim-sulphamethoxazole (TS)
Prophylaxis
Studies have demonstrated that TS prophylaxis
significantly reduces the risk of Pneumocystis jiroveci
(PCP) pneumonia, invasive bacterial infections and
malaria in HIV-infected adults. A randomized controlled
trial of TS prophylaxis in HIV-infected Zambian
children of 2 years and older showed significant
survival benefit. 37 Routine TS prophylaxis is
recommended by WHO for all HIV-infected children
including those with TB. TS prophylaxis is also
recommended for HIV-exposed, but uninfected infants
as PCP is also common in this group.38
221
Immune Reconstitution Inflammatory

Syndrome (IRIS)
Transient worsening of symptoms such as fever, increasing
lymphadenopathy, exacerbation of intracerebral
tuberculomas, pleural effusions and even adult respiratory
distress syndrome have been reported after the initiation of
ART in severely immunocompromised patients. This
temporary exacerbation of TB symptoms and signs is mainly
ascribed to the effects of immune reconstitution, although a
hypersensitivity reaction to antigens released by killed
TB bacilli may also contribute. It does not indicate treatment
failure and usually subsides spontaneously, although
severe cases may require treatment with corticosteroids. In
a recent prospective survey of 152 Thai children with low
CD4 % (<15%), IRIS was documented in 19%, usually
within 4 weeks of ART initiation. The majority of IRIS cases
were due to atypical mycobacteria; 3/14 were due to M
tuberculosis and 2 due to BCG.39 BCG-related IRIS, presenting
with massive right sided axillary adenitis, is a well
documented complication following HAART initiation.40
BCG Vaccination
BCG offers variable protection in different settings, but it is
generally accepted that BCG offers significant protection
against disseminated (miliary) disease in young HIVuninfected children (<2 years of age). The protection
provided by BCG vaccination in HIV-infected children
remains uncertain, while it poses a considerable risk of
disseminated BCG disease. 40 In the absence of a
comprehensive risk-benefit analysis, current consensus
guidelines advise BCG vaccination of all asymptomatic HIVexposed infants in TB endemic areas with careful
monitoring for the development of BCG-related disease.41
HIGHLIGHTS
The burden of child TB is highest in areas where the
adult epidemic is poorly controlled.
HIV-infected children are particularly vulnerable to
TB infection and disease.
Routine HIV testing should be viewed as an essential
part of the diagnostic work-up in HIV affected
areas, as it guides diagnostic interpretation and
management.
Inspite of multiple challenges, the management
of HIV-infected children with TB exposure/infection
or disease can be greatly improved by better
implementation of readily available interventions.
222
15.2 TUBERCULOSIS AND HIV INFECTION

Tuberculosis is increasing in prevalence in many

countries. It is now the leading cause of death due to
infectious disease worldwide. HIV infection has emerged
as the most important predisposing factor for developing
overt tuberculosis in people coinfected with M. tuberculosis
and an important reason for the recent worsening of the
global tuberculosis epidemic.
EPIDEMIOLOGY OF HIV-TUBERCULOSIS
Pediatric HIV infection today represents a major setback to
child health. HIV infection affects the health of children in
India and other high incident countries and by itself can
cause fungus infection of pulmonary organs. HIV also
increases the risk of deadly infection in immune
compromised children such as cancer, kidney disease for
which the children are on long term steroid therapy and
cancer chemotherapy. In vertical transmission (from the
mother) children cannot be protected by BCG which is
available in the universal program of immunization,
because it precipitates a severe reaction and at times TB
disease. At the end of December 2008, it was estimated that
approximately 33.4 million (potential range 31.1-35.8
million) people were living with HIV/AIDS worldwide. Of
these 2.1 million (potential range 1.2-2.9 million) were
children under 15 years of age. In the same year, it was
estimated that there were 2.7million people newly infected
with HIV, of which 0.43 million were children and there
were 2 million deaths.1 Latest estimates show that about 2.5
million (1.8-2.9 million) people were living with HIV in India
in 2007; with an estimated adult HIV prevalence of 0.34%
(0.25-0.43%).2 Serious epidemics are underway in several
states in India. In TamilNadu, HIV prevalence of 50 percent
has been found among sex workers, while in Andhra
Pradesh, Karnataka, Maharashtra and Nagaland, HIV
prevalence has crossed the 1 percent mark among pregnant
women.2 It is quite disheartening that inspite of aggressive
efforts of National Aids Control Organization (NACO) with
financial help of government of India and International
agencies, the prevalence in southern states (Tamil Nadu) in
sex workers is as high as 50 percent.
The major burden of HIV infection is in the sub-Saharan
Africa and Asia; these areas are the parts of world where
tuberculosis is rampant. Advent of HIV epidemic has led
to a significant increase in the number of all new TB cases.
WHO estimates that the largest number of new TB cases in
2008 occurred in the South-East Asia Region, which
accounted for 34% of incident cases globally. However,
the estimated incidence rate in sub-Saharan Africa is
nearly twice that of the South-East Asia Region with over
350 cases per 100,000 population.3
An estimated 1.3 million people died from TB in 2008.

The highest number of deaths was in the South-East Asia
Region, while the highest mortality per capita was in the
Africa Region.
In 2008, the estimated per capita TB incidence was
stable or falling in all six high incident WHO regions.
However, the slow decline in incidence rates per capita is
offset by population growth. Consequently, the number of
new cases arising each year is still increasing globally in
the WHO regions of Africa, the Eastern Mediterranean
and South-East Asia.
HIV and TB form a lethal combination, each speeding
the other's progress. HIV weakens the immune system.
Someone who is HIV-positive and infected with TB is at a
much higher risk of developing serious form of TB in
comparison to that who is HIV-negative. TB is a leading
cause of death among people who are HIV-positive. It
accounts for about 13 percent of AIDS deaths worldwide.
In Africa, HIV is the single most important factor
determining the increased incidence of TB in the past 10
years.3 Historically HIV and TB coinfection has been a
problem since 1990s as emphasised by Bakshi et al3a in
New York. Epidemiology and clinical features of infection
with Mycobacterium tuberculosis in human immunodeficiency virus (HIV)-infected children and their families
has been described. Sixty families of children with HIVinfection and seroreverters uderwent follow-up in a
comprehensive multidisciplinary program for children
and families. Infection with M. tuberculosis was diagnosed
either by TST positivity or a positive culture, M. tuberculosis
infection was detected in seven children from four families.
Six of seven children had a history of exposure to M.
tuberculosis in an HIV-infected adult (parent) who was
either an intravenous drug user, homeless or a
noncompliant with the medical regimen. Pulmonary
tuberculosis was found in all HIV-infected children and
one serorevertor. Only one child died of complications of
tuberculosis and HIV infection. M. tuberculosis isolated
from this child was resistant to isoniazid, rifampicin and
streptomycin sulfate. It is concluded that tuberculosis is a
growing problem among children born to HIV-infected
parents. Tuberculosis was of the severe variety as a
reflection of what was prevalent in the community at that
time. The burden of tuberculosis (TB) worldwide is
influenced by the human immunodeficiency virus (HIV)
epidemic. Between 1990 and 2004, the incidence of
tuberculosis stabilized or fell steadily with the exception
of Africa. HIV and HIV-associated TB affects young adults
which may result in increased rate of TB transmission in
children. HIV-infected children are at increased risk of TB
and of more severe forms of TB compared with
223

immunocompetent children. TB is more common in
children living in households affected by HIV. Owing to
higher mortality during and after treatment of TB, the
outcome of TB is also worse among HIV-infected children,
with lower cure and higher recurrence rates. Available
reports still show low levels of drug resistance among
children. Continued surveillance will be important to detect
any increase in TB. Research needs to be focused on better
methods of preventing TB as BCG is still the only vaccine
available. The development of better diagnostics for
infection and disease will improve the management of TB
in children.3b
The impact of the HIV epidemic on pediatric TB has
been reported in several studies. A prospective cohort
study of children with TB diagnosed in Addis Ababa
from December 1995 to January 1997 in which HIVpositive children were compared with HIV-negative
children, reported that HIV-positive children were
younger, more underweight and had a six-fold higher
mortality than HIV-negative children.4 The tuberculin
skin test was less sensitive and chest radiography was
less specific in HIV-infected patients. Adherence to
treatment was high (96%), and the cure rate was 58
percent for HIV-positive and 89 percent for HIV-negative
pediatric TB patients. The study concluded that HIVpositive children are at increased risk of diagnostic error
and hence delayed diagnosis of TB. Clinical
manifestations were more severe and progression to death
was more rapid than in HIV-negative children.
Malnutrition estimated by weight for age may be used to
identify children at high risk of a fatal outcome.
In a retrospective study of 118 culture proven
tuberculosis patients in Durban, South Africa; 57 (48%)
children were detected to be HIV-1 infected, 44 (37%) nonHIV-1-infected, and in 17 (14%) HIV-1 status was not
determined.5 In contrast to previous studies, this study
has shown that TB-HIV coinfection in children is
common (48% of all culture-proven cases), the
presentation of tuberculosis may be acute (43%), and
supportive tests are individually useful in confirming
the diagnosis in a third of cases. All cultures for M.
tuberculosis were positive by 8 weeks. Clubbing and age
over two years were the most reliable indicators of
underlying HIV-1 disease in a child with tuberculosis,
while clinical features, radiology and supportive tests
were found to be similar between HIV-infected and
noninfected TB cases. Hospital-related mortality was
higher (17.5%) in HIV-1-infected children compared to
the noninfected group (11.4%). The changing pattern of
presentation of childhood tuberculosis and the high
prevalence of TB in HIV endemic areas have made it
imperative to maintain a high index of suspicion, with
culture evaluation being an important part of clinical
practice.5
PREVALENCE OF TUBERCULOSIS IN
HIV-INFECTED CHILDREN
It is estimated that by end of 2000, 11.5 million HIV-infected
adults worldwide were coinfected with M. tuberculosis;
Africa and South-East Asia accounted for 70 percent and
20 percent respectively.6 In India, it is estimated that about
half of all HIV-infected individuals are co-infected with M.
tuberculosis and approximately 200,000 of these coinfected
individuals will develop active TB disease each year.7
Similar pediatric data is now available in India. Some
conclusions can be drawn upon from various reports in
children with HIV infection. In contrast to the developed
countries, tuberculosis has been reported in 14 to 54 percent
of Indian children with HIV/AIDS8-15 (Table 15.2.1). In
the series, at AIIMS,14 10 of the 29 children with HIV-TB
co-infection, had disseminated/miliary TB. In a report from
Tambaram (Chennai), 1115 of 1768 HIV infected children
who accessed care had tuberculosis; 14.9 and 20.6 percent
children had extra-pulmonary TB and disseminated TB
respectively.15
HIV Seroprevalence in Children with Tuberculosis

The HIV seroprevalence in children with tuberculosis is
likely to vary with the background HIV seroprevalence.
The rates will be higher in areas where HIV infection is
more prevalent. The figures are likely to increase as HIV
seroprevalence increases. HIV seroprevalence in adults
with tuberculosis at a tertiary care hospital in New Delhi
was reported to have increased from 0.4 percent in 19941999 to 9.4 percent in 2000-2002.16,17 In another study from
the same center, a seropositivity rate of 8.3% was reported
in adults with TB.18 In a South African study on children
hospitalized with tuberculosis, the HIV prevalence was
found to be 42 percent.19 In other African studies the
prevalence of tuberculosis in HIV-infected children has
been reported to be between 10 percent20 and 56 percent.21
It indicates that almost half of the children having TB run
the risk of being HIV positive.
A few Indian studies have addressed this issue.
Merchant and Shroff reported HIV seroprevalence of 18
percent in children with disseminated TB.22 Karande et al23
Table 15.2.1: Tuberculosis in HIV-infected children in India
Author
N Tuberculosis (%)
8
Shah I, 2005
Shah SR, et al 20059
Madhivanan P, et al 200410
Verghese VP, et al 200211
Merchant RH, et al 200112
Dhurat R, et al 200013
Lodha R, et al 200014
Rajasekaran S, et al15
317
50
58
88
285
55
29
1768
43.4
38
35
12
29.5
67.5
26.7
63
224
reported prevalence of 16.2 percent in children with

disseminated tuberculosis. In a more recently published
study, Shahab et al reported 2 percent HIV seroprevalence
in children with tuberculosis; all 5 children with HIV-TB
coinfection had disseminated tuberculosis.24 Unlike the
other studies, this study is from a low HIV seroprevalence
area. In a another study, 270 pediatric patients with active
Tuberculosis (TB) disease attending the OPD of a medical
college in Agra were screened for Human Immunodeficiency
Virus (HIV)-1/2 antibodies. Of these, 23 (8.5%) were found
to be HIV-positive.25 Among the HIV-positive children with
TB 86 (75%) were of pulmonary and 13.04% were of
extra-pulmonary type. All these studies suggest that the
prevalence of HIV-TB coinfection varies with the
geographical region. There is a greater probability of
detecting HIV infection in children with disseminated
tuberculosis.
Genemapping of People in India for HIV

Genemapping exercise of the "people of India" has shown
that Indians are more vulnerable to HIV-AIDS than many
other population groups around the world. This is because
of the virtual absence of a protective gene marker against
HIV-1. It has also been shown that there is increase in risk
as one moves from north to south India. Further Indian
genepool is quite varied and is not homogenous at all. It
includes several variations across population groups
spread across the country.
Antenatal clinical HIV prevalence survey done in
2005 reports a high frequency of HIV in South Indian
population. This gene mapping study was carried out by
more than 150 scientists and researchers from six control
centers of Council of Scientific and Industrial Research
(CSIR) of India.
This has been perhaps the largest scientific endeavor
since the green revolution effort of 1970 of Indian Council of
Agricultural Research. The mapping covered four main
linguistic families of Indian-Austro-Asciatic, TibetoBurman, Indo-European and Dravidian. The study
encompasses Indian population defined by distinct
religious communities, hierarchial castes and subcastes,
and isolated tribal groups.
The study part of the Indian Genome Variation
Initiative has generated information on over 4,000 genetic
markers from more than 1,000 biomedically important and
pharmacogenetically relevant genes in reference groups.
The study reveals a high degree of genetic differentiation
among Indian Ethnic groups. Hence, in India "pooling" of
endogenous population without regard to "ethnolinguistic factors" will result in false inference. Hence it is
not right to refer people of India as 'Indian' in many
population genetic studies because Indian population is
not genetically homogenous. However, it is possible to
identify large clusters of ethnic groups that have
substantial genetic homogeneity.

This mapping is expected to help in constructing
"specific drug response/disease predisposition maps"
to help in making policy decision for drug dosage
interventions and disease risk management especially
infectious diseases.
A new subtype of AIDS virus was found by French
scientists which jumped from gorilla to humans. The new
strain was found in a woman from Cameron, West Africa. It
is a part of the HIV-1 family of microbes that account for the
vast majority of cases of human immunodeficiency virus
(HIV). The new subtype is called P, adding to the three
established HIV-1 subtypes. M being the most prevalent, O
and N are rare (Times of India, 3rd August 2009).
There is also an HIV-2 which is a minority viral family.
This also has origin in nonhuman primates. The women
carrying this virus had moved from Africa to Paris where
she tested positive for HIV. She responded to diagnostic
tests for HIV-1 but further subtype could not be pinpointed.
In 2006 a form of HIV was found in wild gorillas in
western Central Africa. It was the first time the virus was
identified in primates other than chimps and humans.
The gorilla virus was widespread and was closely
correlated to HIV-1 group 0, one of three HIV groups known
to infect humans. The same virus was detected from the
chimpanzees in South East Cameron which is the primary
reservoir of the HIV-1 group M virus. At the same time it
was detected that for Group N strain of HIV-I, chimps
were the reservoir and was extremely rare in human
population.
PATHOGENESIS
HIV and TB form a lethal combination, each speeding the
other's progress. The estimated annual risk of reactivation
among those co-infected with HIV and TB is about 5 to 8
percent with a cumulative lifetime risk of 30 percent or
more compared to a cumulative lifetime risk of 5 to 10
percent in HIV-negative adult patients.26,27
Cell-mediated immune response is essential for defence
against M. tuberculosis. HIV infection primarily affects the
components of cell- mediated immunity. This leads to
increased susceptibility to M. tuberculosis. After primary
infection, there is poor containment of the infection, leading
to progressive disease and also risk of dissemination. In
individuals with latent TB infection (LTBI), HIV-induced
immunosuppression leads to increased risk of reactivation.28
In addition to the evidence that HIV infection worsens
the risk and course of TB, there is increasing clinical
evidence that coinfection with M. tuberculosis accelerates
the progression of disease. It has been observed in HIVinfected adults matched for CD4 counts, that the mortality
in patients with HIV/TB coinfection was higher in those
having lower CD4 counts than in patients with higher
count.29,30 The increase in mortality is not due to TB but to

an increased occurrence of other opportunistic infections.
Recent studies have documented increase in viral
replication in TB patients. Areas of lungs involved with
tuberculosis have an upto 1000 fold increase in HIV-1 viral
particles in comparison to uninvolved lung areas.31 The
viral load is higher in bronchoalveolar lavage fluid than
that found in plasma, suggesting that there is high local
viral replication in the lung.
The immune response to pulmonary tuberculosis is
characterized by delayed type hypersensitivity. There is
granuloma formation, recruitment of CD4 cells to the lung,
and elaboration of various cytokines-TNF-, IFN- , IL-1,
IL-6 and IL-8. TNF- , M. tuberculosis and its cell wall
component-lipoarabinomannan, increase HIV-1 viral
replication.32 There is increased risk of mutations in these
areas of high viral replication.
Spread of HIV epidemic in sub-Saharan Africa has
resulted in notification rates of TB increasing upto 10 times.
When there is an overlap of TB and HIV-coinfection, it is
due to the increase in the occurrence of TB on an underlying
HIV infection/AIDS disease. Even in countries with a well
established and control program of TB, associated HIV
infection becomes a major killer due to massive TB disease.
Hence TB and HIV/AIDS control programs have to go hand
in hand. India has started action in this direction.
Incidence of TB is 1.8 million cases occurring annually.
With the presence of HIV, TB could go upto 2 million. Hence
the task/major control of this dual infections is a real
challenge.
During the initial (primary) infection of immunocompetent person with M. tuberculosis, macrophages ingest
the organisms and after processing present the antigen to T
cells. CD4+ T cells secrete lymphokines and then enhance
the ingestion and killing of M. bacilli by macrophages. In
most people the tuberculosis infection does not become a
disease. It is only 10% of individuals who are immunocompetent develop the disease either soon after primary
infection or years later (reactivation of latent TB infection).
These are due to defects in the functioning of T cells or
macrophages.
Hallmark of HIV infection is a progressive
lymphocytes depletion and dysfunction of CD4+ T
lymphocyte cells coupled with defects in monocyte and
macrophage function. These cells have a central role in
anti-mycobacterial defenses; dysfunction of these cells
exposes the individual to high risk of primary TB infection
or reactivation of latent TB which is quite significant.
Natural History of HIV-Infection

Without treatment, a HIV infected individual has a life
span of approximately nine years with a range of 8-12
years. With the advent of effective highly active
antiretroviral therapy, (HAART) life span has been
extended. This is dependent upon the stage of HIV
225
infection called primary "HIV infection or acute

seroconversion syndrome". Incubation period is short (2
to 4 weeks), the clinical symptoms vary from fever to a
variety of neurological symptoms. Diagnosis is made
infrequently as one usually does not suspect it and the
standard ELISA tests are negative. Demonstration of HIV
RNA in plasma is diagnostic of the disease.
i. The next stage is asymptomatic HIV Infection having
a long and variable latent period for onset of AIDS.
Duration could be as long as 10 years in adults. In
children it is about 2 years.
ii. Persistent generalized lymphadenopathy (PGL). It is
defined as persistent generalized lymphnodes (PGL)
involving atleast two sites often cervical and inguinal
nodes. This is followed by HIV related disease and
AIDS. This last stage is the stage of advanced
immunosuppression, referred to as AIDS.
Impact of HIV on TB
About a third of HIV infected individuals world wide are
coinfected with TB infection. In sub-Saharan Africa, upto
70% patients with smear-positive pulmonary TB are HIVpositive. HIV promotes the progression to active disease
both in people with recently acquired TB infection and
with latent M. tuberculosis infection which is reactivated to
active disease by HIV infection. HIV increases the rate of
recurrence of TB disease which may be due to either
endogenous reactivation (true relapse) or exogenous
infection. This increase in tuberculosis cases poses an
increased risk of TB transmission to general community.
In developing countries like India, the potential burden of
extra TB cases attributable to HIV could tilt the balance of
health budget in countries like sub-Saharan Africa.
Impact of HIV on the Clinical Course of TB

In addition to the increase in the number of TB cases, HIV
also alters the course of disease. Due to increase in
immunosuppression due to HIV infection, there is increase
in the incidence of smear negative pulmonary TB and
extrapulmoanry TB. TB is more disseminated and more
difficult to diagnose. The mortality in coinfected patients is
also very high, to the tune of 25% in smear positive and 4050 % in smear negative pulmonary TB patients.
Immunopathology in HIV Infection

HIV replication and disease progression is increased in
HIV-infected individuals. This is due to increased immune
activation. Plasma markers of immune activation are
neopterin, beta-2-microglobulin (2M) and soluble tumor
necrosis factor alpha receptor type 1 (sTNF -R1). These
are increased and can be measured by ELISA in patients
with active TB. CD4+T cells count 200 cells / l have the
highest level at baseline. There is steep fall in neopterin
226
and sTNF-R1 during treatment. However, the levels do

not drop to normal. 2M levels remain persistently high
despite completing TB treatment. These findings suggest
the synergism between TB and HIV infection. The
persistence of these immune markers in TB and HIV
coinfection indicate underlying immune activation.
However, none of the markers are specific enough and
cannot be used to assess cure of TB. The three diagnostic
markers which have significance in relation to HIV infection
are HIV viral load, CD4+T cells levels and plasma levels of
the above mentioned soluble markers.32a
p24 antigen level correlated well with that of CD4

lymphocyte count (<50 CD4 cells r = 0.626, p= <0.001 and
50-200 CD4 cells, r=0.531, p=0.016). The lowest level of
p24 antigen measurable was 1,905 fg/ml in a patient with
CD4 cell count of 222 cells/l. p24 antigen could be
estimated even in patients on ART with stably suppressed
viremia.
Hence to summarize it can be stated that plasma
concentration of immune activation markers are elevated
in patients infected with HIV and the increase is related to
the stage of HIV disease. This coinfection has additive
effects on the immune system resulting in mutually
Immune Status in HIV Infection
unfavorable effects. This incomplete recovery of immune
Immune stimulation occurs very early in HIV infection system even after 6 months of ATT indicates that rate of
indicated by seroconversion. In addition to specific immune restoration does not match the microbiological
immune response, there is occurrence of widespread
clearance and resolution of TB.
activation of CD4+ and CD8+T cells, B cells, natural killer
(NK) cells and macrophages. Immune cell activation results
CLINICAL FEATURES
in increased production of many cytokines and increased
expression of cytokine receptors. Soluble products of Tuberculosis can occur in HIV-infected individuals at any
activation can be quantified in plasma or serum. Presence CD4 count. This is in contrast with other opportunistic
of clinical TB in HIV infected individuals results in infections which generally occur when there is significant
continuous cellular activation resulting in viral decline in CD4 counts percent. When HIV infected children
replication and progression of disease. Changes in soluble develop tuberculosis, the clinical picture tends to be typical
activation markers are more closely related to viral load of childhood tuberculosis as in the immunocompetent
than to CD4+T cells changes. Immune activity is indicated
patient, although the disease, as in adults, tends to progress
by increased levels of neopterin in blood and urine.
more rapidly and the clinical manifestations are more
Increased production of 2M in plasma strongly reflects
severe.33-36 There may be an increased tendency for
the progression of HIV infection to AIDS. sTNF- receptor
levels correlate with their induction by TNF- resulting extrapulmonary disease and dissemination along with
in active expression of HIV in monocytes and lymphocytes. involvement of unusual sites and atypical chest
There is progressive increase in levels of IFN? and radiograph. The most striking feature of tuberculosis in
neopterin when HIV-seropositive individuals are stratified patients with HIV infection is the extremely high frequency
on the basis of CD4+ T cell counts, with the highest levels of extrapulmonary involvement usually with concomitant
in those patients who have CD4+ T cell counts < 200 cells pulmonary involvement. Extra-pulmonary involvement
/l. Treatment with ATT results in the decreased plasma occurs in more than 70 percent of patients with tuberculosis
levels of neopterin and sTNF-R1 in both HIV-positive and and preexisting AIDS or AIDS diagnosed soon after but
only in 24 to 45 percent of patients with tuberculosis and
HIV negative TB patients.
37,38
Thus extrapulmonary
ATT results in successful elimination of the pathogen in less advanced HIV infection.
tuberculosis
appears
to
be
more
common
in patients with
six months, but the effect of TB in HIV positive patients on
more
severe
HIV-induced
immunosuppression.
immune system takes much longer to resolve. sTNF-R1 is
Diagnosing extrapulmonary tuberculosis in patients
predominantly associated with TB and 2M with HIV and
with
HIV infection is important because it is an AIDS
hence these could serve as independent markers of TB and
defining illness while pulmonary tuberculosis is not. Adult
HIV-disease activity.
HIV and tuberculosis coinfected patients have been noted
Status of CD4+ T Cell Counts and its Relation to p24 to have lesser upper zone involvement, greater nodal
disease, higher rates of pleural/pericardial disease.
antigen
Although they are less likely to be smear-positive, but are
Baveja et al32b demonstrated a correlation of CD4T cells equally infectious to close contacts. The most important
counts and levels of p24 antigen. CD4T cell counts at denominator, however, is the degree or stage of
baseline showed that the superiority of p24 measurement immunosuppression since the more atypical the clinical
was more pronounced at lower levels of CD4 cells (< 200 features, the more likely is the CD4+ T cell count to be low.
cells/l). p24 antigen level may be of interest as a simple In adults, the clinical features were typical until CD4+ cell
and inexpensive predictive marker of disease progression. count was less than 500/cumm.

In a child infected with HIV-1, evaluation of M.
tuberculosis is mostly undertaken after failure to respond
to broad spectrum antibiotics started due to prolonged
fever, respiratory symptoms, and atypical chest
radiograph. HIV disease manifestations in children are
distinct from that of adults with early signs and symptoms
being nonspecific and distinguished only by their
persistence and severity, e.g. failure to thrive, generalized
lymphadenopathy, persistent diarrhea and oral thrush.
Frequently, these children develop diseases which can
mimic an initial picture of tuberculosis. Many children
with HIV-1 infection have features of chronic lung disease
with abnormal chest radiograph thus making the diagnosis
of pulmonary tuberculosis even more difficult.39
Clinical signs that suggest HIV infection in a child
include:
i. Failure to thrive in a breast-fed infant before 6 months
of age
ii. Recurrent bacterial infections
iii. Generalized symmetrical lymphadenopathy
iv. Extensive oropharyngeal candidiasis
v. Generalized rash
vi. Bilateral nontender parotid gland enlargement
vii. Clubbing.
HIV infection makes the diagnosis and management
of tuberculosis in children even more difficult than usual
for the following reasons:
i. Several HIV-related diseases may present in a similar
way as TB.
ii. A HIV-infected child is more likely to have a negative
tuberculin test.
iii. Management of TB may be more difficult as the family
is likely to have more than one HIV-infected
individual.
In a study carried out in Johannesburg, South Africa to
define the prevalence of human immunodeficiency virus
(HIV) coinfection and differences in clinical presentation
between HIV-infected and noninfected hospitalized
children with tuberculosis, 161 children were enrolled. Forty
two percent children were HIV-infected, including 67/137
(about 50%) with pulmonary tuberculosis (PTB) and 1/24
(4%) with extra-pulmonary disease (EPTB).19 Positive
microscopy or bacteriology did not differ by HIV status for
children with either pulmonary tuberculosis (PTB) or
extrapulmonary tuberculosis (EPTB). Although age did not
differ between HIV-infected and noninfected children with
PTB, non-HIV-infected children with EPTB were
significantly older than those with PTB only (median age
32 months versus 14.5 months, p = 0.004). Chronic weight
loss, malnutrition and the absence of BCG scar were more
common in HIV-infected children with PTB. HIV-infected
children were also more likely to show cavitation (p = 0.001)
and miliary TB (p = 0.01) on chest X-ray. Reactivity to
tuberculin (> 5 mm and > 10 mm in HIV-infected and
noninfected children, respectively) was significantly lower
in HIV-infected children, as were CD4+ lymphocyte levels.
227
The mortality rate during the study was 13.4 percent in

HIV-infected children compared with 1.5 percent in nonHIV infected children (P = 0.03).
Kumar et al have reported the clinical feature of culture
confirmed TB in children with HIV infection.40 In their
cohort of 213 children with vertically transmitted HIV
infection, a total of 76 (36%) children were suspected to
have tuberculosis based on their clinical presentation
together with either a positive Mantoux test or AFB
positivity and treated for TB. Twenty four children had
culture positive TB. The median age at diagnosis of TB in
these children was 16 months. Over half of these children
had some immunodeficiency. Common presentations were
fever (87%), history of contact with an open case of TB
(79%), cough for more than 2 weeks (75%), malnutrition
(71%), hepatosplenomegaly (71%), chronic diarrhea (67%)
and generalized lymphadenopathy (58%). Chest
roentgenograms were abnormal in all the children, with
hilar and/or paratracheal nodes (62%) and lobar or
segmental opacification (57%). Twenty one (87%) children
had pulmonary TB at the time of their diagnosis. One or
more sites of extrapulmonary TB were confirmed in 10
(41%) patients.
DIFFERENTIAL DIAGNOSIS
i. Lymphocytic Interstitial Pneumonitis
Lymphocytic interstitial pneumonitis (LIP) is a very
common cause of lung disease in HIV-infected children
over 2 years of age. LIP may be difficult to differentiate
from PTB or miliary TB. Clinical features (other than
respiratory symptoms/signs) that are commonly
associated with LIP include symmetrical, generalized
lymphadenopathy (painless and mobile), bilateral chronic
nontender parotid enlargement, and finger clubbing.
Diagnosis is often clinical as it can only be confirmed by
lung biopsy. Typical chest radiograph findings are bilateral
diffuse reticulonodular pattern and enlarged mediastinal/
hilar lymph nodes. In pulmonary tuberculosis, the
radiological abnormalities are often unilateral. However,
LIP presents with a broad spectrum of clinical and
radiological features. Bacterial pneumonia is a common
complication and further confuses the radiological
findings.
ii. Pneumocystis Jiroveci (Previously Carinii) Pneumonia

Pneumocystis jiroveci pneumonia (PCP) is a common
problem in HIV-infected children and usually presents as
an acute, severe pneumonia in infants less than 6 months
of age. Compared with TB in infants, PCP is characterized
by hypoxia. The commonest chest radiograph abnormalities are diffuse interstitial infiltration and
hyperinflation. In developing countries, PCP is a very
unlikely diagnosis of persistent respiratory disease in
children after infancy. In countries where there is antenatal
228
HIV screening and routine cotrimoxazole prophylaxis in

HIV-infected infants, PCP is now unusual.
disorders whose radiologic findings are similar to those in

iii. Bacterial Pneumonia
Interferon-Release Assays
Bacterial pneumonia is common in HIV-infected children

and recurrent bacterial pneumonia is a feature of children
with AIDS. The commonest cause is Streptococcus pneumoniae
and response to treatment is usually satisfactory. Other
causes include Haemophilus influenzae, Salmonella,
Staphylococcus aureus, Klebsiella pneumoniae and Escherichia
coli. The presentation of PTB in infants can be acute, so
PTB should be considered when there is a poor clinical
response to standard antibiotics and a family member has
tuberculosis. Pneumonia due to Staphylococcus or Klebsiella
may be a problem in HIV-infected children with chronic
lung disease. These bacteria can cause cystic changes and
cavitation.
These are new assays for diagnosis of latent TB infection

(For details please refer to chapter on Tuberculin test). These
tests have been evaluated in children with HIV-TB coinfection. In a recently published study on 36 HIV-1
infected children and adolescents, with microbiologically
and/or histopathologically confirmed TB co-infection the
sensitivity was 38.8% for TST, 47.2% for IGRA
(QuatiFERON Gold In tube test) and 11.1% for ELISA.43
Out of 24 patients with severe immunosuppression (CD4+
< 200 cells/mm3), 6 had positive TST, i.e. sensitivity 25%,
10 positive QFT-G results, i.e. sensitivity 41.6%. In another
study, the aim was to measure the agreement of two
interferon-gamma release assays (IGRAs) and the
tuberculin skin test (TST) for the detection of M. tuberculosis
infection in human immunodeficiency virus (HIV) infected
adults and children in a setting highly endemic for
tuberculosis (TB).44 The authors concluded that there was
a poor to moderate agreement between the TST and IGRAs
in HIV-infected adults and children. T-SPOT. TB may have
improved sensitivity for detection of M. tuberculosis infection
in HIV-infected individuals compared to the Quantiferon
test and the TST.
Bronchiectasis
This is usually a complication of LIP but may also
complicate TB. A cough productive of copious purulent
and sometimes blood-stained sputum, finger clubbing,
and halitosis are typical features.
Others
Other conditions to be considered in the differential
diagnosis includes fungal pneumonia, e.g. due to candida
or cryptococcus, nocardiosis and pulmonary lymphoma, and
rarely pulmonary Kaposi sarcoma.
Investigations
Diagnosis of tuberculosis in HIV-infected children poses
at least as many difficulties as in non-HIV-infected child.
Bacteriology
Demonstration of M. tuberculosis on smear or culture
remains the gold standard. However, there are difficulties
in obtaining appropriate specimen (please see Chapter on
Pulmonary tuberculosis). However, all efforts should be
made to demonstrate the organism. This may be achieved
by sputum examination in older children, gastric aspirate
or induced sputum in younger children. Bronchoalveolar
lavage (BAL) may be performed in tertiary care centers.
There are some reports that suggest lower yields on culture
in HIV-infected children.41
Tuberculin Test
The tuberculin test is less sensitive, especially in children
with low CD4 counts.42 Chest radiograph is also less specific
in HIV-infected children because of presence of other
Pediatric Tuberculosis Score Chart

The pediatric tuberculosis score chart (TSC) has a low
specificity in diagnosing tuberculosis in HIV endemic
areas and leads to overdiagnosis of tuberculosis.45
Radiology
The radiologic findings in pulmonary tuberculosis are
likely to be same as in non-HIV-infected children,
particularly those without severe immunosuppression.
However, children with both HIV and TB may have
atypical radiographic features and cavitation.39
The diagnostic work up for extrapulmonary tuberculosis
is similar to that in immunocompetent children.
Immunity Test for AIDS

The CD+4 count test used to gauge immunity levels of an
HIV-infected patient and was considered sufficient to
decide that the damage caused by the virus requires lifesaving antiretroviral therapy (ART). CD count test is done
at no cost to all patients. This was the decision of National
Aids Control Organization (NACO). The objective was to
detect the cases early and reduce mortality. At present India
has 58 CD-4 counting machines.
Blood samples of HIV patients are taken at ART centers
and then processed at centers where the CD-4 cell count

machines are available. This test only predicts risk of future
infections to 52,000 patients who are on ART in India
against estimated 5.2 million who are infected with HIV.
The CD-4 count is used in combination with the viral load
test which measures the level of HIV in blood. The test is
ordered as a baseline measure when the patient is first
diagnosed. Test are repeated in every 6 months. The CD4
count in healthy adults ranges from 500 to 1,500 cells per
cubic millimeter of blood. In HIV infected people it goes
down by 60 cells per cubic millimeter of blood per year as
HIV progresses. ART is administered when an HIVpositive person registers a CD-4 count under 200.
Other Tests for Diagnosis of HIV

A simple gum swab in place of an invasive blood test can
tell whether one is positive for HIV. What is even better
that the result is obtained in just 10-20 minutes. This saliva
based test has been standardized by a team of IndoCanadian scientists. The accuracy rate is 100%. The Indian
scientists are from Mahatma Gandhi Institute of Medical
Sciences (MAIMS) Sevagram. The test is based on oral
mucosal transudate (OMT), a fluid that is secreted at the
base of the gums before it becomes saliva.46
Level of antibodies in oral mucosal test (OMT) is
comparable to that of blood plasma, making it an excellent
sample for HIV testing. This wide-spread use of oral tests
for HIV available over the counter will not scare the
patients from undergoing the test for HIV. The test requires
only rubbing the stick against the gum twice to collect oral
fluid and hence easy to adopt in the field conditions. The
test has got easy application to test the pregnant women
for HIV and if positive, the patient can be referred for
treatment with in 40 to 60 minutes. Globally in 2007, about
2.1 million children were detected positive for HIV
infection. 90% of them had acquired it via maternal fetal
transmission. No available intervention to prevent mother
to child transmission (PMTCT) is possible unless a rapid
diagnostic test is available. With antiretroviral drugs the
probability of transmission is 30 to 35%.
In the labor room, due to inconsistent availability of
blood-based rapid tests, many women fail to get tested. In
2005, 4,755 infants were detected for HIV positivity due to
mother to child transmission.
The advantages of the oral test are that the test result is
available with in minutes and can be performed by health
workers with minimal training eliminating the need for
specialist laboratory technicians. 450 individuals tested
for HIV infection at Mahatma Gandhi Institute of Medical
Sciences found 32% to be positive for HIV. The IndoCanadian team then compared the accuracy of the
Oraquick test for two samples-one obtained from oral fluid
(gums) and the other blood-based finger prick-with
traditional blood tests. There was only one false positive
case with the oral gum swab test having 99.7% specificity.
The added advantage was that there was no discomfort
reported with the oral test as compared to 60% of the
229
subjects who complained of discomfort with the finger

testing method.
Oral test just requires rubbing the stick against the gum
twice, once against the upper jaw and then on the lower
jaw from one end to the other to collect the oral mucosal
transudate fluid normally secreted in the oral cavity. The
applicator on the stick is a strip of synthetic proteins which
detects HIV antibodies just in 20 minutes. In the standard
HIV test with blood sample, the patient has to wait for two
weeks for the result. According to CDC Atlanta, 33% of
tested never pick up their results.
Oraquick test has been approved by the US Food and
Drug Administration. This being a noninvasive, simple,
accurate and oral fluid-based has the potential to make a
big impact on HIV screening. This makes it almost a homebased HIV testing facility.
New Test to Detect Drug-Resistant Virus in AIDS

Patients
Scientists at Duke University Medical Center have
developed a new blood test that detects whether the HIV/
AIDS patient is infected with a drug-resistant virus.
Detecting resistant strain quicker will help the doctor to
keep patients healthy longer, reduce treatment costs and
help to cut an infected person's risk of spreading HIV. At
present tests available pick up drug-resistant strains when
they represent a significant portion of the virus circulating
in the blood stream. This development will help countries
like India and South Africa which have a heavy HIV
burden.
An estimated 5.2 million people are living with HIV in
India of which only 52,000 patients are on life saving
antiretroviral drugs. India provides just the first-line drugs.
According to India's National AIDS Control Organization
only 2.3% of the 52,000 patients have become resistant to
first line drugs. A test for knowing resistance costs Rs 15,000.
India had planned to upscale therapy to 100,000 people by
2007. The new test is able to pick up resistant strains that
make up less than 1% of the virus circulating in the patient's
blood. Existing tests pick up drug-resistant HIV strains only
if they make up 20% or more of the total virus in the patient's
system.
The present test detects resistance when drug treatment
fails and virus spreads in the blood, making an infected
person more contagious. The new test, 1000 times more
sensitive than current methods will save time which is a
crucial factor for an HIV infected person.
Lacunae in Treatment
(Times of India, Oct 1 2009)
Some lightening facts about HIV-infection.
33 million people lives with HIV globally.
4 million HIV positive people were receiving
antiretroviral therapy at the end of 2008.
5 million HIV positive still have no access to treatment.
230
1/3rd of HIV positive children die before the age of 1.5

yrs., by 2 years.
27 lakh people, new infections recorded in 2007; 3.7
lakh were kids.
40% drop in the case of most commonly antiretroviral
drugs.
37% was the coverage in South East Asia region in
2008 up from 29% in 2007.
21 % of pregnant women receive HIV test in 2008 world
wide up from 15% in 2007.
45% HIV positive pregnant women received ART to
prevent mother-child transmission. At the end of 2008,
more than four million HIV positive adults and
children were receiving the life saving antiretroviral
drugs in low and middle income countries and it was
one million more than the figures in 2007 and a 10 fold
increase in the last five years. More than 9.5 million
out the total 10 million HIV positive have no access to
antiretroviral therapy. 33 million are living with HIV.
India is among the top 20 countries which recorded
the highest percentage increase in the number of people
receiving ART between 2007 and 2008 from 1.58 lakhs
to 2.34 lakhs (48% increase). The number of facilities
with HIV testing and counselling facilities in India
increased from 4269 in 2007 to 4817 in 2008.
According to a new report released by WHO, UNICEF,
UNAIDS on 30th Sep 2009 the situation looks grim for
India. While 80,000 pregnant women living with HIV
positivity require treatment with ART to prevent passage
of deadly virus to the infants only 10,673 received specific
therapy. Only 16 % of pregnant women get tested during
pregnancy.
Children
Just about 22% children born to HIV positive infected
mothers were receiving ART to prevent mother-to-child
transmission. Only 56% of the target sex workers in India
have been reached with HIV preventive program in the
past 12 months. Only 34% of sex workers and 32% of men
who have sex with men in India, population most at risk
of infection were tested in the past one year for infection
and who know the results. Around 7% of injecting drug
users of India have got infection with HIV.
According to the report more than half of the people
having HIV infection know their results. WHO Director
General Margrat Chan said, "This report shows
tremendous progress in global HIV/AIDS response". But
at least 5 million people living with HIV infection have no
access to life prolonging treatment and care. Although
there is increasing emphasis on women and children in
the global HIV/AIDS response, the disease continues to
have its devastating impact on their health, livelihood and
survival.
The South East Asian region too has abysmal figures
of 4.43 lakhs who received ART till December 2008 while
11 lakhs require it. The number of children younger than

15 years who received ART in this period is 23,400 while
47,000 require its 49% coverage only.
TREATMENT OF TB
In HIV infected patients, early diagnosis of TB and its
treatment is critical for curing TB. Its negative effect on TB
and reduction in the transmission of TB in the community
is worth while. Even in the absence of HAART, proper
case management of active TB can significantly prolong
the lives of HIV positive persons with tuberculosis.
Standardized regimens of RNTCP for treating TB are
equally effective both in HIV positive or HIV negative
individuals.
Due to opportunistic infections, mortality in HIVinfected patients is higher. Worse outcome is due to delayed
diagnosis of TB in HIV infected patients, short-course
therapy is more effective as compared to 12 months course
in HIV infected patients. This is due to broad range activity
of rifampicin which is responsible for decreased death
rates in HIV infected patients.
Direct observation of treatment of TB in HIV infected
patients is very important. Self administration of drugs is
responsible for increased death rates. In HIV-infected patients
adherence to therapy is very important. Relapse rate of TB in
fully compliant, rifampicin containing RNTCP regimen
lowers the death rates in HIV-infected patients. Regimen
containing isonizid and ethambutol and unsupervised long
regimen is responsible for high death rates.
The DOTS strategy can prevent the emergence of multidrug resistant TB (MDR-TB). Failure to persue DOTS can
lead to an explosive spread of TB and rapid increase in
drug resistance among HIV-infected individual.
Standard RNTCP regimens containing rifamcipin
should be used.
Combating TB-HIV Infection

The two epidemics need a joint effort from both TB as well
as HIV/AIDS control programs. With prevention and
intervention, the HIV epidemic should be curbed since a
cure is not yet available. In India since 2001, this synergetic
action plan is in place.
National Action Plan for Joint TB-HIV Coordination

Sensitization of key policy-makers to address the
importance of TB-HIV co-infection.
Joint Training Program for service providers involved
in RNTCP and NACP
Voluntary counselling program and confidential
testing centers (VCCTC)-Designated Microscopy
Centers (DMC) coordination

Sensitization of NGOs and PPs working for NACP and
RNTCP
Infection control measures
Information, education, and communication
Treatment services for tuberculosis and HIV
Monitoring and evaluation of coordination of both the
programs:
a. Revised national tuberculosis control program.
b. National AIDS control program.
c. Voluntary counseling and confidential testing
centers.
d. Designated microscopy centers.
The key part in the action plan is the coordination
between the designated microscopy center (DMC) of the
TB control program and the voluntary counselling
program and confidential testing centers (VCCTCS) of the
HIV/AIDS control program for minimizing stigma due to
HIV/AIDS coinfection, confidentially is maintained by
VCCTCS. TB is treated irrespective of HIV status.
Anti-retroviral Therapy Rollout

Six highly prevalent states in India are Andhra Pradesh,
Karnataka, Maharashtra, Manipur, Nagaland and Tamil
Nadu. Eight states with modest HIV prevalence are Delhi,
Gujarat, Himachal Pradesh, Kerala, Orissa, Punjab,
Rajasthan and West Bengal. The National HIV/AIDS
control program has started the roll-out of anti-retroviral
drugs from 1st April 2004. Stavudine, + Lamivudine +
Nevirapine are the three drugs being given to high prevalent
areas. Due to interaction between nevirapin and rifampicin
leading to unpredictable bioavailability of both of these
drugs, there is limitations in the program.
Actions of Anti-Retroviral Treatment

Life is prolonged due to reduction of viral replication
in HIV/AIDS patients.
Appropriate drug combination are nucleoside reverse
transcriptase inhibitors (NsRTIs) like zidovudine (ZDV),
didanosin (ddl) stavudine (d4t), Lamivudine (3TC) and
abacavir (ABC) can be safely coadminstered with anti TB
drugs.
Coadministration of rifampicin and protease inhibitors
(PIS) or nonnucleoside reverse transcriptase inhibitors
(NNRTIs) is not recommended due to drug interactions.
Rifamycin induces P450 and PIs/NNRTIs may
induce/inhibit the isoenzymes resulting in nonreliable
concentration of rifamycin in serum. Rifabutin is less
potent inducer of cytochrome P450 and can be
concurrently used with NNRITs and certain PIS, e.g.
indianavir, nelfinavir. Rifabutin is presently not
available in India.
If a PI or (NsRTIs) is to be started after giving rifampicin,
that should be given atleast two weeks after the last
dose of rifampicin. This time gap is necessary for
231
induction of the enzyme inducing activity of rifampicin

prior to commencement of antiretroviral therapy
(ARVS).
ATT for patient on ARTS: If a patient on ARTS
drugs develops TB then the antiretroviral therapy
should be modified, to be compatible with RNTCP
regime.
Treatment of TB patients coinfected with HIV cannot
be envisaged without rifampicin. In these co-infected
patients, TB should be treated first with one of the
RNTCP regimens and ART should be started only after
completing the antiTB regimen. Very low CD4+ T cell
counts require concomitant ART therapy and anti-TB
therapy in which ART regimen should be modified by
replacing nevirapine with favirenz on completion of
anti-TB regimen.
Prevention of TB Disease among

Coinfected Individuals
Primary onus lies with the VCCTCS to identify the potential
beneficiaries. Then comes the use of tuberculosis
preventive therapy with isoniazid and use of
antiretrovirals.
Isoniazid Preventive Therapy

Isoniazid preventive therapy (IPT) for TB/HIV coinfected
patients reduces the development of TB in HIV infected
individuals. TB in these individuals is usually reactivation
of endogenous infection of dormant focus.
Preventive therapy in developing countries has been
difficult because:
Difficulty in identifying high-risk patients among a
large number of infected couples
Difficulties in ensuring compliance
Limited benefit as the rate of active disease in
seronegative individuals is comparatively low
Correctly ruling out the individuals with active disease
in extrapulmonary and smear negative cases.
Need of the hour in India is also strengthening control
program for TB/HIV co infected patients.
TREATMENT OF CHILDREN
Treatment of tuberculosis in children with HIV infection
follows the same principles as treatment of HIV-uninfected
children. However, there are several important differences
between children with and without HIV infection. These
differences include following:
i. The potential for drug interactions, especially between
the rifampicin and antiretroviral agents.
ii. Paradoxical reactions that may be interpreted as
clinical worsening.
iii. The potential for the development of acquired
resistance to rifampicin when treated with highly
intermittent therapy.
232
Antiretroviral Drugs (ARV)
Starting HAART
ARV drugs belong to two main classes:

a. Reverse transcriptase inhibitors (RTIs)
b. Protease inhibitors. (PIs)
When to start antiretroviral therapy in patients who have

tuberculosis is a balance between potential overlapping
toxicities, drug interactions and possible immune
reconstitution versus the risk of further immune
suppression with its associated increase in morbidity and
mortality. As per BHIVA HIV treatment guidance, the
patients who have a CD4+ counts consistently > 200 cells/
ul while receiving antituberculosis therapy should wait
until their antituberculosis therapy is completed before
starting HIV therapy. For patients with CD4 counts
between 100 and 200 cells/ul, HIV therapy is deferred
RTIs are further divided into three groups:

i. Nucleoside reverse transcriptase inhibitors (NsRTIs)
ii. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
iii. Nucleotide reverse transcriptase inhibitors (NTRTIs).
The following table gives the antiretroviral drugs in
each group with abbreviations and dose (Table 15.2.2).
Table 15.2.2: Antiretroviral drugs with respect to there age, weight and dose.
Name of the Drug
Age Group/weight
Dose in mgs.
Nucleoside reverse transcriptase inhibitors (NsRTIs)
< 4 weeks
4 mg/kg BD
Zidovudine (ZDV)
4 weeks to 13 year
Lamivudine (3TC)
> 13 yrs
< 30 days
> 30 days and < 60 kg
180 mg/m2 BD
Maximum dose
300 mg BD
2 mg/kg BD
4 mg/kg BD
Maximum dose:
150 mg BD
> 60 kg
Didanosine (ddl dideoxyinosine)
< 3 months
3 months to 13 yrs
13 years or > 60 kg
Stavudine (d 4T)
< 30 kg
30-60 kg
> 60 kg
Abacavir (ABC)
(over age 3 months)
< 16 years or < 37.5 kg

> 16 years or > 37.5 kg
50 mg/m2 BD
90 mg/m2BD
Maximum dose
200 mg BD
1 mg/kg BD
30 mg BD
Maximum dose
40 mg BD
8 mg/kg BD
Maximum dose
300 mg BD
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Nevirapine (NVP)
Cannot be used with rifampicin
15 to 30 days
to 13 years
> 30 days
> 13 years
Efavirenz (EFZ)
(Only for children over 3 years)
5 mg/kg OD for
2 weeks, then
200 mg/m2 BD
120 mg/m2 OD
200 mg/m2 BD
Maximum dose
200 mg OD for
2 weeks, then 200 mg
10-15 kg
200 mg OD
15-25 kg
25-33 kg
33-40 kg
250-300 mg OD
350 mg OD
400 mg OD
Maximum dose
600 mg OD
> 40 kg
Contd....
233

Contd....
Protease Inhibitors (PIs)
Nelfinavir (NFV)
< 1 yr
> 1 yr to < 13yrs
> 13 yrs
Lopinavir / ritonavir (LPV/r)

(For 6 months of age or older)
7-15 kg
15-40 kg
> 40 kg
40-50 mg/kg
TDS or 75 mg/kg
BD
60 mg/kg BD
Maximum dose
1250 mg BD
12 mg/kg
LPV
3 mg/kg
Ritonavir BD
10 mg/kg LPV
2-5 mg/kg
ritonavir BD
Maximum dose
400 mg LPV
100 mg ritonavir
For estimating the surface area, consult a standard textbook of pediatrics.
until completion of intensive phase of antituberculosis

treatment. For patients with < 100 cells/ul, they should be
recruited to ongoing clinical trials as far as possible.
Short-course Chemotherapy with Antituberculosis

Drugs
It is generally accepted that short-course chemotherapy is
adequate for the treatment of tuberculosis in persons with
HIV infection.47,48 There is evidence that response to
treatment is similar in HIV-infected and HIV seronegative
adult patients given short-course chemotherapy.49 Similar
controlled trials in children are not reported. In observational
studies it has been noticed that HIV-infected children have
higher mortality and also significant side effects.50 The
higher mortality in the intensive phase of therapy may be
due to tuberculosis and that later in the course due to other
AIDS-related infections/illnesses.
The American Thoracic Society recommends the
minimum duration of therapy for tuberculosis in HIVinfected adults of 6 months which may be extended if the
response is sub-optimal.51 Although there is no such data
on which to base recommendations, in children, the
American Academy of Pediatrics recommends that for
HIV-infected children the minimum duration of therapy
of tuberculosis should be 9 months.52
Treatment of HIV-TB Coinfection

Availability of highly active antiretroviral therapy (HAART)
has significantly improved the outcome of HIV/AIDS, in
terms of prevention of overt illness as well as mortality.
However, substantial pharmacokinetic interactions occur

between the rifampicin component of antituberculosis
treatment and antiretroviral drugs especially, protease
inhibitors (PIs) and nonnucleoside reverse transcriptase
inhibitors (NNRTIs).53
The key therapeutic principles underlying the
treatment of HIV-TB are:
i. Treatment of TB always takes precedence over the
treatment of HIV infection.54
ii. In patients who are already on HAART, the same has
to be continued with appropriate modifications both
in HAART and antituberculosis treatment.55
iii. In patients who are not receiving HAART, the need
and timing of initiation of HAART have to be decided
after assessing the short-term risk of disease
progression and death, based on CD4+ count and
type of TB, on an individualised basis.56 There are no
separate pediatric guidelines available.
Treatment of TB/HIV in Relation to Immune Status of

the Child
i. If a HIV-infected child is diagnosed to have
tuberculosis, and immunosuppression is not severe
(CD4 counts > 15%) and there are no significant HIVrelated illnesses, the child should be treated for
tuberculosis first and the child should be monitored
carefully for any worsening of the immune status.
ii. If a HIV-infected child is diagnosed to have
tuberculosis, and immunosuppression is severe (CD4
counts < 15%) or there are significant HIV-related
illnesses, the child should be treated concurrently with
234
antitubercular therapy and modified efavirenz based

antiretroviral therapy.
iii. If a child is on antiretroviral therapy (protease
inhibitor or nevirapine based regimes) and develops
tuberculosis, the antiretroviral therapy is modified
and efavirenz is used instead of nevirapine or
protease inhibitor and antitubercular therapy is
started. After completion of antitubercular therapy,
one may switch to the initial antiretroviral therapy
regime.
In adults, immune reconstitution inflammatory
syndromes (IRIS) have been described. This paradoxical
reaction might occur during the course of tuberculosis
treatment when anti-retroviral therapy restores the immune
function. Hectic fever, lymphadenopathy and worsening
of ongoing tuberculous lesions can occur, however, patients
generally feel well and in exceptional circumstances, shortterm steroids can be used.
In a recently published trial in adults to determine the
optimal time to initiate antiretroviral therapy in patients
with HIV and tuberculosis coinfection who were receiving
tuberculosis therapy, the initiation of antiretroviral therapy
during tuberculosis therapy significantly improved
survival.57
In a study to assess the effect of anti-tubercular therapy
on the CD4 count in HIV infected children with tuberculosis, Mukherjee et al58 demonstrated that children who
received both ART and ATT had a rise in CD4 count
(209.33 381.62/L), while those who received ATT alone
showed a fall in CD4 count (-75.3 247.69/L, p< 0.01) at
6 months. Of 13 children who received ATT alone, 9 showed
a decline in the CD4 count in 6 months compared with 4
out of 12 children who received both ATT and ART
(p=0.07).
Treatment and Prevention of Latent Tuberculosis

In patients with HIV, as in others, chemopro-phylaxis with
INH appears to be highly effective in inhibiting progression
of tuberculous infection to active tuberculous disease.54-57
Preventive therapy in HIV infected children should be given
if tuberculin positivity is 5 mm or more with no signs of
active tuberculous disease irrespective of BCG status and to
those allergic children exposed to active tuberculosis if the
organism is known to be sensitive to INH. To identify high
risk patients, besides tuberculin status and irrespective of
BCG, treatment of latent tuberculosis is to be done after careful
exclusion of active tuberculosis.59 However, probably 6
months of a regimen containing. INH and rifampicin will
also be sufficient in developing countries. Due to high rate
of relapse of tuberculosis in absence of continued INH
prophylaxis, some authors in absence of continued INH
prophylaxis, have even advocated INH for life in patients
with dual infection.60-62
Interestingly in a study by the Cochrane database to
study drugs to prevent tuberculosis in HIV-infected
persons with a positive tuberculin skin test but with no

evidence of active disease, found that isoniazid alone,
isoniazid plus rifampicin, isoniazid plus rifampicin plus
pyrazinamide or rifampicin plus pyrazinamide had
similar protective effects against active tuberculosis for
people with positive skin tests.63
Because of problems with adherence, toxicity, and
increasing resistance associated with 6- to 12-month
isoniazid regimens, an alternative short-course tuberculosis
preventive regimens are needed. An international
randomized trial done in adults showed that a daily 2month regimen of rifampicin and pyrazinamide is similar
in safety and efficacy to a daily 12-month regimen of
isoniazid. This shorter regimen offers practical advantages
to both patients and tuberculosis control programs.64
However, this protocol has been abandoned in view of high
toxicity.65
A study had been carried out by Zar et al to investigate
the impact of isoniazid prophylaxis on mortality and
incidence of tuberculosis in children with HIV.66 Data on
263 children (median age 24.7 months) were available
when the data safety monitoring board recommended
discontinuing the placebo arm; 132 (50%) were taking
isoniazid. Median follow-up was 5.7 (interquartile range
2.0-9.7) months. The mortality was lower in the isoniazid
group than in the placebo group (11 (8%) Vs 21 (16%),
hazard ratio 0.46, 95% confidence interval 0.22 to 0.95,
P=0.015) by intention to treat analysis. The incidence of
tuberculosis was lower in the isoniazid group (5 cases,
3.8%) than in the placebo group (13 cases, 9.9%) (hazard
ratio 0.28, 0.10 to 0.78, P=0.005). All cases of tuberculosis
confirmed by culture were in children in the placebo group.
The authors concluded that prophylaxis with isoniazid
had an early survival benefit and reduced the incidence of
tuberculosis in children with HIV. Prophylaxis with
isoniazid in children significantly reduced mortality by
about 50% and incidence of tuberculosis by about 70%.
The reduction in mortality occurred in all categories of
clinical disease, in children in all age groups, and for
varying degree of immune suppression.
Thus it has been demonstrated that prophylaxis with
izoniazid has an early survival benefit and reduces
incident of tuberculosis in children with HIV. Prophylaxis
may offer an effective public health intervention to reduce
mortality in such children in settings with a high
prevalence of tuberculosis.
PROGNOSIS
When tuberculosis disease develops in an HIV- infected
child, the prognosis is often poor, though it depends on
the individual's degree of immunosuppression and
response to appro-priate treatment. The adverse
interactions between tuberculosis and HIV have been
discussed above. The observed mortality rate for HIVinfected adults with tuberculosis is approximately 4 times

greater than the rate of tuberculosis patients not infected
with HIV and the one year mortality rate for treated HIV
related tuberculosis ranges for 20 to 35 percent with little
variation between cohorts from industrialized and
developing countries.67-68 A case control study from South
Africa has shown poor response to antituberculosis
treatment in the form of poor patient survival after 6 months
of treatment in children with dual infection, as compared
to those without HIV infection.69 A definite cause for this
finding could not be ascertained, but residual tuberculosis
disease was considered as the most likely reason;
continuing HIV infection, other opportunistic infections,
malabsorption of ATT and multidrug-resistance were other
speculated factors. The mortality of culture proven
tuberculosis in HIV-infected adults from a developing
country, in one recent study was 21 percent but was still
considered low since the patients could not afford any
antiretroviral treatment.70 Despite few reports, treatment
of tuberculosis in HIV-infected children is by and large
effective and mortality results mainly from failure to
diagnose, poor compliance, drug resistance, and advanced
HIV disease. HIV related immunosuppression with its
attendant reduction of CD4+ T cell count has been
observed to be a critical risk factor in prognosis of childhood
tuberculosis patients with HIV.71
Drug Toxicity
HIV-infected individuals are more prone to develop adverse
reactions to antituberculosis drugs and need to be carefully
monitored. The risk of adverse drug reactions (ADRs)
increases with advanced immunosuppression and majority
of the ADRs occur in the first two months of treatment.72
These include skin rash, usually caused by thiacetazone
and sometimes by rifampicin and streptomycin,
gastrointestinal disturbances and drug-induced
hepatotoxicity among others.5 Thiacetazone can cause fatal
ADRs and hence is contraindicated in HIV- infected
patients.73 HIV-infected patients are more prone to develop
isoniazid-induced peripheral neuropathy and all HIV-TB
patients receiving isoniazid should be given pyridoxine
supplementation (10-25 mg/day).68 The guidelines for
children are not available but similar principles may apply.
The use of rifampicin with protease inhibitors or
nonnucleoside reverse transcriptase inhibitor is
contraindicated due to untoward effects resulting from
the interaction of these drugs on the hepatic cytochrome
P450 enzyme system. The nucleoside reverse transcriptase
inhibitors (zidovudine and lamivudine) however, are not
metabolized by cytochrome P450 enzyme system and thus
can be used along with rifampicin. Efavirenz can be used
with rifampicin. The commonly used antifungal agents
ketoconazole and fluconazole also interact with isoniazid
and rifampicin (both hepatic enzyme inducers) and results
in reduced serum levels and ineffective antifungal
235
treatment; also rifampicin absorption may be affected by

ketoconazole resulting in possible failure of tuberculosis
treatment. Finally, one also has to keep in mind that
malabsorption of ATT is also a known influence of HIV
infection on M. tuberculosis infection. Therefore, monthly
follow-up is recommended to monitor for signs and
symptoms of adverse effects, especially liver damage, along
with compliance and development of active tuberculosis.
BCG Vaccination
The WHO has recommended that all asymptomatic HIVinfected children should receive BCG except those with
symptoms of AIDS related complex (ARC)/AIDS. The local
adverse reaction rates to BCG vaccination in
immunocompetent children have been found to be
comparable to adverse reaction rates in children with HIV
infection.69 Therefore, in developing countries, where
prevalence of tuberculosis is high; and where extensive
testing for HIV serotype is neither practical nor possible,
BCG vaccination is recommended in all infants (irrespective
of HIV serotype) since the risks of tuberculosis far outweigh
the complications for immunization. Profoundly
immunocompromised patients may develop disseminated
infection after BCG vaccination; however, the true incidence
of long-term dissemination in an immunocompetent HIVinfected child after BCG vaccination is still unknown. In a
prospective study from Africa, it was documented that the
bloodstream dissemination of M. tuberculosis and M. bovis
BCG is uncommon in HIV-infected children vaccinated with
BCG.74
World Health Organization policy on BCG vaccination
in infants and children infected with HIV is as follows:
There are few case reports of local complication after
BCG and disseminated BCG disease in HIV infected
children. In vast majority of cases BCG immunization is
considered safe.
HIGHLIGHTS
i. Patterns of HIV infection and disease are changing.
HIV will soon enter the top five causes of death
worldwide and is now believed to cause more
deaths than malaria.
ii. HIV infection is lowering life expectancy and
reversing gains in child survival. HIV-TB coinfection
is an important problem in most of the developing
countries.
iii. A great deal of work has been accomplished in AIDS
research and associated infections especially
tuberculosis. However, unlike adults, the natural
history of tuberculosis in HIV-infected children still
has to be elucidated, especially in relation to the
epidemiological parameters prevailing in
developing countries.
236
iv. HIV infection per se does not appear to be a

predisposing factor for the development of MDRTB. Studies by Asch et al75 and Spellman et al76 have
found that drug resistant TB including MDR-TB is
not more common among people infected with HIV.
v. Intermittent therapy including isoniazid and
rifamycin increase the risk of acquired rifamycin
resistance among TB patients with advanced
HIV disease with very low CD4+ cell count (<60/
mm3)77,78 such patients should receive daily therapy
both during intensive and continuation phase.
vi. With the situation of the dual epidemic of HIV and
tuberculosis infection set to worsen, both the
pediatric and adult, HIV/tuberculosis infection has
to be tackled simultaneously.
vii. Specific strategies to screen for and manage HIV
infection and tuberculosis along with performance
indicators have to be outlined and implemented on
a war footing with cooperation from all sectors.
REFERENCES
15.1 TB in HIV-Infected Children
1. Grange J, Zumla A. Tuberculosis and the poverty-disease
cycle. J Royal Soc Med 1999; 92: 107.
2. Barr RG, Menzies R. The effect of war on tuberculosis.
Results of a tuberculin survey among displaced persons
in El Salvador and a review of literature. Tuberc Lung Dis
1994.;75: 251-9.
3. Marais BJ, Graham SM, Cotton MF, et al. Diagnostic and
management challenges for childhood tuberculosis in the
era of HIV. J Infect Dis 2007; 196 Suppl 1: S76-85.
4. Corbett EL. The growing burden of tuberculosis. Global
trends and interactions with the HIV epidemic. Arch
Intern Med 2003; 163: 1009-21
5. Harries AD, Hargreaves NJ, Kemp J, et al. Deaths from
tuberculosis in sub-Saharan African countries with a high
prevalence of HIV-1. Lancet 2001; 357: 1519-23.
6. Marais BJ, Esser M, Godwin S, et al. Poverty and HIV in
children a view from the Western Cape, South Africa. Ann
N Y Acad Sci 2008; 1136: 21-7
7. Marais BJ, Hesseling AC, Gie RP, et al. The burden of
childhood tuberculosis and the accuracy of communitybased surveillance data. Int J Tuberc Lung Dis 2006; 10:
259-63.
8. Donald P R. Childhood tuberculosis: out of control? Curr
Opinion Pulm Med 2002; 8 : 178-82
9. World Health Organization. Guidelines for HIV
surveillance among tuberculosis patients, Geneva 2004,
WHO/HTM/TB 2004.339.
10. World Health Organization. Guidance for National
Tuberculosis Programmes on the Management of
Tuberculosis in Children. WHO, Geneva, Switzerland
WHO/HTM/TB/2006.371.
10a Global Tuberculosis Control Report. 2009. Available soon:
URL http://www.who.int/tb/publications/global/2009/
pdf/full report.pdf. Accessed April 4, 2009.
11. Lucas SB, Peacock CS, Hounnou A, et al. Disease in children

infected with HIV in Abidjan, Cote dIvoire. Lancet 1996;
312: 335-8.
12. Ikeogu MO, Wolf B, Mathe S. Pulmonary manifestations
in HIV seropositivity and malnutrition in Zimbabwe. Arch
Dis Child 1997; 76: 124-8.
13. Coovadia H, Jeena P, Wilkinson D.Childhood human
immunodeficiency infection and tuberculosis coinfections: reconciling conflicting data. Int J Tuberc Lung
Dis 1998; 2: 844-51.
14. Chintu C, Mudenda V, Lucas S, et al. Lung diseases at
necropsy in African children dying from respiratory
illnesses: a descriptive necropsy study. Lancet 2002; 360:
985-90.
immunodeficiency virus 1 infection on clinical presentation,
treatment outcome and survival in a cohort of Ethiopian
children with tuberculosis. Pediatr Infect Dis J 2002; 21: 105361.
16. Jeena PM, Pillay P, Pillay T, et al. Impact of HIV-1 co-infection
on presentation and hospital-related mortality in children
with culture proven pulmonary tuberculosis in Durban,
South Africa. Int J Tuberc Lung Dis 2002; 6: 672-8.
17. Madhi SA, Petersen K, Madhi A, et al. Increased disease
burden and antibiotic resistance of bacteria causing severe
community-acquired lower respiratory tract infections in
human immunodeficiency virus type 1-infected children.
Clin Infect Dis 2000; 31: 170-6.
18. McNally LM, Jeena PM, Gajee K, et al. Effect of age,
polymicrobial disease, and maternal HIV status on
treatment response and cause of severe pneumonia in
South African children: a prospective descriptive study.
Lancet 2007; 369: 1440-51.
19. Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid
prophylaxis on mortality and incidence of tuberculosis in
children with HIV: randomized controlled trial BMJ 2007;
334: 136.
20. Harries AD, Parry C, Mbewe LN, et al. The pattern of
tuberculosis in Queen Elizabeth Central Hospital,
Blantyre, Malawi 1986-1995. Int J Tuberc Lung Dis 1997;
1: 346-51.
21. Lawn SD, Bekker LG, Middelkoop K, et al. Impact of HIV
infection on the epidemiology of tuberculosis in a periurban community in South Africa: the need for age-specific
interventions. Clin Infect Dis 2006; 42: 1040-7.
22. Cotton MF, Schaaf HS, Lottering G, et.al. Tuberculosis
exposure in HIV-exposed infants in a high-prevalence
setting. Int J Tuberc Lung Dis 2008; 12: 225-7.
23. Egwaga SM. The impact of HIV on transmission of
tuberculosis in Tanzania. Tuberculosis 2003; 83: 66-7.
24. Kenyon TA, Creek T, Laserson K, et al. Risk factors for
transmission of Mycobacterium tuberculosis from HIVinfected tuberculosis patients, Botswana. Int J Tuberc Lung
Dis 2002; 6: 843-50.
25. Marais BJ, Gie RP, Schaaf HS et al. The natural history of
childhood intra-thoracic tuberculosis A critical review
of the pre-chemotherapy literature. Int J Tuberc L Dis
2004; 8: 392-402.
26. Mukadi YD, Wiktor S, Coulibaly I, et al. Impact of HIV
infection on the development, clinical presentation, and
27.
28.
29.
30.
31.
32.
33.
33a.
34.
35.
36.
37.
38.
39.
40.
41.
outcome of tuberculosis among children in Abidjan, Cote

dIvoire. AIDS 1997; 11: 1151-8.
Walters E, Cotton MF, Rabie H, et al. Clinical presentation
and outcome of TB in HIV-infected children on HAART.
BMC Pediatrics 2008; 8:1.
Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary
tuberculosis: Old wisdom and new challenges. Am J Resp
Crit Care Med 2006; 173: 1078-90.
Kiwanuka J, Graham SM, Coulter JB, et al. Diagnosis of
pulmonary tuberculosis in children in an HIV-endemic
area, Malawi. Ann Trop Paediatr 2001; 21: 5-14.
Madhi S, Gray G, Huebner RE, et al. Correlation between
CD4+ lymphocyte counts, concurrent antigen skin test
and tuberculin skin test reactivity in HIV type 1infected
and uninfected children with tuberculosis. Pediatr Infect
Dis J 1999; 18: 800-5.
Marais BJ, Pai M. New Approaches and emerging
technologies in the diagnosis of childhood tuberculosis.
Paediatr Respir Rev 2007; 8: 124-33.
Marais BJ, Gie RP, Schaaf HS, et al. The spectrum of disease
in children treated for tuberculosis in a highly endemic
area. Int J Tuberc Lung Dis 2006; 10: 732-8.
Marais BJ, van Zyl S, Schaaf HS, et al. Adherence to
isoniazid preventive chemotherapy, a prospective
community based study. Arch Dis Child 2006; 91: 762-5.
Seth Vimlesh, Khosla PK, Semwal OP, et al. Visual evoked
responses in tuberculosis children on ethambutol
treatment. Indian Pediatr 1991; 28:713-7.
Donald PR, Maher D, Maritz JS, et al. Ethambutol dosage
for the treatment of children: literature review and
recommendations. Int J Tuberc Lung Dis 2006; 10: 131830.
Schaaf HS, Krook S, Hollemans DW, et al. Recurrent
culture-confirmed
tuberculosis
in
human
immunodeficiency virus-infected children. Pediatr Infect
Dis J 2005; 24: 685-91.
http://www.cdc.gov/nchstp/tb/
Chintu C, Bhat GJ, Walker AS. Cotrimoxazole as
prophylaxis against opportunistic infections in HIVinfected Zambian children (CHAP): a double-blind
randomised placebo-controlled trial. Lancet
2004;364:1865-71.
Guidelines on cotrimoxazole prophylaxis for HIV-related
infections among children, adolescents and adults in
resource-limited settings. World Health Organization,
Geneva, 2006. http://www.who.int/3by5/ mediacentre/
news32/en/index.html
Puthanakit T, Oberdorfer PM, Akarathum N, et al.
Immune Reconstitution Syndrome after highly active
antiretroviral therapy in human Immunodeficiency virusinfected Thai children. Pediatr Infect Dis J 2006; 25: 53-8.
Hesseling AC, Rabie H, Marais BJ, et al. Bacille CalmetteGuerin (BCG) vaccine-induced complications and HIV
infection in children. Clin Infect Dis 2006, 42: 548-58.
Hesseling AC, Cotton MF, Fordham von Reyn C, et al.
Consensus statement on the revised WHO recommendations for BCG vaccination in HIV-infected infants:
Submitted on behalf of the BCG Working Group, Child
Lung Health Section, International Union Against
Tuberculosis and Lung Disease. Int J Tuberc Lung Dis
2008; 12: 1376-9.
237
15.2 Tuberculosis and the HIV Infection

1. AIDS epidemic update. November 2009. UNAIDS/WHO
2009. Joint United Nations Program on HIV/AIDS
(UNAIDS), World Health Organization (WHO).
2. National AIDS Control Organization. HIV Data. Available
at: http://www.nacoonline.org/Quick_Links/HIV_
Data/ Accessed on March 25, 2010.
3. WHO. Tuberculosis. Available at http://www.who.int/
mediacentre /factsheets/fs104/en/index.html Accessed
on March 25, 2010.
3a. Bakshi SS, Alverez D, Hilfer CL and Kairam R.
Tuberculosis in human immunodeficiency virus-infected
children. A family infection. AM J Dis Children 1993; 147:
320-4.
3b. Rekha B, Swaminathan S. Childhood tuberculosis a global
epidemiology and the impact of HIV. Pediatr Respir Rev
2007; 8: 99-106. Eupub 2007, June 4, 2007.
immunodeficiency virus-1 infection on clinical
presentation, treatment outcome and survival in a cohort
of Ethiopian children with tuberculosis. Pediatr Infect Dis
J 2002; 21:1053-61.
5. Jeena PM, Pillay P, Pillay T, et al. Impact of HIV-1
coinfection on presentation and hospital-related mortality
in children with culture proven pulmonary tuberculosis
in Durban, South Africa. Int J Tuberc Lung Dis 2002;6:
672-8.
6. Harries A, Maher D, Graham S. (Eds) TB/HIV: a clinical
manual. 2nd edition. Geneva: World Health Organization;
2004; WHO/HTM/TB/ 2004; 23-40.
7. Khatri GR, Frieden TR. Controlling tuberculosis in India.
N Engl J Med 2002;34:1420-5.
8. Shah I. Age Related Clinical Manifestations of HIV
Infection in Indian Children. J Trop Pediatr 2005 Jun 24;
Epub.
9. Shah SR, Tullu MS, Kamat JR. Clinical profile of pediatric
HIV infection from India. Arch Med Res 2005;361:24-31.
10. Madhivanan P, Mothi SN, Kumarasamy N, et al. Clinical
manifestations of HIV-infected children. Indian J Pediatr
2003;708:615-20.
11. Verghese VP, Cherian T, Cherian AJ, et al. Clinical
manifestations of HIV-1 infection. Indian Pediatr
2002;39:57-63.
12. Merchant RH, Oswal JS, Bhagwat RV, et al. Clinical profile
of HIV infection. Indian Pediatr 2001;383:239-46.
13. Dhurat R, Manglani M, Sharma R, et al. Clinical spectrum
of HIV infection. Indian Pediatr 2000; 378:831-6.
14. Lodha R, Upadhyay A, Kapoor V, et al. Clinical profile
and natural history of children with HIV infection. Indian
J Pediatr 2006; 73: 201-4.
15. Rajasekaran S, Jeyaseelan L, Raja K, et al. Demographic
and clinical profile of HIV infected children accessing care
at Tambaram, Chennai, India. Indian J Med Res
2009;129:42-9.
16. Sharma SK, Saha PK, Dixit Y, et al. HIV seropositivity
among adult tuberculosis patients in Delhi. Indian J Chest
Dis Allied Sci 2000;42:157-60.
17. Sharma SK, Aggarwal G, Seth P, et al. Increasing HIV
seropositivity among adult tuberculosis patients in Delhi.
Indian J Med Res 2003; 117: 239-42.
238
18. Piramanayagam P, Tahir M, Sharma SK, et al. Persistently

high HIV seroprevalence among adult tuberculosis
patients at a tertiary care center in Delhi under DOTS
program of Government of India. Indian J Med Res
2007;125:163-7.
19. Madhi SA, Huebner RE, Doedens L, et al. HIV-1
coinfection in children hospitalized with tuberculosis in
South Africa. Int J Tuberc Lung Dis 2000; 45:448-54.
20. Sassan-Morokro M, De Cock KM, et al. Tuberculosis and
HIV infection in children in Abidjan, Cote d'Ivoire. Trans
R Soc Trop Med Hyg 1994; 882:178-81.
21. Luo C, Chintu C, Bhat G, et al. Human immunodeficiency
virus type-1 infection in Zambian children with
tuberculosis: changing seroprevalence and evaluation of
a thiacetazone-free regimen. Tuber Lung Dis
1994;752:110-15.
22. Merchant RH, Shroff RC. HIV seroprevalence in
disseminated tuberculosis and chronic diarrhea. Indian
Pediatr 1998;35:883-7.
23. Karande S, Bhalke S, Kelkar A, et al. Utility of clinicallydirected selective screening to diagnose HIV infection in
hospitalized children in Bombay, India. J Trop Pediatr
2002;483:149-55.
24. Shahab T, Zoha MS, Malik MA, et al. Prevalence of human
immunodeficiency virus infection in children with
tuberculosis. Indian Pediatr 2004;41: 595-9.
25. Hussain T, Sinha S, Talan S, et al Seroprevalence of HIV
infection among paediatric tuberculosis patients in Agra,
India: a hospital-based study. Tuberculosis (Edinb)
2007;87:7-11.
26. Corbett EL, Watt CJ, Walker N, et al. The growing burden
of tuberculosis: global trends and interactions with the
HIV epidemic. Arch Intern Med 2003;163:1009-21.
27. Narain JP, Raviglione MC, Kochi A. HIV-associated
tuberculosis in developing countries: Epidemiology and
strategies for prevention. Tuber Lung Dis 1992;73:31121.
28. FitzGerald JM, Houston S. Tuberculosis: The disease in
association with HIV infection. CMAJ 1999;161:47-51.
29. Whalen C, Horsburgh CR, Hom D, et al. Acce-lerated
course of human immunodeficiency virus infection after
tuberculosis. Am J Resp Crit Care Med 1995;151:129-35.
30. Toossi Z, Mayanja-Kizza H, Hirsch CS, et al. Impact of
tuberculosis on HIV-1 activity in dually infected patients.
Clin Exp Immunol 2000;123: 233-8.
31. Nakata K, Rom WN, Honda Y, et al. Mycobacterium
tuberculosis enhances human immunodeficiency virus-1
replication in the lung. Am J Respir Crit Care Med
1997;155:996-1003.
32. Bernstein MS, Tong-Starksen SE, Locksley RM. Activation
of human-monocyte derived macrophages with
lipopolysaccharide decreases human immunodeficiency
virus replication at the level of gene expression. J Clin
Invest 1991;88:540-5.
32a. Hanna LE, Nayak K, Subramanyam S, et al. Incomplete
immunological recovery following antituberculosis
treatment in HIV-infected individuals with active
tuberculosis. Indian J Med Res 2009; 129: 548-54.
32b. Baveja UK, Verghese A, Chattopadhya D, et al. Evaluation
of levels of p24 antigen in HIV/AIDS cases and correlation
with CD4+ cell counts. JIACM 2008; 9: 103-7.
33. Khouri Y, Mastrucci M, Hutto C, et al. M. tuberculosis in

children with HIV type-1 infection. Pediatr Infect Dis J
1992;11:950-5.
34. Moss WJ, Dedyo I, Suarez M, et al. Tuberculosis in children
infected with human immuno-deficiency virus. A report
of 5 cases. Pediatr Infect Dis J 1992; 11:114-20.
35. Jeena PM, Mitha T. Bamber S, et al. Effects of HIV virus
on tuberculosis in children. Tuberc Lung Dis 1996;77:43743.
36. Chan SP, Bimbaum J, Rao M. Clinical manifestation and
outcome of tuberculosis in children with AIDS. Pediatr
Infect Dis J 1996;15:443-7.
37. Starke JR, Smith MHD. Tuberculosis. In: Feigin RD, Cherry
JD (Eds.) Textbook of Pediatrics Infectious Diseases, 4th
edn. Philadelphia: WB Saunders Company 1998;1196-1239.
38. Jeena PM, Coovadia HM, Thula SA, et al. Persistent and
chronic lung disease in HIV-1 infected and uninfected
African children. AIDS 1998;12:1185-93.
39. Haller JO, Ginsburg KJ. Tuberculosis in children with
acquired immunodeficiency syndrome. Pediatr Radiol
1997;27:186-8.
40. Kumar A, Upadhyay S, Kumari G. Clinical presentation,
treatment outcome and survival among the HIV infected
children with culture confirmed tuberculosis. Curr HIV
Res 2007;5:499-504.
41. Berggren Palme I, Gudetta B, Bruchfeld J, et al. Detection
of Mycobacterium tuberculosis in gastric aspirate and
sputum collected from Ethiopian HIV-positive and HIVnegative children in a mixed in- and outpatient setting.
Acta Paediatr 2004;93: 311-5.
42. Iriso R, Mudido PM, Karamagi C, et al. The diagnosis of
childhood tuberculosis in an HIV-endemic setting and
the use of induced sputum. Int J Tuberc Lung Dis
2005;9:716-26.
43. Stavri H, Ene L, Popa GL, et al. Comparison of tuberculin
skin test with a whole-blood interferon gamma assay
and ELISA, in HIV positive children and adolescents with
TB. Roum Arch Microbiol Immunol. 2009; 68: 14-9.
44. Mandalakas AM, Hesseling AC, Chegou NN, et al. High
level of discordant IGRA results in HIV-infected adults
and children. Int J Tuberc Lung Dis 2008;12: 417-23.
45. Van Rheenen P. The use of the pediatric tuberculosis score
chart in an HIV-endemic area. Trop Med Int Health
2002;75:435-41.
46. Pai NP, Joshi R, Dogra S, et al. Evaluation of diagnostic
accuracy, feasibility and client preference for rapid oral
fluid-based diagnosis of HIV infection in rural India. April
2007/issue4/e367 PLOS ONE: e367.doi: 10, 1371/Journal
pone. 0000367.
47. Perriens JH, St. Louis ME, Mukadi YB, et al. Pulmonary
tuberculosis in HIV-infected patients in Zaire: a controlled
trial of treatment for either 6 or 12 months. N Engl J Med
1995;332:779-84.
48. Kennedy N, Berger L, Curram J, et al. Randomized
controlled trial of a drug regimen that includes
ciprofloxacin for the treatment of pulmonary tuberculosis.
Clin Infect Dis 1996;22: 827-33.
49. El-Sadr WM, Perlman DC, Matts JP, et al. Evaluation of
an intensive intermittent-induction regimen and duration
of short-course treatment for human immunodeficiency
virus-related pulmonary tuberculosis. Terry Beirn
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
Community Programs for Clinical Research on AIDS

(CPCRA) and the AIDS Clinical Trials Group (ACTG).
Vernon, A, Burman W, Benator D, et al. Acquired
rifampicin monoresistance in patients with HIV-related
tuberculosis treated with once-weekly rifapentine and
isoniazid. Tuberculosis Trials Consortium. Lancet
1999;353:1843-7.
American Thoracic Society/Centers for Disease Control
and Prevention/Infectious Diseases Society of America.
Treatment of Tuberculosis. Am J Respir Crit Care Med
2003;167:603-62.
American Academy of Pediatrics. Tuberculosis. In:
Pickering LJ, (Ed). Red book report of the Committee on
Infectious Diseases, 25th edn. Elk Grove Village, IL: Amer
Acad Ped 2000;593-613.
Piscitelli SC, Gallicano KD. Interactions among drugs for
HIV and opportunistic infections. N Engl J Med
2001;344:984-96.
Centers for Disease Control and Prevention. Prevention
and treatment of tuberculosis among patients infected
with human immunodeficiency virus: principles of
therapy and revised recommendations. MMWR Morb
Mortal Wkly Rep 1998; 47:1-25.
Pape, IW, Jean SS, Ho JL, et al. Effect of isoniazid
prophylaxis on incidence of active tuberculosis and
progression of HIV infection. Lancet 1993;342: 268-72.
Whalen CC, Johnson JL, Okwera A, et al. A trial of three
regimens to prevent tuberculosis in Ugandan adults
infected with the human immunodeficiency virus. N Engl
J Med 1997; 337: 801-8.
Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of
initiation of antiretroviral drugs during tuberculosis
therapy. N Engl J Med 2010; 362: 697-706.
Mukherjee A, Lodha R, Kabra SK. Changes in CD4 count
with antitubercular therapy in HIV infected children with
tuberculosis. J Trop Pediatr 2009; 55: 125-7.
Hawken MP, Meme HK, Elliot HC, et al. lsoniazid
preventive therapy for tuberculosis in HIV-1-infected
adults: results of a randomized controlled trial. AIDS
1997;11:875-82.
Mwinga A, Hosp M, Godfrey-Faussett P, et al. Twice
weekly tuberculosis preventive therapy in HIV infection
in Zambia. AIDS 1998;12:2447-57.
Diseases and Global Program on AIDS and the
Tuberculosis Program of World Health Organization.
Tuberculosis preventive therapy in HIV-infected
individuals. Tuberc Lung Dis 1994; 75:96-8.
Isaeman MD. Is standard chemotherapy adequate in
tuberculosis patients infected with HIV? Am Rev Respir
Dis 1987; 136: 26.
Wilkinson D. Drugs for preventing tuberculosis in HIVinfected persons. Cochrane Database Syst Rev 2000; 2:
CD000171.
Gordin F, Chaisson RE, Matts JP, et al. Rifampicin and
pyrazinamide versus isoniazid for prevention of
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
239
tuberculosis in HIV-infected persons: an international

randomized trial. JAMA 2000; 283: 1445-50.
Tortajada C, Martinez-Lacasa J, Sanchez F, et al.
Tuberculosis Prevention Working Group. Is the
combination of pyrazinamide plus rifampicin safe for
treating latent tuberculosis infection in persons not
infected by the human immunodeficiency virus? Int J
Tuberc Lung Dis 2005; 9: 276-81.
Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid
prophylaxis on mortality and incidence of tuberculosis in
children with HIV: randomised controlled trial. BMJ 2007;
334: 136.
Connolly C, Reid A, Davies G, et al. Relapse and mortality
among HIV-infected and uninfected patients with
tuberculosis successfully treated with twice weekly
directly observed therapy in rural South Africa. AIDS
1999; 13: 1543-7.
Kang'ombe CT, Harries AD, Ito K, et al. Long-term
outcome in patients registered with tuberculosis in
Zomba, Malawi: mortality at 7 years according to initial
HIV status and type of TB. Int J Tuberc Lung Dis 2004; 8:
829-36.
Schaaf HS, Geldenduys A, Gle RP, et al. Culture- positive
tuberculosis in HIV type-1 infected children. Pediatr Infect
Dis J 1988; 17: 599-604.
Sharma SK, Mohan A. Coinfection of human
immunodeficiency virus (HIV) and tuberculosis: an
adult study Indian perspective. Indian J Tuberc 2004;
51:5-16.
Jones BE, Young SM, Antoniskis D, et al. Relationship of
the manifestations of tuberculosis to CD4 cell counts in
patients with human immunodeficiency virus infection.
Am Rev Respir Dis 1993; 148: 1292-7.
Blumberg HM, Burman WJ, Chaisson RE, et al. American
Thoracic Society, Centers for Disease Control and
Prevention and the Infectious Diseases Society of America:
treatment of tuberculosis. Am J Respir Crit Care Med
2003; 167: 603-62.
Parks W. Human Immunodeficiency Virus. In: Behrman
RE, Kliegman RM, Arvin AM (Eds). Nelson's Textbook of
Pediatrics, 15th edn. Philadelphia: WB Saunders company
1996;916-9.
Archibald LK, Kazembe PN, Nwanyanwu O, et al.
Epidemiology of bloodstream infections in a bacille
Calmette-Guerin-vaccinated pediatric population in
Malawi. J Infect Dis 2003; 188: 202-8.
Asch S, Knowles L, et al. Relationship of isoniazid
resistance to human immunodeficiency virus infection in
patient with tuberculosis. Am J Respir Crit Care Med
1996; 153: 1708-10.
Spellman CW, Matty KJ, Weis SE. A survey of drugresistance Mycobacterium tuberculosis and its relationship
with HIV infection. AIDS 1998; 12: 191-5.
Burman W, Benator D, Vernon A, et al. Tuberculosis trials
consortium. Acquired rifamycin resistance with twiceweekly treatment of HIV-related tuberculosis AMJ Respir
Crit Care Med 2006; 173: 356-66.
240

78. Nahid P, Gonzalez LC, Ruday I, et al. HIV and tuberculosis.
Am J Respir Crit Care Med 2007; 175: 1199-206.
SUGGESTED READINGS
1. World Health Organization Regional Office for South East
Asia. HIV/AIDS. SEARO Publication on HIV/AID,
Tuberculosis and HIV-some questions and answers
available at URL; http://www.searo.who.int/en/
section10/section18/section356/section421-1624.htm.
Accessed on November 3, 2008.
2. Tripathy S, Myo panng, Narain Jai P. Tuberculosis and
HIV human Immunodeficiency Virus infection. In
tuberculosis 2nd edition. Surendra K Sharma & Alladi
Mohan(Eds) Jaypee Brothers Medical Publishers (P) Ltd.
New Delhi 2009; 534-90.
3. World Health Organization. Addressing the threat of
tuberculosis caused by extensively drug-resistant
tuberculosis WKLY Epidemiol Rec 2006; 81: 386-90.
4. World Health Organization. Case definition for
extensively drug-resistant tuberculosis. Wkly Epidemiol
Rec 2006; 81: 408.
5. Shah NS, Wright A, Bai GH, et al. World wide emergence

of extensively drug resistant tuberculosis Emerg Infect
Dis 2007; 13: 380-7.
6. Graham SM. Nontuberculous opportunistic infections and
other lung diseases in HIV-infected infants and children.
Int J Tubere Lung Dis 2005; 9:592-602.
7. Kwara A, Roahen-Harrisions, Prystowky E, et al.
Manifestations and outcome of extrapulmonary
tuberculosis: Impact of human immunodeficiency virus
coinfection. Int J Tuberc Lung Dis 2005;9: 485-539.
8. Chintu C, Mwaba P. Tuberculosis in children with human
immunodeficiency virus infection. Int J Tuberc Lung Dis
2005;9:477-84.
9. Geoghagen M, Farr JA, Hambleton I, et al. Tuberculosis
and HIV coinfection in Jamaican children. West Indian
Med J 2004;53:339-45.
10. Cotton MF, Schaaf HS, Hesseling AC. HIV and childhood
tuberculosis: the way forward. Int J Tuber Lung Dis
2004;8:675-82.
11. Poznik AL, Miller RF, MCI Lipman, et al. BHIVA guidelines for TB/HIV infection February 2005. http:
www.bhiva.org.
16
Tuberculosis and Childhood

Malignancy
Rachna Seth
INTRODUCTION
Pulmonary infections are the most common complications
in immune compromised cancer patients and may progress
rapidly to cause respiratory failure. Mucosal destruction,
humoral and cellular immune deficiency secondary to
primary disease itself and chemotherapy facilitate local
infection and may lessen clearance of aspirated microorganisms. Immune compromised patients such as those
undergoing chemotherapy for a childhood malignancy
theoretically are at an increased risk for developing
infections from unusual pathogens like mycobacteria,
nocardia, aspergillus and chlamydia. This is specially true
for leukemia and lymphomas. There is paucity of
information in this regard.
There are some reports in the literature on patients
with malignancy who developed tuberculosis (TB) during
or after intensive chemotherapy.1,2 Also, the role of repeat
tuberculin testing and INH prophylaxis for children who
have a positive tuberculin test but no evidence of
active disease in such children needs to be ascertained.
Clinically evident TB can antedate malignancy, both may
present simultaneously or TB may develop after treatment
of the malignant disorder.3,4
The overall survival of children with cancer has
increased over the past few years. This is attributed to
advances in diagnostics, therapeutics and improvements
in supportive care. This has resulted in better follow-up,
identification of atypical infections such as tuberculosis, their
unusual presentations and outcomes. Also the increased
utilization of antineoplastic agents in the treatment of acute
leukemia and other malignancies is associated with an
increase in the incidence of opportunistic infections like M.
tuberculosis that may be complicated by systemic
dissemination and multiorgan failure.5
In literature, there are opposing views on whether
leukemia was a risk factor for development of
tuberculosis. Miller stated that leukemia was a risk factor
for the development of mycobacterial infections.6
According to other experts, Mycobacterial infections were
uncommon in children with cancer. There are sporadic
cases of mycobacterial infections in non-HIV immune
compromised children.6,7 Pizzo and Poplack suggest that
mycobacterial infections are uncommon in children with
cancer.8
The clinical profile at presentation may be altered in

such children as is suggested by sporadic cases.9 The use
of broad spectrum antibiotics some with antitubercular
activity are likely to contribute to this variability.
There is scarcity of data on the incidence of reactivation
of TB in patients undergoing anticancer chemotherapy. The
available literature is also conflicting. Certain malignancies
and anticancer therapy schedules are considered a risk
factor for development of TB.10 The prevalence of TB in
patients with hematological malignancies has been
reported to be from 0.72 to 2.6%.11 It has the potential to be
particularly high in hematological malignancies with
T-cell immune deficiency caused by disease or by treatment.
In patients with underlying malignancy, there are
three main issues when TB is considered:
i. Diagnostic dilemma between TB and malignancy
versus coexistence of both.
ii. Increased predisposition for TB due to impaired
immunity underlying malignancy and cytotoxic
therapy.
iii. Atypical presentation and or behavior of TB
resulting in delayed diagnosis and possibility of poor
outcome with standard antitubercular treatment.
The following aspects need elaboration
Immunology of tubercular infection
Prevalence of TB in leukemia
Differences in clinical features
Diagnosis
Misdiagnosis as pulmonary metastasis
TB in bone marrow transplant recipients
Reactivation of TB by chemotherapy
Response to therapy.
IMMUNOLOGY OF TUBERCULAR INFECTION

Challenges
It is not easy to ascertain the burden of tuberculosis in
children. This is primarily because of difficulties in
establishing a definite diagnosis, lack of a standard case
definition, increased prevalence of pulmonary tuberculosis
in adults and low priority of childhood tuberculosis on
public health agenda. The WHO data for tuberculosis in
children are specified only for smear-positive cases for acid
fast bacilli (AFB). Children are not always positive for AFB
242
and with the understanding that many children may present

with unusual symptoms more true for immune
compromised children, cough not being a constant
symptom for such children. Also the clinical presentation
of pulmonary TB overlaps with other opportunistic
pulmonary infections. Immune compromised children may
have TB and other pulmonary diseases concurrently and
thus initially improve with broad spectrum antibiotics like
amino-glycosides and quinolones.
Disease and Infection

No standard case definition exists that may be applied
easily to childhood TB. Diagnosis of TB infection in
children is based on a positive Mantoux test with no
signs/symptoms of TB and a normal chest X-ray.
Diagnosis of TB disease is based on isolation of AFB,
gastric aspirates (staining for AFB, culture), Mantoux test,
positive family history and chest X-ray. Suggestive
symptomatology of fever, persistent cough in the absence
of AFB is given significant weightage.
Children are more likely to develop TB disease after
infection compared to adults. The risk of developing
TB disease after infection in non-HIV infected children
is estimated at 15% in adolescents, 24% in children
below 5 years and as high as 43% in children under
1 year.12
Host Infection
It is a known fact that only a minority of people develop
disease after becoming infected with M. tuberculosis. This
is dependent on many factors like nutrition, intercurrent
infection, age at infection, length of time after acquiring
infection, recent versus old infection and host resistance,
i.e. effective functioning of the cell-mediated and humoral
immunity. This is further exemplified by the epidemic of
HIV which reduces cell mediated immunity. Studies have
shown a variability of clinical presentation in HIV positive
children with tuberculosis varying with the level of cell mediated immune function.13
Immunopathology of TB
Mycobacterial infection is asymptomatic in majority of
healthy persons as the infection is contained by the host
immune system. A positive tuberculin test simply
indicates presence of infection. Whether this will cause
disease depends on a large number of factors as
discussed. In subjects who are immune suppressed for
any reason, the proportion who develop disease is much
greater.14 The state of immune system plays a significant
role in the development of disease. It is the cell mediated
immunity that is more important in dealing with
intracellular organisms like M. tuberculosis.
Pathophysiology of Infections in Cancer

Cellular immune deficiency can lead to infections with
intracellular pathogens like cytomegalovirus (CMV),
Herpes simplex, HIV, candida, aspergillus, pneumocystis
and mycobacterium. T-cells elaborate an array of
cytokines capable of activating macrophage bacterial
activities. It is this cell mediated response to infection with
M. tuberculosis that controls the spread of primary
infection. Factors that compromise this cell mediated
immunity like HIV infection, therapy with steroids or
chemotherapeutic drugs and malignancy permit the
infection to spread to cause disease. It is because of this
that TB in immune compromised patients is most of the
times already in advanced stages before they are
recognized by the physician.15
Prevalence of TB Infection and Disease in Children with

Acute Leukemia
Immune compromised patients such as those diagnosed
with leukemia and are on chemotherapy are at increased
risk of developing tuberculosis. Medina et al16 studied the
prevalence of TB infection and disease among children
with acute leukemia on maintenance phase of
chemotherapy. Of the 29 patients that were included, 45%
had TB infection, but none of the patients proved to have
active disease. There was thus a high rate of TB infection
but a low rate of TB disease in this population of patients.
The authors have emphasized the importance of tuberculin testing as the rate of anergy was low and have
recommended annual testing for patients with continuous
exposure to TB.16 The proposed explanations for the low
occurrence of TB disease in children with leukemia are
that the chemotherapeutic drugs given to these patients
are also effective against mycobacterium . The widespread
use of antibiotics with antitubercular action could also be
responsible for this observation.
Indian data is also not very conclusive. Choudhary et
al.17 do not suggest higher prevalence of tuberculosis in
immune compromised children.17
In a study by Mishra et al.18 130 consecutive cases of
adult acute leukemia over a 2 year period were followed
prospectively for possible development of TB. They
identified 9 cases (6.9%) with active tuberculosis. Eight
patients with TB had acute myeloid leukemia. The
incidence of active TB disease is less despite the fact that
in patients with acute lymphocytic leukemia (ALL), there
is wider use of steroids, the duration of therapy is longer
leading to prolonged immune suppression and use of
radiotherapy in ALL protocols. Most of these patients were
managed with standard antitubercular therapy. Treatment
of TB did not delay the course of chemotherapy.18
Chapter 16 Tuberculosis and Childhood Malignancy
CLINICAL FEATURES
Children who undergo treatment for malignancies are at
high risk for infection with both typical and opportunistic
pathogens. Fever in these children prompts extensive
evaluation and empiric treatment with broad spectrum
antimicrobials. Children are not always positive for AFB
and many children may present with unusual symptoms
this being more true for immune compromised children,
cough not being a constant symptom for such children.
Also, the clinical presentation of pulmonary TB overlaps
with other opportunistic pulmonary infections.
There have been a few reports about the differences
in clinical findings between immune compromised
patients and nonimmune compromised patients with
pulmonary tuberculosis. Retrospective data of 840 adult
patients (312 immune compromised and 528 nonimmunecompromised) with pulmonary tuberculosis
(culture positive for M. tuberculosis) over a period of 10
years was reviewed by Yoshihiro et al. 19 The main
differences as observed in the immune compromised
patients were:
i. An increase in number of patients with respiratory
symptoms during the period of follow-up of
underlying diseases.
ii. An increase in the number of patients in an
undernutritional state and with a negative response
for the tuberculin skin test.
iii. An increase in the number of microbio-logically
smear-positive sputum specimens.
iv. An increase in the number of patients with atypical
radiological findings such as a few cavities or
calcification, bilateral and expansive consolidation,
miliary shadows and mediastinal and/or hilar
lymphadenopathy.
v. An increase in the patients with a misdiagnosis as
pneumonia at admission.
vi. An increase in the mortality rate.
Therefore, among the immune compromised patients
with pulmonary tuberculosis, there were many patients
with atypical radiological findings and with smearpositive findings for acid fast bacilli examination.
Sputum examination for acid fast bacilli must be done in
patients with fever and continuous cough and
antituberculosis therapy started as early as possible.
Tuberculosis (TB) should also be considered as a
possible cause of hepatosplenic abscesses during the
prolonged periods of neutropenia following the courses
of cytotoxic chemotherapy given to such patients in areas
that are endemic for TB.20
Lim et al.21 retrospectively evaluated the importance
of prevention and early diagnosis of tuberculosis in cancer
patients. Twelve patients were diagnosed as having
tuberculosis during cancer chemotherapy in a hospital
243
at Korea over a period of 18 years. The median age of

these patients was 14 (2 to 18) years. The underlying
diseases were acute lymphoblatsic leukemia (ALL) in
seven, acute undifferentiated leukemia (two), acute nonlymphoblastic leukemia (one) , mixed lineage leukemia
(one) and Burkitt lymphoma (one). The disease categories
were seven pulmonary tuberculosis, two acutetuberculous pleurisy, one miliary tuberculosis, one bone
and endobronchial TB and one tuberculous meningitis.
The famiily history of TB was positive in one case. The
suggestions towards the disease were persistent fever
despite broad spectrum antibiotics, and/or antifungal
agent therapy in 9 children.
Two children had chronic cough and one child had
chest pain. Diagnosis was based on AFB positivity in
culture in 4, AFB smear positivity in 3, polymerase chain
reaction (PCR) was positive in 2; one child was diagnosed
by pleural biopsy, transbronchial biopsy and chest Xray and CSF examination each.21
At times, an empirical antituberculous therapy should
be employed to prevent further clinical deteriorations
and a possible lethal outcome that may be associated
with delayed diagnosis and late institution of anti TB
drugs.22
RISK FACTORS
i. Certain malignancies and anticancer therapy
schedule are considered as high risk for development of TB.10
ii. Impairment of host defenses.
iii. Poor nutrition and debility.
DIAGNOSIS
The clinical diagnosis of tuberculosis in immune
competent children is straight forward and consists of a
suggestive history, often an exposure to a case, a positive
tuberculin test, and an abnormal chest radiograph.
In contrast, clinical symptoms are much less specific
among children who are malnourished, immune
compromised or suffering from HIV. Often these children
present with prolonged fever.
The gold standard for establishing the diagnosis of
tuberculosis is sputum smear microscopy for acid fast
bacilli which may be confirmed by mycobacterial culture.
As many as 95% of children younger than 12 years of
age have negative sputum smears,23 this diagnostic tool
is not freely available. Culture of gastric aspirate/
bronchoalveolar lavage is positive in less than 50% of
cases.24,25
Induced sputum may be used for demonstration of
AFB in smear and culture. Sputum induction can be
performed with hypertonic saline delivered by ultrasonic
nebulization.
244
Radiological
Evidence of pulmonary tuberculosis usually includes
lymphadenopathy (hilar/mediastinal) and lung
parenchymal changes. The most common parenchymal
changes are segmental hyperinflation, atelectasis,
alveolar consolidation ,pleural effusion and rarely a focal
mass.26 Cavitation is rare in young children. Delacourt et
al27 found that 60% of children with tuberculous infection
had normal chest radiographs. In such cases, contrast
enhanced CT scan of chest may, however, be a more
useful modality for diagnosis of tuberculosis. CT scan
findings suggestive of tuberculosis include enlarged
lymph nodes which frequently are necrotic, parenchymal
lesion, early cavitation pleural effusion and bronchiectasis
may be seen.26,27
Role of Bronchoscopy and bronchoalveolar Lavage (BAL)

Fluid Examination
The role for BAL in diagnosis of tuberculosis is still
controversial and not many centers have facilities for this
procedure. The culture from BAL fluid for M. tuberculosis
is usually lower than for three properly obtained gastric
aspirates.25 However, BAL may be useful in the diagnosis
of endobronchial tuberculosis and excluding/isolating
other causative agents such as opportunistic infections
particularly in immunocompromised children. The major
limitation of the bronchoscopy for BAL fluid examination
besides availability is the presence of thrombocytopenia
in many children who are on chemotherapy which
precludes its usage.
Pleural biopsy or lung biopsy (transbronchial or
otherwise) may also be used occasionally. Serological tests
are of not much use in diagnosis.
Misdiagnosis as Pulmonary Metastasis

The differential diagnosis for a pulmonary nodule in
cancer patients undergoing chemotherapy should include
pulmonary tuberculosis, particularly in developing
countries like India.
In a retrospective analysis of 422 cancer children less
than 18 years undergoing cancer therapy, the medical
records were reviewed to ascertain the incidence and
clinical features of pulmonary tuberculosis that were
misdiagnosed as pulmonary metastasis radiologically
during their period of follow-up. Episodes of lung
metastasis of primary tumor and tuberculosis were
reviewed. There were five cases of tuberculosis confirmed
after surgery which were initially regarded as metastasis.
Two patients had respiratory symptoms such as cough
and sputum but other three patients had no respiratory
symptoms. One child had history of contact with a
tuberculosis patient. Mantoux test was positive in 2 cases.9
Experience at All India Institute of Medical Sciences New

Delhi India (AIIMS)
A Case Study
An 11-year-old female child treated for Hodgkin
lymphoma at the Pediatric Oncology Clinic at AIIMS;
after completion of chemotherapy for continued
remission, it posed a problem. This child developed fever,
cough with expectoration and weight loss. There was no
history of contact with tuberculosis. Chest X-ray had
shown a nodular opacity which was confirmed on CT
chest. A radiological diagnosis of recurrence of disease
with metastasis was considered. However, a clinical
possibility of tuberculosis was also entertained which was
confirmed by sputum positivity for acid fast bacilli. The
child was treated with antituberculosis drugs and
responded favorably.
Pulmonary metastasis might be a close differential
but one should be aware of other medical conditions
for a pulmonary nodule that may coexist. It is necessary
to consider the possibility of tuberculosis when a lung
mass is newly detected during treatment or follow-up
in patients with childhood cancer in an endemic
area.
PULMONARY TUBERCULOSIS AND BONE MARROW

TRANSPLANT (BMT) RECIPIENTS
Bone marrow transplantation (BMT) is associated with
extreme iatrogenic bone marrow suppression during
which the recipient is highly susceptible to opportunistic
infections. Little is known about the profile of infection
with M. tuberculosis in bone marrow transplant recipients.
Series that have reviewed infections in bone marrow
transplant recipients have reported incidences of M.
tuberculosis to the tune of less than 0.1 to 2.2%.28-32
Following this, Mary et al. 33 conducted a prospective
evaluation of 183 consecutive BMT recipients and 10
patients were found to develop pulmonary tuberculosis
post BMT, yielding an incidence of 5.5%. The median age
of the 10 patients who developed tuberculosis was 29
years. The median time for onset of symptoms was 150
days following the transplant. The presenting complaints
primarily were fever, cough and pulmonary infiltrates. The
sputum was positive for acid fast bacilli in 3 of these
patients and culture for M. tuberculosis was positive in 8 of
these patients. Antitubercular treatment was given for a
longer duration (10 months in place of 6 months) and was
found to be effective. The absence of relapse after
termination of treatment suggested that secondary
prophylaxis would not be necessary as long as the immune
function has been restored. The risk factors identified in
this population, cohort for the development of tuberculosis
included allergenic BMT, total body irradiation and chronic
graft versus host disease.33

It is to be noted that the immune suppressed state
would magnify infectious disease that are endemic in the
locality explaining the high incidence of pulmonary
tuberculosis as 5.5% in this setting at Hong Kong.
Similarly a BMT center in Spain where TB is also endemic,
an incidence as high as 2.2% (higher than that reported
in the US and UK) has been observed. It is important to
bear a high index of suspicion of M. tuberculosis as a
pathogen in marrow transplant recipients.
SHORT-COURSE CHEMOTHERAPY AND REACTIVATION

OF TB
There is scarcity of data on the incidence of reactivation
of TB in patients undergoing anticancer chemotherapy.
The available literature is also conflicting. Certain
malignancies and anticancer therapy schedules are
considered as risk factor for development of TB. 10
Impairment of host defenses, poor nutrition, and debility
were proposed as attributing factors for the high
incidence of TB in this group in few studies. The
prevalence of TB in patients with hematological
malignancies has been reported to be from 0.72 to 2.6%.11
The prevalence is particularly high in hematological
malignancies with T-cell immune deficiency caused by
disease or by treatment.
These observations have been negated in a study
which prospectively followed 174 patients with newly
diagnosed lymphoproliferative disorders for more than
two years. None of the patients developed reactivation
of TB despite lack of antitubercular prophylaxis.34
In a retrospective analysis of 141 adult treated
patients with high grade nonHodgkin lymphoma 8
patients had a past history of tuberculosis. These 8
patients were followed for a median period of 5 years
after receiving cyclical high dose chemotherapy. None
of these developed reactivation of tuberculosis.
The proposed mechanisms suggested that
cytotoxic chemotherapy induces short-term and cyclical
immunesuppression not enough to cause the reactivation
of tuberculosis, and the suppression of T-cell immunity
may not be significant with above used chemotherapy
which is a major defense mechanism against M.
tuberculosis.
Gulen et al. 35 have reported a seven-year-old girl
diagnosed with T-cell nonHodgkin lymphoma who was
admitted after completion of chemotherapy with the
complaints of fever, cough and respiratory distress. She
was found to be hypoxemic. Chest X-ray showed
pneumonic infiltration in middle and lower lobe of right
lung. The child did not respond to broad spectrum
antimicrobials. Tuberculin test was negative; sputum and
gastric aspirates were negative for AFB. In view of no
response and persistence of radiologic infiltrates, the child
underwent a CT chest which showed the presence of
245
diffuse pneumonic consolidation with right paratracheal,

precarinal mass image consisting of conglomerated
lymph nodes. Bronchoalveolar lavage was done. The
sample was positive for M. tuberculosis on culture. The
child responded to antituberculosis therapy of 9 months
[2 months of intensive phase (3 drug) and 7 months of
consolidation phase (2 drug)]. Follow-up CT scan
revealed a normal scan after completion of therapy except
thickening of right major fissure.
In the series of 400 childhood cancer survivors at the
Pediatric Cancer Survivor Clinic at AIIMS (acute
leukemia, Hodgkin lymphoma, nonHodgkin lymphoma,
retinoblastoma, LCH, etc.) there has been history of
tuberculosis in one child of acute lymphoblastic leukemia
while on chemotherapy. This child is under follow-up
for one year post chemotherapy and has not developed
reactivation of TB.
The proposed mechanism for absence of reactivation
are that immune suppression induced by cytotoxic
chemotherapy is short lasting and cyclical not significant
enough to cause the reactivation of tuberculosis (TB).
Suppression of T-cell immunity may not be significant
with the above used chemotherapy.
CLINICAL CHARACTERISTICS AND TREATMENT RESPONSES

OF TUBERCULOSIS IN PATIENTS WITH MALIGNANCY
RECEIVING ANTICANCER THERAPY
Although, the risk of tuberculosis increases in patients
with malignant disease, the clinical response of
tuberculosis to antituberculosis treatment in patients
receiving anticancer therapy has not been well known
except in a few case series36-39 involving a small number
of patients with inconsistent results.
The efficacy of anti-TB chemotherapy in patients with
hematological malignancies is well documented.10,40
However, drug-resistance, noncompliance with
medications and the presence of advanced and miliary
forms of TB remain real challenges. Kim et al.40 studied
the clinical characteristics and treatment responses of
tuberculosis developing in adult patients receiving
anticancer therapy. With regard to radiographic and
clinical responses to antitubercular treatment TB
developing during anticancer chemotherapy is not
clinically different from TB developing in ordinary
situations. Findings in this study suggest that anticancer
chemotherapy is not an obstacle to treating TB.
Mishra et al.18 studied 130 adult consecutive cases of
acute leukemia over a period of 2 years and identified 9
cases (6.9%) with active TB. Eight patients with TB had
acute myeloid leukemia (AML). Patients with AML were
more prone to develop TB as compared to acute
lymphoblastic leukemia despite the use of steroids and
radiotherapy in ALL protocols. This may partly be
because in adults the commoner hematological
246
malignancy is AML and not ALL. All but one of the

diseased children were successfully managed using
current antituberculosis therapy. TB neither causes delay
in chemotherapy nor flare-up during subsequent
chemotherapy.
Gulen et al. 35 have reported a seven-year-old girl
diagnosed with T-cell nonHodgkin lymphoma at the age
of 6 years complaining of fever, persistent cough and
respiratory distress after completion of chemotherapy. Chest
X-ray showed a pneumonic infiltration in middle and lower
lobe of right lung. The child did not respond to broad
spectrum antibiotics. Tuberculin test and gastric aspirates
for AFB were negative. CT chest showed diffuse pneumonic
consolidation with right paratracheal precarinal mass image
consisting of conglomerated lymph nodes. Bronchoscopy
and bronchoalveolar lavage were done which revealed M.
tuberculosis. The child responded to 9 months of
antituberculosis therapy.
HIGHLIGHTS
Pulmonary infections frequently complicate the
course of cancer treatment in children. These are
empirically treated with broad spectrum antibiotics
and antifungals in most of oncology centers in
developing countries
Optimal treatment of lung infections in cancer
patients requires identification of the infectious
agent. A high index of suspicion should be present
for such uncommon infections. Infections such as
tuberculosis should be included in the diagnostic
workup of such immune compromised children,
particularly with pulmonary symptoms that are
unusually prolonged, are not responsive to conventional therapy or in situations where fever persists
for prolonged periods without obvious focus
Children cannot produce sputum easily, gastric
aspirates/bronchoalveolar lavage fluid induced
sputum should be obtained at early stages for
microbial identification
The course of antituberculosis therapy may also be
prolonged in cases which are diagnosed with
tubercular disease.
REFERENCES
1. Waecker NJ, Stefanova R, Cave MD, et al. Nosocomial
transmission of Mycobacterium bovis bacilli CalmetteGurin to children receiving cancer therapy and their
health care providers. Clin Infect Dis 2000;30:338-62.
2. Aljurf M, Gyger M, Alrajhi A, et al. Mycobacterium
tuberculosis infection in allogenic bone marrow
transplantation patients. Bone Marrow Transplant.
1999;24:551-4.
3. Libshitz HL, Pannu HK, Elting LS, et al. Tuberculosis in
cancer patients: An update. J Thoracic imaging 1997;12:
41-6.
4. Kindler T, Schindel C, Brass U, et al. Fatal sepsis due to

Mycobacterium tuberculosis after allogenic bone marropw
transplantation. Bone Marrow Transplant 2001;27:217-8.
5. Misonou J, Kikuchi Y, Aizawa M, et al. An autopsy case
of severe miliary tuberculosis in a patient with acute
lymphoblastic leukemia. Gan No Rinsho 1987;33:703-13.
6. Menon BS, Maziah WM, Aiyer S, et al. Disseminated
tuberculosis in acute leukemia. Pediatrics International
2001;43:161-3.
7. Kornreich L, Goshen Y, Horev G, et al. Mycobacterial
respiratory infection in leukemic children. European J
Radiol 1995;21:44-4.
8. Pizzo P, Poplack D. Infectious complications in pediatric
cancer. In: Principles and Practice of Pediatric Oncology
5th edns Pizzo P, Poplack D (Eds): Lippincott Williams
and Wilkins, 2002; 1269-329.
9. Lee HJ, Kim DW, Lee KM, et al. Pulmonary tuberculosis
misdiagnosed as lung metastasis in childhood cancer
patients. Korean J Pediatr 2009;52:904-9.
10. Kaplan MH, Armstrong D, Rosen P. Tuberculosis
complicating neoplastic disease: A review of 201 cases.
Cancer 1974;33:850-8.
11. Karachunski MA, Pivnik AV, Luldasheva NE.
Tuberculosis in patients with hemosiderosis. Probl
Tuberk 2002;12:24-7.
12. Walls T, Shingadia D. The epidemiology of tuberculosis
in Europe. Arch Dis Child 2007;92: 726-9.
13. Jones BE, Ryu R, Yang Z, et al. Chest radiographic studies
in patients with tuberculosis with recent or remote
infection. AM J Resp Crit Care Med 1997;156:1270-3.
14. Selwyn PA, Sikell BM, Alcabes P, et al. High risk of active
TB in HIV infected drug users with cutaneous anergy.
JAMA 1992;268:504-9.
15. Furst D, et al. Preliminary guidelines for diagnosing and
treating tuberculosis in patients with rheumatoid
arthritis in immunesuppressive trials or being treated
with biological agents. Ann Rheum Dis 2002; 61(Suple
II)ii62-ii63.
16. Medina MYL, Lazarte CM. The prevalence of TB infection
and disease among children with acute leukemia. PIDSP
Journal 2009;10(1).
17. Pulmonary tuberculosis in children with acute lymphatic
leukemia. Indian J of Pediatr 1981.
18. Mishra P, Kumar R, Mahapatra M, et al. Tuberculosis in
acute leukemia: A clinico-hematological profile.
Hematology 2006;11:335-40.
19. Yoshihiro Y, Mouri K, Yagi S, et al. J Infect Chemother
2007;13:405-10.
20. Lee DG, Chol JH, Kim YJ, et al. Hepatosplenic tuberculosis
mimicking disseminated candidiasis in patients with acute
leukemia. Int J Hemato 2001;73:119-21
21. Lim JH, Lee YJ, Choi EJ, et al. Tuberculosis in pediatric
cancer patients during chemotherapy. Korean J Pediatr
Hematol-Oncol 2000;2:278-86.
22. Luldashiva NE, Karachunskii MA, Pivnik AV. Various
approaches to tuberculosis diagnosis in patients with
hemoblastosis. TerArkh 2002; 74:35-8.
23. Jereb JA, Kelly GD, Porterfield DS: The epidemiology of
tuberculosis in children. Semin Pediatr Infect Dis
1993;4:220-31.

24. Pomputius WF 3rd, Rost J, Dennehy PH, et al.
Standardization of gastric aspirate technique improves
yield in the diagnosis of tuberculosis in children. Pediatr
Infect Dis J 1997;16:222-6.
25. Abadco D, Steiner P. Gastric aspirate is better than
tuberculosis in childhood tuberculosis. Pediatr Infect Dis
J 1993;11:735-8.
26. Shingadia D, Novelli V. Diagnosis and treatment of
tuberculosis in children. Lancet Infect Dis 2003;3:624-32.
27. Delacourt C, Mani TM, Bonnerot V, et al. Computed
tomography with normal chest radiograph in tuberculous
infection. Arch Dis Child 1993;69:430-2.
28. Navari RM, Sullivan KM, Springmeyer SC, et al.
Mycobacterial infections in marrow transplant patients.
Transplantation 1983;36:509-13.
29. Kurrock R, Zander A, Vellekoop L, et al. Mycobacterial
infections after allogenic bone marrow transplantation. Am
J Med 1984;77:35-40.
30. Hoyle C, Goddman JM. On behalf of 18 UK bone marrow
transplant teams. Life threatening infections occurring
more than 3 months after BMT. Bone Marrow Transplant
1994;14:247-52.
31. Roy V, Weisdorf D. Mycobacterial infections following
bone marrow transplant (BMT): A retrospective review
of 20 year-experience. Blood 1995;86(Suppl 1):861A.
32. Martino R, Martinez C, Brunet S, et al. Tuberculosis in
bone marrow transplant recipients: report of two cases
and review of the literature. Bone Marrow Transplant
1996;18:809-12.
247
33. Mary S M IP, Yuen K Y, Patrick C V Woo, et al. Risk factors

for pulmonary tuberculosis in bone marrow transplant
recipients. Am J Respir Crit Care Med 1998;158:1173-7.
34. Harakati SE. Tuberculosis in patients with
lymphoproliferative disorders: Is it as common as
historically stated? Kuwait Med J 2001;33:325-28.
35. Gulen HG, Erbay A, Gulen F, et al. Resistant pneumonia
in a child with non Hodgkin lymphoma In remission: A
case of M. tuberculosis. The Internet journal of Hematology
2005;2(1).
36. Tubura E. Pulmonary tuberculosis in the compromised
host: Report of the 30th B series of controlled trials of
chemotherapy: Cooperative Study unit of chemotherapy
of tuberculosis of the national sanatoria in Japan. Kekkaku
1991:66:95-9.
37. Liu SF, Liu JW, Lin MC. Characteristics of patients
suffering from tuberculous pleuritis with pleural effusion
culture positive and negative for Mycobacterium
tuberculosis and risk factors for fatality. Int J Tuberc Lung
Dis 2005; 9:111-5.
38. Tamura A, Hebisawa A, Tanaka G, et al. Active
pulmonary tuberculosis in patients with lung cancer.
Kekkaku 1999;74:797-802.
39. Komatsu H, Nagai H, Satou K, et al. Association of active
pulmonary tuberculosis and malignant diseases: A
clinical study. Kekkaku 1995; 70: 281-4.
40. Kim DK, Lee SW, Ko DS, et al. Clinical characteristics
and treatment responses of tuberculosis in patients with
malignancy receiving anti-cancer chemotherapy. Chest
2005;128:2218-22.
17
Unusual Manifestations of
Tuberculosis
Vimlesh Seth
TUBERCULOSIS OF EYE AND CONJUNCTIVA

Tuberculous lesion of the eye are usually thought to be
uncommon but its knowledge is of great importance in
the diagnosis and understanding of the natural history of
primary infection.
Primary Infection of Conjunctiva

Infection of the conjunctival sac can occur without
producing any local symptoms. First complain may be
softening, swelling of the preauricular lymph node. At
times tonsillar glands may be enlarged. On evertion, upper
and lower eyelids are swollen and may show hypertrophic
granulation tissue. Biopsy is recommended but often a
therapeutic test proves diagnosis by showing instant
improvement.
and the scleral vessels are not affected. In the early stage,
the phlyctenule has a round surface but in a day or two
this is eroded, and becomes irregular with the
disappearance of the nodule. With the fading of one crop,
the others erupt so the attack seems continuous. With the
ulceration of the cornea, the left over opacities can affect
vision. There is free lacrimation but if there is purulent
discharge it indicates secondary infection. The
preauricular nodes are not enlarged.
Incidence
Like erythema nodosum, the common age affected is 5 to 15
years but is more frequent in children less than five years.
Malnutrition is a common association. Conjunctivitis due
to other infections can follow phlycetenular conjunctivitis.
Differential Diagnosis
Preauricular node can be affected due to any infective lesion

of the eyelid or conjunctiva. In tuberculosis there is no
pain and it appears slowly. Viral infection, foreign body,
trachoma can be the other causes of conjunctival infection.
Gray spots are characteristic and hence diagnosis from

other infections is not difficult. If there is sharp foreign
body embedded in the conjunctiva or sclera, it can pose
difficulty in diagnosis. Herpes virus can be the other cause
of corneal ulceration. Clinical diagnosis depends upon
seeing a fresh phlyctenule, and the presence of other
symptoms and signs suggestive of tuberculosis.
Phlyctenular Conjunctivitis
It is a painful, recurrent form of conjunctivitis due to the
hypersensitivity phenomenon in the early stage of the
disease.1 Unlike erythema nodosum, it can be caused by
antigens other than those arising from M. tuberculosis,
e.g. other acid-fast organisms such as BCG 2 or by
B. hemolytic streptococcal infection. It marks the onset of
primary infection. Phlyctenular conjunctivitis can occur
at any time in a tuberculin sensitive person, and is often
recurrent.
Treatment
In the presence of primary infectionsystemic therapy is
required. If the lesion is localized to the eyes, local therapy
with steroids is sufficient. In the presence of corneal
ulceration due to causes other than tuberculosis, local
therapy with steroids is contraindicated.
Choroid Tubercles
Clinical Picture
Each attack begins with irritation, lacrimation and
soreness in one or both eyes simultaneously or with a
short interval in between. With the infection of cornea,
pain and photophobia are intense. On examination it can
be recognized as a small gray spot, single or grouped, at
the limbus (junction of cornea and sclera) in a number of
places around the circumference. There is a small leash of
infected conjunctival vessels. Iris and pupils are normal
The presence of choroid tubercles establishes the

diagnosis of tuberculosis even when there is no
radiological evidence of TB. If the choroid tubercles are
numerous and the child is looking ill, it is an indication of
disseminated disease such as miliary tuberculosis or
tubercular meningitis. It is uncommon in recent primary
infection but is present in almost 60 to 70 % of children
with radiological evidence of miliary tuberculosis. It is
less in tubercular meningitis.
Chapter 17 Unusual Manifestations of Tuberculosis
Description and Course of Healing of Tubercle
Cardiac Complications
Usually more than one tubercle is present and at times

they are numerous. They are located along the line of a
branch of the central artery. Most of the tubercles are
present within two disk diameters of the center of the disk.
Sometimes the vessel seems to run through the faintly
yellow, rounded body within an indefinite edge which is
the appearance of a recent tubercle. It is usually half the
radius of the disk. On chemotherapy, the tubercles recede
quickly. Even without chemotherapy, the smallest may
never progress beyond the first stage of yellow center,
indefinite edge and ultimate recession does not leave any
trace.
In large tubercles, the edge slowly becomes more
clearly defined, central area fades imperceptibly from
yellow to white with the appearance of spots of black
pigment at the periphery. This results in a white scar with
a deeply pigmented black edge and is sharply defined
from the pink of the fundus. It takes three months to reach
this stage. If followed, the white patches progressively get
completely filled with black pigment. This is the natural
course. On systemic therapy, the lesions are yellow areas
with illdefined edges. These disappear without a trace
with the use of local steroids given along with systemic
steroids in miliary and meningeal tuberculosis.
Pericardial Abscess
Panophthalmitis
It is a rare manifestation and has been reported as a case
report3 in a 12-year-old female child in a tertiary care center.
The child had painless progressive loss of vision in the
right eye for two months duration. Examination revealed
diffuse corneal haze with deep vascularization, iris
nodules and scleral necrosis. Enucleation of the eye had
to be done and histopathology revealed necrotizing
granulomatous inflammation. Multiple epithelioid cell
granulomas and cells along with large area of caseous
necrosis were found. Chest X-ray revealed right hilar
lymphadenopathy with right lower zone infiltration with
a small pleural effusion. It was diagnosed as disseminated
tuberculosis and child was treated with four drugs in the
intensive phase (HRZE), and two drugs (HR) in the
maintenance phase, i.e. 2HRZE, 4HR.
Review of literature by Chawla et al.3 revealed that in
some cases local steroids had to be used along with their
systemic administration. If the cornea is involved, the
ophthalmologists opinion must be sought. Absence of
pain, presence of nodule on or within the eyeball,
spontaneous perforation are clinical features and high
index of suspicion is necessary for early diagnosis to
prevent the development of panophthalmitis. Ocular
tuberculosis has been described in a five months old
infant.4
249
Pericardial abscess due to tuberculosis is a rare

manifestation and is a complication of constrictive
pericarditis.5 The diagnosis is suspected when a patient
shows symptoms and signs of constrictive pericarditis
clinically. Echocardiography shows a pericardial mass.
Computed tomography (CT) and magnetic resonance
imaging (MRI) T2-weighted are required to give the
diagnostic clue of pericardial abscess. Thirteen patients
out of 120 over a period of 9 years (1-15 years age group)
were diagnosed by CT and MRI.
HEMATOLOGICAL COMPLICATIONS
The hematological complication such as severe
autoimmune hemolytic anemia (AIHA) as a complication
of disseminated childhood tuberculosis has been reported
by Bakshi et al.6 in an 8-year-old girl who presented with
severe autoimmune hemolytic anemia in association with
mediastinal widening on chest X-ray. CT scan of chest
showed large paratracheal, pretracheal, precarinal,
retrocarinal and bilateral hilar lymphadenopathy.
Mantoux test was nonreactive. FNAC of the
supraclavicular lymph node was unsuccessful for
diagnosis by mediastinoscopy. Biopsy of mediastinal
lymph nodes was performed. This revealed large areas of
confluent necrotizing granulomatous inflammation which
confirmed the diagnosis of tuberculosis.
Treatment
In addition to multiple transfusions, the patient was started
on 2HRZE in the intensive phase, with which the patients
hemoglobin normalized with no evidence of hemolysis on
peripheral blood smear. There was regression of hepatosplenomegaly to normal. Patient became afebrile with
regression in size of the left supraclavicular lymph node.
The child had a relapse of hemolytic anemia after 2 months
still being on antituberculosis therapy. For this, along with
antitubercular drugs, she was put on steroids in the dose of
2 mg/kg to start with. She still had poor response and hence
the steroid dose was increased to 4 mg/kg/day.
In the continuation phase the child in addition to
antituberculosis therapy (4HR) along with steroids in the
dose of 2 mg/kg/day, tapered to 1 mg/kg/day followed
by 1 mg/kg on alternate days till the last month when
only 0.5 mg/kg/day of steroids were given. She is doing
fine, the regimen followed was 2HRZE 4HR with tapering
doses of steroids. In the literature only 7 cases of tuberculosis associated with AIHA have been reported.7-13
Table 17.1 shows the association of AIHA with different
types of tuberculosis.
250

Table 17.1: Characteristics of TB-related autoimmune hemolytic anemia (AIHA) cases
reported in English literature7-13
Author/year
Country
Age/sex
Cameron SJ
19747
Semchyshyn et al
19758
Murray HW
19789
Kim SW et al
199510
Siribaddana et al
199711
Blanche P et al
200012
Kuo PH et al
200113
England
58 M
Canada
Site
Hb
(g/dL)
Retic (%)
Pulmonary
4.4
15
39 F
Genitourinary
7.5
8.8
USA
49 M
Pulmonary
10.3
Korea
52 M
Cutaneous
11.2
1.2
Sri Lanka
37 M
Lymph Nodal
6.6
10
France
42 M
Miliary
3.7
Taiwan
26 M
Disseminated
21
Treatment
Blood transfusion,
ATT, Prednisolone
ATT, Prednisolone
ATT
ATT, Prednisolone,
Azathioprine
ATT
ATT, Prednisolone,
Splenectomy
ATT
Ref. 6 Indian J Pediatric 2004; 71: 549-51.
ESOPHAGEAL TUBERCULOSIS
14
Sathiyascbararn and Shivbalan have described a case

of esophageal tuberculosis in a 14-year- old boy. He
presented with vomiting, cough, low grade fever and
anorexia for two months. Vomiting was nonbilious, not
associated with pain in the abdomen but occurred while
eating or soon after taking food. Family history of TB was
positive. The child did not have significant clinical
findings of pulmonary TB except few crepitations at the
left base.
Investigations
Mantoux test was strongly positive. Upper GI endoscopy
showed an irregular ulcer with raised edges in the mid
esophagus. Histopathology of the lesion showed caseating
granuloma suggestive of tuberculosis, no AFB were seen.
Chest CT showed findings of consolidation, pleural
thickening with mediastinal and hilar adenopathy. Hence,
a diagnosis of pulmonary tuberculosis with secondary
involvement of esophagus was made. He was put on 2
HRZE + 7HR. Repeat endoscopy was normal, child
became asymptomatic.
Esophageal tuberculosis is the least common among
all tuberculous lesions of the gastrointestinal tract.15 The
squamous epithelium, peristalsis, mucus and saliva
coating the esophagus have a protective effect. It is of two
types:
i. Primary
ii. Secondary
The primary disease of the esophagus is uncommon
and the secondary infection of the esophagus can occur
due to swallowed infected sputum, direct involvement
from lungs, mediastinal lymph nodes or thoracic spine,

by retrograde lymphatic or hematogenous spread.16 There
are very few indications of diagnosing pulmonary
tuberculosis in children by CT scan. However, if a child
has difficulty in swallowing, vomiting without pain in
the abdomen, Chest CT is a must which will give a clue to
diagnosis of tuberculosis of the chest as an etiology of
gastrointestinal symptoms.
The usual signs of esophegeal TB are dysphagia,
cough, pain in the chest in addition to weight loss and
fever. The other complications which can occur are
bleeding, perforation or fistula formation.17
There are three types seen on gross examination:
i. Hypertrophic
ii. Granular
iii. Ulcerative
The patient described above had the secondary
ulcerative form of tuberculosis of esophagus. He being
immune competent, responded to chemotherapy with
antituberculosis drugs.
TUBERCULOUS OTITIS MEDIA AND MASTOIDITIS

It presents as a chronic painless, suppurative disease
which may be associated with hearing loss, lower motor
neuron facial palsy and cervical lymphadenopathy.
Tuberculosis of the lung is often associated. It is relatively
rare and is seen most commonly during the first year of
life. On examination, beyond the tympanic membrane,
granulomatous middle ear mucosa is seen. If perforation
of the membrane occurs, it protrudes through the tympanic
membrane. Although uncommon, the possibility of
tuberculosis of the middle ear should be considered in

any case who is not responding to conventional therapy.
It may be more common in children with HIV infection
and AIDS.
ISOLATED HEPATIC INFERIOR VENA CAVA THROMBOSIS

IN A CASE OF TUBERCULOSIS
Gogna et al.18 have reported a case of pleuropulmonary
tuberculosis developing isolated inferior vena cava (IVC)
thrombosis with raised anticardiolipin antibodies and
antinuclear factors during the course of therapy. Recently
the association between inflammation and acute phase
reactants with hemostatic changes is thought to result in
hypercoagulable state which may cause deep vein
thrombosis in cases of severe pulmonary tuberculosis.19
In these cases there is thrombocytosis, elevated plasma
fibrinogen, fibrin degradation products, tissue
plasminogen activator (t-pa) and inhibitor (t-pi) with
depressed antithrombin level. Fibrinogen is seen to rise
within the first two weeks of therapy, which normalizes
within 12 weeks. This coupled with impaired fibrinolysis
may result in deep vein thrombosis. The increased levels
of anticardiolipin antibodies and antinuclear factors can
be associated with deep vein thrombosis, but also isolated
venous thrombosis at unusual sites like hepatic IVC.
Casanova-Roman manuel et al.20 from Spain have reported
transient elevation of proteins and anticardiolipin
antibodies in a 4-year-old boy with pulmonary tuberculosis
and deep vein thrombosis. They observed that two or more
anomalies in the coagulation system are necessary for
causing venous thrombosis.20
CEMENT KIDNEY: RENAL TUBERCULOSIS

Punia and Kumar21 presented an 18-year-old girl with
fever and anorexia since twenty days, and recurrent
painless hematuria with oliguria since one year. There
was history of pulmonary tuberculosis in her childhood
for which she had received antituberculosis therapy for 6
months. Physical examination was normal except for
presence of pallor.
Urinalysis showed albumin +, 25 to 30 RBCs/hpf, 10 to
12 pus cells/hpf, no urinary casts, malignant cells or
bacteria. Repeated urine cultures were bacteriologically
sterile. Hemoglobin 7.3 gm/dl, ESR 65 mm/1st hr,
serum creatinine 5.1 mg/dl, blood urea 278 mg/dl,
serum Na+ 136 mEq/L, serum K+ 3.4 mg/dl, serum
calcium 10.6 mg/dl, serum phosphorus 3.4 mg/dl,
serum alkaline phosphate 77 IU/L, serum parathyroid
hormone 35 pg/ml. Coagulation tests were normal. ELISA
for M. tuberculosis IgG antibody was positive. Mantoux test
was positive. Early morning urine cultures on three
successive days yielded acid-fast bacilli.
251
Plain abdominal radiograph showed a reniform shaped

calcification with lobulations suggesting calcified right
kidney (cement kidney) and a beaded, tubular-shaped
calcification extending parallel to the vertebral column (L4
S2) suggestive of calcified right ureter. Chest X-ray showed
old, healed, calcified parenchymal and pleural lesions in the
left upper zone. Ultrasonographic examination of abdomen
revealed a calcified right kidney with compensatory
enlargement of the left kidney.
A diagnosis of renal tuberculosis with renal failure was
made. Antitubercular therapy with modified dosages was
started. Fever subsided and hematuria stopped alongwith
improvement in general condition of patient. After two
months of follow-up, the patient was doing well.
PRIMARY TUBERCULOSIS CLINICALLY PRESENTING AS

GINGIVAL ENLARGEMENT: A CASE REPORT
Tuberculosis is a chronic systemic granulomatous disease
which rarely affects the oral cavity. Oral lesions can be
either primary or secondary to systemic tuberculosis, the
former being rare. Sharma et al.22 reported a case of
primary tuberculosis presenting as a localized diffuse
gingival enlargement in an 11-year-old Indian female
patient. The diagnosis was established by identification
of posture histopathological features, tuberculosis test,
presence of antitubercular antibodies confirmed by a
polymerse chain reaction (PCR). It is suggested that in
view of the recent increase in the incidence and provalence
of tuberculosis it is reasonable to include tuberculosis in
the differential diagnosis of gingival enlargment.
SIMULTANEOUS TUBERCULOUS
MENINGOENCEPHALITIS IN TWO SIBLINGS
Meyer et al.23 reported two siblings (2-year-old boy and 4year-old girl) with simultaneous tubercular
meningoencephalitis (TBM) in Germany. Early diagnosis
of TBM was delayed and antituberculosis treatment was
not initiated syspecting it to be viral meningoencephalitis.
There was hydrocephalous and signs of inflammatory
cerebral disease. After the diagnosis of TBM was
established the boy died due to drug induced hepatic
failure, the sister survived with severe neurological
sequlae. Contact tracing revealed that TB had been
transmitted by a household contact with proven
pulmonary TB who had refused antituberculosis
treatment. It was concluded by the authors that to prevent
severe neurological sequelae, early antituberculosis
therapy should be considered in infants and children with
a clinical impression of meningitis. A rigid implementation
of antituberculosis treatment of infected individuals and
252
contact tracing is mandatory in order to prevent

dissemination of TB in the community particularly
vulnerable section of children. BCG is a must for all
newborns to prevent the development of dissemination.
CHILDHOOD TUBERCULOSIS DIAGNOSED AND

MANAGED AS ASTHMA: A CASE REPORT
Kurokawa et al.24 have emphasized that although the
diagnosis of tuberculosis is well established in adults, in
children it is difficult. They reported a 3 years and 8 months
old child who had chronic wheezing, classified as moderate
to severe asthma, had recurrent pneumonia, and was not
responding to the management with beta adrenergic agents.
Chest X-ray showed heterogeneous opacity in the middle
lobe and in the CT scan there was an increase in pulmonary
transparency in the same lobe. After four months of treatment
with antituberculosis agents, there was a significant
improvement in symptoms, disappearance of pulmonary
medium lobe consolidation and persistent fibroatelectic band
in lingula.
TUBERCULOSIS OF THE BREAST IN AN ADOLESCENT

GIRL
Tuberculosis (TB) of the breast is a rare condition and
usually affects women in the reproductive age group. It is
further rare in children even in India, where TB is rampant,
poses challenges in its diagnosis. Histopathology plays an
important role in the diagnosis of the condition. Indumathi
et al.25 have reported a case of TB of the breast in a 15-yearold girl proved by histopathological study.
ESOPHAGEAL STENT IMPROVES VENTILATION IN A

CHILD WITH A BRONCHOESOPHAGEAL FISTULA CAUSED
BY MYCOBACTERIUM TUBERCULOSIS
Goussard et al.26 have described in a 12-month-old boy
the role of an esophageal stent who presented with
respiratory failure requiring ventilation. The child had
tubercular bronchoesophageal fistula and air leak via the
fistula led to inadequate mechanical ventilation. The
deployment of a stent resulted in successful ventilation,
closure of the fistula and eventual successful treatment.
PITUITARY STALK TUBERCULOSIS

Stalldecker et al.27 have reported an exceptionally rare
manifestations of pituitary stalk tuberculoma. The authors
have suggested that even with no evidence of systemic
tuberculosis, it is important to recognize these lesions in
the differential diagnosis of the intrasuprasellar tumors
because they are curable. In developed countries the
frequency of intracranial tuberculoma of the nervous
system tumor is around 0.5 to 4%, where as in developing

countries it is 15 to 30%. It mainly affects children and
young adults. An accurate diagnosis by biological,
hormonal and imaging scan examination can be made
and medically treated. The case described by the authors
encountered difficulties in diagnosis because of a normal
scan due to thickening of pituitary stalk. PCR was helpful
in the diagnosis.
MULTIFOCAL SKELETAL TUBERCULOSIS

Multifocal skeletal tuberculosis is an uncommon
manifestation in immunocompetent children. Nonspecific
clinical manifestations and multiple osteolytic
radiological lesions of multifocal skeletal tuberculosis
mimic hematological malignancies, neuroblastoma and
secondary metastases. Histopathological examination is
mandatory for the confirmation of the diagnosis.
Antituberculosis therapy is the cornerstone of treatment
with surgery having a limited role. Indumathi et al.28
reported this entity in a female child, aged 15 years who
presented with intermittent fever of five months duration.
She had significant weight loss followed by swelling of
dorsum of right foot since a month. She also gave history
of pain in the left foot 2 months ago which subsided after
a week. There was no cough or history of contact with
tuberculosis. There was no history of arthalgia, arthritis,
rash, progressive pallor or bleeding manifestations.
The child was malnourished and had mild pallor. There
was no significant lymphadenopathy, rash or skin bleeds.
Systemic examination was unremarkable. There was
nonpitting edema on the right foot along with tenderness.
Investigations revealed HB 8.2 gm/dl, TLC = 6800/
cumm, DLC-N-78%, L-18%, E-2%, M-2%, platelets 4.2
lakhs/mm. 3 Peripheral smear was suggestive of
normocytic normochromic anemia ESR 86 mm/hr. HIV
was negative, so was Mantoux test. Chest X-ray showed
miliary tuberculosis and induced sputum was negative
for AFB. Ultrasound of the abdomen revealed granuloma
in liver. MRI of foot revealed multiple lytic lesions with
sclerotic borders in most of the right tarsal bones, lower
ends of right tibia and right fibula as well as in the left
tibia. A bone biopsy showed nonspecific inflammatory
changes with acid-fast bacilli. She was put on category I
antituberculosis therapy 2HRZE 7HR. During hospital
stay she developed left pneumothorax. During first followup after 2 months of intensive therapy she gained 3
kilograms and was afebrile. Then she was lost to followup.
Skeletal tuberculosis accounts for 10 to 35% of
extrapulmonary tuberculosis and 2% of all cases of
tuberculosis. Lung is the primary focus in 75% of cases
and it is secondary to hematogenous dissemination.
Common sites include spine, hip, and knee joints followed
by short bones of hands and feet. Skeletal lesions can be

solitary or multiple. Osteoarticular lesions that occur
simultaneously at two or more locations in the skeletal
system, are termed multifocal skeletal tuberculosis. This
is an uncommon entity even in endemic countries and
accounts for <5% skeletal tuberculosis in all age.
Multiple lesions are commoner in children compared
to adults. Peripheral skeleton is involved more in children
where as there is axial skeleton involvement more
predominant in adults. It has insidious onset with vague
symptomatology like low grade fever, loss of weight and
appetite. Soft tissue swelling, pain and restricted mobility
at involved sites are also common symptoms. Active
tuberculosis is present in 50% of cases.
Plain radiograph of bones may be normal and subtle
changes are often missed. An MRI is the investigation of
choice that reveals osteolytic cystic lesions without
significant marginal sclerosis or reactive bone formation.
Lesion are less sclerotic in children (<20%) as compared to
adults. Nonspecific clinical presentation, functional
disability and radiological lesions of multifocal skeletal
tuberculosis mimic rheumatological conditions,
hematological malignancies, pyogenic and mycotic
osteomyelitis, chronic relapsing multifocal osteomyelitis,
neuroblastoma and secondary metastases. It is rare and is
considered after a diagnosis of malignancy. Bone Scan is
helpful in detecting other lesions.
Eighty-five to ninety percent of cases respond to
antituberculosis therapy alone in 6-12 months. Excision of
sinus tract for removal of necrotic tissue is required in 10 to
15% of cases. Early diagnosis is associated with good
prognosis. High index of suspicion and institution of prompt
therapy is essential to prevent progression of the disease.
BCG RELATED COMPLICATIONS

The complication of BCG vaccination can lead to local
abscesses, secondary bacterial infections, lupus vulgaris,
lymphadenitis, scrofuloderma like lesions, papulonecrotic
tuberculide and local keloid formation. In immune
compromised children, it can be fatal.
Skin biopsy and the opinion of a dermatologist may be
required to give a definite diagnosis of tuberculosis of the
skin.
Primary inoculation tuberculosis may resemble as an
indolent pyogenic infection and a typical mycobacterial
infection must be considered.
Cat scratch fever may cause a slow-healing skin lesion
accompanied by regional adenitis like deep fungal
disease and leishmaniasis
In scrofuloderma, actinomycosis, discoid lupus
erythematosus, sarcoidosis, leprosy must be
distinguished
253
Lupus vulgarissyphilis need to be distinguished

Papulonecrotic tuberculosispapular urticaria in young
children.
HIGHLIGHTS
Unusual manifestations involving different systems
by tuberculosis in children have been described
Eye and conjunctiva
Cardiac complicationpericardial abscess
Hematologicalautoimmune hemolytic anemia
Cement kidney a rare tuberculosis
Esophageal tuberculosis
Skelatal tuberculosis
Pituitary stalk tuberculosis
BCG related complication
Isolated inferior vena cava thrombosis.
REFERENCES
1. Stein H, Freiman I. Phlyctenular conjunctivitis in African
children. Arch Dis Childhood 1958;33:292-4.
2. Domato FJ. BCG vaccine and phlyctenular conjunctivitis.
British J Ophthalmol 1951;35:416.
3. Chawla R, Grag S, Verikatgh P, et al. Case report of
tuberculosis panophthalmitis. Med Sci Monit
2004;10:CS57-9.
4. Morese ML, Karr DJ, Mandman OM. Ocular tuberculosis
in a five months old infant. Infect Dis J 1988;7:514-6.
5. Gulati GS, Sharma S. Pericardial abscess occurring after
tuberculous pericarditis: Image morphology on
computed tomography and magnetic resonance
imaging. Clin Radiol 2004;59:514-9.
6. Bakshi S, Rao IS, Jain V, et al. Autoimmune hemolytic
anemia complicating disseminated childhood
tuberculosis. Indian J Pediar 2004;71: 549-51.
7. Cameron SJ. Tuberculosis and the blood: A special
relationship? Tubercle 1974;55:55-7.
8. Semchyshyn S, Cecutti A. Abdominal pregnancy
complicated by genital and renal tuberculosis and
hemolytic anemia. Fertile Steril 1975;26:1142-5.
9. Murray HW. Transient autoimmune hemolytic anemia
and pulmonary tuberculosis. N Engl J Med 1978;299:488.
10. Kim SW, Choi SW, Cho BK, et al. Tuberculosis cutis
orificialis: An association with Evans syndrome. Acta
Derm Venereol 1995;75:84-5.
11. Siribaddana S, Wijesundara A. Autoimmune hemolytic
anemia responding to antituberculous treatment. Tropical
Doctor 1997;27:243-4.
12. Blanche P, Rigolet A, Massault D, et al. Auto-immune
hemolytic anemia revealing miliary tuberculosis. J Infect
2000;40:292.
13. Kuo PH, Yang PC, Kuo SS, et al. Severe immune
hemolytic anemia in disseminated tuberculosis with
response to antituberculosis therapy. Chest 2001;119:
1961-3.
14. Sathiyascbararn M, Shivbalan SO. Esophageal
254

15. Sood A, Sood N, Raj Kumar, et al. Primary tuberculosis of esophagus. Indian J Gastroenterol 1996;
15:75.
16. Gordon AH, Marshall JB. Esophageal tuberculosis;
definitive diagnosis by endoscopy. Am J Gastroenterol
1990;85:174-7.
17. Fahmy AR, Guinde R, Farid R. Tuberculosis of esophagus.
Thorax 1992;24:254-6.
18. Gogna A, Grover SB, Prun S, et al. Isolated hepatic inferior
vena cava thrombosis in a case of tuberculosis. JIACM
2004;5:266-8.
19. Robson SC, White NW, Aronson I, et al. Acute-phase
response and the hypercoagulable state in pulmonary
tuberculosis. Brit J Haematol 1996;93:943-9.
20. Casanova- Roman manuel, Rios, Jesus, Sanchez-Porto
Antonio, et al. Deep venous thrombosis associated with
pulmonary tuberculosis and transient protein S
deficiency. Scan J Infect Dis 2002;34:393-4.
21. Punia VPS and Kumar S. Cement kidney renal
tuberculosis-a case report. JIACM 2008; 9: 216-7.
22. Sharma CG, Pradeep AR, Karthikeyan BV. Primary

tuberculosis clinically presenting as gingival enlargement
a case report. J Contemp Dent Pract 2006; 7: 108-14.
23. Meyer S, Shamdein MG, Wiillenweber J, et al. Simultaneous
tuberculosis meningo-encephalitis in two siblings. Wien
Med Wochenschr 2007; 157: 37-42.
24. Kurokawa La Scale CS, La Scale CR, et al. Childhood
tuberculosis diagnosed and managed as asthma: case
report. Altergol Immunopathol (Madr) 2006; 34: 276-9.
25. Indumathi CK, Alladi A, Dinakar C, et al. Tuberculosis of
the breast in an adolescent girl-a rare presentation. J
Troop Pediatr 2006; Dec 10[Epub-ahead of print].
26. Goussard P, Sidler D, Kling S, et al. Esophageal stent
improves ventilation in a child with a bronchoesophageal
fistula caused by Mycobacterium tuberculosis. Pediatr
Pulmonol 2007; 42:93-7.
27. Stalldecker G, et al. Pituitary stalk tuberculosis. Pituitary
2002; 5:147-8.
28. Indumathi CK, Vikram Kumar S, Lewin S, et al. Multifocal
skeletal tuberculosis. Pediatr Infectious Disease 2010; II: 45-7.
18
Cutaneous Tuberculosis
Neena Khanna, Seemab Rasool
EPIDEMIOLOGY
Prevalence
Childhood tuberculosis represents 5 to 15% of all cases
of tuberculosis, with pulmonary tuberculosis being
commonest form of tuberculosis seen in children.
Cutaneous tuberculosis represents 1.5 % of all cases of
extra pulmonary tuberculosis.1 In an Indian series of 402
patients with cutaneous tuberculosis 18.7% were found
to be children.2
Demographic Parameters
Most cutaneous tuberculosis is seen in the age group of
10 to 14 years, 2 with no significant gender preponderance.
ETIOLOGY
Cutaneous tuberculosis is caused:
Usually by Mycobacterium tuberculosis
And rarely by :
M. bovis
Attenuated bacille Calmette-Guerin (BCG)
organism.
Underlying systemic involvement is commoner in
children compared with adults, being seen in 12.7 to 53.4%
of the children (Table 18.1).3-6
Table 18.1: Underlying systemic involvement in

cutaneous tuberculosis
Underlying tuberculosis
Prevalence (%)
Lymphadenitis
Lungs
Bone
Abdomen
29.2
12.620
5.810
5.8
quiescent, with reactivation of the organism occurring

when conditions become favorable for the bacilli.
Reinfection: May also occur in patients with healed
infection after many years, especially in regions of
high prevalence.
CLASSIFICATION
Cutaneous tuberculosis is classified based on morphology, mode of infection and previous sensitization (Table
18.2). The two most common forms of skin tuberculosis
reported in India are scrofuloderma and lupus vulgaris.5
CLINICAL FEATURES
Scrofuloderma
Scrofuloderma is the most common form of cutaneous
tuberculosis in children.2 It results from the direct invasion of the tubercle bacilli into the skin from an underlying tuberculous focus, usually in the lymph nodes and
less frequently in the bones, joints and testes.6, 7
PATHOGENESIS (TABLE 18.2)

Skin is infected by M. tuberculosis either from an
exogenous source (usually from infected adults)4 or the
organism reaches the skin from an endogenous focus. The
manifestations depend on the immunity of the host and
method of spread.
Exogenous infection: Infection from an exogenous source
leads to tuberculous chancre, if the person who is being
exposed for the first time or tuberculosis verrucosa cutis
in a person who already has a high immunity.
Sometimes lupus vulgaris develops at the site of BCG
vaccination.
Endogenous infection: The focus is most frequently in
the lungs and sometimes in the skin, mucosae or
lymphnodes. Often, the source of infection is clinically
Table 18.2: The classification of cutaneous tuberculosis
Source
Clinical presentation
Endogenous
Contiguous spread
Scrofuloderma
Hematogenous spread Lupus vulgaris
Acute miliary TB
Metastatic TB abscess
Gumma
Auto-inoculation
Orificial TB
Exogenous source
TB chancre (nonsensitized)
TB verrucosa cutis (sensitized)
Tuberculosis caused by
BCG vaccination
Eruptive
Tuberculids
256
Morphology
Scrofuloderma in children is more severe than in
adults.4
Usually starts as firm subcutaneous nodules (Fig.18.1,
see color version, Plate 00) or as well defined freely
movable asymptomatic plaque(s) overlying an
involved lymph node, less frequently bone, joint and
testes which subsequently rupture over a period of
months to form sinuses discharging watery or caseous
material. The mouth of the sinus is typically
undermined and bluish. Ulcers, when present are
typically shallow with bluish undermined margins
(Fig. 18.2, see color version, Plate 00) and a floor with
granulation tissue and the base is formed of the
underlying tubercular focus. Widespread localized
lesions sometimes present as multiple swellings and
ulcers with irregular, finger-like scrofulous extension
involving large areas.8
Spontaneous resolution may occur after many
months or years, healing with characteristic puckered
scars.
Fig.18.1: Scrofuloderma: Firm asymptomatic

subcutaneous nodule (For color version see Plate 5)
Sites of Predilection
Usually unilateral. However multifocal lesions
involving axillary, inguinal, and other bony areas, and
symmetric scrofuloderma from an underlying bony
focus on both ankles have been reported.
Cervical group of lymph nodes are most commonly
affected.2 Other groups of lymph nodes that can be
involved are axillary, inguinal, parasternal,
epitrochlear, pre- and postauricular, submandibular,
occipital, and supraclavicular nodes. Other common
sites include scrofuloderma of shins rising from
tuberculous osteomyelitis of tibia, skin over the
sternoclavicular joint and scrotum.
Fig. 18.2: Scrofuloderma ulcer: Shallow, undermined with bluish

margins and a floor with granulation tissue (For color version see
Plate 5)
Lupus Vulgaris (LV)

Lupus vulgaris is more common in adults than
scrofuloderma but is less frequent in children.2 It is a post
primary, paucibacillary form of skin tuberculosis that
usually occurs in previously sensitized individuals.4
Morphology
Single or few lesions of variable size can affect a large
area of the body.
Begin as asymptomatic, indurated papules and
plaques which spread slowly to form a welldemarcated, skin-colored or erythematous annular
plaque with deep-seated, tiny nodules at the periphery
that can be seen as yellow-brown macules (apple-jelly
nodules) on diascopy. Over time the center becomes
atrophic and paper thin. Healing and scarring in one
Fig.18.3: Lupus vulgaris: Well demarcated annular plaque with

central scarring (For color version see Plate 5)
area and activity in another (in forms of nodules) is

the hallmark of lupus vulgaris (Fig. 18.3, see color
version, Plate 00).
Chapter 18 Cutaneous Tuberculosis
In children, the lower extremities and gluteal region are
the commonly affected sites.4
Variants
Classic plaque LV (keratotic type): Being the most
common.
Hypertrophic LV: Appears as a soft mass with a
nodular hyperkeratotic surface.
Ulcerative LV: Ulceration occurs when underlying
tissue is affected by progressive necrosis.
Atrophic LV: Atrophy may occur with or without prior
ulceration.
Mutilating LV: When fibrosis is prominent mutilation,
deformity and contractures occur.
Rare Variants
Multifocal, symmetric LV: Affecting the knees, possibly
caused by exogenous inoculation of the organism, has
been reported.
Sporotrichoid pattern: Due to lymphatic spread.
Develop on partially healed lesions of scrofuloderma.6
Post BCG vaccination.
LV of mucous membranes: Usually involved as an
extension of the skin lesions and manifest as easily
bleeding small, soft, gray or pink papules, ulcers, or
granulating masses.4
Lupus postexanthematicus: Multiple disseminated
lesions may arise due to hematogenous spread from a
latent focus, after a transient impairment of immunity.
Complications of LV
Ulceration, often slow to heal.
Disfigurement: facial lesions scar and often cause
ectropion, nasal deformities. Genital distortion may
occur due to genital lesions.
Contractures, if close to joint due to scarring.
Squamous cell carcinoma, rarely.
257
vesicles which develop central necrosis and crusts are

seen.
Sometimes, neonates born to tuberculous mothers
develop a milder form of the disease, with limited
visceral involvement and only a few scattered
papules.
Sites/Systemic Involvement
Disseminated lesions occur on all parts of body,
particularly on trunk. Miliary TB may occur in an
individual organ (very rare, <5%), in several organs, or
throughout the whole body (>90%), including the brain.4
Tuberculous Metastatic Abscesses

Also called tuberculous gumma, tuberculous metastatic
abscess, is caused by the hematogenous spread of
Mycobacteria from a primary focus. It is usually seen in
malnourished or immunosuppressed children.
Morphology
Single or multiple non tender dermal or subcutaneous
nodules.
Lesions may invade overlying skin and break down
to form necrotic ulcers and fistulous tracts, quite like
scrofuloderma.
Extremities, trunk and head.
Primary Tuberculous Chancre

Tuberculous chancre, also known as primary inoculation
tuberculosis or tuberculous primary complex, is rare and
is mostly seen in high endemic areas. It is due to
inoculation of Mycobacteria into skin in previously
unsensitized persons forming a tuberculous primary
complex (tuberculous chancre and regional lymph
nodes). The organisms are usually introduced at the site
of minor injury or abrasion.
Acute Miliary Tuberculosis

Acute miliary tuberculosis with skin manifestation is rare
in India, with only a few cases in children having been
reported. 9, 10 It is due to the hematogenous dissemination
of Mycobacteria from an internal focus usually the lungs
or meninges. The disease often manifests after
immunosuppression due to infections such as measles
and HIV.4
Morphology
Cutaneous lesions consist of erythematous papules,
pustules and,purpuric lesions. Rarely umbilicated
Morphology
Skin lesion develops about 4 weeks after inoculation.
It begins as an asymptomatic papule that breaks down
to form a shallow ulcer with granulomatous base and
undermined bluish margins, which heals over a
period of time (similar to a tuberculous primary
complex elsewhere). The organisms remain dormant
and may get reactivated under favorable conditions.
Regional lymphadenopathy develops 3 to 8 weeks
after the inoculation.
Inoculation of the finger may manifest as paronychia.4
258
Tuberculosis Verrucosa Cutis (TVC)

Tuberculosis verrucosa cutis, otherwise known as warty
tuberculosis, occurs as a result of exogenous inoculation
tuberculosis in previously sensitized individuals.
Morphology
Begins as a small single verrucous papule, which
slowly extends to form large irregular verrucous
plaques (Fig. 18.4, see color version, Plate 00). Surface
usually shows deep fissures or clefts that may extrude
pus and perilesional erythema is frequent. Irregular
small areas of scarring often hidden by the
verrucosity.
The lesion may persist for many years and progress
slowly.6, 8 At times, it is difficult to distinguish it from
the hypertrophic variant of lupus vulgaris.
Fig. 18.4: Tuberculosis Verrucosa Cutis: Irregular verrucous plaque

It typically occurs on the acral parts of the extremities

(sites of trauma).
The following are no longer included as tuberculids:

Rosacea-like tuberculid
Lupus miliaris disseminatus faciei
Lichenoid tuberculid.4
Orificial Tuberculosis
Lichen Scrofulosorum
Tuberculosis cutis orificialis is rare form of tuberculosis

caused by autoinoculation of mycobacteria in patients
who have advanced internal tuberculosis.8
Is commonly seen in children and young adults.

Usually indicates an underlying tuberculous focus in
the lymph nodes, especially the cervical, hilar, and
mediastinal nodes, bones, and sometimes lungs.
Rarely, it can be seen in association with tuberculous
meningitis and miliary tuberculosis. 11, 12 It has also
been observed after BCG vaccination.
Morphology
A small yellowish or reddish nodule appears usually
in the mucosa of the mouth or anus.
The nodule breaks down to form a shallow,
granulomatous ulcer with a punched out appearance
and undermined edges.
Tuberculides
Tuberculides are delayed sensitivity reactions to M.
tuberculosis in patients with a strong immune response.
Morphology
It presents as asymptomatic small, scaly yellow-brown,
or lichenoid, firm, follicular papules which may be flat
topped or spiny (Fig. 18.5, see color version, Plate 00).
Completely resolves with ATT.
Criteria for Diagnosis

Absence of organisms in the smear and negative
culture from the lesions.
Strongly positive Mantoux reaction.
Resolution of the lesions with antituberculous
treatment (ATT).
Classification
The tuberculides include:
Lichen scrofulosorum
Papulonecrotic tuberculide
Erythema induratum
Erythema nodosum
Fig. 18.5: Lichen scrofulosorum: Grouped follicular lichenoid papules

259
Complications of BCG Vaccination
Usually confined to the trunk.
BCG vaccine is a live, freeze-dried vaccine derived from

an attenuated strain of M. bovis (BCG). It is given routinely
at birth to all infants at risk of early exposure to
tuberculosis in dose of 0.05 mL intradermally. Usually, 2
weeks after vaccination, a small papule develops which,
over a period of 6 weeks enlarges, ulcerates and
eventually heals with a scar.
Papulonecrotic Tuberculides
A rare condition seen in areas with high prevalence
occurs preferentially in children and young adults.
Morphology
Lesions consist of symmetric eruptions of necrotic
papules.
Resolves spontaneously leaving pitted scars.
Extensor aspect of the extremities and buttocks.
UNUSUAL PATTERNS OF TUBERCULOSIS

Sporotrichoid tuberculosis: Sporotrichoid pattern
though rare (3% of all patients with cutaneous
tuberculosis) is mostly reported in children. Lupus
vulgaris, scrofuloderma, and TVC can all present in
sporotrichoid pattern due to lymphatic spread. It is
characterized by linear lesions confined to an
extremity often with a cord-like thickening of the
lymphatics in between the lesions. Though frequently
confused with sporotrichosis, the presence of
enlarged regional lymph nodes or ulceration favors
the diagnosis of tuberculosis.13, 14
Inverse sporotrichoid pattern: Or segmental form is
characterized by involvement of the proximal half of
the lower limb due to retrograde lymphatic spread
from the inguinal lymph nodes. 15
Tuberculous dactylitis: Presents as granulomatous
swelling of the finger, most often the index or middle
finger. It is always associated with underlying
tuberculous osteomyelitis, especially of the proximal
phalanges. 2
Orofacial tuberculosis: Usually starts as a papule or
plaque in the perioral area usually of the upper lip,
which over course of time, extends into the oral
mucosa, including the tongue and nose. If untreated,
it leads to severe mutilation and complications like
destruction of the nasal septum, and involvement of
the palate, nasolacrimal duct, and middle ear.
Orofacial tuberculosis needs to be differentiated from
orofacial granulomatosis (especially in India), which
is a nonspecific descriptive term used for various
conditions characterized by persistent swelling of the
orofacial tissues histopathologically showing
noncaseating granulomas.16, 17 The important clue to
the diagnosis of tuberculosis is that the biopsy in these
cases demonstrates caseating granulomas, which is
further supported by the Mantoux test.
Nonspecific Complications
BCG vaccination may be followed by several nonspecific
complications like keloids, eczema, maculopapular rash,
erythema nodosum, infections, poor healing, ulceration
and abscess formation.
Specific Complications
Occasionally, M. bovis induced complications like lupus
vulgaris, verrucous tuberculosis, tuberculous chancre,
lymphadenitis, Kochs phenomenon, disseminated BCG
infection and tuberculids have been reported. 4
DIAGNOSIS OF CUTANEOUS TUBERCULOSIS

The diagnosis is usually based on the characteristic
clinical morphology and laboratory testing. In addition
to the routine laboratory evaluation, all children should
be evaluated for underlying systemic tuberculosis.
Histopathology
Though the histopathological hallmark of tuberculosis
is a caseating granulomas, there may be differences
between morphological variants (Table 18.3). The
clinicohistologic correlation can be seen in 64% to 80.6%
cases of cutaneous tuberculosis in children. 3,15 The
histopathologic correlation is found in 47% to 65.7% of
cases of scrofuloderma and 73% to 80% of cases of lupus
vulgaris (Table 18.3). 3, 15
Mantoux or Tuberculin Test

Response to different types of cutaneous tuberculosis is
variable (Table 18.4).
Demonstration of the Organism

The gold standard for the diagnosis of cutaneous
tuberculosis is the direct demonstration of the organism
either in a
Tissue smear
Biopsy
Culture.
Demonstration of organism is often difficult
especially in paucibacillary cases because of the scanty
260

Table 18.3: Histopathology of various types of tuberculosis
Type
Histopathology
Scrofuloderma
Tuberculoid granuloma with considerable necrosis and inflammation.
Lupus vulgaris
Tuberculoid granulomas with epithelioid cells and Langhans giant cells, along with epidermal changes.
Necrosis is usually not seen. Fibrosis may be seen in the areas of scarring and healing.
Acute miliary TB Microabscesses containing neutro-phils and numerous organisms that may be surrounded by macro-phages
and giant cells.
Metastatic TB
Massive necrosis with copious abscess
amounts of mycobacteria.
Orificial TB
Massive nonspecific inflammatory infiltrate and necrosis; in deep dermis tubercles with deep caseation
may be seen.
TB chancre
Nonspecific inflammatory reaction and later there is tuberculoid appearance and caseation.
TB verrucosa cutis Massive pseudoepitheliomatous
(sensitized)
hyperplasia and granulomatous infiltrate with necrosis.
Tuberculids
Vasculitis and a wedge-shaped area of necrosis. Nonspecific infiltrates or tuberculoid granuloma may be seen
surrounding the necrosis. 4
number of organisms. AFB have been seen in the biopsy

sections of scrofuloderma and lupus vulgaris in 36.8%
and 13.6%, respectively 3 while in cytology specimens it
can be demonstrated in 39.5% and 18.2% respectively.
Culturing the organisms in the Lowenstein-Jenson
medium is tedious and positivity is even lower (18.4%
in scrofuloderma and 12.5% in lupus vulgaris). However
with improved techniques using multiple media, and the
use of Kirchners liquid medium for storage of the tissue,
the culture positivity is better.
Table 18.4 Mantoux test in different type of cutaneous

tuberculosis
Clinical manifestations
Mantoux test
Tuberculous chancre
Tuberculosis verrucosa cutis
Negative initially
Positive
Lupus vulgaris
Variable
Acute miliary tuberculosis
Negative
Tuberculids
Strongly positive
Polymerase Chain Reaction (PCR)

Though the diagnostic specifity of PCR in cutaneous
tuberculosis is debatable, it has considerable sensitivity
especially in paucibacillary cases. The combination of dot
hybridization with PCR markedly increases the
sensitivity and specificity of PCR. This may be a useful
tool in the diagnosis of tuberculosis when conventional
methods fail.
Therapeutic Trial of Antituberculous Drugs

A therapeutic trial of antituberculous drugs may be a
useful diagnostic tool in developing countries like India.
A four-drug regimen (HRZE) is usually given over a
period of 6 weeks. Gratifying response at the end of 6
weeks is the rule and proves the diagnosis of cutaneous
tuberculosis. Patients who have not responded by 6 weeks
are unlikely to do so with further treatment and their
diagnosis should be reviewed.
TREATMENT OF CUTANEOUS TUBERCULOSIS

Cutaneous tuberculosis can be treated with the standard
regime used for pulmonary tuberculosis. Currently, the
treatment of cutaneous tuberculosis is by the directly
observed treatment, short-course strategy, implemented
by the World Health Organization. This program has
been fully adopted by the Revised National Tuberculosis
Control Program (RNTCP) of the Government of India.
According to these guidelines, cutaneous tuberculosis is
classified as category III. When the lesions are extensive,
or when more than one group of lymph nodes are involved
as in scrofuloderma, then the category I regime can be
given (Table 18.5).18
Surgical Intervention
In scrofuloderma, reduces morbidity and shortens
period of chemotherapy.
261

Table 18.5: Treatment of cutaneous tuberculosis
Category
Intensive phase 8 weeks
Maintenance phase 16 weeks
Category III
Isoniazid 5 mg/kg
Isoniazid 5 mg/kg
Rifampicin 10 mg/kg
Rifampicin 10 mg/kg
Pyrazinamide 30 mg/kg
Category I
Isoniazid 5 mg/kg
Isoniazid 5 mg/kg
Rifampicin 10 mg/kg
Rifampicin 10 mg/kg
Ethambutol 15 mg/kg
Pyrazinamide 30 mg/kg
Small lesions of lupus vulgaris or tuberculosis

verrucosa cutis can be excised.
Plastic surgery has a role in mutilation due to long
standing cutaneous tuberculosis. 4
HIGHLIGHTS
Cutaneous tuberculosis represents 1.5 % of all cases
of extra-pulmonary tuberculosis.
Skin is infected by M. tuberculosis either from an
exogenous source (usually from infected adults) or the
organism reaches the skin from an endogenous source.
Most common forms of skin tuberculosis reported
in India are scrofuloderma and lupus vulgaris.
Scrofuloderma most common form of skin TB is
usually unilateral and cervical lymph nodes are most
commonly affected.
Lupus vulgaris is less frequent then scrofuloderma,
in children. The lower extremities and gluteal region
are commonly affected sites.
Other less common forms and unusual patterns of
cutaneous tuberculosis are described.
The Gold standard for the diagnosis of cutaneous
tuberculosis is the direct demonstration of the
organism either in a tissue smear, biopsy or culture.
Diagnosis is often based on characteristic clinical
morphology and demonstration of caseating
granulomas on histopathology. Other supportive
diagnostic aids are Mantoux test, polymerase chain
reaction, and therapeutic trial of anti TB drugs.
All children should be evaluated for systemic
tuberculosis.
Cutaneous TB can be treated with the standard
short-course chemotherapy regime used for
pulmonary TB.
Surgical intervention reduces morbidity and

shortens the duration of chemotherapy. Excision or
plastic surgery may be indicated in certain cases.
REFERENCES
1. Kumar B, Muralidhar S. Cutaneous tuberculosis: A
twenty year prospective study. Int J Tuberc Lung Dis
1999;3:494-500.
2. Kumar B, Rai R, Kaur I, et al. Childhood cutaneous
tuberculosis: A study over 25 years from northern India.
Int J Dermatol 2001; 40: 26-32.
3. Banerjee BN. Tuberculosis of the skin and its relation to
pulmonary tuberculosis. Indian J Dermatol 1957;2:
69-72.
4. Tap peiner G, Wolff K. Tuberculosis and infections with
atypical mycobacteria. In: Wolff K, Goldsmith LA, Katz
SI, et al. Eds. Fitzpatricks Dermatology in General
Medicine, 7th edn. New York McGraw Hill 2008 : p. 176877.
5. Vashisht P, Sahoo B, Khurana N. Cutaneous tuberculosis
in children and adolescents: A clinicohistological study.
J Eur Acad Dermatol Venereol 2007; 21:407.
6. Ramam M. Cutaneous tuberculosis. In: Sharma
SK,Mohan A, Eds. Tuberculosis. Delhi (India): Jaypee
Brothers Medical Publishers (P) Ltd. 2nd Edition 2009; p
384-96.
7. Chakraborty AK. MIF in tuberculosis of skin. Indian J
Dermatol 1983;28:63.
8. Sehgal VN. Cutaneous tuberculosis. Dermatol Clin 1994;
42:64553.
9. Raut WK, Sawaiti VK, Bobhate SK, et al. Acute miliary
tuberculosis of the skin: A case report and review of
literature. Indian J Dermatol 2002; 47:579.
10. Sangeeta AT, Sad R. Unusual cutaneous ulcers in miliary
tuberculosis. Indian J Dermatol Venereol Leprol 1993;
59:246.
262

11. Ramesh V, Misra RS, Jain RK. Secondary tuberculosis of
the skin. Clinical features and problems in laboratory
diagnosis. Int J Dermatol 1987; 26: 57881.
12. Hay RJ. Cutaneous infection with Mycobacterium
tuberculosis: How has this altered with the changing
epidemiology of tuberculosis? Curr Opin Infect Dis 2005;
18: 935.
13. Khandpur S, Nanda S, Reddy BS. An unusual episode of
lupus vulgaris masquerading as sporotrichosis. Inter J
of Derm 2001;40:336-9.
14. Hanumanthappa H. Segmental tuberculosis verrucosa
cutis. Indian J Dermatol Venereol Leprol 1994; 60:37.
15. Alawi F. Granulomatous diseases of the oral tissues:

Differential diagnosis and update. Dent Clin North Am
2005; 49: 203-21.
16. Lea O JC, Hodgson T, Scully C, et al. Orofacial granulomatosis. Aliment Pharmacol Ther 2004; 20: 101927.
17. Singhal A, Bhattacharya SN. Lichen scrofulosorum: A
prospective study of 39 patients. Int J Dermatol 2005; 44:
489-93.
18. Ramam M, Tejasvi T, Manchanda Y, et al. What is the
appropriate duration of a therapeutic trial in cutaneous
tuberculosis? Further observations. Indian J Dermatol
Venereol Leprol 2007;73:243-6.
19
Adolescent Tuberculosis:
Prelude to Future Infertility
Suneeta Mittal, JB Sharma, Sangeeta Sharma
Out of eight million people developing active

tuberculosis (TB) each year world-wide about two million
die.1 Developing countries contribute 95% of new TB
cases and deaths. There has been a rise in TB cases
throughout the world due to co-infection with human
immunodeficiency virus (HIV) infection, more liberal
immigration from high risk to low risk areas and
emergence of multidrug-resistant (MDR) and extreme
drug resistant (XDR) TB, which are caused by poor case
management. World Health Organization declared TB a
global emergency in 1993 and promoted Directly
Observed Treatment Short-course (DOTS) strategy. 2
Women including adolescent girls are more prone to
tuberculosis due to poor nutrition, lesser seeking of health
care. Their involvement in care of other pulmonary TB
cases at home makes them more vulnerable to acquire
the disease. A higher incidence of pulmonary
tuberculosis (PTB) in female children at all age groups
has been reported, where overall PTB was affecting 61.7%
girls as compared to 39.3% boys; being 56.2% and 43.8%,
54.5% and 45.5% and 71% and 29%, in <5 yrs, 6-10 years
and >10 years old girls and boys respectively3 The
extrapulmonary tuberculosis was also seen more
commonly in females than in males in cases of TB
lymphadenitis, skeletal TB, TB meningitis and abdominal
TB.4,5
Although pulmonary TB remains the commonest and
the most infectious type of TB, extrapulmonary TB (EPTB)
is becoming more prevalent especially in young women
throughout the world.6 Female Genital TB (FGTB), being
noninfectious has been neglected by health care
providers but is an important cause of significant
morbidity and short- and long-term sequelae for the
affected women.6,7
Epidemiology and Pathogenesis of Adolescent Female

Genital Tuberculosis (FGTB)
Tuberculosis is caused by Mycobacterium tuberculosis complex
(M. tuberculosis, M. bovis, M. africanum). Human disease in
immunocompetent individuals is mostly caused by M.
tuberculosis. Predisposing factors for TB are poverty,
overcrowding with improper ventilation, inadequate access
to health care, malnutrition, diabetes mellitus, smoking,
alcohol and drug abuse especially injectable drugs, end stage
renal disease and renal failure and hemodialysis patients and

coinfection with HIV.1-3,5,6 8 Genital TB almost always occurs
secondary to pulmonary (commonest) or extrapulmonary
TB like gastrointestinal tract, kidneys, skeletal system,
meninges and miliary TB.6-8 The site of involvement in
primary genital TB can be cervix or vulva.6-8 The spread of
TB from lungs and other sites is usually by hematogenous
or lymphatic route. Less commonly, direct contiguous
spread from nearby abdominal organs like intestines or
abdominal lymph nodes can cause genital TB. The various
genital organs affected by TB in order of frequency are
fallopian tubes (90-100% cases), endometrium (50-80%
cases) ovaries (20-30% cases), cervix (5-15%) and rarely
vagina and vulva (1% cases).6-8
The exact incidence of FGTB is not accurately known
as it is under reported due to asymptomatic cases and
lack of reliable confirmatory investigations. 6,7 The
reported incidence varies in different countries from 1%
in USA to 1 to 19% in various parts of India.7,8 Genital TB
was responsible for 0.02% and 1% of all gynecological
admissions in Sweden and India respectively.6-8. Genital
TB was found on autopsy in 1 to 12% of women dying
with pulmonary TB.8 Tripathy and Tripathy 9 performed
diagnostic laparoscopy on sputum positive pulmonary
TB cases and found bands of adhesions, tubercles and
hyperemia in 60% cases, intestinal adhesions in 24%,
tubercles on fallopian tubes in 22% women and adhesions
in pouch of Douglas in 11% women.
Tuberculosis of Fallopian Tubes

The fallopian tubes are involved in almost all women
with genital TB and the involvement is usually
bilateral.8 Depending upon whether it is hematogenous
spread or direct spread from intestines, disease may
start in the muscularis mucosa of tube or on the
peritoneal surface, but involvement of mucosa is always
there. In order of frequency, ampulla is the commonest
site to be involved followed by isthmus and interstitial
part of the tube (rare). The severity and the stage of the
disease affect the gross appearance of the tubes. Initially,
there is congestion of fallopian tubes, ovaries and
peritoneum of the pouch of Douglas with flimsy
adhesions and miliary tubercles on their surface. In later
264
stages, thick and vascular plastic adhesions are formed

between tubes and adjacent pelvic organs.10 In more
severe cases, there may be multiple adhesions in
peritoneal cavity with obliterated pouch of Douglas.10
Varying grades of Fitz-Hugh-Curtis syndrome (violin
string adhesions between liver and diaphragm or
anterior abdominal wall) is often seen in upto 48% cases
of female genital TB.11,12 Usually the characteristic
feature is presence of yellowish grey tubercles on the
peritoneal surface of the tubes and mesosalpinx with
fimbrial end of tube remaining open in half the cases.13,14
In advanced stage, tubes become dilated, retort
shaped and loculated. The leakage of infected material
from tube causes development of peritubal abscesses, TB
peritonitis and ascites. In chronic cases, a fibrotic stage
develops resulting into thickened, hard and beaded tubes
with calcification and tubal blockade. 13,14 In TB of
fallopian tubes, tubal damage is due to endosalpingits,
exosalpingitis or interstitial salpingitis. Tubo-ovarian
masses are due to peri-oophoritis, hydrosalpinx,
pyosalpinx or massive adhesion formation (Fig. 19.1). On
microscopic examination, appearances vary depending
upon the severity and activity of the disease.14 TB
granulomas with Langhans giant cells with chronic
inflammatory cells (lymphocytes) with or without
caseation may be observed. However, tubal mucosa may
be totally destroyed or there may be fusion of papillae in
the endosalpinx making women more prone to ectopic
pregnancy and infertility.13,14
Endometrial TB
8,13,14
Endometrium is involved in 50-80% cases.

Gross
endometrial appearance may be unremarkable due to
repeated menstruation minimizing the disease. Initially,
there is no macroscopic disease but caseation and
ulceration occurs later with progression of TB and in
advanced stages, there is distortion of cavity, varying
from slight distortion to complete obliteration due to
adhesions.14 Total destruction of endometrium may
result in Ashermans syndrome like picture resulting in
amenorrhoea secondary to end organ failure. We found
genital TB to be an important cause of Ashermans
syndrome in India leading to secondary amenorrhea and
infertility with poor prognosis for treatment. 15
Microscopically, TB granulomas with or without
caseation, epithelioid cells and Langhans cells may be
seen especially in the premenstrual phase and close to
the surface of endometrium. However, typical
granulomas may not always be seen due to repeated
shedding of endometrium at the time of menstruation.16
Some authors have suggested that even in absence of
typical granulomas, endometrial TB may be diagnosed
by presence of focal collection of lymphocytes with or
without presence of dilated glands and destruction of
epithelium.16
Fig. 19.1: Operative specimen of tuberculus tubo-ovarian mass

excised on laparotomy (For color version see Plate 6)
Ovarian TB
Isolated TB oophoritis is rare. It is more often seen as
part of TB peritonitis or with TB of other genital organs
(tubes or endometrium). Depending upon the severity
and stage of disease, there may be tubercles on the ovary,
adhesions, caseation, tubo-ovarian cyst or mass
formation. 6,8 Sometimes ovary may be completely
destroyed by the disease. Primary ovarian abscess
secondary to ovarian tuberculosis has been reported.17
Peritoneal TB
TB may involve pelvic or abdominal peritoneum due to
disseminated TB with tubercles all over the peritoneum,
intestines and omentum. This may cause ascites and
abdominal mass and may masquerade as ovarian cancer
as even CA-125 levels are raised in peritoneal TB. CT
scan and MRI also give similar picture and diagnosis may
be made only on laparotomy done for suspected ovarian
cancer. In such cases ascitic fluid tapping for biochemical
analysis and peritoneal biopsy may confirm the diagnosis
of TB and thus avoiding a needless laparotomy.18 On
laparotomy there may be vague masses without a line of
cleavage with adherent loops of bowel or omental masses
mimicking secondaries from ovarian cancer.
Tuberculosis of Cervix, Vagina and Vulva

Their involvement is rare and is usually secondary to
extension from endometrium but may rarely be primary
due to transmission from an infected partner. There may
be a hypertrophic lesion or a non healing ulcer on the
cervix, vulva or vagina mimicking malignancy. Biopsy
and histopathological examination is usually needed to
confirm the diagnosis and to rule out malignancy.19
Rarely TB of the vagina can cause involvement of
Bartholins glands with, vesicovaginal and rectovaginal
fistula formation.20
Chapter 19 Adolescent Tuberculosis: Prelude to Future Infertility
Adolescent Tuberculosis and Future Infertility

Adolescent pulmonary or extrapulmonary TB may
involve genital tract secondarily causing significant
genital morbidity like menstrual dysfunctions especially
hypomenorrhea, oligomenorrhea and amenorrhea.
Sharma observed a very high prevalence of menstrual
dysfunction in pulmonary and extrapulmonary TB in
adolescent girls. Out of 28 girls with tuberculosis only 4
were having normal periods while 24 (85.7%) were having
some menstrual dysfunction like hypomenorrhea,
oligomenorrhea or primary or secondary amenorrhea
which could be due to involvement of endometrium or toxic
effect of TB.21
Infertility is the commonest presentation of genital
TB with reported incidence of infertility being between
40 to 80%. Both primary and secondary infertility may
occur. The average incidence of genital TB in infertility
clinics world over is 5-10 % and varies from 0.69% in
Australia to 17.4% in India.8 The reason for infertility is
involvement of fallopian tubes (blocked and damaged
tubes), endometrium (nonreception and damaged
endometrium with Ashermans syndrome) and ovarian
damage in TB. 8,10,15 Past history of pulmonary or
extrapulmonary TB especially abdominal tuberculosis
can be elicited in many women of genital tuberculosis
presenting in reproductive age group for infertility or
abdominal or pelvic mass or pain. Hence, there is a real
need of diagnosing and treating adolescent pulmonary
or extrapulmonary TB (EPTB) on time to avoid
permanent damage to genital organs which is a cause of
significant long-term reproductive morbidity in women.
Also one needs to make out involvement of genital organs
in cases of pulmonary TB or EPTB especially abdominal
TB, as 6 months standard treatment given for pulmonary
TB may not be sufficient if genital organs are involved,
as until recently a 9 to 12 months ATT treatment was
routinely given for genital TB.
Clinical Presentation of Female Genital

TB in Adolescent Girl
The clinical presentation of genital TB depends upon site
of involvement of genital organs and is shown in Table
19.1. Up to 11% women with genital TB may be
asymptomatic.6,8 Though the age of presentation is
reproductive age group, adolescent girls can also present
with menstrual dysfunction or pelvic mass.
Clinical Signs
The various signs of FGTB depend on the site of
involvement of genital organs and are detailed in Table
19. 2.6,8
Table 19.1: Symptoms in genital TB

1. Asymptomatic (upto 11%)
2. General systemic symptoms
a. Fever with night sweats
b. Anorexia
c. Weight loss
d. Poor general condition
3. Menstrual dysfunction
a. Puberty menorrhagia
b. Menorrhagia
c. Postmenopausal bleeding
d. Oligomenorrhea
e. Hypomenorrhea
f. Amenorrhea (primary and secondary)
4. Infertility (primary and secondary) in married
adolescent girls.
5. Lump in abdomen
6. Abdominal pain
7. Chronic pelvic pain
8. Acute abdomen (in rupture of tubo-ovarian
abscess or flaring up of TB after coitus, exercise,
menstruation)
9. Abnormal vaginal discharge
10.Unusual symptoms
a. Ulcers in vagina or vulva
b. Labial swelling
c. Retention of urine
d. Urinary incontinence
e. Fecal incontinence
Table 19.2: Signs in genital TB
1. No physical sign (common)
2. Systemic examination
a. Fever
b. Lymphadenopathy (in lymph nodes TB)
c. Crackles and rales on chest examination (PTB)
d. Other systemic signs depending on site of
EPTB
3. Abdominal examination
a. Mass abdomen (vague or definite)
b. Ascites
c. Doughy feel of abdomen
4. Vaginal examination ( avoided in unmarried girls)/
Rectal examinations
a. Uterine enlargement (Pyometra)
b. Adnexal tenderness
c. Adnexal induration
d. Adnexal masses
e. Tubo-ovarian mass
f. Fullness and tenderness in pouch of Douglas
5. Unusual signs
a. Hypertrophic lesions in cervix, vagina or
vulva.
b. Ulcerative lesions in cervix, vagina or vulva.
c. Labial mass (Bartholin swelling)
d. Vesicovaginal fistula
e. Rectovaginal fistula
f. Tubovesical fistula
g. Tuboperitoneal fistula
h. Tubointestinal fistula
i. Uterocutaneous fistula
265
266
As genital TB may manifest in different ways with no
characteristic symptoms and signs, the differential diagnosis
varies depending upon the clinical presentation and is shown
in Table 19.3. 6,7,14
Diagnosis
Being a paucibacillary disease, demonstration of M.
tuberculosis is not possible in all the cases. A high index
of suspicion is required. The diagnostic dilemma arises
due to varied clinical presentation, diverse results on
imaging and endoscopy and availability of battery of
bacteriological, serological and histopathological tests
which are often required to get a collective evidence of
the diagnosis of genital TB.6,8 The diagnostic approach
used is family history of TB or history of antituberculous
therapy (ATT) in a close family member or a past history
of TB or ATT in the patient may show recrudescence of
TB in the genital region. Detailed general physical
examination for any lymphadenopathy, any evidence of
TB at any other site in body (bones, joints, skin, etc.), chest
examination (PTB), abdominal examination (abdominal
TB), examination of external genitalia (vulvar or vaginal
TB), speculum examination (cervical TB), bimanual
examination (endometrial or fallopian tube TB) aids in
the diagnosis of genital TB.
Not all tests are required for all cases of genital TB.
The tests will depend upon the site of TB and its clinical
presentation. The various tests done are as follows:
1. Complete Blood Count with erythrocyte sedimentation rate (ESR) may show anemia, leukocytosis
with lymphocytosis and raised ESR in TB. However,
these are nonspecific markers of TB and may be raised
in many other conditions.
2. Chest X-ray (posterior-anterior film) to exclude or
confirm coexisting pulmonary TB.
3. Mantoux (Tuberculin) Test: Its role in genital TB is
controversial as the positive reaction (more than 10
mm of induration) indicates that the person is or has
been infected with M. tuberculosis, but does not prove
that she is suffering from the disease. Moreover, with
severe TB and or advanced immuno-suppression,
tuberculin test may be negative in infected persons.
In women with laparoscopically diagnosed genital
TB, Mantoux test was found to have only limited
utility as it had a sensitivity of 55% and specificity of
80%.22,23 Women with positive tuberculin test may
be subjected to more recent interferon gamma
release assays immunological testing. But, it is
expensive and is not available everywhere.24
4. Serological Tests: They depend upon the 38 k Da
antigen of M. tuberculosis or monoclonal antibody
Table 19.3: Differential diagnosis (DD) of genital TB

The differential diagnosis will vary according to clinical
presentation.
1. For girls presenting with pain and adnexal mass
following possibilities should be considered.
a. Acute and chronic bacterial pelvic infections
b. Ectopic pregnancy
c. Ovarian malignancy
d. Endometriosis
e. Appendicitis
2. The differential diagnosis of granulomatous
lesions in the pelvis after laparotomy should
include the following possibility:
a. Crohns diseases
b. Actinomycosis
c. Leprosy
d. Granuloma inguinale venereum
e. Syphilis
f. Histoplasmosis
g. Brucellosis
h. Silicosis
i. Schistosomiasis
j. Filariasis
3. Ulcerative or hypertrophic lesions
a. Vulval cancer
b. Vaginal cancer
c. Cervical cancer
d. Bartholin abscess
e. Condyloma acuminate
f. Condyloma lata
g. Vulval and vaginal warts
h. Vaginal cyst
based sandwiched enzyme linked immunosorbent

assay (ELISA) and can detect only about half to twothirds of the HIV negative TB positive patients with
multibacillary extensive disease, but few in HIV
positive TB positive cases and paucibacillary patients
like genital TB.24,25 Serological tests are not sensitive
and specific enough to be of great value in diagnosis
of genital TB.
5. Menstrual blood for AFB, microscopy, culture or
polymerase chain reaction (PCR) sample:
Endometrial biopsy or aspiration in the
premenstrual phase is the best method for the
diagnosis of genital TB. However, most adolescent
girls, being unmarried, endometrial biopsy is
avoided in them. Menstrual blood should be
collected in a sterile container and should have
adequate blood or blood clots in it. One part of the
menstrual blood is sent in formalin solution for
histopathological testing for granuloma formation
(it rarely forms). The other part of the blood is sent
in normal saline for acid-fast bacilli (AFB) smear,
culture. Even polymerase chain reaction (PCR) can
be done on the same specimen.

The aspirate, menstrual blood (within 12 hours of
onset of menses in unmarried girls), secretions from
vaginal or cervix, peritoneal fluid or peritoneal or
tubal biopsy from tubercles are subjected to smear
examination for AFB and culture on Lowenstein
Jensen (LJ) medium taking upto 6 to 8 weeks to
provide results. The positive yield of LJ culture was
found to be 57% while guinea pig inoculation showed
positive results in only 11% cases in endometrial TB
cases.26 The latter is not done any more these days as
sophisticated culture media are available.
Sheth et al27 have highlighted the lack of diagnostic
value of guinea pig test for diagnosis of TB. While LJ
culture has a low sensitivity (30-35%), the radiometric
culture BACTEC 460 developed by Becton Dickinson
based on generation of radioactive carbon-dioxide
from substrate palmitic acid has a higher sensitivity
(80-90%) with quicker results (5-10 days) and is
particularly useful for drug susceptibility testing and
is particularly suited for genital TB and multidrug
resistant TB.28 Other rapid diagnostic methods are
Mycobacteria growth inhibitor tube (MGIT,
Radioactive detection system using fluorochromes),
MB/BACT (colorimetric detection of bacterial
growth), Septi-chek system. The growth can be
established by rapid methods based on lipid analysis
and specific gene probes, PCR-RFLP methods and
ribosomal RNA sequencing.28 However, all these tests
are expensive and are not routinely available and are
only performed in research settings or for culture
sensitivity in MDR-TB.
Polymerase Chain Reaction (PCR): It can be done
on menstrual blood or endometrial or peritoneal
biopsy. It is a rapid, sensitive and specific molecular
biological method for detecting mycobacterial DNA
in both PTB and EPTB samples from suspected TB
patients. PCR assays targeting various gene segments
including a 65 k Da protein encoding gene, the IS 6110
element and the mpt 64 gene.28 Bhanu et al29 studied
samples from endometrial aspirates, endometrial
biopsies and fluid from the pouch of Douglas from
25 women with infertility suspected to be suffering
from genital TB on laparoscopic findings for the
presence of mpt 64 gene of M. tuberculosis. Over all
PCR demonstrated M. tuberculosis DNA in 56% cases
compared to 1.6% smear positive and 3.2% culture
positive cases. PCR was positive in all women with
laparoscopic findings suggestive of TB, in 60 % of those
with probable diagnosis, in 33% of those with
incidental findings and even in one case with normal
laparoscopic findings. 30 They recommended a
combination of PCR with the other available
techniques for achieving sufficient sensitivity and
specificity for the diagnosis of FGTB. Microscopic
267
examination of AFB requires the presence of at least

10,000 organisms ml1 in the sample,29 culture is more
sensitive requiring as little as 100 organisms ml1
while PCR may be positive in presence of as low as
1-10 organisms ml.-1 However, PCR has its own share
of disadvantages; it can be false negative due to
contamination with heparin or high salt concentration
of specimen which may interfere with PCR results.
As it cant distinguish between live and killed bacilli,
there is a small risk of false positive results. Some
authors have advised that PCR should not be used
for rapid diagnosis of TB. Because of insufficient
reliability, results obtained by PCR should be used
neither to initiate nor to stop ATT.30 In authors
experience, false positivity of PCR is high as it can
pick up even single M. tuberculosis and may not be
able to differentiate between infection and disease as
most of Indian people may show positive PCR
without suffering from the disease. It is our policy
not to start ATT just on the basis of positive PCR
unless there is some other evidence of FGTB on
clinical examination or on investigations like presence
of tubercles or other stigmata of TB on laparoscopy.
6. Imaging Methods
a. Ultrasonography (USG): Being noninvasive and
with no radiation hazard, USG can be used in
diagnosis of FGTB and may show bilateral solid
adnexal masses with scattered small calcifications
with free fluid in pouch of Douglas.6,7,14 However,
in absence of pelvic masses, USG has a very limited
role in diagnosis of genital TB.22
b. Computerized axial tomography (CT scan): It is a
useful modality for pelvic and abdominal masses
especially when the lesion may resemble malignant
ovarian tumour. In TB, there is low density ascites,
multiple pelvic, abdominal, hepatic or splenic
lesions with or without lymphadenopathy
especially in young infertile women (Fig.19.2).6,7,14
In fallopian tube TB or ovarian TB, CT scan may
help in delineation of tubo-ovarian masses.22
c. Magnetic resonance imaging (MRI): It is used more
often in modern gynecology in presence of
abdominal and pelvic masses and has better
resolution than CT scan and may avoid the
necessity of laparotomy as the differential
diagnosis is usually from ovarian tumor. The
presences of hypodense masses with rim
enhancement abutting the pelvic walls are
suggestive of TB (Fig.19.3).22
7. Blood Markers in Genital TB: CA 125 is a useful
tumor marker for epithelial ovarian cancer in which
levels are markedly raised (normal levels < 35 U/ml).
However, it is a nonspecific marker and is also raised
in endometriosis and in genital TB. Usually, the levels
268
Fig. 19.2: CT scan finding in genital tuberculosis: CT scan image showing

multiple retroperitoneal lymphadenopathy with mesenteric lymph node
enlargement in patient with genital kochs
in genital TB are only moderately raised (usually

< 200 U/ml) and CA 125 is not a very reliable marker
for diagnosis of FGTB.
8. Endoscopy
Laparoscopy: A laparoscopy is the most reliable tool
to diagnose genital TB especially for tubal, ovarian
and peritoneal disease. 10 Morphological abnormalities of the fallopian tubes can be seen directly.
The various abnormalities of genital TB on
laparoscopy by different authors are shown in Table
19.4 and are as follows:10,31,36
1. In sub acute stage: There may be congestion, edema
and adhesions in pelvic organs with multiple fluid
filled pockets. There are miliary tubercles, white
yellow and opaque plaques over the fallopian
tubes and uterus.
2. In chronic stage: There may be following abnormalities:
a. Yellow small nodules on tubes (nodular
salpingitis).
b. Short and swollen tubes with agglutinated
fimbriae (patchy salpingitis) or beaded tubes
with multiple blocks (Fig. 19.4).
Fig. 19.3: MRI finding in genital tuberculosis: MRI film showing bilateral
tubo-ovarian masses her laparoscopic surgery revealed and 6 cm sized
tuboovarian abscess, filled with turbid pus
Fig. 19.4: Laparoscopy showing multiple tubal block with beaded

appearance in a proven case genital Koch (For color version see
Plate 6)
Table 19.4: Laparoscopic findings in genital

tuberculosis10, 31-36
S. No.
Laparoscopy finding
Percentage
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Normal finding
Tubercles on tubes/peritoneum
Caseation/granulomas
Beaded tubes
Blocked tubes
Adhesions
Hydrosalpinx
Tubo-ovarian Mass
Encysted effusions
Fitz Hugh Curtis Syndrome
0-10
30-100
20-100
32-48
45-50
47-100
32-100
15-54
2.5-60
30-45
Fig.19.5: Large hydrosalpinx (Laparoscopy finding in genital

tuberculosis) (For color version see Plate 6)
c. Unilateral or bilateral hydrosalpinx with retortshaped tubes due to agglutination of fimbriae

(Figs 19.4 and 19.5).
d. Pyosalpinx or caseosalpinx : The tube (usually
bilateral is distended with caseous material with
ovoid white yellow distension of ampulla with
poor vascularization

e. Adhesions: Various types of adhesions may be
present in genital TB covering genital organs
with or without omentum and intestines. The
adhesions are usually vascular and it has been
the authors experience that adhesiolysis in such
women may be associated with significant
bleeding and there is risk of injury to the bowel
in presence of dense adhesions. Even peritoneal
biopsy from the lesions can cause excessive
bleeding and needs careful hemostasis with
cautery.
Various other abnormalities on laparoscopy in genital
TB include adhesions, granuloma, plaques, exudates,
tubo-ovarian masses and pelvic congestion in upto 88.6%
cases.36 Mittal et al10 observed dilated, tortuous and
blocked fallopian tubes (32.5%), peritubal and
periovarian adhesions (45%), omental adhesions (45%)
and bowel adhesions (37.5%) with more than one type of
lesions in many women in 40 proven genital TB cases.36
Sharma et al11,12 also observed very high prevalence (48%)
of FitzHughCurtis syndrome on laparoscopy in FGTB
cases.
The final diagnosis is made from good history taking,
careful systemic and gynecological examination and
judicious use of diagnostic modalities like endometrial
biopsy in conjunction with imaging methods and
endoscopic visualization especially with laparoscopy.
Some authors have developed an algorithm for accurate
diagnosis of FGTB by combining history taking,
examination and investigations.36
TREATMENT
Medical Treatment
Treatment and care should take into account each
patients individual needs and preferences and she only
should make informed decision about her care and
treatment. Good communication between health care
professionals and patient is essential, supported by
evidence-based information and should be tailored to the
needs of the individual patient. Treatment, care and
information should be culturally appropriate and the care
takers and relatives should be involved in the care with
the consent of the patient. Multiple drug therapy in
adequate doses and for sufficient duration is the main
stay in the treatment of TB including FGTB. In olden days
before rifampicin, the antituberculous therapy (ATT) was
given for 18 to 24 months with significant side effects
and poor compliance. The development of short-term,
cost effective chemotherapy for TB was a major
achievement for clinical medicine. Short-course
chemotherapy for 6 to 9 months has been found to be
effective for medical treatment of FGTB.36,37
269
DOTS (Directly observed treatment short-course):

American Thoracic Society 38 and British Thoracic
Society and NICE (National Institute of Clinical
Excellence) Guidelines (2006)39 recommend that first
choice of treatment should be the standard
recommended regimen using a daily dosing schedule
using combination tablets and does not consider DOTS
necessary in management of most cases of TB in
developed countries who can adhere to treatment and
recommend DOTS only for street and shelter dwelling
homeless people with active TB or patients likely to have
poor adherence. DOTS was vociferously argued for by
WHO after declaring TB a global emergency in 1993.
Poor compliance with standard long-term treatment
regimens compounded by over crowding, poor living
conditions in low socioeconomic situations has fuelled
the epidemic of multidrug resistant (MDR-TB) in parts
of the world. To prevent MDR and for better results,
DOTS strategy has been proven to be cost effective
throughout the world. The patient is first categorized
to one of the treatment categories and is then given
treatment as per guidelines for national programs by
WHO (Table 19.5).40
Genital TB is classified under category 1 being
seriously ill extrapulmonary disease. As M. tuberculosis
divides very slowly (18 hours), thrice weekly treatment
is as effective as daily treatment. However, it must be
reiterated that intermittent treatment can only be given
under direct observation as even one dose should not be
missed to avoid development of MDR disease. After
diagnosis of FGTB is made and decision to start ATT by
the treating physician is made, she should be sent to a
DOTS center near her area of residence, as in India whole
country is now under DOTS strategy. To ensure quality
assured drugs in adequate doses a full 6 months course
pack box is booked for an individual patient in the DOTS
center. The woman is given a fixed drug combipack (FDC)
of isoniazid (INH), rifampicin, pyrazinamide and
ethambutol thrice a week for first 2 months (intensive
phase) under direct observation in front of a health worker
at DOTS center. Compliance is ensured by the DOTS
center providers of the center by reaching the homes of
any defaulters. In the continuation phase, she is given a
combination blister pack of isoniazid and rifampicin thrice
a week for next four months with at least one of the weekly
dosage administered under direct observation and
compliance is ensured by seeing empty blister packs
brought by the patient on each weekly visit.
Rarely FGTB cases can have relapse or failure
categorizing them into category II (Table 19.5). The
diagnosis of all such cases should be made by the
attending physician and should be supported by culture
or histological evidence of current active TB in these
cases. Such women are categorized as others in category
II and are given treatment accordingly which includes
270

Table 19.5: Category-wise treatment regimens for tuberculosis including FGTB21,40,41
TB diagnostic TB patients
category
TB treatment regimens
Initial phase
(daily or 3 times weekly)
Continuation phase
(daily or 3 times weekly)
2HRZE
4HR
New smear-positive patients.

New smear-negative pulmonary TB
with extensive parenchymal involvement.
Severe concomitant
HIV disease or severe forms of
extrapulmonary TB (FGTB included)
INH 600 mg
Rifampicin 450 (600 mg
if > 50 kg)
Pyrazinamide 1500 mg
Ethambutol 1200 mg for
2 months
Rifampicin 450 (600 mg

if > 50 kg) for 4 months
II
Previously treated sputum smearpositive pulmonary TB:

Relapse (FGTB included)
Treatment after default (FGTB
included)
Treatment failure (FGTB included)
2 HRZES/IHRZE
Dose RHZE as in
category I above.
Injection streptomycin
0.75 gm daily or thrice
weekly (DOTS) for 2
months followed by 1
month of RHZE
5 HRE
Dose
INH 600 mg
Rifampicin 450
(600 mg if >50 kg)
Ethambutol 1200 mg
for 5 months
III
New smear-negative pulmonary TB

(other than in Category 1). Less severe
form of extrapulmonary TB
2HRZ
4HR
IV
Chronic and MDR-TB cases (still

sputum-positive after supervised
re-treatment/or culture positive or
histopathologically proven FGTB).
Drug
Dose (mg)
if weight
< 45 kg
Dose (mg)
if weight
> 45 kg
Kanamycin (IM)
Ofloxacin (O)
Ethionamide (O)
Pyrazinamide (O)
Ethambutol (O)
Cycloserine (O)
Ethionamide (O)
Ethambutol (O)
500
600
500
1250
800
500
500
800
750
800
750
1500
1000
750
750
1000
IM = Intramuscular
O = Oral
two months intramuscular injections of streptomycin

thrice weekly along with other four drugs (RHZE) of
category I under direct supervision of DOTS center health
worker for first two months followed by four drugs
(RHZE) thrice a week for another month (Intensive
phase). The continuation phase is with three drugs
isoniazid (H), rifampicin (R) and ethambutol (E) thrice a
week for another 5 months with at least one of the three
times a week dose being administered under direct
observation.
Alternative Treatment (Non DOTS)

For the adolescent girls who want to buy their medicines,
daily treatment is given. Convenient market, combipacks
are available containing one capsule of rifampicin (450
mg), two tablets of pyrazinamide (750 mg each), one
tablet of ethambutol (800 mg) plus isoniazid 300 mg at a

very economic price which has to be taken every day for
two months, followed by combination of rifampicin (450
mg if body weight <50 kg, 600 mg if >50 kg) and isoniazid
300 mg, as a combipack to be taken daily at a very
economic price.
Monitoring
Most girls tolerate ATT safely. They should be counseled
about the importance of taking ATT regularly and
consumption of good and nutritious diet during ATT and
should report in case of any side effects of the drugs.
Liver function tests are no longer done regularly unless
there are symptoms of hepatic toxicity. Similarly
pyridoxine is not routinely prescribed with ATT unless

there are symptoms of peripheral neuropathy with
isoniazid. Rarely hepatitis can be caused by isoniazid,
rifampicin and pyrazinamide and optic neuritis by
ethambutol and auditory and vestibular toxicity by
streptomycin in which case the opinion of an expert
should be sought for restarting the ATT in a modified
form.
Surgical Treatment
The medical therapy especially the modern shortcourse chemotherapy consisting of rifampicin and
other drugs, is highly effective for the treatment of
FGTB with rare need of surgery. In spite of surgery,
full course of ATT has to be given. With modern shortcourse chemotherapy, need for surgery is very rare. Even
fistulas heal spontaneously on ATT.20 Similarly, MDR
disease needs treatment with DOTS Plus regimen rather
than surgery for best results. There are also much higher
chances of complications during surgery in women with
genital TB like increased perforation rates in
hysteroscopy, more bleeding during adhesiolysis on
laparoscopy and excessive hemorrhage and non
availability of surgical planes at time of laparotomy with
higher risks of injury to the bowel and other pelvic and
abdominal organs. In a case of abdominopelvic TB, bowel
loops may be matted together with no plane between
them and uterus and adnexa may be buried underneath
the plastic adhesions and bowel loops and are
inapproachable. Even trying to perform a diagnostic
laparoscopy or laparotomy in such cases can cause injury
to bowel necessitating a very difficult laparotomy and
resection of injured bowel. It is better to just take biopsies
from the representative areas and close the abdomen
without pelvic clearance in such girls opened for ovarian
tumor but found to be tubercular at laparotomy and give
them full ATT. However, limited surgery like drainage
of abscess from pelvis or tubo-ovarian abscesses,
pyosalpinx can be performed followed by ATT for better
results.
American Thracic Society5,6 only recommends surgery
(drainage) for residual large tubo -ovarian abscesses. In
authors experience women undergoing surgery
(Laparotomy, hysterectomy, laproscopic surgery, etc) with
pelvic and peritoneal TB bleed much more than other
women.
Future of TB Research
There has been a renewed interest in research in TB at
global level.41 New drugs are needed to treat TB because
the current drugs combinations have significant
disadvantages.42 New drugs, effective against strains that
are resistant to conventional drugs and requiring a
shorter treatment regimen are being developed.
271
HIGHLIGHTS
One of the important causes of infertility is
tuberculosis of the reproductive system. This
problem is preventable as its diagnosis in
adolescence is possible by doing ultrasound of
abdomen. The pulmonary tuberculosis with which
these children present is treated for 6 months under
RNTCP program of Government of India. However,
involvement of the reproductive organs would
require longer treatment. If these children (females)
are given only short-course therapy under RNTCP,
they need better follow-up and under the different
categories of treatment, these children would require
longer treatment, i.e. category II or may be I under
the program conditions.
The infertility can be a tell tale mark of pulmonary
tuberculosis in adolescence or earlier age period or
other types of TB. Now enough data is available to
show that almost 40% of children in the age groups
10-18 years of age have fulminant pulmonary
tuberculosis of the adult type, may be sputumpositive or negative but with massive changes in
chest X-ray. Probably this group (females) can be
screened by ultrasound abdomen to see the changes
in the uterus, fallopian tubes and ovaries for
tuberculosis necessitating, optimum (9 months)
antituberculosis chemotherapy to them.
The diagnostic work up of extrapulmonary TB in
adolescent girls as a routine also must have an
ultrasound of the abdomen for diagnosis of TB of
reproductive organs. Treated appropriately to
prevent this becoming a cause of infertility in future
in these girls.
REFERENCES
1. Dye C, Watt CJ, Bleed DM, et al. Evolution of tuberculosis
control and prospects for reducing tuberculosis
incidence, prevalence and deaths globally. JAMA
2005;293:2790-3.
2. WHO Report on the TB epidemic. TB a global emergency.
WHO/ TB/ 94.177. Geneva: World Health Organization,
1994.
3. Sharma S, Sarim R, Khalid UK, et al. The DOTS strategy
for treatment of pediatic pulmonary tuberculosis in South
Delhi, India. Int J Tuberc Lung Dis 2007;11:74-80.
for treatment of pediatric tuberculosis lymphadenitis. Int
J Tuberc (In Press).
for treatment of pediatric tuberculosis pleurisy. Int J
Tuberc (In Press).
6. Kumar S. Female genital tuberculosis. In: Sharma SK,
Mohan A (Eds). Tuberculosis, 2nd edn. Delhi: Jaypee
Medical Publishers (Pvt) Ltd., 2009;463-78.
272

7. Sharma JB. Female genital tuberculosis revisited. Obstet
Gynaecol Today 2007;12:61-3.
8. Schaefer G. Female genital tuberculosis. Clin Obstet
Gynaecol 1976;19:223-39.
9. Tripathy SN. Laparoscopic observations of pelvic organs in
pulmonary tuberculosis. Int J Gynecol Obstet 1990:32:
129-31.
10. Gupta N, Sharma JB, Mittal S, et al. Genital tuberculosis
in India infertility patients. Int J Gynecol Obstet
2007;97:135-8.
11. Sharma JB, Malhotra M, Arora R. Fitz-Hugh-Curtis
syndrome as a result of genital tuberculosis: A report of
three cases. Acta Obstet Gynecol Scand 2003;82:295-7.
12. Sharma JB, Roy KK, Mittal S, et al. High prevalence of
Fitz-Hugh-Curtis syndrome in female genital
tuberculosis. Int J Gynecol Obstet 2007;99(1):63-3. Epub
2007, Apr 24.
13. Schaefer G. Tuberculosis of the genital organs. Am J
Obstet Gynecol 1965:91:714-20.
14. Arora R, Rathore A. Female genital tract tuberculosis. In:
Arora VK, Arora R (Eds). Practical Approach to
Tuberculosis Management, 1st edition. Delhi: Jaypee,
2006;113-9.
15. Sharma JB, Pushparaj M, Mittal S, et al. Genital tuberculosis: An important cause of Ashermans syndrome in
India. Arch Obstet Gynecol Arch Gynecol Obstet
2008;277:37-41.
16. BazazMalik G, Maheshwari B, Lal N. Tuberculosis
endometritis: A clinicopathological study of 1000 cases.
Br J Obstet Gynaecol 1983:90:84-6.
17. Verma A, Mittal S, Kumar S. Primary Ovarian Abscess.
Int J Gynecol Obstet 2000;68,263-4.
18. Barutcu O, Erel HE, Saygili E, et al. Abdominopelvic
tuberculosis simulating disseminated ovarian carcinoma
with elevated CA-125 level: Report of two cases. Abdom
Imaging 2002;27:465-70.
19. Sharma JB, Malhotra M, Pundir P, et al. Cervical tuberculosis masquerading as cervical carcinoma: A rare case.
J Obstet Gynaecol Ind 2001:51:184.
20. Sharma JB, Sharma K, Sarin U. Tuberculosis: A rare cause
of rectovaginal fistula in a young girl. J Obstet Gynaecol
Ind 2001:51:176.
21. Sharma S. Menstrual dysfunction in non-genital
tuberculosis. Int J Gynecol Obstet 2002;79:245-7.
22. Sharma JB. Tuberculosis and Obstetric and Gynaecological Practice. In: Studd J, Tan SL, Chervenak FA (Eds).
Progress in Obstetrics and Gynaecology, Churchill Living
stone, Endinburgh 2008;18:395-427.
23. Raut VS, Mahashur A, Sheth SS. The Mantoux test in the
diagnosis of genital tuberculosis in women. Int J Gynecol
Obstet 2001;72:165-9.
24. Perkins MD. New diagnostic tools for tuberculosis. Int J
25. Rattan A, Gupta SK, Singh S, et al. Detection of antigens
of M. tuberculosis in patients of infertility by monoclonal
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
antibody based sandwiched enzyme linked immunosorbent assay (ELISA). Tuber Lung Dis 1993;74:200-3.
Seward PG, Mitchel RW. Guinea pig inoculation and
culture for mycobacteria in tuberculosis in infertile
women. A study of cost effectiveness. S Afr Med J
1985;67:126-9.
Sheth SS. Lack of diagnostic value of guinea pig test for
tuberculosis. Lancet 1991;337:124.
Katoch VM. Newer diagnostic techniques for
tuberculosis. Indian J Med Res 2004;120:418-28.
Bhanu NV, Singh UB, Chakraborty M, et al. Improved
diagnostic value of PCR in diagnosis of female genital
tuberculosis leading to infertility. J Med Microbiol
2005;54:927-31.
Grosset J, Mouton Y. Is PCR a useful tool for the diagnosis
of tuberculosis in 1995? Tubercl Lung Dis 1995;76:183-4.
Bhide AG, Parulekar SV, Bhattacharya MS. Genital
tuberculosis in females. J Obstet Gynaecol Ind
1987;37:576-8.
Parikh F R, Nadkarni S G, Kamat S A, et al. Genital
tuberculosis: A major pelvic factor causing infertility in
Indian women. Fertil Steril 1997;67:497-500.
Kumari C, Sinha S. Laparoscopic evaluation of tubal
factors in cases of infertility. J Obstet Gynaecol Ind
2000;50:67-70.
Tripathy SN, Tripathy SN. Infertility and pregnancy
outcome in female genital tuberculosis. Int J Gynecol
Obstet 2002;76:159-63.
Sharma JB, Roy KK, Mittal S, et al. Laparoscopic findings
in female genital tuberculosis. Arch Gynecol Obstet 2008
278:359-64.
Jindal UN. An algorithmic approach to female genital
tuberculosis causing infertility. Int J Tuberc Lung Dis
2006;10:1045-50.
Arora R, Rajaram P, Oumachigui A, et al. Prospective
analysis of short course chemotherapy in female genital
tuberculosis. Int J Gynecol Obstet 1992;38:311-4.
American Thoracic Society, Centers for Disease Control
and Prevention, Prevention/Infectious Diseases Society
of America. Controlling tuberculosis in united states. Am
J Respir Crit Care Med 2005; 172:1169-1227.
National Institute for Health and Clinical Excellence.
Tuberculosis. Clinical diagnosis and management of
tuberculosis, and measures for its prevention and control.
Clinical Guideline 33, London 2006. www.nice.org.uk/
CGO33.
World Health Organiza0tion. Treatment of tuberculosis.
Guidelines for national programmes (3rd edn), Geneva,
2003. WHO/CDS/TB/2003. 313.
TB India 2006. Revised National Tuberculosis Control
Programme (RNTCP) Status Report. Central TB Division,
Directorate General of Health Services. Ministry of Health
and Family Welfare. Nirman Bhavan, New Delhi, India.
http://www.tbcindia.org.
Hampton T. TB drug research picks up the pace. JAMA
2005;293:2705-7.
20
Endocrine Manifestations of
Tuberculosis
Anju Seth, Rajni Sharma
The clinical endocrine manifestations of tuberculosis may

be due to tubercular involvement of the particular
endocrine organ or the result of chronic illness due to
systemic disease (Table 20.1).
Table 20.1: Endocrine manifestations of tuberculosis

Organ
Endocrine manifestation
Chronic illness due to

systemic tuberculosis
Short stature
Failure to thrive
Delayed puberty
(hypogonadotrophic
hypogonadism)
Sick euthyroid syndrome
Syndrome of Inappropriate
Antidiuretic Hormone
(SIADH)
Cerebral salt wasting
Diabetes insipidus
Growth hormone
deficiency
Delayed puberty
(hypogonadotrophic
hypogonadism)
ACTH deficiency
Obesity (hypothalamic
hyperphagia)
ENDOCRINE EFFECTS OF TUBERCULOSIS DUE TO

CHRONIC SYSTEMIC DISEASE
Any prolonged systemic illness, including tuberculosis
can result in growth failure affecting the weight and
ultimately the height. Hence tuberculosis should be ruled
out in any child presenting with growth faltering or short
stature, especially if accompanied with a low weight for
height. History and examination generally provide clues
to the diagnosis.
Chronic illness due to systemic TB is also associated with
delayed puberty due to delayed activation of hypothalamopituitary-gonadal axis. In adult males serum testosterone
levels have been reported to fall due to impaired pulse
frequency of LH release. In a study of 50 adult patients with
active pulmonary TB, 72% males had hypogonadotrophic
hypogonadism.1
Sick euthyroid syndrome is often present in
tuberculosis with one study showing a 92% prevalence
in adult patients with pulmonary TB.1 It is characterized
by low free T3, normal or low free T4 state with low or
normal (rarely high) TSH. The exact mechamism
underlying this low thyroid hormone state is not known
but may represent reduced hypothalamic stimulation
leading to reduced stimulation of the thyroid gland. Low
thyroid hormone levels in protracted illness may
represent an adaptive or protective mechanism against a
hypercatabolic state.2
CNS TUBERCULOSIS
CNS tuberculosis due to tubercular meningitis
or tuberculomas results in varied endocrine manifestations apart from the neurological deficits.
Tubercular Meningitis (TBM)

Hyponatremia (serum Na + <135 mmol/l) is often
observed in TBM with a reported incidence of 65%3 in
some studies and prompts one to think of the most
CNS tuberculosis
Tubercular meningitis
Hydrocephalus
Suprasellar/sellar
tuberculoma
Adrenal tuberculosis
Thyroid tuberculosis
* Pancreatic tuberculosis
Genitourinary
Testicular
Ovarian
Precocious puberty
Hypopituitarism
Adrenal insufficiency
Goiter
Thyroid nodule
Hyperthyroidism
Infertility
Infertility
Primary amenorrhea
Secondary amenorrhea
Menstrual abnormalities
* Diagnosis by examination of pathological specimen
common cause, i.e. syndrome of inappropriate

antidiuretic hormone (SIADH).3,4 Nevertheless, it is
important to rule out other causes of hyponatremia such
as cerebral salt wasting or adrenal insufficiency because
restriction of fluids (to treat a wrong diagnosis of SIADH)
may prove fatal in these cases. 5 Mechanisms
for development of SIADH consist of meningeal
inflammation resulting in leakage of ADH from the
274
posterior pituitary, excretion of ADH from granulomas,

and brain edema with raised intracranial tension. SIADH
is essentially a diagnosis of exclusion and one has to rule
out other conditions that may lead to hyponatremia like
renal, adrenal and thyroid insufficiency, congestive heart
failure, nephrotic state, cirrhosis, diuretric use or
dehydration. The urine osmolarity is high, usually
greater than 100 mosm/l and urine Na+ is greater than
25 mmol/l. The treatment consists of restricting
intravenous fluids to two-third maintenance with careful
avoidance of hypovolemia.
Cerebral salt wasting syndrome (CSWS) has been
reported with a variety of cerebral lesions including
TBM.6,7 It is defined as renal loss of sodium due to
intracranial disease leading to hyponatremia, natriuresis,
dehydration in response to volume and salt replacement.
Increased serum brain natriuretric peptide levels is the
most likely of CSWS. In CSWS, the patient is volume
depleted with postural hypotension whereas in SIADH
the patient is euvolemic. Serum osmolarity is decreased
in both but urine output is increased and urine sodium
is extremely higher in CSWS. Serum uric acid and urea
are normal or raised in CSWS but decreased in SIADH.5
Treatment of CSWS consists of aggressive volume and
salt replacement with isotonic fluids. Acute hyponatremia
that has developed rapidly at the rate of >0.5 mmol/l/hour
(due to either CSWS or SIADH) is treated aggressively as
death may result from cerebral edema and herniation.
Unlike chronic hyponatremia, rapid treatment is associated
with marked neurological improvement and less
danger of cerebral pontine myelinolysis. The mineralocorticoid fludrocortisone helps in distal tubular sodium
resorption and may be helpful to reverse the sodium
wasting in CSWS. It is used in a dose of 0.2 to 0.4 mg per
day with careful watch for side effects like hypertension
and hypokalemia.
Sequelae of TBM
Long-term sequelae of TBM in the form of granulation
tissue or calcification may affect the hypothalamicpituitary axis resulting in various endocrine manifestations years later. Involvement of the posterior
pituitary leads to central diabetes insipidus.8,9
Deficiency of one or more anterior pituitary hormones
may be due to direct involvement of the pituitary or of
its stimulatory input from the hypothalamus. In a
retrospective study of 49 patients with TBM in childhood,
10 had hypothalamic-pituitary dysfunction on investigation in follow-up.10 Growth hormone deficiency was
most commonly observed followed by gonadotropin
deficiency. Other abnormalities consisted of hyperprolactinemia and ACTH deficiency.
The classical manifestation of hypothalamic lesions

is Frohlich syndrome consisting of short stature, obesity,
hypogonadism and delayed puberty.11 Hypothalamic
lesions may also result in isolated obesity due to hyperphagia. In contrast, lesions of the posterior hypothalamus
which usually inhibits pituitary gonadotrophin release,
can result in central precocious puberty. This may be due
to direct involvement of the hypothalamus or due to
pressure effect of hydrocephalus.
Pituitary Tuberculoma
Tuberculoma of the sellar and parasellar region is extremely
rare and presents as a mass lesion with panhypopituitarism,
headache, raised intracranial pressure and vision loss. The
diagnosis is often made by biopsy of the lesion which reveals
a granulomatous inflammatory lesion with epitheloid and
Langhans giant cells with central caseous necrosis consistent
with the diagnosis of tuberculosis. Demonstration of AFB
on staining or after culture is rare from these lesions. In a
case series of 18 patients with pituitary tuberculoma, 6 were
under 18 years of age with a female preponderance.12 Only
one third of the patients had a past history of tuberculosis
or coexistent TB elsewhere.12 Pituitary tuberculomas are
seen on computed tomography as an intrasellar enhancing
mass indistinguishable from pituitary adenoma. MRI may
reveal thickening of the pituitary stalk and dura at the skull
base. Extension of the lesion to the sphenoid sinus and
involvement of the clivus are other supportive evidence
for the diagnosis of tuberculosis. A preoperative diagnosis
of pituitary tuberculoma may do away with the need of
surgery unless required for neurological or vision loss. PCR
for M. tuberculosis DNA done on the surgical specimen can
also aid in the diagnosis.
ADRENAL TUBERCULOSIS
Thomas Addison first described autopsy findings in 6
patients with adrenal tuberculosis in 1855 and it
continues to be the most important cause of adrenal
insufficiency in the developing world. In a study from
India, tuberculous etiology was ascribed to 47% of adult
patients of Addisons disease.13 In another study from
China, review of autopsy findings in adult patients with
tuberculosis revealed that out of 871 cases of tuberculosis,
adrenal involvement was found in 52 (6%).14 Among
those with adrenal tuberculosis, isolated adrenal gland
involvement was seen in 25%.
Adrenal insufficiency manifests with weakness,
weight loss and hypotension. Progressive hyperpigmentation may be noticed by the patient. Laboratory
findings consist of hyponatremia, hyperkalemia and
hypoglycemia. Low morning serum cortisol levels and
failure of cortisol to rise with ACTH (Synacthen) injection
is diagnostic.
Chapter 20 Endocrine Manifestations of Tuberculosis

Early in the course of adrenal TB, CT findings consist
of unilaterally or bilaterally enlarged adrenals. The normal
contor of the gland is distorted. Central caseous necrosis
appears as a hypodense area.15 On contrast administration
there is a heterogenous uptake by the mass with peripheral
rim enhancement. Free fluid may be present in the
abdomen. 16 In addition to tuberculosis, adrenal
enlargement may rarely be due to other causes like fungal
infection, hemorrhage or malignancy. Once chronic
tubercular sequelae set in, CT scan reveals atrophic or
normal size adrenals with calcification.15 Extra-adrenal
tuberculosis is present in up-to half the patients of
tubercular adrenal insufficiency which may aid in the
diagnosis. Therapeutic trial of antitubercular drugs, CT
guided aspiration biopsy and follow-up CT scans help to
confirm the diagnosis of tuberculous infection.
Acute adrenal crisis should be managed with
intravenous fluids and parenteral hydrocortisone 100
mg/m2 is divided doses. Maintenance therapy is with
hydrocortisone at 10 mg/m2 and mineralocorticoid
fludrocortisone to augment blood pressure. Overall, the
prognosis for adrenal tuberculosis is good with low
mortality provided regular medical follow-up is ensured.
THYROID TUBERCULOSIS
Thyroid tuberculosis is a rare condition even in countries
with high prevalence of tuberculosis. In one case series
from India, out of 353 thyroidectomies performed for an
enlarged thyroid, only 3 specimens showed evidence of
thyroid TB on histopathology.17 This may be because the
thyroid gland is said to be relatively resistant to tubercular
invasion due the lack of reticuloendothelial cells.
There are two types of tuberculosis of the thyroidmiliary and caseating. The miliary type is commoner, and
is seen at autopsy in association with generalized miliary
TB. The caseating type can present with goiter, isolated
nodule of the thyroid or thyrotoxicosis.18,19 The lesion
may grow rapidly and cause pain and pressure
symptoms like dyspnea, dysphagia and dysphonia. A
slow inflammatory process causing caseation necrosis
may also result in abscess formation. The diagnosis is
made by fine needle aspiration cytology of the thyroid.19
If the diagnosis is not made earlier, the patient may be
operated for a suspicion of thyroid malignancy and the
postoperative specimen may give the diagnosis.
PANCREATIC TUBERCULOSIS
Abdominal infection with tuberculosis commonly affects
the spleen, liver and ileocecal region. Pancreatic
tuberculosis is an extremely rare disease even in regions
with high prevalence of tuberculosis. In a case series of
300 patients of abdominal tuberculosis, not a single case
275
of pancreatic tuberculosis was reported.20 It is postulated

that mycobacterium may be destroyed by the pancreatic
enzymes making the pancreas relatively resistant to
tubercular infection. Three forms of mycobacterial
infection of the pancreas have been described (1)
Generalized (miliary) TB due to M. tuberculosis (2) Spread
to the pancreas from celiac and other retroperitoneal
nodes due to M. bovis infection (3) Localized pancreatic
TB due to M. tuberculosis secondary to primary tubercular
infection of the intestinal tract. The presenting symptoms
of pancreatic TB include abdominal pain, abdominal
mass, anorexia, weight loss, fever, back pain and
jaundice. Ultrasound examination shows a heterogenously echoing mass in the head of the pancreas. CT
scan shows a pancreatic mass with heterogenous opacity
with or without calcification of the pancreas and
peripancreatic nodes. Less than half the patients have
past history of tuberculosis or evidence of pulmonary
tuberculosis on chest X-ray. The diagnosis is made by
the pathological specimen obtained during laparotomy/
laparoscopy or ultrasound guided fine needle aspiration
which shows caseating granulomas with or without
organisms on acid fast staining. 21,22 DNA of M.
tuberculosis may be demonstrated by PCR reaction or on
culture. It may often be difficult to diagnose and
distinguish pancreatic TB from a pancreatic tumor. A
preoperative diagnosis if made, may obviate the need
for surgery since the disease is effectively treated with
antitubercular drugs.
GENITAL TUBERCULOSIS
Female Genital Tuberculosis
Female genital tuberculosis is common in countries with
high incidence of tuberculosis. Genital tuberculosis most
often involves the fallopian tubes (95-100%), uterine
endometrium (50-60%) or ovaries(20-30%). This results in
tubal dilatation and block, endometrial synechiae, peritubal,
periovarian, omental and bowel adhesions.23 In 92% of cases
genital tuberculosis is secondary to a focus in the lungs,
lymph nodes, urinary tract, bones or joints. The clinical
manifestations range from primary or secondary infertility
(45-55%), pelvic pain (50%), menstrual abnormalities (20%)23
to primary or secondary amenorrhea. Tubercular etiology
was implicated in 6.3% of cases of primary amenorrhea seen
at a tertiary care hospital24and 5 to 10% of infertility cases.23
As many as a quarter of patients may have a past history of
tuberculosis. Diagnosis is made by a combination of
ultrasonography, hysterosalpingography, laparascopic
findings and pathology. Demonstration of AFB by stain/
culture or M. tuberculosis DNA. PCR on endometrial
histopathologic studies also aids in diagnosis. 25 The
treatment consists of antitubercular therapy (ATT). Surgery,
if required, should be undertaken only on completion of
ATT.
276
Male Genital Tuberculosis26

The male genital organs most commonly affected by
tuberculosis are the epididymis and prostate; the testes
are affected less commonly. The modes of infection
include descending infection from the kidneys, direct
invasion from the surrounding tissues and
hematogenous spread. The infection may mimic tumors,
cysts and other infections of the genital tract.
HIGHLIGHTS
Systemic tuberculosis can result in various endocrine
manifestations as a result of chronic disease and
should be ruled out in all cases of growth faltering
and delayed puberty.
Isolated endocrine tuberculosis is infrequently seen,
but is a great mimicker of other diseases. It can
manifest in a wide variety of ways and should be
considered in the differential diagnosis especially in
countries with high prevalence of tuberculosis.
Endocrine manifestations are not uncommon in the
course of tuberculous meningitis. The clinician
should be alert to the subsequent development of
hypopituitarism in these patients.
REFERENCES
1. Post FA, Soule G, Willcox PA, et al. The spectrum of
endocrine dysfunction in active pulmonary tuberculosis.
Clin Endocrin 1994;40:367-71.
2. Greet Van den Berghe. Endocrine consequences of
systemic disease: Critical illness. In Brooks Clinical
Pediatric Endocrinology Blackwell Publishing, 5th
edition, 2007,492-504.
3. Singh BS, Patwari AK, Deb M. Serum sodium and
osmolal changes in tuberculous meningitis. Indian
Pediatr.1994;31:1345-50.
4. Cotton MF, Donald PR, Schoeman JF, et al. Plasma
arginine vasopressin and the syndrome of inappropriate
antidiuretic hormone secretion in tuberculous meningitis.
5. MG Zeier. Hyponatremia syndrome in a patient with
tuberculosis always the adrenals? Nephrol Dial
Transplant 2008;23:393-5.
6. Nagotkar L, Shanbag P, Dasarwar N. Cerebral salt
wasting syndrome following neurosurgical intervention
in tuberculous meningitis. IInd Pediatr 2007;45:598-605.
7. Huang SM, Chen CC, Chiu PC, et al. Tuberculous
meningitis complicated with hydrocephalus and cerebral
salt wasting in a three year old boy. Pediatr Infect Dis J
2004;23:884-6.
8. Haslem RHA, Winternitz WW, Howieson J. Selective

hypopituitarism following tuberculous meningitis. Am
J Dis Child 1969;118:903-8.
9. Shenoi A, Deshpande SA, Marwaha RK. Diabetes
insipidus and growth hormone deficiency following
tubercular meningitis. Ind Pediatr 1990;27:624-6.
10. Lam KSL, Sham MMK, Tam SCF, et al. Hypopitituitarism
after tuberculous meningitis in childhood. Ann Intern
Med 1993;118:701-6.
11. Asherson RA, et al. Abnormalities of development
associated with hypothalamic calcification after tuberculosis
meningitis. Br Med J 1965; 2:839-43.
12. Sharma MC, et al. Intrasellar tuberculoma an enigmatic
pituitary infection: a series of 18 cases. Clin Neurology
Neurosurgery 2000;102: 72-7.
13. Agarwal G, Bhatia E, Pandey R, et al. Clinical profile and
prognosis of Addisonss disease in India. Natl Med J India
2001;14:23-5.
14. Lam KY, Lo CY. A critical examination of adrenal
tuberculosis and a 28-year autopsy experience of active
tuberculosis. Clin Endocrinol 2001;54:633-9.
15. Buxi TBS, Vohra RB, Sujatha, et al. CT in adrenal
enlargement due to tuberculosis: a review of literature
with five new cases. Clin Imaging 1992;16:102-8.
16. MM Patnaik, Deshpande AK. Diagnosis Addisons
disease secondary to tuberculosis of the adrenal glands.
Clin Med Research 2008;6:1-29.
17. K Sivanagaman, G Suvarnakumari, CA Aruna, et al.
Tuberculosis of thyroid gland. Ind J Tub 1980;27:33-4.
18. Elmalki HO, Mohsini R, et al. Thyroid tuberculosis:
Diagnosis and treatment. Chemotherapy 2006;52:46-9.
19. Bulbuloglu E, Ciralik H, Okur E, et al. Tuberculosis of the
thyroid gland: Review of literature. World Journal of
Surgery 2006; 30:149-55.
20. Bhansali S. Abdominal tuberculosis. Experience with
300 cases. Am J Gastroenter 1977;67:323-7.
21. Saluja SS, Ray S, Pal S, et al. Hepatobiliary and pancreatic
tuberculosis: A two decade experience. BMC Surg 2007;
24:7-10.
22. Woodfield JC, Windsor JA, Godfrey CC, et al. Diagnosis
and Management of isolated pancreatic tuberculosis:
Recent experience and review of literature. ANZ J Surg
2004;74:368-71.
23. Chowdury NN. Overview of tuberculosis of the female
genital tract. J Indian Med Assoc 1996;94:345-6.
24. Kumar A, Mittal S. Primary amenorrhea: analysis of 48
cases. J Indian Med Assoc 1998;96:119-20.
25. Gupta N, Sharma JB, Mittal S, et al. Genital tuberculosis
in Indian infertility patients. Int J Gynaecol Obstet
2007;97:135-8.
26. Gorse GJ, Belshe RB. Male genital tuberculosis: A review
of literature with instructive case reports. Rev Infect Dis
1985;7:511-24.
21
Vimlesh Seth
INTRODUCTION
Congenital tuberculosis is rare, inspite of tuberculosis
being a common infection with around 300 cases reported
worldwide till 1989.1 With the increase in the number of
multidrug resistant tuberculosis and human immunodeficiency virus (HIV) cases, there is resurgence of
tuberculosis in women of reproductive age and in their
off spring. 58 more cases were reviewed by Abughali et
al1a in 1994. From 2001 to December 2005, 18 more cases
have been reported. Even though tuberculosis among
pregnant women is not uncommon, documented cases of
congenital TB are still rare. It is because placenta forms a
protective barrier against the infection of the fetus by the
tuberculous organisms. It is assumed that infection has
been acquired in utero, because of (i) the age of the infant,
(ii) absence of any known contact with an open case of TB
and (iii) generalized dissemination of the disease. The risk
of TB in pregnancy has increased owing to recent changes
in epidemiology of the disease which has led to an
increased risk of congenital TB. Although a rare disease,
congenital TB should be distinguished from the more
frequent neonatal TB, in which the infant is infected after
birth by an adult suffering from the disease. Congenital
TB may occur as a result of maternal TB when it involves
the genital tract or placenta.
In the decade spanning from 1995 to 2005 there have been
a number of case reports with rare manifestations of this
disease2-4 Chotpitaysunondh and Sangtawesin5 have done
a retrospective analysis of nine patients in Thailand. They
have described in detail the clinical features and
investigations for confirming the diagnosis. Since 2005,
more than 20 cases have been described.6-21 Recent
reports6,8,9 have described congenital tuberculosis as case
reports in preterm neonates born after in vitro fertilization.
These mothers had tuberculosis during pregnancy.
Mouchet et al 22 have investigated the risk of
nosocomial transmission of tuberculosis among infants,
family members and health care workers (HCWs) caring
for a congenitally infected infant. In their prospective
study they used the conversion of tuberculin skin test
(TST), X-ray chest for contact survey for diagnosis. Their
findings are briefly summarized below:
Category
Infants
HCWs
Visitors
Number
97
139
180
TST conversion %
40
19
Nil
All infants and health care workers who had

conversion of TST were given isoniazid prophylaxis.
Given the nonspecific nature of presenting signs and
symptoms (because of lack of host response) and the fatal
outcome in the absence of early therapy, the importance
of early diagnosis is underscored and treatment often
delayed. Most important factor for early diagnosis is the
presence of tuberculosis in the mother. It is still
documented in the literature as case reports only.23-26
However, with increase in cases of multidrug resistant
tuberculosis and HIV there is resurgence of tuberculosis
in women of childbearing age and in children born to
them.27-29 Balaka et al30 have reported from Africa that
despite the rising prevalence of tuberculosis due in part
to HIV pandemic in Africa, there have been few reports
describing neonatal or congenital tuberculosis. In a
prospective study, they investigated all neonates admitted
to the teaching hospital for diagnosis of tuberculosis
having symptoms compatible with tuberculosis. The
clinical profile of tuberculosis in the newborn was
correlated with that of the mother with or without HIV
infection, perinatal tuberculosis was diagnosed in 13 of 79
(about 16%) newborns investigated including 8 whose
mothers were co-infected by HIV and tuberculosis during
a two year study-period. Seven cases (almost 8%) were
classified as congenital tuberculosis.
Diagnosis of maternal HIV and tuberculosis infection
was never made prior to the newborns admission to the
ward. Four newborns and two mothers died within three
months after child birth.
Recently in India31 from a private hospital in Delhi
where comparatively patients with better socioeconomic
status are treated, a case of congenital tuberculosis was
reported diagnosed by liver biopsy in an eight week old
infant presenting with acute abdomen.
PATHOPHYSIOLOGY
Mode of Infection
Congenital tuberculosis is mostly described to be acquired
by two mechanisms: (i) Transplacentally gaining
hematogenous spread through the umbilical vein from an
infected placenta to fetal liver and lungs and (ii) By
aspiration and swallowing of infected amniotic material either
278
in utero or during passage through the birth canal leading

to primary infection in the lungs or gastrointestinal tract.
However, infection can also be acquired early in life by
inhalation or ingestion of infected droplet from the
mother or an open case among the family, friends or
caretakers. Often it is difficult to differentiate in a given
neonate whether the infection is truly congenital or
acquired postnatally. Some authors would consider the
distinction between the two as primarily epidemiological
since the modes of presentation, treatment and prognosis
do not differ significantly.1,24 Transplacental infection
usually occurs late in the pregnancy when tubercle bacilli
reach the fetal liver via umbilical vein leading to the
development of the primary focus with involvement of
periportal lymph nodes. The bacilli may pass through
the liver and hematogenously spread to lung, brain and
adrenals forming multiple foci. However, only the
primary complex in the liver is the sine qua non of
congenital tuberculosis whereas all other lesions may be
acquired either congenitally or postnatally.1
Infection by the ingestion or inhalation of amniotic
fluid may occur when a caseous lesion the placenta
ruptures directly into the amniotic cavity. This usually
leads to multiple primary foci in the lungs or gut and
middle ear with enlarged bronchial or mesenteric lymph
nodes or both. Middle ear involvement leading to
multiple perforations or total destruction of the tympanic
membrane and otorrhea described in some reports is not
surprising because eustachian tube in newborn permit
ready access to pharyngeal fluids thus seeding the
tubercle bacilli.32 Involvement of the liver and parotid
gland are rare.33
Condition of the Mother

In developing countries in spite of rampant tuberculosis,
the cases of congenital tuberculosis are reported rarely.
It is because there are two ways in which the mother
suffers from tuberculosis during pregnancy:
i. There is disseminated infection; either with rapidly
progressive disease and hematog-enous spread with
clinical illness.
ii. Recent primary infection and subclinical dissemination.
In the first category miliary lesions can usually be
found in the placenta whereas in the 2nd category these
are absent. In the European literature, the incidence of
tuberculosis in the infants of tuberculous women is very
low because the caseous lesions are found in the placenta
and the infant usually escapes because the bacilli remain
localized in the placenta and do not enter the infants
blood stream. From this background knowledge it is
worth doing histopathological examination of placenta
looking for caseous granuloma and acid fast bacilli in
the developing countries.
CLINICAL FEATURES
The age at the time of presentation has been noted to be
few hours after birth to beyond neonatal period. The
onset of illness in congenital tuberculosis may be hard to
define given that many of the signs and symptoms are
nonspecific as illustrated in the earlier description.
Diagnosis in our setting should be suspected in (i) any
neonate with persistent pneumonia or fever and
hepatomegaly wherein the usual infective etiologies have
been ruled out or (ii) in an infant with nonspecific
symptoms born to a mother suffering from tuberculosis.18
A number of case reports,34-36 reviews and guidelines for
diagnosis and management of congenital tuberculosis
have been given. Miller37 way back in eighties explained
the mode of transmission of tuberculosis and emphasized
the role of placenta as a barrier to the development of
congenital tuberculosis. From this, it may be derived that
in spite of resurgence of tuberculosis due to associated
HIV/AIDS, and multidrug resistant tuberculosis there
may not be a very large increase in the incidence of
congenital tuberculosis in normal newborns with good
birth weight. However, the clinical suspicion should be
strong and a newborn with pneumonia not responding
to usual effective antibiotic therapy, with significant
hepatomegaly, can be a candidate of congenital
tuberculosis. In Cantwells review38 of the 29 cases
published since 1980 revealed that median age at
presentation was 24 days (range 1 to 84).
Pillet et al39 described three cases, one presenting at
the age of 45 days with bilateral bronchopneumonia, the
second presented at the age of 22 days with respiratory
distress, icterus and hepatosplenomegaly. Both these
babies in spite of starting isoniazid, rifampicin and
pyrazinamide died due to multivisceral failure. In the
second child the postmortem liver biopsy confirmed the
diagnosis of tuberculosis. The third child developed
jaundice on day 4. He had opacities at the top of the right
lung. This baby was given isoniazid, rifampicin and
pyrazinamide as well. He also had hepatomegaly.
Breastfeeding was stopped and the neonate had poor
weight gain upto 25 days but later improved. Thus it is
emphasized that the frequency of congenital tuberculosis
is probably underestimated. Its early diagnosis is essential
but often difficult as the early recognition of initial
manifestation is often delayed. Hence, it is recommended
that improved screening of women at risk in the antenatal
period can result in early diagnosis in the mother and
the same in the newborn.
Another case report has been cited in French literature
by Pham et al40 in 1998. It has been highlighted by them
that congenital tuberculosis is an uncommon but
probably underestimated entity. All cases occurring in
Chapter 21 Congenital Tuberculosis

developing countries are not published. The diagnosis
of congenital tuberculosis is different from postnatal
tuberculosis. Recently defined criteria are bacteriologically proven tuberculosis in a newborn with at least
one of the following:
i. Specific hepatic granulomatosus.
ii. Tuberculosis infection of the placenta or maternal
genital tract.
iii. Exclusion of possible postnatal transmission.
The most common presenting symptoms are
hepatosplenomegaly, respiratory distress, fever, growth
failure and lymphadenopathy. Besides, the other features
described are lethargy, irritability, seizures, meningitis,
ear discharge and jaundice.6-21, 28- 41 Berk and Sylvester2
have described a case of congenital tuberculosis
presenting as progressive liver dysfunction, in the
absence of respiratory symptoms. Several uncommon
features were present, including petechiae, cutaneous
lesions, ascites and peritoneal fluid positive for AFB.
Another case of congenital tuberculosis has been
described by Centers for Disease Control and Prevention
(CDC).4 This child with the usual presentation of
respiratory distress and sepsis had a mother who was
having cerebral tuberculosis. In this rare disease maternal
tuberculosis was associated. There are reports of cases
of congenital tuberculosis presenting as sepsis syndrome
and septic shock.42,43 Mortality resulting from congenital
tuberculosis is very high. In most reviews it is about 50%.
Delay in diagnosis is a significant cause of mortality. In
Hagemans review, 9 of the 12 patients who died were
diagnosed at autopsy whereas of the 17 patients
diagnosed antemortem 14 survived.35 Verma et al44 have
also emphasized that congenital tuberculosis is an under
diagnosed entity. It has been highlighted by them that
diagnosis should be suspected early to have a favorable
outcome. Table 21.1 gives the signs and symptoms which
should alert the pediatrician to keep this diagnosis as
not so rare an entity as thought until now.
Fatality rate was 33.3% with no sequel in the
survivors. Hence, it is suggested that newborn with
pneumonia unresponsive to aggressive appropriate
antibiotics usually lumped as sepsis should be
aggressively investigated for congenital tuberculosis.44
The pulmonary involvement can be so severe though
rarely3 that the neonate may require extracorporeal
membrane oxygenation.
DIAGNOSTIC CRITERIA FOR CONGENITAL

TUBERCULOSIS
In 1935, Beitzke34 presented the following criteria for the
diagnosis of congenital infection:
i. Bacteriological proof of tuberculosis by isolation of
M. tuberculosis from the infant.
279
Table 21.1: Signs and symptoms noted in congenital

tuberculosis
Main findings
Respiratory distress
Fever
Hepatic and/ or splenic enlargement
Poor feeding
Lethargy and/or irritability
Lymphadenopathy
Other findings
Abdominal distension
Failure to thrive
Skin lesions
Obstructive jaundice due to glands in porta hepatis
Seizures
Meningitis is uncommon
In a small percentage of cases, otitis media with or
without mastoditis is the first sign of congenital TB.
ii. Primary complex in liver.

iii. If primary complex is lacking in the liver, then tuberculosis can be considered to be congenital only if:
a. Tuberculous lesions are present in a fetus or a few
days old newborn.
b. Or in an older infant, extrauterine infection can be
excluded with certainty.
Beitzkes criteria are fully met by many of the reported
cases of congenital tuberculosis. These criteria are less
applicable in the present day setting because of the higher
survival rates with proper chemotherapy. This is due to
the difficulty in documentation of hepatic primary
complex. This, as it involved an invasive procedure of liver
biopsy.38, 39 In the present day setting a carefully done
ultrasound guided liver biopsy, demonstration of mesenteric
lymph nodes on CT scan and ultrasound of the abdomen
are available for early diagnosis. These should be done
because it is a treatable condition and very gratifying.
The criteria for diagnosis of congenital tuberculosis
as described by Beitzke in 193534 were modified by
Miller37 into three types:
1. Neonates with a primary focus in the liver and a mass
at porta hepatis. Few of these patients may have a
primary complex of the lung also.
2. Group that does not have a primary lesion in liver
but has a large number of tuberculous foci scattered
throughout both the lung fields and caseation in hilar
and mediastinal lymph nodes.
3. A group in which the mode of transmission of
infection is oropharyngeal, taking place at birth or
shortly afterwards. This is a very rare presentation.
The mode of infection in the first group is
transplacental, whereas that of second and third group
is infection through aspiration of amniotic fluid, material
from the genital tract or mouth to mouth breathing by
an infected adult at childs birth. Of the 29 cases published
280
after 1980 only 3 met Beitzkes criteria.34 Cantwell et al38

in 1994 proposed revised criteria to address the
limitations of Beitzkes criteria. According to them, infant
must have proven tuberculosis lesions and at least one
of the following:
i. Lesions in 1st week of life.
ii. A primary hepatic complex or caseating hepatic
granulomas.
iii. Tuberculosis infection of the placenta or the
maternal genital tract.
iv. Exclusion of the possibility of postnatal transmission
by a thorough investigation of contacts including
the infants hospital attendants or birth attendant.
The advantages of the revised criteria38 include
increased diagnostic sensitivity, better applicability in
present setting and emphasis on evaluating the mothers
of the infants with suspected congenital tuberculosis
potentially improving the detection of subclinical
tuberculosis in these women. Theoretically, there is a
small chance of misclassification as caseating hepatic
granulomas can also occur in postnatally acquired
tuberculosis but they have been found to be extremely
uncommon in a large series (less than 2%).39 Also the
infant of a mother suffering from genital tuberculosis can
acquire infection from her in the postnatal period leading
to overdiagnosis of congenital tuberculosis.
Based on findings from published case reports, Patel
and Destantis45 suggested that congenital tuberculosis
should be considered in the differential diagnosis of
newborns who have (1) nonresponsive, worsening
pneumonia, especially in regions with high rates of
tuberculosis, (2) nonspecific symptoms, have a mother
diagnosed with tuberculosis, (3) high lymphocyte counts
in the cerebrospinal fluid without an identified bacterial
pathogen, or (4) fever and hepatosplenomegaly.45
INVESTIGATIONS
Congenital tuberculosis is a rare entity and diagnosis is
usually delayed due to the non-specific nature of the signs
and symptoms. Imaging studies facilitate the early diagnosis of the disease and institution of appropriate
therapy. Neyaz et al14 reported imaging findings of
congenital tuberculosis in three infants. Imaging findings
of the chest included multiple pulmonary nodules,
consolidation with cavitation, extensive bronchopneumonia and necrotic mediastinal adenopathy. Abdominal
imaging findings included hepatomegaly with or without splenomegaly, multiple focal lesions in the spleen and
retroperitoneal lymphadenopahty.
Once the diagnosis is suspected in an infant,
diagnostic procedures should be carried out rapidly.
i. Chest skiagrams of the infants were abnormal
in upto 80% in Cantwells 38 review and the

abnormalities described were nonspecific. However,
in Hagemans 35 review about 50% infants had
miliary pattern.
ii. Seth46 showed that tuberculin test in the infant is
often negative initially but it is still worth doing
because it is extremely important if reactive. The
administration of BCG at birth may occasionally lead
to false positive results.46 However, the size of
induration in babies after BCG vaccination is usually
up to 5 mm and very few babies have 6 to 9 mm of
induration. Seth has further emphasized that any
baby having more than 10 mm of induration after
tuberculin test should be considered as infected and
treated with antituberculosis drugs.46
iii. Hageman33 showed that gastric aspirates provided
the diagnosis of tuberculosis in 10 of the 12 patients.
Similarly, high yields from gastric aspirates were
found by Cantwell and Coworkers.38 Now with the
availability of rapid methods of staining of smear
and culture for AFB, these investigations should be
given their due importance. More than 3 gastric
aspirates need to be examined.
iv. Bone marrow aspiration cytology and/or biopsy of
lymph node and liver would be other diagnostic
modalities which should be considered.
v. Positive smear and/or culture results can often be
obtained from gastric washings, spinal fluid, ear
discharge and endotracheal aspirate.
vi. Newer modalities like polymerase chain reaction
(PCR) are highly beneficial in the diagnosis of
congenital TB.
vii. Recently, phage typing has been used to establish
the identity of mycobacteria isolated from mother
and the infant.
Obtaining mothers history regarding symptoms of
tuberculosis during pregnancy especially pleural effusion,
miliary or meningeal disease suggesting primary
lymphohematogenous spread or history of endometritis
is an important diagnostic tool. Work-up of the mother
should include a histological examination of placenta at
birth, Mantoux test, chest X-ray and endometrial aspiration
and curettage.34,36,47,48
The diagnosis is based on positive smear and/or
culture results obtained from gastric washings, liver
biopsy, lymph node biopsy, spinal fluid, ear discharge,
endotracheal aspirate or bone marrow biopsy and
mothers history of tuberculosis in antenatal period.
To summarize congenital tuberculosis is still
presented as case reports even with the availability of
modern diagnostic techniques. To illustrate this a few
case studies reported in the last five years are discussed
below.
Congenital Tuberculosis with Multisystem Involvement:

A Case Report
Boro et al49 reported a three-month old boy, first child of
nonconsanguineous parents, presented with a history of
fever, cough, vomiting since birth. He had bronchopneumonia and splenomegaly at first week of life. He was
started on nonspecific antibiotics. He was fed on formula.
On examination, he had pallor, fever 38.7C, tachycardia,
tachypnea, malnutrition, bronchopneumonia and
congestive heart failure. His liver was 5 cm, splenic
enlargement of 3 cm. He had leukocytosis, elevated
serum CRP levels, respiratory acidosis and impaired liver
function tests. In spite of antibiotics, his liver increased
to 7 cm and spleen was 10 cm below costal margin. Xray chest showed extensive broncho-pneumonia.
Abdominal ultrasound showed portal lymphanodes
besides hepatosple-nomegaly. Because of poor response
to antibiotics, possibility of congenital TB was
entertained. Tuberculin test was 16 mm positive. Early
morning gastric aspirate yielded acid fast bacilli on smear
microscopy on three consecutive days. Cerebrospinal
fluid showed proteins 117 mg/dl, glucose 3 mg/dl, with
serum glucose level of 88 mg/dl, 55 polymorphs,
lymphocytes 44/mm. 3 Tomography chest revealed
broncho-pneumonic changes, cavitation and hilarmediastinal lymphadenopathy. Family history was strongly
positive. Both parents and one of the uncles had
pulmonary TB.
The infant was administered antituberculosis
treatment INH (10 mg/kg), rifampicin (RMP) (10 mg/
kg), pyrazinamide (PZA) and streptomycin (30 mg/kg)
for 2 months followed by INH and rifampicin for 9
months. He responded and after completion of therapy
(ATT), liver was only 2 cm and spleen of 1 cm only. Xray chest was completely normal.
Late Neonatal Respiratory Distress: A Presentation of

Prasad et al50 reported a case of late neonatal respiratory
distress: a presentation of congenital tuberculosis. A twenty
day old male neonate, weighing 2.6 kg presented with a
history of fever for ten days, fast breathing for 2 days and
refusal to feed for one day. It was a normal full term delivery.
On examination, the child had 102F fever, was icteric and
dyspnoeic with respiratory rate of 90/minute. On
examination of chest, there was marked subcostal retraction
on inspection, rest of the examination of chest was normal.
There was profuse nasal secretion and hepatosplenomegly
(liver span: 10 cm and spleen: 2 cm below left subcostal
margin). Liver function tests were markedly deranged.
Blood, CSF and urine culture were sterile. Gastric aspirate
showed M. tuberculosis by PCR. Gastric aspirate also showed
281
+++ AFB on smear. Ultrasonography of abdomen was

normal except hepatosplenomegaly. On screening of family,
the mother was the source of infection. She had pleural
effusion, sputum was positive for AFB. The endometrial
biopsy showed noncaseating epitheloid cell granulomas in
between endometrial glands, Langhans giant cells and
collection of epitheloid cells suggestive of tubercular infection.
Treatment was given with four drugs HRZS. Hepatic
functions were monitored. Child improved over a period
of 10 days, started breast feeding. It is inferred that for the
diagnosis of congenital tuberculosis, high index of suspicion
is necessary and antitubercular therapy is life saving.
Wanjari et al10 reported a 2-day-old male premature infant
(28weeks) with fever, respiratory distress syndrome and
hyperbilirubinemia. The baby had septicemia due to
Candida krusci. Mother had miliary tuberculosis. The baby
was investigated on the line of tuberculosis. Treated
successfully with antitubercular and antifungal therapy.
Thapar et al51 also reported a neonate presenting as
septicemia at the age of 2 months. The source was mother.
Infant was investigated on the line of congenital tuberculosis
and treated successfully.
TREATMENT
Treatment with antituberculosis drugs instituted in time
can result in a favorable outcome in the neonate.41
Congenital tuberculosis being so rare, no therapeutic trial
can determine optimal treatment. Cantwell et al38 suggest
treatment with INH 10 to 15 mg/kg, rifampicin 10 to 20
mg/kg, pyrazinamide 15 to 30 mg/kg/day. It is further
recommended by them that streptomycin 20 to 30 mg/
kg/day or ethambutol 15 to 25 mg/kg/day for the first
2 months followed by INH and rifampicin for 4 to 10
months depending on the severity of the disease. This 3drug regimen, though easier to administer than
streptomycin containing initial 4 drugs regimen suffers
from the danger of nonresponse to treatment in case the
disease causing strain is resistant to INH. The prompt
treatment with specific drugs is necessary because of the
seriousness of the disease.
A Paradoxical Reaction during Antituberculosis Therapy

for Congenital Tuberculosis
A paradoxical tuberculosis (TB) reaction is defined as the
clinical or radiological worsening of preexisting TB
lesions or the development of new lesions during
treatment. Park et al52 reported a paradoxical reaction in
a 21-day-old female infant who was diagnosed with
congenital TB and was being treated with antituberculous
drugs. A paradoxical reaction has been reported in 5 to
35% of patients receiving treatment for tuberculosis (TB)
mostly immunocompromised patients (such as those
with HIV). A 21-day-old female child was admitted with
282
respiratory distress symptoms and signs and was being

treated with antibiotics for sepsis and pneumonia. With
this therapy, the child did not have any improvement.
Patients mother was diagnosed TB with pleursy one
month ago. The baby was investigated for TB. Gastric
aspirate contained acid fast bacilli (AFB) on smear and
culture. PCR for M. tuberculosis was positive.
Computerized tomography (CT) of the lung revealed
enlargement of the lymphnodes in the sybcarinal and
bilateral hilar regions along with diffuse multiple nodules
in both lung fields. A diagnosis of congenital TB was
made. Baby was put on ATT, INH, RMP, pyrazinamide
and streptomycin was started in the dose of 10 mg/kg
for isoniazid and rifampicin, 25mg/kg of pyrazinamide
and streptomycin 20 mg/kg. The clinical symptoms
improved and she was discharged. However, she was
readmitted to hospital two months later with fever,
cough, wheezing and respiratory difficulty. Follow-up
showed aggravation of findings on CT. There was no
evidence of Mycoplasma pneumoniae or Pneumocystis
jiroveci. Oral prednisolone was added in the dose of 1
mg/kg which was gradually topered off over 6 weeks.
The clinical symptoms improved and chest radiograph
showed nearly complete resolution of the TB lesions.
Paradoxical reaction (PR) is defined as the worsening of
clinical or radiological findings following the initiation
of anti-TB drugs. Pathogenesis of a PR is unclear but
probably has an immunological basis. There are two
hypothesis, the reconstitution of host immune responses
after the initiation of antituberculosis therapy and a
hypersensitivity reaction to the antigens released from
dying tubercle bacilli; lipoarabinomannan, a protein
found in the cell wall of M. tuberculosis, induces tumor
necrosis factor from mononuclear phagocytes. This is
the first case reported and hence possibility of PR should
be considered when there is deterioration on treatment.
Corticosteroid therapy appears to be effective and need
to be given for 4 to 6 weeks.
As an analogy to prevent tuberculosis in children the
need of aggressive and prompt treatment of an infectious
adult, the prompt diagnosis and treatment of an infected
mother is very important during pregnancy
demonstrated in our description of cases earlier. Skevaki
and Kafetzis53 have reported in 2005 from Greece, the
importance of early diagnosis to the extent of treating
latent tuberculosis in the mother to prevent this so called
rare disease. They have suggested that all the recent
available diagnostic modalities should be used. It has
been further suggested by them that the therapy should
be aggressive with HRZE/HRZS in the intensive phase
followed by HR for 4 to 10 months depending upon the
severity of the disease. It has been highlighted by them
that even novel therapeutic modalities which stimulate
the immune system of the host such as interleukin IL-2,
IL-12, interferon-gamma and tumor necrosis factor have
been tested with promising results.
HIGHLIGHTS
M. tuberculosis infection in utero can be indistinguishable from perinatal or early postpartum
infection.
The most common presenting symptoms are
hepatosplenomegaly, respiratory distress, fever,
growth failure and lymphadenopathy.
Newborn with pneumonia unresponsive to
aggressive antibiotic therapy usually lumped as
sepsis should be aggressively investigated for
congenital tuberculosis.
The most recent set of criteria for congenital TB
requires the infant to have tuberculosis lesions
(infiltrates on the chest radiograph) and at least one
of the following:
i. Onset during the first week of life, reported range
is 1 to 84 days.
ii. A primary hepatic TB complex or caseating hepatic
granuloma.
iii. Infection of the placenta or maternal genital tract.
iv. Exclusion of postnatal transmission by a contact
investigation.
REFERENCES
1. Hassan G, Qureshi W, Kadri SM. Congenital tuberculosis
mini review. JK Science 2006;8:193-4.
1a. Abughali N, V ander Kuyp F, Annable W, et al. Congenital
tuberculosis. Pediatr Infec Dis J 1994;13:773-91.
2. Beok DR, Sylvester KG. Congenital tuberculosis
presenting as progressive liver dysfunction. Pediatr Infec
Dis J 2004;23:78-80.
3. Weisoly DL, Khan AM, Elidermir O. Congenital
tuberculosis requiring extracorporeal membrane
oxygenation. Pediatr Pulmonol 2004;37:470-3.
4. MMWR Mor Mort Wkl Report. Congenital pulmonary
tuberculosis associated with maternal cerebral
tuberculosis-2005;54:1062-6
5. Chotpitaysunondh T, sangtawesin V. Congenital
tuberculosis. J Med Assoc Thai 2003;86suppl:S689-95.
6. Abalain ML, Petsaris O, Hery-Arnaud G, et al. Fatal
congenital tuberculosis due to Beijing strain in a
premature neonate. J Med Microbiol 2010 Mar 4. [Epub
ahead of print]
7. Diar H, Velaphi S. Congenital tuberculosis as a proxy to
maternal tuberculosis: a case report. J Perinatol
2009;29:709-11.
8. Thapa R, Mallick D, Biswas B. Perinatal malaria and
tuberculosis coinfection: A case report. Int J Infect Dis
2010;14:e254-e256.
9. Stuart RL, Lewis A, Ramsden CA, et al. Congenital
tuberculosis after in vitro fertilisation. Med J Aust
2009;191:41-2.
10. Wanjari K, Mathur M, Baradkar VP, et al. Congenital
tuberculosis with candidal sepsis in a neonate. Indian J
Pathol Microbiol 2008; 51:289-91.
11. Pal P, Ghosh A. Congenital tuberculosis: Late
manifestation of the maternal infection. Indian J Pediatr
2008;75:516-8.

12. Das A, Arora J, Rana T, et al. Congenital tuberculosis:
The value of laboratory investi-gations in diagnosis. Ann
Trop Paediatr 2008;28:137-41.
13. Kumar A, Ghosh SB, Varshney MK, et al. Congenital
spinal tuberculosis associated with asymptomatic
endometrial tuberculosis: A rare case report. Joint Bone
Spine 2008;75:353-5.
14. Neyaz Z, Gadodia A, Gamanagatti S, et al. Imaging
findings of congenital tuberculosis in three infants.
Singapore Med J 2008;49:e42-6.
15. Bhat RY, Rao A, Althaf, et al. An evolved diagnosis of
congenital tuberculosis in a very low birth weight
premature neonate. Int J Tuberc Lung Dis 2008;12:344-5.
16. Doudier B, Mosnier E, Rovery C, et al. Congenital
tuberculosis after in vitro fertilization. Pediatr Infect Dis J
2008;27:277-8.
17. Al-Katawee YA, Al-Mahmood LA, Al-Showaier AS.
Congenital tuberculosis presenting as cutaneous disease
in a premature infant. Saudi Med J 2007;28:1739-40.
18. Vilarinho LC. Congenital tuberculosis: a case report. Braz
J Infect Dis 2006;10:368-70.
19. Singh M, Kothur K, Dayal D, et al. Perinatal tuberculosis
a case series. J Trop Pediatr 2007;53:135-8.
20. Kumar R, Gupta N, Sabharwal A, et al. Congenital
21. Nicolaidou P, Psychou F, Stefanaki K, et al. Congenital tuberculosis: A case report. Clin Pediatr (Phila) 2005;44:451-3.
22. Mouchet F, Hansen V, Van Heroeweghe, et al. Tuberculosis in health care workers caring for a congenitally
infected infant. Infect Control Hosp Epidemiol
2004;25:1062-6.
23. Popli MB, Mehta N, Nijhavan VS, et al. Congenital
tuberculosis. Austr Radiol 1998;42:256-7.
24. Spark RP, Pock NA, Pedron SL, et al. Perinatal
tuberculosis and its public health impact: A case report.
Tex Med 1996;92:50-3
25. Lee LH, Levea CM, Graman PS. Congenital tuberculosis
in a neonatal intensive care unit: Case report,
epidemiological investigation, and management of
exposures. Clin Infec Dis 1999; 29:467-8.
26. Balasubramanian S, Shivram R, Padamasani LM, et al.
Congenital tuberculosis. Indian J Pediatr 1999;66:148-50.
27. Hageman JR. Congenital and perinatal tuberculosis:
Discussion of the difficult issues of diagnosis and
management. J Perinatol 1998;18: 389-94.
28. Adhikari M, Pillay T, Pillay DG. Tuberculosis in the
newborn: An emerging disease. Pediatr Infect Dis J
1997;16:1108-12.
29. Starke JR. Tuberculosis. An old disease but a new threat
to the mother fetus and neonate. Clin Perinatol
1997;24:107-27.
30. Balaka B, Bakande B, Douti K, et al. Tuberculosis in the
newborn: Recrudescence in areas with high endemic HIV
infection. Med Trop (mars) 2004; 64:367-71.
31. Kumar R, Nomeeta G, Arvind S, et al. Congenital
32. Naranbai RC. Congenital tuberculosis localised to the ear.
33. Scnbil N, Sahin F, Caglar MK, et al. Congenital
tuberculosis of the ear and parotid gland. Pediatr Infect
Dis 1997;16:1090-1.
283
34. Beitzke H. Uber die angeborene tuberculose infektion.

Ergebn Tuberk Forsch 1935;7:1-30.
35. Hageman J, Shulman S, Schreiber M, et al. Congenital
tuberculosis: Critical reappraisal of clinical findings and
diagnostic procedures. Pediatrics 1980;66:980-4.
36. Nemir RL, OHare D. Congenital tuberculosis: Review
and guidelines. Am J Dis Child 1985;139:284-7.
37. Miller FJW. Tuberculosis in children. Evaluation,
Epidemiology, Treatment, Prevention. (1st edn). New
Delhi, Churchill Livingstone 1982;220-4.
38. Cantwell MF, Shehab ZM, Costello AM, et al. Brief report:
Congenital tuberculosis. N Engl J Med 1994;330:1051-4.
39. Pillet P, Grill J, Rakotomrina G, et al. Congenital
tuberculosis: difficulties in early diagnosis. Arch Pediatr
1999;6:635-9.
40. Pham Duy L, Le Van N, Trumg Nguc Cuc H. Congenital
miliary tuberculosis. A case report. Rev Pneumol Clin
1998;54:207-9.
41. Treatment of tuberculosis and tuberculosis infection in
adults and children: Official statement of the American
Thoracic Society. Am J Respir Crit Care Med 1994;
149:1359-75.
42. Chanta C, Jariyapongpaibul Y, Triratanapa K. Congenital
tuberculosis presenting as sepsis syndrome. J Med Assoc
Thai 2004;87:573-7.
43. Mazade MA, Evans EM, Starke JR, et al. Congenital
tuberculosis presenting as sepsis syndrome: case report
and review of literature. Pediatr Infect Dis J 2001;20:43942.
44. Verma M, Chatwal J, Sarin YK, et al. Congenital
tuberculosis: An underdiagnosed entity. Indian Pediatr
1996;33:51-4.
45. Patel S, De Santis ER. Treatment of congenital
tuberculosis. Am J Health Syst Pharm 2008;65:2027-31.
46. Seth V. BCG Vaccination. In: Seth Vimlesh (Ed). Essentials
of Tuberculosis in Children, (1st edn). New Delhi: Jaypee
Brothers Medical Publishers (P) Ltd 1997;35-47.
47. Kabra SK, Jain Y, Kabra M, et al. Congenital tuberculosis
(letter). N Engl J Med 1994;331:548.
48. Vuciccuic Z, Suskovi T, Ferencic Z. A female patient with
tuberculosis, polyserositis, and congenital tuberculosis
in her newborn child. Tuber Lung Dis 1995;76:460-2.
49. Boro O, Dinleyici E C, Kocak K, et al. Congenital
tuberculosis with multi system involvement a case report.
Turkish Respiratory Journal 2007;8:36-8.
50. Prasad R, Muthusami S, Pandey M, et al. Late neonatal
respiratory distress. A presentation of congenital
tuberculosis. The Internet Journal of Pediatrics and
Neonatology 2007;7: Number 1.
51. Thapar K, Dhawan G. Congenital tuberculosis presenting
as sepsis syndrome. Pediatric on cell [serial online] 2006
[cited 2006 August 1] 3, Art # 28.
52. Park Ji AE, Park SS, Park SE. A paradoxical reaction
during anti tuberculosis therapy for congenital
tuberculosis. International Journal of Infectious Diseases
2009;13:e 279-e281.
53. Skevaki CL, Kafetzis DA. Tuberculosis in neonates and
infants: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management issues. Paediatr
Drugs 2005;7:219-34.
SECTION 5
DIAGNOSIS
Pitfalls in Diagnosis and Treatment of Childhood

Tuberculosis
Tuberculin Test
Newer Tuberculins: Profile in Developing Countries
Laboratory Diagnosis of Mycobacterial

(Tuberculosis) Infection in Children
Conventional Methods
Molecular Diagnostic Methods
Imaging of Tuberculosis in Children
Pathologic Spectrum
New Approaches to TB Diagnosis in Children
22
Pitfalls in Diagnosis and Treatment of

Childhood Tuberculosis
YK Amdekar, Vimlesh Seth
Establishing diagnosis of tuberculosis in children can be

challenging. This is true especially in early stages of the
disease and much more in diagnosing latent infection
that may progress into a disease, if not suitably managed.
Early stage of the disease is often silent in the majority of
children with only vague symptoms that may be easily
overlooked. Physical examination is mostly normal. Thus
diagnosis must depend upon high degree of suspicion.
Triad of confirming diagnosis in children consists of
contact with tuberculosis, positive tuberculin test and
chest radiograph demonstrating pulmonary lesion. Each
of these three factors has their own limitations. Demonstration of AFB is still the gold standard of diagnosis and
can be positive at best only in 30% of children. Further,
with the disease being common in India and with the
threat of dissemination especially in infancy and early
childhood, overdiagnosis is a rule, often based on flimsy
grounds. While at times, early diagnosis is missed due
to improper interpretation of history, physical
examination and laboratory tests.
Treatment also poses few problems. Standard protocols have been updated by RNTCP (Revised National
Tuberculosis Control Program) and IAP (Indian
Academy of Pediatrics) that ensure cure in the majority
of patients. Unfortunately they are often not followed
for various reasons. Compliance is a major issue and at
times non-availability of drugs adds to the problem. Irregular treatment leads to drug resistance and poses a great
challenge. Logistic issues come in the way of ideal
therapy.
No wonder, there exist many pitfalls in the diagnosis
and treatment of childhood tuberculosis in clinical
practice. Problems lie at multiple levels such as private
practitioners, medical institutions and government
programs. Many of these issues can be addressed
properly with commitment from everyone concerned.
This chapter discusses existing pitfalls in diagnosis and
treatment of childhood tuberculosis and probable
solutions. It is the pulmonary primary complex which is
a starting point, irrespective of further course of disease
and hence discussion will be mainly focused to PPC.
PITFALLS IN HISTORY ANALYSIS

Fever and/or cough of recent onset lasting for > 3 weeks
should initially arouse suspicion of tuberculosis. It is
important to document fever and not depend on mere

impression. Fever can be of any type though rarely high.
Cold and wheezing accompanying fever and cough
denotes involvement of upper and lower respiratory tract
and is commonly due to viral infection and not due to
tuberculosis. Symptoms of tuberculosis are known to be
off and on. However, recurrent symptoms with normal
intervening period are not relevant for suspicion of
tuberculosis. In such a situation, it is important to confirm
normality during intervening period. Mere absence of
fever and cough is not an evidence of normality but
normal intervening period is better defined by regaining
of appetite, weight and normal activity. Recent loss of
appetite may be relevant but unexplained recent loss of
weight adds to the suspicion of tuberculosis; static
weight/not growing well, especially beyond infancy, in
absence of any other complaints, are not significant
symptoms. However, presence of a contact in the family
should arouse suspicion of latent tuberculosis.
Positive contact history is a strong contributory
factor. In a symptomatic child, contact with a person with
any form of active tuberculosis within last two years is
considered significant. Prolonged contact carries far more
risk than occasional contact. It is not only the history of
contact that must be enquired but definite attempt must
be made to trace the contact. In clinical practice, it is not
uncommon for parents to deny any history of TB in the
family. History of chronic cough in any of family
members and history of prolonged treatment for cough
may suggest probable TB and further enquiry may
confirm it. Family members at risk of TB include elderly
persons with cough and those with diabetes. If necessary,
they need to be proactively screened for tuberculosis. On
the other hand, diagnosis of tuberculosis in an adult
demands screening of all children in the family. This is
often ignored in clinical practice.
Diagnosis is more likely in presence of risk factors
such as age < 1 year, recent episode of Measles or
whooping cough, protein energy malnutrition (PEM)
grade 3 and 4 and immunocompromised state including
prolonged steroid therapy. Persistent lower respiratory
tract infection not responding to antibiotics may suggest
a probable diagnosis of tuberculosis.
It is important to realize that none of the above
mentioned facts in isolation can help in diagnosis of
288
Section 5 Diagnosis
tuberculosis but it is a constellation of multiple factors

that need proper evaluation. Finally, beyond infancy, if
history does not lead to suspect tuberculosis strongly,
close observation and periodic follow-up evaluation
would sort the problem and hurried investigations may
not be justified as they may end up in further confusion.
However, in an infant, even a small degree of suspicion
demands further work-up.
Amongst extra-pulmonary TB, meningitis is a serious
disease that must be diagnosed in an early stage. TB
meningitis is more common < 5 years of age and so in a
high-risk setting mentioned above, any undiagnosed
fever with vague neurological symptoms should arouse
suspicion and immediate further work-up would be
mandatory. It is important to suspect TBM in stage 1 so
as to improve outcome of therapy.
Unexplained failure to thrive even without any
significant suggestive symptoms of tuberculosis does
justify further investigations.
Resolution of symptoms under nontuberculous
therapy does not rule out tuberculosis as at times,
symptoms seem to abate temporarily to reappear again.
Moreover, even when presenting symptoms disappear,
other minor symptoms such as not being well and loss
of weight/appetite go unnoticed.
On the other hand, history of improvement after antiTB treatment may not prove the diagnosis, especially if
sequence of recovery do not match with expected
outcome.
Similarly past history of tuberculosis must be
enquired into details as more often than not, diagnosis
may have been made on flimsy grounds and one may
have to ignore such a history when deciding further
management.
Pitfalls in Physical Examination

In majority of patients of pulmonary primary complex
(PPC), physical examination does not reveal any
abnormality. Rarely hilar lymphadenopathy may result
in localized collapse or emphysema that is evident on
physical examination.
Presence of enlarged superficial lymph nodes must
be looked for in every case of suspected PPC, as they
may be picked up in nearly 40-50% of children. Lymph
nodes are considered pathological if they are more than
1.5 cm in inguinal region and more than 1 cm in other
superficial sites. Clinical correlate of diagnosis of
tuberculosis includes progressive enlargement of lymph
nodes for more than 2 weeks, firm, minimally tender or
not tender, fluctuating, further may get matted and
develop chronic sinus formation.
It is a common mistake to consider persistent palpable
superficial lymph nodes as due to tuberculosis. They are
commonly caused by recurrent infections in draining area

such as enlarged posterior cervical lymph nodes due to
scalp infection or submandibular lymph nodes due to
repeated tonsillar infections. In majority of such
situations, such lymph nodes do settle with antibiotics
and even if they persist, they are not enlarging. Thus
clinical follow-up does help to rule in or rule out
diagnosis of tuberculosis. Only when tuberculosis is
strongly suspected, further tests are useful. Otherwise it
is not uncommon to end up with inconclusive test results.
Physical findings suggestive of pleural effusion or
chronic fibrocaceous cavitory lesions strongly support
probable diagnosis of tuberculosis and can be easily
confirmed further by appropriate laboratory tests.
Hepatosplenomegaly of unexplained etiology may be a
presentation of disseminated tuberculosis and needs
proper evaluation in case of corroborative history.
TBM in stage 1 must be recognized with minimum
physical signs such as mild drowsiness and subtle
meningeal signs. On close careful examination, one may
be able to pick up signs of hydrocephalus and raised
intracranial pressure.
Phlyctenular conjunctivitis and erythema nodosum
are nonspecific signs of immune response to antigens
not necessarily of tuberculosis. Though with other
corroborative evidence, further tests may be justified.
Diagnosis of tuberculosis should never be made on
the basis of history and physical examination alone. Every
attempt must be made to prove the diagnosis on
laboratory tests. Therapeutic trial with anti-TB drugs has
no place in clinical practice.
Pitfalls in Laboratory Tests

When should the tests be ordered?
As majority of laboratory tests have their own limitations,
it is important to emphasize that strong clinical suspicion
on history and physical examination is a prerequisite to
ordering laboratory tests. It is not uncommon in clinical
practice to observe diagnosis made on laboratory tests
without correlation with symptoms and physical signs.
No single test in isolation is diagnostic of tuberculosis
except gold standard of bacteriological proof. Thus
laboratory tests must be used in conjunction with clinical
profile and then only reasonably correct diagnosis is
possible.
Pitfalls in Tuberculin Test

This is an important test in support of natural infection
and needs proper technique and cautious interpretation.
There are many variables such as amount of antigen,
depth of injection and host immune response.
Test material must be clearly mentioned on the report
as different strength of tuberculin is used in different
Chapter 22 Pitfalls in Diagnosis and Treatment of Childhood Tuberculosis

laboratories. Test material must be injected intradermally
and it is not easy to do so without experience. Even
measurement of reaction is observer dependent and there
is inter-observer variation up to 4 mmthat may make
a difference in interpretation.
Standard tuberculin test is Mantoux test. Till recently
commercially available tuberculin was PPD RT23 5 TU,
but now ITU PPD RT23 with tween 80 is also available.
Test is read 48 to 72 hours after an injection and maximum
diameter of reaction in any plane is noted for
interpretation. It is an induration and not the erythema
that should be measured. Reaction of 10 mm or more is
taken as evidence of natural infection.
Besides many variable factors mentioned above,
interpretation of test result is most controversial. Even then,
attempts are made to standardize it as per the protocol
formulated by IAP.
Reaction of 10 mm or more as depicted of natural
infection is based on epidemiological studies in India. It
also takes into account that prior BCG vaccine usually
does not result in reaction 10 mm or more.
However, earlier studies were done with PPDS that
considered 10 mm of reaction as a cut-off point for natural
infection. This was generally equivalent to 2 TU PPD
RT23. As 5 TU PPD RT23 is commercially available and
is used commonly in clinical practice, it is seen to result
in higher reaction by 5 mm, Hence, National Tuberculosis
Institute survey considered 14 mm as a cut-off point for
natural infection in India.
In immunocompromised children and children
suffering from PEM grade III and IV, lower cut off point
for natural infection may be considered as 5 mm
Any cut-off point is likely to overlap naturally infected
and not infected population. Cut off point of 14 mm may
miss few patients of active disease but cut off point of 10
mm may over diagnose normal children as diseased.
Our problem is mainly over diagnosis and hence cut
off point of 14 mm may be ideal. This is irrespective of
previous BCG vaccine as BCG vaccine is unlikely to
induce a reaction more than 12 mm. It is also well
accepted that hypersensitivity after BCG vaccine does
wane off over a year and hence would not pose difficulty
in interpretation of tuberculin test. It is important to
reiterate that cut-off point refers to natural infection and
not active disease.
Risk of disease after natural infection varies with age
and hence age is an important criterion in interpretation
of tuberculin test in the diagnosis of active disease.
Younger the age more the risk of active disease as
depicted below. By adolescence risk increases again.
30 to 40% < 1 year
10 to 20% between 1 and 2 years
5 between 2 and 5 years
2% between 5 and 10 years
289
10 to 20% > 10 years

General risk of disease 5 to 10% during lifetime
It is important for clinicians to realize limitations
of tuberculin test. Though as it is the most useful test
in diagnosis of childhood tuberculosis, adequate
caution in technique and interpretation is mandatory.
Of course it is well known that test may be negative in
active disease. In any case, tuberculin test is always
interpreted in conjunction with other parameters and is
never considered alone in diagnosis of tuberculosis.
Bacillus Calmette-Guerin (BCG) Test

Few reports in Indian literature led to misinterpretation
of this test. Unfortunately it continues to be used at times
in clinical practice, especially when tuberculin test is
negative. However, there is no place for BCG test in the
diagnosis of childhood tuberculosis.
This test has many variables and so is not useful in
the diagnosis of tuberculosis. Unlike Mantoux test, it is a
poorly standardized test in terms of tuberculin
concentration, measurement of response and evolution
of reaction over time. Interpretation of tuberculin reaction
is standardized. BCG test introduces variable high
concentration of tuberculin and hence cannot differentiate natural infection from vaccine-induced infection,
infection from disease and active disease from old healed
disease. The test has high sensitivity at the cost of poor
specificity that leads to overdiagnosis. As tuberculosis is
still common in India, test must be more specific than
sensitive though ideal test should have both high
specificity and sensitivity. Thus BCG test is not
recommended in diagnosis of tuberculosis.
Pitfalls in Chest Radiograph

It is important to ensure ideal technique for correct
interpretation. It must be preferably done in upright
position, has to be well centered, in an inspiratory phase
and with optimum exposure. Posterioanterior view is
mostly adequate. However, localizing lesion near the
hilum or heart borders can be better visualized by lateral
view.
Digital X-ray is highly technician dependent and
should not be interpreted on same parameters as
conventional X-ray though it can offer an advantage
provided experienced reader interprets it correctly.
As it is difficult to obtain an ideal chest X-ray, clinician
must be cautious to interpret soft signs that may be false
positive. Expiratory film may reveal apparent mediastinal widening with hilar prominence and widened
cranial angle that may wrongly be diagnosed as enlarged
lymph nodes. Similarly shadows on rotated film may
appear as enlarged lymph nodes while in effect they may
represent part of bony structures of thoracic cage.
290
Section 5 Diagnosis
Presence of thymus in infants is confused with

mediastinal lymphadenopathy. Further even if enlarged
lymph nodes are diagnosed on chest X-ray, it may not
suggest tuberculosis, as lymphoma may be a close
differential diagnosis. Prominent costochondral junctions
as seen in rickets may often be mistaken for lung lesions.
Prominent minor interlobar fissure may be mistaken for
lung lesion.
In case of doubt, it is better to repeat a chest X-ray for
comparative interpretation. It is not rare for radiological
abnormalities to disappear after few weeks. As a rule, in
case of clinical recovery, persistent radiological lesion
should not be a reason to diagnose tuberculosis.
Chest X-ray defines pathology and not etiology. There
are no pathognomonic radiological signs of tuberculosis.
Normal chest X-ray does not rule out active disease as
10% of culture positive patients have normal chest Xray. In relevant clinical setting, following radiological
lesions may strongly suggest tuberculosis and they
include military, chronic fibrocaceous cavitatory and
unilateral pleural effusion. Unresolving pneumonia after
adequate antibiotic trial in a symptomatic child raises
the possibility of tuberculosis. However, right upper lobe
lesion in infants may persist radiologically even after
clinical improvement and may disappear over weeks
without further intervention.
Repeat chest X-ray in tuberculosis may be necessary
ideally at the end of successful treatment to confirm
radiological clearance. However, it may be considered
early in case of unanticipated clinical progress.
Ultrasonography of chest is helpful to assess pleural
fluid collection, although decubitus chest xray film may
also reveal similar information.
CT scan is rarely necessary and is not cost and
radiation effective.
Chest CT scan may reveal additional information such
as mediastinal caseating necrotic lymphadenopathy that
may favor tuberculosis and may offer an opportunity for
CT guided biopsy for tissue diagnosis. Such modalities
are reserved for situations of uncertain diagnosis.
CT scan of brain is useful for diagnosis of TBM. Basal
exudates, hydrocephalus, infarcts and cerebral edema are
features suggestive of TBM.
Pitfalls in Bacteriology
Demonstration of AFB in sputum is the gold standard of
diagnosis of tuberculosis. Such a proof is often lacking
in childhood tuberculosis because of difficulty in collection of sputum sample and also due to paucibacillary
disease in children. However, studies do show as high
as 77% yield in advanced cases and 33% even in hilar
adenopathy and thus every attempt must be made to
prove the diagnosis in every case of suspected
tuberculosis.
Most of the clinicians lack motivation and have

developed culture of not looking for AFB. Under the
pretext of limitations of bacteriological tests, it has been
a routine to diagnose tuberculosis without bacteriological
proof. This is also true in most of infective diseases. For
example, typhoid fever is rarely proved by culture in
private practice even when it is easy to culture Salmonella
for definitive proof. Though in teaching institutions, it is
a rule to prove the diagnosis of typhoid fever and so also
an attempt to prove diagnosis of tuberculosis.
Sputum collection: It is possible in older children with
extensive and cavitatory disease. However, induction of
sputum by nebulized hypertonic saline may be tried in
children > 4 months of age. It may occasionally lead to
bronchospasm in a child and exposure of tubercle bacilli
to the investigator. One sample of induced sputum may
equal to three samples of gastric aspirates in terms of
bacillary yield. Gastric aspirate can be collected on three
consecutive mornings even in an ambulatory patient and
the yield on microscopy in progressive primary complex
in infants and in extensive disease may be as high as 60
to 70%. There is no need to hospitalize a child for collection of gastric sample as studies have shown no statistical
difference between yield of tubercle bacilli in hospitalized
and ambulatory patients. Thus, gastric aspirate offers
equal benefits and is much easy to carry out.
Nasopharyngeal aspiration and bronchoalvelolar lavage: These
are other modalities to collect samples for bacteriological
examination but in routine clinical practice, gastric
aspirate is the most suitable sample to examine. String
test with a capsule is another method but still in
experimental stage and the yield may not be as high.
Attempts have been made to find out body fluids that
are easy to collect and may grow AFB. Urine culture has
been found to be helpful in few patients. This may need
further research to define sensitivity and specificity vis-vis sputum examination.1 There is no role of urine
examination in routine practice for diagnosis of
tuberculosis.
Ziehl-Neelsen stain can reveal AFB only if sample
contains > 10,000 bacilli per ml. Different culture methods
are used, such as LJ medium, BECTEC and MIGT but
they are all equal in efficacy. Culture assumes special
significance in case of suspected MDR-TB.
Clinicians must get used to prove diagnosis of tuberculosis in children by appropriate bacteriological tests.
They are possible at all levels of practice and it is a sheer
habit of not doing such a test. Once clinicians start
conducting such procedures to collect appropriate
samples for detection of AFB, laboratories would also
get used to find AFB. It is time that pediatricians try to
prove the diagnosis of tuberculosis so as to minimize

errors in diagnosis. This is the only way we can succeed
in early and correct diagnosis that would pave the way
for better control of TB in India.
Pitfalls in Other Diagnostic Tests

With limitations of bacteriology in routine practice,
several newer tests have been tried but most of them have
failed to fulfill the need of diagnosing suspected case of
tuberculosis or to differentiate infection from active
disease.
As mycobacterial antigens overlap in different stages
of infection and disease, there are no specific antigens
that can confirm natural infection or active disease.
Besides, antigen tests vary widely and are often negative
in paucibacillary disease. Antibody tests share similar
problems for interpretation and in addition cannot
differentiate natural infection from BCG vaccine induced
infection and active disease from old healed disease. Thus
both antigen and antibody tests are in general poorly
sensitive and specific. There have been attempts to
evaluate role of specific antigens and antibody in
diagnosis of tuberculosis.2 However, no sufficient data
exists at present to recommend serological tests in the
diagnosis of tuberculosis.
It is a pity that serological tests are often pursued in
private practice for diagnosis of tuberculosis. Laboratories report such tests without mentioning specific
antigen or antibody that is tested. For an average
practitioner, positive tests mean so much and so also for
a patient or his parents. Such tests are worth banning in
clinical practice, as all attempts at educating pediatricians
seem to have failed. Laboratory personnel also owe a
responsibility by performing such useless tests.
QuantiFERON and Gold tests measure interferon
gamma in response to PPD and are just sophisticated
Mantoux test. Elispot and T-spot tests measure T-cells
producing interferon gamma and offer no more
information. At present, most of these tests are not yet
standardized and hence these tests do not add to the
diagnostic yield of tuberculosis in children. However,
they may hold promise for future application. There is
some evidence to suggest that QuantiFERON test would
become positive before tuberculin test and could be of
some use especially in starting early treatment.3 It is
therefore not recommended to use these tests in routine
clinical practice.
PCR is highly technical test with wide variability in
sensitivity and specificity as implemented in most of the
laboratories. It cannot differentiate living from dead
bacilli and so continues to be positive even after
successful treatment. PCR is +ve in 95 to 100% of culture
+ve cases but only in 50 to 60% of culture ve cases. It
may be false +ve in 1% to 30% of cases.
291
Thus, no decisions can be made only on the basis of

serology or PCR tests and hence these tests are not
recommended in clinical practice at present.
There are several laboratories in the country that
perform PCR but their competence and reproducibility
is in question and so clinicians should not depend on
such tests carried out by commercial laboratories.
Pitfalls in Diagnosis of MDR-TB

Initial drug resistance to INH varies from 10 to 20% and
for RMP 1 to 2% and acquired drug resistance to INH 40
to 70% and for RMP 20 to 30% Thus, MDR-TB does exist
in India and clinicians must be aware of it. Diagnosis of
MDR-TB essentially must be proved bacteriologically.
However, it can be suspected by a clinician and then further
proved by appropriate tests. Delay in diagnosis of MDRTB may be dangerous, far more than delay in diagnosis of
drug sensitive disease.
It may be suspected prior to starting therapy in case
of contact with known MDR-TB. It is also likely in a child
who has had ATT in the past or had been non-compliant
with prescribed therapy. Unanticipated deterioration on
compliant treatment may warrant looking for multidrug
resistance. Persistence of positive sputum for more than
5 months in spite of compliant therapy is a proof of drug
resistance and culture would prove diagnosis of MDRTB. Polybacillary lesions are more likely to be drug
resistant than paucibacillary. HIV infection itself does not
predispose to MDR-TB. However, malabsorption of antiTB drugs in such patients may lead to suboptimal
concentration of drugs in spite of compliance. Due to
frequent hospital visits, they may come in contact with
MDR-TB.
Common pitfall in the diagnosis of tuberculosis in
children is not to prove the diagnosis by gold standard.
If this trend continues, MDR-TB will be difficult to
diagnose and hence not treated properly. It would be a
threat to the community and a big hurdle in control of
tuberculosis in India. It is not acceptable to treat a child
with second line of drugs on clinical basis of diagnosis of
MDR-TB. While it may be prudent to start such a treatment
on strong clinical judgment, it is equally mandatory to
prove MDR-TB and more importantly to select right
combination of sensitive drugs. So, general clinicians must
develop a habit of looking for bacteriological proof.
Pitfalls in Treatment of Tuberculosis

Treatment of tuberculosis is very much standardized as
per the protocol of RNTCP and IAP. IAP has recently
updated treatment protocol and it is in line with that
devised by RNTCP so as to bring in uniformity and avoid
confusion. These protocols are based on scientific
foundations and have been tried with success.
292
Section 5 Diagnosis
Choice of anti-TB drugs is based on several determinants such as bacillary and metabolic subpopulation,
bacillary load, drug resistant strains, lag period of
bacterial population, pharmacokinetic profile and
pathological factors There are different types of bacillary
population in every case of tuberculosis and hence
specialized drugs are selected to be administered in
combination to attack entire bacillary population for total
success.
INH and RMP contain fast growing bacilli, PZA takes
care of intracellular organisms in acidic medium while
extracellular slow growing bacilli are best controlled by
RMP. Thus every case of tuberculosis must be treated
minimally with these three drugs. There are naturally
occurring mutants to the tune of 105 to 10.7 Higher the
bacillary load, higher would be the resistant mutants.
Thus in case of disease caused by higher bacillary load,
more drugs are necessary including additional drugs in
intensive therapy especially in smear, positive cases. .
Single daily peak of a drug is adequate as dividing
time of TB bacilli is about 21 hours. All the drugs are
administered in such a way that they achieve peak
concentration all at one time so as to hit bacilli hard. Thus
multiple drugs are employed in a single daily dose.
Early bactericidal activity makes a patient noninfectious quickly while sterilizing efficacy of drug makes
relapse less likely. Both facts are as much relevant in
effective control of tuberculosis.
Based on above mentioned facts, disease is
categorized into three types for the purpose of uniform
treatment protocol.
Category 1 includes newly diagnosed smear +ve
cases, sputum ve severe and extensive disease and TB
with HIV. Hence, category 1 justifies four drug intensive
phase therapy for two months followed by two drug
therapy in continuation phase for next four months. TBM
is treated with one extra drugStreptomycin in intensive
phase.
Category 2 includes relapsers, treatment defaulters
and treatment failures due to drug resistance. They need
five drug therapy in intensive phase followed by three
drugs in continuation phase for five months.
Category 3 includes smear ve less severe forms of
diseases such as primary pulmonary complex, isolated
lymphadenitis and unilateral pleural effusion. This is best
treated with three-drug therapy in intensive phase for
two months followed by two-drug therapy in continuation phase for four months.
It is clear that every case of tuberculosis must be
treated with minimum three drugs in intensive phase,
irrespective of type of lesion. In clinical practice, it is often
not followed and it is a disturbing fact that even a single
drug is used or two-drug treatment is not uncommon.
Physician needs to understand the logic behind minimum
three-drug intensive phase that cannot be modified.
This protocol as applied to children has been

debatable. However, it has been tested in children and
found to be feasible and practical. 4 Three disease
categories primarily depend upon results of smear testing
and this can be objectionable as majority of children are
diagnosed without smear microscopy and more so in
routine clinical practice. Category 3 includes smear
negative tuberculosis and so there is no problem to apply
it in children. Category 1 includes progressive primary
complex that is estimated to be smear-positive in at least
60% of cases. Other diseases included in this category
are more serious and disseminated forms of disease and
hence are rather easily recognizable irrespective of smear
positivity. As mentioned earlier in this chapter, it is ideal
to attempt smear microscopy and even in absence of such
a smear examination, disease categories do make sense
for effective uniform application.
Unfortunately, many practitioners are unaware of
such a protocol and hence prescribe drugs in a haphazard
manner. Such a practice is hazardous as it would pave
the way for suboptimal response leading to increasing
drug resistance.
It is a common knowledge that in case of suspicion of
drug resistance, minimum two drugs must be added to
pre-existing regime. However, in RNTCP, in category 2,
only one drug has been recommended to be added to
the pre-existing regime. While this may not be totally
scientific, it serves better purpose in community program
for the reasons cited below.
Issues Regarding Category to Therapy

This category includes relapsers, treatment defaulters
and treatment failures due to drug resistance. It is
important to realize that there is no risk of drug resistance
in a relapser and hence same drug schedules can be used
safely.
Treatment defaulters and treatment failures due to
drug resistance obviously need modification of therapy.
It is generally considered to add two drugs to the failed
regime till culture and drug sensitivity reports are
available. However, RNTCP has considered addition of
a single drugstreptomycinto a failed regime. This
apparently may sound irrational. However, such a
protocol is based on ground level reality. Considering
the fact that INH resistance is around 10% and combined
RMP/INH resistance around 5%, addition of a single
drug like streptomycin to four-drug regime would ensure
therapeutic success with three or four sensitive drugs.
Most often drug resistance is limited to two-drug
resistanceeither HR or HE. Except for multidrug resistance with bacilli resistant to three or more drugs, this
regime would work well. Such a regime is also cost
effective as second line drugs are not only costly but also
toxic. This is of course a waiting regime till culture and

drug sensitivity reports guide ideal therapy or there is
clinical treatment failure.
However, in clinical practice, one may opt for a
waiting regime or add two or more drugs as per the
facility and affordability. In any case, proper bacteriological evaluation is mandatory for further therapeutic
planning.
RNTCP suggests intermittent therapy under DOTS
program. This has an edge over daily therapy. Defaulter
rate is around 18% in daily regime as against 6% in
intermittent therapy. It is also comparatively easy to
supervise intermittent therapy than daily therapy. Both
daily and intermittent regimes will work equally well
provided compliance is assured and in clinical practice,
one could opt for either of them based on individual
convenience. Far more important is to ensure compliance;
it is an important step next only to correct diagnosis and
standard treatment.
Latent Infection
Risk of disease after infection varies with age. Infants
have 43% risk of developing active disease after an
infection while toddlers up to 5 years of age run a risk of
around 24%. Children >5 years of age have low risk of
developing disease after infection but risk increases again
during adolescence up to 15%. In general, there is 10 to
15% lifetime risk of developing disease after infection
and half the infected population develops disease within
first 5 years after infection.
Chemoprophylaxis is considered based on risk of
developing disease and 6 hr or 3 hr is recommended.
Same regime is considered for primary chemoprophylaxis in high-risk situation. Chemoprophylaxis in case of
MDR-TB has not been worked out and at present there
is no recommendation for the same.
Such a recommendation assumes no drug resistance
in an index patient. 3 hr may be a better option if cost is
not an issue. It is important to realize that RNTCP and
IAP protocols serve good purpose for the community
with minimum intervention. However, competence of
the regime may be marginally improved in clinical
practice by small modification. However, the principle
of management does not differ. Hence these recommendations are useful for baseline application, over
which one may modify to an extent that serves better
purpose to an individual patient.
Steroids in Tuberculosis
Definite indications include military TB, TBM and
pericarditis. There is no clear evidence in favor of steroids
in TBM in HIV infected children. They are not indicated
in lymphadenitis and pleural effusion. They may be used
in endobronchial tuberculosis.
293
In clinical practice, steroids are often misused and it

is important to follow the recommended protocol. If
steroids are used prior to firm diagnosis, it may cause
harm as well. Duration of steroid therapy needs to be
individualized as it depends upon therapeutic indication.
As an immunosuppressant, it must be continued for a
period that inflammation persists as evident clinically
or by investigations. Routinely duration of steroid
therapy may extend up to 3 months but at times longer.
Fixed Drug Combination (FDC)

While FDC is patient friendly, there are some relevant
issues about them. Firstly there is no data on clinical
efficacy of FDC in children. Though, INH and RMP
combination has been shown to be effective in children.
While INH is absorbed from intestine, other drugs are
absorbed from stomach. Bioavailability of liquid
formulations is not dependable and splitting of a tablet
is not recommended. Serious problem with FDC is
inability to titrate the dose to the individual needs and
hence FDC may prove to be toxic due to overdosing in
infants. Four drug fixed drug combination has been
shown to be equally effective in adults in attaining ve
sputum status within 2 months as compared to drugs
given separately. In fact side effects such as GI upsets
were less common with FDC and so also muscle and joint
pains. For convenience, four-drug combination
formulation may be used.
Pitfalls in Implementation of Effective Therapy

With MDR-TB and TB with HIV, burden of disease has
increased. In spite of effective chemotherapy, control has
not been achieved due to poor implementation and
compliance of therapy. RNTCP has evolved to take care
of these problems that includes DOTS. RNTCP embarks
on diagnosis by sputum microscopy, supervised drug
therapy at least in intensive phase (followed by weekly
visit to the clinic when one dose is administered under
supervision and two doses are given to the patient to
take them at home subsequently), regular drug supply,
patient tracking (progress to be monitored till end of
therapy) and administrative and political commitment.
Each patient on diagnosis has entire box of drugs
allocated though not handed over to ensure supervised
uninterrupted therapy. DOTS is expected to achieve
>85% patients completing therapy as prescribed. DOTS
may not be necessary for all patients but should be
considered in patients likely to default for various
reasons.
Though RNTCP has strived hard to formulate
uniform guidelines for diagnosis and management of
tuberculosis and also strategies to implement the same,
there have been many gaps in actual execution of the
program.
294
Section 5 Diagnosis
Gaps in Effectiveness of RNTCP

Health service related factors, health provider related
barriers and drug related issues pose problems in RNTCP
that come in the way of intended success.
Health service related factors include need for long
distance to travel, inconvenient clinic timing and lack of
facility in case of family emergency.
This resulted in poor compliance at each point of
diagnosis, registration, treatment and monitoring. Study
from West Bengal showed 14% patients did not give three
samples for diagnosis, 90% completed intensive phase
and 67% continuation phase and 30% found inconvenient
to attend DOTS center regularly. 28 percent centers
lacked expected facilities and they had inconsistency in
supplied drug boxes. 75 percent of recorded addresses
could not be verified and so defaulter retrieval was not
possible in 45% of patients.5
Provider related issues include lack of attention and
support, poor interpersonal communication and difficulties in reentering the program in case of defaulting.
Patients conception of equating well-being with cure and
inability of staff to take care of side effects add to poor
compliance.6
Provider delays is a major contributory factor as
patients have to visit several times before definitive
diagnosis is made. It is much better when private practitioner is a part of such a process. Once registered in
RNTCP, there was no delay in starting treatment.7 Thus,
publicprivate mix should be encouraged. Unfortunately,
provider adherence to standard protocols is suboptimum
at all levels including private practitioners and institutions.8-9 Tertiary care center had far better success rate
due to availability of senior faculty member in the
center.10 Defaulter, failure and death prevalence in
tertiary DOTS center was 3%, 2% and 1% respectively
due to better communication by senior member of the
team.11
Success rate of RNTCP has gone beyond benchmark
of 85%. MDR-TB is a challenge as diagnosis of MDR-TB
needs sophisticated laboratory help. If not treated
properly, there could be increasing prevalence of drug
resistant TB in the country and that needs to be avoided.12
Five percent of patients diagnosed in RNTCP did not
start treatment and there is a need to trace them.13
Males are diagnosed three times more often than
females in RNTCP14
Molecular polymorphism in the population decided
variable prevalence of hepatic drug toxicity and further
research is needed to define such a variation in the
population.15
Practical measures must be employed in terms of
flexible clinic hours, allowances for poor patients to come
to the clinic and training of health workers for respectful
communication and monitoring side effects. Label of

defaulter may have to be changed as it is disturbing a
patient and may lead to noncooperation.
DOTS could be replaced by POTS parent observed
therapy. Any health care facility including private clinics
can function as DOTS center.
Problems with RNTCP Dosing

The program offers ready packets for different weight
groups of 6-11/11-17/18-25/26-30 kg. Each weight group
gets the same dose so it is right dose for first 1 to 2 kg
weight in the group and other children in the group
would be underdosed. Further if child gains weight over
a month of treatment and happens to go into succeeding
group, he would be further underdosed as he continues
to get the previous group drug dose. Hence it may be
ideal to device two subgroups in each group for ideal
dosing. However, it may pose logistic problems.
Drug packages that are supplied in RNTCP have
product code and schedule numbers that are very
confusing. It may be much easy if package carries simple
label that is self-explanatory. For example, for 5 kg weight
group, label could be Ped TB I5 and Ped TB C5I denotes
intensive phase and C denotes continuation phase while
5 denotes weight group. Such simple changes would help
in easy implementation of treatment protocols.
Though there may be technical difficulty at the
manufacturing level to produce many pediatric weight
categories, the overall compliance will definitely be better
as even paramedicals and parents will easily understand
the above. Instead of allotting the work to one pharmaceutical company if few are chosen to manufacture same
composition, the job will be simplified.
All the pharmaceutical companies should be advised
to follow the same formula to avoid confusion. However,
the pharmaceutical company can add their company
name as suffix or prefix along with the recommended
uniform guidelines. The implementation of the above may
reduce inadvertent errors. Since the success of the entire
program depends on the appropriate drug supply to the
patient, the pharmaceutical company should be advised to
follow the same strictly.
HIGHLIGHTS
Pitfalls in diagnosis and treatment of childhood
tuberculosis result from scientific and logistic
limitations but more often are due to nonimplementation of standardized protocols that are
devised after careful analysis of available studies. It
is only when physicians adhere to standard protocols
of diagnosis and treatment that the disease is likely
to be controlled. If not, problems would increase in

terms of increasing drug resistance and spread of
tuberculosis
At all levels, it is best to document points in favor of
diagnosis and assign a patient a category that would
automatically pave the way for standardized
treatment protocol. This is especially important to
follow for private practitioners who take individual
decisions without any supervision and patients do
hold them in high esteem and in good faith and thus
are likely to follow their adviceirrespective of it
being right or wrong. Institutions are better placed
for adherence to standardized protocols though it
may not be taken for granted and adequate
supervision by a senior member is essential
At the community level, in RNTCP, emphasis must
be on patient friendly management that would
ensure better compliance. Finally, it is the tripartite
responsibility of government agencies, research
institutions and private practitioners that would
minimize pitfalls that seem to occur presently,
coming in the way of anticipated control of
tuberculosis.
REFERENCES
1. Gopinath K, Singh S. Urine as an adjunct speciment for
the diagnosis of active pulmonary tuberculosis. Int J
Infect Dis 2008 Nov 1.
2. Kumar G, Dagur PK, Katoch VM, et al. Diagnostic
potential of Ag85C in comparison to various secretary
antigens for childhood tuberculosis. Scand J Immunol
2008;68:177-83.
3. Mosby Inc. (copyright) Performance of QuantiFERON
TB testing in a tuberculosis outbreak at a primary school.
J Pediatr 2008;52(4).
295
4. Kabra SK, Lodha R, Seth V. Category based treatment of

tuberculosis in children. Indian Pediatr 2005;41:299.
5. Sen TK, Das DK, Saha S. Persistence of gaps in
implementation of revised national tuberculosis control
program in an area of West Bengal. Indian J of Public
health 2007;51:246-8.
6. Jaiswal A, Singh V, Ogden JA, et al. Adherence to
tuberculosis treatment: lessons from the urban setting of
Delhi, India. Trop Med Int Health 2003;8:625-33.
7. Kelkar-Khambate A, Klelmann K, Pawar S, et al. Indias
Revised National Tuberculosis Control Program: looking
beyond detection and cure. Int J Tuberc Lung Dis
2008;12:87-92.
8. Davidson H, Schluger NW, Feldman PH, et al. The effects
of increasing incentives on adherence to tuberculosis
directly observed therapy. Int J Tuberc Lung Dis 2000;4:
860-5.
9. Greaves F, Ouyang H, Pefole M, et al. Compliance with
DOTS diagnosis and treatment. Recommendations by
private practitioners in Kerala, India. Int J Tuberc Lung
Dis 2007;11:110-2.
10. Tahir M, Sharma SK, Rohrberg DS, et al. DOTS at a
tertiary care center in northern India: successes,
challenges and the next steps in tuberculosis control.
Indian J Med Res 2006;123:702-6.
South Delhi India. Int J Tuberc Lung Dis 2008;2:74-80.
12. Chauhan LS. RNTCP 2007; looking ahead to future
challenges. J Indian Med Assoc 2007;105:192,194-6.
13. Sai Babu B, Satyanarayana AV, Venkateshwaralu G, et
al. Initial default among diagnosed sputum smear
positive pulmonary tuberculosis patients in Andhra
Pradesh India. Int J Tuberc Lung Dis 2008;12:1055-8.
14. Ganapathy S, Thomas BE, Jawahar MS, et al. Perceptions
of gender and tuberculosis in a south Indian urban
community Indian. J Tuberc 2008;55:9-14.
15. Roy PS, Majumder M, Roy B. Pharmacogenomics of antiTB drugs-related hepatotoxicity. Pharmacogenomics
2008;9: 311-21.
23
Tuberculin Test
The tuberculin skin test has been the traditional method

of diagnosing infection with M. tuberculosis. Appropriate
use of the skin test requires a knowledge of antigen used
(tuberculin), the immunologic basis for the reaction to
this antigen, the technique(s) of administering and
reading the test; and the results of epidemiologic and
clinical experience with the test.1 Simple questions which
need to be answered before discussing the test in details
are as follows:
What is Tuberculin Skin Test?

The tuberculin skin test (also known as PPD test) is a test
used to determine if some one has developed an immune
response to the bacterium that causes tuberculosis (TB).
This response can occur if some one currently has TB, if
they were exposed to it in the past or if they received
BCG vaccine against TB. The World Health Organization
estimates that 2 billion people world wide have latent
TB, while 3 million people die of the disease each year
over the world.
Basis of Tuberculin Test

Infection with M. tuberculosis produces a delayed-type
hypersensitivity skin reaction to certain components of
the bacterium. These are contained in extracts of culture
filtrates and the core elements of the classic tuberculin
PPD (purified protein derivative). This material is used
for skin testing for tuberculosis. Reaction in the skin to
tuberculin PPD begins when specialized immune cells
called T cells, which have been sensitized by prior
infection, are recruited by the immune system to the skin
site. There they release lymphokines which are called
chemical messengers. The induration is induced by
lymphokines through local vasodilation leading to
edema, fibrin deposition, recruitment of other types of
inflammatory cells to the area. For the PPD test to be
positive, the incubation period varies from 2 to 12 weeks
after exposure to TB. The details are discussed further in
the chapter.
Are there any Risks from Having the

PPD Skin Test?
There is a very slight risk of having a severe reaction to
the test, including swelling and redness of the arm, in
people who have had either tuberculosis or have received
BCG. Allergic reaction are also rare.
Till date, tuberculin skin test was the only method to
diagnose latent tuberculosis infection. Recently a new
test quantiFERON-TB test (QFT) was approved by the
United States Food and Drug Administration (USFDA)
as an aid for diagnosing latent M. tuberculosis infection.1a
This is an in vitro diagnostic aid that measures a
component of cell-mediated immune reactivity of
M. tuberculosis. It is based on the quantification of
interferon-gamma (IFN-) released from sensitized
lymphocytes in whole blood incubated overnight with
purified protein derivative (PPD) from M. tuberculosis and
control antigens. In this method whole-blood specimens
of donors is stimulated with ESAT-6 and CFP-10 antigen
and then cultured. Plasma concentration of interferongamma discharged is determined with quantiFERONCMI. The optimum cut-off level determined by Harada
et al2 was 0.35 units/ml for both ESAT-6 and CFP-10.
This gave the test a sensitivity of 89.0% and specificity of
98.1% in detecting tuberculosis infection. This test is not
affected by previous BCG vaccination, presence of
nontuberculous mycobacteria in the environment. As in
the case of clinical tests in general, the cut-off should be
set at a lower level when the test is applied to high
prevalence situation.
Harada et al3 used this test for detecting tuberculosis
infection among contacts of a tuberculosis patient by
determining the wholeblood interferon-gamma response
to specific antigens. It is unaffected by BCG-caused
tuberculin allergy. In the case of an outbreak, QFT greatly
reduced the indication of chemoprophylaxis, from 28%
of all the contacts solely based on tuberculin test to only
7%. It is emphasized by Harada et al3 that this will
provide a high possibility for wider and more accurate
Chapter 23 Tuberculin Test

indication of chemoprophylaxis and will be one of the
essential tools of tuberculosis control of the 21st century
in Japan. Pai et al4 used this test to estimate latent
tuberculosis infection prevalence in health care workers
along with the tuberculin skin test (TST) to determine
agreement between the two. They compared their
correlation with risk factors. A large proportion of the
health care workers were latently infected. Fifty percent
were positive by either TST or IFN-gamma assay, 31%
were positive by both. There was high agreement between
TST and IFN-gamma assay and similar association
between positive test result and risk factors. Therefore,
they concluded that decision to select one test over the
other will depend upon population, purpose of testing
and resource availability.
Kang et al5 evaluated these two tests in Korean adult
population and concluded that this is a better indicator
of the risk of M. tuberculosis infection than TST in a BCG
vaccinated population.
HISTORY
In 1890, Robert Koch announced a cure for tuberculosis.
This consisted of giving patients subcutaneous doses of
a filtrate of heat-killed culture of tubercle bacilli. This was
known as Kochs lymph or Kochs remedy.6 The use of
tuberculin for the cure of tuberculosis was based on his
observations of altered response to tuberculin in
previously infected guinea pigs. There was quick healing
at the site of second injection of viable organisms (Kochs
phenomenon). Within a year of announcement of this
therapy, it was disapproved as a cure for tuberculosis.
However, this discovery became the most widely used
diagnostic test ever developed.
Von Pirquet demonstrated that if a child with
tuberculosis was inoculated with a solution of old
tuberculin (OT), a papule 5 to 20 mm in diameter
developed at the site of scarification. It took 8 days or so
for it to disappear. This term was designated allergy.
Bleiker, a Polish researcher named Kochs remedy as
tuberculin in 1891 and thus the Tuberculin test was born.7
Various methods of administration were tested: Pirquet
cutaneous test, the Moro percutaneous patch test, the
Mantoux intracutaneous test, and the Calmette
conjunctival test.8
Seibert9 in 1934 described that in the culture filtrate
of tubercle bacillus, besides tuberculoprotein impurities,
other cell wall components were contained in this form
of tuberculin. This was called old tuberculin (OT)
resulting in nonspecific reactions. Due to this
standardization of the dose the maintenance of potency
was difficult. In 1941 Seibert and Glenn10 separated a
product with predictable qualities and called it purified
protein derivative (PPD). This is now injected intradermally
for tuberculin test.
297
TUBERCULINS
The tuberculin skin test is based on the fact that infection
with M. tuberculosis results in sensitivity to certain
antigens of this organism that are also contained in the
culture extracts called tuberculins. There are two main
types of tuberculin: Old tuberculin (OT) and Purified
protein derivative (PPD). Old Tuberculin (OT) is a filtrate
obtained from heat-sterilized concentrated broth culture
of tubercle bacilli. Initially, glycerinated meat broth was
used as the medium; synthetic media later replaced this.
Currently this preparation is rarely used. Florence
Seibert9 coined the term Purified protein derivative
(PPD) in 1934 for the product from heat-concentrated
synthetic medium OT by precipitating the protein
initially with trichloroacetic acid.7 The PPD resulting
from these experiments was called SOTT (synthetic
medium old tuberculin trichloroacetic acid) precipitate.
In the same year Joseph Aronson gave a detailed
description of its use and designed a kit for field use,
including a 1 ml glass syringes and 26 gauge platinum
needles.7 Later, in 1941 Seibert prepared a large batch of
PPD in which ammonium sulfate was used for
precipitation to obtain a highly purified preparation.10
This material, lot 49608, was designated the standard
tuberculin PPD-S, and became the International
Standard for all tuberculins.11
Another commonly used tuberculin, PPD RT23, is a
large batch of purified tuberculin produced by the Statens
Serum Institute, Copenhagen and issued since July 1,
1958.12 Recently in view of short supply of PPD-S, a new
standard has been manufactured and tested.13
The International Standard tuberculins are in the
custody of the laboratory for the Biological Standards,
Statens Serum Institute, Copenhagen, Denmark.14
In India, currently there is shortage of PPD. The BCG
laboratory, Guindy, has stopped manufacturing PPD
RT23 of 1TU with tween 80, as it has exhausted the stock
of PPD RT23.15 At present, Span Diagnostics Limited is
marketing a tuberculin that has been calibrated against
PPD RT23 in 3 strengths: 1 TU, 5 TU, and 10 TU.16 The
use of 10TU is not recommended for use in pediatrics.
COMPOSITION
Two commonly used methods for the preparation of PPD
are ammonium sulfate and trichloroacetic acid
precipitation. M. tuberculosis is grown in liquid medium,
sterilized using steam at 100C for three hours. Filtration,
precipitation, and washing procedures give PPD higher
concentration of protein and polysaccharide, whereas
trichloroacetic acid preparation method results in PPD
with higher percentage of nucleic acid.
The potency of PPD is expressed as Tuberculin Units
(TU) instead of International Units (IU). The standard
298
Section 5 Diagnosis
5 Tuberculin Unit (TU) dose of PPD-S is defined as the

delayed skin test activity contained in a 0.1 mg/0.1 ml
dose of PPD-S. One TU of PPD RT23 has been defined as
0.02 mg in 0.1 ml of phosphate buffered saline with
0.005% Tween 80 (polyoxyethylene sorbiton monocleate).
The standard dose of a commercial PPD preparation is
defined as the dose of that product which is biologically
equivalent to that contained in 5 TU of PPD-S (i.e. it elicits
skin reactions of equivalent size + 20%).17 One TU of PPD
RT23 (with Tween 80) corresponds fairly well to 5 TU of
RT 19-20-21 and to 6 or 7 TU of RT 22.18 One TU of PPD
RT23 (with Tween 80) corresponds to 3 TU of PPD-S.
Therefore, 2 TU of PPD RT23 was used for diagnosis or
surveys.19 However, these values are approximations,
with the ratios likely to vary in different populations.18
Therefore, prior to comparison of utility of any two
tuberculins, one must consider the abovementioned facts.
PPD RT23 in saline buffer containing tween 80 is
approximately twice as potent as PPD-S in phosphate
buffer saline without Tween 80, if similar protein weights
are used. Since reaction to RT 23 tends to be some what
softer in appearance and generally less severe, all tests
with this tuberculin can be carried out at a strength of 2
TU.
1 TU and 250 TU preparations contain one-fifth and
fifty times the concentration of antigen determined to be
equivalent to 5 TU PPD-S. 20 These have limited
usefulness in the diagnosis of tuberculous infection.7
Tuberculin preparations retain their potency for nearly
6 months if stored in cool (2 to 20C) dark place. The
optimum temperature for storage is 2 to 8C. Opened
vials of tuberculin should not be kept for more than 2
days.19 They should not be frozen. When diluted, PPD is
absorbed on glass and plastic surfaces. To minimize this,
a small amount of detergent, Tween 80, is added to the
diluent for PPD and the solution is kept refrigerated in
the dark.11 The other antigens used for screening for
nontuberculous
mycobacterial
cervicofacial
lymphadenitis in children are from Mycobacterium kansasii,
Mycobacterium avium and Mycobacterium scrophulaceum.
In these cases optimal cut-off for a positive test is 5 mm.
Tuberculin skin testing with these antigens had a
sensitivity and specificity of 70% and 98% respectively
as reported by Lindeboom et al.20a It was recommended
by them21 that in the diagnostic analysis of cervicofacial
lymphadenitis in children without a history of TB
exposure or bacilli Calmette-Guerin vaccination,
tuberculin skin test is a valuable first step in the diagnostic
analysis.
In order to minimize the reduction in potency:
i. Tuberculin should never be transferred from one
container to another,
ii. Skin test should be given as soon as possible after
the syringe is filled,
iii. The remaining solution should not be frozen, and

iv. The tuberculin should be stored in a dark place as
far as possible.
IMMUNE BASIS OF TUBERCULIN REACTIVITY

Initial infection with tubercle bacilli is followed by the
development of allergy to tuberculoprotein approximately after 4 to 6 weeks. This is in the form of a cell
mediated, delayed hypersensitivity reaction (Type IV)
(Fig. 23.1).
The Mantoux tuberculin reaction is a classic example
of delayed-type hypersensitivity (DTH). Infection with
M. tuberculosis sensitizes the person to the antigenic
components contained in tuberculin. The process of
sensitization takes place mainly in the regional lymph
nodes, as a result of which sensitized T lymphocytes enter
the blood stream and circulate for long periods of time.
The sensitization of lymphocytes usually reaches a level
adequate to produce a detectable DTH response at 2 to
10 weeks after the initial infection with M. tuberculosis.
Their subsequent restimulation with the same or a similar
antigen, such as an intracutaneous injection of tuberculin
elicits a characteristic delayed hypersensitivity reaction
with induration and erythema that peaks at 48 to 72 hours
and subsides over a period of 5 to 7 days.
Histologically, the earliest phase of the reaction is seen
as a perivascular cuffing with mononuclear cells
followed by a more extensive exudation of mono- and
polymorphonuclear cells. The latter soon migrate out of
the lesion leaving behind a predominantly mononuclear
cell infiltrate consisting of lymphocytes and cells of the
monocyte-macrophage series. When the sensitized T cells
Fig. 23.1: The tuberculin response

come in contact with the specific antigen they secrete
lymphokines which in turn recruit nonsensitized
lymphocytes to the site of inflammation, retain them at
the site where they become activated, thus amplifying
the immune response and giving rise to the characteristic
type IV hypersensitivity response (Fig. 23.1). This is also
accompanied by increased vascular permeability. There
is usually a 2- to 3-fold increase in the thickness of the
dermis in the classical reaction and this peaks a day later
than the erythema. This increase in the volume is much
greater than that of infiltrating cells measured by
histometry (20-30%).21,22 Therefore, edema fluid accounts
for much of swelling.17,18 In fact, the usual clinical method
of determining tuberculin sensitivity relies more on the
secondary effect of edema rather than the cell
infiltration.22
Delayed-type reactivity cannot be transferred from a
sensitized to a nonsensitized individual with serum
antibody. Lymphoid cells, especially the T-lymphocytes
are required for the same. 23 Hence, three major
components of the delayed hypersensitivity skin reaction
are:24
i. Antigen recognition (afferent limb).
ii. Antigen sensitized cell reactivity (efferent limb).
iii. Cutaneous inflammation.
TUBERCULOSIS AND IMMUNE SYSTEM

Hegde et al25 have elaborated on the tuberculosis and
immune system. Table 23.1 summarizes the clinical
situations described by them.
Immunochemistry of Tuberculin Skin Test

Mycobacterium tuberculosis produces a delayed type
hypersensitivity reaction to certain antigenic components
of the organism that are contained in the extracts of
culture filtrates called tuberculins. Tuberculin PPD
(purified protein derivative) is isolated from a culture
filtrate of bacilli by protein precipitation. PPD is injected
intradermally into the volar surface of the forearm
(Mantoux test). Test should be read after 48 and 72 hr
after injection when the induration is maximum. In some

individuals zero mm induration (pseudoanergy) may be
recorded despite the fact that he/she has tuberculin
sensitivity. In such cases biopsy findings are similar to
that of positive tuberculin test cases. Pseudoanergy has
been reported in HIV-seronegative hemophiliacs and in
chronic obstructive pulmonary disease patients receiving
prednisolone. In children, this pseudoanergy can be
present in those who are on long-term steroid therapy
because of certain diseases like nephrotic syndrome and
malignancy (lymphatic leukemia). In preliminary
evaluation of patients with active tuberculosis, falsenegative results can be noted in 25% cases. Tissue
specimens were taken after Mantoux test in children who
had received BCG. Specimens were processed in the
usual manner and embedded in paraffin. Then 5 m thick
sections were cut and stained with hematoxylineosin. In
addition, 5 m thick sections were added to polylysine
coated slides and stained with streptovodin biotin
method using CD45, CD3, CD68 and CD20 antibodies.
In immunohistochemistry, positivity of cells were
assessed semiquantitativaly. In all cases hematoxylineosin sections revealed a mononuclear cell infiltration
around the dermal vasculature and dermal adnexa. A
granulomatous reaction with or without necrosis was not
seen in any sample. With immunohistochemical stains
CD45+ (leukocyte common antigen) and CD3+ (a T-cell
antigen) cells comprised the majority of the infiltrate.
CD68 positivity was also noted, although in a lower
percentage of cells. On the other hand CD20 (a B-cell
marker) did not stain any cells of the infiltrate.
In the material, the great majority of cells were CD45+
cells, and at least 50% of these cells were CD3+ T cells. It
is proposed that determination of T-lymphocytes
dominating infiltration may be used in pseudoanergy
cases in which an induration is not observed. If clinical
observation and laboratory findings are consistent with
tuberculin sensitivity in a particular anergic patient, a
punch biopsy from the test site can help in diagnosing
pseudoanrgy cases from real anergic ones.
Table 23.1: Host responses to exposure to the tubercle bacillus

Immune status
Clinical situation
Tuberculin test (Mantoux)
Activated helper and cytotoxic
No clinical disease (e.g.
+ ve
cells CD45 RO (Memory cells)
BCG vaccination)
Normal CMI Nonactivated
May or may not show
ve to +ve in 2-8 weeks
Helper cells CD45RA (Nave cells)
clinical disease
Impaired CMI*
Clinical disease
ve or diminished or +ve
Total lack of CMI
Fulminant disorders
likely ve
*CMI = cell-mediated immunity
299
300
Section 5 Diagnosis
Biomarkers Changes Associated with Tuberculin Skin

Test (TST) Conversion: A Two Year-Longitudinal Followup in Exposed Household Contacts
A high prevalence (50-80%) of tuberculin skin test
positivity (TST+ > 10 mm induration) has been reported
in TB endemic countries. This pool forms a huge reservoir
for new incident MTB cases. The measurement of
biomarkers in household contacts of a recently TB
exposed cohort revealed that there was significant
suppression of IFN-, raised IL-10 and raised TNR in
response to mycobacterial culture filtrate (CF)
irrespective of their TST status.25a
Post TST conversion was associated with significant
increase of culture filtrate induced IFN-, IL-10 and IL-6
levels. CF induced IFN- was higher in recently infected
household contact groups. Mitogen induced cytokine
secretion showed similar differences for different groups.
ADMINISTRATION OF TUBERCULIN TEST

There are two techniques of applying the tuberculin
testthe intracutaneous Mantoux test and the
percutaneous multiple-puncture skin test. The multiplepuncture tests are cheaper and easier to administer and
are in routine use in many developed countries.
However, their results are not diagnostic and a Mantoux
test is needed before tuberculous infection can be
diagnosed.26 In India, Mantoux test has been in popular
use and hence, will be the only test detailed here.
The Mantoux Test

The test is performed by the intracutaneous injection of
0.1 ml of PPD containing 5 TU PPD-S or an equivalent
dose of other PPD into the volar (ventral) surface of long
axis of the forearm. This raises a wheal 6 to 10 mm in
diameter. It is suggested that a wheal of 7 to 8 mm is also
sufficient. The injection is administered with a short
26/27 gauge steel or platinum needle with short bevel
with a glass or plastic (disposable) tuberculin syringe.11,22
It is important to note that the test should not be repeated
at the same site where previous test has been done. It is
because repeat test at the same site will have boosting effect
and a larger reaction will occur which does not indicate
active disease. This boosting effect does not occur in the
1st week but lasts for 18 months. Hence, it is suggested
that when a confirmatory repeat test is necessary, it should
be done within one week. The boosting effect will have
disappeared if 18 months have elapsed between the first
tuberculin test and the repeat test.
Injection Technique
The skin of the arm is lightly stretched length wise and
the pointer of the needle is inserted length wise, with
bevel upward, into the superficial layer of the skin

(intradermal). The syringe is held by the barrel only and
the plunger is not touched until the point of the needle
has been satisfactorily inserted. After injecting 0.1 ml of
the PPD, the finger is removed from the end of the
plunger before the needle is withdrawn. The injection
should raise a flat anemic wheal with pronounced pits
and a steep border. If the injection is given into the deeper
layer of the skin, it will affect the size of the resultant
tuberculin reaction and make interpretation difficult.
In order to reduce the discomfort of the injection,
topical anesthesia may be applied. In a recently published
randomized study, it has been observed that topical
lidocaine-prilocaine did not affect the TST size reaction.27
Reading the Mantoux Test

The test should be read 48 to 72 hours after injection, as
the delayed hypersensitivity reaction is maximal at 48 to
72 hours.28 An immediate hypersensitivity response is
of no significance.29 The reading should be made in good
light, with the forearm slightly flexed at the elbow. It is
based on the presence or absence of induration which
can be determined by either palpation or the pen
method.30 A ballpoint pen is lightly run transversely from
the side of the arm towards the indurated area, starting
approximately 4 cm away. When the border of the
induration is reached, a slight resistance is felt, and the
pen is lifted. The procedure is repeated from the opposite
side and the distance between the two end marks is
measured in millimeters. The diameter of induration
should be measured transversely to the long axis of the
forearm and recorded in millimeters.
A recent study questions the reliability of health care
workers in accurately reading a tuberculin skin test
reaction in a known tuberculin positive individual.31 In
this study, 93% of 107 health care professionals underread the tuberculin reaction. This suggests marked interobserver variability. It appears that educational strategies
directed toward improving the accuracy of tuberculin skin
test reading are needed for health care professionals at
each center.
Interpretation of Test Results

The aim of the tuberculin skin test is correct identification
of past infection with M. tuberculosis. In clinical practice,
it helps in diagnosis of tuberculosis disease in younger
children under five years of age. Therefore, the definition
of significant tuberculin reaction should be based on the
degree to which this definition allows a clear separation
between reactions resulting from infection with
M. tuberculosis and reactions to tuberculin that result from
other mycobacteria and after BCG.

A positive test conveys that the patient has been
infected with M. tuberculosis either recently or in the past.
In a population, percentage of positive test will steadily
increase with age. Actual interpretation of tuberculin test
must have distinct cut-off point for positive and negative
results. Bigger the size of induration the more is its
significance in detecting disease (younger than 5 years
of age). This is based on the premise that tuberculin, being
derived from M. tuberculosis, would elicit a greater
reaction in an individual exposed to M. tuberculosis than
to other organisms. Less than 5 mm size of induration is
definitely a negative test. Size below 10 mm (5-9 mm) is
not definitely positive except in a child with associated
HIV/AIDS as there are so many factors such as
malnutrition, severe tuberculous disease, viral and other
infections, patient on steroid therapy, presence of
malignancy, etc. that can produce lesser degree of
induration.11 Therefore, it is very important to consider
other factors in an individual for proper interpretation
of positive or negative test result. In a strongly positive
test we may be dealing with active tuberculosis especially
in children but many healthy adults also can have
strongly positive test. Similarly, a negative test does not
exclude active tuberculosis.
The reaction to tuberculin skin test is interpreted as
follows:
Size of induration with 5TU PPD-S / 1TU PPD with
RT 23 and Tween 80
<10 mm - Negative
10 mm
- Borderline
>10 mm - Positive
Tuberculin reaction is more specific in younger age
group, i.e. 0 to 9 years. If a child below 2 years is found
to be tuberculin positive, it may be an indirect evidence
of an active tuberculous focus in the body. Use of PPD in
high doses, i.e. 10 TU, etc. should be avoided, because,
reaction elicited is due to dose response rather than due
to real infection. In every country there should exist a
national consensus and one should be careful in using
the type and dose of PPD as per the recommendations of
the national authorities.
Causes of a False-negative Reaction

to Mantoux Test
These have been enumerated in Table 23.2.
Causes of False-positive Reaction to Mantoux Test

In a small number of individuals tuberculin reactions
maybe due to errors in administering the test or reading
the results; however, the more common causes of falsepositive reactions are infection with nontuberculous
mycobacteria or recent vaccination with bacille CalmetteGurin (BCG).
301
Table 23.2: Causes of a false-negative

reaction to Mantoux test
Infections:
Viral (mumps, measles, chickenpox, HIV infection)
Bacterial (recent or overwhelming tubercular infection,
leprosy, brucellosis), associated fungal infection
Faulty technique
Improper storage and dilution of tuberculin
Desensitization due to heavy load of antigen as in miliary
tuberculosis and tuberculous meningitis
Attenuated viral vaccination (measles, mumps, polio)
Metabolic derangements (chronic renal failure)
Protein energy malnutrition (grade III & IV)
Lymphoreticular disorders
Lack of available circulating T lymphocytes (congenital
hypotrophy or atrophy of thymus)
Presence of abnormally high number of T-suppressor
cells at the site of skin test
Intake of corticosteroids, immunosuppressive drugs
Extremes of age (newborn or elderly)
Stress (surgery, burns, graft versus host disease)
Denatured/contaminated tuberculin
Errors in recording
INFECTION WITH NONTUBERCULOUS MYCOBACTERIA

Infection with M. avium or other members of the genus
nontuberculous Mycobacterium can result in tuberculin
sensitivity. These cross-reactions occur in many parts of
the world. In principle, the larger the induration size,
the greater the likelihood of true infection with
M. tuberculosis. Lindeboom et al20a has emphasized the
role of tuberculin skin testing in the diagnosis of
nontuberculous mycobacterial cervicofacial lymphadenitis
in children described earlier.
BCG VACCINATION
The effect of BCG vaccination on the subsequent Mantoux
test is highly variable as it partly depends on the strain
of BCG used. In BCG vaccinated children, the reaction
to tuberculin ranges from 3 to 10 mm. The presence or
size of postvaccination tuberculin skin test reaction does
not reliably predict the degree of protection afforded by
BCG because it is a hypersensitivity reaction. Tuberculin
skin reactivity due to BCG vaccination wanes with time
and is unlikely to persist beyond 10 years after
vaccination. Several studies have shown that at least 50%
of the children after BCG vaccination do not become
tuberculin positive and 80 to 90% of those who show
weak positive test initially become negative after 2 to 3
years of BCG vaccination. Seth et al32 have demonstrated
that, there is 50 to 60% waning in the first year itself.
Hence, with other supportive criteria for diagnosis of
tuberculosis, positive tuberculin test must not be ignored
302
Section 5 Diagnosis
and attributed to BCG vaccination. The following features

suggest infection with tuberculosis in a tuberculin
positive child who has received BCG.
i. Size of the reaction >10 mm.
ii. Household contact with a tuberculosis patient.
iii. High prevalence countries
iv. Long time interval between vaccination and
tuberculin testing.
Al-Kassimi et al33 have described the significance of
positive Mantoux reactions in BCG-vaccinated children.
They demonstrated that tuberculin sensitivity rises more
steeply with age in the BCG vaccinated than the
unvaccinated children. BCG vaccinated children display
an increased ability to respond immunologically to
encounter environmental mycobacteria. In countries with
low prevalence of environmental mycobacteria, this
results in a slow but persistent rise of skin reactivity to
tuberculin14 more in vaccinated than unvaccinated
subjects.
Wang et al34 in a recent meta-analysis, showed that
(a) BCG significantly increases the likelihood of a positive
tuberculin skin test, (b) the effect was less after 15 years,
and (c) reactions > 15 mm were more likely to be the
result of tuberculosis infection rather than of BCG
vaccination.
VARIABLES AFFECTING INTERPRETATION

There are many reasons (operating individually or
together) for a false-negative Mantoux test reaction
(Table 23.2).11,24 A physician must keep them in mind
when interpreting a tuberculin test reading. Most of the
errors in administration and reading can be avoided by
careful attention. However, some situations need special
mention in relation to the tuberculin test and are
described below:
Cross Reactivity
Tuberculin reactivity due to infection with mycobacterial
species other than M. tuberculosis frequently complicates
tuberculin test interpretation. 35, 36 Generally these
reactions are less than 10 mm in diameter (which is the
general cut-off point), but depending on the exposure of
the population to nontuberculous mycobacteria, some
reactions can be greater.37 The reverse may also be true,
i.e. some persons infected with M. tuberculosis may
develop reactions less than 10 mm diameter to the 5 TU
dose of tuberculin.37 Stanford et al38,39 and Ly et al40 have
put forward useful information on the environmental
mycobacterial profile of different cities in India and
Vietnam. In India, a high level of initial sensitization to
mycobacteria was observed in a multiple skin test study
of school children in Agra.38 Conversely, a low level of
sensitization was found in Ahmednagar, Maharashtra39

where BCG is expected to be more protective. In a
multiple skin test survey using newer tuberculins
conducted in Hanoi and Nba Trang cities of Vietnam,
low levels of mycobacterial sensitization with remarkable
regional differences were recorded.40 Similar tuberculin
testing has also been carried out in other countries
showing differing profiles.41 Logically, therefore, one
must consider the cross-reactivity profile of the
population and the risk of exposure of the individual
before interpreting a tuberculin test.38
One approach to determine the extent of crossreaction may be to determine the correlation between
reactions to PPD-S and to PPD-B (indicator of sensitivity
to atypical mycobacteria). Some studies have shown that
from the results of dual testing in those with medium
size induration of 6 to 11 mm to 5 TU PPD-S, those
infected with M. tuberculosis could be clearly separated
from those not so infected.42 However, similar distinction
was not possible in the Indian setting.43
Booster Phenomenon
On sequential tuberculin testing some persons show a
marked increase in the size of their skin reactions that
may not be due to recent or past tuberculous infection.
This enhancing or boosting phenomenon has been
reported for more than four decades and was attributed
to faulty administration of the test, observers error,
stability of the antigen, previous BCG vaccination, race,
contact with tuberculosis and recent illness or
immunization.44 The increase seems to occur as the initial
test stimulates the factors that determine reaction size in
the subsequent test. 11,44-47 However, most of these
correlations are difficult to explain.44 Boosting is probably
a situation in which hypersensitivity to tuberculin has
waned so that an initial reaction to PPD is not significant
but provides the stimulus to boost the size of a reaction
to a second test, sometimes leading to tuberculin
conversion.11,47 Sensitivity caused by one or more of the
nontuberculous mycobacteria can also be a cause. It is
important to determine whether or not the cause is
infection with M. tuberculosis and if so, whether this
infection is of recent or past occurrence; for appropriate
therapy of subclinical infection detected in people after
a positive tuberculin test and epidemiological surveillance
programs depend on its correct interpretation.44
The booster effect can occur as soon as a week after
the initial test and persist for as long as a year.20 It contributes
significantly to false conversions. Alexander and Roper48
reported 28% conversions while Morse et al49 reported a
31% change in tuberculin test status. However, it occurs
rarely in children, increases in frequency with age and is
seen more frequently in persons over 50 years of age.45

As yet its relationship with the progress of tuberculosis
disease and healing has not been studied.
Biologic variability as well as difference in administration and reading can result in change of less than 6
mm in 9% of subjects if tuberculin test is administered
again. Therefore, an increase of 6 mm or more should be
considered to represent a true biologic phenomenon; this
may be due to boosting or conversion.50 Boosting is
maximal if the interval between the two tests is between
1 to 5 weeks.51 The boosting phenomenon is common as
it is roughly correlated with the prevalence of initial
tuberculin reaction. It is, however, nonspecific as it is
associated with remote TB infection, non-tuberculosis
mycobacterial sensitization and BCG vaccination. 50
Boosting can be differentiated from conversion based on
the clinical situation (exposure in the interval between
the two tests), the size of the reaction (as the size of second
reaction increases, the likelihood that it represent true
conversion, increases).
In most situations, an individual whose tuberculin
reaction changes from less than 10 mm in diameter to
more than 10 mm in diameter and increases by 6 mm
within a period of 2 years, should be considered recently
infected.9 In order to classify as recent convertor, the
following criteria should be met:
i. The skin reaction must have increased by > 6 mm.
ii. The increase must have been from less than 10 mm
to more than 10 mm.
iii. The increase occurred over a time period of less than
24 months.
Tuberculin Reaction in Relation

to Isoniazid Therapy
It has been reported that isoniazid treatment of tuberculosis in children had no significant effect on tuberculin
sensitivity.52 Studies conducted over a period of ten years
concluded that isoniazid treatment did not reduce the
tuberculin sensitivity and that conversion rate was
similar to patients receiving placebo therapy.53,54 It has
been suggested that a positive tuberculin reaction in
the isoniazid treated patient is to childs advantage. With
the risk of endogenous disease removed by treatment,
the patient gains cellmediated immunity which protects
the child from future exogenous reinfections.55-57
Inter-observer Bias
Significant variability in performance and interpretation
of the Mantoux test has been observed in various
studies.31,34,58-60 It was noted that differences in size of
reactions recorded by experienced readers were as
variable as those of inexperienced readers. Variability of
15% in reading by the same person, extending up to 50%
303
of the reaction size at times was also seen.57 Patients

reading of their own results were also inaccurate and
unreliable. It is best to have one person, who is skilled in
the procedure, to do the testing in a medical facility.
Persistently Negative Tuberculin Reactions

A study by Steiner et al61 identified a small number of
children with culture proven tuberculosis who did not
have severe disease but consistently failed to react to
tuberculin for no apparent reason. Culture and biopsy
techniques have to be relied upon for diagnosis in these
cases. By as early as 1968, and subsequently reinforced
by many studies by Seth and coworkers (AIIMS, New
Delhi),62 it has been established that severe malnutrition
interferes with the elicitation of DTH, i.e. Mantoux
test.63-65 Hence, in spite of having tuberculosis infection
or disease the test can be negative.
Indications for Tuberculin Testing

Table 23.3 lists the indications for tuberculin testing as
recommended by the American Academy of Pediatrics.
HIV infection is also an indication for tuberculin testing.20
We especially recommend tuberculin testing on a priority
basis in children who are in contact with sputumpositive
tuberculosis cases as they are at higher risk of infection
and the disease. Sometimes tuberculosis is also found in
patients with diseases which are likely to render them
anergic.20
HIV Infection and Tuberculin Test

There is paucity of data regarding tuberculin skin test
reactivity in HIV-infected children. It has not been shown
that HIV-infected children are able to mount antigenspecific cell-mediated immune responses that
are qualitatively similar to those of age-matched
control subjects.66 Moreover, the loss of delayed-type
hypersensitivity responses corresponds to both clinical
and immunological progression to HIV-disease.
Tuberculin test is also indicated in HIV-seropositive
children and in this group tuberculin negative children
require annual testing.26,67 This is to enable timely
detection and treatment of tuberculosis in HIV-infected
children because progression of HIV infection to disease
(AIDS) on one hand, renders the patient anergic (to
tuberculin), on the other hand, in patients with clinical
disease (AIDS) tuberculosis presents in atypical forms
which is difficult to diagnose. Garcia-Garcia et al68 have
demonstrated that PPD reactivity is useful to diagnose
tuberculosis only among HIV-infected individuals with
CD4+ counts more than or equal to 500 cell/mm3. Among
individuals with lower counts, lowering cut-off levels or
using anergy panels such as candida and tetanus toxoid
did not permit comparable reactivity as that observed
among HIV-infected children.
304
Section 5 Diagnosis
Table 23.3: Indications for tuberculin testing

Children for whom immediate skin testing is indicated
Children with suspected tuberculosis on radiographic
or clinical findings
Contacts of confirmed or suspected infectious
tuberculosis cases
Children immigrating from endemic areas (Asia,
Africa, Latin America, etc.) to nonendemic areas
Children who should be tested annually
Children infected with HIV
Children who should be tested every 2-3 years
Children exposed to following individuals: HIV
infected, homeless, drug-addicts, prison-inmates
Children who should be considered for testing at ages 4
to 6 and 11 to 16 years
Children (without high risk factors) residing in high
prevalence areas (notified high tuberculosis rates)
Children whose parents immigrated from high
tuberculosis prevalence regions (countries) of the
world
Risk of progression to disease
Children with other medical risk factors: malnutrition, congenital or acquired immunodeficiencies,
diabetes mellitus, chronic renal failure (Underlying
immune deficiencies would enhance the possibility
for progression to disease; and initial Mantoux
tuberculin test should be performed before initiation
of immunosuppressive therapy as indicated in a child)
BCG vaccination is not a contraindication to tuberculin

testing
Some of the indications may not be of practical importance
in developing countries like India
(Modified from: American Academy of Pediatrics,
Committee on Infectious Diseases; update on tuberculosis
skin testing of children. Pediatrics 1996; 97: 282-4) and
pediatrics 2001; 107: e54 down loaded by Indian Council
of Medical Research on July 2010.
Uses
A significant reaction to 5TU of PPD-S or equivalent dose
of other tuberculin demonstrates presence of hypersensitivity to tubercle bacilli. The larger the reaction, the
greater is the probability that the responsible organism
is M. tuberculosis. Tuberculin skin test is useful in
evaluation of children suspected of having tuberculosis
in as much that a significant reaction supports the
diagnosis.
In any population, the probability that a positive skin
test represents a true infection, depends on the prevalence
of infection with M. tuberculosis. The tuberculin test has
a specificity of approximately 99% in populations that
have no other mycobacterial exposures or BCG
vaccination. Specificity is lower (approx. 95%) in populations where cross-reactivity with other mycobacteria
is common. Therefore, the positive predictive value of a
tuberculin test depends on probability of tubercular
infection in a patient/ prevalence of tubercular infection

in the population and the specificity of the test in that
population.
Some studies suggested that stronger the reactions
to tuberculin, greater the chances of active disease.69-71
As the test is simply a delayed-type hypersensitivity
reaction giving information about previous exposure to
tubercular infection, it does not seem plausible that it
can accurately predict the presence of active disease.
In a review by Udani et al71 tuberculin testing using
1TU PPD RT 23 was positive in 52.3% (19.3-73.3%) of
children with tuberculosis. The positivity was lower in
children with severe malnutrition, disseminated
tuberculosis, miliary tuberculosis, and tubercular
meningitis. Another study reported 41% test positivity
in 61 children with definite tuberculosis.72 In this study
the sensitivity improved if 5 TU or 10 TU were used.
However, it is not recommended to use 10TU strength.
In a community, tuberculin test can be used to determine
the overall prevalence of a positive skin reaction. The
annual incidence and prevalence of infection helps to
determine the problem of infection due to tuberculosis.
Population vaccinated with BCG shows a lack of
correlation between the positive reaction after vaccination
reported retrospectively by the subject and the current
skin reaction observed by the physician. Repeat BCG in
a population previously vaccinated results in a booster
effect of tuberculin in Mantoux test due to mycobacteria
circulating in the general population.
Nagelkerke et al73 have described that tuberculin
surveys of children can be used to estimate national or
regional infection prevalence and are commonly
designed as multistage surveys. It is emphasized that
increasing the number of selected districts is more
efficient for increasing the precision of the estimate than
increasing the number of children per district beyond
several hundred to a few thousand.
The benefits of screening for latent tuberculosis has
gained importance in the wake of a large number of highrisk categories. To name a few, concurrent infection of
tuberculosis and HIV/AIDS, immune compromised
states such as malignancies, intravenous drug abuse, endstage renal disease and the children exposed to an open
adult case. Rose74 in 2000 did a MEDLINE search to
determine tuberculosis risk. Tuberculin skin test
screening and preventive therapy for 3 years old and
30-year-old persons with positive test results was done.
Outcome measures were life time and 10-year risk,
including spread to others, life expectancy extension and
number needed to screen to prevent 1 case was 10 to 6888,
and the number needed to treat was 2 to 179. The benefits
of screening and preventive therapy varied widely,
although the benefits outweigh the risks for all risk
groups.
305
Other Tests to Detect Tuberculosis Infection:

Interferon- Release Assays
3. QFT- does not trigger anamnestic response (i.e.

booster reaction with repeated testing) as does TST.
Till a few years ago, the tuberculin skin test was the only
investigation available to confirm the diagnosis of
tuberculosis infection. In the recent years, Interferon-
Release Assays (IGRA) have been developed. These tests
measure the cell mediated response in infected
individuals by the levels of interferon gamma released.
During tuberculosis infection, T cells from the individual
will be sensitized (via MHC proteins) to the antigens
presented by cells of the M. tuberculosis. T cells will thus
be able to bind to foreign infecting cells, releasing
interferon-gamma. Interferon-gamma Release Assays
take advantage of this natural process in infected
immunocompetent individuals. When antigens specific
for a given infecting agent (often in the form of purified
protein derivatives) are applied to whole-blood samples
from infected individuals, T cells sensitized to the
antigens will be present in the blood, and will bind to
the antigen. The T cells will then release Interferongamma. The presence of sensitized T-cells in infected
individuals will result in far higher levels of IFN- release
than among uninfected individuals. The presence of
IFN- can then be quantified using a single step enzymelinked immunosorbent assay (ELISA) using anti-IFN-
antibodies.
IGRAs differ from each other mainly with respect
to the technique of IFN- detection (enzyme linked
immunospot; ELISPOT vs enzyme linked immunosorbent
assay; ELISA) and the samples utilized (peripheral blood
mononuclear cells vs whole blood). There are two
commercial IGRAs and both measure overnight IFN-
responses (<24 h) to overlapping ESAT-6 and CFP-10
peptides. The T-SPOT. TB assay (Oxford Immunotec,
Oxford, England) is an ELISPOT assay that uses
peripheral blood mononuclear cells and QuantiFERONTB Gold (QFT-) and QuantiFERON-TB Gold In Tube
(QFT-GIT Cellestis, Victoria, Australia) are ELISA assays
utilizing whole blood. The QFT-GIT assay has replaced
the QFT- test and also contains the TB 7.7 peptides.
1. The QFT- test offers some distinct advantages over
the TST. First, it requires only one patient encounter
to draw the blood, and not two as in TST.
2. The proteins used in the QFT- are absent from all
bacille Calmette-Guerin (BCG) strains and from
commonly encountered nontuberculous mycobacteria
except, M. kansasii, M. szulgai and M. marinum. This
should make the test more specific for M. tuberculosis
infection than the Quanti FERON-TST, both of which
use PPD as the antigen. This could make QFT- more
attractive for use in children who have received BCG
vaccination.
Limitations of the Test

1. As with TST, the QFT- cannot differentiate between
tuberculosis infection and disease.
2. QFT- test may be less sensitive (though more specific)
than TST for tuberculosis infection.
3. The predictive value of the QFT- depends upon the
prevalence of M. tuberculosis infection in the
population being tested. Therefore, false-positive tests
will occur when the test is applied to persons from a
low-prevalence population.
4. QFT- cannot be used alone to exclude tuberculosis
disease in patients suspected of disease.
5. It has been evaluated in response to ESAT-6 and
CFP-10 antigen.
Performance of the Tuberculin Skin Test and

Interferon- Release Assay for Detection of
Tuberculosis Infection in Immunocompromised
Patients in a BCG-Vaccinated Population
Kim et al 75 reported that in immunocompromised
patients, the QFT- may be more sensitive than the TST
for detection of LTBI, but it resulted in a considerable
proportion of indeterminate results. Therefore, both tests
may maximize the efficacy of screening for LTBI in
immunocompromised patients.
Comparison of Tuberculin Skin Testing and

T-SPOT: TB for Diagnosing Latent and Active
Tuberculosis
Simsek et al76 have evaluated the performance of T-SPOT.
TB and TST for diagnosing LTBI and found that they were
comparable (54.8%) in the diagnosis of latent TB.
However, T-SPOT. TB was superior in terms of sensitivity
(83.0%), TST detected 18 where as T-SPOT. TB test
detected 39 out of 47 patients with active TB. TST has
more false negative results.
Recommendations for Use of IGRAs in the CDC Issues
Updated Guidelines for Testing for Tuberculosis
Infection
To assist in diagnosing infection with M. tuberculosis
tuberculin skin tests and IGRAs may be used for
surveillance or to identify persons likely to benefit
from treatment.
Established protocols using FDA-approved test
formats are required for performance and interpretation
of IGRAs in compliance with clinical laboratory
improvement amendment standards.
Both the standard qualitative test interpretation and
the quantitative assay measurements should be
306
Section 5 Diagnosis
Table 23.4: Comparison of the features of the tuberculin skin test and the interferon-g release assays
Feature
Technique
Tuberculin skin test in vivo
Cross reactivity with BCG

/environmental bacteria
Results
Present
Results reported as
mm induration
Booster phenomenon (by TST)

Cost
Other requirements
Yes
Low
Needs cold chain; safe
injection practices
IGRAs
In-vitro test
(QuantiFERON- g ELISA; T-SPOT.TB: ELISPOT
Subjective; the results are dependent

on observer and technique
Needs a return visit for the
determination of result
reported along with the criteria used for interpretation

of the test.
Arrangements for IGRAs testing should be made for
collection of blood in proper tubes for performance
of the test within the required time frame.
Before implementing testing with IGRAs, each
institution and Tuberculosis Control Program facility
should consider availability, overall cost, potential
benefits of IGRAs and characteristics of the test
population in their own setting.
Neither the tuberculin test nor the IGRAs should
typically be used to test persons at low risk for both
infection and progression to active tuberculosis if
infected, unless they are likely to be at increased risk
in the future.
An IGRA is preferred for testing persons from groups
that typically have low rates of returning and to those
who have received BCG. The latter can have falsepositive skin test.
IGRAs or the tuberculin skin test may be used to test
recent contacts of persons with infectious
tuberculosis.
IGRAs or the tuberculin skin test may be used for
periodic screening for occupational exposure.
For testing children younger than 5 years, the
tuberculin test is preferred Vs the IGRAs.
Guidelines summarize that although substantial
progress has been made in documenting the utility of
IGRAs, additional research is needed that focuses on
the value and limitations of IGRAs in situations of
importance to medical care or tuberculosis control.
A limitation of IGRAs is their relatively high cost and
need for laboratory infrastructure. However, one would
need to demonstrate significant advantage over the TST,
to justify the investment for developing countries. The
outstanding question to resolve now is whether IGRAs
Relatively specific for

M. tuberculosis
For a chosen cut-off, provides
yes/no answer
Needs single visit for collection of
blood sample; test is performed in
the laboratory
QuantiFERON: Interferon- units
T-SPOT.TB: Spot-forming units
Yes
High
Requires expensive lab set-up and
expertise.
show improved predictive value for progression to active

disease, once an individual is infected with M.
tuberculosis. The IGRAs have been shown to perform
similar to the skin test in multiple studies in children.77, 78
Table 23.4 compares the feature of tuberculin skin test
and the interferon release assays. While the IGRAs have
revolutionized the diagnosis of LTBI in low burden
countries, the performance of IGRAs may be modulated
by several factors in high-burden settings.79-90 In all
settings, IGRAs retain specificity in those who are BCG
vaccinated or have a false-positive TST due to
environmental mycobacteria.
HIGHLIGHTS
The tuberculosis skin test is also known as the
tuberculin test or PPD test.
The PPD test is used to determine if some one has
developed an immune response to the bacterium that
cause tuberculosis (TB).
The standard tuberculin test is the MANTOUX test,
which is administered by injecting 0.1 ml volume
containing 1 or 5 TU (tuberculin units of) PPD into
the top layers of skin of the forearm.
Skin test should be read 48 to 72 hours after the
injection.
The basis of the reading of the skin test is the presence
or absence and the amount of induration.
A negative test does not always mean that a person
is free of tuberculosis
A person after BCG vaccine may also have a positive
skin reaction to the TB test.
Primary infection with M. tuberculosis is followed by
the development of cell-mediated delayed-type skin
hypersensitivity after 4 to 6 weeks.
The skin test only measures the degree of
hypersensitivity and not immunity to tuberculosis.
Contd..

A number of causes of false-positive and falsenegative for tuberculin test have been enumerated.
Repeat testing ever after a year may lead to
boosting of response. It does not mean fresh
infection.
As the presence of mycobacteria other than
M. tuberculosis can cause same response at the test
site, there is a need for developing species-specific
antigens.
Interferon- release assays are new generation in
vitro tests to detect TB infection. They compare well
with the tuberculin skin test and have some
advantages. However, high cost and need for
expensive lab set-up and expertise limit its utility in
REFERENCES
1. Herchline, Thomas, and Judith K. Amorosa Tuberculosise
Medicine. Com. May 18, 2010, http:/emedicine.
medscape.com/article/230802-overview.
1a. Mazurek GH, Villarino ME. Guidelines for using
the quanti FERON-TB test for diagnosing latent
M. tuberculosis infection. Morb Mortal Wkly Rep
2002;51:1-5.
2. Harada N, Higuchi K, Sckiya Y, et al. Basic characteristics
of a novel diagnostic method (quanti FERON TB 2G) for
latent tuberculosis infection with the use of Mycobacterium
tuberculosisspecific antigens, ESAT-6 and CFP-10.
Kekkaku 2004;79:725-35.
3. Harada N, Mori T, Shishido S, et al. Usefulness of a novel
diagnostic method of tuberculosis infection,
quantiFERON TB-2G, in an outbreak of tuberculosis.
Kekkaku 2004;79:637-43.
4. Pai M, Gokhale K, Joshi R, et al. Mycobacterium tuberculosis
infection in health care workers in rural India:
Comparison of a whole-blood interferon-gamma assay
with tuberculin skin tesing. JAMA 2005;293:2785-7.
5. Kang YA, Lee HW, Yoon HI, et al. Discrepancy between
the tuberculin skin test and the whole blood interferongamma assay for the diagnosis of latent tuberculosis
infection in an intermediate tuberculosis burden country.
JAMA 2005;293: 2756-61.
6. Koch R. Ueber bakteriologische Forschung. Dtsch Med
Wochenschr 1890;16:756.
7. Bleiker JHA. The past, the present and the future of the
tuberculin test in tuberculosis control. Bull Int Union
8. Edwards PQ, Edwards LB. Story of the tuberculin test
from an epidemiologic view point. Am Rev Respir Dis
1960;81:1-47.
9. Seibert, FB. The isolation and properties of the purified
protein derivative of tuberculin. Am Re of Tuberc
1934;30:713.
10. Siebert FB, Glenn JT. Tuberculin purified protein
derivative. Preparation and analysis of a large quantity for
standard. Am Rev Tuberc 1941;44: 9.
11. American Thoracic Society. The Tuberculin skin testOfficial ATS statement. Am Rev Respir Dis 1984;
124:356-63.
307
12. Magnusson M, Bentzon MW. Preparation of purified

tuberculin RT 23. Bull World Health Org 1958;19:829-43.
13. Villarino ME, Brennan MJ, Nolan CM, et al. Comparison
testing of current (PPD-S1) and proposed (PPD-S2)
reference tuberculin standards. Am J Respir Crit Care
Med 2000;161:1167-71.
14. World Health Organization Expert Committee on
Biological Standardization. Fifth report. Geneva World
Health Organisation (WHO) technical report series No.
56,1952;6.
15. John TJ. Shortage of tuberculin in India: Reasons and
remedy. Indian Pediatr 2004;41:293-4.
16. Jani T. Tuberculin in India. Indian Pediatr 2004; 41:
1185-6.
17. American Thoracic Society. Diagnostic standards and
classification of tuberculosis in adults and children. Am
J Respir Crit Care Med 2000;161: 1376-95.
18. Guld J, Bentzon MW, Bleiker MA, et al. Standardization
of a new batch of purified tuberculin (PPD) intended for
international use. Bull World Health Org 1958;19:845-951.
19. Crofton J, Horne N, Miller F. Clinical Tuberculosis (2nd
edn), MacMillan 1999.
20. US Department of Health, Education, and Welfare, Food
and Drug Administration. Skin test antigens. Proposed
implementation of efficacy review. Fed Reg 1977;42:
674-723.
20a. Lindeboom JA, Kuijper EJ, Prins JM, et al. Tuberculin skin
testing is useful in the screening for nontuberculous
mycobacterial cervicofacial lymphadenitis in children.
Clin Infec Dis. 2006; 43: 1552-4.
21. Beck JS, Gibbs JH, Potts RC, et al. The relation between
cutaneous blood flow and cell content in the tuberculin
reaction. Scand J Immunol 1989; 29:33-9.
22. Beck JS. Skin changes in the tuberculin test. Tubercle
1991;72:81-7.
23. Weir DM. Immunology 5th edn. Singapore, Longman
Singapore Publishers Pvt. 1983;192-5.
24. Khanna SP. Tuberculin skin test. Cardiothorac 1996;2:
49-52.
25. Hegde HR, Leung KC, Robson LM. Delayed hypersen sitivity reaction and tuberculosis: Review of a hypothesis.
J Assoc Physic India 1994;42: 723-5.
25a. Hussain R, Talat N, Shahid F, et al. Biomarker changes
associated with skin test (TST) conversion. A two year
longitudinal follow-up study in exposed household
contacts. Plus one/www.plus one.orgoct2009/volume4/
Issue10/e744. MMWR Morb Mortdity Wkly Rep 2010;
59: 1-28.
26. Committee on Infectious Diseases, Screening for
tuberculosis in infants and children. Pediatrics 1994;
93:131-4.
27. Beydon N, Lebras MN, de Lauzanne A, et al. Randomized
study of the effect of topical anesthesia on tuberculin skin
test reaction size in children. Pediatr Infect Dis J
2010;29:180-2.
308
Section 5 Diagnosis
28. Howard TP, Solomon DA. Reading the tuberculin skin
test. Who, when and how? Arch Intern Med
1988;148:2457-9.
29. Palmer CE, Bates LE. Tuberculin sensitivity of
tuberculous patients. Bull WHO 1952;7:171-88.
30. Jordan TJ, Sunderam G, Thomas L, et al. Tuberculin
reaction size measurement by the pen method compared
to traditional palpation. Chest 1987;92:234-6.
31. Kendig EL, Barry VK. Underreading of the tuberculin
skin test reaction. Chest 1998;113: 1175-7.
32. Seth Vimlesh, Kukreja N, Sunderam KR, et al. Waning
of cell-mediated immune response in preschool children
given BCG at birth. Indian J Med Res 1982;76:710-15.
33. Al-Kassimi FA, Abdullah AK, Al-Oraineg IO, et al. The
significance of positive Mantoux reactions in BCGvaccinated children. Tubercle 1991;72:101-4.
34. Wang L, Turner MO, Elwood RL, et al. A meta-analysis
of the effect of Bacille Calmette-Guerin vaccination on
tuberculin skin test measurements. Thorax 2002;57:8047.
35. Edward LB, Hopwood L, Palmer CE. Identifica-tion of
the mycobacterial infection. Bull WHO 1965;33:405-12.
36. Vandiviere HM, Melvin IG, Narrain R, et al. Profiles of
skin test reactivity to antigens of various mycobacterial
species in a human population and in experimental
infections. Tubercle 1980;61:245-57.
37. Chaparas SD, Vandiviere HM, Melvin I, et al. Tuberculin
test. Commentary on variability with the Mantoux
procedure. Am Rev Respir Dis 1985; 132:175-7.
38. Stanford JL, Mehrotra ML, Cunningham F, et al. A
prospective study of BCG given to young children in
Agra, India - A region of high contact with environmental
mycobacteria. Tubercle 1987; 68:39-49.
39. Stanford JL, Sheikh N, Bogle G, et al. Protective effect of
40. Ly HM, Trach DD, Long HT, et al. Skin test
responsiveness to a series of new tuberculins of children
living in three Vietnamese cities. Tubercle 1989;70:27-36.
41. Morse DL, Hansen RE, Grabou JC, et al. Tuberculin
conversions in Indo-Chinese refugees. Am Rev Respire
Dis 1985;132:516-9.
42. Palmer CE, Edwards LB. Identification of the tuberculosis
infected. JAMA 1968;205:167-78.
43. RajNarain, Vallishayee RS, Venshayee RA. Value of dual
testing with PPD-S and PPD-B. Indian J Med Res
1978;68:204-12.
44. Thompson NJ, Glassroth JL, Snider DE, et al. The booster
phenomenon in serial tuberculin testing. Am Rev Respir
Dis 1979;119:587-97.
45. American Thoracic Society. Preventive therapy of
tuberculous infection-Official ATS statement. Am Rev
Respir Dis 1974;110:371-4.
46. American Thoracic Society. Diagnostic standards and
classification of tuberculosis and other mycobacterial
diseases. Am Rev Respir Dis 1981; 123:343-58.
47. DAmelio R, Stroffolino T, Bislelli R, et al. Tuberculin
skin reactivity in Italian military recruits tested in 199697. Eur J Clin Microbial Infect Dis 2000;198:200-4.
48. Alexander WJ, Roper WL. Boosted tuberculin reaction
among Cambodian refugees. JAMA 1982; 248:1177.
49. Morse DL, Hansen RE, Swalbach G, et al. High rate of

tuberculin conversion in Indo-Chinese refugees. JAMA
1982;248:2983-6.
50. Menzies D. Interpretation of repeated tuberculin tests:
Boosting, conversion and reversion. Am J Respir Crit
Care Med 1999;159:15-21.
51. Cauther GM, Snider DE, Onorato IM. Boosting of
tuberculosis sensitivity among Southeast Asian refugees.
Am J Respir Crit Care Med 1994;149: 1597-1600.
52. Hsu KHK. Tuberculin reaction in children treated with
isoniazid. Am J Dis Child 1983;137:1090-2.
53. Ferebee SH. Controlled chemoprophylaxis trials in
tuberculosis - A general review. Adv Tuberc Res
1970;17:28-106.
54. Felten MK, Merwe CAVD. Random variation in
tuberculin sensitivity in school children. Am Rev Respir
Dis 1989;140:1001-6.
55. Truitt GL, Mackaness GB. Cell-mediated resistance to
aerogenic infection of the lung. Am Rev Respir Dis
1971;104:829-43.
56. Grzybowski S, Galbraith JD, Dorken E. Chemoprophylaxis trials in Canadian Eskimos. Tubercle
1976;57:263-9.
57. Comstock GW, Baum G, Snider DE. Isoniazid
prophylaxis among Alaskan Eskimos: A final report of
the Bethel isoniazid studies. Am Rev Respir Dis
1979;119:827-30.
58. London RG, Lawson RA Jr Brown J. Variation in
tuberculin test reading. Am Rev Respir Dis 1963; 87:85261.
59. Bearman JE, Kleinman H, Glyer VV, et al. A study of
variability in tuberculin test readings. Am Rev Respir
Dis 1964;90:913-9.
60. Houk VN, Kent DC, Baker JH, et al. Comparison of paired
tuberculins. Arch Environ Health 1968; 16:36-45.
61. Steiner P, Rao M, Victoria MS, et al. Persistently negative
tuberculin reactions. Am J Dis Child 1980; 134:747-50.
62. Seth Vimlesh. Clinicoimmunological Profile: Indian
scenario. In: Seth Vimlesh (Ed). Essentials of Tuberculosis
in Children, 1st edn. Delhi: Jaypee Brother Medical
Publishers 1997;96-105.
63. Lloyd AV. Tuberculin test in children with malnutrition.
BMJ 1968;529-31.
64. Razzak SV, Moriarty R, Ottolini MG, et al. Delayed-type
(DTH) skin testing in HIV infected pediatric patients. J
Pediatr 1996;129:245-50.
65. American Academy of Pediatrics. Committee on
Infectious Diseases. Update on tuberculosis skin testing
of children. Pediatrics 1996;97:282-4.
66. Palmer C, Jablon S, Edwards PO. Tuberculosis morbidity
in young men in relation to tuberculin sensitivity and
body build. Am Rev Tuberc 1957; 76:517-24.
67. Smly DP, Shennan DH. The significance of the strongly
positive tuberculin reaction. Cent Afr J Med 1957;3:255.
68. Garcia-Garcia ML, Val dispino Gomez JL, et al.
Underestimation of Mycobacterium tuberculosis infection
in HIV infected subjects using reactivity to tuberculin
and anergy panel. Int J Epidemiol 2000;29:369-75.

69. Mehta R, Sain L, Mittal SK. A critical evaluation of BCG
test applicability in pediatric practice. Indian Pediatr
1986;23:419-28.
70. Nagel Kerke NJ. Borgdorff MW. Kalisvarrt NA, et al. The
design of multistage tuberculin surveys. Some
suggestions for sampling. Int J Tuberc Lung Dis 2000;
4:314-20.
71. Udani PM. Evaluation of tuberculin test in pediatric
practice. Indian Pediatr 1982;19:469-86.
72. Milburn HJ, Gibilaro J, Atkinson H, et al. High incidence
of primary tuberculosis. Arch Dis Child 2000;82:386-7.
73. Nagelkerke NJ, Borgdorff MW, Kalisvarot NA, et al. The
design of multistage tuberculin surveys some suggestions
for sampling. Int J Tuberc Lung Dis 2000;4:1573-1621.
74. Rose DN. Benefits of screening for latent Mycobacterium
tuberculosis infection. Arch Intern Med 2000;160:1513-21.
75. Kim EU, Lim JE, Jung JI, et al. Performance of the
tuberculin skin test and interferon- release assay for
detection of tuberculosis infection in immunocompromised patients in a BCG vaccinated population.
BMC Infectious Diseases 2009; 207 Doi:10, 1186/14712334-9-207.
76. Simesk H, Alpar S, Ucar N, et al. Comparison of
tuberculin skin testing and T-SPOT. TB for diagnosis of
latent and active tuberculosis, Jpn J Infect Dis 2010; 63:
99-102.
77. Nicol MP, Davies MA, Wood K, et al. Comparison of
T-SPOT.TB assay and tuberculin skin test for the
evaluation of young children at high risk for tuberculosis
in a community setting. Pediatrics 2009;123:38-43.
78. Grare M, Derelle J, Dailloux M, et al. Quanti FERON(R)TB Gold In-Tube as help for the diagnosis of tuberculosis
in a French pediatric hospital. Diagn Microbiol Infect Dis
2010;66:366-72.
79. Adetifa IM, Ota MO, Jeffries DJ, et al. Commercial
Interferon-gamma Release Assays Compared to
the Tuberculin Skin Test for Diagnosis of Latent
M. tuberculosis Infection in Childhood Contacts in
Gambia. Pediatr Infect Dis J 2010 Jan 11. [Epub ahead of
print].
309
80. Lewinsohn DA, Lobato MN, Jereb JA. Interferon-gamma

release assays: New diagnostic tests for Mycobacterium
tuberculosis infection, and their use in children. Curr Opin
Pediatr 2010; 22: 71-6.
81. Bamford AR, Crook AM, Clark J, et al. Comparison of
Interferon-gamma release assays and Tuberculin Skin
Test in predicting active tuberculosis (TB) in children in
the UK- a Paediatric TB Network Study. Arch Dis Child
2009 Nov 20. [Epub ahead of print].
82. Bianchi L, Galli L, Moriondo M, et al. Interferon-gamma
release assay improves the diagnosis of tuberculosis in
children. Pediatr Infect Dis J 2009; 28: 510-4.
83. Hansted E, Andriuskeviciene A, Sakalauskas R, et al.
T-cell-based diagnosis of tuberculosis infection in children
in Lithuania: A country of high incidence despite a high
coverage with bacille Calmette-Guerin vaccination. BMC
Pulm Med 2009; 9: 41.
84. Kampmann B, Whittaker E, Williams A, et al. Interferongamma release assays do not identify more children with
active tuberculosis than the tuberculin skin test. Eur
Respir J 2009; 33: 1374-82.
85. Nicol MP, Davies MA, Wood K, et al. Comparison of
T-SPOT.TB assay and tuberculin skin test for the
evaluation of young children at high risk for tuberculosis
in a community setting. Pediatrics 2009;123:38-43.
86. Lighter J, Rigaud M, Eduardo R, et al. Latent tuberculosis
diagnosis in children by using the QuantiFERON-TB
Gold In-Tube test. Pediatrics 2009;123:30-7.
87. Connell TG, Ritz N, Paxton GA, et al. A three-way
comparison of tuberculin skin testing, QuantiFERON-TB
gold and T-SPOT.TB in children. PLoS One. 2008; 3: e2624.
88. Okada K, Mao TE, Mori T, et al. Performance of an
interferon-gamma release assay for diagnosing latent
tuberculosis infection in children. Epidemiol Infect
2008;136:1179-87.
89. Dheda K, Smit RZ, Badri M, et al. T-cell interferon-gamma
release assays for the rapid immunodiagnosis of tuberculosis: Clinical utility in high-burden vs. low-burden
settings. Curr Opin Pulm Med 2009;15:188-200.
90. Barclay L. CDC issues updated guidelines for testing for
tuberculosis. MMWR Morb Mortal Wkly Rep 2010;
59(RR-5): 1-28.
24
Newer Tuberculins:
Profile in Developing Countries
JL Stanford
THE REAGENTS
It is now more than 110 years since Robert Koch first
introduced, as a potential immunotherapeutic reagents
for tuberculosis,1 which subsequently became known as
old tuberculin (OT). Later studies showed that although
the reagent could be very dangerous in the doses used in
treatment, minute doses were useful in epidemiology and
to some extent in diagnosis. Old tuberculin consisted of
a biologically standardized dilution of medium in which
tubercle bacilli had been grown, and heat killed. It had
the disadvantages of containing the nutrients required
for bacterial growth together with the heat degraded
substances released by live and dead tubercle bacilli.
When such a reagent was used for skin testing, it was
necessary to test the person simultaneously with a control
dilution of heated, uninoculated medium.
The problem of medium constituents in the reagent
was overcome by precipitating out the tuberculoprotein,
washing it, and redissolving it in a buffer solution.
However, such purified protein derivatives (PPDs) still
had the disadvantage of containing material partially
degraded by incubation in the culture medium, and
material damaged by the heat sterilization process.
To overcome the problem of heat degradation,
reagents known as new tuberculins (NTs) were prepared
from organisms harvested from nonantigenic media and
broken with ultrasound.2 The sonicate is then sterilized
by centrifugation and filtration to 0.2 m pore size, and
diluted to 1mg of protein per ml with M/15 borate
buffered saline at pH 8 for storage at 4C. Such reagents
are then diluted to a standard skin test strength for use (2
g/ml in most cases).
The Antigens in Skin Test Reagents

Because of their different ways of production, OTs and
PPDs on one hand will have different concentrations of
mycobacterial antigens than have NTs (Table 24.1). Thus,
when prepared from slow-growing mycobacteria, OTs
and PPDs are particularly rich in slow-grower associated,
group II antigens, 3 presumably because these are
relatively resistant to degradation.
However, they also contain some common mycobacterial, group I antigen, and some specific, group IV
antigen of the species from which they were made. Newer

tuberculins made from the same species will contain
plenty of groups I and IV antigens, and little group II
antigen.
Skin Test Responses and Antigens

Antigens of groups I, II and IV can all elicit positive skin
reactions in individuals.2,4,5 However, so far there is no
evidence that the fast-grower associated, group III
antigens play a part in skin tests. Thus to a single skin
test with tuberculin (from M. tuberculosis) a person may
make a positive response to antigens shared by all
mycobacterial species, to antigens shared by slowgrowing mycobacterial species, to antigens specific to the
tubercle bacillus, or to various combinations of these.
Differentiating the Results

Fortunately there are two ways that help determine which
of these antigen groups a response is directed towards.
Responses to Groups of Antigens Distinguished by Size

In the 1990s studies were carried out on Finnish school
children, in which PPDs prepared from tubercle bacilli
and from M. scrofulaceum have been compared with each
other and with two batches of newer tuberculins (NTs)
prepared from tubercle bacilli.
Analysis of the results indicates that, within the
protective type of response, reactions to one group of
antigens (e.g. species specific) are of small size and that
when the reaction is to two or more groups of antigens
(e.g. species specific and slow-grower associated), the
response size is larger.
The Protective vs the Koch-types of Response6,7

There are two qualitatively different types of response
both giving areas of induration palpable at 48 to 96 hours.
One of these is usually accompanied by slight edema and
pink erythema, is not painful, but may be tender to touch.
It has rather soft induration with an ill-defined edge, and
may be directed to any of the groups of antigens. This
type of response to tuberculin usually follows vaccination
Chapter 24 Newer Tuberculins: Profile in Developing Countries
311
Table 24.1: Relative concentrations of the groups of antigens demonstrable in sonicates of

mycobacteria known to be present in the different types of skin test preparation
Groups
of
antigens
Old tuberculin
or
PPD tuberculin
New tuberculin
I
Common
mycobacterial
II
Slow-grower
associated
III
Fast-grower*
associated
IV
Species
specific
++++
++
+++
* Not known to activate in skin test responses
with BCG in the United Kingdom and is thought to

correlate with protective immunity.
The second type may or may not have surrounding
edema, and has a zone of central purplish/brick red
erythema overlying a hard and sharply demarcated area
of induration, which may be surrounded by a corolla of
pink erythema.8 The reaction is often painful and tender
to touch, the skin overlying may have small bullae, hair
follicles and sweat gland puncta, and sometimes may
ulcerate.
Responses of this type are to species specific antigens,
occasionally to slow-grower associated antigens, and
never to common mycobacterial, group I antigens.
Reactions of this type are expressions of immunopathology with necrotizing elements analogous to the
Kochs phenomenon. Thus, they are often referred to as
necrotizing or Koch responses.9
Though the qualitative differences are appreciable
around 72 hours after injection, the two reaction types
have different time courses. The response thought to
correlate with protection is maximal at 48 hours and
disappears within 7 days or so. That of the Koch-type is
maximal around 72 to 96 hours and resolves much more
slowly. The difference between the two types of response

is thought to lie in the release of different cytokines,10,11
as well as the infiltration including different cell types.
Thus, tumor necrosis factor (TNF) and interleukins 4 and
6 (IL4 and IL6) are important mediators in Koch
responses,6 but not in protective responses. Interleukin2
(IL2), and possibly gamma interferon may be involved
in both types of reaction. The protection type of response
appears to be mediated by T helper lymphocytes,
whereas Koch responses are thought to be due to a
combination of Th1 and Th2 lymphocyte activity.
Quadruple Skin Testing and Categorization of

Responders4,12
Interpretation of skin test results is also helped by
carrying out tests with reagents prepared from four
separate species of mycobacteria simultaneously. These
two should consist of tuberculin itself, a reagent from
another slow-growing species, and reagents from two
fast-growing species (1 of which may be replaced with
Leprosin A made from M. leprae harvested from infected
armadillos). Table 24.2 shows the antigenic contents of
the four reagents and how different patterns of response
Table 24.2: Quadruple skin testing, the groups of antigens injected and the interpretation
of possible responses to them
Right arm
Left arm
Scrofulin
Gr IV M. scrofulaceum
Gr II slow-grower associated
Gr I common mycobacterial
Vaccine
Gr IV M. vaccae
Tuberculin
Gr IV M. tuberculosis
Gr II slow-grower associated
Flavescin
Gr IV M. flavescens
Gr III fast-grower associated
Interpretation of results
+ ve to all 4: Cat 1 responder to Gr I Ags
ve to all 4: Cat 2 nonresponder: skin test suppression
+ ve to upper 2: Cat 3 responder to Gr IV Ags of both species (or Cat 4 responder to Gr II Agsrequires confirmation by
further tests with reagents of other slow growing species)
+ve to lower 2: Cat 3 responder to Gr IV Ags of both species
Gr = Group; Cat = Category; Ags = Antigens
312
Section 5 Diagnosis
to them can divide any group of people tested into

categories of responders. Errors due to chance
sensitization to the group IV, specific antigens of all four
species, and to chance inexperience of all four species,
can be corrected mathematically. As a rough rule of
thumb for adults, 10 to 15% will be category 1 responders
to the group I antigens in all four reagents. About the
same proportion will be category 2 nonresponders to any
of the reagents, due to a suppressor mechanism
apparently preventing the release of cytokines when the
dose of antigen is small. This can usually be broken
through by repeating the tests with reagents 10 times
stronger. The remaining 70 to 80% of people will mainly
be responders there will also be a proportion of category
4 responders to group II, slow grower associated
antigens,13 but proof of this requires additional tests with
reagents made from further slow-growing species.
Using the System

Infants are negative to all four reagents due to inexperience, but this changes at a rate dependent upon how
often they meet mycobacteria in their environment, until at
some point during childhood they acquire the adult pattern
(Fig. 24.1).14,15
At any age the frequency of sensitization by given
species can be roughly gauged from the category 3
responders. The prevalence of tuberculosis disease can
then be estimated on the basis of the proportion of
responses to tuberculin that are of Koch-type16 (Table
24.3).
Example
Of 75% positive tuberculin reactors, 55% were category
3 responders, of whom 5% were also category 4
Table 24.3: Example of the way in which the True

percentage of a population sensitized by contact with
tubercle bacilli can be calculated from the categorized
quadruple skin test results
Categorization of the tested population
Category
Category
Category
Category
1
2
3
responders
responders
responders
20%
15%
65%
responders
5%
responders to slow-grower-associated antigens.

Therefore at least 50% of people were reacting to species
specific antigens of M. tuberculosis. Since a similar
distribution is likely in categories 1 and 2, the true
number of people actually sensitized by contact with
tubercle bacilli would be: 50% + 10% + 7.5% = 67.5%.
22% of the category 3 responders were recorded to
have Koch-type responses and there were none amongst
category 1 responders. Some category 2 nonresponders
may have had suppressed Koch type responses (15 22/
50 = 70). Therefore, the likely proportion of the
population with subclinical or latent tuberculosis would
be 22 + 7 = 29%.
The Size of Positive Response

With the use of OT and PPDs in determining who has
been infected with tubercle bacilli, or who is suitable for
BCG vaccination, it has been expedient to select a
particular cut-off size of response, above which it is
considered positive, and below it negative. Although this
has practical value, for our purposes such an approach
would be quite unsuitable. If immune cells infiltrate a
site where particular antigens have been injected, then
their presence has been recognized and the response
cannot be considered negative. In fact for our purposes,
even taking the smallest appreciable induration (usually
2 mm) underestimates the true proportion of responders
as shown by histology of needle biopsies of some zeroinduration responses.17
The actual size in mm of the response may also be
useful. To some extent this can indicate the frequency of
contact with an organism, may distinguish between a
healthy contact of leprosy patients and a person with
paucibacillary disease, and may help to distinguish
between protective and Koch-types of responses6-8
(Fig. 24.2).
Sensitization by Environmental Mycobacteria
Fig. 24.1:The development of the adult pattern of responder

categories, and the effect of vaccination with BCG
The great majority of mycobacterial species live free in

the environment, although others are constantly being
released into the environment by diseased persons or
animals. Thus, tuberculosis and leprosy patients
313
Fig. 24.2: Tuberculin responses of Ethiopian school children with or

without BCG scars, showing those considered to have a Koch-type of
response or qualitative criteria
contaminate the environment via respiratory discharges

as droplet nuclei.
Skin test reagents can be used to monitor the rate of
immunologically effective contact of children with
individual mycobacterial species, and it can easily be
shown in non-BCG vaccinated children that an increased
percentage of positive responses accompanies increasing
age and experience.18,19 There are wide differences in

percentages of positive responders amongst children of
the same age living in different places, as shown in Table
24.4. Beside from their frequency in the environment,
species differ in their skin test sensitizing ability, some
species switching off positive responses to their antigens
if they are met too frequently.20 Thus several fast-growing
species such as M. nonchromogenicum and M. vaccae rarely
induce more than 30% positivity to NTs produced from
themselves.14,15 With such species there is increasing
positivity with age until a plateau is reached, which
appears to be due to the numbers of new persons
becoming sensitized being equal to the numbers of
persons whose responses are suppressed by repeated
contact.
The mechanism by which responses are switched in
this way is probably an homeostatic one based on control
of cytokine release, which determines the presence of
induration rather than some inhibition in migration of
cells to the injection site. This is similar to that seen in
category 2 nonresponders where the antigens triggering
cytokine control appear to be of group I, rather than
group IV specificity. One would expect the lymphocytes
of such a person to transform in vitro despite their lack
of skin test induration, as indeed they do. This is one of
the explanations for the lack of conformity between
lymphocyte transformation test (LTT) and skin test
results.
Other species, including many of the slow-growers
induce increasing positivity with age until all persons
are positive except the category 2 nonresponders.
Amongst such species are those capable of inducing
Table 24.4: Geographical differences in responses to new tuberculins for children

aged 11+ years without BCG scars
New tuberculins
Tuberculin
Leprosin A
Kansasin
Marinin
Scrofulin
Gordonin
Aviumin A
Aviumin C
Vaccin
Gilvin
Nonchromogenicin
Flavescin
Chitin
Ranin 2
Dierhoferin
Rhodesin
Neoaurumin
Tuberculin response (%)

Agra
Ahmednagar
Bombay
Lebanon
Kenya
Libya
82
48
60
89
84
35
75
95
47
41
29
16
24
22
4
24
41
20
67
25
4
5
3
23
35
38
68
62
33
25
28
8
2
2
26
15
19
2
40
22
51
24
12
3
Note: In many instances the batches of reagents used were the same
17
24
31
35
58
314
Section 5 Diagnosis
either the protective or the Koch-type of response.

Thus, taking M. scrofulaceum as an example, occasional
contact produces the soft induration typical of
protective responses (such as the 25% positivity to
scrofulin found in Iran), and frequent contact, instead
of suppressing the response, converts it to one of the
Koch-type (as reflected in the 85% positivity to
scrofulin found in Burma now Myanmar).6,21 This is a
very significant deleterious effect of the environment
in some situations.
Environmental Mycobacteria and Disease Susceptibility

Since all mycobacteria share group I antigens, and these
antigens are those recognized in protective immunity,
contact with any species will give some protection from
a challenge with any other. Thus natural protection
steadily increases due to contact with environmental
mycobacteria until it becomes as good as that provided
by BCG vaccine (perhaps the explanation for the poor
protection provided by BCG in the trial in Georgia and
Alabama,USA), although it may take some years to do
so.22,23 This naturally acquired protection seems to be
more readily undermined by conversion to the Koch
response by excessive contact with some species as
explained above, than is the protective immunity
provided by BCG vaccination (as seen in the trial of BCG
against leprosy in Burma-Myanmar).24 Once a Kochs
phenomenon has been induced, BCG vaccination is
ineffective, and disease susceptibility is increased. Indeed
BCG vaccination may make things worse by further
overloading the immune system to no benefit (first
reports of the trial of BCG against tuberculosis in South
India indicated a negative protective effect of the
vaccine).25
SKIN TEST AND THE ASSESSMENT OF VACCINE EFFICACY

Vaccination with BCG
The effect of BCG vaccination is to lower the threshold
of immunological recognition for subsequently
encountered mycobacterial speciespathogenic and
nonpathogenic. Thus, as well as the increase in positivity
to tuberculin directly due to the group IV antigens of
tubercle bacilli in the vaccine, the rate of acquisition of
skin test positivity to other species increases after
vaccination more than can be explained by the expansion
of category 1 responders to group I antigens. This is
thought to be due to priming via responsiveness to group
I antigens leading to easier recognition of group IV
antigens. This mechanism may be the same as that
producing protective immunity through the rapid
recognition and destruction of small challenges with
virulent tubercle or leprosy bacilli.
The Evolution of Skin Test Responses after BCG

Vaccination
Within 12 weeks of vaccination of tuberculin negative
(<5 mm to 2TU or its equivalent) children with a good
quality BCG, more than 95% of them become positive to
tuberculin (responses >5 mm). These responses directly
due to the vaccine are of small size compared with
responses developing later, can be thought of as priming
responses and are short-lasting in many people (half-life
about 1 year).26 They are either followed by a return to
negativity, or are supplanted by a longer-lasting response
type following contact with tubercle bacilli in the
environment. Normally this is the soft induration thought
to correlate with protective immunity, and has a mean
size of a few mm more than that of the priming response
(Fig. 24.3). Such a response may last for many years.27,28
Fluctuating from time to time according to the experience
of the individual.
If, on the other hand, BCG is inadvertantly given to a
child who already has a Koch-type response to M.
tuberculosis or some other species, the vaccine will be
followed by a larger-sized response to tuberculin of Kochtype. This may, or may not persist; it is not associated
with protective immunity and may herald the
development of clinical disease.
Assessing BCG Program

Skin tests can be used to assess BCG that has already
been given in several ways:
Tuberculin can be used alone to compare groups, one
with BCG scars and the other without.2,16 Because of a
whole series of variables such as sex,28 social class, and
whether or not tuberculin testing is used to select who is
to be vaccinated, such groups are difficult to match.
Nonetheless, the reduction in the proportion of persons
producing a Koch response to tuberculin among the
vaccinated, as compared with the nonvaccinated can be a
useful measure (Fig. 24.2).
Fig. 24.3: Pooled data from several studies carried out in India. The
figure shows the percentages of children two years after BCG
vaccination responding to tuberculin according to the mean diameter
of induration of their responses. Equivalent results for the same age
range of children (3 to 15 years) without BCG scars are shown for
comparison

This was used to assess the efficacy of BCG
vaccination among school children in Shoa district of
Ethiopia;16 it suggested:
1. Level of protection of about 80%.
2. Reagents prepared from any mycobacterial species
can be used to assess the usefulness of BCG to some
extent, but they are best used as part of a set of 4
reagents as discussed above.18,29 It can then be shown
that where BCG is effective it expands category 1 of
responders to common mycobacterial antigen,
decreases category 2 nonresponders, and increases
the category 3 responders to reagents prepared from
organisms present in the environment.30
3. Studies are currently in progress to determine the
optimum time after birth for the administration of
BCG vaccine, and in part these depend on skin testing.
In Finland it has been shown that BCG given in the
first few weeks of life produces a significantly
different size of tuberculin response, measured years
later, than does BCG given to a child just a few weeks
older. Correlations of this with actual prevention of
disease have still to be made (E Tala, personal
communication).
A number of studies have been carried out showing
that when BCG is given at birth, only a small proportion
of children remain tuberculin positive by the time they
are 5 to 6 years old,31 unless the frequency of meeting
tubercle bacilli is high. Subsequently, Tuberculin
positivity may rise, but it is not certain whether BCG
revaccination should be considered.28
Seth et al have conducted a number of studies, to see
the effect of age and nutrition on the take-up of BCG
vaccine.22-35 It can be summarized that the take-up of BCG
vaccine was similar when it was given to full-term and
preterm babies who had weight appropriate for
gestation. Further, they found that children who were
given BCG at birth and later became malnourished, the
retention of cell-mediated immune response (CMIR)
tested by Mantoux test and leukocyte migration
inhibition test (LMIT) was poor in them in comparison
to normal nourished children. The waning of delayed
hypersensitivity was maximum in the first year as only
30 to 40% of the children had positive Mantoux test. This
positivity decreased further to 16.7% children in the age
group of 3 to 6 years.
DEVELOPMENT OF NEW VACCINES

The only new vaccines being tested in the field at the
moment are directed primarily at preventing leprosy,
and it would be very useful if skin tests could be used to
assess their likely relative efficacy. So far, most
publications on this have addressed the question of
obtaining the most positivity either to Lepromin (which
is not a reagent of the type being discussing), or to
315
Leprosin A or an analogous soluble preparation of

leprosy bacilli.
The only vaccine known to work against leprosy is
BCG itself,36 which may be more effective against leprosy
then it is against tuberculosis, 37 highlighting the
importance of group I antigens in protective immunity.
Thus new vaccines need to compare advantageously with
BCG. Considerable care is needed in making sure that
what is measured after the vaccine is not the direct, and,
therefore, perhaps ephemeral, effect of the vaccine, but
its long-lasting effect. This requires the follow-up skin
tests to be performed at least one year, and preferably
two years after the vaccine has been given. An effective
vaccine should show an increasing not a decreasing level
of positivity over this timescale to Leprosin A, or an
equivalent, and should show the proportion of category
1 responders to be at least as high as after BCG alone.38
Without the ability to distinguish between the
protective and Koch-types of response to tuberculin,
which are particularly properties of the NT reagent,
single tuberculin tests are of little help in assessing the
efficacy of BCG against Leprosin A in this context. In
fact, except in some patients with paucibacillary disease,
responses to Leprosin A are always of the protective type,
suggesting that enhancing positivity is enhancing
protective immunity. In support of this new cases of
disease have been found to occur amongst the previously
Leprosin A negative (reaction less than 2 mm) portion of
the population (Dr K Desikan, personal communication).
However, additional evidence on this point would be
very valuable.
Recent studies in Maldiv have shown that responses
to NTs made from fast growing mycobacterial species
are associated with protection from both leprosy and
tuberculosis.39
NEW TUBERCULINS AND DIAGNOSIS OF

MYCOBACTERIAL DISEASE
Tuberculosis
Unfortunately, in the diagnosis of tuberculosis among
adults the NTs offer no advantage over OTs or PPDs
except perhaps in the ease of differentiating between
response types, since the responses only differ in
proportion from those of persons infected, but without
disease. Some 10 to 15% of bacteriologically confirmed
newly diagnosed cases of pulmonary disease are
completely negative to tuberculin. These are not always
the patients with most extensive disease as used to be
thought, although their prognosis for surviving the
period of chemotherapy may not be good (P Byass and T
Corrah, personal communication).
In childhood, in the absence of a BCG scar, a strongly
positive response to tuberculin (10 mm or more to 2TU
316
Section 5 Diagnosis
or its equivalent) can be a useful indicator of infection,

although in many developing countries infection without
disease is so common that the test becomes irrelevant.
Several studies have shown that the proportion of
category 1 responders to skin tests are significantly
reduced amongst both tuberculosis and leprosy
patients.40,41 The same lack of ability to respond to group
I antigens can be shown in LTTs.42
Leprosy
Most cases of leprosy are either completely negative to
Leprosin A, or have large sized (>10 mm diameter)
responses to it. If quadruple testing is carried out almost
all untreated multibacillary cases and half of
paucibacillary cases will be category 2 nonresponders to
all 4 reagents.43 Beyond this, skin testing is of little help
in diagnosis, and soluble M. leprae reagents are less
efficient in separating multibacillary from paucibacillary
disease than is Lepromin (an autoclaved suspension of
whole leprosy bacilli). There is a possibility that large
sized responses to Leprosin A in apparently healthy
persons may herald the onset of tuberculoid disease
(unpublished observation).
Cervical Lymph Node Tuberculosis

In developing countries many children have this
condition caused by M. tuberculosis itself and the
comments above are true for it. However, in developed
countries, disease of this type is usually caused by other
species such as Mycobacterium avium, M. intracellulare, M.
malmoense or M. scrofulaceum. Specific reagents to these
can be very helpful in indicating the species responsible,
and I regularly send sets of these reagents to requesting
pediatricians in the United Kingdom. Unfortunately it
is often difficult to obtain bacteriological confirmation
of the results, but the clinician is often reassured in his

decision not to treat a disease, which, if it were caused
by tubercle bacilli, would require chemotherapy.
Table 24.5 lists some of the results achieved with these
reagents.
Mycobacterium Ulcerans Disease

The diagnosis of this disease is correctly clinical, but skin
testing with Burulin (prepared from M. ulcerans) can be
useful in deciding the stage of the disease,44-47 and the
kind of treatment required. Treatment of a Burulin
negative (< 2 mm) case should include active antibacterial therapy, or wide excision, whereas treatment of a
Burulin positive case should be more conservative with
clean dressing, debridement, and postage stamp skin
grafts, etc. There is some evidence that Burulin testing
of healthy persons may help delineate regions where M.
ulcerans is casually encountered, and where sporadic
cases of the disease might be expected.
STUDIES OF CLOSE CONTACTS OF PATIENTS WITH

DISEASE
Thus testing of the families of index cases may help in
disease control, although this is probably much more
useful in developed countries where other sources of
contact with mycobacterial disease are uncommon or
rare. Nonetheless, quadruple skin testing of families in
developing countries can provide useful information and
insight into the delicate balance between health and
disease. Relatives of tuberculosis patients who have
Koch-type responses to tuberculin should be given
preventive chemotherapy. It may be safe not to offer such
treatment to non and those with small responses to
tuberculin if there are financial constraints.
Table 24.5: Results of quadruple skin tests in children with cervical adenitis
Subjects
Skin test in response (mm) with reagents
(age in years)
AA
AC
AA (5)
MU (3)
DW (8)
MQ (16)
CS (5)
MW (2)
LD (5)
LH (4)
SM (2)
TS (14)
0
4
8
0
0
0
0
0
0
0
12
12
15
0
15*
8
3
5
0
12
5
28*
10
28
12
12
0
0
6
0
8
0
10
9
0
Mal
8
5
10
10
T = Tuberculin; AA = Aviumin A (M. avium); AC = Aviumin C (M. intracellulare); S = Scrofulin; Mal = Malmoensin; *M.
intracellulare grown from operative specimen
317
Contacts of Tuberculosis Patients
Contacts of other Mycobacterial Diseases
Most cases of tuberculosis develop amongst persons

producing large sizes responses of Koch-type, to
tuberculin. Thus, anyone with this type of tuberculosis
should be examined clinically, and sputum samples
should be taken for acid-fast bacilli examination. Some
clinicians would advise prescribing a course of
prophylactic antituberculosis chemotherapy, but this is
probably not advisable in countries where drug
resistance is common.
Children living with proven cases of pulmonary
tuberculosis and who are completely negative to all four
reagents, or have Koch responses to tuberculin should
be examined particularly carefully for signs of disease.
Such children without clinical signs of disease should be
selected for chest X-rays. Only if these are clear should
tuberculin negative children be given BCG vaccination.
Children who have the protective type of response to
tuberculin, especially if they respond to all four skin tests,
are unlikely to develop disease.
Since none of these diseases are associated with direct

infectiousness, there is no need to examine close contacts.
However, skin testing of family contacts of such patients
often gives evidence of infection without establishment
of disease. Thus the parents of a child with M. avium
infection are generally very strongly skin test positive to
Aviumin.
Contacts of Leprosy Patients

Although it is often said that paucibacillary leprosy is
not infectious, there is evidence that it can be, and this
should not be allowed to give a false sense of security.
Most children in close contact with leprosy patients
rapidly acquire positivity to Leprosin A, especially if they
have BCG scars. Children with large responses to
Leprosin A should be examined for patches of
tuberculoid disease, and children over 5 years of age who
remain skin test negative should be checked by slit skin
smears for the presence of acid-fast bacilli if they have
been living with an untreated patient.
In a study of contacts of multibacillary leprosy, it was
found that although the eventual plateau of positivity to
Leprosin A was the same in close and casual contacts,
the rate of acquisition of positivity during childhood was
much greater in the close contacts.47 Superimposed on
this were geographical differences suggesting that
frequent contact with environmental mycobacteria might
offer some synergistic influenes on the development of
Leprosin A positivity. This synergism maybe related to
that associated with BCG vaccination.
Recent studies of families of leprosy patients have
shown differences according to whether the family case
has lepromatous or tuberculoid disease. In Tamil Nadu
(India) the children of such families have reacted
differently in their responses to quadruple skin test after
vaccination. This has been further investigated in
Argentina, where it has been shown that family members
consanguineous with the patient have similar responses
whatever the type of disease.
DETECTION OF RISK FACTOR

Potential risk factors increasing the chances of developing
mycobacterial diseases can also be investigated with
tuberculin tests, and especially with the quadruple test
system.
Infection with the Human Immunodeficiency Virus

(HIV)
This has proved to be a very important risk factor for
tuberculosis, although this may be less evident in
congenital or neonatal infections. However, the risk to
such children of BCG vaccination is still uncertain,
although lack of accurate knowledge of which infant may
be infected makes the question somewhat academic.
Most doctors advise that BCG should be given according
to the practice in the district unless the infant is clearly
known to be at special risk of HIV infection.
The value of skin tests in determining which HIV
infected individuals are likely to develop tuberculosis
has not been assessed in a tuberculosis endemic situation,
although in the United States of America a positive
tuberculin test in such a person would be taken as an
indication to treat. Comparative quadruple skin test
studies have shown that HIV seropositive persons do
not respond to common mycobacterial antigens; thus,
none of them are category 1 responders.48 Category 3
responders are present early in HIV disease, but as the
CD4 count falls, these too disappear. Lymphocyte
transformation studies have shown that the recovery of
CD4 counts with highly active antiretroviral therapy
(HAART) is not accompanied by a return of immune
recognition of the common mycobacterial antigens (GM
Bahr, personal communication). Thus a positive
tuberculin reaction in an HIV seropositive person
indicates sensitization by meeting M. tuberculosis and not
cross-reaction with other species. It is not yet known
whether HIV patients can be differentiated into Kochtype and protective responses to tuberculin. If they can,
then scarce resources for tuberculosis prevention could
be reserved for Koch responders.
318
Section 5 Diagnosis
PREVACCINATION SKIN TESTS

Parasitic Disease
Studies in Africa of patients infested with schistosomes
have shown them to have reduced responsiveness to
tuberculin, suggesting that such infestations maybe a risk
factor for tuberculosis. Studies with quadruple skin tests
in Argentina show that the same is true for patients
seropositive for Chagas disease, and that such patients
have specifically lost responses to group I, common
mycobacterial antigens.49 This makes it highly likely that
Chagas disease is a risk factor for tuberculosis and
leprosy, both of which are endemic in the regions where
the reduvid bug abounds. These interesting findings are
being actively expanded (O Bottasso, per-sonal
communication).
Selecting Candidates for BCG Vaccination Against

Tuberculosis
This is one of the major uses of the tuberculin test, and
there is no doubt that if it can be afforded, and if it does
not lead to loss of individuals by their failing to turn up
for the test to be read and the vaccine to be given, then it
is to be recommended. The advantages of prevaccination
tuberculin tests are several:
1. Persons likely to already have tuberculosis can be
identified, examined and treated, without the
complication of superimposed vaccination.
2. Those with large responses to tuberculin do not
receive a further dose of M. tuberculosis antigens, and
perhaps precipitate disease.
3. Many of those likely to have severe reactions to BCG,
or complications following it can be identified by their
large tuberculin responses and should not be vaccinated.
In some places BCG has obtained a bad name among
the population because of numerous postvaccination
complications which could have been avoided.
Using new tuberculin, take 5 mm mean diameter of

induration as the cut-off point below which give BCG if
there is no definite scar of previous vaccination. Others
using OT or PPD recommend a 5 mm or 10 mm cut-off
point, depending on the reagent strength being
employed. For infants below 1 year of age it is reasonable
not to carry out a prevaccine test, unless the child is a
close contact of a patient.
Selecting Persons to be Given Vaccines Against Leprosy

There are several important aspects of this for which there
is really no substitute for skin testing:
1. If the vaccine incorporates BCG, then the same
constraints are needed that have been considered for
the use of this vaccine alone.
2. If the vaccine is in short supply, then its use needs to
be directed toward those most at risk.
3. There is little point in giving a novel vaccine to
persons who already have evidence of good
protective immunity.
4. Since these vaccines are still within the period of
their assessment of efficacy, a prevaccination test is
needed for later comparative purposes. However,
these advantages depend on the availability of a
reagent like Leprosin A containing both group I
antigens and the specific group IV antigens of the
leprosy bacillus. The quadruple skin test system
allows us to determine to which of these antigen
groups a tested individual is responding. Table 24.6
illustrates the use of Leprosin A in the assessment
of a potential improvement on BCG as a leprosy
vaccine. This consists of the addition of 107 killed
Mycobacterium vaccae per dose of BCG, following
which an increased recognition of Leprosin A is seen,
in comparison with BCG alone, in close contacts of
multibacillary disease. Table 24.6 also shows the
effect on Leprosin A positivity of vaccinating with
Table 24.6: Studies of vaccines in close contacts of multibacillary leprosy patients. Leprosin A results obtained before,
and 1 to 2 years after, (I) vaccination with BCG alone or in combination with 107 killed M. vaccae, (II) vaccination with 108
killed M. vaccae alone results from Tamil Nadu and Vietnam
(I)
BCG alone
BCG + M. vaccae
Initial result
0/64
p < 0.00001
30/64 (47%)
Tamil Nadu
0/88
p < 0.00001
62/88 (70%)
Vietnam
1-2 years result

(II)
Children with scars of previous BCG
Initial result
1-2 years result
Children Tuberculin positive, but without BCG scars
Initial result
1-2 years result
p < 0.003
4/32 (13%)
p < 0.001
22/32 (69%)
5/39 (13%)
p < 0.0001
18/29 (62%)
0/18 (0%)
p < 0.002
8/18 (44 %)
7/33 (21%)
p < 0.0001
16/21 (76%)

10 8
killed M. vaccae alone, in persons in whom one

might wish not to use BCG.
Skin Testing in the Assessment of Immunotherapy

It is just 110 years since Koch advocated immunotherapy
in the treatment of tuberculosis,1 as mentioned in the first
sentence of this paper. The problems of treatment of both
tuberculosis and leprosy, and the failure of worldwide
control of these diseases, have led to a modern reconsideration of the immunotherapeutic approach. A
combination of the bacterial killing power of modern
chemotherapeutics together with the correction of
immune mechanisms to eradicate persisters in
tuberculosis and to alleviate reactions in leprosy is an
attractive proposition. It combines savings in cost with
reductions in treatment time and better compliance with
therapy.
Assessment of Immunotherapy for Tuberculosis

Skin testing can be used to demonstrate the conversion from
Koch-type responsiveness to the kind of response
considered to be a correlate to protective immunity. This
was used to assess a preliminary study of the use of an
injection of killed M. vaccae as an adjunct to chemotherapy
in the treatment of tuberculosis,50 although subsequent
studies have shown lymphocyte transformation tests
(LTTs) to be of greater value.51 Further evaluation of skin
testing in this field is in progress.
Assessment of Immunotherapy for Leprosy

The potential value of M. vaccae as an adjunct to
chemotherapy in the treatment of multibacillary leprosy
has been shown by skin testing. Reacquisition of skin
test positivity to group I mycobacterial antigents and to
the specific group IV antigens of leprosy bacilli has been
shown in Spain.51 Current studies are investigating the
clinical benefits of such a treatment.
CONCLUSION
Skin testing with modern mycobacterial reagents, such
as the new tuberculins, can be used to investigate many
aspects of mycobacterial diseases of man, their
prevention and treatment. No expensive equipment is
needed, and with no more than the judicious selection
of tests any intelligent person can make discoveries about
the human immune system in unsophisticated
surroundings, and at minimal cost. The development of
sensitization due to contact with different species of
environmental mycobacteria can be followed through
childhood, and its effects on protective immunity and
susceptibility to disease can be determined.
319
By the qualitative evaluation of reactions, two

variants of a positive response to some reagents can be
recognized of different immunological significance. One
is thought to be a correlate of protective immunity, and
the other the mechanism of immunopathology.
The system of skin testing with reagents prepared
from four different species allows the recognition of four
categories of responders to mycobacterial antigens. By
such quadruple tests the immunologic anomalies of the
major mycobacterioses, and the processes by which
immunity or susceptibility to them are developed have
been partly elucidated.
Practical uses of the tests include selection of persons
for BCG vaccination and assessment of its efficacy, the
development of new vaccines, 30 new methods of
immunotherapy,50, 51and the discovery of the etiology of
some idiopathic disease. Stanford et al52 have described
the importance of common mycobacterial antigens in the
treatment of disease.
REFERENCES
1. Koch R. An address on bacteriological research delivered
before the International Medical Congress, held in Berlin,
August1890. Br Med J 1890;2:380-3.
2. Shield MJ, Stanford JL, Paul RC, et al. Multiple skin
testing of tuberculosis patients with a range of new
tuberculins, and a comparison with leprosy and
Mycobacterium ulcerans infection. J Hyg 1977;78:331-48.
3. Stanford JL, Grange JM. The meaning and structure of
species as applied to mycobacteria. Tubercle 1974;55:14352.
4. Stanford JL, Nye PM, Rook GAW, et al. A preliminary
investigation of the responsiveness or otherwise of
patients and staff of a leprosy hospital groups of shared
or species specific antigens of mycobacteria. Lepr Rev
1981;52:321-7.
5. Stanford JL, Rook GAW, Samuel N, et al. Preliminary
immunological studies in search of correlates of
protective immunity carried out on some Iranian leprosy
patients and their families. Lepr Rev 1980;51:303-14.
6. Stanford JL, Shield MJ, Rook GAW. How environmental
mycobacteria may predetermine the protective efficacy
of BCG. Tubercle 1981;62:55-62.
7. Rook GAW, Bahr GM, Stanford JL. The effect of two
distinct forms of cell-mediated response to mycobacteria
on the protective efficacy of BCG. Tubercle 1981;62:63-8.
8. Stanford JL, Shield MJ, Rook GAW. Mycobacterium
leprae,other mycobacteria and a possible vaccine.
Proceedings of the XI International Leprosy Congress,
Maxico City, November 1978, Excerpta Medica,
International Conference Series Number 466.
9. Rook GAW, Taverne J, Leveton C, et al. The role of
gamma interferon, vitamin D3 metabolites and tumour
necrosis factor in the pathogenesis of tuberculosis.
Immunology 1987;62:229-34.
10. Rook GAW, Al-Attiyah R, Foley N. The role of cytokines
in the immunopathology of tuberculosis, and the
320
Section 5 Diagnosis
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
regulation of agalactosyl IgG. Lymphokine Res

1989;8:323-8.
Moreno C, Taverne J, Mehlert A, et al. Lipoarabinomannan from Mycobacterium tuberculosis induces the
production of tumor necrosis factor from human and
murine macrophages. Clin Exp Immunol 1989;76:240-5.
Lockwood DNJ, McManus IC, Stanford JL, Thomas A.
Abeyagunawardana DVP. Three types of response to
mycobacterial antigens. Eur J Respir Dis 1987;71:348-55.
McManus IC, Lockwood DNJ, Stanford JL, et al.
Recognition of a category of responders to group II, slowgrower associated antigens amongst senior school
children using a statistical model. Tubercle 1988;69:27581.
Paul RC, Stanford JL, Misljenovic O, et al. Multiple skin
testing of Kenyan school children with a series of new
tuberculins. J Hyg 1975;75:303-13.
Stanford JL, Paul RC, Penketh A, et al. A preliminary
study of the effect of contact with environmental
mycobacteria on the pattern of sensitivity to a range of
new tuberculins amongst Ugandan adults. J Hyg
1976;76:205-14.
Stanford JL, Eshetu Lemma. The use of a sonicate
preparation of Mycobacterium tuberculosis (new
tuberculin) in the assessment of BCG vaccination.
Tubercle 1983;64:275-82.
Swanson Beck J, Morley SM, Gibbs JH, et al. The cellular
responses of tuberculosis and leprosy patients and of
healthy controls in skin tests to New Tuberculin and
Leprosin A. Clin Exp Immunol 1986;64:484-94.
Stanford JL, Sheikh N, Bogle G, et al. Protective effect of
Eshetu Lemma, Stanford JL. Skin-test sensitization by
tubercle bacilli and by other mycobacteria in Ethiopian
school children. Tubercle 1984;65:285-93.
Shield MJ, Stanford JL, Garbajosa G, et al. The
epidemiological evaluation, in Burma, of the skin test
reagent LRA6; a cell-free extract from armadillo-derived
Mycobacterium leprae. Part 1. Leprosy patients. Int J Lepr
1982;50:436-45.
Shield MJ, Stanford JL. The epidemiological evaluation,
in Burma, of the skin test reagent LRA6; a cellfree extract
from armadillo-derived Mycobacterium leprae. Part 2:
Close contacts and noncontacts of bacilliferous leprosy
patients. Int J Lepr 1982;50:446-54.
Comstock GW, Palmer CE. Long-term results of BCG
vaccination in the Southern United States. Am Rev Respir
Dis 1966;93:877-907.
Palmer CE, Long MW. Effects of infection with atypical
mycobacteria on BCG vaccination and tuberculosis. Am
Rev Respir Dis 1966;94:678-94.
Bechelli LM, Lwin K, Gallego Garbajosa P, et al. BCG
vaccination of children against leprosy: Nine-year
findings of the controlled WHO trial in Burma. Bull WHO
1974;51:93-9.
Tuberculosis Prevention Trial, Madras. Trial of BCG
vaccines in South India for tuberculosis prevention.
Bahr GM, Stanford JL, Rook GAW, et al. Two potential
improvements to BCG and their effect on skin test
reactivity in the Lebanon. Tubercle 1986;67: 205-18.
27. Bahr GM, Chugh TD, Behbehani K, et al. Unexpected

findings amongst the skin test responses to mycobacteria
of BCG vaccinated Kuwaiti school children. Tubercle
1987;68:105-12.
28. Shaaban MA, Abdul-Ati M, Bahr GM, et al. Revaccination
with BCG: its effects on skin tests in Kuwaiti senior school
children. Eur Res J 1990; 3:187-99.
29. Stanford JL, Cunningham F, Pilkington A, et al. A
prospective study of BCG given to young children in
Agra, IndiaA region of high contact with
environmental mycobacteria. Tubercle 1987;68: 39-49.
30. Stanford JL. Improving on BCG. Acta Pathol Microbiol
Immunol Scand 1990;99:103-13.
31. Karalliedde S, Katugaha LP, Uragoda CG. Tuberculin
response of Sri Lankan children after BCG vaccination at
birth. Tubercle 1987;68:33-8.
32. Seth V, Kukreja N, Sundaram KR, Seth SD. Wanning of
cell mediated immune response in preschool children
33. Seth V, Kukreja N, Beotra A, et al. Cell mediated immune
response at varying age periods in relation to their
nutritional status among preschool children given BCG
at birth. J Trop Pediatr 1984;30:210-3.
34. Kathipari K, Seth V, Sinclair S, et al. Cell-mediated
immune response after BCG as a determinant of optimum
age of vaccination. Indian J Med Res 1982;76:508-11.
35. Seth V, Kukreja N, Sundaram KR, et al. In vivo correlation
of cell-mediated immune response in preschool children
after BCG in relation to their nutritional status. Indian J
Med Res 1982;75:360-5.
36. Brown JK, Stone M, Sutherland I. BCG vaccination of
children against leprosy: First and second results of trial
in Uganda. Br Med J 1966;1:7-14; 1968,1:24-7.
37. Karonga Prevention Trial Group. Randomised controlled
trial of single BCG, repeated BCG, or combined BCG and
killed Mycobacterium leprae vaccine for prevention of
leprosy and tuberculosis in Malawi. Lancet 1996;348:1724.
38. Bottasso O, Merlin V, Cannon L, et al. Studies of
vaccination of person in close contact with leprosy in
Argentina. Vaccine 1998;16:1166-71.
39. Fine PEM, Floyd S, Stanford JL, et al. Environmental
mycobacteria in Northern Malawi: Implications for the
epidemiology of tuberculosis and leprosy. Epidemiol
Infection 2001;126:379-87.
40. Kardjito T, Swanson Beck J, Grange JM, et al. A
comparison of the responsiveness to four new tuberculins
among Indonesian patients with pulmonary tuberculosis
and healthy controls. Eur J Respir Dis 1986;69:142-5.
41. Bahr GM, Sattar MA, Stanford JL, et al. HLA-DR and
tuberculin tests in rheumatoid arthritis and tuberculosis.
Ann Rheum Dis 1989;48:63-8.
42. Bahr GM, Shaaban MA, Gabriel M, et al. Improved
immunotherapy for pulmonary tuberculosis with
Mycobacterium vaccae. Tubercle 1990;71:259-66.
43. Stanford JL. Skin testing with mycobacterial reagents in
leprosy. Tubercle 1984;65:63-74.
44. Stanford JL, Revill WD, Gunthorpe WJ, et al. The
production and preliminary investigation of Burulin, a
new skin test reagent for Mycobacterium ulcerans infection.
J Hyg 1975;74:7-16.

45. Stanford JL, Hutt MSR, Phillips I, et al. Antibiotic
treatment in Mycobacterium ulcerans infection. Ain Shams
Med J 1973;25(Suppl):258-61.
46. Lord R, Naish C, Taylor T, et al. Skin test studies on close
contacts of leprosy patients in India. Int J Lepr
1989;57:801-09.
47. Pozniak A, Stanford JL, Johnson NMcI, et al. Preliminary
studies of immunotherapy of tuberculosis in man.
Proceedings of the International Tuberculosis Congress,
Singapore 1986. Bull Int Union Tuber Lung Dis
1987;62:39-40.
48. Khoo SH, Wilkins EGL. Fraser I, et al. Multiple skin
testing of HIV-infected persons with new tuberculins.
Thorax 1996;51:932-5.
321
49. Bottasso OA, Ingledew N, Keni M, et al. Cellular immune

response to common mycobacterial antigens in subjects
seropositive for Trypanosoma cruzi. Lancet 1994;344:1540-1.
50. Stanford JL, Bahr GM, Rook GAW, et al. Immunotherapy
with Mycobacterium vaccae as an adjunct to chemotherapy
in the treatment of pulmonary tuberculosis. Tubercle
1990;71:87-93.
51. Stanford JL, Terencio de las Aguas J, Torres P, et al.
Studies on the effects of a potential immuno-therapeutic
agent in leprosy patients.Health Cooperation Papers
1987;7:201-6.
52. Stanford J, Stanford C, Stansby G, et al. The common
mycobacterial antigens and their importance in the
treatment of disease. Curr Pharm Des 2009;15:1248-60.
25
Laboratory Diagnosis of Mycobacterial

(Tuberculosis) Infection in Children
25.1 CONVENTIONAL METHODS

Bansidhar Tarai, Nimrat Bawa, Sarman Singh, Ashok Rattan
THE DIAGNOSTIC CHALLENGES

Children with tuberculosis usually have paucibacillary
disease and contribute little to disease transmission
within the community. Consequently the treatment of
children with tuberculosis is often not considered a
priority by tuberculosis control program. However,
children carry a huge tuberculosis disease burden,
particularly in endemic areas.1,2 Accurate information on
the global distribution of the childhood tuberculosis
epidemic is scarce,3 but of the estimated 8.3 million new
cases of tuberculosis reported globally in 2000,8,84,019
(11%) were children. 2 The extent of the childhood
tuberculosis burden is well recognized, but not well
quantified in many endemic areas.46 Another common
misconception is that children develop mild forms of
tuberculosis and that severe disease manifestations are
the exception. However, almost 15% of all pediatric
deaths have been reported to be caused by tuberculosis
in some Indian hospitals.7
The absence of a practical gold standard test
complicates the diagnosis of childhood tuberculosis.8,9
Sputum microscopy, often the only diagnostic test
available in endemic areas, is positive in 10 to 15% of
children with probable tuberculosis, and culture yields
are also low (3040%).10,11 For this reason, alternative
strategies were developed to diagnose tuberculosis in
children with sputum smear-negative disease. In
nonendemic areas, the triad of (1) known contact with an
adult index case, (2) a positive tuberculin skin test (TST)
as evidence of latent tuberculosis infection (LTBI), and
(3) suggestive signs on chest X-ray (CXR) is used in clinical
practice.12 Also International Standards for Tuberculosis
Care recommends this approach;13 however, the accuracy
of the triad is greatly reduced in endemic areas, where
most of the population acquire M. tuberculosis infection
during childhood and where transmission is not restricted
to the household. 14,15 This limits the diagnostic
contribution of both documented household exposure
and a positive TST. Consequently, in endemic settings,

the diagnosis of childhood tuberculosis depends mainly
on clinical features and the subjective interpretation of
the CXR. 16,17
Sputum smear-positive TB is rarely present in
children. Although this reduces their risk of actively
spreading the disease, it makes it more challenging to
establish a definitive diagnosis. In contrast to adults,
where the sensitivity of sputum culture approximates 80
to 90%, young children are unable to expectorate,
alternative specimens such as gastric aspirates or induced
sputum are difficult to collect and culture yields are low
(widely reported as 30-40%).18,19 Traditionally, three
fasting gastric aspirate samples are collected on three
consecutive mornings, requiring hospitalization of the
child and, frequently, the caregiver.
Novel culture methods have been developed in an
attempt to circumvent the slow turnaround times, poor
sensitivity and cost of conventional automated liquid
broth systems. The most feasible alternative to date has
been the microscopic observation drug susceptibility
assay (MODS), which uses an inverted light microscope
to rapidly detect spindle and cord formation in selective
broth culture that is indicative of mycobacterial growth.20
Phage amplification assays that use bacteriophages to
detect the presence of live M. tuberculosis have been less
successful.21
There is abundant literature utilizing commercial and
in-house polymerase chain reaction (PCR) for the
diagnosis of mycobacterial infection in sputum and body
fluids such as cerebral spinal fluid, but results in the
literature are highly variable and have not been well
validated in children.21 Recent reviews and meta-analyses
of PCR in TB meningitis, pleuritis and sputum smearnegative pulmonary TB have demonstrated poor
sensitivity.22 PCR may play an invaluable role in offering
rapid species identification and detection of drug
Chapter 25 Laboratory Diagnosis of Mycobacterial (Tuberculosis) Infection in Children

resistance in patient with smear-positive TB. 20 The
application in patients with sputum smear-negative or
extra-pulmonary TB requires further evaluation, and use
in low-income countries remains limited due to cost
constraints.
T-cell assays that measure interferon-gamma released
by lymphocytes in peripheral blood, after exposure to
M. tuberculosis specific antigens, have been hailed as
reliable TB tests. Two commercial tests are available: TSPOT . TB (Oxford Immunotec, Oxford, UK) and
QuantiFERON -TB Gold (Cellestis, Carnegie, VIC,
Australia). However, study results are highly variable,
and experience in children remains limited. Current
consensus is that these tests are unable to distinguish
latent infection (a third of the world population is latently
infected) from active disease and adds little to the
traditional tuberculin skin test (TST). These tests are also
too expensive and complex for routine use in low-income
countries.20,21,23,24
TUBERCULIN SKIN TEST (MANTOUX TEST)

Tuberculin skin test (TST) has been the standard
diagnostic tests for M. tuberculosis infection in the last
100 years. Today the Mantoux test uses 1, 2 and five
tuberculin units of purified protein derivative (PPD). A
delayed hypersensitivity reaction appears in infected
individuals at 48 to 72 hours when tuberculin is injected
properly and a wheal of fluid measuring 6 to 10 mm in
diameter is raised. Mantoux positivity is based on the

size of induration and epidemiological risk factors. The
Centers for Disease Control (CDC) and the American
Association of Pediatrics (AAP) recommend specific
interpretations of skin reactions (Table 25.1.1). 25,26
Children in the highest risk category (e.g. had contact
with an index case, are infected with HIV, or have clinical
evidence of TB) are considered infected with M.
tuberculosis if the Mantoux test result is indurated at least
5 mm. For children with moderate risk factors, a reactive
diameter 10 mm or more is considered a positive result.
Fifteen millimeters of induration or greater is considered
to be positive for any child, including those children with
low risk. A negative TST does not necessarily exclude
infection with M. tuberculosis. A decreased response to
TST may be caused due to a number of factors including
concurrent illnesses or infections, along with active TB.
Nearly about 25% of people with active TB are found to
be nonreactive to 5 TU of tuberculin.27 It is likely that
these individuals have suppressed immune responses
and may convert to a negative skin test after several
months of anti-TB medication.28 In addition, if a child
was exposed to M. tuberculosis within a month of
implanting a skin test, it may be too early to elicit a
delayed hypersensitivity reaction, as it can take up to
3 months for tuberculin reactivity to become apparent.
The false negative rate has been increased by the failure
to administer the PPD intradermally and the complexity
in reading the indurated reactions.
Table 25.1.1: Definitions of positive tuberculin skin test (TST) results in infants, children, and adolescents
Induration >5 mm:
1. Children in close contact with known or suspected contagious people with tuberculosis disease.
2. Children suspected to have tuberculosis disease:
Findings on chest radiograph consistent with active or previous tuberculosis disease
Clinical evidence of tuberculosis disease
3. Children receiving immunosuppressive therapy or with immunosuppressive conditions, including HIV infection.
Induration >10 mm:
Children at increased risk of disseminated tuberculosis disease:
Children younger than 4 years of age
Children with other medical conditions, including Hodgkins disease, lymphoma, diabetes mellitus, chronic renal
failure, or malnutrition
Children with increased exposure to tuberculosis disease:
Children born in high-prevalence regions of the world
Children frequently exposed to adults who are HIV infected, homeless, users of illicit drugs, residents of nursing
homes, incarcerated or institutionalized, or migrant farm workers
Children who travel to high-prevalence regions of the world.
Induration >15 mm
Children 4 years of age or older without any risk factors.
323
Evidence by physical examination or laboratory assessment that would include tuberculosis in the working differential
diagnosis (e.g. meningitis).
Including immunosuppressive doses of corticosteroids.

Reproduced with permission from the American Academy of Pediatrics.26
324
Section 5 Diagnosis
RADIOLOGY-BASED APPROACHES
The diagnosis of TB in endemic areas depends
predominantly on the subjective interpretation of the
chest X-ray (CXR). Despite its many limitations, the CXR
remains the most practical and helpful test in everyday
practice. It usually provides an accurate diagnosis, at least
in HIV-uninfected children with suspicious symptoms,
if evaluated by an experienced clinician.29 The most
sensitive tool currently available to detect hilar
adenopathy and/or early cavitations is High-resolution
computed tomography.30 This technique (if available) has
definite application in rare problem cases, but the natural
history of disease demonstrates that particular caution
is required when interpreting the relevance of these
findings29 as a limited degree of hilar adenopathy is
common following recent primary infection. These signs
are usually transient and not indicative of disease in the
absence of symptoms. Therefore, it is important to
evaluate the presence of other clinical signs and
symptoms, and not to base a diagnosis of TB solely on
the radiographic findings.
FINE NEEDLE ASPIRATION CYTOLOGY (FNAC)

FNAC has been less widely utilized in pediatrics as a
diagnostic modality. However, in developing countries
with a high burden of infectious diseases such as TB and
HIV, FNAC can be of remarkable value in confirming
the diagnosis of mycobacterial infection, permitting early
appropriate therapy as well as a means to obtain
specimens for histopathology culture, bacterial species
determination and sensitivity testing.31 FNAC is a simple
and minimally invasive technique that can be performed
at the bedside, and is well tolerated by children. Most
aspirates in children taken are from cervical and axiliary
lymph nodes that are easily accessible. If the procedures
are performed correctly, with a small gauge needle (2223 G or smaller), complications such as a small hematoma
are rare. In developing countries where TB is endemic
and specimens for bacteriological diagnosis are difficult,
if not impossible, to obtain from children, FNAC provides
the means for accurate diagnosis in a significant
percentage of children with mycobacterial infection. This
is particularly important in countries with a high HIV
rate, as well as increasing rates of multidrug resistant
(MDR) and extremely drug resistant (XDR) TB. FNAC
can be performed as an out-patient procedure and is a
cost-effective diagnostic modality procedure.
adequate specimen for culture. Efforts are to be made to

obtain specimens from any body cavity in which the
organism may reside before starting antimicrobials. In
addition, several specimens should be sent for evaluation
to increase the chances of capturing the bacilli. Possible
microscopy and culture sites include the following: whole
blood, bone marrow (in miliary disease), biopsy
specimens (i.e. lymph node or bone), cerebrospinal fluid,
sterile fluids (i.e. pleural), first morning urine, and
bronchoalveolar lavage fluid. Sterile leak-proof containers
without fixative agents should be used for collection and
quickly transported to the laboratory where examination
should be performed on the day of receipt. If brief storage
is necessary, specimens other than blood should be
refrigerated to inhibit the growth of contaminating
microorganisms. General guidelines for collection of
various types of specimens are listed in Table 25.1.2.
Different types of collected specimens including
gastric aspirates, induced sputum, bronchoalveolar
lavage or specimen collected using the string test have
been used for confirmation of pulmonary TB. Whichever
technique is used, at least three specimens are evaluated
to ensure recovery of low numbers of mycobacteria. On
arrival in the laboratory, most specimens are
homogenized with a mucolytic agent and decontaminated before inoculation to culture media to inhibit
the normal flora. The stain and culture yield from three
properly obtained gastric aspirates, was found to be
higher than from bronchoalveolar lavage by Abadco and
Steiner32 and Somu et al.33 Collection of gastric content
is best performed after a child has fasted for at least 8
hours and is still in bed. A silastic nasogastric tube is
usually used to perform aspiration, which is inserted
before the child had taken anything by mouth. When
aspiration of gastric secretions is unsuccessful, sterile
Table 25.1.2: Specimen for examination and
diagnostic studies
Specimen
Aspirates, fluids
Sterile syringe, container, or direct

inoculation to culture media
Bone marrow
Direct inoculation to broth culture
media designed for mycobacterial
blood cultures or ISOLATOR tube/
Myco F lytic bottle (BACTEC)
Bronchial washings Sterile container
Gastric lavage
Obtain when patient awakes 50 mL
gastric aspirate in sterile container
with 100 mg of sodium carbonate
Sputum
Exudates from lungs by a productive
cough (not saliva), sterile container
Stool
Clean container
Tissues, biopsy
Sterile container
specimens
Urine
First morning void, do not pool
CONVENTIONAL LAB DIAGNOSIS

Specimen Collection and Transport
In children, TB is often paucibacillary and extrapulmonary and it is therefore challenging to obtain
Procedure

distilled water can be instilled and aspirated. If gastric
aspiration is performed under these conditions, M.
tuberculosis will be recovered in up to 50% of children
with TB disease.34 Nonhospitalized children can also
undergo gastric aspiration for Acid-fast bacilli (AFB)
staining and culture, but the yield is found to be lower.35
Induced sputum in older children is easily performed
in an outpatient setting, which is an advantage over the
hospitalization required when obtaining specimens via
gastric lavage. Excess oral flora should be removed by
rinsing the oral cavity of the child with water before
collecting induced sputum. Infection control measures
to be taken to reduce exposure to other patients and staff.
The collection of a single hypertonic-saline induced
sputum specimen reportedly provides the same yield as
three gastric aspirate specimens.36 Unfortunately, the
safety and feasibility of this technique has not been
studied outside the hospital setting. In addition, induced
coughing may pose a transmission risk to healthcare
workers, and also to other children, if the procedure is
not performed in a separate, well-ventilated room and/
or equipment is not adequately sterilized. It also requires
the administration of a bronchodilator by nebulization to
prevent bronchospasm.
The string test which is a novel approach has recently
been evaluated for its ability to retrieve M. tuberculosis
from sputum smear-negative adults infected with HIV.37
A gelatin capsule that adheres to gastric contents over a
couple of hours is swallowed and then pulled back up
for investigation. In a recent study the string test was
shown to be well tolerated in children over 4 years of
age, yet there were no positive TB cultures detected
within this small study.38
Specimen Processing
Specimens derived from normally sterile body sites, such
as aspirated body fluids, blood, bone marrow, and tissue
(grind in sterile 0.85% saline), should be inoculated
directly to culture media. Digestion and decontamination
is needed for specimens contaminated with normal flora
microorganisms before inoculating to culture media. This
step will help to prevent the overgrowth of more rapidly
growing microbes, and also digest the mucin that may
bind any mycobacteria present, inhibiting their recovery.
The goal, however, is to inhibit the normal flora but not
the hardier mycobacteria. It is important for the
laboratory to monitor the overall rate of the specimen
contamination. The goal is not to reduce this rate to zero,
since that would indicate too many mycobacteria are
being lost in the decontamination process; instead it is to
be expected that under normal circumstances, between
2 to 5% of specimens will be overgrown by normal
flora. If overtime contamination rates are more than
5%, the decontamination technique employed is likely
325
inadequate, while if the rate is less than 3%, it is too

harsh.
A number of methods for the digestion and
decontamination of the specimens are available: The most
commonly used and widely preferred reagent is sodium
hydroxide (NaOH), usually in combination with
N-acetyl-L-cysteine (NALC). While NaOH alone is
effective as both a mucolytic and decontaminating agent,
final concentration of 2% or greater are often required
for maximum efficacy. Following digestion/decontamination, the specimen is centrifuged to sediment the
mycobacteria. The relative centrifugal force (RCF)
applied to the sample must be monitored closely.
Extreme care must be taken to prevent contamination
with other specimen during specimen processing.
Biosafety Pertinent to Mycobacteriology

The single most important piece of laboratory equipment
in a mycobacteriology laboratory is a well-maintained
properly functioning biological safety cabinet (BSC).
Although Class I or Class II BSCs can be used in the
mycobacteriology laboratory, most laboratories employ
a class II BSC, which is a vertical, laminar-flow BSC
that blows HEPA-filtered air over the work area.
Technologists should be trained in operating and
cleaning the cabinet and in organizing the work surface,
so the air circulation is not compromised. Technologist
should also be conscious of the airflow in a BSL-3
laboratory and have a method to verify that the air
pressure is lower than the adjacent areas. In addition,
periodic checks on the airflow should be performed and
the airflow should be tested and recertified at least yearly
by trained personnel. After the completion of work UV
lights should be turned on for a minimum of one hour.
Centrifugation of a specimen suspected of containing
mycobacteria must be done in an aerosol-proof
centrifuge, the carrier should be opened, and the tubes
removed in a BSC at a BSL-3 laboratory.
A BSC should be used to prepare and dry the AFB
smears from concentrated and liquefied specimens.
Despite it being fixed, organisms on the dried and heated
slide can still be viable but aerosolizaton is less of a
concern. Manipulations of viable cultures done for
identification or susceptibility testing should be
performed in a BSC at a BSL-3 laboratory. All manipulations with cultures or specimens should be done with
protecting garments, gloved hands, and face protection.
For the mycobacteriology laboratory, the minimum level
of respiratory protection is an aspirator that contains a
National Institute of Occupational Safety and Health
(NIOSH)- certified N Series filter with a 95% efficiency
rating (N-95). Procedures for spills in the mycobacteriology laboratory should address spills and the
disinfectant should be applied. After atleast 20 minutes
326
Section 5 Diagnosis
of contact time, the items can be removed for transport

to an autoclave.
AFB Microscopy
Microscopic examination of acid-fast-stained smears is
one of the easiest, most inexpensive and rapid method
for demonstrating the presence of mycobacteria in clinical
specimens and cultures. AFB smear continues to be the
backbone of TB diagnosis under the RNTCP (Revised
National TB Control Program) in India. Although the
technique is more than 100 years old and it is grossly
inadequate, as it has low and variable sensitivity and
cannot identify drug-resistant/ MDR-TB strains. HIV
coinfection complicates the clinical presentation and
diagnosis of active TB and further limits the sensitivity
of AFB sputum smear. Fluid and solid specimens which
have been liquefied can easily be stained. Stains used in
the process, penetrate the bacillis cell wall. Once applied,
the stain is difficult to remove even when mineral acids
are applied to it, and hence, comes the name acid fast.
Ziehl-Neelsen Stain
Fuchsin-stained smears are examined with a Brightfield
microscope under oil immersion field (Fig. 25.1.1). AFB
appears as red and rod-shaped filaments. Ziehl-Neelsen
staining is the most common technique used to identify
AFB in which the bright red stained bacteria stand out
clearly against a blue background (Fig. 25.1.2). Another
method is the Kinyoun method, in which the bacteria
are stained bright red and stand out clearly against a
green background. The slide is examined by making three
parallel sweeps along the length of the smear, or
alternatively, by making nine parallel sweeps across the
width (as per the following diagram). This procedure
allows up to 100 fields per slide to be viewed.
The positive and negative ZN QC smears from each
batch of smears stained should be examined first. The
Fig. 25.1.2: ZN stain: bacteria are stained bright red against blue
background (For color version see Plate 6)
positive control smear ensures the staining capability of

the stain solutions and the negative control smear
confirms presence or absence of contaminants.
Reporting Smear Results (Table 25.1.3):
1. A slide with no acid-fast bacilli visible in 100 fields is
reported No AFB seen.
2. Slides positive for AFB must be examined by at least
two technicians before the result is reported.
3. If the slide is positive, fewer fields need to be
examined and a count can be reported according to
the smear evaluation table as follows:
Fluorescence Stain
AFB can also be visualized by fluorescence microscopy
using specific fluorescent dyes, such as auramine and
rhodamine. Fluorescence-stained AFB smears have
similar morphology and will fluorescent yellow when
examined with a fluorescent microscope (Fig. 25.1.3). In
a systematic review of 45 studies comparing the two
methods found that fluorescence microscopy yielded an
average increase in sensitivity of 10%, without loss of
specificity. 39 Thus fluorescence microscopy has
advantages over light microscopy for detection of
pulmonary TB. However, the equipment cost for
fluorescence microscopy are high, so its utility has been
limited to regions that can afford it.
All mycobacteria exhibit various degrees of acid
fastness so microscopy alone cannot be used to determine
Table 25.1.3: AFB smears grading
Fig. 25.1.1: Recommended method for examining acid-fast

stained smears
Carbol fuchsin 1000X
Report
0
1-9/100 F
10-99/100 F
1-10/F
>10/F
No AFB seen
Report exact count
1+
2+
3+
Fig. 25.1.3: Fluorescence-stained AFB smearbacteria

fluorescent yellow (For color version see Plate 6)
the individual species of mycobacteria including

M. tuberculosis. Despite this, staining has significant
advantages because it remains the most rapid technique
and is of significant value in identifying the most
infectious patients for hospital and community infection
control. The number of microorganisms seen on the
microscopic examination of the stained smears reflects
the burden of bacterial infection. The sensitivity of
positive sputum smear examination indicates a
concentration of at least 104 bacteria/mL. 39 Higher
grading of results (1_ to 3_) indicates greater concentration of bacteria. Environmental contamination, which
usually involves only a few organisms, rarely results in
a positive smear examination.
Given the paucibacillary nature of pediatric TB, most
children are smear-negative. Less than 10 to 15% of
children with proven TB will have a sputum or gastric
aspirate stain positive for AFB.40 The rates of positive
smears from other specimen sources are even lower.41
Adolescents, however, often develop adult type disease
and have higher bacteriological yield. 42 Further,
microscopy evaluation in low-income settings is often
performed on unconcentrated sputum and the sensitivity
of this method for detecting mycobacteria is limited.
Traditional Culture Methods

Culture is more sensitive than microscopy and can detect
as few as 10 to 100 bacteria/mL of specimen43 but is
positive in less than 50% of children with active disease.
There are two major forms of media which are routinely
used in mycobacteriology laboratories, solid and liquid
media. The main advantage of solid media is that it allows
the determination of characteristic features of colonial
morphology, growth rate, and pigment production,
which can yield significant preliminary information. The
two types of solid media commonly used are egg-based
327
and agar-based media. Lowenstein-Jensen (LJ) is an eggbased media and most commonly used globally. To
suppress the growth of contaminating bacteria and fungi,
the LJ contains malachite green, thus LJ is used for both
detection and susceptibility testing. In resourcechallenged countries LJ is often the only media used,
while in the USA it is used in conjunction with liquid
media.
It is easier to observe colony morphology and
enumerate colonies on agar-based media Middlebrook
7H10 and 7H11. Middlebrook 7H11 is better than LJ at
establishing resistant M. tuberculosis isolates. The average
time for M. tuberculosis detection on LJ and Middlebrook
7H11 media is 4 and 3 weeks, respectively. Physiologic
tests are performed to identify mycobacterial species,
after a colony appears on the culture. Such tests include
pigment inspection, microscopy examination for
recording, colony morphology, and biochemical tests.
Use of chromatography for the analysis of fatty acids
extracted from the mycobacterial cell wall is a more
reliable method for identifying mycobacteria. Molecular
methods used to speciate mycobacterium include the use
of gene probes in hybridization assays, amplification with
subsequent DNA sequencing, or restriction fragment
length polymorphism analysis.
Liquid-Based Culture Systems

Liquid media supports growth of the M. tuberculosis
complex better than solid media with an increased
recovery of positive cultures,44 even in cases in which a
child was started on anti-TB medication before obtaining
cultures.45 An important advantage of the liquid media
over the solid one is the shorter time taken for detection
of positive cultures. Isolation and susceptibility testing
of M. tuberculosis in liquid media can be reported on an
average of 2 and 4 weeks, respectively.46 The average
time for recovery of smear-positive specimens is only 8
days compared with 18 days taken by solid conventional
media.47 Because of the significant increase in the positive
culture rates and the timesaving, the CDC has
recommended the use of commercially available liquid
media for detection as well as for drug susceptibility
testing of M. tuberculosis in the USA.48 The first brothbased mycobacterial detection system was the BACTEC
460, which uses modified Middlebrook broth and a novel
radiometric detection scheme. Mycobacterial growth can
be periodically ascertained by the liberation of 14CO2 as
metabolized by the mycobacteria and detected by the
BACTEC instrument. Most recently, a nonradiometric
liquid culture system has been developed to minimize
the handling and disposal of radioactive waste.44
The Mycobacterial Growth Indicator Tube (MGIT;
Becton Dickinson, Baltimore, MD) is supplemented with
enriched growth media and antibiotics and processes all
328
Section 5 Diagnosis
types of clinical specimens other than blood and urine;

however, a recent study in India found high sensitivity
when using concentrated urine specimens. 49 The
automated MGIT system has slightly superior sensitivity
and reduced turnaround time compared with
conventional LJ culture.50 There is a manual MGIT system
that allows anti-TB drug susceptibility testing. Tubes are
placed on a 365-nm UV transluminator and are examined
for fluorescence. However, the high cost of even the
manual MGIT system and laboratory infrastructure
required remain major limitations in resource-challenged
regions.
It is customary to use at least two types of media to
maximize the recovery of M. tuberculosis: liquid media
to assure rapid results and solid media to examine clinical
morphology (which is not possible in liquid media).
Moreover, using solid media provides a backup in case
of any kind of contamination occurring in the liquid
media.45
Because mycobacteremia and miliary TB occur more
often in children with TB than adults, it is always
important to obtain blood cultures in children with
suspected TB disease. The ISOLATOR tube (Wampole
Laboratories, Princeton, NJ) provides a unique approach
to the recovery of mycobacteria, which tend to circulate
intracellularly. Saponin is used to lyses leukocytes
releasing any intracellular microbes in the ISOLATOR
system. After centrifugation, the sediment can be used
to inoculate a variety of mycobacterial media. BD
(BACTEC) also has Myco/F lytic bottles for mycobacteria
blood culture.
Susceptibility Testing
The incidence of multidrug-resistance (MDR) TB, defined
as resistance to both isoniazid and rifampin, has increased
in many parts of the world. As children have lower rates
of TB isolation, MDR-TB is often initially identified
exclusively in the adult index case.
The unique mechanisms by which mycob-acteria
acquire drug resistance are chromosomal alternations
such as mutations or deletions. These chromosomal
alterations affect either the drug target itself or the
bacterial enzymes activating the prodrug. In the United
States, drug susceptibility is performed on all initial
isolates and on any isolate from patients with persistent
positive cultures or relapse of clinical symptoms. In
addition to the immediate benefit in planning a
therapeutic regimen, drug susceptibility information is
valuable for public health. Understanding resistance
patterns in a particular region provides strategic policy
advantage for the treatment and control of TB.
There are a variety of methods to determine the
susceptibility of M. tuberculosis to anti-TB drugs. From a
technical perspective point of view, drug susceptibility
is determined on the basis of growth (or metabolic)

inhibition induced by the drug by means of (1)
macroscopic observation of growth in drug-free and
drug-containing media; (2) detection or measurement of
the metabolic activity or products ( 3) lysis with
mycobacteriophage; and (4) detection of genetic
mutations using molecular techniques.
A direct test uses the processed clinical specimen for
susceptibility testing, whereas the indirect method uses
the primary isolate culture for testing. Conventional or
rapid techniques can be used to perform both direct and
indirect tests. Conventional techniques involve
inoculating the microorganisms to a solid medium that
contains a known concentration of the test drug. The
proportion method is the most commonly used
conventional techniques in the USA. Dilutions of the
inoculum are made so that growth on control media
results in the production of a number of colonies that is
counted and compared to the number of colonies that
grow on the drug containing media. Thus, the proportion
of organisms resistant to a drug can be measured and
expressed as a percentage of the total population. If more
than 1% of the test population is resistant to the drug
being tested, it is established that resistance to that drug
has developed. Results usually take about 3 weeks by
the conventional method. In contrast, BACTEC
susceptibility results are usually available in as little as 4
to 6 days after inoculation and provide results with a
high degree of correlation to the proportion method.
Newer techniques including the microscopic
observation drug susceptibility (MODS) and the phage
based assays enable laboratories, particularly those in
resource-limited regions where the incidence of MDR-TB
is the highest, to have access to modern drug susceptibility
methods. The luciferase reporter mycobacte-riophage is
reported to be a rapid method that is highly accurate,51
but its specificity may vary.52 The MODS technique is a
liquid-based methodology that also enables rapid (within
10 days) detection of drug resistance.53,54
Quality Control
Quality control (QC) is an important integral part of
laboratory testing. Laboratory should establish a protocol
of all the aspects of quality control testing. The frequency
of the QC testing depends upon the workload in a
laboratory, type of media used, and laboratoryestablished policies. All QC procedures should be written
and results of QC testing documented in the laboratory
records. In case there is a situation of unsatisfactory
performances, corrective measures should be taken and
their outcome should be documented.
AFB smear: With each run, and whenever new
reagents are introduced, a known positive and known

negative smear is read. It is preferable to use actual
sediment from clinical specimens to prepare these
controls, but if that is not available, a suspension of
M. gordonae for the positive and E.coli for the negative
control can be used.
Culture media: Records of batch numbers and expiry
date of all media and reagents should be documented.
QC records of commercial media may be obtained from
the manufacturer and should be kept in the file. Quality
control should be carried out both on culture media
and reagents.
The following three mycobacterial cultures are
recommended for quality control testing.
M. tuberculosis H37Ra ATCC 25177
M. kansasii ATCC 12478
M. fortuitum ATCC 6841
Susceptibility testing: Quality control of Mycobacterial
tuberculosis culture (MTBC) susceptibility testing
should include an isolate that is completely
susceptible to the antimicrobial agents being tested.
The strain M. tuberculosis H37Rv (ATCC 27294) is well
suited for use as a pan-susceptible control organism
and its performance is well documented.
Alternatively, M. tuberculosis H37Ra, which is
believed to be avirulent could be used. Quality control
testing using M. tuberculosis H37Rv (ATCC 27294)
should be performed once each week when patient
isolate is tested.
IMMUNE-BASED DIAGNOSIS
Fluid ChemistryADA
Adenosine deaminase (ADA) is an enzyme found at the
cell surface of lymphocytes and macrophages. It catalyzes
the conversion of adenosine to inosine and is generally
elevated in regions of active lymphocyte proliferation.
Several studies have consistently shown high ADA levels
in the pleural, peritoneal, and cerebrospinal fluids in case
of patients infected with M. tuberculosis55-58 in the
respective anatomic cavities. One meta-analysis found
that ADA levels over 36 to 40 IU/L had a sensitivity of
100% and specificity of 97%.58 A study in adults with
meningitis found an ADA level above 5 U/L in the CSF
had a 81% sensitivity in culture-confirmed TB meningitis
and 86% specificity in the non-TB meningitis group.59
Giusti colorimetric method based on simple reaction to
form ammonia is usually used to determine ADA. Since
ADA determination is a fast, inexpensive, and
discriminating test, effusions and CSF should be
analyzed when working up a patient with active TB.
A common finding in M. tuberculosis infected fluid is
a low-glucose and high-protein level secondary to the
leukocytes recruited to the site of infection. The doubling
time of mycobacteria is much slower than other bacteria;
329
hence the glucose levels are usually not as low as that

observed in other bacterial infections. The chronic nature
of TB infection also causes a lymphocytic predominance
in CSF and pleural fluid.
Antibody-based Assay
A number of serologic tests for TB have been developed
recently using a variety of antigens to detect certain
antibodies in the blood. As of yet, none of these tests have
shown adequate accuracy due to great heterogeneity of
humoral responses in patients with TB and crossreactivity with other mycobacterial species. Therefore,
no serological test has been widely implemented in
clinical care.60 A particular problem in pediatrics is that
children tend to have lower antibody titers than adults.61
A recent comparison of seven serologic tests for active
TB in adults found poor to moderate sensitivity ranging
from 16 to 57% and variable specificity of 62 to 100%.62
Higher accuracy can be achieved by a combination of
two serological tests, that is, sensitivity 66% and
specificity 86%.62
Various antigens, such as antigen 85A, antigen 85B,
38-kDa protein, alpha-crystallin (16 kDa), and 19-kDa
lipoprotein, have been recognized to have significant
diagnostic value. It has been found that specific antibody
profiles vary according to the stage of TB disease. Only a
few published studies report on antibody detection in
primary infection, a condition that predominantly occurs
in children. Scientists examined serologic response to
only two antigens, the 30 kDa and 16 kDa, in 26 children
with biologically proven or suspected active TB and
found a sensitivity of 84% and 73% for the 30- and 16kDa antigens, respectively.63 A study performed in India
with the 38-kDa IgG antibody was found to be positive
in 37% of children with pulmonary TB, 86% of children
with TB lymphadenitis, and 27% of controls (who may
have been latently infected).64 It is believed that in the
future serologic assays will contain various specific
antigens to evaluate the humoral immune response to
M. tuberculosis during different stages of infection.
Antigen-based Assay
Antigen detection has the potential to overcome some of
the well-recognized problems with antibody detection
assays, especially in populations infected with HIV.
Attempts have been made to detect M. tuberculosis
antigens directly in body fluids. Assays using serum or
urine may have particular application in extrapulmonary
disease, which tends to occur more often in children or
people coinfected with HIV and TB. Recent development
of monoclonal antibodies to target proteins and
glycolipids such as lipoarabinomannan(LAM), a heatstable high-molecular-weight glycolipid present in the
330
Section 5 Diagnosis
cell wall of mycobacteria, has proved to be an important

achievement in the detection of level of M. tuberculosis.
Several groups have demonstrated elevated LAM levels
in the sputum,65 serum,65 and urine66,67 of TB patients.
Recently a large study in Ethiopia found a urine LAMELISA was slightly more sensitive than smear
microscopy (74% versus 69%) in culture-proven TB
patients.66 A urine test called LAM-ELISA was first
developed by a US company, Chemogen and
subsequently by Inverness Medical Innovations
(Waltham, MA, USA), which marketed the test as
Clearview TB ELISA.
Interferon- Release Assays: (IGRAs)

A new generation of immune-based rapid blood tests for
the diagnosis of LTBI, called IGRAs, offers particular
advantages over the century-old TST. The basis of these
tests is host response to M. tuberculosis infection, by
measuring the IFN-g produced by T-cell responses to M.
tuberculosis -specific antigens called early secreted
antigenic target 6 (ESAT-6) and culture filtrate protein
10. These antigens are encoded by the region of
difference_1 (RD-1), a segment of the genome specific
for M. tuberculosis and absent in BCG and most species
of NTM, therefore being more specific to M. tuberculosis
than tuberculin (PPD). Two assays are currently available
as commercial kits and have recently been approved by
the US Food and Drug Administration (FDA). First the
QuantiFERON-TB Gold assay (Cellestis, Carnegie,
Australia) which is based on Whole-Blood EnzymeLinked Immunosorbent Assay (ELISA). The latest and
the most preferred version of this assay, the
QuantiFERON-TB Gold In-tube (QFT), includes an
additional M. tuberculosis specific antigen TB 7.7. Second
is the T-Spot.TB (T-Spot) test (Oxford Immunotec,
Abingdon, UK) which is based on the ex vivo overnight
enzyme-linked immunospot assay. The T-Spot
enumerates individual T-cells producing IFN-g after
antigenic stimulation, while the QFT measures the level
of IFN-g in the supernatant of the stimulated whole
blood. Both the QFT and the T-Spot have an internal
positive control (a mitogen) that elicits robust IFN-g
responses in immunocompetent people. The mitogen
provides information regarding the validity of the assays
in a subject with questionable immune status, such as
HIV-infected individuals or very young children. The TSPOT.TB is licensed for use in Europe, Canada and other
countries, but has been still awaiting US FDA approval.
The use of T-cell assays in children is currently limited
by high cost, the relatively large volume of blood (4-5
ml) required, the non-availability of adequate laboratory
infrastructure to perform enzyme-linked immunospot
(ELISPOT) assays in particular, and the absence of
conclusive evidence on which to base formal

recommendations.
The sensitivity and specificity of IGRAs cannot be
calculated with certainty mainly due to lack of a gold
standard test to detect latent tuberculosis infection (LTBI).
Recently, the US Centers for Disease Control and
Prevention recommended that the QFT-G assay could
be used in place of the TST for all indications, including
screening of children.68 However, there are limited data
on the performance of the QFTG assay in children. A
recent study from Italy raised concerns about the
diagnostic accuracy of the QFT-G assay in young
children, as indeterminate results were recorded in 32%
of children, 5 years of age. 69 An Australian study
substantiated this observation by reporting that 17% of
the QFT-G assays yielded indeterminate results in
children, and the concordance between QFT-G and the
TST was poor (k = 0.3).70 By contrast, a study among
hospitalized children in rural India showed strong
agreement (k = 0.73) between the TST and QFT-G In Tube,
but data were inadequate to estimate sensitivity among
confirmed tuberculosis cases.71
Evidence for the ELISPOT assay indicate that it is a
more sensitive marker of M. tuberculosis infection than
the TST, as reflected by better correlation with the degree
of exposure following a school tuberculosis outbreak in
the UK.72 Improved sensitivity was also shown in HIVinfected children diagnosed with tuberculosis and in
those with malnutrition, although the improved
performance in malnourished children was not
substantiated after correction for the HIV status of the
child.73 Despite its superior sensitivity, a study from
South Africa reported that ELISPOT responses to ESAT6 and CFP-10 were detectable in only two-thirds of
children with a clinical diagnosis of tuberculosis and in
83% with culture-confirmed disease. 74 In a recent
household contact study conducted on Gambian
children, the ELISPOT assay was slightly less sensitive
than the TST in detecting M. tuberculosis infection and
neither test was confounded by prior BCG vaccination.75
In a head-to-head comparison between the Quanti
FERON-TB Gold and TSPOT.TB assays, T-SPOT.TB gave
considerably less indeterminate results, particularly in
high-risk groups such as immunocompromised adults
and young children.69 Although the agreement between
the various T-cell assays and TST results are fairly high,
the interpretation of discordant results remain
problematic.
Overall, it appears that T-cell assays are good at
detecting M. tuberculosis infection, but in the absence of
symptoms or radiological signs, novel T-cell assays, like

the TST, fail to make the crucial distinction between LTBI
and active disease. The main application of these assays is in
nonendemic areas, where disease elimination is a realistic
target. The aim of this target would be the screening of groups
with known or expected tuberculosis exposure to identify and
treat everyone with LTBI. In tuberculosis-endemic areas
where transmission is poorly controlled, tuberculosis
exposure and infection are extremely common and the
benefit of preventive treatment is reduced by the high
likelihood of reinfection. However, the provision of
preventive treatment remains a high priority in
individuals who are at high risk of progressing to active
disease after infection, such as young and/or
immunocompromised children. In tuberculosis-endemic
areas, the superior ability of the ELISPOT assay to detect
M. tuberculosis infection in high risk groups, 76,77
particularly in children infected with HIV, in whom the
TST performs poorly,78 seems to offer particular value.
In this group, where the diagnostic dilemma is most
pronounced, a sensitive test for M. tuberculosis infection
may also provide supportive evidence to establish or
refute a diagnosis of active tuberculosis. Formal
recommendations on the use of T-cells assay for children
from tuberculosis endemic areas require further research
to take place.80, 81
NOVEL CULTURE SYSTEMS AND DETECTION

METHODS
Major limitations of traditional culture methods are slow
turnaround times, suboptimal sensitivity, and the
excessive cost of using automated liquid broth systems.
TK Medium (Salubris, Cambridge, Massachusetts, USA)
is a novel colorimetric system that indicates growth of
mycobacteria and allows for early positive identification,
before visible bacterial colonies appear.81 It also allows
susceptibility testing for drug resistance, and can allow
for differentiation between M. tuberculosis and NTM.
Although TK Medium promises to be a practical, lowcost and simple test, published evidence is limited and
the test is currently not FDA-approved.82 Also no data
exist on its value in the diagnosis of childhood
tuberculosis.
Bacteriophage-based tests use bacteriophages to infect
live M. tuberculosis and detect the presence of
mycobacteria using either phage amplification or the
detection of light.83,84 In general, phage assays have a turn
around time of 2 to 3 days, and require a laboratory
infrastructure similar to that required for performing
cultures. Commercial kits are available for phage
amplification assay like the FASTPlaque-TB (Biotec
Laboratories, Ipswich, Suffolk, UK) assay that can be used
directly on sputum specimens for diagnosis, and a
variant, the FASTPlaque-TB Response kit, is designed to
331
detect rifampicin resistance in sputum specimens. The

FASTPlaque-TB kits are currently not FDA approved,
but are CE marked for use in Europe. No information
exists on its utility in the diagnosis of childhood
tuberculosis. The FASTPlaque-TB Response assay detects
rifampicin resistance, a reliable marker of multi-drug
resistant disease, with a fair degree of accuracy in adults,
especially when used on culture isolates.84
The microscopic observation drug susceptibility assay
(MODS) is a novel assay that uses an inverted light
microscope and Middlebrook 7H9 broth culture to
rapidly detect mycobacterial growth. Early growth of M.
tuberculosis is visualized as strings and tangles of
bacterial cells in the broth medium, which may contain
antimicrobial drugs for susceptibility testing. In a recent
study from Peru, MODS detected 94% of 1908 positive
sputum cultures, whereas conventional LJ culture
detected only 87%.85 MODS also had a shorter time to
culture positivity (average of 8 days) compared with
Lowenstein Jensen culture. Although MODS are a
promising and inexpensive tool, limited information
exists on its utility in children. The potential of a gas
sensor array electronic nose; E-Nose to detect different
Mycobacterium species in the headspaces of cultures and
sputum samples is another innovative approach that is
currently in development. The array uses 14 sensors to
profile a smell by assessing the change in each sensors
electrical properties when exposed to a specific odor
mixture. In an initial study using spiked sputa and
sputum samples from patients with culture-confirmed
tuberculosis and those without tuberculosis, after
training of the neural network, the E-Nose correctly
predicted 89% of culture-positive patients with a
specificity of 91%.86 Further applications of this test,
including its potential value in the diagnosis of child
tuberculosis, are under investigation.
DIAGNOSIS OF TB IN HIV INFECTED CHILDREN

The diagnosis of TB in HIV infected children is
complicated by the reduced sensitivity of immunological
diagnostic techniques such as the TST and gammainterferon assays. There is also greater clinical need to
make a firm diagnosis, and a wider range of alternative
pathological processes to consider. The use of a 5-mm
cut-off for a positive Mantoux test is recommended.
Gamma-interferon assays may be preferable to the TST
in this population,87 but a negative test cannot exclude
tubercular disease. On biological grounds it would be
reasonable to assume that smear, culture and possibly
NAD (Nucleic acid detection) assays would have a
greater diagnostic role in HIV infected children due to
an increased bacillary load. However, yields from smear
and culture have not always been higher in HIV positive
children.88 Also, firm data regarding the performance of
332
Section 5 Diagnosis
NAD assays in this setting are lacking. Positive NAD

assays may lend support to the diagnosis, particularly
the commercial assays which have better specificity.
Bronchoscopy may be worthwhile, if the diagnosis
remains unclear even after first-line investigations such
as gastric aspirates and induced sputa have been
performed. Since TB may be rapidly progressive in HIV
positive children, empirical therapy may be required
more commonly than in immunocompetent children.
HIGHLIGHTS
Many promising advances have been made in the
development of novel tools to diagnose tuberculosis
in adults, but none of these tests are capable enough
to replace microscopy or culture. Few of these novel
approaches have been tested in children, the group
in which the diagnostic dilemma is most
pronounced. At present, the use of adequately
validated symptom-based diagnostic approaches
and improved access to chest radiography and
antituberculosis treatment seem to offer the most
immediate benefit to children in tuberculosisendemic countries with limited resources.
IGRAs
Improved sensitivity and specificity offered by
new IGRAs may assist tuberculosis eradication
efforts in nonendemic countries and the diagnosis
of M. tuberculosis infection in high-risk individuals.
IGRAs appear to be sensitive in children over 2
years of age, and unlike the TST, are specific for M.
tuberculosis. In conjunction with clinical and
radiologic findings, both these tests are also used to
aid in the diagnosis of active TB.
An effort should be made to obtain several
specimen samples in any child being evaluated for
active TB, as the paucibacillary nature of pediatric

TB limits the rates of positive AFB smear and culture.
The gold standard remains solid traditional culture,
and it is recommended to perform the liquid-based
culture in conjunction with solid agar to decrease
the time to detection.
In TB-endemic settings, limited access to diagnostic
services often results in substantial diagnostic delay
and patients often received a diagnosis after as many
as 3 to 6 months of being symptomatic. This delay
fuels disease transmission and increases severity of
disease when it is finally diagnosed. A suitable TB
diagnostic would need to be sensitive, simple, have
a rapid turnaround time, and be able to detect MDRTB. Such a test would combine these features in a
simple point-of-care format that could replace
microscopy and culture in the first clinic visit. In
general, assays based on the immunological
responses to M. tuberculosis are preferred to the
current bacteriologic methods of TB diagnosis
because they do not depend on the detection of
mycobacteria and exposure risk is minimized.
Till date many promising advances have been made
in the diagnosis of TB, still there is no test that is
highly accurate in children, also none of the tests
developed so far are currently in a position to replace
microscopy or culture in TB-endemic regions.
There is a great need for innovative and novel assays
to be tested in children, a population most
vulnerable to severe disease. The pathophysiologic
response to M. tuberculosis in young children is
different from that observed in adults, hence these
distinctions should be considered as future
diagnostic tests are developed and evaluated in
clinical trials.
25.2 MOLECULAR DIAGNOSTIC METHODS

S Kumar, Bansidhar Tarai, Nimrat Bawa, Sarman Singh, Ashok Rattan
INTRODUCTION
Tuberculosis (TB), caused by Mycobacterium tuberculosis,
is an old and serious infectious disease in humans, and it
is still a major public health problem worldwide.1, 2 It is
estimated that nearly 1 billion people will be newly
infected with TB between 2000 and 2020 and,
furthermore, two hundred million people will develop
disease and 35 million will die from TB within this period.
In India 1.8 million tuberculosis cases occur annually,
accounting for one-fifth of the worlds new TB cases and
two-thirds of the cases in the South-East Asia Region.

This makes India the highest TB burden country in the
world.3, 4
TB remains one of the major causes of death in India.
Early diagnosis, together with adequate therapy and
prevention measures against further transmission are
essential for TB control. Traditional smear microscopy
and culture-based routine diagnostics in M. tuberculosis
are commonly used in clinical Mycobacteriology
laboratories. However, traditional methods are
inadequate for the effective control of TB due to the fact

that they are time-consuming, cumbersome and high
concentrations of bacteria must be present in the sample
to be detected. A rapid, sensitive, and accurate diagnostic
tool for detection of M. tuberculosis in clinical specimens
is essential for the successful diagnosis of TB patients.
Over the last few years, new molecular methods have
been introduced, including PCR-Restriction Fragment
Length Polymorphism, real-time PCR, DNA sequencing,
DNA strip assays as mycobacterial diagnostic tools,
leading to considerable improvement of both speed and
accuracy of identification.
The prevalence of TB is further complicated by the
appearance of strains with multidrug resistance (MDR)
in almost 3% of all newly diagnosed patients.5 The
conventional phenotypic methods for assessing drug
resistance are slow and in order to avoid delays in both
therapy and prevention of MDR transmission, various
genotypic methods based on line probe assays, DNA
sequencing or real-time PCR, have been proposed for
detection of the mutations associated with resistance to
anti-tuberculosis drugs. The molecular methods used in
Mycobacterial diagnostics and their diagnostic usefulness
in a modern clinical Mycobacteriology laboratory is
reviewed.
Direct Detection of Mycobacteria in Clinical

Specimens: In-house PCR for Detection of
Mycobacteria from Clinical Specimens
In the last decade, nucleic acid amplification-based
techniques have become accessible to the clinical
mycobacteriology laboratory. PCR protocols amplifying
a large variety of chromosomal DNA have concentrated
on detection of both genus-specific and M. tuberculosis
complex-specific DNA regions. The insertion element IS
6110 and the 16S rDNA are the most common targets
used. Other regions used for amplification include the
rpoB gene encoding the -subunit of the RNA
polymerase, the gene coding for the 32 kD protein, the
recA gene, the hsp65 gene, the dnaJ gene, the sodA gene
and the 16S-23S rRNA internal transcriber spacer.6-8
In research laboratories, nucleic acid amplification
tests (NAATs) are very sensitive and detect as few as 10
bacilli. These tests are highly sensitive in clinical samples
and studies have shown that sensitivity and specificity
are ranging as high as 90 to 100%. NAATs may be tested
on any specimen thought to contain bacilli (blood, urine,
cerebrospinal fluid (CSF)) but there is even less sensitivity
reported in nonrespiratory samples. Sensitivity is
improved when multiple samples are tested, because not
all samples necessarily contain detectable nucleic acid.9,10
Most of in-house PCR procedures achieve a sensitivity
never matched by commercial systems but are often
burdened by the high incidence of false positive results
333
due to amplicon cross-contamination of specimens. To

minimize the risk of specimen-to-specimen contamination, a physical separation of processes, equipment, and
reagents is recommended. Four different work areas are
suggested, including a reagent preparation area to
prepare PCR master mix, a sample processing area where
procedures, including nucleic acid extraction, occurs, a
target loading area where the specimen is added to the
PCR master mix in the reaction vessel, and an
amplification area where thermocycling and probe
detection occurs.11 The reagent preparation area should
be kept free of all patient specimens and DNA extracts.
Protocols for the sample preparation area should
minimize the number of tubes that are simultaneously
open. Each of the work areas should contain dedicated
working materials, reagents, and pipetting devices.
Reagents should be prepared and aliquoted into single
use or small volumes. This ensures ease of use and less
chance of contamination. All working surfaces should
be cleaned before and after use, preferably with a reagent
that destroys nucleic acid such as a 5% bleach solution.
Gloves should be changed frequently, at least before
beginning each of the separate tasks required in a
dedicated work area and should always be changed if
moving from one work area to another work area. The
use of aerosol-resistant pipette tips and pipette tips long
enough to prevent specimen contact with the pipetter
aids in the prevention of specimen contamination.12
Enzyme contamination control systems such as uracilN-glycosylase can be incorporated into the real-time PCR
master mix as an added safeguard to sterilize amplified
product that may be carried over to subsequent batches
of tests.13
Over the last few years, real-time PCR systems have
been increasingly used in routine mycobacteriology
laboratories. The technique allows real-time monitoring
of a DNA amplification reaction by measuring an
accumulating uorescence signal. Real-time PCR provided
improved sensitivity and specificity, reducing
turnaround time and avoiding the use of ethidium
bromide-stained gels. Different real-time instruments are
now available in the market.
Real-time PCR detection technology has been widely
evaluated. The majority of real-time PCR methods
reported to date for mycobacteria focus on detection of
the M. tuberculosis complex. Several publications address
the detection of Mycobacteria at the genus level. The risk
of contamination is considerably less with real-time PCR
compared to conventional PCR, but it still can occur.
Specimen-to-specimen contamination has become a
greater challenge than amplified product contamination.
The most obvious situation where specimen-to-specimen
contamination can occur is with the transfer of specimen
to the PCR vessel or to the DNA extraction tube.14,15
334
Section 5 Diagnosis
COMMERCIALLY AVAILABLE ASSAYS

Amplicor MTB Test
The Amplicor MTB Test (Roche Molecular Systems,
Basel, Switzerland) relies on standard PCR. A 584 bp
fragment of the 16S ribosomal RNA gene, comprising a
species-specific region flanked by genus-specific
sequences, is amplified using biotinylated primers. In the
master mix, an unusual combination of nucleotides is
present as an adjunct to adenine, guanidine and
cytosine, uracil is used in place of thymine. As a
consequence, the amplification product differs from the
target DNA in that it contains uracil instead of thymine.
This device is part of a contamination-control system
based on the use of uracil-N-glycosylase, an enzyme that
fragments DNA wherever uracil is present. The enzyme,
added to the samples before amplification, destroys any
amplicon resulting from previous amplifications without
damaging the uracil-free target DNA. Because of the
genus-specific nature of the annealing regions, 16S
ribosomal DNA belonging to any Mycobacterial species
is amplified by this PCR. The use, in the revealing phase,
of magnetic beads coated with M. tuberculosis complexspecific probes allows the removal, by washing, of any
other DNA. The detection of the specific amplification
product is performed by adding an avidin-enzyme
conjugate and a chromogenic substrate.16
The amplification and detection steps are carried out
automatically by the Cobas Amplicor instrument (Fig.
25.2.1). Once the sample extraction has been performed
by heating (95C), the tube is placed in the thermal cycler
Fig. 25.2.1: Cobas Amplicor Instrument
integrated in the Cobas instrument. Without further

handling, the amplification product will be automatically
transferred into the detection station where the
chromogenic reaction is developed and read. The
turnaround time is 6-7 hours. The method is approved
by the Food and Drug Administration of United State of
America (US FDA) for testing smear-positive respiratory
samples. It includes an internal control, composed of
synthetic DNA characterized by identical annealing
sequences as the mycobac-terial target; when this is not
amplified, it signals the presence of inhibitors. The
detection of M. tuberculosis complex DNA can also be
carried out without the Cobas instrument, using a manual
kit that, however, does not include an internal control.
Other Amplicor kits are available for detection of M.
avium and M. intracellulare DNA in clinical samples. From
the literature review, specificity is close to 100% while
sensitivity ranges from 90 to 100% in smear-positive
samples and from 50 to 95.9% in smear-negative ones.17
Amplified MTD
Amplified M. tuberculosis Direct Test (AMTD), developed
by GenProbe (San Diego, CA, USA), is an isothermal
(42C) transcriptase-mediated amplification system. A
M. tuberculosis complex-specific region of the 16S
ribosomal RNA gene produces double-stranded
ribosomal DNA, due to the combined action of reverse
transcriptase and ribonuclease. In turn, RNA polymerase
catalyzes the synthesis of multiple stretches of ribosomal
RNA from the ribosomal DNA synthesized before. A new
cycle starts when the newly produced ribosomal RNA
undergoes further transcription by reverse transcriptase.
The sensitivity of the method is increased by the presence,
in each bacterium, of a high number of 16S ribosomal
RNA target molecules (about 2,000) compared to only
one copy of 16S ribosomal DNA. Another advantage of
the amplification from RNA relies on the low stability of
such a molecule; this minimizes both the risk of
contamination and the incidence of false-positive results
due to the persistency of stable nucleic acids (DNA) in
the host organism, even after the complete eradication
of the infection. The detection of amplification products
relies on hybridization with a specific, single-strand DNA
probe labeled with a chemilumin-escent molecule
(Hybridization Protection Assay). The whole process is
performed manually, starting with the extraction by
means of sonication, continuing with the addition of
different reagents until the final reading with the
luminometer. Thermal cyclers are not needed and the
whole amplification step is carried out on a heating block
at 42C. The turnaround time is 2.5 hours. No internal
control is provided in the kit to monitor the presence of
inhibitors. The method is approved by the US FDA for
testing smear-positive and smear-negative respiratory

samples. The overall sensitivity for respiratory specimens
was found in the range between 90.9% and 95.2% and
the specificity between 97.6% and 100%.18,19
335
M. avium, M. intracellulare and M. kansasii. The literature

reports a rate of sensitivity ranging from 98.5 to 100%
for smear-positive samples and very variable (0.33-100%)
for smear-negative ones.20,21
BD ProbeTec ET
The BD ProbeTec ET (Becton Dickinson, Sparks, MD)
uses DNA polymerase and isothermal strand
displacement amplification to produce multiple copies
of IS6110, an insertion element unique to M. tuberculosis
complex. The rationale of strand displacement
amplification is extremely complex; what is presented
here is an extreme simplification. In the initial phase
(target amplification), amplification is started by two
pairs of primers complementary to contiguous sequences
delimiting the target. The elongation of the upstream
primer, also named bumper, determines the
displacement of the simulta-neously elongating
downstream primer and finally releases the produced
amplicon. A restriction site, present in the downstream
primer, will also be present in the released amplicon. In
the exponential amplification phase, a new primer
anneals to the amplicon and, following digestion by the
restriction enzyme, the upstream fragment acts as
bumper and displaces the downstream fragment. Realtime detection is based on the energy transfer technology.
A hair-pin-shaped probe, complementary to IS6110, is
marked by two fluorescent molecules, one of which, the
donor, is quenched by the other, the acceptor;
furthermore, it presents a restriction site in the sequence
between the two markers. Once its free end has
hybridized with the amplification product, the probe
undergoes elongation before being displaced by a primer
annealed upstream to the same amplicon. The elongation
makes the probe able to bind a new primer which, while
elongating, stretches out the hair-pin and moves the
acceptor away from the donor. The nicking of the
restriction site by a proper enzyme further separates
donor and acceptor and allows the first to free a
fluorescence signal. Some manipulation is required
before introduction of the sample into the automatic
instrument; each sample is first inactivated at 105C, and
then sonicated to extract the DNA, transferred into a
priming well at 72.5C, and subsequently into an
amplification well at 54C. In the BD ProbeTec ET
instrument, the microplate containing the samples and
the amplification reagents is incubated at 52.5C and the
fluorescence emitted is continuously monitored. A
thermal cycler is not required. The turnaround time is
3.5 to 4 hours. An internal control is present, characterized
by the same annealing sequences as the mycobacterial
target. In case of amplification failure, this control alerts
for the presence of inhibitors.
The system is not yet approved by the US FDA. Kits
are also available for the amplification of nucleic acids of
Genotype Mycobacteria Direct Assay

It is for detection of M. tuberculosis complex and four
atypical mycobacteria (Hain Lifescience, Nehren,
Germany). This novel assay is based on the nucleic acid
sequence-based amplification (NASBA) applied to DNA
strip technology. According to the manufacturer, the
assay has three steps. The first step consists of isolation
of 23S rRNA, the second step includes amplification of
RNA by NASBA method, and the third step involves the
reverse hybridization of the amplified products on
membrane strips using an automated system. The assay
has the ability for simultaneous detection of M. avium,
M. intracellulare, M. kansasii, M. malmoense and MTBC.
Isolation of highly specific RNA is achieved by the use
of the magnetic bead capturing method. This assay is
useful, reliable and rapid, with sensitivity and specificity
of 92% and 100%, respectively.22
LCx MTBC Assay (Abbott Laboratories, Diagnostic

Division, Chicago, USA)
The assay uses the ligase chain reaction for amplification
of a target sequence within the chromosomal gene that
codes for protein antigen b, which is specific for members
of the MTBC. The overall sensitivity and specificity of
the assay was 74% and 98%, respectively. For smearpositive samples the sensitivity reached 100%, but for
smear-negative it was only 57%. In a multicenter
evaluation of Amplicor and LCx, the sensitivity of both
methods was significantly better when only respiratory
specimens were considered (78% and 88%, respectively).
When nonrespiratory samples were used, the sensitivity
was reduced to 59% for Amlicor and 65% for LCx.23,24
In conclusion, it should be noted that, although the
traditional methods for diagnosis of tuberculosis, such
as microscopy and culture, cannot be replaced by direct
amplification tests, these assays provide a major
improvement in terms of speed. They could be used for
rapid confirmation in patients with smear-positive
samples. In smear-negative patients, the amplification
tests are recommended only when suspicion for TB is
high and always in relation to clinical data. For
extrapulmonary specimens, the use of the amplification
methods is advocated, since rapid and accurate
laboratory diagnosis is critical (e.g. tuberculous
meningitis). The specificities of amplification methods
are very high, whereas, the sensitivities vary greatly.
Multiple specimens from the same patient, proper
decontamination procedures, improved extraction
336
Section 5 Diagnosis
methods and use of internal controls decrease the

frequency of false-negative results.
IDENTIFICATION OF MYCOBACTERIAL SPECIES FROM

CULTURE BY MOLECULAR METHODS
For many decades, the identification of mycobacterial
isolates was performed on the basis of biochemical
reactions and phenotypic characteristics, which are timeconsuming and often give ambiguous results. The
molecular methods for mycobacterial identification are
now providing rapid and accurate results. Several
methodologies have been used.
PCR-based Sequencing
This methodology is considered the gold standard for
identification of mycobacteria. Initially, a PCR
amplification takes place followed by sequencing of the
amplicons in an automatic sequencer. The identification
of an unknown strain is completed by comparison of the
nucleotide sequence with a library of known sequences.
The databases for this purpose are available in the
internet. Such databases are the GenBank, the Ribosomal
Differentiation of Medical Microsystems database
(RIDOM) and that of the European Molecular Biology
Laboratory (EMBL). Several target genes have been used
for the procedure but the most common is the 16S rRNA
gene.25 This gene has been widely sequenced because it
contains both highly conserved and variable regions. It
consists of more than 1500 bp but usually the first 500 bp
are adequate for identification of a common
mycobacterium species. As previously mentioned, other
important target genes are those encoding for the 65-kDa
heat shock protein, the 32 kDa protein, the 16S-23S rRNA
internal transcribed spacer (ITS) and the recA gene. The
MicroSeq System (Applied Biosystems, CA) is a
commercial 16S ribosomal DNA sequencing system.
Evaluations of the MicroSeq System for routine use were
performed by and with good results. The system offers
the ability to mycobacteriology laboratories to identify
many of the recently described mycobacteria.26,27
DNA probe Technology

The DNA probe technology for identification of bacteria
is one of the most successful molecular methods. The
AccuProbe (Gen-Probe, San Diego, CA, USA) is the assay
based on this technology that is used by the majority of
clinical mycobacterial laboratories worldwide. It has the
ability to identify a series of clinically important
mycobacteria. These are M. tuberculosis complex, M. avium
complex, M. avium, M. kansasii, and M. gordonae. The DNA
probes are single-stranded DNA oligonucleotides labeled
with acridinum ester that are complementary to the
target, which is the rRNA. After sonication, the probes
are added to the broken mycobacterial cells, to form a

stable DNA-RNA complex. Following separation of the
labeled complex from unhybridized DNA, the
hybridization is detected by light emission in a
luminometer. The AccuProbe can be used for both solid
and liquid cultures. The method is easy to perform and
only a sonicator and luminometer are required as
equipment. The method has been widely evaluated with
good results. The AccuProbe kits are rapid, highly
sensitive and specific. The procedure can be completed
in less than two hours.28
Line Probe Technology (hybridization in strips)

The line probe technology includes PCR (with
biotinylated primers), reverse hybridization with
different specific DNA probes, immobilized in parallel
lines on a strip and colorimetric detection in an
automated instrument. The banding pattern is indicative
of the species of the isolate. The turnaround time is
approximately five hours. Two systems of line probe
assay are commercially available: (a) the Inno LiPA
Mycobacteria v2 and (b) the GenoType Mycobacterium:
Inno LiPA Mycobacteria v2, (Innogenetics, Ghent,

Belgium)
This assay is based on the amplification of the
mycobacterial spacer region 16S-23S rRNA for the
simultaneous identification, in just one strip test, of
the 17 most frequently isolated mycobacterial species:
M. tuberculosis complex, M. avium, M. intracellulare, M.
scrofulaceum, M. kansasii, M. xenopi, M. chelonae, M. gordonae,
M. fortuitum complex, M. malmoense, M. genavense, M.
simiae, M. smegmatis, M. haemophilum, M. marinum/M.
ulcerans and M. celatum. Moreover, it has the ability
to discriminate subgroups within M. kansasii and M.
chelonae on the same strip. Mixed populations are easily
identified. The overall sensitivity and specificity was
100% and 94.4%, respectively. The probes specific for M.
fortuitum complex, for M. avium-intracellulare-scrofulaceum
group and for M. intracellulare type 2 cross-reacted with
several mycobacteria rarely isolated from clinical
specimens.29
GenoType Mycobacterium (Hain Lifescience, Nehren,

Germany)
The procedure includes a multiplex PCR, followed by
reverse hybridization and line probe technology. There
are three kits: (a) the GenoType MTBC for distinguishing
members of the M. tuberculosis complex, and (b) the
GenoType Mycobacterium CM (Common Mycobacteria),
and GenoType Mycobacterium AS (Additional Species)
for NTM. The GenoType MTBC is based on the gyrB gene
polymorphism. The AS and CM assays use 23S rDNA as

their target, thus the amplicon generated in the CM assay
can be used for the AS assay without the need to perform
a second PCR. The combined use of CM and AS can
distinguish almost 30 different NTM including the
following species: M. avium, M. chelonae, M. abscessus, M.
fortuitum, M. gordonae, M. intracellulare, M. scrofulaceum,
M. interjectum, M. kansasii, M. malmoense, M. marinum,
M. ulcerans, M. peregrinum, M. xenopi, M. simiae, M.
mucogenicum, M. goodii, M. celatum, M. smegmatis, M.
genovense, M. lentiavum, M. heckeshornense, M. szulgai,
M. phlei, M. hemophilum, M. gastri, M. asiaticum and M.
shimoidei. The GenoType assays are rapid, easy-toperform and easy-to-interpret. They have allowed clinical
mycobacteriology laboratories to detect infrequent
mycobacterial species, without the need of sophisticated
techniques. The sensitivity and the specificity compared
with 16S rRNA gene sequencing were 97.9% and 92.4%
for CM and 99.3% and 99.4% for AS, respectively.30,31
PRA Method (Polymerase Chain Reaction and

Restriction Enzyme Analysis for Identification of
Mycobacteria from Culture)
Telenti et al. (1993) developed a rapid method, based on
the amplification of the gene encoding the 65-kDa heat
shock protein, followed by restriction-fragment-length
polymorphism, using two restriction enzymes BstEII and
HaeIII. Isolates from both solid and liquid cultures can
be used. The fragments of the restriction enzyme
digestion are analyzed by agarose gel electrophoresis and
compared. The test can be completed within a day. It is a
cost-effective and reliable assay that can be used by lowbudget laboratories as well.32
Pyrosequencing
Pyrosequencing (Biotage, Uppsala, Sweden)
technology is a novel method of nucleic acid sequencingby-synthesis that is based on the detection of released
pyrophosphate (PPi) during DNA synthesis. The cascade
of enzymatic reactions generates visible light. The
generated light is proportional to the number of
incorporated nucleotides. The method is optimal for
determining short sequences (typically 20-30 bases of a
DNA) rapidly and in a semi-automated format.33
DNA Microarrays (DNA chips)

The method is based on hybridization of fluorescently
labeled PCR amplicons of an unknown strain to a DNA
array, containing nucleotide probes for 16S ribosomal
RNA gene. The hybridization pattern and intensity is
determined by scanning the chip using laser confocal
fluorescence microscopy. The process of generating the
337
target, its hybridization and reading on the chip requires

approximately two hours. It allows the identification of
a large number of strains in one reaction. Sequences of
regions from the 16S rRNA and rpoB loci had been
developed. Unique hybridization patterns allowed for
the identification of mycobacterium species and the RMPresistant alleles. A great disadvantage is, however, the
current high cost of the required equipment.34
MOLECULAR METHODS FOR DETECTING DRUG

RESISTANCE IN MYCOBACTERIAL STRAINS
The emergence of strains of M. tuberculosis that are
resistant to antimicrobial agents is a global problem.
MDR-TB strains are generally defined as resistant to at
least isoniazid (INH) and rifampin (RIF). Drug resistance
develops either due to infection with a resistant strain,
or as a result of inadequate treatment such as when a
patient is exposed to a single drug, or because of selective
drug intake, poor compliance, use of inappropriate nonstandardized treatment regimens, irregular drug supply,
poor drug quality, or rarely erratic absorption of
medications. Knowledge of the susceptibility pattern of
the isolate is crucial for successful therapy.35
Existence of MDR-TB strains poses a serious threat
to TB control programs in many countries. As per the
estimates from the State representative drug resistance
surveillance (DRS) survey in Gujarat and various district
level DRS studies, the prevalence of MDR-TB in new
smear-positive pulmonary TB (PTB) cases is 1.1 to 5.3%
and 12 to 17% amongst smear-positive previously treated
PTB cases. These data from India on MDR-TB had been
collected from referral centers and institutions, and did
not reflect the overall status of drug resistance problem
in India. Prevalence of drug resistant tuberculosis varies
considerably throughout the world and particularly in
India. The reasons for this variation in different studies
were poor study design, inadequate laboratory support
and reporting systems.36
The detection of resistant M. tuberculosis strains is
generally performed by phenotypic assays, which require
the isolate to be cultured in the presence of the different
drugs. Despite the use of new liquid medium cultures
(BACTEC TB-460 (Becton Dikinson, Sparks, MD),
BACTEC MGIT 960, or Bact/Allert 3D (bioMerieux,
Durham, NC)]), the isolation of M. tuberculosis is still time
consuming (i.e. 1-2 weeks) and leads to delays in
obtaining susceptibility patterns. Rapid methods to detect
resistance are necessary to optimize antituberculous
treatment and avoid the transmission of resistant strains.
Several molecular methods to detect resistance mutations
in M. tuberculosis have been described as the molecular
basis of resistance to anti-TB drugs is becoming more
clearer.
338
Section 5 Diagnosis
Resistance to anti-tuberculosis drugs is primarily due

to mutations in a series of genes. The most frequently
found mutations in RMP resistant isolates (96%) are
mutations in an 81-bp segment of the rpoB gene that
encodes the -subunit of RNA polymerase. In 75 to 85%
of INH resistant M. tuberculosis strains there are mutations
in two genes, katG encoding catalase-peroxidase and
inhA that takes part in fatty acid elongation. Mutations
in the embB gene, which plays a role in the synthesis of
lipoarabinomanan and arabinogalactam, are connected
with ethambutol resistance. More than 70% of
pyrazinamide resistance is due to mutations in the pncA
gene, which encodes for pyrazinamidase that converts
pyrazinamide to its active form. Mutations in the 16S
rRNA gene or the rpsL gene that encodes for the
ribosomal protein 12S cause approximately 65 to 75% of
resistance to streptomycin. Molecular assays have the
ability to detect these mutations and reveal the
underlying resistance mechanism within hours.37-40
PCR-DNA Sequencing
Among the many techniques used to identify drug
resistance-associated mutations, automated DNA
sequencing of PCR products has been the most widely
applied. This is considered as the reference method for
detection of drug resistance mutations. One important
advantage of sequence-based approaches is that the
resulting data are virtually unambiguous because a
resistance-associated mutation is either present or absent.
Initially, the region that is most frequently associated with
resistance mutations is amplified. Then, the amplicons
are sequenced in order to determine the presence or
absence of a specific mutation. The expensive equipment
and the expertize needed are probably the most serious
drawbacks of the method.
Hybridization-based Techniques
Line Probe Technology
There are two commercially available assays: the InnoLiPA Rifotuberculosis (Inno-LiPA RFTB; Innogenetics,
Belgium) and the GenoType MTBDR plus, (HAIN,
Lifescience; Nehren, Germany). These assays use probes
specific only for the M. tuberculosis complex and
additionally for the detection of the mutations responsible
for drug resistance.
Inno-LiPA RifTB (Innogenetics, Ghent, Belgium). The
kit contains 10 oligonucleotide probes: one specific for
M. tuberculosis complex, five wild type probes (S1-S5),
and four probes (R) for the detection of the most frequent
mutations that cause resistance to RMP. More than 95%
of the RMP-resistant strains have mutations within an
81-bp hot spot region (codons 507-533) of the rpoB gene.
The R probes used are: R2: Asp516Val, R4: His526Tyr,
R4b: His526Asp, R5: Ser531Leu. All the probes are

immobilized on a nitrocellulose strip. A M. tuberculosis
isolate is considered susceptible to RMP, if all the wild
type probes give a positive signal and all the probes for
resistance are negative. The absence of hybridization of
one or more of the S probes is indicative of a mutation
that may be identified by one of the R probes. Inno-LiPA
Rif TB to be a reliable, simple and informative tool with
absolute correlation (100%) between its results and those
obtained by the classic susceptibility testing, and the M.
tuberculosis probe to be completely specific. Although the
assay is recommended for use only on isolates where the
amount of DNA is large, it can be used directly on clinical
specimens after modifications of the protocol (nested
PCR). Studies evaluating the line probe assay directly to
clinical samples are limited. Inno LiPA assay provides a
rapid and reliable detection of RMP resistance in 78.3%
of clinical specimens, compared to Bactec 460 and to rpoB
gene sequencing.41,42
GenoType MTBDR plus (Hain Lifescience, Germany).
This assay offers the simultaneous identification of M.
tuberculosis complex and detection of the most common
resistance mutations in rpoB (RMP resistance), katG and
inhA gene (INH resistance). This assay is the newer
version of the GenoType MTBDR assay, which did not
have the ability to detect INH resistance, caused by
mutation in inhA. The previous and the new version of
the assay could correctly identify rifampicin-resistance
in 98.7% of the cases, when compared to conventional
susceptibility testing. Furthermore, the new GenoType
MTBDR plus achieved better sensitivity for INH
resistance (92% vs. 88.0% of the previous version).
GenoType MTBDR plus is a reliable tool for the detection
of INH and RMP resistance either in strains or directly
in smear positive specimens.43,44
Hybridization on DNA Chips

The DNA microarrays can also be used for rapid
detection of mutations responsible for drug resistance.
It can simultaneously detect different drug resistant
mutations of M. tuberculosis. The DNA chip technology
seems to be the most promising method for future
investigation on drug resistance. A drug resistance
detection DNA chip (CombiChip Mycobacteria, Geneln,
Pusan, South Korea) is avialable for identifying mutations
associated with resistance to INH and RMP (katG, inhA
and rpoB genes). It is an oligonucleotide microchip
coupled to PCR for the detection of mutations. The results
were compared to DNA sequencing and culture based
drug susceptibility tests. The CombiChip detected all
RMP resistant isolates by screening 7 codons in the rpoB
hot spot region and it correctly identified 84.1% of INH
resistant isolates by screening the katG codon 315 and
inhA.45
PCR-SSCP (single-strand-conformationpoly-morphisms)
SSCP is based on the conformational distortion that a
nucleotide substitution can cause in a single strand DNA
fragment. This conformational change leads to an
electrophoretic mobility different to that of the wild-type
single-strand fragment. The procedure involves
amplification of a DNA fragment including the region
of interest by PCR, denaturation and running of this
fragment in a polyacrylamide gel together with a
denaturated wild-type reference sample. Mobility shifts
in the clinical sample indicate presence of mutation.
This method has 100% specificity for RMP and INH
resistance and sensitivity for RMP 96% and for INH 87%,
using four genetic regions (rpoB, katG, inhA, ahpC,). A
nested PCR- linked SSCP analysis is also used directly
on sputum samples, to detect M. tuberculosis and
determine RMP susceptibility. In this study, the target
was a 157 bp portion of rpoB gene, which has been widely
used for PCR-SSCP. The results were concordant with
those of conventional drug susceptibility testing and
DNA sequencing of culture isolates. Furthermore, the
nested PCR-SSCP method enabled the direct detection
of RMP resistance from primary clinical specimens.
However, it should be noted that the assay does not
identify the precise mutation and, consequently, the
method is significantly less precise than sequencing. Its
usefulness is restricted by extensive labor required and
high level of technical skills.46
Pyrosequencing
Rapid detection of rifampicin resistance using
Pyrosequencing technology is available. The target was
an 180-bp region of the rpoB gene, amplified by PCR and
subjected to Pyroseque-ncing analysis, using four
different sequencing primers in four overlapping
reactions. The results were compared to other molecular
methods (line probe assay and cycle sequencing) and the
phenotypic BACTEC 460 method. There was full
agreement with the molecular methods showing that
Pyrosequecing analysis offers high accuracy.47
Real-time PCR methodology

Real-time PCR has been used for detection of mutations
responsible for INH and RMP resistance. This method
exhibited 85% and 98% sensitivity for the detection of
mutations responsible for INH and RMP resistance
respectively and complete specificity for both
antibiotics.48
339
HIGHLIGHTS
Laboratory diagnostic tests for TB have evolved
rapidly as new technology has been introduced and
provide unprecedented opportunities for the rapid,
sensitive and specific diagnosis of M. tuberculosis
itself in clinical samples and the status of its drug
sensitivity.
Some of the molecular tests have now been
incorporated into routine laboratory usage allowing
the physicians to more rapidly initiate proper drug
regimens.
Due to certain limitations in these molecular tests,
however, conventional tests such as those based on
microscopy and culture should be applied in parallel
with any new molecular tests for diagnosis of TB.
In addition, particular emphasis should be applied
to quality control and quality assurance programs
in clinical laboratories which employ any new
diagnostic approaches.
REFERENCES
1. Nelson LJ, Wells CD. Tuberculosis in children:
Considerations for children from developing countries.
Semin Pediatr Infect Dis 2004;15:150-4.
3. Walls T, Shingadia D. Global epidemiology of paediatric
tuberculosis. J Infect 2004;48:13-22.
4. Gocmen A, Cengizlier R, Ozcelik U, et al. Childhood tuberculosis: A report of 2,205 cases. Turk J Pediatr 1997;
39:14958.
5. Somu N, Vijayasekaran D, Ravikumar T, et al.
Tuberculous disease in a pediatric referral centre: 16 years
experience. Indian Pediatr 1994;31:12459.
6. Lemos AC, Matos ED, Pedral-Sampaio DB, et al. Risk of
tuberculosis among household contacts in Salvador,
Bahia. Braz J Infect Dis 2004;8:42430.
7. Mubarik M, Nabi B, Ladakhi GM, et al. Childhood
tuberculosis (Part-I). Epidemiology, pathogenesis,
clinical profile. J K Pract 2000;7:125.
8. Starke JR. Childhood tuberculosis. A diagnostic dilemma.
Chest 1993;104:32930.
9. Eamranond P, Jaramillo E. Tuberculosis in children:
Reassessing the need for improved diagnosis in global
control strategies. Int J Tuberc Lung Dis 2001;5:594603.
10. Starke JR. Pediatric tuberculosis: Time for a new
approach. Tuberculosis (Edinb) 2003;83:20812.
A prospective study. Lancet 2005;365:1304.
12. Starke JR. Diagnosis of tuberculosis in children. Pediatr
Infect Dis J 2000;19:10956.
340
Section 5 Diagnosis
13. Tuberculosis Coalition for Technical Assistance.
International Standards for Tuberculosis Care. http://
www.tbcta.org The Hague: Tuberculosis Coalition for
Technical Assistance, 2006:267.
14. Schaaf HS, Michaelis IA, Richardson M, et al. Adult-tochild transmission of tuberculosis: household or
community contact? Int J Tuberc Lung Dis 2003;7:
42631.
15. Verver S, Warren RM, Munch Z, et al. Proportion of
tuberculosis transmission that takes place in households
in a high-incidence area. Lancet 2004;363:2124.
16. Enarson PM, Enarson DA, Gie RP. Management of
tuberculosis in children in low-income countries. Int J
Tuberc Lung Dis 2006;10:119232.
17. Weismuller MM, Graham SM, Claessens NJ, et al.
Diagnosis of childhood tuberculosis in Malawi: An audit
of hospital practice. Int J Tuberc Lung Dis 2002;6:
4328.
18. Zar HJ, Hanslo D, Appoles P. Induced sputum versus
A prospective study. Lancet 2005; 365: 1304.
19. Gie RP, Beyers N, Schaaf HS, et al. The challenge of
diagnosing tuberculosis in children: a perspective from
a high incidence area. Paediatr Respir Rev 2004; 5 (Suppl):
S147 S9.
20. Marais BJ, Pai M. Recent advances in the diagnosis of
childhood tuberculosis. Arch Dis Child 2007;92:446-52.
21. Marais BJ, Pai M. New approaches and emerging
Paediatr Respir Rev 2007; 8: 12433.
22. Pai M, Flores LL, Pai N. Diagnostic accuracy of nucleic
acid amplification tests for tuberculous meningitis: a
systematic review and meta-analysis. Lancet Infect Dis
2003; 3: 63343.
23. Coulter JBS. Diagnosis of pulmonary tuberculosis in
young children. Ann Trop Paediatr 2008; 28: 312.
24. Pai M, Riley LW, Colford JMJ. Interferon-gamma assays
in the immune diagnosis of tuberculosis: A systematic
review. Lancet Infect Dis 2004; 4: 761-76.
25. Guidelines for the investigation of contacts of persons
with infectious tuberculosis. Recommendations from the
National Tuberculosis Controllers Association and CDC.
MMWR Recomm Rep 2005;54(RR-15): 1-47.
26. American Academy of Pediatrics CoID. Red book. 27th
Edition. Elk Grove Village (IL): American Academy of
Pediatrics; 2006.
27. Nash DR, Douglass JE. Anergy in active pulmonary
tuberculosis. A comparison between positive and
negative reactors and an evaluation of 5 TU and 250 TU
skin test doses. Chest 1980; 77: 32-7.
28. Steiner P, Rao M, Victoria MS, et al. Persistently negative
tuberculin reactions: Their presence among children with
culture positive for Mycobacterium tuberculosis (tuberculinnegative tuberculosis). Am J Dis Child 1980;134:747-50.
29. Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary
tuberculosis old wisdom and new challenges. Am J Resp
Crit Care Med 2006; 173: 107890.
tomography with normal chest radiograph in tuberculous
infection. Arch Dis Child 1993;69:4302.
31. Wright CA, van der Burg M, Geiger D, et al. Diagnosing

mycobacterial lymphadenitis in children using fine
needle aspiration biopsy: Cytomorphology, ZN staining
and autofluores-cence making more of less. Diagn
Cytopathol 2008; 36: 24551.
Infect Dis J 1992;11:735-8.
diagnosis of pulmonary tuberculosis in children. Tuber
Lung Dis 1995;76:295-9.
34. Pomputius WF III, Rost J, Dennehy PH, et al.
Standardization of gastric aspirate technique improves
yield in the diagnosis of tuberculosis in children. Pediatr
Infect Dis J 1997;16:222-6.
35. Lobato MN, Loeffler AM, Furst K, et al. Detection of
Mycobacterium tuberculosis in gastric aspirates collected
from children: hospitalization is not necessary. Pediatrics
1998;102:E40.
37. Vargas D, Garcia L, Gilman RH, et al. Diagnosis of
sputum-scarce HIVassociated pulmonary tuberculosis in
Lima, Peru. Lancet 2005;365:150-2.
38. Chow F, Espiritu N, Gilman RH, et al. La cuerda dulce
a tolerability and acceptability study of a novel approach
to specimen collection for diagnosis of paediatric
pulmonary tuberculosis. BMC Infect Dis 2006;6:67.
39. Diagnostic Standards and Classification of Tuberculosis
in Adults and Children. This official statement of the
American Thoracic Society and the Centers for Disease
Control and Prevention was adopted by the ATS Board
of Directors, July 1999. This statement was endorsed by
the Council of the Infectious Disease Society of America,
September 1999. Am J Respir Crit Care Med 2000;161(4
Pt. 1):1376-95.
40. Starke JR. Pediatric tuberculosis: Time for a new
approach. Tuberculosis (Edinb) 2003;83:208-12.
41. Lipsky BA, Gates J, Tenover FC, et al. Factors affecting
the clinical value of microscopy for acid-fast bacilli. Rev
Infect Dis 1984;6:214-22.
management challenges for childhood tuberculosis in the
era of HIV. J Infect Dis 2007;196 (Suppl 1):S76-85.
43. Yeager H Jr, Lacy J, Smith LR, et al. Quantitative studies
of mycobacterial populations in sputum and saliva. Am
Rev Respir Dis 1967;95:998-1004.
44. Hanna BA. Laboratory diagnosis. In: Rom WN, Garay
SM (Eds). Tuberculosis. 2nd edition. Philadelphia (PA):
Lippincott Williams and Wilkins; 2004. p.164-76.
45. Stager CE, Libonati JP, Siddiqi SH, et al. Role of solid
media when used in conjunction with the BACTEC
system for mycobacterial isolation and identification. J
Clin Microbiol 1991;29:154-7.
46. Morgan MA, Horstmeier CD, DeYoung DR, et al.
Comparison of a radiometric method (BACTEC) and
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
conventional culture media for recovery of mycobacteria

from smear-negative specimens. J Clin Microbiol 1983;18:
384-8.
Roberts GD, Goodman NL, Heifets L, et al. Evaluation
of the BACTEC radiometric method for recovery of
mycobacteria and drug susceptibility testing of
Mycobacterium tuberculosis from acid-fast smear-positive
specimens. J Clin Microbiol 1983; 18:689-96.
Bird BR, Denniston MM, Huebner RE, et al. Changing
practices in mycobacteriology: A follow-up survey of
state and territorial public health laboratories. J Clin
Microbiol 1996;34:554-9.
Chan DS, Choy MY, Wang S, et al. An evaluation of the
recovery of mycobacteria from urine specimens using
the automated Mycobacteria Growth Indicator Tube
system (BACTEC MGIT 960). J Med Microbiol 2008;57:
1220-2.
Gray JW. Childhood tuberculosis and its early diagnosis.
Clin Biochem 2004;37:450-5.
Banaiee N, January V, Barthus C, et al. Evaluation of a
semi-automated reporter phage assay for susceptibility
testing of Mycobacterium tuberculosis isolates in South
Africa. Tuberculosis (Edinb) 2008;88:64-8.
Pai M, Kalantri S, Pascopella L, et al. Bacteriophage-based
assays for the rapid detection of rifampicin resistance in
Mycobacterium tuberculosis: a meta-analysis. J Infect
2005;51:175-87.
Moore DA, Evans CA, Gilman RH, et al. Microscopicobservation drug-susceptibility assay for the diagnosis
of TB. N Engl J Med 2006;355:1539-50.
Caviedes L, Lee TS, Gilman RH, et al. Rapid, efficient
detection and drug susceptibility testing of Mycobacterium
tuberculosis in sputum by microscopic observation of
broth cultures. The Tuberculosis Working Group in Peru.
J Clin Microbiol 2000;38: 1203-8.
Merino JM, Carpintero I, Alvarez T, et al. Tuberculous
pleural effusion in children. Chest 1999;115:26-30.
Choi SH, Kim YS, Bae IG, et al. The possible role of
cerebrospinal fluid adenosine deaminase activity in the
diagnosis of tuberculous meningitis in adults. Clin
Neurol Neurosurg 2002;104:10-5.
Gautam N, Aryal M, Bhatta N, et al. Comparative study
of cerebrospinal fluid adenosine deaminase activity in
patients with meningitis. Nepal Med Coll J 2007;9:104-6.
Riquelme A, Calvo M, Salech F, et al. Value of adenosine
deaminase (ADA) in ascitic fluid for the diagnosis
of tuberculous peritonitis: A meta-analysis. J Clin
Kashyap RS, Ramteke SP, Deshpande PS, et al.
Comparison of an adenosine deaminase assay with
ELISA for the diagnosis of tuberculous meningitis
infection. Med Sci Monit 2007;13:BR200-4.
Al Zahrani K, Al Jahdali H, Poirier L, et al. Accuracy and
utility of commercially available amplification and
serologic tests for the diagnosis of minimal pulmonary
tuberculosis. Am J Respir Crit Care Med 2000;162:
1323-9.
Mahadevan S. Clinical utility of serodiagnosis of
341
62. Pottumarthy S, Wells VC, Morris AJ. A comparison of

seven tests for serological diagnosis of tuberculosis. J Clin
Microbiol 2000;38:2227-31.
63. Raja A, Ranganathan UD, Bethunaickan R, et al. Serologic
response to a secreted and a cytosolic antigen of
Mycobacterium tuberculosis in childhood tuberculosis.
64. Swaminathan S, Umadevi P, Shantha S, et al. Serodiagnosis
of tuberculosis in children using two ELISA kits. Indian
J Pediatr 1999;66:837-42.
65. Sada E, Aguilar D, Torres M, et al. Detection of
lipoarabinomannan as a diagnostic test for tuberculosis.
J Clin Microbiol 1992;30:2415-8.
66. Tessema TA, Hamasur B, Bjun G, et al. Diagnostic
evaluation of urinary lipoarabino-mannan at an
Ethiopian tuberculosis centre. Scand J Infect Dis
2001;33:279-84.
67. Tessema TA, Bjune G, Hamasur B, et al. Circulating
antibodies to lipoarabinomannan in relation to sputum
microscopy, clinical features and urinary antilipoarabinomannan detection in pulmonary tuberculosis.
Scand J Infect Dis 2002;34:97-103.
68. Mazurek GH, Jereb J, Lobue P, et al. Guidelines for using
the QuantiFERON-TB Gold test for detecting
Mycobacterium tuberculosis infection, United States.
MMWR Recomm Rep 2005;54:4955.
69. Ferrara G, Losi M, DAmico R, et al. Use in routine clinical
practice of two commercial blood tests for diagnosis of
infection with Mycobacterium tuberculosis: a prospective
study. Lancet 2006;367:132834.
70. Connell TG, Curtis N, Ranganathan SC, et al. Performance
of a whole blood interferon gamma assay in detecting
latent infection with Mycobacterium tuberculosis in children.
Thorax 2006;61:61620.
71. Dogra S, Narang P, Mendiratta DK, et al. Comparison of
a whole blood interferon-gamma assay with tuberculin
skin testing for the detection of tuberculosis infection in
hospitalized children in rural India. J Infect 2006. Epub
ahead of print.
72. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cellbased assay with tuberculin skin test for diagnosis of M.
tuberculosis infection in a school tuberculosis outbreak.
Lancet 2003; 361:116873.
73. Liebeschuetz S, Bamber S, Ewer K, et al. Diagnosis of
assay: A prospective cohort study. Lancet 2004;364:2196
203.
74. Nicol MP, Pienaar D, Wood K, et al. Enzyme-linked
immunospot assay responses to early secretory antigenic
target 6, culture filtrate protein 10, and purified protein
derivative among children with tuberculosis:
Implications for diagnosis and monitoring of therapy.
Clin Infect Dis 2005;40:13018.
75. Hill PC, Brookes RH, Adetifa IMO, et al. Comparison of
enzyme-linked immunospot assay and tuberculin skin
test in healthy children exposed to Mycobacterium
tuberculosis. Pediatrics 2006;117:15428.
76. Richeldi L. An update on the diagnosis of tuberculosis
infection. Am J Resp Crit Care Med 2006;174:73642.
342
Section 5 Diagnosis
77. Barnes PF. Weighing gold or counting spots: which is
more sensitive to diagnose latent tuberculosis infection?
Am J Resp Crit Care Med 2006;174:7312.
78. Madhi SA, Gray GE, Huebner RE, et al. Correlation
between CD4+ lymphocyte counts, concurrent antigen
skin test and tuberculin skin test reactivity in human
immunodeficiency virus type 1-infected and -uninfected
children with tuberculosis. Pediatr Infect Dis J 1999;
18:8005.
79. Starke JR. Interferon gamma release assays for diagnosis
of tuberculosis in children. Pediatr Infect Dis J
2006;25:9412.
80. Connel TG, Rangaka MX, Curtis N, et al. QuantiferonTB gold: state of the art for the diagnosis of TB infection?
Expert Rev Mol Diagn 2006;6:66377.
81. Kocagoz T, OBrien R, Perkins M. A new colorimetric
culture system for the diagnosis of tuberculosis. Int J
Tuberc Lung Dis. 2004;8: 1512; (author reply 3).
82. Laal S, Skeiky YAW. Immune-based methods. In: Cole
ST, Eisenach KD, McMurray DN, Jacobs WR Jr, (Eds).
Tuberculosis and the tubercle bacillus. Washington, DC:
ASM Press, 2005:7183.
83. Kalantri S, Pai M, Pascopella L, et al. Bacteriophage-based
tests for the detection of Mycobacterium tuberculosis in
clinical specimens: a systematic review and metaanalysis. BMC Infect Dis 2005;5:59.
84. Pai M, Kalantri S, Pascopella L, et al. Bacteriophage-based
assays for the rapid detection of rifampicin resistance in
Mycobacterium tuberculosis: a meta-analysis. J Infect
2005;51:17587.
85. Moore DA, Mendoza D, Gilman RH, et al. Microscopic
observation drug susceptibility assay, a rapid, reliable
diagnostic test for multidrug-resistant tuberculosis
suitable for use in resource-poor settings. J Clin Microbiol
2004;42:44327.
86. Fend R, Kolk AHJ, Bessant C, et al. Prospects for clinical
application of electronicnose technology to early
detection of Mycobacterium tuberculosis in culture and
sputum. J Clin Microbiol 2006;44:203945.
87. Liebeschuetz S, Bamber S, Ewer K, et al. Diagnosis of
assay: A prospective cohort study. Lancet 2004; 364: 2196
2203.
88. Berggren Palme I, Gudetta B, Bruchfeld J, et al. Detection
of Mycobacterium tuberculosis on gastric aspirates collected
from Ethiopian HIV-positive and HIV-negative children
in a mixed in- and outpatient setting. Acta Paediatr 2004;
93:3115.
Molecular Diagnostic Methods for Diagnosis of

Tuberculosis
1. Global Tuberculosis Control Report. 2009. Available
from: URL http://www.int/tb/publications/global/
2. World Health Organization, 2004. The WHO/IUATLD,
Global project on antituberculosis drug resistance
surveillance 1999-2002. World Health Organization,
Geneva, witzerland.
3. Amdekar Y. Tuberculosis - persistent threat to human

health. Indian J Pediatr 2005; 72: 3338.
4. Centers for Disease Control and Prevention (CDC).
Trends in tuberculosis-United States, 2005. MMWR Morb
Mortal Wkly Rep 2006; 24: 305-8.
5. Dye C, Espinal MA, Watt CJ, et al. Worldwide incidence
of multidrug-resistant tuberculosis. J Infect Dis 2002; 185:
1197-1202.
6. Thierry D, Brisson-Noel A, Vincent-Levy-Frebault, et al.
Characterization of a Mycobacterium tuberculosis
insertion sequence, IS6110, and its application in
diagnosis. J Clin Microbiol 1990; 28: 266873.
7. Kirschner P, Rosenau J, Springer B, et al. Diagnosis of
mycobacterial infections by nucleic acid amplification:
18-month prospective study. J Clin Microbiol 1996; 34:
30412.
8. Kox LF, van Leeuwen J, Knijper S, et al. PCR assay based
on DNA coding for 16S rRNA for detection and
identification of mycobacteria in clinical samples. J Clin
Microbiol 1995; 33: 322533.
9. Shinnick TM, Good RC. Diagnostic mycobacteriology
laboratory practices. Clin Infect Dis 1995; 21: 2919.
10. Noordhoek GT, Kolk AH, Bjune GD, et al. Sensitivity
and specificity of PCR for detection of Mycobacterium
tuberculosis: A blind comparison study among seven
laboratories, J Clin Microbiol 1994; 32: 27784.
11. Newton CR. Setting up a PCR laboratory. In: PCR:
Essential data. (ed. C.R. Newton), p. 216. Wiley, New
York 1995.
12. Kwok S, Higuchi R. Avoiding false positives with PCR.
Nature 1989; 339: 237-8.
13. Thornton CG, Hartley JL, and Rashtchian A. Utilizing
uracil DNA glycosylase to control carryover contamination in PCR: Characteri-zation of residual UDG activity
following thermal cycling. BioTechniques 1992;13:
1804.
14. Drosten C, Panning M, Kramme S. Detection of
Mycobacterium tuberculosis by real-time PCR using panmycobacterial primers and a pair of fluorescence
resonance energy transfer probes specific for the M.
tuberculosis complex. Clin Chem 2003;49:165961
15. Parashar D, Chauhan D.S, Katoch VM, et al. Application
of real time PCR technology in mycobacterial research.
Indian J Med Res 2006; 124: 385-98.
16. Bergmann JS, Woods GL. Clinical evaluation of the Roche
AMPLICOR PCR Mycobacterium tuberculosis test for
detection of M. tuberculosis in respiratory specimens. J
Clin Microbiol 1996; 34:1083-5.
17. Soini H, Musser JM. Molecular diagnosis of mycobacteria.
Clin Chem 2001; 47: 80914.
18. Pfyffer GE, Kissling P, Wirth R, et al. Direct detection of
Mycobacterium tuberculosis complex in respiratory
specimens by a target-amplified test system. J Clin
Microbiol 1994; 32: 91823.
19. Gamboa F, Fernandez G, Padilla E, et al. Comparative
evaluation of initial and new versions of the Gen-Probe
amplified Mycobacterium tuberculosis direct test for direct
detection of Mycobacterium tuberculosis in respiratory and
nonrespiratory specimens. J Clin Microbiol 1998; 36:
6849.

20. Barrett A, Magee JG, Freeman R. An evaluation of the
BD ProbeTec ET system for the direct detection of
Mycobacterium tuberculosis in respiratory samples. J Med
Microbiol 2002; 51: 895-8.
21. Piersimoni C, Scarparo C, Piccoli P, et al. Performance
assessment of two commercial amplification assays for
direct detection of Mycobacterium tuberculosis complex
from respiratory and extrapulmonary specimens. J Clin
Microbiol 2002; 40: 4138-42.
22. Franco-Alvarez de Luna F, Ruiz P, Gutierrez J, et al.
Evaluation of the GenoType mycobacteria direct assay
for detection of Mycobacterium tuberculosis complex and
four atypical mycobacterial species in clinical samples. J
Clin Microbiol 2006;44:30257.
23. Moore DF, Curry JI. Detection and identification of
Mycobacterium tuberculosis directly from sputum
sediments by ligase chain reaction. J Clin Microbiol 1998;
36: 102831.
24. Tortoli E, Tronci M, Tosi CP, et al. Multicenter evaluation
of two commercial amplification kits (Amplicor, Roche
and LCx, Abbott) for direct detection of Mycobacterium
tuberculosis in pulmonary and extrapulmonary
specimens. Diagn Microbiol Infect Dis 1999;33:1739.
25. Harmsen D, Rothganger J, Frosch M, et al. RIDOM:
ribosomal differentiation of medical micro-organisms
database. Nucleic Acids Res 2002;30:416-7.
26. Kox LF, van Leeuwen J, Knijper S, et al. PCR assay based
on DNA coding for 16S rRNA for detection and
identification of mycobacteria in clinical samples. J Clin
Microbiol 1995;33:3225-33.
27. Cloud JL, Neal H, Rosenberry R, et al. Identification of
Mycobacterium spp. by using a commercial 16S
ribosomal DNA sequencing kit and additional
sequencing libraries. J Clin Microbiol 2002; 40: 400-6.
28. Badak FZ, Goksel S, Sertoz R, et al. Use of nucleic acid
probes for identification of Mycobacterium tuberculosis
directly from MB/BacT bottles. J Clin Microbiol 1999;
37: 1602-5.
29. Tortoli E. Impact of genotypic studies on mycobacterial
taxonomy: The new mycobacteria of the 1990s. Clin
Microbiol Rev 2003; 16: 319-54.
30. Russo C, Tortoli E, Menichella D. Evaluation of the
new GenoType Mycobacterium assay for identification
of mycobacterial species. J Clin Microbiol 2006;44:
334-9.
31. Neonakis IK, Gitti Z, Petinaki E, et al. Evaluation of the
GenoType MTBC assay for differentiating 120 clinical
Mycobacterium tuberculosis complex isolates. Eur J Clin
Microbiol Infect. Dis. 2007;26:151-2.
32. Telenti A, Marchesi F, Balz M, et al. Rapid identification
of mycobacteria to the species level by polymerase chain
reaction and restriction enzyme analysis. J Clin Microbiol
1993;31:1758.
33. Tuohy MJ, Hall GS, Sholtis M, et al. Pyrosequencing as a
tool for the identification of common isolates of
Mycobacterium sp. Diagn Microbiol Infect Dis 2005; 51:
245-50.
34. Gingeras TR, Ghandour G, Wang E, et al. Simultaneous genotyping and species identification using hybridization
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
343
pattern recognition analysis of generic Mycobacterium

DNA arrays. Genome Res 1998; 8: 435-48.
Sharma SK, Mohan A. Multidrug-resistant tuberculosis.
Indian J Med Res 2004; 120: 354-76.
Thomas A, Ramachandran R, Rehaman F. Management of
multi-drug resistance tuberculosis in the field: Tuberculosis
Research Centre experience. Indian J Tuberc 2007;54:
117-24.
Ramaswamy S, Musser JM. Molecular genetic basis of
antimicrobial agent resistance in Mycobacterium
tuberculosis: 1998 update. Tuber Lung Dis 1998; 79: 3-29.
Zhang M, Yue J, Yang YP, et al. Detection of mutations
associated with isoniazid resistance in Mycobacterium
tuberculosis isolates from China. J Clin Microbiol 2005;
43: 5477-82.
Sreevatsan S, Stockbauer KE, Pan X, et al. Ethambutol
resistance in Mycobacterium tuberculosis: critical role of
embB mutations. Antimicrob Agents Chemother 1997; 41,
1677-81.
Fukuda M, Koga, H, Ohno H, et al. Relationship between
genetic alteration of the rpsL gene and streptomycin
susceptibility of Mycobacterium tuberculosis in Japan. J
Antimicrob Chemother 1999; 43: 281-4.
Kim BJ, Lee KH, Park B.N, et al. Detection of rifampinresistant Mycobacterium tuberculosis in sputa by nested
PCR-linked single-strand conformation polymorphism
and DNA sequencing. J Clin Microbiol 2001; 39: 2610-17.
Morgan M, Kalantri S, Flores L, et al. A commercial line
probe assay for the rapid detection of rifampicin
resistance in Mycobacterium tuberculosis: a systematic
review and meta-analysis. BMC Infect Dis 2005; 5: 62.
Johansen IS, Lundgren B, Sosnovskaja A, et al. Direct
detection of multidrug-resistant Mycobacterium tuberculosis in clinical specimens in low- and high-incidence
countries by line probe assay. J Clin Microbiol 2003; 41:
4454-56.
Somoskovi A, Dormandy J, Mitsani D, et al. Use of smearpositive samples to assess the PCR-based genotype
MTBDR assay for rapid, direct detection of the
Mycobacterium tuberculosis complex as well as its
resistance to isoniazid and rifampin. J Clin Microbiol
2006; 44: 4459-63.
Kim SY, Park YJ, Song E, et al. Evaluation of the
CombiChip mycobacteria drug-resistance detection DNA
chip for identifying mutations associated with resistance
to isoniazid and rifampin in Mycobacterium tuberculosis.
Diagn Microbiol Infect Dis 2006; 54: 203-10.
Kim BJ, Lee KH, Park BN, et al. Detection of rifampinresistant Mycobacterium tuberculosis in sputa by nested
PCR-linked single-strand conformation polymorphism
and DNA sequencing. J Clin Microbiol 2001; 39: 2610-7.
Jureen P, Engstrand L, Eriksson S, et al. Rapid detection
of rifampin resistance in Mycobacterium tuberculosis by
pyrosequencing technology. J Clin Microbiol 2006;
44:1925-9.
Piatek AS, Telenti A, Murray M.R, et al. Genotypic
analysis of Mycobacterium tuberculosis in two distinct
populations using molecular beacons: implications for
rapid susceptibility testing. Antimicrob Agents
Chemother 2000; 44: 103-10.
26
Imaging of Tuberculosis in Children

Ashu Seith Bhalla, A Kumar, AK Gupta, S Mukhopadhyaya
Tuberculosis continues to be a major health problem all

over the world, especially in developing countries. The
incidence of tuberculosis has risen steadily since 1985,
despite a preexisting decrease of its frequency due to
effective chemotherapy. This is related to the occurrence
of AIDS epidemic, together with increasing prevalence of
multidrug resistant TB. In all cases, pulmonary tuberculosis
remains a common disease. Pediatric cases are particularly
important epidemiologically because each usually
represents a new infection rather than reactivation of prior
disease. Indeed it is said that, Children with primary
tuberculosis are the reservoir from which future cases will
emerge. 1, 1a
Pathologically, in tuberculosis two processes are in
play: caseationdestructive and dangerous and the other
sclerosis- conservative and healing. The ultimate result
in a given case depends upon the capabili-ties of the body
to restrict and limit the growth of the bacilli. Hence a
widespectrum of tuberculous lesions are encountered
radiographically. In this article, imaging of the
tuberculous lesions affecting different organ systems of
children is discussed.
PULMONARY TUBERCULOSIS
Lungs are the most common and usually the first site of
involvement in tuberculosis. Bacterio-logical confirmation
of pulmonary tuberculosis in pediatric age group is
difficult. The lung lesions do not cavitate as frequently as
in adults. Sputum collection is difficult. Gastric contents
with swallowed organisms show positive-smear in about
5% and positive culture in about 40% children. Less than
50 percent of children with tuberculosis are diagnosed
without bacteriological confirmation.2
Imaging plays an important role in pediatric pulmonary
tuberculosis. The patients who are exposed to tuberculous
infection for the first time have pathological, clinical and
roentgenological features different from those who have
reactivation of previous disease or superinfection.3 But there
are overlap of findings in these two groups.
The radiographic findings can be divided into primary
and post primary or reactivation forms. Primary
tuberculosis represents the initial infection with M.
tuberculosis in an unsensitized host. Postprimary
tuberculosis is caused by reactivation of latent foci of

infection implanted during primary tuberculosis. Earlier,
primary tuberculosis was considered a disease of
children. A significant change has occurred in the pattern,
as primary tuberculosis is being encountered in adult
population with more frequency. Primary tuberculosis
is an air borne infection, resulting from inhalation of
mycobacterial aerosol. It consists of a small focal
parenchymal infiltrate or consolidation, with lymphatic
spread to mediastinal and hilar nodes, known as the
Ghons complex. It usually heals, but may progress to
progressive pulmonary tuberculosis in 5-10% of patients
with primary TB, involving multiple lobes and more
extensive lesions. Primary tuberculosis usually shows
lympho-hematogenous spread, while post primary predominantly shows endobronchial spread. Endobronchial
spread results from cavitation of the tuberculous
consolidation or rupture of necrotic lymph nodes into
the bronchi. Hematogenous spread may also occur.
Congenital TB is an unusual entity resulting from
hematogenous spread across the placenta or fetal
ingestion of infected amniotic fluid.4
IMAGING MODALITIES
Plain Radiographs
A patient suspected of pulmonary tuberculosis is evaluated
by a posteroanterior (PA) chest roentgenograph. Mostly a
PA view is adequate for diagnosis and subsequent followup. Lateral view is indicated to evaluate lesions not well
seen in PA view.
Ultrasound (US)
While chest radiography is the primary imaging modality
in evaluation of chest diseases, US may be helpful in
evaluation of persistent or unusual areas of increased
opacity in the peripheral lung, pleural abnormalities, and
mediastinal widening. In tuberculosis, US is particularly
useful in follow-up of patients with pleural effusion/
empyema. US also helps guided interventions such as
empyema drainage and mediastinal nodes sampling,
when large.5
Chapter 26 Imaging of Tuberculosis in Children
345
Computerized Tomography (CT)
IMAGING FINDINGS
Computerized tomography (CT) can give important

information in deciding presence and nature of
lymphadenopathy, diagnosis and extent of bronchiectasis,
pleural and chest wall lesions. Contrast enhanced CT
(CECT) may detect a number of abnormalities which are
not visible on chest radiographs. Several times, CT may
be the only modality to detect them, thus, aiding in making
a confident diagnosis of tuberculosis.6, 7 CT is hence useful
in patients who are symptomatic Mantoux positive (SMP)
with normal chest X-ray. It also helps in assessing disease
activity in equivocal cases.
A study at All India Institute of Medical Sciences
(AIIMS), New Delhi, India over 3 years (2003-06) was
conducted to evaluate the role of CT in chest
tuberculosis in children. A total of 91 patients with
clinical and laboratory evidence, or chest radiograph,
suggestive of pulmonary tuberculosis were studied.
All these patients underwent chest radiography and
CECT of the chest and were given antitubercular
treatment (ATT) for 6 months. Out of these 91 patients,
46 were lost to follow-up. Rest of the 45 patients
underwent repeat CECT within 30 days of completion
of ATT. Chest radiographs were normal in 8 patients
in the pre-treatment phase, in whom the disease was
diagnosed on CECT. Even, in those patients, with
abnormal radiographs, CT revealed additional
findings and hence, helped in making a specific
diagnosis. After 6 months of ATT, chest radiographs
were normal in 4 patients, where as CECT still showed
enlarged nodes. CT also detected complications, like
empyema in 5 patients, and other complications in 9
patients.8
The main concern with use of CT is the exposure of
children to ionizing radiation, especially as repeat studies
maybe required on follow-up. All CT studies should hence
use specific pediatric protocols to minimize the radiation
dose.
The disease may be described under the following

headings:9
1. Pulmonary primary complex (PPC)
Parenchymal involvement
Nodal involvement
Parenchymal and nodal involvement
Airway involvement
Mild pleural involvement
2. Progressive primary disease (PPD)
Consolidation
Collapse
Collapse with consolidation
Cavitation
Significant pleural involvement
Bronchopneumonic spread
Miliary spread
3. Post primary lesion (PPL)
Calcification
Fibrosis
4. Symptomatic Mantoux positive (SMP)
Over the past 30 years patients attending the Pediatric
Tuberculosis Clinic of All India Institute of Medical
Sciences (AIIMS), New Delhi, were assessed
roentgenologically under these four broad heads. There
were 2,677 patients of pulmonary tuberculosis, among
whom 50% were in PPC, 13% in PPD, 16% PPL, and 21%
in SMP group.9
Magnetic Resonance Imaging (MRI)

MRI is not routinely used in evaluation of the lungs due
to low proton density of lungs, physiological motion and
extensive air-tissue interfaces; all resulting in poor signal.
It has however, found utility in evaluation of
mediastinum as an alternative to CT, being associated
with no risk of radition exposures. However, its cost, long
examination times and need for patient cooperation are
still limiting factors. MRI maybe used in older children
and young adults for initial and follow-up evaluation of
suspected mediastinal nodes.
Pulmonary Primary Complex (PPC)

Primary tuberculosis of the chest usually affects one or
more of the four structures, i.e. pulmo-nary parenchyma,
lymph nodes, tracheobron-chial tree and pleura.2
Parenchymal Involvement
The typical roentgen appearance is that of an airspace
consolidation of variable size, usually unifocal,
homogenous, ill-defined margins except when it abuts a
fissure (Figs 26.1A and B). It is often indistinguishable
from typical bacterial pneumonia. In tuberculous
consolidation and in PPC there is lack of systemic toxicity,
presence of significant number of associated lymphadenopathy and failure to respond to antibacterial
therapy. Cavitation and endobronchial spread of disease
is rare in children with uncomplicated primary
tuberculosis.10-13 There is no consensus as to the most
common site of paren-chymal involvement in primary
tuberculosis, different series documenting upper lobe10,
lower lobes14,15, no regional predominance16 and equal
involvement of upper and lower lung zones13. For
346
Section 5 Diagnosis
paratracheal and less commonly, the subcarinal region.
When associated with parenchymal lesion, the nodes of
the same side are involved. Although typically unilateral
and right sided, bilateral adenopathy may occur in up to
31% cases.13,22 A recent study has reported the subcarinal
region as the most frequently involved site seen in 90 of
92 pateients.7 Adenopathy may be the sole radiographic
manifestation of primary tuberculosis. Adenopathy alone
is a finding that decreases in frequency with age,22 being
encountered in up to 49% of children aged 0 to 3 years,13
in 9% children age 4 to 15 years,23 and only rarely in
adults24,25 (Figs 26.2A and B).
CT in Evaluation of Lymphadenopathy
Contrast enhanced CT scan can show the nature of an
enlarged lymph node. Tuberculous nodes larger than
2 cm in diameter usually show central areas of
multifocal relative low density with rim enhancement
of irregular thick wall. With CT-histologic correlation,
excised nodes exhibiting this pattern of enhancement
have been found to contain complete central necrosis
in association with a highly vascular, inflam-matory,
capsular and perinodal reaction.26, 27 Other findings in
Figs 26.1A and B: Pulmonary primary complex: Chest radiograph (A)

and chest CT (B) shows an ill-defined consolidation involving the left
upper lobe, abutting the major fissure
practical purpose, primary tuberculosis can cause

consolidation of any lobe.17 Persistent mass like lesion
or tuberculoma is uncommon in children. In the series
by Seth et al9 at Pediatric Tuberculosis Clinic, All India
Institute of Medical Sciences New Delhi (AIIMS), 39%
patients of PPC group had only parenchymal
involvement. As in lymphadenopathy, CT is superior to
plain X-rays in demonstrating the parenchymal changes.
Consolidation is seen as a homogeneous soft tissue
attenuation lesion with air bronchogram or areas of
breakdown within. Parenchymal changes are better
appreciated on high resolution CT (HRCT).18 CT is
superior to MRI in the demonstration of lung
parenchymal changes.
Lymph Node Involvement

Lymphadenopathy is a common feature of primary
tuberculosis and is seen in up to 96% of children.6,13,19 It
is the radiologic hallmark of disease in children.20-23
Enlarged lymph nodes are usually in the hila, the right
Figs 26.2A and B: Pulmonary primary complex: Chest radiograph (A)

and contrast enhanced chest CT (B) show enlarged right paratracheal
and right hilar adenopathy, which appears heterogeneous on CT

tuberculous nodes being varying degree of homogenous
enhancement, large central low density with uniform
thin rim- enhancement with preserved or obliterated
perinodal fat.28 Androkinou et al7 describe ghost-like
ring enhancement in a group of matted nodes as the
common pattern of enhancement rather than discreet
rim-enhancement of single large nodes. Necrosis with
rim enhancement is not a usual finding in lymphoma
but reported in various fungal diseases and malignant
nodes undergoing central necrosis2 (Figs 26.3A to D).
Calcification is uncommon and seen in 10 to 21%
children with tuberculosis and is never present in
children less than 6 months of age.7,29 Figures 26.4A and
B show lymph node calcification on CT. Figure 26.4B
shows noncontrast and shows 26.4C Figure 26.4C shows
contrast enhanced CT scan of two different patients
showing calcification in the paratracheal nodes. In the
study of 91 patients, nodal involvement was the most
common abnormality (96.7%).8 The most frequent nodal
groups to be involved were paratracheal (84%), followed
347
by subcarinal, pretracheal, precarinal and right hilar

nodes, with largest nodes found in the prevascular,
subcarinal, and paratracheal location. The enhancement
pattern was most commonly homogenous, followed by
inhomo-genous and peripheral rim like pattern. A
combination of these patterns was also seen in a
significant portion of patients. Majority of the nodes were
conglomerate and had obscured perinodal fat.
Calcification was also found in a few patients without any
prior treatment.8 Mediastinal and hilar nodes are equally
well demonstrated on MRI. Focal necrosis is seen as areas
of increased signal intensity on T2- weighted images.18
In the Pediatric Tuberculosis Clinic of AIIMS, 29%
children of PPC group had both parenchymal as well as
nodal involvement (Fig. 26.5).9
Airway Involvement
Thirty percent patients of primary tuberculosis in Webers
series 10 showed atelectasis caused by tuberculous
Figs 26.3A to D: CT scout (A), contrast enhanced chest CT (B) and abdomen (C) reveal enlarged right paratracheal lymph nodes which show
classical central necrosis and rim-enhancement. Enlarged and matted left axillary, periportal, peripancreatic nodes are also present. Lung window
(D) reveals left upper lobe consolidation
348
Section 5 Diagnosis
Fig. 26.5: Pulmonary primary complex: Chest radiograph reveals

right midzone parenchymal lesion and right paratracheal adenopathy
tracheobronchial disease. Atelectasis in primary

tuberculosis typically affects anterior segment of upper
lobe or medial segment of middle lobe due to
compression by lymph node enlargement. In the AIIMS
series8 31 of 91 about 34% children showed airway
involvement. However, some of these cases showed
features of PPD.
Pleural Involvement
Pleural involvement in the form of effusion is not very
common in primary tuberculosis. Weber et al10 observed
pleural effusion in 10% of their pediatric patients. Mostly,
effusion is mild to moderate in quantity and usually
associated with parenchymal lesion. In the AIIMS series,9
pleural effusion was very uncommon in PPC, and if
present was very mild in quantity.
Progressive Primary Disease (PPD)
Figs 26.4A to C: (A) Lymph node calcification, Noncontrast (B) and

contrast enhanced (C) CT scans of two different patients showing
calcification in paratracheal nodes
A primary lesion may disseminate through tracheobronchial tree resulting in bronchopneu-monic spread
or may erode into a vascular channel causing miliary
dissemination into lungs and in many other organs.
Progressive primary disease is the result of
progression or reactivation of the primary disease. This
includes large consolidation, atelectasis, a combination
of consolidation and atelectasis and cavitating lesions.
In AIIMS series 9 of 2,677 patients, 13% were in the
PPD group. At times after initial good response to
treatment, the typical picture of primary tuberculosis
becomes confusing by the continuing progression or
reinfection of the disease. Patients may report for
treatment first time at this stage and it becomes
difficult to ascertain whether this is PPC or PPD.
349
Parenchymal Involvement
Consolidation in PPD is usually heterogenous, poorly
marginated with predilection of involvement of apical or
posterior segments of upper lobe or superior segment of
lower lobe.3, 19 Often more than one pulmonary segment is
involved.14 Segmental consolidation if not adequately
treated results in lobar or complete lung involvement.
Consolidation of PPD has propensity for cavitation in some
cases (Figs 26.6 and 26.7A to C).
Untreated consolidation may lead to collapse.
Endobronchial tuberculosis or pressure on bron-chus by
enlarged lymph nodes may lead to collapse. If not treated
actively and adequately, the collapse may become
irreversible (Fig. 26.8). On HRCT bronchial compression
by enlarged nodes as well as endobronchial involvement
is well detailed. Acute tracheobronchial tuberculosis
manifests on HRCT as irregular or smooth bronchial wall
thickening associated with luminal narrowing.30 One of
the most striking feature of juvenile pulmonary
tuberculosis is the absence of proliferative apical
tuberculosis before onset of adolescence.31
Consolidation may be associated with collapse of the
same lobe or different lobes of the lung (Fig. 26.9).
Lobar or segmental consolidation may progress and
breakdown into necrotic areas when some of the content
is drained via bronchus, a cavity is formed (Fig. 26.10).
Cavities are more frequently multiple and typically
within area of consolidation. The cavity wall is initially
thick and irregular, then progressively becomes thin with
healing. This progression is well demonstratrated on
HRCT.26 In the AIIMS series9 of PPD there were only 1%
cavitating lesions (Fig. 26.11).
Fig. 26.6: Progressive primary disease: Chest radiograph shows

massive right side consolidation
Figs 26.7A to C: Progressive primary disease: Chest radiograph (A)

shows a large area of heterogeneous consolidation involving right upper
lobe. Multiple cavitary lesions are seen in right lower lobe. CT scan (B
and C) reveals cavitation in the upper lobe lesion and bilateral lower
lobe cavities
350
Section 5 Diagnosis
Fig 26.8: Collapse of left lower lobe seen as a triangular opacity

through cardiac shadow in the chest radiograph
Fig. 26.10: Progressive primary disease: Chest radiograph showing

consolidation with cavitation in left lower lobe, with adjoining multiple
air-space nodules
Fig. 26.9: Progressive primary disease: Chest radiograph showing

consolidation and cavitation involving left upper lobe, with volume loss
of the lobe
Fig. 26.11: Progressive primary disease: CT scan showing a thickwalled cavity with surrounding consolidation with collapse in the right
upper lobe
Pleural Involvement
become loculated, causing a tuberculous empyema

(Figs 26.13A and B). In chronic tuberculous empyema, CT
shows right sided pyopneumothorax, a focal fluid
collection with pleural thickening with or without
extrapleural fat proliferation. As a consequence of post
primary tuberculosis, pleural disease can result in
bronchopleural fistula due to rupture of a cavity or
secondary to empyema. CT may demonstrate directly
the communication between the pleural space and
bronchial tree or lung parenchyma in these patients. At
times, the effusion may not clear completely and leaves
residual encysted sac of thick pleura with or without
residual fluid in it. Fibrothorax with diffuse pleural
thickening with calcification, but without pleural effusion
Tuberculous infection of the pleura is more com-mon in

adults and teenagers than in children19 but may occur
from infancy to old age. With appropriate therapy pleural
effusion carries the best prognosis of all types of
tuberculosis and is least likely to subsequent
complication. Usually pleural effusion in PPD is
moderate to large in quantity, unilateral, free flowing and
with or without lung lesion (Fig. 26.12). It commonly
develops on the same side as the site of initial tuberculous
infection. Primary pleural effusion tends to clear
completely or results merely in obliteration of the
costophrenic angle. Tuberculous pleurisy, however, may
351
and was seen in 3% of children with PPD. In the

subsequent study with CT, however, pleural lesions were
seen in 18 of 91 patients. Majority (n = 9) of them had
only pleural thickening, 4 had pleural effusion while 5
showed CT feature of empyema.8
Tuberculous Bronchopneumonia
Fig. 26.12: Chest radiograph shows massive right sided

free pleural effusion
When a tuberculous necrotic parenchymal lesion

extends locally and erodes into the tracheobronchial
lumen, there may be wide dissemination through the
bronchial tree to ipsilateral or bilateral lung
parenchyma. Such endobronchial spread results in
formation of multiple foci of alveolar shadows very
suggestive of bronchogenic spread. The disease process
may extend through surrounding airspaces leading to
acute confluent air space pneumonia. The lesions usually
occur in clusters and vary widely in size. Usually the open
cavity or consolidation in remote areas gives clue to the
primary site of dissemination (Figs 26.14A and B).
Bronchopneumonic spread is better appreciated on CT
Figs 26.13A and B: (A) Right sided loculated pleural effusion seen in
chest radiograph (B) Empyema CT scan of another patient with right
sided pyopneumothorax
on CT, suggests inactivity.30 Loculated fluid may be

mistaken for pneumonia or round consolidations.
In AIIMS series with chest radiographs9 pleural
effusion was most commonly seen in school going age,
Figs 26.14A and B: Bronchopneumonic spread: (A) Chest radiograph

reveals extensive bronchopneumonic tuberculosis with consolidation
in left lower lobe of right lung. (B) After adequate therapy there is diffuse
healed calcified foci in right lung and a large calcified node in left
paratracheal region
352
Section 5 Diagnosis
particularly HRCT compared to plain radiographs. The

appearance is widespread, bilateral but not always
symmetrical fluffy densities (alveolar nodules) (Figs
26.15A to C). Early lesions are seen as small, ill-defined
centrilobular nodules with branching (tree-in-bud
appearance). This sign results from the impaction of
bronchioles with exudates and when present is
indicative of active disease.
Figs 26.15A to C: Progressive primary disease: (A) Chest radiograph

reveals mediastinal widening with multiple, bilateral pulmonary nodules.
(B) Chest CT shows extensive necrotic mediastinal adenopathy. (C)
Lung fields on CT reveal extensive brochopneumonic spread with
consolidation in the right lower lobe
Miliary Tuberculosis
A primary lesion may erode into a vascular channel
causing miliary dissemination into the lungs and many
organs. In the early stage of miliary dissemination chest
roentgenogram may be normal. The interval between
dissemination of bacilli and development of
roentgenographically discernible disease is probably 6
weeks or more. When these lesions increase in size they
are tiny, discrete pinpoint opacities evenly distributed
throughout both lungs with some basal predominance,
reflecting gravity induced more blood flow to the base.
HRCT is sensitive to the depiction of even early changes
in miliary tuberculosis (Figs 26.16A and B). Initially, they
are about 1 mm in diameter and may reach 3 to 5 mm size
if adequate therapy is not given. The lesions may become
confluent presenting a snow storm appearance.3
Associated lymph adenopathy is seen in 95% of the
children as compared to 12% in adults.32 Affected nodes
are mostly on the right side in paratracheal region.
The primary site of dissemination is not always
recognized on a chest X-ray. With adequate therapy
roentgenographic clearance is usually compelete without
any residue and clearance may be extremely rapid.
In AIIMS series, only 3% children had bronchopneumonic and miliary tuberculosis.9
Figs 26.16A and B: Miliary spread: Chest radiograph (A) and (B) HRCT
show bilateral, diffuse, tiny, discrete, pinpoint opacities
353
Post-Primary Lesion (PPL)
FOLLOW-UP
This group includes patients with parenchymal or nodal

calcification and/or fibrotic lesions. In AIIMS series of
2677 patient, 9 16% patients were in this group.
Lymph node enlargement may be massive; in a series
of 15 children of primary tuberculosis by Giammona et
al23 with hilar and mediastinal lymphadenopathy, 10
children, all 5 years or younger had massive nodal
enlargement.
In this series9 of 1350 patients in PPC group, 32%
children had only nodal involvement.
At AIIMS, in collaboration with Pediatric Department a

routine of serial radiological evaluation of children with
pulmonary tuberculosis is followed. The first X-ray is
taken at presentation/diagnosis of tuberculosis. Repeat
X-ray is taken after 3 months of therapy, then every 3
months in first year and every 6 months in the second
year. After this the patient is kept under surveillance and
in case of development of signs and symptoms, he is
assessed again clinically and radiologically. CECT is a
useful tool after chest radiograph, not only for the
diagnosis, but also for monitoring the response to ATT.8
However because it entails significantly greater radiation
exposure, its routine use cannot be advocated. MRI can
be used in older children with nodal disease.
Symptomatic Mantoux Positive Group (SMP)

This group forms 21% of the cases. These are children
who are symptomatic, have positive Mantoux test and
normal chest X-ray. They comprise 21% of the total cases
of pulmonary tuberculosis in the Pediatric TB clinic.9 CT
scan of chest in 10 patients of SMP group revealed
lymphadenopathy not appreciated on a chest
X-ray. One report comparing the findings of radiographs,
showing that up to 60% of children with normal
radiographs had lymphadenopathy on CT.6 A normal
chest radiograph can hence be misleading.6, 7
PREDICTION OF ACTIVITY OF TUBERCULOUS LESION

A radiologist or a clinician should never be dogmatic
about assessment of activity of a tuber-culous lesion on
a single radiograph. There may be a typical exudative
lesion on X-ray but repeated gastric lavage for AFB are
negative. The lesion may remain unchanged for a long
time. On the other hand a typical fibrotic lesion may have
active granulomatous lesion. A static lesion for a long
time (6 months or more) may indicate inactivity. CT can
help predict the disease activity on the basis of specific
findings in nodes and parenchyma. These features can
therefore be used to monitor response on imaging. HRCT
has a definite role in prediction of activity of parenchymal
lesions. The presence of thick-walled cavities,
consolidation and centilobular nodules indicate active
disease. Whereas, thin-walled cavities, fibrotic bands and
well defined nodules are seen in inactive disease. CT
picture can, however, be equivocal and clinical
correlation in this regard is imperative.8 Evaluation of
activity in nodes is difficult, though presence of low
attenuation areas has been suggested as a sign of activity.
However, this sign is of limited reliability as
enhancement patterns of the nodes can be quite variable
as discussed previously.30
In the CT study of AIIMS 8 node enhancement
(homogeneous or inhomogeneous), conglomeration and
obscuration of fat were found as indicators of disease
activity in nodes.
Imaging Follow-Up
The parenchymal and nodal lesions may regress till there
is complete clearance, calcification or fibrosis. The
majority of children with PPC on follow-up show no
roentgen sign of the initial lesion, the sole evidence of
disease being a positive Mantoux test. Calcification of
paren-chymal or nodal lesion is not very common in PPC.
In the series of Weber et al10 children with adequate
follow-up, calcification was seen in 17% of the
parenchymal and 36% of nodal lesions. Thirty two
percent of children showed residual parenchymal
scarring. Decrease in the size of enlarged lymph nodes
usually, parallel resolution of parenchymal lesion. Some
children who had atelectasis in active stage of the disease,
have residual dilated and distorted bronchial tree or
bronchiectasis.
Bronchiectasis in PPD can develop by two mechanisms:
(i) destruction and fibrosis of lung parenchyma resulting
in retraction and irreversible bronchial dilatation,
and (ii) cicatricial bronchostenosis secondary to localized
endobronchial infection resulting in obstructive
pneumonitis and distal bronchiectasis.3 CT plays important
role in the diagnosis and evaluation of extent of bronchiectasis, thereby helping in surgical excision (Figs 26.17A
and B).
Family Survey
All children with pulmonary tuberculosis should have
family survey to detect asymptomatic contact positive
cases. Chest radiograph should be taken for all adults
and children. Mantoux test should be done for those
below 12 years. Any family member with suspicious
lesion in chest radiography should be further investigated
and treated. In AIIMS series in the Pediatric TB clinic
there was positive family history in about 30% of children
with pulmonary tuberculosis.9 Radiological screening of
adult contacts, taking a child with PPC as an index case,
354
Section 5 Diagnosis
Figs 26.18A and B: CT guided trucut biopsy from partially calcified

right paratracheal node, using posterior approach and co-axial
technique. Histopathology revealed active disease
Figs 22.17A and B: (A) Collapse of left lower lobe with bronchiectasis
seen in chest radiograph (B) Chest CT scan reveals loss of volume of
left lower lobe with cystic bronchiectasis, mediastinal shift to the left
and herniation of right lung into left hemithorax
showed active pulmonary lesions in 4 to 5% of those

screened. Hence it is advocated rightly in Revised
National Tuberculosis Control Program (RNTCP) in
India that children of a pulmonary tuberculosis put on
DOTS must be screened for tuberculosis.
Interventions in Thoracic TB
Both diagnosic and therapeutic image guided
interventions may be required in thoracic TB
occasionally. These include FNAC or trucut biopsy of
mediastinal nodes in equivocal cases.(Figs 26.18A and
B). Image guided drainage of pleural collections may
be performed, especially in loculated effusions (Figs
26.19A and B). Similarly large mediastinal (pre or
paravertebral) abscesses can also be drained. These
may be ultrasound or CT guided depending on the
location of the lesion. Rarely, presence of massive or

moderate hemoptysis may necessitate need for
bronchial artery embolization, especially in those with
extensive parenchymal involvement.
INTRACRANIAL TUBERCULOSIS (33-39)

It is almost always secondary to hematogenous
dissemination from a primary focus elsewhere, usually in
the lungs. Rarely, it may also result from direct spread
from calvarial or middle ear infection. On the basis of
location it is described as either meningeal or parenchymal.
Depending on the type, however, it is classified as diffuse
meningeal (TBM); tuberculomas, tuberculous abscess and
focal cerebritis.
Tuberculous Meningitis (TBM)

It is a common clinical problem in India. The diagnosis
of tubercular meningitis is based on clinical suspicion
and CSF examination for biochemical analysis, AFB and
polymerase chain reaction. Imaging has a role in
355
Fig. 26.20: Axial CECT image shows extensive enhancing exudates

in the basal cisterns
Figs 26.19A and B: CT guided drainage of loculated empyema with

malecot catheter
corroborating the diagnosis and is especially useful for

assessing complications including hydrocephalus and
infarcts.
Pathological lesions observed on CT/MRI scan of
head are: exudates in the basal cisterns; hydrocephalus,
infarct, associated tuberculoma or cerebritis.
On a noncontrast CT, exudates are visible as either
isoattenuating or minimally hyper-attenuating which has
been described as the most specific sign of TBM. 33
Following intravenous contrast administration, however,
there is intense enhancement (Fig. 26.20). The abnormal
meningeal enhancement or enhancing exudates are
usually seen in the basal cisterns including suprasellar
cistern and cisterns around the brainstem and in the
sylvian fissures. 34,35 Enhancement may extend over
cerebral and cerebellar hemispheres. The enhancement
seen is usually thick, continuous with ill-defined edges or
nodular differentiating it from normal vascular
enhancement. We have observed a good correlation
between the degree of exudates and the clinical outcome.
At times exudates may be localized to only one cistern
(Fig. 26.21). On follow-up scan (Fig. 26.22) calcification is
the sequelae.
Fig. 26.21: TBM: Localized exudate in left sylvian fissure only on CT
Hydrocephalus, although a sequelae of basal exudates,

may be the first manifestation on CT. It is a very common
finding and is usually of the communicating type due to
blockage at the level of cistterns. Associated periventricular
ooze suggests high pressure hydrocephalus (Fig. 26.23)
which is more commonly seen when it is a noncommunicating hydrocephalus.
Infarcts due to basal arteritis are an important and
not an uncommon finding. Basal ganglia infarcts due to
the involvement of medial striate and thalamoperforating
arteries in the basal exudates is a very characteristic
infarct location for TBM (Fig. 26.24). However, infarcts
may also occur in the adjoining areas of localized
meningeal or cisternal enhancement.33
356
Section 5 Diagnosis
Fig. 26.22: TBM: Healed calcified exudates in the suprasellar

cisterns on follow-up NCCT
Fig. 26.24: Axial CT image of the same patient as in Figure 26.23

performed 4 days later, shows a left basal ganglia infarct
Fig. 26.23: Axial CT shows hydrocephalus with periventricular ooze

in a patient with tubercular meningitis
Fig. 26.25: Axial CECT shows multiple ring enhancing lesions in bilateral
temporal lobes with perilesional edema consistent with multiple
tuberculomas
Late sequelae of TBM include atrophy, meningeal

calcifications and focal infarcts. Contrast enhanced MRI
is more sensitive than CT for detecting subtle meningeal
enhancement. However, because of its high cost it is
reserved for problem solving cases when the CT findings
are equivocal. Moreover, CT is almost equally sensitive
as MRI to detect the major complications.
On noncontrast CT (NCCT), tuberculomas have a low

or minimal high attenuation. After intravenous contrast,
they enhance either homogenously or in a ring fashion
(Fig. 26.25) with a smooth or a lobulated margin.36 They
have been described as immature (small discs and rings
with massive edema) and mature form (large rings or
lobu-lated masses with lesser edema). Tuberculoma
cannot be reliably differentiated on CT from granuloma
due to other infectious diseases like neurocysticercosis,
fungal and even pyogenic infection. Radiological features
which favor a tuberculoma over an neurocysticercus are
Intracranial Tuberculomas
It may occur either alone or in association with TBM,
may be single or multiple, latter being more common.

larger size (2 cm), thicker walls, intense perilesional edema,
hyperdensity on plain scan, conglomeration and adjacent
meningeal enhancement. (Fig. 26.26) With specific
treatment, surrounding edema diminishes and disappears
first before reduction in the size of the tuberculoma takes
place which may either disappear totally or calcify (Fig.
26.27).
Magnetic Resonance Imaging (MRI) of Intracranial

Tuberculoma
MRI appearance depends on whether the
tuberculoma is noncaseating, caseating with a solid
center or caseating with a liquid centre.37 The signal
characteristics are shown in Table 26.1. Based on these
signal intensity characteristics it may be helpful to
differentiate it from neurocysticercosis.
Advanced MR imaging techniques including
spectroscopy and magnetization transfer imaging have
also been shown to be helpful in differentiating
tuberculomas from other lesions. Tuberculomas on MR
spectroscopy characteristi-cally show lipid peak with or
Fig. 26.26: Tuberculomas. Axial CECT shows large (>2 cm) sized
conglomerate lesions in right temporo-occipital region with extensive
perilesional edema
357
without raised choline.38 Magnetisation transfer images

have been shown to be more sensitive than T2 weighted
images in detecting small tuberculomas (Figs 26.28A and
B).39
Tuberculous Abscess
It is a rare presentation of intracranial tuber-culosis. CT
morphology is similar to pyogenic abscess, i.e. thin
enhancing wall with low density center (Figs 26.29A to
C).
A noncaseating tuberculoma with ring enhan-cement
is differentiated from a tuberculous abscess by noting
the attenuation values of the center of the lesion which
will be similar to normal brain in the former and low in
the latter. MR spectroscopy of a tubercular abscess also
shows lactate and lipid peaks without any amino acid
peak which helps in differentiating it from pyogenic
abscess.
Abscess may not respond to chemotherapy and then
surgical intervention would be required.
Fig. 26.27: Postgradolinium MRI scan shows in enhancement

with a solid center
Table 26.1: MRI features of intracranial tuberculoma

Types of tuberculoma
T1WI
T2WI
Postgadolinium
Noncaseating
Caseating with
solid center
Caseating with
liquid center
Hypointense
Hypo-to
isointense
Centrally
hypointense
Hyperintense
Iso- to hypointense
with hypointense rim
Centrally
hyperintense with
hypointense rim
Homogeneous enhancement
Rim enhancement rim (Fig. 21.27)*
*Surrounding edema will be hypointense of T1W1 and hyperintense on T2W1
Rim enhancement
358
Section 5 Diagnosis
Figs 26.28A and B: Tuberculoma. T2-weighted axial MRI image (A) shows a ring lesion with hypointense walls and
iso to hypointense center. The lesion shows peripheral enhancement on post contrast T1-weighted axial image (B)
Figs 26.29A to C: Tuberculous abscess. T2-weighted axial (A) and post contrast T1-weighted axial (B) MRI images show a
large thick walled peripheral enhancing lesion with hypointense wall and hyperintense centre on T2 with marked perilesional
edema in the right cerebellar hemisphere. The MR spectroscopy (C) from the lesion shows significantly elevated lipid peak
Focal Cerebritis
It is usually associated with TBM. Focal edema with gyral
enhancement without an evident abscess or tuberculoma
in the same region points to the diagnosis of focal
cerebritis.
URINARY TRACT TUBERCULOSIS 40-46

Symptomatic tuberculosis affecting the urinary tract
occurs only rarely below the age of 20 years because there
is a time lag of 2 to 20 years (average 8 years) between
the initial pulmonary infection and the diagnosis of
secondary genitourinary tuberculosis.
This long time interval probably accounts for the

small number of children with genito-urinary
tuberculosis. Nowadays, it is seen in children almost
exclusively with miliary disease.
It is suggested that: (i) all children (and adults) with a
history of pulmonary tuberculosis should have a periodic
urine culture for acid-fast-bacilli, and (ii) tuberculosis should
always be suspected in all children with chronic or recurrent
urinary tract infections which do not respond to the usual
antibacterial medications. A high clinical index of suspicion
is required to diagnose these cases at an early stage. Majority
of urinary tract tuberculous cases are secondary to
Imaging
Imaging plays a vital role in the overall management
of these patients. One must remember that imaging
can only suggest imaging is compatible with
disease but diagnosis is always by urinary culture
for M. tuberculosis.
Plain X-rays
They are valuable and might show the following features:
i. Calcification in the genitourinary tract areas is a late
feature and is, therefore, seen mostly in adults.
Characteristic features are lobar calcification, and
putty-like appearance of the calcification.
ii. Other tuberculous lesions, e.g. evidence of vertebral
tuberculosis, mesenteric or retro-peritoneal lymph
node calcification or adrenal calcification.
iii. Chest X-rays positive for tuberculosis either active
or healed sequelae. In the overall group of
genitourinary tuberculosis (including adults) less
than 50% of patients are reported to have chest
abnormality indicative of tuberculosis.
359
caliectasis (Fig. 26.31) where-as complete stricture

of it will cut-off the cavity from the collecting system
resulting in a tuberculous abscess (Fig. 26.32).
v. Stricture at the inferior margin of the renal pelvis
results in its cephalic retraction producing the socalled hike-up-pelvis.
vi. Advanced disease results in diffuse fibrosis and the
kidney becomes nonfunctional, the so-called
autonephrectomy. Amorphous calcification may
be seen within this kidney. This stage is usually seen
only in adults.
Intravenous Urography (IVU)

This remains the key investigation for the radiological
diagnosis of early urinary tract tuberculosis. The newer
imaging modalities like ultrasonography, computed
tomography and magnetic resonance imaging do not
have the spatial resolution capable of demonstrating the
early, fine erosive changes affecting the uroepithelium.
Following findings may be seen on IVU.
Kidney
i. In the earliest stage granuloma is localized to the
glomerular arterioles and IVU will be normal at this
stage although urine is positive for AFB.
ii. Spread of infection to medulla results in papillary
ulceration which produces the earliest changes
detectable radiologically. These are seen as poor
definition of minor calyx/calyces or moth-eaten
calyx. At this stage, clinically patients have either
minimal or nonspecific symptoms and therefore IVU
is usually not done and hence, these lesions are
rarely detected.
iii. In the next stage, papillary granulomas caseate, and
rupture into a collecting system, thereby, forming
a small commu-nicating cavity-single or multiple,
but usually unilateral. On IVU these are seen as
round areas with irregular shaggy walls and are
outlined by contrast at its periphery (Fig. 26.30).
iv. Infection now spreads to the uroepithelium where
fibrotic reaction is initiated. Stenosis of the
infundibulum results in proximal dilatation and
Fig. 26.30: IVU: Tuberculous kidney-note irregular, fuzzy outline in a

cavity and a noncommunicating focal mass around which superior calyx
is draping
Fig. 26.31: IVU: Tuberculous kidney-amputation of superior calyx

with caliectasis of middle calyx
360
Section 5 Diagnosis
Urinary Bladder
Mucosal irregularity occurs at an early stage but small,
contracted bladder with reduced capacity results at a later
stage.
CT Scanning
It can readily demonstrate type and distribution of
calcification, morphological changes like scars,
hydronephrosis, caliectasis, nature of dilated system (Figs
26.34 and 26.35); functional status of the kidney and lastly
extrarenal spread of infection. CT, therefore, is a very useful
imaging tool.
Fig. 26.32: IVU: Tuberculous kidney-large tuberculous cavity filled
with contrast
Ureters
Ureteric involvement is almost always asso-ciated with
ipsilateral kidney disease. On IVP one or more of the
following may be seen:
i. Stricture at single or usually multiple sites with
dilatation in between resulting in a beaded
appearance (Fig. 26.33).
ii. Stricture extending over several centimeters which
is a characteristic feature of tuberculous involvement.
iii. Pipe stem ureter occurs in advanced, end-stage
disease in adults due to the extensive mural fibrosis.
Even ureteric wall calcification may be present.
iv. Vesicoureteric junction involvement produces either
a stricture or patulous opening.
Fig. 26.34: CECT in same patient as in Figure 21.30, contrast filled

renal pelvis is seen separate from noncommunicating tuberculous
abscesses visible as low attenuating masses
Fig. 26.33: IVP: Tuberculous ureteritis-producing beaded

appearance
Fig. 26.35: CT in tuberculous kidney: NECT: Note calcified

mesenteric nodes and low attenuating focal areas in right kidney
361
Ultrasound
It can provide only part of the information avail-able on
CT. Sonography, however, is useful as a screening
modality and for carrying out inter-vention procedures,
e.g. guided aspiration of a focal mass lesion in a kidney
or nephrostomy.
ABDOMINAL TUBERCULOSIS47-51
It is not as common in children as in adults. Four clinical
presentations of abdominal tuberculosis are:
1. Gastrointestinal
2. Adenopathy
3. Peritoneal
4. Visceral
Gastrointestinal Tuberculosis
It is usually secondary to either ingestion of infected
sputum, infected milk or to hemato-genous spread from
a primary focus in the lungs. Clinical complaints include
fever, anorexia, pain abdomen, abdominal distension
and weight loss.
Plain X-ray Findings in Abdominal TB

i. Intestinal obstruction
ii. Calcified mesenteric/retroperitoneal lymph nodes
(Fig. 26.36)
iii. Enterolithsusually seen in adults
iv. A positive chest X-ray for tuberculosis
v. Associated tuberculous lesion, e.g. verteb-ral
tuberculosis, psoas abscess which may even be
calcified.
Fig. 26.36: Plain X-ray

abdomen, anteroposterior
view: Extensive mesenteric
and retroperitoneal calcified
nodes
Fig. 26.37: Barium swallow study:

Esophageal tuberculosis with a
fistulous communication with
bronchus
affect the colon, either alone or in association with ileocecal

disease.
CT Scanning
Circumferential wall thickening or more typi-cally an
asymmetric thickening of the ileocecal valve, medial wall
of the cecum and terminal ileum along with pericecal
regional lymphadenopathy is highly suggestive of
Barium Study
Barium study is the single most important investigation
to demonstrate the presence and extent of tubercular
pathology affecting the gastrointestinal tract. Although
the mural and extramural disease may be detected with
ultra-sound or CT but definite mucosal evaluation is
possible only with a good barium study.
Very rarely, tuberculous mediastinal nodes may
secondarily involve the esophagus producing narrowing
with resultant dysphagia. More uncommon in this age
group is the formation of a fistula between esophagus and
tracheobronchial tree (Fig. 26.37). Classically, the ileocecal
area is commonly involved (Fig. 26.38) which in later stages
would produce a shrunken cecum and proximal ascending
colon which are also pulled-up resulting in an alteration in
the angle of entry of terminal ileum which is also dilated.
Ulcerations/strictures in one or more areas of small bowel,
sparing the ileocecal area, are also not unknown. These
result in proximal dilatation and delay in clearance of small
bowel contrast. Uncommonly, tuberculous process may
Fig. 26.38: Barium study classical ileocecal tuberculosis extending to

involve right colon also. Marked dilatation of terminal small bowel is
seen
362
Section 5 Diagnosis
ileocecal tuberculosis on CT. Ultrasonography may also

demonstrate bowel wall thickening as a hypo-echoic halo.
Abdominal Adenopathy
It is a very common presentation of abdominal
tuberculosis either alone or along with other pathological
abnormalities. Although it is a nonspecific finding, the
clues indicating tuberculous etiology are:
i. Tendency for involvement of mesenteric and
peripancreatic lymph nodes
ii. On a contrast enhanced CT, demonstration of low
density centers with enhancing peripheral rim
(which may even give it a multilocular appearance).
Peritoneal Tuberculosis (Fig. 26.39)

It is an uncommon presentation of abdominal
tuberculosis. Etiopathological mechanism is believed to
be rupture of mesenteric lymph nodes seeded from a
primary pulmonary lesion via. hematogenous route.
Clinically there is pain, distension and fever. Although
three forms of peritoneal tuberculosis have been described:
wet-ascitic type, dry-plastic type and fibrotic-fixed
type, but there may be considerable overlap in the imaging
features. The spectrum of findings in peritoneal
tuberculosis as a whole are as follows:
i. Ascitic fluid of high density (25-45 HU on CT) which
reflects the exudative nature, with multiple fine
delicate septations and incomplete mobile fibrin
strands seen on sonography only.
ii. A disorganized appearance of soft tissue densities,
loculated ascitic fluid and matted bowel loops
forming a poorly defined mass.
Fig. 26.39: Barium meal and follow through study: Peritoneal

tuberculosis: Bowel loops show tacking indicative of adhesions
iii. Omental masses (caking).

iv. Stellate mesentery.
v. Sliced bread appearance on sonography.
vi. Low density masses surrounded by thick solid rims.
In addition, abdominal adenopathy is com-monly
seen either as low density masses or with a multilocular
appearance.
Visceral Tuberculosis
Liver, spleen and rarely pancreas may be involved with
disseminated disease. There is usually only
hepatomegaly or splenomegaly but uncommonly focal
masses may also be visible. Following healing, multiple
calcific foci may be seen in the liver and splenic
parenchyma indicative of residual sequelae.
OSTEOARTICULAR TUBERCULOSIS52-56
Overall incidence of tuberculosis of bones and joints is
approximately 4% among patients with all types of
tuberculosis. Osteoarticular tuber-culosis is always
secondary to primary focus elsewhere, usually in the chest.
Mode of spread is usually by hematogenous
dissemination.
Tuberculous Osteitis/Osteomyelitis
Involvement of Long Bones of Extremities
Typically metaphyses are the common sites of affection
usually around the hip, knee and ankle joints. On X-ray:
(i) focal destructive lesion with poorly defined edges and
regional osteoporosis is usually present (Fig. 26.40), (ii)
Fig. 26.40: X-ray, lower limb: Large oval destructive lesion in tibial
diaphysis with varying degress of sclerosis around it
363
infection may spread to rest of the bone and/or to the

neigh-boring joint. Transphyseal spread of infection is
an important feature of tuberculosis differen-tiating it
from pyogenic osteomyelitis, (iii) at times, predominant
proliferative reaction produces dense sclerotic lesion.
Tuberculosis of Short Bones of Hands and Feet

(Tuberculous Dactylitis)
Involvement of these bones is considered a disease of
childhood. It is known by the name of spina ventosa due
to the cystic, ballooned out appearance of the involved
bone (Fig. 26.41). Radiographically: (i) soft tissue
swelling, often large in size and fusiform in shape, is a
common finding; (ii) periostitis indicates the earliest
involvement of bone; this periosteal sheath at a later stage
may be very thick enveloping the cystic lesion, (iii) with
destruction of underlying bone a cyst-like cavity appears
with expansion of medullary space, (iv) sequestrum may
be formed. It is important to remember that these bone
changes indicate chronic osteomyelitis and may be
produced by many other pathological conditions, e.g.
fungal osteomyelitis.
Usually, these lesions have no evidence of new bone

formation. Ribs may be involved either by hematogenous
route or by contiguous involvement from a vertebral
lesion.
Tuberculosis of Ribs
Multifocal Tuberculosis (Cystic Tuberculosis)
Clinically it may present with or without palp-able soft

tissue swelling due to the cold abscess. On X-ray three
types of lesions are seen:
i. Expanding, cyst like lesion entirely within the rib.
ii. Destruction of lower margin of rib (Fig. 26.42).
iii. Complete destruction as seen in metastatic
malignancy.
Multiple bone involvement by tuberculous pathology is

more common in adolescents females rather than in
children. In the long bones lesions are usually diaphyseal
rather than metaphyseal in location. X-ray appearance
is similar to the solitary lesions described earlier with a
tendency to form cyst-like lesions (Figs 26.43A and B),
i.e. lesions are radiolucent, well- defined, round or oval
in shape with variable amounts of sclerosis. Lesions may
also be solitary rather than multifocal.
Fig. 26.42: X-ray, chest: Tuberculosis involving multiple ribs. Note

irregularity, undulation of inferior margin of lower right ribs
Tuberculous Arthritis
Fig. 26.41: X-ray, hand: Spina-ventosa: first and fifth metacarpals are
involve in disease process, with expansion, periosteal reaction in the
latter
It has an insidious onset. Typically it is a mono-articular

disease with preference for weight bearing joints.
Infection may initially involve either the synovium or
the bone. Radiological findings are nonspecific and at an
early stage include joint effusion with soft tissue edema
with normal appearing bones. Later, significant peri-articular osteopenia and at a still later stage characteristic
marginal erosions appear. Perio-steal reaction and
sclerosis are not the usual features of tuberculous
arthritis. Later the joint space decreases. The triad of juxtaarticular osteoporosis, marginal bony erosions and
gradual narrowing of joint space is termed Phemisters
triad and is characteristic of tuberculous arthritis.
Synovial involvement in young patients leads to
chronic hyperemia, hypertrophy of epiphyseal centers
and an early epiphyseal fusion with resultant leg-length
discrepancy. This is similar to that seen in hemophilics
or juvenile rheumatoid arthritis.
364
Section 5 Diagnosis
Fig. 26.44: Tuberculosis of hip joint ankylosis of hip joint with suggestion
of intrapelvic abscess as reflected by bladder displacement
Tuberculosis of Sacroiliac (SI) Joint

It has a characteristic appearance: (i) in the early stage
haziness and loss of definition of joint margins occur; (ii)
later, the articular surface is eroded (iii) following healing,
sclerosis with decreased joint space occurs; but (iv) if the
disease progresses then destruction and later ankylosis
result.
Tuberculosis of the Spine: Tuberculous Spondylitis

(Potts Disease)
Figs 26.43A and B: Multifocal tuberculosis (A) X-ray forearm bones

show extensive lytic lesions involving both forearm bones. (B) X-ray
anteroposterior view of pelvis shows lytic lesion in left iliac bone
Tuberculosis of Hip Joint

It is the most common lesion after spinal involvement
and shows the following features:
i. Earliest change is atrophy of muscular tissue and
bones about the joint seen as decreased soft tissue
mass and rarefaction of bones.
ii. Joint space usually decreases but it may increase if
effusion develops. In the later instance fat planes
about the joint are displaced laterally.
iii. Bony contours become hazy and indistinct.
iv. In the late stage (Fig. 26.44) joint destruction, bony
ankylosis and interference with growth occurs.
It may manifest during early stages of primary

pulmonary infection or years later after the primary
infection has subsided. Either a single (uncommon) or
multiple vertebrae may be affected and in the latter
instance involvement may be contiguous or at multiple
levels. It is more common in the thoracic and lumbar
spine. Bone lesions may either be destructive or
proliferative (sclerotic). Primarily tuberculosis commonly
involves the body of a vertebra and rarely its appendages.
The X-ray appearances are:
i. Destructive changes usually appear first in the upper
and lower margins of the vertebral bodies
(commonly in the anterior part of the body). Usually
the destructive focus is associated with sclerosis at
the periphery. Tuberculous focus completely
localized within the vertebral body may be difficult
to differentiate from lesions of pyogenic or fungal
infections.
ii. Next, the intervertebral space is narrowed or
obliterated due to the contiguous spread of infection.
iii. Compression-collapse of vertebra ensues with
formation of gibbus (Fig. 26.45) and paraspinal
abscess (Fig. 26.46). The combi-nation of vertebral
body destruction, decreased disc space and
365
Role of CT and MRI in Tuberculous Spondylitis

Both CT and MRI are highly sensitive, providing much more
information than plain radiographs, information, which is
not only important for clinical management but also for
follow-up of the patient. CT is comparatively cheaper,
faster especially with helical CT and is the preferred
modality for assessment of osteomyelitis, sequestrum and
for interventional procedures. MRI has higher contrast
resolution, multiplanar imaging capability, ability to detect
marrow infiltration and ready assessment of extradural
disease but it lacks the excellent bony details possible with
CT.
CT of Vertebral Tuberculosis
Fig. 26.45: X-ray, vertebrae: Tuberculosis of the vertebra collapse of

vertebral body, decreased disc space and gibbus formation
Bone destruction with fragmentation is the most common

type of lesion. Bone fragments may extend into the
paravertebral soft tissue mass or into the spinal canal.
Associated soft tissue masses (Figs 26.47A and B) may
extend much beyond the site of destruction, they may
calcify and after intravenous contrast may show
enhancement either diffuse or typical of an abscess, i.e.
rim enhancement. Disc narrowing and multilevel
involvement are also readily visualized on CT. After
successful treatment the vertebral bone density increases
and the size of paravertebral soft tissue masses decreases.
Fig. 26.46: X-ray, vertebrae: Spinal tuberculosis: bilateral paraspinal

abscess in an anteroposterior spine X-ray
iv.
v.
vi.
vii.
formation of paravertebral abscess is highly

suggestive of tuberculosis in Indian settings though
some other conditions can also produce similar
picture.
Paraspinal abscesses may later calcify.
Paraspinal abscess may run along the anterior
surfaces of vertebrae and may cause erosion of
multiple contiguous vertebrae.
Rarely, osteoblastic changes may predomi-nate.
In late stagefused vertebrae, kyphosis and
osteoporosis occur.
Figs 26.47A and B: Para- and prevertebral abscess (A) Plain X-ray
and barium swallow (B) CT: shows large abscess as well as underlying
bony changes
366
Section 5 Diagnosis
MRI of Vertebral Tuberculosis

T1WI, T2WI and postcontrast enhancement images in
axial, sagittal and coronal planes are usually carried out.
T1WI Typically shows decreased signal within the
affected vertebral marrow as normal fat is replaced by
inflammatory fluid. Later, disc height is reduced,
paravertebral soft tissue masses and loss of uniform psoas
muscle signal intensity are seen and extradural mass with
compression of thecal sac may be evident.
T2WI It demonstrates a relative increase in signal
intensity in the affected areas. On post-contrast MRI
characteristic rim enhancement of the abscesses is seen.
HIGHLIGHTS
Tuberculosis can involve almost any organ system in
the pediatric age group.
Pulmonary tuberculosis
There are changes in imaging modalities for
practically every organ. To start with in pulmonary
TB, a cautious use of CT chest has been highlighted
in a few selected patients with difficulty in diagnosis
on plain X-ray chest.
Magnetic resonance imaging also has a place but
only in cases with difficulty in diagnosis of lymph
node mass in the mediastinum.
Both diagnostic and therapeutic image-guided
interventions may be required in thoracic TB
occasionally. These include FNAC or tru-cut biopsy
of mediastinal nodes in equivocal cases.
Image guided drainage of pleural collections may
be performed especially in loculated effusions.
Intracranial tuberculosis
On non-contrast CT-exudates are visible as either
isoattenuating or minimally hyperattenuating is a
most specific signs of TBM.
Contrast enhanced CT shows abnormal meningeal
enhancement with enhancing exudates at the basal
cisterns.
Magnetic resonant imaging (MRI) is more sensitive
than CT but because of its high cost, it is reserved
for problem cases only. Advanced MRS, i.e.
magnetic
resonance
spectroscopy
and
magnetization transfer images have been shown to
be helpful to in detecting small tuberculosis.
Urinary tract tuberculosis, the following modalities
are in use:
Plain X-ray abdomen
Intravenous pyelography
CT scanning
Ultrasound
Abdominal tuberculosis
Plain X-ray
Barium study
CT scanning
Osteoarticular TB
CT, MRI, and MRS are investigations of choice.
REFERENCES
1. Guidance for national tuberculosis programs on the
management of tuberculosis in children: World Health
Organization available: WHO/HTM/TB/2006.371.
1a. Agrons G, Markowitz R, Kramer S. Pulmonary
Tuberculosis in children. Seminars in Roentgenology
1993; 28:158-72.
2. Schulger NW, Harkin TJ. In: Sahn SA, Heffner JE (Eds):
Tuberculosis Pearls. Philadelphia: Mosby. 1955;17-85.
3. Fraser RG, Pare JA, Fraser RS, et al. In: Diagnosis of
Diseases of the Chest. Vol II, 3rd edn. Philadelphia: W B
Saunders Co. 1989;882-933.
4. Leung AN. Pulmonary Tuberculosis: The essentials.
Radiology 1999;210:307-22.
5. Kim OH, Kim WS, Kim MJ, et al. US in the Diagnosis of
Pediatric Chest Diseases Radiographics 2000; 20:653-71.
tomography with a normal chest radiograph in
tuberculous infection. Arch Dis Child 1993;69:430-2.
7. Andronikou S, Joseph E, Lucas S, et al. CT scanning for
the detection of tuberculous mediastinal and hilar
adenopathy. Pediatr Radiol 2004;33:232-6.
8. Gupta R, Gupta AK, Seith A, et al. Chest Tuberculosis in
children: CT findings in active and post-treatment cases.
Unpublished data, AIIMS, New Delhi, 2003-06.
9. Mukhopadhyaya S, Gupta AK, Seith Ashu. Imaging of
Tuberculosis in children in Essentials of Tuberculosis
in children 3rd edn. In Seth Vimlesh, Kabra SK. (Eds)
Jaypee Brothers Medical Publisher (P) Ltd. New Delhi
2006;375-404.
10. Weber AL, Bird KT, Janower ML. Primary tuberculosis in
childhood with particular emphasis on changes affecting
the tracheobronchial tree. Am J Roentgenol 1968;103:12332.
11. Stansberry SD. Tuberculosis in infants and children. J
Thorac Imag 1990; 5:17-27.
12. Solomon A, Rabinowitz L. Primary cavitating tuberculosis in childhood. Clin Radiol 1972;23:483-5.
13. Leung AN, Muller NL, Pineda PR, et al. Primary
tuberculosis in childhood: Radiographic manifestations
1992;182:87-91.
14. Woodering JW, Vandiviere HM, Fried AM, et al. Update:
The radiographic features of pulmonary tuberculosis. Am
J Roetgenol 1986;148:497-506.
15. Stead WW, Kerby GR, Sehlueter DP, et al. The clinical
spectrum of primary tuberculosis in adults. Ann Intern
Med 1968;68:731-45.
16. Starke JR, Taylor Watts KT. Tuberculosis in the pediatric
population of Houston, Texas. Pediatrics 1989;84:28-35.
17. McAdams HP, Erasmus J, Winter JA. Radiologic
manifestations of pulmonary tuberculosis. Radiol Clin
North Am 1995;33:655-78.
18. Buxi TBS, Sud S, Vohra R. CT and MRI in the diagnosis
of tuberculosis. Indian J of Paediatr ie 2002;69:965-72.
19. Palmer PES. Pulmonary tuberculosis usual and unusual
radigraphic presentations. Semin Roentgenol
1979;14:204-42.
20. Dannenberg AM. Pathogenesis of pulmonary
tuberculosis. Am Rev Respir Dis 1982;125:25-30.
21. Seith A, Mukhopadhyaya S. Pediatric chest: medical
conditions. In: Diagnostic Radiology Pediatric Imaging, 2nd
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
Ed. Jaypee Brothers Medical Publishers (P) Ltd. New Delhi:

2004;16-40.
Lamont AC, Cremin BJ, Pelteret RM. Radiological patterns
of pulmonary tuberculosis in pediatric age group. Pediatr
Radiol 1986;16:2-7.
Giammona ST, Poole CA, Zelkowitz P, et al. Massive
lymphadenopathy in primary pulmonary tuberculosis
in children. Am Rev Resp Dis 1969;10:480.
Amorosa JK, Smith PR, Cohen JR, et al. Tuberculous
mediastinal lymphadenitis in the adult. Radiology
1978;126:365-8.
Liu C, Fields WR, Shaw C. Tuberculous mediastinal
lymphadenopathy in adults. Radiology 1978;126:369-71.
Leung AN. Pulmonary Tuberculosis. The Essentials of
Radiology 1999;210:307-22.
Pombo F, Rodriguez E, Mato J, et al. Patterns of contrast
enhancement of tuberculous lymph nodes demonstrated
by computed tomography. Clin Radiol 1992;46:13-7.
Jug-Gi-IM, Song KS, Kang HS, et al. Mediastinal
tuberculous lymphadenitis. CT manifestations.
Radiology 1987;164:115-9.
Kim WS, Moon WK, Kim IO, et al. Pulmonary
tuberculosis in children: Evaluation with CT. Amer J
Radiol 1997;168:1005-9.
Dyck PV, Vanhoenacker, Brande PVD, et al. Imaging of
pulmonary tuberculosis. Eur Radiol 2003;13:1771-85.
Kuhn JP. Primary pulmonry tuberculosis. In Cafey J (Ed):
Pediatric X-ray Diagnosis, vol, 2, 8th edn. Chicago, Year
Book Medical Publishers Inc, 1985;1210-27.
Moon WK, Im JG, Yeon KM, et al. Mediastinal
tuberculous lymphadenopathy: CT findings of active and
inactive disease. Amer J Radiol 1996;170:715-8.
Andronikou S, Smith B, Hatherhill DH, et al. Definitive
neuroradiological diagnostic features of tuberculous
meningitis in children. Pediatr Radiol 2004;34:876-85.
Bhargava S, Gupta AK, Tandon PN. Tuberculous
meningitisa CT study. Br J Radiol 1982;55:189-92.
Jenkins JR. CT of intracranial tuberculosis.
Neuroradiology 1991;33:126-35.
Bhargava S, Tandon PN. Intracranial tuberculo-mas. A
CT study. Br J Radiol 1980;53:935-45.
Gupta RK, Jena A, Sharma A, et al. MR imaging of
intracranial tuberculomas. J Comput Assist Tomography
1988;12:280-5.
Gupta RK, Roy R, Dev R, et al. Finger printing of
Mycobacterium tuberculosis in patients with intracranial
tuberculomas by using in vivo, ex vivo, and in vitro
magnetic resonance spectroscopy. Magn Reson Med
367
1996;36:829-33.
39. Gupta RK, Kathuria MK, Pradhan S. Magnetization
transfer MR imaging in CNS tuberculosis. Am J
Neuroradiol. 1999;20:867-75.
40. Aaronson IA. Urogenital Tuberculosis in children. S Afr
Med J 1987;71:424.
41. Becker JA. Renal tuberculosis. Urol Radiol 1988;10:25.
42. Prem Kumar A, Lattimer J, Newhouse JH. CT and
Sonography of advanced urinary tract tuberculo-sis. Am
J Roentgenol 1987;148:65-9.
43. Merchant SA. Tuberculosis of the genitourinary system.
In: Subbarao K, Banerjee S, Aggarwal SK, Bhargava SK
(Eds). Diagnostic Radiology and Imaging, New Delhi:
Jaypee Brothers Medical Publishers (P) Ltd., 1997;1:61946.
44. Ehrlich RM, Lattimer JK. Urogenital tuberculosis in
children. J Urol 1971;105:461-5.
45. Pastemack MS, Rubin RH. Urinary tract tuberculosis. In
Schrier RW, Gottschalk CW (Eds): Diseases of the kidney,
4th edn. Boston: Little Brown and Company, 1988;9931014.
46. Cremin BJ. Radiological imaging of urogenital
tuberculosis in children with emphasis on ultrasound.
Pediatr Radiol 1987;17:34-8.
47. Extrathoracic tuberculosis. In: Semin Roentgenol
1979;14(No.4).
48. Carrera GF, Young S, Lewicki AM. Intestinal
tuberculosis. Gastrointest Radiol 1977;1:147-55.
49. Gupta SK, Pandey RP. Radiologic diagnosis of
gastrointestinal tuberculosis. Indian J Radiol Imaging
1971;25:236-46.
50. Negi B, Duggal R, Gupta R, Mehta S. Tuberculous
peritonitis in children. Pediatr Radiol 1987;17:282-4.
51. Ozkon, Gurses N. Ultrasonic appearance of tubercu-lous
peritonitis. J Clin Ultrasound 1987;15:350-2.
52. Versfeld GA, Solomon A. A diagnostic approach to
tuberculosis of bones and joints. J Bone Joint Surg
1982;64B:446-9.
53. Desai SS. Early diagnosis of spinal tuberculosis by MRI.
J Bone Joint Surg 1994;76B:863-9.
54. Smith AS, Weinstein MA, Mizushima A, et al. MR
imaging characteristics of tuberculous spondylitis vs
vertebral osteomyelitis. AJNR 1989;10:619-25.
55. Whelan MA, Naidich DP, Post ill, et al. CT of spinal
tuberculosis, J Comput Assist Tomography 1983;7:25.
56. Silverman FN. Tuberculosis of bones. In: Pediatric X-ray
diagnosis, 8th edn. Chicago: Year Book Medical Publishers
Inc, 1985;319-21, and 831-4.
27
Pathologic Spectrum
Sandeep R Mathur, Kusum Verma
PATHOLOGIC SPECTRUM OF
Tuberculosis has continued to be a major cause of
morbidity and mortality in children all over the world,
especially in the developing countries.1 In recent years,
worldwide resurgence of pediatric tuberculosis is being
witnessed due to many factors like HIV epidemic,
emergence of drug resistance and inadequate public
health infrastructure in developing countries. However,
the disease is often underdiagnosed, misdiag-nosed or
even overtreated because of presence of nonspecific
clinical manifestations and diagnostic problems. Delay
in diagnosis of tuberculosis leads to prolonged morbidity
and mortality.
Tuberculosis can involve any organ in the body
although lung, lymph nodes and meninges are the
common sites of involvement in children. Disease may
be a manifestation of primary infection or reinfection.
Hallmark of tuberculosis is a granulomatous inflammation.
However, granulomas can be seen in a number of
nontuberculous conditions and it is thus important to
have a clear understanding of the term granuloma and
their different types.
Fig. 27.1: A typical epithelioid cell granuloma seen in histologic section

comprising of epithelioid cells, lymphocytes, Langhans giant cell and
necrosis (For color version see Plate 7)
Granuloma
It is a compact (organized) collection of mature
mononuclear phagocytes (macrophages and/or
epithelioid cells) which may or may not be accompanied
by accessory features such as necrosis or the infiltration
of other inflammatory leukocytes.2 Granulomas can be
necrotizing, nonnecrotizing or a combination of both.
Necrotizing granulomas: Granulomas of this type most
commonly occur in tuberculosis, but may also be seen in
fungal infections, Wegeners granulomatosis, rheumatoid
arthritis, and even sometimes in sarcoidosis.
Nonnecrotizing granulomas: These are typically seen in
noninfectious conditions like sarcoidosis, berylliosis,
foreign body reactions, drug reactions, hypersensitivity
pneumonitis, tuberculoid leprosy and Crohns disease.
Presence of nonnecrotizing granulomas does not rule out
tuberculosis.
Immune granulomas: These occur as a result of immune
T-cell mediated reactions. Immune granulomas, the
prototype of which is tuberculosis, generally show a
prominent lymphocytic component.
Nonimmune granulomas: They occur as a response to a
persistent, nondegradable organism or product. These
Fig. 27.2: Epithelioid cells with elongated slipper shaped, vesicular

nuclei seen in a FNAC smear (For color version see Plate 7)
Chapter 27 Pathologic Spectrum
Fig. 27.3: Confluent granulomas in histologic sections showing

large areas of necrosis (For color version see Plate 7)
usually lack the lymphocytic response and show

prominent numbers of foreign body type of giant cells.
Epithelioid cell granulomas: These are organized
collection of epithelioid macrophages surrounded by a
collar of mononuclear cells, mainly lymphocytes and
rarely plasma cells (Fig. 27.1). Epithelioid cells are
modified macrophages with elongated slipper shaped,
vesicular nuclei and abundant pale eosinophilic
cytoplasm with ill-defined margins (Fig. 27.2). Epithelioid
cells may fuse to form giant cells.
Granulomas in Tuberculosis
Epithelioid cell granulomas are classically seen in
tuberculosis. Two types of giant cells are encountered in
tuberculosis, the Langhans giant cells (Fig. 27.1) where
nuclei are arranged in a horse-shoe pattern at the
periphery of the cytoplasm and the foreign-body type of
giant cell where nuclei do not show any specific pattern
of arrangement. In histological sections the granulomas
may appear discrete or they may appear to coalesce
forming confluent granulomas. Presence of necrosis
is commonly seen in the center of these granulomas when
it is called as necrotizing granulomatous inflam-mation
(Fig. 27.3).
The term caseous, meaning cheese-like has often
been loosely applied to the structure-less necrosis seen
in tuberculosis, although this is strictly a terminology for
the naked eye/gross appearance of necrosis encountered
in tuberculosis. The caseous necrosis results from the
exuberant killing of infected macrophages presenting
mycobacterial antigen by Mycobacterium tuberculosis
specific cytotoxic T lymphocytes along with the damage
to surrounding tissues by the hydrolytic proteases and
lipases released by activated macrophages and other
dying host cells. 3 Presence of confluent necrotizing
epithelioid cell granulomas is the hallmark of tuberculosis.
369
Tuberculous lesions can also be broadly classified

as exudative and proliferative lesions. Exudative
lesions (soft granulomas), comprise of polymorphs,
lymphocytes, macrophages and epithelioid cells
arranged loosely, with an insignificant fibroblastic
response. Acid fast bacilli (AFB) are easier to find in
such lesions. Proliferative lesions (hard granulomas) have
a more organized collection of epithelioid histiocytes,
with lymphocytic rimming, fibrosis, and more
Langhans giant cells. AFBs are more difficult to
demonstrate in these lesions. Ultimately the entire
granuloma or necrotic focus undergoes fibrosis,
calcification or even necrosis.
It is not always possible to pinpoint the exact etiology
of a granulomatous lesion on histology. An accurate or
definitive diagnosis of tuberculosis would perhaps only
be possible in the event of demonstration of acid-fast
bacilli using special stain. In endemic areas presences of
necrotizing epithelioid cell granulomas with or without
giant cells, even in the absence of acid fast bacilli are
highly suggestive of tuberculosis. A histological
diagnosis of tuberculosis is often made in the presence
of this morphological scenario, if the clinical picture is
not contradictory. In all other situations a definitive
diagnosis of tuberculosis would perhaps not be possible,
although it is well known that the commonest cause of
granulomatous inflammation in our country is still
tuberculosis and other causes of granulomatous
inflammation like sarcoidosis, etc. are rare in the pediatric
age group.
Pathologic Diagnosis
Various samples helpful in rendering histopathologic/
cytologic diagnosis of pulmonary or extrapulmonary
tuberculosis in pediatric age group are as given in the
Table 27.1.
Cytological Criteria for Diagnosis of Tuberculosis

Histologic diagnosis of tuberculosis is based on
granuloma as detailed earlier. A cytologic diagnosis of
tuberculosis can be rendered on FNAC from various
body sites or a number of cytologic specimens like
bronchoalveolar lavage, pleural fluid, pericardial fluid,
cerebrospinal fluid, etc. A definitive diagnosis on FNAC
specimens is by identification of epithelioid cell
granulomas, necrosis and AFB. However, a spectrum of
morphological changes are seen in FNAC smears of
tuberculous lesions. These may be classified into five
groups according to the combination of each of the
morphologic features4 (Figs 27.4 to 27.8).
Group Iepithelioid granulomas with necrosis with or
without giant cells.
Group IIepithelioid cell granulomas only.
370
Section 5 Diagnosis
Table 27.1: Samples helpful for histopathologic or cytologic diagnosis of pulmonary
or extrapulmonary tuberculosis in pediatric age group
Site of lesion
Histopathologic assessment
Pulmonary
Transbronchial lung biopsy

Transthoracic lung biopsy
Lymph node
Biopsy
CNS
Biopsy
Pleura/pericardium/
peritoneum
GIT
Biopsy
Endoscopic biopsy
Liver
Biopsy
Genitourinary
Biopsy
Bone and joint
Biopsy
Cold-abscess
Microbiologic assessment
(culture)
Sputum (induced)
Gastric lavage
Transbronchial aspirate
Bronchoalveolar lavage
Biopsy
FNAC
Biopsy
CSF
Biopsy
Effusion fluid
Biopsy
Biopsy
FNAC
Biopsy
FNAC
Biopsy
FNAC
FNAC
Cytopathologic
assessment
Bronchoalveolar lavage
Transbronchial FNAC
Transthoracic FNAC
FNAC
CSF
Guided FNAC
Squash cytology
Effusion cytology
FNAC (in case of a mass)

FNAC
FNAC
Urine cytology
FNAC
FNAC
FNAC: fine needle aspiration cytology
Group IIIgranular necrotic material only.

Group IVacute inflammatory exudate with focal
granulomas.
Group Vacute inflammatory exudate only.
A morphological diagnosis of tuberculosis can only
be confidently rendered in group I smears, i.e. cases
showing epithelioid cell granulomas with necrosis. These
account for approximately 60 to 70% of cases. In all other
combination of morphological patterns, a definitive
diagnosis of tuberculosis can only be made in the event of
demonstration of AFB in the smears using special stains.
Fig. 27.5A: Smear showing epithelioid cell granulomas only (group
II) as seen on Papanicolaou stain (For color version see Plate 7)
Fig. 27.4: FNAC smear depicting classical picture of epithelioid cell

granuloma with necrosis (group I) (For color version see Plate 7)
Fig. 27.5B: Epithelioid cell granulomas as seen in May-Grunwald

Giemsa stained preparation (For color version see Plate 7)
Fig. 27.6: FNAC smears may at times yield only necrotic material
(group III) (For color version see Plate 8)
Fig. 27.8: Aspirates in tuberculosis may at times yield an acute

inflammatory exudate only (group V) (For color version see Plate 8)
Table 27.2 summarizes the cytomorphological spectrums

and the AFB positivity in smears from tuberculous
lesions.5-10
Smears may at times reveal only an acute inflammatory
exudate and be misinterpreted as a pyogenic abscess if
special stains for AFB are not performed. This is especially
relevant in AIDS and other immunosuppressed
conditions. A meticulous search for acid fast bacilli is very
important in all such smears.
Cytomorphologic diagnosis is difficult in exfoliative
cytology specimens like sputum, bronchoalveolar lavage,
urine, etc. Epithelioid cell collections forming ill-defined
granulomas are rarely encountered. Tubercular pleural
and peritoneal effusions are exudative in nature and
show large numbers of lymphocytes with paucity of
mesothelial cells. This appearance is, however, not
diagnostic as maybe seen in viral infections also.
371
Fig. 27.7: Smear showing an acute inflammatory exudate

with granuloma (group IV) (For color version see Plate 8)
Table 27.2: Cytomorphological spectrum and AFB

positivity in FNAC smears of tuberculous lesions
Cytologic
Authors
Positivity
% Spectrum
(ZN stain)
Group I
Necrosis and
Bezabih et al5
61.9
14.3
granulomas
Kumar et al6
31.9
Das et al7
19.1
Prasoon8
Group II
20.0
Epithelioid cell
Bezabih et al5
01.9
granulomas
Prasoon8
Group III
69.7
Necrosis only
Bezabih et al5
26.2
Kumar et al6
Das et al7
36.6
17.8
Radhika et al9
Group IV
47.5
Acute inflamKumar et al6
matory exudate
with focal
granulomas
Group V
35.8
Acute inflamKumar et al6
matory exudate
only
59.4
All Cases
Bezabih et al5
Handa U10
37.4
23.6
Radhika et al9
33.5
Kumar et al6
Demonstration of Acid Fast Bacilli

As per the new guidelines in the Consensus Statement
on Childhood Tuberculosis published by the Working
Group on Tuberculosis, Indian Academy of Pediatrics,
every attempt must be made to demonstrate acid fast
bacilli before arriving at a diagnosis of tuberculosis.11
Some studies have reported as high as 33% bacteriological
372
Section 5 Diagnosis
Fig. 27.9A: Smear from neck swelling in an immunocompromised

patient showing numerous foamy macrophages in a necrotic background
Fig. 27.9B: AFB stained smear of the same patient showing

macrophages packed with tubercle bacilli (For color version see
Plate 8)
positivity even in primary disease such as hilar

adenopathy.12, 13
Acid-fastness is regarded as the hallmark of
mycobacteria. It is due to the ability to form stable
mycolate complexes with certain aryl methane dyes like
carbol-fuchsin, crystal violet, auramine-rhodamine,
which are not removed even by rinsing with 95% ethanol
plus hydrochloric acid. The bacilli appear red with carbolfuchsin (ZN stain), purple with crystal violet and exhibit
yellow-green fluorescence under ultraviolet light (AR
stain). ZN stain and AR stains can be used to demonstrate
AFB in both FNAC smears as well as tissue sections. But
the detection rate of AFB positivity in tissue sections is
much lower than that observed in smears possibly as a
result of the damage to mycobacterial cell wall during
the rigorous processing of tissue. Fluorescent microscopy
with auramine-rhodamine stain is superior to ZN stain
when the bacterial load is low as the AFB are readily
seen as yellowish-green beaded rod-like structures
against a dark background. The overall AFB positivity is
lower using ZN stain alone and higher positivity rates
are reported using a combination of ZN and AR stains.
AFB positivity is also higher in group IV and V (Table
27.2) where a diagnosis of tuberculosis on morphology
alone would be impossible. Three consecutive specimens
of gastric aspirate obtained in the early morning by a
nasogastric tube are useful to detect AFB in children.14,15
In the context of atypical mycobacterial infection in
immunocompromised host a peculiar pattern may be
seen. The smear or section shows numerous foamy
macrophages with pale blue cytoplasm in a necrotic background (Fig. 27.9A). ZN staining will demonstrate
numerous AFB inside these macrophages (Fig. 23.9B).
Conversely when such a picture is encountered in
sections or smears, the clinician must be cautioned to
investigate the patient for an immunocompromised state
and also perform culture studies.
Mycobacterial Culture of Biopsy on FNA Material

Material for culture studies can be conveniently collected
at the same setting as the FNAC procedure and is very
useful in situation of multidrug resistant tuberculosis
(MDR-TB) to determine drug sensitivity. Because of
the delay (4 to 6 weeks) in growing mycobacteria,
culture studies are generally restricted to situations of
drug resistant forms of tuberculosis. Nataraj
et al16 isolated mycobacteria on culture of FNA material
in 82.6% of cases where tuberculosis was also diagnosed
cytomorphologically. In addition they picked up
mycobacteria in 28 cases on culture which were
undetected on cytological screening. Radhika et al9
reported an overall rate of isolation of mycobacteria on
culture from FNA material as 35%, while their overall
AFB positivity in smears was 23.58%. Atypical mycobacteria can also be readily identified on culture. The
BACTEK system utilizes radiolabelled compounds in
liquid media and radiometrically detects release of CO2
by the growing AFB. This may reduce the average
reporting time to 1 to 2 weeks as opposed to 6 to 8 weeks
with conventional culture.
Polymerase Chain Reaction in Diagnosis of Tuberculosis

Molecular diagnostic methods like polymerase chain
reaction (PCR), uses amplification of the DNA sequences
of mycobacteria to detect tuberculosis. This is especially
useful in problem situations where the bacillary load is
low or it is difficult to detect evidence of tuberculosis on
morphology or special stains.
Gong et al17 performed nested PCR for diagnosis of
tuberculosis in material obtained by FNAC of tuberculous
lymphadenitis and compared it with conventional ZN
staining. They reported 77.8% detection rate with PCR as
compared to 39.7% by ZN staining and concluded that
PCR is more sensitive for detection of Mycobacterium
tuberculosis in FNAC than ZN stain. Baeck et al18 reported

a detection rate of 76.4% using PCR on material obtained
by FNAC of cervical tubercular lymphadenitis. In a pilot
study by Singh et al19 the sensitivity of PCR on tissues
from biopsies (68%) was not significantly higher when
compared to that on material obtained by FNAC (55%).
Shankar et al20 used PCR in the rapid diagnosis of TB
meningitis and found it to be far more sensitive than ELISA
and conventional culture.
One of the important drawbacks of PCR is the false
positivity due to contaminants from the environment.
PCR may serve as a useful adjunct but not a replacement
for the conventional methods for a reliable diagnosis of
tuberculosis.
SPECTRUM OF MORPHOLOGIC CHANGES

Primary Pulmonary Tuberculosis
Lung is the portal of entry of tubercular bacilli in 95% of
cases in children. An incubation period of around 4 to 8
weeks is required between the time the bacilli enter the
body and the development of cutaneous hypersensitivity.
Around this time there maybe a febrile reaction and the
primary complex may become visible on chest X-ray.
Primary complex, also termed as Ghons complex is
constituted by a parenchymal, often subpleural focus of
consolidation (Ghons focus), the draining lymphatics,
and the enlarged draining in hilar lymph nodes. The hilar
lymph nodes are generally much larger than the
parenchymal lesion and are seen in vast majority of
children with primary tuberculosis.21 The parenchymal
portion of the primary complex undergoes caseous
necrosis and encapsulation and most often heals by
fibrosis and calcification. In the event of intensive
caseation, the center of the lesion may liquify and empty
into associated bronchus leaving a residual cavity or there
may be spread of bacilli from the primary focus via the
blood stream and lymphatics to other foci. The liver,
spleen, lung apices, meninges, lymph nodes, peritoneum
and bones are the common sites of dissemination. These
metastatic foci maybe clinically asymptomatic or maybe
the origin of both extrapulmonary tuberculosis and
reactivation tuberculosis later in some children.
Tubercular bacilli may remain viable for decades in
the hilar lymph nodes even after development of fibrosis
and calcification in the nodes. At times the hilar and
paratracheal lymph nodes may enlarge and cause external
compression of the regional bronchus, leading to either
hyperinflation (partial obstruction) or atelactasis
(complete obstruction) of the lung segment. Epituberculosis
or collapseconsolidation or segmental tuberculosis is the
radiologic term used to describe the combination of
pneumonia and atelactasis which results when in
373
addition to causing compression and atelactasis, an

inflamed caseous lymph node erodes through a bronchus
and transmits infection to the lung parenchyma.
Commonest site is the anterior segment of the upper lobe
or the medial segment of the middle lobe.22
Progressive Pulmonary Tuberculosis

The primary focus at times may enlarge with the
development of a large caseous center. Although rare, it is
a serious complication resulting in development of a thin
walled cavity with a large caseous center and numerous
tubercle bacilli. This cyst may rupture into adjacent
bronchus or pleural cavity leading to intrapulmonary
dissemination or pyopneumothorax. Significant signs and
symptoms usually accompany this lesion.
Chronic Pulmonary Disease

It is similar to the adult or reactivation type of
tuberculosis. This presumably is thought to be due to
the endogenous reactivation of previous site of
tuberculous infection. This form of tuberculosis is
extremely uncommon in children. It is more common in
children who acquire the initial infection after 7 years of
age.23 Common sites are the original parenchymal focus,
the regional lymph nodes or the apical seeding (Simons
focus). This form usually remains localized to the lungs.
Lymphohematogenous Dissemination
or Early Generalization
It appears that in all cases there is early lymphohematogenous dissemination from the caseous center of
the primary complex.24,25 This hematogenous dissemination may or may not be symptomatic depending upon
the quantity of the organisms. Many organs may thus be
seeded during this process, and may be the source of
reactivation tuberculosis.26
Miliary Tuberculosis
This form of tuberculosis arises when very large number
of bacilli are released into the blood stream, resulting in
simultaneous disease in multiple organs. It is more
common in infants and younger children.26,27 This may
occur as a result of erosion of the wall of blood vessel
by a caseous focus. Malnutrition, malignancy or
immunosuppressed status may predispose to this
condition.
Hepatosplenomegaly and generalized lymphadenopathy occur in 20 to 30% of cases. Although chest X-ray
may be normal initially, they show numerous tubercles
over a course of 3 to 4 weeks in majority of cases. Miliary
tubercles maybe seen in organs like kidney, intestine,
fallopian tubes, epididymis, prostate, adrenals, bone,
374
Section 5 Diagnosis
meninges, brain, lymph nodes, etc. Cutaneous

papulonecrotic tuberculids may appear in crops. Culture
confirmation is more difficult and a liver or bonemarrow
biopsy maybe needed for diagnosis.28
Classical findings include, multiple, 1 to 2 mm sized,
discrete nodules, grayish on cut surface. Some of the
older lesions may have a caseous appearance on cut
surface. Microscopically they resemble the classical
granulomatous lesion of tuberculosis, with or without
caseous necrosis.
This is a consequence of the reactivation of the foci that
were seeded during lymphohematogenous dissemination
of the tubercle bacilli. Tuberculous lymphadenitis is the
most common form of extrapulmonary tuberculosis in
children followed by tuberculous meningitis. Skeletal,
abdominal and genitourinary tract tuberculosis are very
uncommon in children and adolescent.29
Lymph Node Tuberculosis (Scrofula)

This is the commonest form of extrapulmonary tuberculosis.
It is estimated that up to 22% of children with persistent
cervical lymphadenopathy and no obvious local factor may
have tuberculous adenitis.30 They commonly present as
painless lymphadenopathy, most often in the cervical region
although other lymph node groups may also be affected.
Tonsillar and submandibular group of lymph nodes are
the commonest superficial lymph nodes affected,
possibly as a result of spread from the tonsils. However,
it is now believed that it may also be due to extension
from paratracheal lymph nodes. The hilar and
paratracheal group of lymph nodes are always involved
in primary pulmonary tuberculosis or in cases of
reactivation of previous infection. In adolescent and
young adults the onset of lymphadenopathy may herald
the reactivation of tuberculous infection. The lymph
nodes may be multiple, discrete to begin with and later
become matted together as a result of periadenitis. The
consistency may vary from firm to soft or cystic
depending upon the presence of necrosis and abscess
formation. The lymph nodes forming an abscess can
perforate the deep fascia and present as a fluctuant
subcutaneous swelling (collar-stud abscess). Lymph node
abscess may burst giving rise to discharging sinus and
ulcer formation. Jones and Campbell have described 5
stages of lymph node tuberculosis.31
Stage 1enlarged, firm, mobile, discreet nodes
Stage 2large, rubbery nodes, fixed to surrounding
tissues due to periadenitis
Stage 3central softening due to abscess formation
Stage 4collar-stud abscess formation
Stage 5sinus tract formation.
BCG Adenitis
In children receiving BCG vaccination the usual reaction
is that of induration followed by ulceration and regional
lymphadenopathy, with healing of all these lesions in
due course of time. At times lymphadenopathy may
persist and needs to be distinguished from tuberculosis.
Gupta et al 32 found that granulomas in a reactive
background are rare in BCG adenitis as compared to
tuberculosis. AFB positivity (76.8%) was found to be more
common in BCG adenitis, when compared to tuberculous
lymphadenitis. In a recent study the incidence of BCG
adenitis was found to be 0.1% in children vaccinated.33
Pleural Tuberculosis
This is categorized as an extrapulmonary form of
tuberculosis. Pleural effusion is very uncommon in
children less than 6 years of age and is encountered in 2 to
38% of children with pulmonary disease. It may be the
only radiologic manifestation of primary pulmonary
tuberculosis in 38 to 63% of cases.21 Few reports have
emphasized upon the utility of pleural fluid adenosine
deaminase (ADA) levels in the diagnosis of tuberculosis.34,35 In one study the sensitivity of this test for
values >40 U/L approached 90%.36 Utility of pleural fluid
interferon levels for diagnosis of tuberculosis has also
been demonstrated in some studies. 37 Tubercular
effusions classically show a marked preponderance of
lymphocytes on cytological examination. Acid fast stains
usually fail to demonstrate the bacilli and culture
positivity rates are also low. Hence the diagnosis of tuberculous pleural effusion maybe difficult to make.
Pericardial Tuberculosis
This is reported to occur in 0.4 to 4% of tuberculosis cases
in children.38 The pericarditis is initially serofibrinous or
hemorrhagic and with continued fibrosis it leads to
constrictive pericarditis. The pericardial fluid shows a
preponderance of lymphocytes. Culture studies or biopsy
are more useful as the AFB stains on pericardial effusions
generally fail to demons-trate tubercle bacilli.39
Liver and Spleen

They are often involved during the initial lymphohematogenous spread but this involvement is generally
asymptomatic. The reported incidence of hepatic
granulomas in Indian studies has ranged from 1.6 to
10.4%.40 Approximately 12% of patients showed presence
of hepatic granulomas in a study of pediatric tuberculosis.41
Nonspecific changes like Kupffer cell hyperplasia, fatty
infiltration and focal cell necrosis have also been reported
in patients with tuberculosis. Bharathi et al reported a
case of hepatic tuberculoma in an eight-year-old girl

which simulated a liver tumor clinically and as well as
on imaging.42
Skeletal Tuberculosis
Clinically significant bone and joint lesions of
tuberculosis usually appear after 1 year of primary
infection.43 The bones most commonly affected are the
thoracic and lumbar vertebrae and the weight bearing
joints like hip and knee along with small bones of hand
and feet. Necrosis of the vertebral bodies, which are
affected most often, leads to spread through the
intervertebral discs to involve adjacent vertebrae and
even soft tissues causing paravertebral and parapharyngeal abscesses. The upper extremities and bones like the
skull and clavicle are rarely involved.44 Children may be
more prone to skeletal tuberculosis because of the rich
vascularity of the growing bones.45 The infection reaches
the site commonly by blood from a focus of active visceral
disease. The lesion usually starts as an endarteritis in the
metaphysial region of long bones. 45 It may also be
affected by direct extension via lymphatics from a
pretracheal or paravertebral lymph node. Destruction of
bones may even lead to spread to adjacent joint spaces.
Necrosis of bone gives rise to the sequestrum. The new
bone formation resulting from extension of lesion
through cortex with elevation of periosteum gives rise
to the involucrum.
The kidneys are usually infected due to hematogenous
spread from a pulmonary focus of infection. Although
the renal tubercular granulomas are localized initially in
the cortex, the preferred site of involvement is the renal
medulla. Damage to vessels may lead to papillary
necrosis. Tuberculous pyonephrosis may ensue as a result
of spread to the renal pelvis. Spread of infection outside
the renal capsule may give rise to a mass lesion
mimicking a neoplasm. Long standing pulmonary
tuberculosis can give rise to renal amyloidosis. 46
Interstitial fibrosis, membranous glomerulonephritis,
focal lymphoid aggregates and cloudy swelling of the
renal tubular epithelial cells are some of the microscopic
changes described in kidneys of patients with pulmonary
tuberculosis.47 Infection may spread down into the
bladder giving rise to mucosal and mural granulomatous
lesions and scarring leading to a small capacity bladder
(thimble bladder). Ureteric strictures and segmental
dilatation may be seen as a result of ureteric involvement
leading to obstruction or reflux.
Associated renal tuberculosis is detected in most cases
of seminal vesicle and prostatic tuberculosis, although
involvement of these organs is uncommon in the
pediatric population.
375
Chronic tubercular epididymoorchitis is most

commonly tubercular in etiology. The infection is either
as a result of retrograde spread from an infected seminal
vesicle along the vas deferens, or may be blood borne.
The disease begins as a tender nodule and as the disease
progresses more nodules appear. The entire epididymis
becomes beaded in nature due to presence of submucosal
tubercles. Rarely the epididymo-orchitis may present as
a cold abscess in the lower and posterior aspect of the
scrotum or as a discharging sinus. A FNAC can be very
useful to obtain material for diagnosis. The kidneys must
be investigated for involvement by tuberculosis in cases
of tubercular epididymo-orchitis.
Central Nervous System Tuberculosis

The tubercle bacilli can infect the central nervous system
in many ways manifesting as tubercular meningitis,48,49
serous meningitis,50 tubercular brain abscess, tuberculoma
or spinal leptomeningitis.51 The caseous foci located at
the superficial cortex or meninges (Rich focus),
discharge tubercle bacilli into the subarachnoid space.52
A thick gelatinous exudate forms around the piaarachnoid. The exudate has a predilection for the base
of the brain, hence the III, VI, VII cranial nerves and the
optic chiasma are commonly involved. Vasculitis
affecting the vessels entrapped in this exudate leads to
periarteritis and endarteritis, causing vascular
thrombosis and infarction of the region supplied by
these vessels. Branches of the middle cerebral artery,
especially the perforating vessels to the basal ganglia
are commonly affected.
Tubercular Meningitis
It is more common in children less than 4 years of age,
occurring usually within 3 to 6 months of initial infection.
The cerebrospinal fluid (CSF) shows pleocytosis with
preponderance of polymorphs in the early stage and later
dominated by lymphocytes. The protein level is markedly
elevated, while the glucose is in the range of 20 to 40
mg/dl.
On gross examination a fibrinous or gelati-nous
exudate is seen, more often at the base of the brain and
encasing the cranial nerves. Discrete gray-white granules
may also be seen scattered over the leptomeninges. There
is also evidence of border-zone encephalitis due to
impingement of meningeal exudate on the brain
parenchyma. Microscopically there is an admixture of
lymphocytes, plasma cells and macrophages, with
presence of epithelioid cell granulomas, caseous necrosis
and giant cells in florid cases. A fibrous adhesive
arachnoiditis may be seen in long standing cases. The
brain underlying the exudate usually shows edema,
perivascular inflammatory infiltrate and micro-glial
reaction.
376
Section 5 Diagnosis
Hydrocephalus may occur because of blockage of the

CSF flow by the thick inflammatory exudate, along with
interference to the absorption by the pachinion bodies.
Ventriculitis may be seen due to involvement of the
ependy-mal lining and choroid plexus.
Tuberculomas
These are well circumscribed intraparenchymal lesions,
which may measure a few centimeters in diameter. They
may clinically mimic a brain tumor.53,54 Tuberculomas
are more often infratentorial in children as compared to
adults. Long standing lesions may appear calcified.
Microscopically they show the typical tuberculous
granulomatous inflammation.
Tubercular Brain Abscess

It is generally lacking; the usual granulomas and giant cells
leading to misdiagnosis of pyogenic abscess. The pus is,
however, rich in acid-fast bacilli.
Peritoneal Tuberculosis
Tubercular peritonitis can result from primary intestinal
focus, enlarged mesenteric nodes, tubercular pyosalpinx,
or due to blood-borne infection from pulmonary
tuberculosis, usually the miliary form.55 The peritonitis
may have an ascitic form, where the peritoneum and
omentum are studded with tubercles along with a straw
colored peritoneal fluid collection. The peritoneal fluid
is rich in lymphocytes.56 Acid fast bacilli are very difficult
to demonstrate, although culture may at times be
positive.56 The fibrous or plastic form of peritonitis is
characterized by dense adhesions between coils of
intestine which become matted and distended. These
patients may present with subacute or acute intestinal
obstruction. Dinler et al57 found laparoscopy and
peritoneal biopsy as the most reliable and safe methods
for the diagnosis of tuberculous peritonitis. According
to them, tuberculous peritonitis should be clinically
suspected in all patients with slowly progressive
abdominal distension, particularly when it is
accompanied by fever and pain.57
Intestinal Tuberculosis
Primary gastrointestinal tuberculosis is uncommon,
unlike in the past when there was a higher prevalence of
Mycobacterium bovis infection due to use of unpasteurized
milk. Intestinal infection occurs by direct ingestion of
bacilli, hematogenous, lymphatic spread or rarely by
direct extension of disease from neighboring organs.
Commonest sites of involvement are the ileum, ileocecal
region and rarely the colon, duodenum, jejunum,
appendix, stomach, esophagus or ano-rectum. In patients
with pulmonary tuberculosis, the tubercle bacilli reach
the intestinal mucosa via ingested sputum. The bacilli

are carried by macrophages to the submucosa where they
evoke granulomatous inflammation followed by caseous
necrosis and spread of inflammatory process. Endarteritis
of the vessels supplying mucosa in the affected intestinal
segment leads to ischemia and ulceration of the mucosa.58
The mesenteric lymph nodes may become enlarged
because of spread of inflammation along the lymphatics.
The mesenteric lymph nodes may also undergo caseous
necrosis and become matted.
Grossly intestinal tuberculosis can appear as
ulcerative, hypertrophic or ulcerohypertrophic. In the
ulcerative form, the intestinal mucosa reveals superficial,
transversely oriented, and circumferential ulcers with
undermined edges. The underlying intestinal wall is
indurated. Small tubercles maybe present on the serosal
aspect. The ulcerohypertrophic type has a combination
of features. There are superficial ulcers as well as marked
thickening of the bowel wall. The mesenteric lymph
nodes may appear markedly enlarged giving rise to an
appearance termed as tabes mesenterica. Colonic
tuberculosis may show marked mucosal granularity
similar in appearance to other chronic inflammatory
bowel diseases. Microscopically these lesions show
characteristic granulomatous inflammation with or
without necrosis. Older lesions show transmural
involvement by granulomatous process, while in early
lesions these are restricted to the mucosa and Peyers
patches. Fibrosis maybe seen in older lesions and
sometimes only extensive areas of hyalinization are seen
in the intestine whereas the draining lymph nodes show
features of granulomatous inflammation.
Tuberculosis of the Eye and Middle Ear

The conjunctiva and cornea are the areas involved in this
uncommon form of childhood tuberculosis. Conjunctiva
may serve rarely as the site of primary infection with
enlargement of the submandibular and cervical lymph
nodes. Phlyctenular conjunctivitis represents a hypersensitivity phenomenon to childhood tuberculosis.
Choroids tubercles have also been described in children
with miliary tuberculosis.59
The middle ear is an uncommon site of primary focus
and may be seen in area of eustachean tube of neonates,
who have aspirated infected amniotic fluid. The
preauricular lymph node is usually involved when it
is a primary focus.
Congenital and Perinatal Tuberculosis

The newborn can be infected via the placenta or the
amniotic fluid.60,61 Transplacental spread occurs via the
umbilical vein from an infected mother. In such cases
the liver is enlarged with enlarged lymph nodes at the
portahepatis with or without evidence of miliary disease.

Congenital infection can also occur due to ingestion of
infected amniotic fluid, in utero or at the time of delivery.
It can also occur due to inhalation from infected mother,
attendants, etc. widespread involvement of lungs, hilar
and mediastinal lymph nodes without associated hepatic
lesions indicate aspiration of infected amniotic fluid.
Demonstration of tubercle bacilli in gastric washings,
middle ear fluid, endotracheal aspirate and lymph node,
lung or skin biopsy is essential for diagnosis. Congenital
tuberculosis is characterized by a nonreactive response.
Multiple primary foci and miliary spread are commonly
seen. The regional lymph nodes show marked caseous
necrosis and many bacilli. Granuloma and giant cell
formation is rare. Neonatal infection is most often
due to inhalation of tubercle bacilli from an infected
mother.62
Tuberculosis in Adolescents
This may represent an initial infection during adolescent
age or a reactivation or exacerbation of infection acquired
during early life.63 In both sexes there is an increased
risk of acquiring active tuberculosis at the time of
adolescent growth spurt. A primary infection acquired
between 7 to 10 years of age is more likely to result in
active infection (disease) during adolescent as compared
to a primary infection acquired during early infancy.
Most often they develop classical primary complex which
is asymptomatic. It may occasionally progress to cavitary
disease or chronic pulmonary tuberculosis.
HIGHLIGHTS
Concept of granuloma and its types

Morphology of granulomas in tuberculosis
Samples for pathologic diagnosis of tuberculosis
Cytologic criteria for diagnosis of tuberculosis
Stains for demonstration of tubercle bacilli
Role of culture and PCR
Spectrum of morphologic changes in pediatric
tuberculosis (pulmonary and extrapulmonary
Congenital and perinatal tuberculosis
Tuberculosis in adolescents
REFERENCES
1. Guidance for national tuberculosis programs on the
management of tuberculosis in children: World Health
Organization. Available at: WHO/HTM/TB/2006.371.
2. Adams DO. The granulomatous inflammatory response.
Am J Pathol 1976;84:163-92.
3. Piessens WF, Nardell EA. Pathogenesis of Tuberculosis.
In: Lee B Reichman LB, Hershfield ES, Eds. Lung biology
in health and disease. (2nd ed) New York: Marcel Dekker
Inc; 2000;241-60.
377
4. Verma K, Kapila K. Aspiration cytology for diagnosis of

tuberculosisperspectives in India. Indian J Pediatr
2002;69:S39-43.
5. Bezabih M, Mariam DW, Selassie SG. Fine needle
aspiration cytology of suspected tuberculous
lymphadenitis. Cytopathology 2002;13:284-90.
6. Kumar N, Tiwari MC, Verma K. AFB staining in
cytodiagnosis of tuberculosis without classical features:
A comparison of Ziehl-Neelsen and Fluorescent methods.
Cytopathology 1998; 9:208-14.
7. Das DK, Bambhani S, Pant JN, et al. Superficial and deep
seated tuberculous lesions: Fine needle aspiration
cytology diagnosis of 574 cases. Diagn Cytopathol
1992;8:211-5.
8. Prasoon D. Acid fast bacilli in fine needle aspiration smears
from tuberculous lymphnodes. Where to look for them
Acta Cytol 2000;44:297-300.
9. Radhika S, Gupta SK, Chakrabarti A, et al. Role of culture
for mycobacteria in fine needle aspiration in diagnosis
of tuberculous lymphadenitis. Diagn Cytopathol
1989;5:260-2.
10. Handa U, Palta A, Mohan H, et al. Fine needle aspiration
diagnosis of tuberculous lymphadenitis. Trop Doct
2002;32:147-9.
11. Amdekar YK. Consensus statement on childhood
tuberculosis working group on tuberculosis, Indian
Academy of Pediatrics (IAP) Indian Pediatr 2010; 47: 4255.
12. Somu N, Swaminathan S, Paramasivan CN,
et al. Value of bronchoalveolar lavage and gastric lavage
in the diagnosis of pulmonary tuberculosis in children.
Pediatr 2000;37:947-51.
Infect Dis J 1992;11:735-8.
15. Vallejo J, Ong LT, Starke JR. Clinical features, diagnosis
and treatment of tuberculosis in infants. Pediatrics
1994;94:1-7.
16. Nataraj G, Kurup S, Pandit A, et al. Correlation of fine
needle aspiration cytology, smear and culture in
tuberculous lymphadenitis: A prospective study. J Postgrad
Med 2002;48:113-6.
17. Gong G, Lee H, Kang GH, et al. Nested PCR for diagnosis
of tuberculous lymphadenitis and PCR-SSCP for
identification of rifampicin resistance in fine needle
aspirates. Diagn Cytopathol 2002;26:228-31.
18. Baek CH, Kim SI, Ko YH, et al. Polymerase chain reaction
detection of Mycobacterium tuberculosis from fine needle
aspirate for the diagnosis of cervical tuberculous
lymphadenitis. Laryngoscope 2000;110:30-4.
19. Singh KK, Muralidhar M, Kumar A, et al. Comparison
of in house polymerase chain reaction with conventional
techniques for the detection of Mycobacterium tuberculosis
DNA in granulomatous lymphadenopathy. J Clin Pathol
2000;53:355-61.
378
Section 5 Diagnosis
20. Shankar P, Manjunath N, Mohan KK, et al. Rapid
diagnosis of tuberculous meningitis by polymerase chain
reaction. Lancet 1991;337:5-7.
21. Mc Adams HP, Erasmus J, Winter JA. Radiologic
manifestations of pulmonary tuberculosis. Radiol Clin
North Am 1995;33:655-78.
22. Frostad S. Segmental atelectasis in children with primary
tuberculosis. Am Rev Respir Dis 1959; 79:597-605.
23. Munoz FM, Starke JR. Tuberculosis in children. In: Lee B
Reichman LB, Hershfield ES, Eds. Lung biology in health
and disease 144 Marcel Dekker, Inc New York, (2nd Ed).
Ex Editor Enfant Claude. Tuberculosis. A comprehensive
international approach. 2000;443-85.
24. Smith DW. Bacillemia in primary tuberculosis. Ann
Intern Med 1971;75:479-80.
25. Stead WW, Bates J. Evidence of a silent bacillemia in
primary tuberculosis. Ann Intern Med 1971;74:559-61.
26. Hussey G, Chisolm T, Kibel M. Miliary tuberculosis in
children: A review of 94 cases. Pediatr Infect Dis J
1991;10:832-6.
27. Scuitt KE. Miliary tuberculosis in children. Clinical and
laboratory manifestations in 19 patients. Am J Dis Child
1979;133:538-85.
28. Salvin RE, Walsh TJ, Pokkak AD. Late generalized
tuberculosis: A clinical and pathologic analysis and
comparison of 100 cases in the preantibiotic and antibiotic
eras. Medicine 1980;59:352-66.
29. Datta M, Samdani PM, Udani PM, et al. Tuber-culosis in
children in India-I. The National Medical Journal of India
1992;5:226-34.
30. Wright CA, Warren RM, Marais BJ. Fine needle aspiration
biopsy: An undervalued diagnostic modality in
paediatric mycobacterial disease. Int J Tuberc Lung Dis.
2009;13:1467-75.
31. Jones PG, Campbell PE. Tuberculous lymph-adenitis in
childhood: The significance of anony-mous mycobacteria.
Br J Surg 1962;50:202.
32. Gupta K, Singh N, Bhatia A, et al. Cytomor-phologic
patterns in Calmette Guerin Bacillus Lymphadenitis.
Acta Cytol 1997;41:348-50.
33. Dommergues MA, de La Rocque F, Guy C,
et al. Local and regional adverse reactions to BCG-SSI
vaccination: A 12-month cohort follow-up study. Vaccine
2009; 27:6967-73.
34. Ocana I, Martinez-Vazquez JM, Segura RM, et al.
Adenosine deaminase in pleural fluids: Test for diagnosis
of tuberculous pleural effusion. Chest 1983;84:51-3.
35. Valdes L, San Jose E, Alvarez D, et al. Diagnosiso
f
tuberculous pleurisy using the biologic parameters
Adenosine Deaminase, lysozyme and interferon gamma.
Chest 1993;103:458-65.
36. Merino JM, Carpintero I, Alvarez T, et al. Tuberculous
pleural effusion in children. Chest 1999;115:26-30.
37. Rebera E, Ocana I, Martinez-Vazquez JM, et al. High level
of interferon gamma in tuberculous pleural effusion.
Chest 1998;93:308-11.
38. Hugo-Hammon CT, Scher H, DeMoor MMA.
Tuberculous pericarditis in children: A review of 44 cases.
39. Fowler NO. Tuberculous pericarditis. JAMA 1991;266:
99-103.
40. Malik MA, Ahmad P, Prasad M, et al. Liver biopsy in

the diagnosis of tuberculosis in children. Indian Pediatr
1978;15:127-31.
41. Shakil AO, Korula J, Kanel GC, et al. Diagnostic features
of tuberculous peritonitis and presence of chronic liver
disease. A case control study. Am J Med 1996;100:
179-85.
42. Bharathi A, Nagarjuna K, Prasad G, et al. Tuberculoma
of the liver. J Indian Assoc Pediatr Surg 2008;13:149-50.
43. Zahraad J, Johnson D, Lim-Dunham JE, et al. Unusual
forms of osteoarticular tuberculosis in children. J Pediatr
1996;129:597-602.
44. Smith MHD, Starke JR and Marquis JR. Tuber-culosis
and opportunistic Mycobacterial infections. In: Feigin
RD, Cherry JD, Eds. Textbook of pediatric infectious
diseases. (3rd ed). Philadelphia: WB Saunders company,
Harcourt Brace Jovanovich Inc. 1992;1321-62.
45. Shannon FB, Moore M, Houkom JA, et al. Multifocal
cystic tuberculosis of bone. J Bone Joint Surg 1990;72:108992.
46. Gupta SD, Ray R, Gill SS. Pathology. In Sharma SK, ed.
Tuberculosis. New Delhi: Jaypee Brothers; Medical
Publisher 2001;38-90.
47. Shah PKD, Jain HK, Mangel HN, et al. Kidney changes
in pulmonary tuberculosis- a study by kidney biopsy.
Indian J Tuberc 1975;22:23.
48. Idris ZH, Sinno A and Kronfol NM. Tuberculous
meningitis in childhood: Forty-three cases. Am J Dis
Child 1976;130:364-7.
49. Udani PM, Parekh UC and Dastur DK. Neuro-logical and
related syndromes in CNS tuberculosis: Clinical features
and pathogenesis. J Neurol Sci 1971;14:341-57.
50. Lincoln EM. Tuberculous meningitis in children: With
special reference to serous meningitis. Am Rev Tuberc
1947;56:75-94.
51. Traub M, Colchester AC, Kingsley DP, et al. Tuberculosis
of the central nervous system. Q J Med 1984;53:81-100.
52. Rich AR and Mc Cordock HA. The pathogenesis of
tuberculous meningitis. Bull Johns Hopkins Hosp
1933;52:5-35.
53. Sibley WA and O Brien JL. Intracranial tuber-culomas:
Review of clinical features and treatment. Neurology
1956;6:157-65.
54. Bagga A, Kalra V and Ghai OP. Intracranial tuberculoma.
Evaluation and treatment. Clinical Pediatrics 1988;27:
487-90.
55. Dineen P, Homan WP, Grafe WR. Tuberculous
peritonitis: 43 years experience in diagnosis and
treatment. Ann surg 1976;184:717-22.
56. Karney WW, ODhonghue JM, Ostrow JH, et al. The
spectrum of tuberculous peritonitis. Chest 1977;72:
310-5.
57. Dinler G, Sensoy G, Helek D, et al. Tuberculous
peritonitis in children: Report of nine patients and review
of the literature. World J Gastroenterol 2008;14:7235-9.
58. Chuttani HK, Sarin SK. Intestinal tuberculosis. Indian
Tuberc 1989;32:117.
59. Morese ML, Karr DJ, Manddman OM. Ocular
tuberculosis in a five month-old. Infect Dis J 1988;7:
514-6.

60. Hageman J, Shulman S, Schrieben M, et al. Congenital
tuberculosis: Critical reappraisal of clinical findings and
diagnostic procedures. Pediatrics 1980;66:980-5.
61. Nemir RL, OHare D. Congenital tuberculosis: Review and
diagnostic guidelines. Am J Dis Child 1985;139:284-7.
379
62. Jakob RF, Abernathy RS. Management of tuberculosis in

pregnancy and the newborn. Clin Perinatol 1988;15:30519.
63. Smith MHD. Tuberculosis in adolescents: Characteristics,
recognition, management. Clin Pediatr 1967;6:9-15.
28
New Approaches to
TB Diagnosis in Children
Ben J Marais, Daphne Ling, Madhukar Pai
INTRODUCTION
Globally, there is increasing awareness that children
suffer from severe tuberculosis (TB)-related morbidity
and mortality in TB endemic countries. The World Health
Organization (WHO) published its first guidance for
national TB programs on the management of TB in
children in 2006,1 and the Global Drug Facility (GDF) has
made child friendly drug formulations available to
deserving poor countries since 2008. However, these
positive developments focus more attention on the
tenacious problem of establishing an accurate TB
diagnosis in children, particularly in settings with limited
resources that carry the brunt of the disease burden. This
chapter introduces important disease concepts, discuss
new approaches to contact screening and TB in children,
and outlines the new diagnostic tools in the pipeline.
Robert Koch (1843-1910) identified Mycobacterium
tuberculosis as the biological agent causing TB in 1882.
However, it was soon recognized that although M.
tuberculosis is a necessary cause for the development of
active TB it is not a sufficient cause, since many perfectly
healthy people are infected with the organism; as
indicated by a positive tuberculin skin test (TST).2 It is
estimated that up to a third of the worlds population is
infected
with
M. tuberculosis of whom only a small fraction (less than
10%) will progress to active disease over a lifetime. It
remains an intriguing and largely unexplained
observation that only a small minority of immune
competent people infected with M. tuberculosis ever
progress to active disease. This explains why the
diagnostic challenge is more pronounced in TB endemic
countries where TB infection is exceedingly common;
thereby increasing the need to accurately differentiate TB
infection from active disease, and the need to develop a
test that can identify those at risk for progressing from
latent infection to active TB.
Standards for TB care made the same recommendation.3

Most national TB guidelines still regard the TST and chest
radiograph (CXR) as prerequisite screening tests to
exclude active disease in child TB contacts, which serves
as a huge barrier to access preventive therapy in resource
limited settings. It has been recognized that symptombased screening may have considerable value to improve
access to preventive therapy in settings where even the
most basic tests are not readily available.4 The WHO
guidelines promote symptom-based screening in these
settings (Figure 28.1).1 In settings where the TST is used
for screening purposes it is important to be conscious of
the multiple reasons for a false negative result, including
awareness that TST conversion may be delayed for up to
three months after exposure. In fact, the contribution
made by the TST in routine TB contact screening is
extremely limited, since infection can only be excluded
SCREENING CHILD CONTACTS FOR ACTIVE DISEASE

Current WHO guidelines advise that all children under
five years of age in close contact with a sputum smearpositive index case should be actively traced, screened
for TB and provided preventive chemotherapy once
active TB has been ruled-out. 1 The International
Isoniazid 5/mg/kg daily for 6 months

Unless the child is HIV-infected (in which case isoniazid 5/mg/kg daily for 6
months is indicated)
Adapted from: WHO Guidance for National Tuberculosis Programmes on the

Management of Tuberculosis in Children. WHO, Geneva, Switzerland. WHO/
HTM/TB/2006.371
Fig. 28.1: Suggested approach (WHO 2006) to contact management

when chest X-ray and tuberculin skin testing are not readily available.
Chapter 28 New Approaches to TB Diagnosis in Children

in non-anergic children three months after exposure
occurred. Therefore, the decision to initiate preventive
therapy is not influenced by the TST result following
documented exposure (Fig. 28.1).
The WHO guidelines indicate that any close contact
with a sputum-smear positive source case is important, even
if this occurs outside the household. The main factors
influencing the risk of infection in close contacts are the
infectiousness of the source case, as well as the proximity
and duration of contact. However, the guidelines fail to
address the frequency with which children in settings where
TB/HIV coinfection is common are exposed to adults with
sputum smear-negative pulmonary TB and the
transmission risk that this exposure poses. It seems prudent
to also consider intimate contact with a primary caregiver
who has sputum smear-negative pulmonary TB (diagnosed
on culture or CXR) as a significant exposure risk. In addition
to children <5 years of age, WHO guidelines also state that
HIV-infected (immune compromised) children should be
regarded as high-risk contacts that require preventive
therapy, irrespective of their age. The problem is that in
most TB endemic areas health systems are already
overburdened with the provision of curative treatment to
patients with active TB and are reluctant and/or unable to
perform contact screening and provide preventive therapy
to large numbers of children. In these settings, it is of
particular importance to focus preventive therapy
interventions on those children who are at greatest risk to
progress to active disease following documented TB
exposure and/or infection.
Figure 28.2 presents a simplified screening approach
that takes these considerations into account.
381
It is important to understand differences in the

rationale that motivates discrepant approaches in lowburden countries with adequate resources where TB
eradication is an achievable goal and TB endemic areas
with limited resources where the primary aim is to reduce
TB associated morbidity and mortality and to achieve
epidemic control (limit transmission). In non-endemic
areas, the provision of preventive chemotherapy to
everyone with documented TB infection is justified to
assist TB eradication, since resource constraints are not a
major consideration and eradicating the pool of latent TB
infection is important to prevent future reactivation
disease, which is the most common cause of adult disease.
In TB endemic areas, the converse is true. Resources are
highly constrained, and careful priority setting is essential.
Due to ongoing transmission, re-infection is common,
which makes it impossible to eradicate the pool of latent
infection before adequate epidemic control is achieved.
In these settings, re-infection rather than re-activation
seems to be the major cause of adult disease and therefore,
the primary aim is to limit ongoing transmission which
sustains the epidemic. In addition, everything possible
should be done to protect the most vulnerable subgroups
following documented exposure and/or infection in an
attempt to limit TB associated morbidity and mortality.
Interferon-Gamma Release Assays (IGRAs)

These novel T-cell assays measure interferon-gamma
(IFN-gamma) released after stimulation by M. tuberculosis
specific antigens. Two assays are currently available as
commercial kits; the T-SPOT.TB [Oxford Immunotec,
Adapted from: Marais BJ, Pai M. New Approaches and emerging technologies in the diagnosis of childhood tuberculosis. Paediatr Respir Rev 2007;8:124-33
Fig. 28.2: Proposed algorithm to screen children with documented exposure to a confirmed TB index case in resource-limited settings.
382
Section 5 Diagnosis
Oxford, UK] and the QuantiFERON-TB Gold In Tube

assay [Cellestis Limited, Victoria, Australia]. In general
these tests are regarded as more specific and potentially
more sensitive than the traditional TST.5,6 However,
although the US Centres for Disease Control and
Prevention (CDC) recommend the routine use of these
assays in children there is little evidence to support this
recommendation.6 Pediatric studies remain limited and
results inconsistent, with no clear evidence of benefit from
studies conducted in TB endemic areas such as India.7 In
the absence of symptoms or radiologic signs, T-cell assays
like the TST, fail to make the crucial distinction between
latent TB infection (LTBI) and active disease. A possible
application of these assays may be the screening of high
risk groups (close contacts and HIV-infected children)
to help guide the provision of preventive therapy, but
meticulous documentation of TB exposure is likely to be
more effective. As with the TST, there are multiple causes
of indeterminate or false negative results and test
conversion occurs a few weeks (probably around 4-8
weeks) after primary infection. Following documented
TB exposure, the first priority remains the provision of
preventive therapy to high risk contacts irrespective of
the IGRA (or TST) result.
If these assays are shown to be more predictive of
active TB than the TST then their application may expand.
Currently the inclusion of additional antigens is explored
to assist the distinction between LTBI, incipient disease
and active disease. There is also the opportunity to
improve the existing TST by replacing the non-specific
antigens currently used [purified protein derivative
(PPD)] with M. tuberculosis specific antigens, similar to
those used in IGRAs. This should result in a more specific
skin test that may be a feasible and more cost-effective
alternative for developing countries.
In 2009, the American Academy of Pediatrics (AAP)
Red Book (http://aapredbook. aappublications.org/)
concluded that neither an IGRA nor the TST can be
considered a gold standard for diagnosis of LTBI. The
new AAP Red Book recommendations for use of IGRAs
in children are as follows:
For immunocompetent children five years of age and
older, IGRAs can be used in place of a TST to confirm
cases of tuberculosis or cases of LTBI and likely will
yield fewer false-positive test results.
Children with a positive result from an IGRA should
be considered infected with M tuberculosis complex.
A negative IGRA result cannot universally be
interpreted as absence of infection.
Because of their higher specificity and lack of crossreaction with BCG, IGRAs may be useful in children
who have received BCG vaccine. IGRAs may be useful
to determine whether a BCG-immunized child with
a reactive TST more likely has LTBI or has a falsepositive TST reaction caused by the BCG.
IGRAs cannot be recommended routinely for use in

children younger than five years of age or for
immunocompromised children of any age because of
a lack of published data about their utility with these
groups.
Indeterminate IGRA results do not exclude
tuberculosis infection and should not be used to make
clinical decisions.
APPROACHES TO CONFIRM ACTIVE DISEASE

Establishing a definitive diagnosis of childhood TB
remains a major challenge. Sputum smear-microscopy is
positive in less than 10 to 15% of children with TB, and
culture yields are generally low (30-40%),8 although it may
be considerably higher in children with advanced disease.9
In low-burden countries the triad of; 1) known contact with
an infectious source case, 2) a positive TST, and 3) a
suggestive CXR is frequently used to establish a diagnosis
of childhood TB.9 This provides a reasonably accurate
diagnosis in non-endemic settings, but it has limited value
in endemic areas where exposure to, and/or infection with
M. tuberculosis, is common and often undocumented. The
diagnosis of TB in children is further complicated by the
great diversity of disease manifestations, which
necessitates accurate disease classification at least for
research purposes. 10-11 Seth et al12 has described a
clinicoimmunological spectrum of childhood tuberculosis
which can be used to grade the severity of the infection
and disease. Table 28.1 summarizes traditional and novel
diagnostic approaches, their potential application and the
perceived problems and/or benefits of each.
Symptom-Based Approaches
Due to the diagnostic limitations mentioned and the
difficulty of obtaining a CXR in TB endemic areas with
limited resources, a variety of clinical scoring systems
have been developed to diagnose active TB. A critical
review of these scoring systems concluded that they are
severely limited by the absence of standard symptom
definitions and inadequate validation. 13 Accurate
symptom definition is important to differentiate TB from
other common conditions, as poorly defined symptoms
(such as a cough of >3 weeks duration) have poor
discriminatory power.14 However, the diagnostic use of
well-defined symptoms with a persistent, non-remitting
character holds definite promise in low-risk children
(immune competent children >3 years) in whom TB is
usually a slowly progressive disease. 15 The most helpful
symptoms include; 1) persistent, non-remittent coughing
or wheezing, 2) documented failure to thrive despite food
supplementation (food scarcity is not a concern) and 3)
fatigue or reduced playfulness; clinical follow-up is also
a valuable diagnostic tool, particularly in children who
are at low risk of rapid disease progression.16
383

Table 28.1: Traditional and novel diagnostic approaches; potential application and perceived problems
and/or benefits
Traditional diagnostic
approaches
Application
Problems/ Benefits
Validation
TB culture using solid

or liquid broth media
Bacteriologic
confirmation of active TB
Slow turn around time; too

expensive for most poor
countries; poor sensitivity in
children
Accepted gold standard
Chest radiography
Diagnosis of probable
active TB
Rarely available in endemic

areas with limited resources;
accurate disease classification
important
Marked inter and intra

observer variability;
reliable in expert hands
and in presence of
suspicious symptoms
Symptom-based
approaches
active TB
Poor symptom definition
Not well validated

(TST)
Diagnosis of
M. tuberculosis infection
Rarely available in endemic

areas with limited resources;
does not differentiate latent
TB infection (LTBI) from
active disease; not sensitive in
immune compromised
children; simple to use and
less expensive than bloodbased tests
Various cut-offs advised

in different settings
Novel diagnostic
approaches
Application
Problems/Benefits
Validation
Organism-based
Colorimetric culture
systems (e.g. TKMedium)
Bacteriologic
confirmation of active TB
Simple and feasible, limited

resources required; potential
for contamination in field
conditions
Not well validated in

children
Phage-based tests
(e.g. FASTPlaque-TB)
active TB, and detection of
rifampin resistance
Requires laboratory
infrastructure; performs
relatively poorly when used
on clinical specimens

children but evidence
from adults suggests
poov performance
Microscopic
observation drug
susceptibility assay
drug resistance
Simple and feasible, limited

resources required

from adults suggests
promise
PCR-based tests
rifampin resistance
- Rarely available in endemic

areas
- Sensitivity tends to be poor
in paucibacillary TB
- Specificity a concern in
endemic areas, where LTBI is
common
- Requires adequate quality
control systems
Simple, point of care testing;
limited clinical data on
accuracy
- Extensively evaluated,
but evidence not in
favor of widespread use
Antigen-based
assays
LAM detection assay
active TB
Not well validated but

evidence from adults
shows inconsistent performance
Contd....
384
Section 5 Diagnosis
Contd....
Novel diagnostic
approaches
Immune-based
Antibody-based
assays
Application
active TB
MPB64 skin test
active TB
T-cell assays
Diagnosis of LTBI
Symptom-based
Symptom-based
screening
Screening child contacts of

adult TB cases
Refined symptombased diagnosis
active TB
Problems/Benefits
Validation
Simple, point of care testing,

variable accuracy and
difficulty in distinguishing
LTBI from active TB

form adults not in favor
of routine use
Simple, point of care testing,

require a second visit to read
the result
Not sufficiently
validated
No studies in children
Limited data in children,

inability to differentiate LTBI
from active TB; blood volume
required (3-5ml); expensive;
may have particular relevance
in high-risk children, where
LTBI treatment is warranted

young children; evidence
is not consistent and no
strong evidence that
IGRAs are superior to
TST in high-incidence
countries.
Limited resources required;

should improve access to
preventive chemotherapy for
asymptomatic high-risk
contacts in endemic areas
Additional validation
preferable
Limited resources required;

should improve access to
chemotherapy in resourcelimited settings; poor
performance in HIV-infected
children
Additional validation
preferable
Abbreviations: LAM - lipoarabinomannan; LTBI - latent tuberculosis infection; TB - tuberculosis; TST - tuberculin skin test
Adapted from: Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 2007; 92: 446-452.
Current evidence on various TB tests is available at: http://www.tbevidence.org/
The most common extrathoracic manifestation of TB

in children is cervical lymphadenitis. A simple clinical
algorithm that identify children with a persistent (>4
weeks) cervical mass of 2x2 cm, without a visible local
cause or response to first-line antibiotics, has shown
excellent diagnostic accuracy in a TB endemic area.
However, establishing a definitive tissue and/or culture
diagnosis remains preferable and this can be done in a
minimally invasive fashion using fine needle aspiration
biopsy (FNAB).
adenopathy and/or early cavitation. However, although

HRCT has definite application in rare problem cases, the
natural history of disease demonstrates that particular
caution is required when interpreting the relevance of these
findings, since a limited degree of hilar adenopathy is
common following recent primary infection and not
necessarily indicative of disease in the absence of symptoms.
9
Therefore, it is important to evaluate the presence of other
clinical signs and symptoms in conjunction with the CXR,
and not to base a TB diagnosis solely on the radiographic
findings.
Radiology-Based Approaches
In everyday clinical practice, the diagnosis of TB in endemic
areas depends predominantly on the subjective
interpretation of the CXR. Despite its many limitations the
CXR remains the single most helpful test and usually
provides a fairly accurate diagnosis, at least in HIVuninfected children, if evaluated by an experienced
clinician.9 High-resolution computed tomography (HRCT)
is the most sensitive tool currently available to detect hilar
Immune-Based Approaches
Immune-based diagnosis is complicated by the wide
clinical disease spectrum (ranging from subclinical latent
infection to various manifestations of active disease) and
other factors that influence the immune response such as
BCG vaccination, exposure to environmental nontuberculous mycobacteria (NTM) and HIV co-infection;
all of which are particularly prevalent in TB-endemic

areas.5 No serological assay is currently accurate enough
to replace microscopy and culture. A recent systematic
review showed that currently available serological,
antibody-based tests have highly variable sensitivity and
specificity.17 However, various serological tests are
marketed as diagnostic tests despite the absence of
evidence, particularly in TB endemic countries where
regulatory control is less well established.17 The use of
novel T-cell assays have been discussed and like the TST,
current IGRAs fail to differentiate TB infection from active
disease. Identifying novel ways to differentiate LTBI from
active TB and finding the correct application for these tools
in TB-endemic areas remain top priorities for future
research.6
Another innovative approach measures the immune
response (delayed type hypersensitivity response similar
to the TST) to transdermal application of the MPB64
antigen.5 In initial pilot studies, the MPB64 skin patch
test successfully distinguished active TB from LTBI, but
results from more extensive field trials and information
of its ability to detect active TB in children are eagerly
awaited.
Organism-Based Approaches
A positive culture is regarded as the gold standard test
to establish a definitive diagnosis of TB in a symptomatic
child. However, it is limited by sub-optimal sensitivity,
slow turn-around times, excessive cost (automated liquid
broth systems) and the fact that organisms may be
isolated from non-diseased (asymptomatic) children
shortly after primary infection; during the initial period
of organism multiplication. This is rarely a problem in
clinical practice where children present with symptoms
suspicious of TB, but it may be a major confounder in
studies where asymptomatic children are routine
cultured for TB following documented TB exposure.9 It
is important to point out that adolescent children (>10
yrs of age) frequently develop sputum smear-positive
disease that may be diagnosed using traditional
methods.9 Novel culture-based approaches include
simple colorimetric and microcolony methods with
reduced turn-around times, but their accuracy and
robustness in field conditions have not been confirmed.5
The Microscopic Observation Drug Susceptibility
(MODS) assay uses an inverted light microscope to
rapidly detect mycobacterial growth in liquid growth
media. It is an inexpensive method that has demonstrated
excellent performance under field conditions (both in
adults and children)18-19 being more sensitive than
automated liquid media systems. Unfortunately the test
is not widely available at present, while it remains highly
operator dependent and labor intensive. A recent
pediatric study demonstrated reduced times to detection
385
and possible increased bacteriological yield with the

addition of a nutrient broth to standard liquid media
using automated systems.20 Further research is required
to identify optimal growth conditions that can be coupled
to a variety of detection systems. Thin layer agar (TLA)
and nitrate reductase assay (NRA) are other noncommercial, but promising approaches.
Other innovative organism-based approaches include
the detection of TB-specific antigens such as
lipoarabinomannan (LAM) in sputum and/or urine.
Initial field trials demonstrated sub-optimal sensitivity,
although improved sensitivity was achieved in HIVinfected adults and those with disseminated disease. No
results from pediatric studies have been reported to date.
The phage amplification assay utilizes bacteriophages to
infect live M. tuberculosis and is commercially available
as FASTPlaque-TB; a variant (FASTPlaque-TB Response)
was designed for the rapid detection of rifampicin (RMP)
resistance. The phage assay has a turn-around time of
only 2 to 3 days, but is less sensitive than traditional
culture methods and no information exists on its utility
in children.5 The test has proven ability to rapidly
differentiate between rifampicin susceptible and
potential multidrug resistant (MDR) cases, but has been
superseded by polymerase chain reaction (PCR)-based
tests.5 Recent field studies of FASTPlaque-TB tests has
raised concern about contamination and false-positive
results.
Nucleic acid amplification tests (NAATs) amplify
regions specific to the M. tuberculosis complex. These tests
have shown highly variable results and limited utility in
children to date. As demonstrated in several metaanalyses (available at www.tbevidence.org), existing
NAATs have high specificity, but modest and variable
sensitivity, especially in smear-negative and extrapulmonary TB. Several newer NAATs have been
developed recently, including the loop-mediated
isothermal amplification [LAMP] (Eiken Chemical Co.
Ltd., Tokyo, Japan), a simplified manual NAAT designed
for peripheral laboratory facilities, and the Xpert MTB/
RIF assay (Cepheid, Sunnyvale, Calif, USA), a fully
automated NAAT platform that can detect TB as well as
rifampin resistance. These tests have shown promise in
early studies, although published evidence is still limited,
especially in children.
Specimen Collection Methods in Children

Collecting an adequate specimen presents a significant
challenge, particularly in small children who are unable
to expectorate. In young children (<8 years of age), the
routine specimens collected are two to three fasting gastric
aspirates. However, the collection of 2 to 3 fasting, early
morning gastric aspirate specimens is cumbersome and
usually requires hospitalization. In an initial
386
Section 5 Diagnosis
study, the collection of a single hypertonic-saline induced

sputum specimen provided the same yield as three gastric
aspirate specimens,21 but subsequent studies have not been
able to substantiate this observation.22 However, induced
sputum seems at least as good as a gastric aspirate sample
and can be done as an outpatient procedure; the value/
risk of the technique is currently being tested in a primary
health care clinic setting. The string test is an innovative
collection method that has been used with great success
to retrieve M. tuberculosis from sputum smear-negative
HIV-infected adults, demonstrating superior sensitivity
compared to induced sputum.23 A major limitation at
present is the inability of young children (<5 years of
age) to swallow the string containing capsule, while this
is precisely the age-group that suffers the greatest burden

of disease. Fine needle aspiration biopsy (FNAB), is a
robust and simple technique that provides a rapid and
definitive diagnosis. In a comparative study FNAB
specimens provided superior yields compared to
standard respiratory specimens in child TB suspects with
a palpable lymph node mass. 24 The use of a small 23gauge needle is well-tolerated and associated with
minimal side-effects; the technique can be performed as
an outpatient procedure by well-trained doctors or
nurses.25 Table 28.2 provides a summary of various
specimen collection methods and the perceived problems
and/or benefits of each.
Table 28.2: Specimen collection methods; perceived problems and/or benefits

Specimen collection
method
Problems/ Benefits
Potential clinical application
Sputum
Not feasible in very young children;

Assistance and supervision may
improve the quality of the specimen
Routine sample to be collected in

children >7yrs of age (all children who
can produce a good quality specimen)
Induced sputum
Increased yield compared to gastric

aspirate; No age restriction; Specialized
technique, which requires nebulization
and suction facilities; Use outside
hospital setting not studied; Potential
transmission risk
To be considered in the hospital setting

on an in- or out-patient basis
Gastric aspirate
Difficult and invasive procedure; Not

easily performed on an outpatient basis;
Requires prolonged fasting;Sample
collection advised on 3 consecutive days
Routine sample to be collected in

hospitalized who cannot produce a
good quality sputum specimen
Nasopharyngeal
aspiration
Less invasive than gastric aspirate; No

fasting required;Comparable yield to
gastric aspirate
To be considered in primary health care

clinics or on an outpatient basis
String test
Less invasive than gastric aspirate;

Tolerated well in children >4 years;
Bacteriologic yield and feasibility
requires further investigation
Potential to become the routine sample

collected in children who can swallow
the capsule, but cannot produce a good
quality sputum specimen
Bronchoalveolar
lavage
Extremely invasive
Only for use in patients who are

intubated or who require diagnostic
bronchoscopy
Urine/Stool
Not invasive; Excretion of M. tuberculosis

well documented
To be considered with novel sensitive

bacteriologic or antigen-based tests
Blood/Bone marrow
Good sample sources to consider in the

case of probable disseminated TB
To be considered for the confirmation

of probable disseminated TB in
hospitalized patients
Cerebrospinal fluid
(CSF)
Fairly invasive; bacteriologic yield low
To be considered if signs of tuberculous

meningitis
Fine needle
aspiration biopsy
(FNAB)
Minimally invasive using a fine 23G

needle; excellent bacteriologic yield,
minimal side-effects
Procedure of choice in children with

superficial lymphadenopathy
Adapted from: Marais BJ. Pai M. Specimen collection methods in the diagnosis of childhood tuberculosis. Indian J Med Microbiol
2006; 24: 249-251
387
From World Health Organization & Stop TB Partnership. New laboratory diagnostic tools for tuberculosis control. World Health Organization, Geneva, 2008
Fig. 28.3: Summary of new technologies by the Retooling Task Force and Stop TB Partnerships New Diagnostics Working Group
Section 5 Diagnosis
388
Courtesy: Stop TB Partnerships New Diagnostics Working Group

Find = Foundation for Innovative new diagnostic
TDR = Tropical disease research.
Fig. 28.4 New website resource for Evidence-based TB Diagnosis (www.tbevidence.org)
HIV-infection
HIV-related immune compromise is one of the main risk
factors that increases the vulnerability to develop active TB
following infection. Since children get TB where adult source
cases spread the infection, both HIV-infected and uninfected
children experience high rates of TB exposure in HIVendemic areas where the TB epidemic is poorly controlled.
Among HIV-infected children, TB is a major cause of
morbidity and mortality and is often under-diagnosed in
resource-limited settings. However, unlike the situation with
adults in many HIV-endemic areas, the majority of child TB
cases remain HIV-uninfected, since relatively few children
become infected in areas with adequate prevention of mother
to child transmission (PMTCT) programs. Very young
children are highly vulnerable to develop TB following
documented exposure, irrespective of their HIV-status.
The diagnostic challenge is greatly pronounced in HIVinfected children due to a number of factors:26
HIV-infected adult patients are more likely to
have sputum smear-negative pulmonary TB.
Although not in accordance with current
international guidelines, it seems prudent to provide
preventive therapy to high risk contacts who are in
intimate contact such as the children of the source
case.
The TST and IGRAs have reduced sensitivity in
HIV-infected children. Although test sensitivity is
influenced by the degree of immune compromise,
389
the TST is positive in the minority of HIV-infected

children with bacteriologically confirmed TB despite
using a reduced induration size cut-off of 5 mm.
Chronic pulmonary symptoms from other HIVrelated conditions are common and failure to thrive
is a typical feature of both TB and HIV, which greatly
reduces the specificity of symptom-based diagnostic
approaches. Rapid disease progression may also
occur, thereby reducing the sensitivity of diagnostic
approaches that focus on persistent, non-remitting
symptoms.
CXR interpretation is complicated by HIV-related
comorbidity such as bacterial pneumonia,
lymphocytic interstitial pneumonitis (LIP),
bronchiectasis, pulmonary Kaposi sarcoma (KS) and
the atypical presentation of TB in immune
compromised children.
Expanding TB Diagnostics Pipeline and Current Evidence

The new diagnostics pipeline for TB is rapidly expanding.
In 2008, the Stop TB Partnerships Retooling Task Force
(RTF) and New Diagnostics Working Group (NDWG)
produced a detailed brochure on the diagnostics pipeline,
mainly to provide guidance to National TB Programs
(NTPs), and for funding the technical agencies that may
wish to support the development, evaluation or
implementation of new tools. Figure 28.3
shows the pipeline, where the tools are stratified as WHO-
In nonendemic areas where the risk of reinfection is low and where TB eradication is an achievable goal, it would be desirable to provide
preventive treatment to all individuals with documented TB infection
Adapted from: Marais BJ, Gie RP, Schaaf HS et.al. Childhood pulmonary tuberculosis Old wisdom and new challenges. Am J Resp Crit
Care Med 2006;173:1078-90
Fig. 28. 5: Algorithm to guide the diagnosis and management of children with suspected pulmonary TB
390
Section 5 Diagnosis
endorsed, Tools in late-stage development/evaluation,

or Tools in early phase development. The figure not only
describes the various tests, but also provides some
information on the commercial kits available, training
requirements, and estimated costs.
Other reviews of various TB technologies have also
been published by Perkins and Cunningham27, and Pai
and OBrien. 28 The existing evidence-base on TB
diagnosis was recently reviewed by Pai et al.29 and this
led to the development of a comprehensive, web-based
resource entitled Evidence-based TB Diagnosis
available at www.tbevidence.org (Figure 28.4).
With all these advances, it is likely that more evidence
will emerge on the role and applicability of new tools in
children. Figure 28.5 gives the algorithm to guide the
diagnosis and management of children with suspected
pulmonary TB.
HIGHLIGHTS
Increased commitment at an International and
National level to limit TB-related mobility and
mortality.
Two groups should be prioritized to access to
therapy in TB endemic areas like India.
High risk, exposed and or infected children
require effective preventive therapy.
All children with active disease require early
diagnosis and effective treatment.
The provision of practical guidelines that are robust
and implementable in areas with limited resources
remains a major challenge.
Individual patient management, should be based on
answering five simple questions, irrespective of the
resources available in a particular setting.25
Is the child exposed to or infected with M.
tuberculosis?
Does the child have active TB?
If the child is exposed or infected and active TB has
been excluded, is preventive chemotherapy
indicated?
If the child has active TB, what is the appropriate
treatment regimen?
Evidence based diagnosis of tuberculosis has been
discussed.
ACKNOWLEDGMENTS
This book chapter draws heavily on several previous
review papers, including those published in Indian J Med
Microbiol 2006; 24: 249-51; Arch Dis Child 2007; 92: 44652; Pediatr Respir Rev 2007; 8: 124-33; Semin Respir Crit
Care Med. 2008;29(5):560-8; and PLoS Med. 2008 Jul
22;5(7):e156. Adapted tables and figures have been
acknowledged with due credit.
REFERENCES
Tuberculosis Programmes on the Management of
Tuberculosis in Children. WHO, Geneva, Switzerland.
WHO/HTM/TB/2006.371.
2. Marais BJ, Gie RP, Schaaf HS, et.al. The natural history
of childhood intra-thoracic tuberculosis A critical
review of the pre-chemotherapy literature. Int J Tuberc
Lung Dis. 2004;8:392-402.
3. Hopewell PC, Pai M, Maher D, et al. International
standards for tuberculosis care. Lancet Infect Dis
2006;6:710-25.
4. Kruk A, Gie RP, Schaaf HS, et.al. Symptom-based
screening of child tuberculosis contacts: improved
feasibility in resource-limited settings. Pediatrics 2008;
121:e1646-52.
5. Marais BJ, Pai M. New approaches and emerging
Paediatr Respir Rev 2007;8:124-33.
6. Pai M, Zwerling A, Menzies D. T-cell Based Assays for
the diagnosis of latent tuberculosis infection: An Update.
Ann Intern Med 2008;149:177-84.
7. Dogra S, Narang P, Mendiratta DK, et.al. Comparison of
a whole blood interferon-gamma assay with tuberculin
skin testing for the detection of tuberculosis infection in
hospitalized children in rural India. J Infect 2007;54 :26776.
8. Eamranond P, Jaramillo E. Tuberculosis in children:
reassessing the need for improved diagnosis in global
control strategies. Int J Tuberc Lung Dis 2001;5:594-603.
9. Marais BJ, Gie RP, Schaaf HS, et.al. Childhood pulmonary
tuberculosis Old wisdom and new challenges. Am J
Resp Crit Care Med 2006;173: 1078-90.
10. Marais BJ, Gie RP, Starke JR, et al. A proposed
radiological classification of childhood intra-thoracic
tuberculosis. Ped Rad 2004;33:886-94.
11. Marais BJ, Gie RP, Schaaf HS, et.al. The spectrum of
childhood tuberculosis in a highly endemic area. Int J
12. Seth Vimlesh, Kabra SK, Seth Rachna. Clinicoimmunological profile: Indian scenario, in Essential of
Tuberculosis in Children. Seth Vimlesh Kabra SK (eds),
3rded New Delhi, Jaypee Brothers Medical Publisher (P)
Ltd 2006; 95-105.
13. Hesseling AC, Schaaf HS, Gie RP, et al. A critical review
of diagnostic approaches used in the diagnosis of
childhood tuberculosis. Int J Tuberc Lung Dis
2002;6:1038-45.
14. Marais BJ, Obihara CC, Gie RP, et. al. The prevalence of
symptoms associated with pulmonary tuberculosis in the
average child from a high-burden community. Arch Dis
Child 2005;90:1166-70.
15. Marais BJ, Gie RP, Obihara CC, et. al. Well-defined
symptoms have improved value in the diagnosis of
childhood pulmonary tuberculosis. Arch Dis Child
2005:90:1162-5.
16. Marais BJ, Gie RP, Schaaf HS, et al. A refined symptombased approach to diagnose pulmonary tuberculosis in
children. Pediatrics 2006.118:e1350-9.

17. Steingart KR, Henry M, Laal S, et al. A systematic review
of commercial serological antibody detection tests for the
diagnosis of extrapulmonary tuberculosis. Thorax
2007;83: 705-12.
18. Moore DAJ, Evans CAW, Gilman RH, et al. Microscopicobservation drug-susceptibility assay for the diagnosis
of TB. N Engl J Med 2006;355:1539-50.
19. Oberhelman RA, Soto-Castellares G, Caviedes L, et al.
Improved recovery of Mycobacterium tuberculosis from
children using the microscopic observation and drug
susceptibility method. Pediatrics 2006;118:e100-6.
20. Brittle EW, Marais BJ, Hesseling AC, et al. Improved
mycobacterial yield and reduced time-to-detection in
pediatric samples using a nutrient broth growth
supplement. J Clin Microbiol 2009;47:1287-9.
a prospective study. Lancet 2005;365:130-4.
22. Hatherill M, Hawkridge T, Zar HJ, et al. Induced sputum
or gastric lavage for community-based diagnosis of
childhood pulmonary tuberculosis? Arch Dis Child
2009;94:195-201.
23. Vargas D, Garcia L, Gilman RH, et al. Diagnosis of
sputum-scarce HIV-associated pulmonary tuberculosis in
Lima, Peru. Lancet 2005;365:150-2.
391
24. Wright CA, Hesseling AC, Warren RW, et al. Fine needle
aspiration biopsy a first line diagnostic procedure in
pediatric tuberculosis suspects with peripheral
lymphadenopathy. Int J Tuberc Lung Dis 2009; In press.
25. Wright CA, Warren RW, Marais BJ. Fine needle
aspiration biopsy: an undervalued diagnostic modality
in pediatric mycobacterial disease. Int J Tuberc Lung Dis
2009; In press.
management challenges of childhood TB in the era of HIV.
J Infect Dis 2007;196:S76-85.
27. Perkins MD, Cunningham J. Facing the crisis: improving
the diagnosis of tuberculosis in the HIV era. J Infect Dis
2007;196:S15-27.
28. Pai M, OBrien R. New diagnostics for latent and active
tuberculosis: state of the art and future prospects. Semin
Respir Crit Care Med 2008; 29:560-8.
29. Pai M, Ramsay A, OBrien R. Evidence-based
tuberculosis diagnosis. PLoS Med 2008;5:e156./
www.plosmedicine.rog
SUGGESTED READING
Ichhpujani RL, Agarwal SP, Chauhan LS. Diagnostic needs
and status of new diagnostic tools for tuberculosis in TB book,
by TB Division of Ministry of Health and Family Welfare,
Government of India. Chapter 18. 2008;165-78.
SECTION 6
MANAGEMENT
Principles of Therapy
Antituberculosis Drugs: First-line Agents
Antituberculosis Drugs: Second-line and

Newer Agents
Antituberculosis Drugs: Pharmacokinetics
Pharmacogenetics of Tuberculosis
Management of Tuberculosis
Consensus Statement on Childhood Tuberculosis,

2010 IAP Working Group on Tuberculosis
Drug-resistant Tuberculosis in Children
Drug-resistant Tuberculosis
Multidrug-resistant Tuberculosis
Organization of Pediatric Tuberculosis and

HIV Clinic
29
Principles of Therapy
Standard medical therapy of tuberculosis for decades was

focused on rest, the sanatorium, a good climate and a
proper diet. This continued for some time even after the
discovery of the tubercle bacillus by Koch and
establishment of infective etiology of tuberculosis. The
first principle of the modern treatment of tuberculosis is
the recognition of the primacy of drug treatment over all
other forms of therapy. This was established in the 1940s
with the discovery of effective antituberculosis
chemotherapeutic agents. The principles of chemotherapy of tuberculosis in the era of short-course
treatment regimens were developed when isoniazid
(INH), para-aminosalicylic acid (PAS), and streptomycin
became available. When drugs like pyrazinamide,
ethambutol and most importantly rifampicin were
introduced with the better understanding of their
mechanisms of action, came the concept of short-course
chemotherapy. There has been redefining of the
principles of tuberculosis in adults and lately in children.
It was the laboratory and field work of seminal figures
such as Fox 1 and Mitchison 2 of the Tuberculosis
Elimination Bureau of the British Medical Research
Association working in conjunction with colleagues in
East Africa and India, that lead to the development of
modern principles of chemotherapy.
The aim of therapy in tuberculosis is to cure; cure all
patients with disease at various sites, of varying severity
and resistance pattern. Patients who may have received
treatment before, with variable compliance pose further
problems. With the current regimens of treatment of
tuberculosis, available at low cost, if not free for all, there
should be minimal relapses, and side effects. Thus the
aims can be summarized as follows: (i) Cure patients with
minimal interference with their living, in shortest possible
time, whether the pretreatment organisms are susceptible
or resistant to the drugs; (ii) Prevent death from active
disease or its late effects; (iii) Avoid relapse; (iv) Prevent
emergence of acquired drug resistance and (v) Protect
the community from infection. To add to this, Seth3,3a
recommends that the children should be tackled
simultaneously both for prevention and treatment of the
disease, using proper regimens with clear case definitions
which may differ from adults. Different case definitions
in children have been described by her based on

clinicoimmunologic profile. These should be followed.3,3a
MICROBIOLOGICAL PRINCIPLES
Mycobacterial Population
Mycobacteria exist in any diseased site in four distinct
but mutually interchangeable population group. Not all
drugs work equally well on all bacillary sub-population.
It is customary to discuss antituberculosis drugs in terms
of their effect on these different population of
mycobacteria.
Group I
Rapidly multiplying organisms in extracellular
environment of pulmonary cavities. They multiply
rapidly due to the presence of a neutral pH and an
abundance of oxygen. They are killed by isoniazid
followed by rifampicin (RIF), pyrazinamide (PZA) and
streptomycin (SM) and less so by bacteriostatic drugs,
such as ethambutol (EMB), para-aminosalicylic acid
(PAS) and thiacetazone (THA).
Group II
Intermittently multiplying organisms (semi-dormant) in
relatively hypoxic or acid environ-ment of solid caseous
material. They are specifically acted upon by rifampicin
which has the property of being able to act very soon
after the multiplication of bacilli starts. This drug has its
action only when the bacteria are multiplying.
Group III
Occasionally dividing organisms (dormant) in the
activated macrophages. These mycobacteria are
specifically acted upon by pyrazinamide and much less
by other drugs.
Group IV
Drug resistant mutants. Pyrazinamide (PZA) and
isoniazid (INH) are the main drugs which help in the
prevention of emergence of drug resistant mutants.
396
Section 6 Management
Table 29.1 grades the activity of antituberculosis

drugs on the various groups of myco-bacteria existing
at disease site.
Population Load
The second major biological determinant of the success
of antituberculosis chemotherapy is the size and type of
the bacillary population within the host. Patients with
cavities or extensive infiltrates have large bacterial
population whereas patients with infection (reactive skin
test) but no disease have a small bacterial population load.
In adults, there are studies which indicate the bacterial
load in relation to the extent of lesion in pulmonary
tuberculosis, e.g. X-ray positive but sputum negative,
both sputum and chest X-ray positive. In the former, the
bacillary load will be less as compared to the latter. In
children this has not been worked out and hence, no
literature is available. As a corollary to this Seth3,3a has
described a clinicoradioimmunological spectrum as (i)
Asymptomatic Mantoux positive (ASMP); (ii) Symptomatic
Mantoux positive (SMP); (iii) Pulmonary primary
complex (PPC); (iv) Progressive primary disease (PPD);
(v) Bronchopneumonia; (vi) Pleural effusion; (vii) Post
primary lesion PPL having calcification or fibrosis; (viii)
Miliary types of lesion and (ix) Extrapulmonary form of
tuberculosis are lymphadenitis, osteoarticular and
meningeal tuberculosis. The most common being
tubercular lymphadenitis. Bronchopneumonia will have
a larger load of bacilli in comparison to ASMP, SMP and
PPC. The miliary and meningeal are dissemination
complications of PPC. Table 29.2 gives the size of bacterial
load in adults and other host and pathogen
characteristics. The early bactericidal activity 4 of
antituberculosis drugs is the most important factor for
their efficacy in the treatment, particularly of pulmonary
tuberculosis.
Resistance
The other microbiological principle in the chemotherapy
of tuberculosis is of innate resistance to drugs. Resistance
Agent
Isoniazid
Rifampicin
Pyrazinamide*
Streptomycin
Ethambutol**
in Mycobacterium tuberculosis develops by mutation.

Infection by organisms which are resistant to drugs prior
to exposure leads to primary resistance. Such naturally
resistant organisms are present within large populations
of M. tuberculosis. All known genes that encode for drug
resistance are located on a chromosome, transfer of
resistance between organisms does not occur. The
estimated frequency of these naturally drug resistant
organisms is about 106 but varies among drugs, with
streptomycin it is 105, with isoniazid 106, rifampicin
108 and pyrazinamide 108. The natural occurrence of
resistance to one drug is independent of resistance to
any other drug. The chance that an organism is naturally
resistant to both INH and RIF is of the order of 10.14
Because populations of this size do not occur in patients,
the chances that organisms naturally resistant to two
drugs exist in a patient are almost negligible. However,
acquired resistance to these two drugs referred to as
Table 29.2: Population of bacilli within a host (adult)
Parameter
Cavity
Population
size
Metabolism and
active replication
pH
107-109
Most effective
drug
Neutral/
Alkaline
H, R, S
Closed
caseous
104-105
Macrophages
104-105
slow/
intermittent
Neutral
slow
Acid
R, H
Z, R, H
Table 29.3 shows the size of bacillary load in children.

Table 29.3: Size of bacillary load (children)
Parameter
Bacillary
Drug resistant
load
mutants
Cavity
109
++
Positive Mantoux
103-104
Rare
Pulmonary
+
primary complex
104-105
Table 29.1: Activity of antituberculosis drugs on different bacterial population

Bacterial population
Active*
Semi dormant*
Dormant**
(extracellular)
(caseous )
(intracellular)
+++
++
+
+++
+++
++
+++
+++
++
++
* Bactericidal action , ** Sterilizing action, *** Prevention of emergence of resistance

* Bactericidal drug active against intracellular organisms
** Bacteriostatic drug active against both intracellular and extracellular organisms
Resistant ***
(mutants)
+++
+++
++
++
Chapter 29 Principles of Therapy

multidrug resistance (MDT-TB) has become a problem
of significance. This laboratory evidence was provided
by the work of Fox1 and Canetti.5 This formed the basis
for understanding the principle that multi-agent
chemotherapy is required for the treatment of active
tuberculosis. This was further proved when initial
studies, in which, streptomycin alone was used to treat
active pulmonary tuberculosis had significant treatment
failures and high relapse rates. The relapses were by
organism resistant to streptomycin.6
If a patient with extensive pulmonary tuberculosis is
given a single medication, the subpopulation of bacilli
susceptible to that drug will be eliminated but the
subpopulation of bacilli resistant to this drug have the
opportunity to multiply and become the dominant strain.
The patient after temporary improvement, will suffer a
relapse and that will be drug resistant. Also, if all the
organisms have initial (primary) resistance to a drug and
the patient is treated with that plus one other drug, he/
she will be getting only one effective drug. This results
in relapse with tuberculosis that is resistant to both drugs
(secondary resistance). The phenomenon of drug
resistant mutants and bacterial population size explains
why poor patient compliance can lead to rapid
development of drug resistance.
Hence, the following points should be kept in mind
while introducing antituberculosis chemotherapy for the
prevention of emergence of resistance:7
Monotherapy is the most potent stimulus for
development of resistance and has a substantial
chance for relapse, and, therefore, should be avoided.
Achieve rapid reduction of bacterial load
Initial therapy should begin before sensitivity data
are available, but should be based on the prevailing
sensitivity pattern of isolates in the community.
Never add a single drug to a failing regime.
Compliance with drugs is a major determinant of the
success of therapy.
The major biological determinant of success of
antituberculosis drugs is the size of the bacillary
population in the host. Adults with cavities or extensive
infiltrates have large bacillary load and many naturally
resistant organisms are present. For such patients, at least
three antituberculosis drugs must be used to affect a cure.
Conversely, in patients with infection (skin test positive)
but no disease, the bacillary population is small and drug
resistant organisms are few or nonexistent. For such
patients, theoretically, two drugs can be used. For
example, in a child who is otherwise asymptomatic, but
found to be a recent Mantoux conver-ter due to the
exposure to a contact in the family, the type of bacilli
will be similar to that of the source case. In such a child,
X-ray chest and Mantoux test must be done and child
treated accordingly. Details are discussed elsewhere.
397
Disease in children is a direct consequence of the

primary infection and they typically have closed caseous
lesion with relatively few mycobacteria. Since the
likelihood of developing resistance to any antimicrobial
drug depends primarily upon the size of the bacillary
population, resistance that emerges during therapy, i.e.
secondary drug resistance, is rare in children. Most
resistance encountered is primary resistance, i.e. infection
develops by an already resistant organism.4
Pharmacological Principles
The aim of treatment with antituberculosis drugs is to
cure the individual patient and to prevent the emergence
of drug-resistant organisms. This is achieved by: (1)
Rapid reduction of the organism load; (2) Ensuring
effective eradication of dormant and intermittently
metabolizing (persistent) bacilli; and (3) Achieving this
with minimal adverse effects for the child.8-12
Mitchison2 described antituberculosis drugs in terms
of their activity, in three areas: (i) Early bactericidal
activity; (ii) Sterilizing activity and (iii) Prevention of
drug resistance. This is depicted in Table 29.4.
Early Bactericidal Activity

It is the ability of the drug to reduce the number of bacilli
during the initial part of therapy.4 INH is the most potent
bactericidal agent.
Sterilizing Activity
It is the ability of a drug to kill semidormant bacteria
and is measured by the speed with which the last few
viable bacteria are killed.13 Rifampicin and pyrazinamide
are the most potent sterilizing agents.
Each of the first-line drugs makes a specific
contribution during different periods of drug action.
Immediate effect in first 2-3 days include killing of fastgrowing extracellular bacilli,14 mainly by the excellent
bactericidal activity of isoniazid (INH). 15 In the
Table 29.4: Relative activities of antituberculosis medications
Early bactericidal Preventing Sterilizing Status
activity
drug
activity
of
resistance
activity
In vitro In vivo
INH INH
INH
RIF
High
RIF
RIF
PZA
SM
EBM EMB
SM
INH
PZA RIF
EMB
SM
THA
EMB
THA SM
PAS PZA
THA
PAS
PZA
THA
Low
398
subsequent phase that lasts for 4 to 8 weeks, extracellular

bacilli that are growing slowly are killed, this action is
more dependent on physiological state of the bacilli and
less by the bactericidal activity of the drug. During this
period, the bactericidal activity of rifampicin (RMP) is
important and pyrazinamide (PZA) contributes by killing
extracellular bacilli that persist in acidic areas of
inflammation.16 During maintenance phase of treatment
that lasts for 4-6 months, persistent intracellular bacilli
are eradicated mainly by rifampicin, although INH will
continue to offer protection against the development of
resistance and may assist with organism eradication,
especially in fibrocaseous tissue with poor drug
penetration.17 Host immunity plays an important role
throughout, but is of particular importance to effect
organism eradication and prevent disease relapse, as
indicated by the high relapse rate in HIV-infected
children.17
administered in the initial weeks of therapy with

isoniazid and para-aminosalicylic acid, the failure rate
evaluated by bacteriological conversion at 6 months was
much lower. After rifampicin emerged as the most
effective antituberculosis medication, the most effective
and modern short-course regimen were formulated.
Prevention of Drug Resistance
Standardized TB Treatment Regimens
Drugs that are highly active in the prevention of drug

resistance, suppress the growth of the entire bacterial
population to prevent the emergence of mutants resistant
to another drug. Isoniazid and rifampicin have the
highest activity in preventing the emergence of drug
resistance, followed by streptomycin and ethambutol.
The activity of pyrazinamide in this area is poor.
There are many different possible anti-TB treatment

regimens. The World Health Organization (WHO) and
the International Union Against Tuberculosis and Lung
Disease (IUATLD) recommend standardized TB
treatment regimens. The regimens are affordable. The
World Bank recognizes short-course chemotherapy
(SCC) as one of the most cost-effective health
interventions.
Development of the Concept of

Two Phase Chemotherapy
Short-Course Therapy
Bactericidal drugs ensure rapid reduction of the organism

load, which improves clinical symptoms, limits disease
progression, terminates transmission, and prevents the
emergence of drug resistance. Sterilizing drugs ensure
the effective eradication of dormant and intermittently
metabolizing (persistent) bacilli, thus preventing disease
relapse. These principles provide the rationale behind
the intensive and continuation phases of current
antituberculosis treatment regimens.18
Soon after the development of the principle of
multidrug therapy for active infection came the
theoretical notion that an initial intensive phase of
therapy with more than two drugs followed by a
continuous phase during which fewer drugs could be
given, would be more effective in achieving good
outcome. The justification for this was based on the notion
that larger numbers of organisms contain greater number
of bacilli that may be resistant to initial agents, so that by
adding several agents at once in the initial phase more
effective killing could be achieved.
In 1960s several studies provided strong evidence for
the concept of initial intensive phase using multiple
drugs. 4 It was found that when streptomycin was
It was realized that long-term therapy of 18 to 24 months

though effective was expensive and leads to
noncompliance on the part of the patient. This led to field
trials of several short-course regimens. The British
Medical Research Council and its collaborators through
field trials provided useful insight into formulation of
effective short-course chemotherapy and also provided
framework for future investigation. 9-11 These trials
established that:
i. RIF containing regimes could allow effec-tive shortcourse therapy of active, smear-positive, cavitary
disease.19-21
ii. Inclusion of at least two bactericidal drugs is
necessary in short-course chemotherapy.
iii. Relapses in short-course tend to occur within the
first year after completion of therapy.
iv. Multidrug therapy can be given with minimal
toxicity.
v. Relapses occurring after short-course, multi-agent
therapy were almost always caused by organisms
that retain their original sensitivity pattern, i.e.
multi-agents are effective in prevention of
emergence of drug resistance.
Effective Anti-TB Drug TreatmentProperly Applied

Short-course Chemotherapy
It is known for over 100 years that M. tuberculosis causes
TB and effective anti-TB drugs are available for nearly
50 years. Yet the worlds TB problem is now bigger than
ever, why? The problem is not the lack of an effective
treatment. Properly applied short-course chemotherapy
(SCC) fulfills the above aims of anti-TB drug treatment.
The problem is how to apply SCC properly. The answer
is a properly managed TB control program.
Shortest-Course Therapy
Several trials in the 1980s by British Medical Research
Council, tried to shorten the duration of therapy to even
less than 6 months by using more effective drugs in the
initial intensive phase.21 The general consensus that
emerged was that regimens shorter than 6 months were
likely to be associated with significant relapse rates even
if most active agents were used.
Intermittent Treatment
Researchers noticed that the major cause of treatment
failure, relapse and the emergence of drug resistance was
the nonadherence to therapy by the patient. Two methods
to address these problems were studied:
i. Supervised therapy
ii. Intermittent therapy.
Supervised therapy involves watching the patient
swallow each dose of medication. This was found to be
an effective way to address nonadherence. To make it
more-effective, intermittent (2 to 3 times/week) rather
than daily therapy was tried. 22 It was found that
efficiency of INH did not change significantly as interval
of dosage was increased from daily to every 4 days.
Moreover, ethambutol and rifampicin were found to be
actually more effective when given intermittently.
Intermittent regimens have proved to be effective and
no more toxic than daily regimens.23 Based on these
principles, directly observed therapy strategy have been
developed. Intermittent regimens have been documented
to be as effective as daily regimen in the pediatric
population.24-27 There are no randomized controlled trials
comparing thrice weekly regimen with daily treatment.
A meta- analysis of twice weekly regimen with that of
daily regimen has concluded that twice weekly
intermittent short-course therapy is less likely to cure
tuberculosis in children as compared to daily therapy.
There is a need for better quality randomized controlled
trials for assessing efficacy of alternate schedule for
intermittent therapy for childhood tuberculosis.28 Thrice
weekly intermittent therapy has been used in children
under DOTS. 29,30 Indian Academy of Pediatrics
recommend use of supervised thrice weekly intermittent
therapy till new data are available.
Socioeconomic Principles
The major determinant of the outcome of treatment is
patient adherence to the drug regimens. The length of
treatment programs, adverse effects of drugs,
symptomatic improve-ment of the patient before they
complete therapy and the cost of therapy make
compliance with antituberculosis chemotherapy difficult
even in the best of circumstances. Noncompliance leads
399
to problems not only for the individual but for the

community at large since it is a contagious disease.
Moreover, it leads to selections of drug-resistant strains
of mycobacteria.
In response to the problem of noncomp-liance, a
variety of solutions have been propo-sed, including
programs of directly observed therapy under which
patients receive incentives to complete their treatment
while being supervised.31-33 Further, the use of fixed dose
combination may enhance patient adherence
and may reduce the risk of inappropriate monotherapy.
For this reason, the use of such fixed dose combinations
is encouraged.34
HIV TB Coinfection
Infection with HIV and tuberculosis is a major challenge
due to drug interaction. WHO recommendations advise
starting ART once ATT is established (after a period of
2-8 weeks) for all WHO clinical stage 4 HIV-infected
children and stage 3 children with advanced or severe
immunosuppression; for children in WHO clinical stage
3 with mild or no immuno-suppression, ART may be
deferred until 6 months till ATT are completed.35 There
are reports suggesting benefits of early addition of
antiretroviral drugs with ATT. 36,37 There is need to
identify precise time when ART can be introduced with
ATT.
Disease Principles Specific to Pediatrics

Children with tuberculosis typically have closed caseous
lesions and thus the bacillary load is less. As already
discussed, the likelihood of developing drug resistance
during therapy is less and most commonly encountered
resistance in children is infection with already resistant
organism acquired from an adult.
Children have higher propensity than adults to
develop extrapulmonary forms of tubercu-losis,
particularly disseminated disease and meningitis. It is
important that antituberculosis drugs used in children
penetrate a variety of tissues and fluids, specially the
meninges.
The pharmacokinetics of antituberculosis drugs differ
in children and adults. In general, children tolerate larger
doses per kilogram of body weight and have less side
effects than adults. It is unclear whether the higher serum
concentration of antituberculosis drugs, achie-ved in
children provide a therapeutic advantage. In general,
children with more severe forms of tuberculosis, or those
with malnutrition, expe-rience more significant
hepatotoxic effects than less severely ill children treated
with same dosage per kilogram.
Antituberculosis formulations for children should
avoid the usage of suspensions or crushing of tablets as
it leads to inadequate absorption.
400
Case Definitions in Children

There is necessity of making case definitions in children.
DOTS has been described in details about children
elsewhere. However, there is no mention of separate case
definitions. In Chapter 9 on pulmonary tuberculosis, we
have analyzed our data from the Pediatric TB clinic and
categorized it as per WHO classification used in DOTS.
For children, case definitions as described in the earlier
part of chapter based on the clinico-immunoradiological
profile by Seth3,3a should be followed. Case definitions
are necessary for two purposes:
i. To determine treatment
ii. For recording and reporting.
Why do case definitions determine treatment?
The reasons are:
i. To identify priority cases.
ii. To make the most cost-effective use of resources (by
targeting resources on priority cases).
iii. To minimize side-effects for patients, (by using the
most intensive regimens only for certain cases).
What determines case definitions?
There are four determinants:
i. Site of TB
ii. Result of sputum-smear status (Adole-scence age
period)
iii. Previous TB treatment
iv. Severity of TB.
Always ask a new TB patient if he or she has ever had TB
treatment before.
Case definition by previous treatment. Seth et al (Chapter
9) has proposed under this, when to continue the same
regimen, when to reassess the patient and restart either
the same regimen or new, depending upon the type of
tuberculosis. This is dependent upon for how long the
child has taken treatment.
In DOTS or otherwise, all the child patients must be
given due importance to the treatment/management of
children under five years in the family of an adult with

sputum-positive PTB or severe sputum ve PTB.
Till this date, the contact survey for children under
five years is only on paper, and in the program, it is hardly
being followed. PPD of the desired strength, i.e. 1TU with
Tween 80 is now available for the children in the program.
Some pediatricians are using Span PPD of 5TU strength.
This is also not a bad practical solution as an interim
arrangement because a sizable population of preschool
children under five years have associated grade
II and III malnutrition. Seth in Chapter 8 on
clinicoimmunological profile has demonstrated that
delayed type hypersensitivity is better elicited with 5TU
of PPD particularly in malnourished children.
The other basic investigation is radiology, or good
X-ray chest of the child. Pediatricians would not compro
mise if at least these two tests are not made available in
the program situations, otherwise making a committee
involving few so called renowned pediatricians
(members of Indian Academy of Pediatrics) is futile.
Now, there is ample literature that childhood contacts
are potential sources for transmission of the TB disease.
Merely treating adults will not control tuberculosis. For
diagnosing tuberculosis in children, also under RNTCP,
described elsewhere, specific guidelines have been laid
down. Again, as has been happening in the past, scoring
system for diagnosis are being given as a soother.
However, these are far from satisfac-tory, though can also
be tried along as a supple-ment but not as a substitute to
tuberculin test and X-ray chest. In DOTS, now it is very
rightly emphasized to involve medical colleges and
practitioners including pediatricians for better coverage
of this valuable section. However, the ground reality is
that pediatricians will not be satisfied for diagnosis of
tuberculosis, based on the scoring system which is being
recommended to start with alone. Tuberculin test *(PPD
of 5TU strength) is being used not only by private
practitioners, and pediatricians, but also by pediatric
Fig. 29.1: Case definitions in tuberculosis

departments of medical colleges. X-ray chest is another
basic minimum investigation which must be done. Sarin
has very rightly emphasized the lacunae in the DOTS
(described elsewhere) regarding management of children
in the younger age groups, particularly < 5 years. Hence,
it is time that necessary steps, as out-lined above, must
be taken from now onward. Otherwise the delay will
hamper the program.
For children, besides designing of proper regimens
for ensuring adherence to the regimen, the medication
has to be made available in the palatable form so that, it
can be administered in proper dosage. We have been
following international guidelines for dosages of antituberculosis drugs. Seth et al have described elsewhere
(Chapter 32) their findings of pharmacokinetics in
relation to disease severity, nutritional status and
acetylator phenotyping done by high performance liquid
chromatography (HPLC) of isoniazid, rifampicin,
pyrazinamide, singly and in combination forms, as drugs
are now available in the syrup and dispersible kid tablets.
Doses based on these are less hepatotoxic but have equal
efficacy. In DOTS the concept of combipacks is good but
one has to ensure that the drugs supplied are in the
palatable form. Keeping in mind the age of the baby,
nutritional status, site of the disease, an algorithm
describes the case definitions (Figure 29.1) followed
under DOTS. This can be modified a little as described
by Seth3 and will suffice.
HIGHLIGHTS
Drug therapy is the only effective measure for the
treatment of active tuberculosis.
The aim is to the sterilize the tuberculosis lesions, at
various sites in the body, to prevent spread of disease
both local as well as hematogenous from primary
infection.
Single drug therapy for active tuberculosis results in
a substantial relapse rate and development of isolates
resistant to the initial agent.
Patients should receive an initial intensive phase of
treatment with at least 3 to 4 drugs, followed by 2
drugs for 4 to 6 months.
Never add a single drug to a failing regimen.
Short-course, intermittent therapy is the most
effective and least costly approach to treatment that
now exists.
An appropriate combination of drugs prescribed in
correct dosage should be ensured.
Compliance with therapy is the major issue in
determing the effectiveness of drug treatment.
Case definitions defined by Seth3 should be followed.
401
REFERENCES
1. Fox W. John Barnwell lecture. Changing concepts in the
chemotherapy of pulmonary tuberculosis. Am Rev
Respir Dis 1968;97:767-90.
2. Mitchison DA. The action of antituberculosis drugs in
short-course chemotherapy. Tubercle 1985; 66:219-25.
3. Seth Vimlesh. Clinicoradioimmunological profile of
tuberculosis in childrenIndian scenario. In: Seth
Vimlesh (Ed): Essentials of Tuberculosis in Children. 1st
edn. New Delhi: Jaypee Brothers Medical Publishers (P)
Ltd. 1997;312-33.
3a. Seth Vimlesh, Kabra SK, Seth Rachna.
Clinicoimmunological profile: India scenario, in Seth
Vimlesh, Kabra SK (Eds) Essentials of Tuberculosis in
Children 3rd edn. New Delhi: Jaypee Brothers Medical
Publisher (P) Ltd. 2006; 95-105.
4. Jindani A, Abu VR, Edwards FA, et al. The early
bactericidal activity of drugs in patients with pulmonary
5. Canetti G. Host factors and chemotherapy of
tuberculosis. In: Barry VC (Ed): Chemotherapy of
Tuberculosis.
London,
Butterworth
1964;
20-38.
6. McDermott W, et al. Streptomycin in the treatment of
tuberculosis in humans. Ann Intern Med 1947;27:769-72.
7. Chan SL. Chemotherapy of tuberculosis. In: Davies PDO
(Ed): Clinical Tuberculosis. 1st edn. London: Chapman
and Hall 1994;141-56.
8. Fox W, Ellard GA, Mitchison DA. Studies on the
treatment of tuberculosis undertaken by the British
Medical Research Council Tuberculosis Units, 19461986,
with relevant subsequent publications. Int J Tuberc Lung
Dis 1999;3:S231-S279.
9. British Thoracic Society. Chemotherapy and
management of tuberculosis in the UK: Recommendations 1998. Thorax 1998;53:536-48.
10. World Health Organization. Treatment of tuberculosis:
Guidelines for national programs. 3rd edn. Geneva,
Switzerland: World Health Organization; 2003. WHO/
CDS/TB/2003.313.
11. Blumberg HM, Burman WJ, Chaisson RE, et al. American
Thoracic Society, Centers for Disease Control and
Prevention, Infectious Diseases Society. Treatment of
tuberculosis. Am J Respir Crit Care Med 2003;167:60362.
12. European Respiratory Society Task Force. Tuberculosis
management in Europe: Recommendations of a Task
Force of the European Respiratory Society, the World
Health Organisation and the International Union against
Tuberculosis and Lung DiseaseEurope Region. Eur
Respir J 1999;14:978-92.
13. Grosset J. The sterilizing value of rifampicin and
pyrazinamide in experimental short-course
chemotherapy. Tubercle 1978;59:287-97.
14. Mitchison DA. Role of individual drugs in the
chemotherapy of tuberculosis. Int J Tuberc Lung Dis
2000;4:796-806.
402
15. Mitchison DA. The diagnosis and therapy of tuberculosis
during the past 100 years. Am J Respir Crit Care Med
2005;171:699-706.
16. Donald PR. Childhood tuberculosis. Curr Opin Pulm
Med 2000;6:187-92.
17. Schaaf HS, Krook S, Donald PR, et al. Recurrent cultureconfirmed tuberculosis in human immunodeficiency
virus-infected children. Pediatr Infect Dis J 2005;24:68591.
18. Marais BJ, Gie RP, Schaaf HS, Donald PR, et al. Childhood
Pulmonary Tuberculosis: Old Wisdom and New
Challenges. Am J Respir Crit Care Med 2006;173:107890.
19. East African/British Medical Research Council.
Controlled clinical trial of four short-course (6 months)
regimens of chemotherapy for treatment of pulmonary
tuberculosis. Third report. Lancet 1974;2:237-40.
20. Newman R. Rifampicin in initial treatment of tuberculosis.
Am Rev Respir Dis 1971;103:461-76
21. East African/British Medical Council Controlled trial of
5 short-course (4 months) chemotherapy regimens in
pulmonary tuberculosis. First report of 4th study. Lancet
1978;2:334-8.
22. Tuberculosis Chemotherapy Centre, Madras. A
concurrent comparison of intermittent (twice wkly) INH
+ SM+ and daily INH + PAS in the domiciliary treatment
of pulmonary tuberculosis. Bull WHO 1964;34:247-71.
23. Tuberculosis Chemotherapy Centre, Madras. Controlled
comparison of oral twiceweekly and oral daily
INH+PAS in newly diagnosed pulmonary tuberculosis.
Br Med J 1973;2:7-11.
tuberculosis. Pediatr Infect Dis J 1990; 9:794-801.
25. Kumar L, Dhand R, Singhi PD, et al. A rando-mized trial
of fully intermittent vs daily followed by intermittent
short-course chemotherapy for childhood tuberculosis.
Pediatr Infect Dis J 1990; 9:802-6.
26. Kiper N, Gocmen A, Dilber E, et al. Effectiveness of shortcourse intermittent chemotherapy for tuberculosis in
young infants aged less than 6 months. Clin Pediatr
1998;37:433-6.
27. Te Water Naude JM, Donald PR, et al. Twice weekly vs

daily chemotherapy for childhood tuberculosis. Pediatr
Infect Dis J 2000;19:405-10.
28. Menon PR, Lodha R, Sivanandan S, et al. Intermittent or
daily short-course chemotherapy for tuberculosis in
children: Meta-analysis of randomized controlled trials.
Indian Pediatr 2010; 47: 67-73.
29. Indumathi CK, Prasanna KK, Dinakar C, Shet A, Lewin
S. Intermittent short-course therapy for pediatric
tuberculosis. Indian Pediatr 2010; 47: 93-6.
for treatment of paediatric pulmonary tuberculosis in
South Delhi, India. Int J Tuberc Lung Dis 2008;12:74-80.
31. Iseman MD, Cohn DL, et al. Directly observed treatment
of tuberculosis. We cannot afford not to try it. N Eng J
Med 1993;328:576-8.
32. Chauhlte CP. The public health tuberculosis guidelines
panel. Directly observed therapy for treatment
completion of pulmonary tuber-culosis. Consensus
statement of the public health tuberculosis guidelines
panel. JAMA 1998;279:943-8.
33. Fujiwar PI, B Simone PM, Munsiff SS. Treatment of
tuberculosis. In: Reichman LB (Ed). Tuber-culosis, A
Comprehensive International Approach, Marcel Dekker
Inc 2000;402-31.
34. Schluger NW, Harlin TJ. Principles of therapy of
tuberculosis. In: Rom and Garey (Eds): The Modern Era
in Tuberculosis. 1st edn. Little Brown and Company
1996;751-62.
35. WHO. Considerations for infants and children coinfected
with tuberculosis and HIV. Antiretroviral therapy of HIV
in infants and children: Towards universal access. WHO
2006:43-8.
36. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of
initiation of antiretroviral drugs during tuberculosis
therapy. N Engl J Med 2010; 362: 697-706.
37. Mukherjee A, Lodha R, Kabra SK. Changes in CD4 count
with antitubercular therapy in HIV infected children
with tuberculosis. J Trop Pediatr 2009;55:125-7.
30
Antituberculosis Drugs:
First-line Agents
INTRODUCTION
Despite the availability of effective treatment for over fifty
years, tuberculosis continues to pose a serious threat to
global health with nearly a million new cases every year.
DOTS has been expanded all over India. To sustain DOTS,
Global TB Drug Facility (GDF) has been developed by
the Global partnership (STOP.TB) to address these issues.
The aim being to increase and secure access to high quality
TB drugs. GDF was launched on 24 March in 2001 with
the financial help from the government of Canada.
Further details of the GDF are available on the website at
http://www.STOPTb.org/GDF/. The GDFs primary
support mechanism is in the form of grants in kind of
first-line TB drugs. The quantity of drugs provided is
calculated on the basis of the number of additional
patients to be treated in accordance with a national DOTS
expansion plan. The lessons learnt through the GDF could
increase access to medicines for disease other than TB,
specially HIV/AIDS. The lessons include the need to:
1. Link demand, supply and monitoring, to facilitate
increased access while ensuring rational use.
2. Establish a virtual organization through a partnership
of agencies.
3. Use product packaging as a means to simplify
logistics, promote rational use by health workers, and
enhance patient acceptability and compliance.
GDF provides a standardized catalog of TB drugs.
It ensures supply of fixed-dose combination (FDC)
tablets in the package of individual patient. Four and
two drug FDCs are the core products provided by
the GDF. This strategy promotes patient acceptance
and adherence to treatment.
4. Use grant of drug to catalyse improvement in the
quality of health services provision.
5. Establish a disease funding base.
The TB drugs supplied are carefully selected with a
view to improve the success of treatment. Procurement
of drugs through international mechanisms has not only
reduced the price but has increased the reliability of the
supplies.
Centuries of human suffering and deaths from
tuberculosis led to widespread efforts to interrupt the
devastating effects of the disease. Treatment methods
varied from bizarre exotic methods to very simple
strategies like change in diet, residence, climate or

employment. These methods have had varied results and
probably might have provided benefit to some patients
by increasing their cellular immune response. Paraamino
salicylic acid (PAS) was the first antituber-culosis drug
and was also the first effective agent administered to a
TB patient, antedating the introduction of streptomycin
by one month.1 Streptomycin was discovered by Albert
Schatz a graduate student of the famed Dr. Waksmans
laboratory who was a pioneer in the field of soil
microbiology.2 Streptomycin was a powerful, clinically
proven antituberculosis drug, but by the end of 1940s it
became apparent that the clinical usefulness of streptomycin
was being severely curtailed by the emergence of drug
resistance. PAS was the first agent available that
effectively prevented the emergence of streptomycin
resistance when the two drugs were given concurrently.
Isoniazid (INH) first became available in 1952. Treatment
of this dreaded disease evolved so much that in a decade
from 1944 to 1954 the prognosis of an individual with
tuberculosis changed from a dismal outlook to the
expectation of complete cure. By this time it was apparent
that if streptomycin, isoniazid and PAS were taken for a
sufficient period of time, it virtually ensured control of
the disease except for the most virulent forms of
tuberculosis. Even after the introduction of chemotherapy,
traditional approaches such as those outlined above were
still thought to play a role in treatment. It was not until
after several controlled studies provided evidence to the
contrary that the primacy of drug therapy was undeniably
established.
As we have moved into the 21st century, it appears
that newer antituberculosis drugs will arise from four
new categories: (i) New use of old drugs; (ii) New
delivery of old drugs; (iii) New drugs within old classes;
(iv) Newer classes of drugs. 3 Old drugs such as
clofazimine and its analogs, rifamycins, the macrolides,
aminoglyco-sides, quinolones and perhaps vitamin D
may find a way into better regimens. New therapy may
also arise from new uses of current antituberculosis
drugs. New drugs are being developed in the rifamycin,
fluoroquinolone and nitroimidazole families. Several
immune amplifiers such as gamma interferon,
interleukin-2 and 12 have undergone pilot testing.3
Counter-acting adhesion molecules are being tested for
404
several infectious diseases. With the unraveling of the

tuberculosis genome, attacking enzymes unique to M.
tuberculosis is easier and allows us to hit elements in both
a metabolic pathway and its alternate pathway.4
CLASSIFICATION OF DRUGS
Traditionally, antituberculosis drugs have been classified
as first-line drugs having superior efficacy with acceptable
toxicity and second-line drugs either having less efficacy,
greater toxicity or both.5,6 Antituberculosis drugs vary
according to bactericidal action and their effect in different
bacterial populations. All the first-line agents are
bactericidal except ethambutol. This drug also becomes
bactericidal in higher plasma concent-ration. The drugs
are classified as shown in Tables 30.1 to 30.4.
Table 30.1: Classification of antituberculosis drugs
First line drugs
Second line drugs

Broad spectrum
Narrow spectrum
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
Streptomycin
Fluoroquinolones
Ciprofloxacin
Ofloxacin
Levofloxacin
Moxifloxacin
Gatifloxacin
Amikacin
Capreomycin
Kanamycin
Viomycin
Ethionamide
Prothionamide
Rifamycins
(other than
Rifampicin)
Rifapentine
+Thiacetazone
Rifabutin
*Para-amino
salicylic acid
Macrolides
Clarithromycin
Azithromycin
Cycloserine
* not used, + practically not being used.
The other drugs potentially useful for the treatment of

multidrug-resistant tuberculosis are given in Tables 30.2
and 30.3.
Table 30.2: Classification of antituberculosis drugs

Tuberculocidal
+
Tuberculostatic
Isoniazid , Rifampicin
Streptomycin, Amikacin
Pyrazinamide
Ethambutol* (except in
inflamed meninges),
Thiacetazone,
Ethionamide
Capreomycin,
Quinolones, Rifamycins
Paraamino salicylic acid

Cycloserine*
+ Bacteriostatic for resting bacilli

* Becomes bactericidal in higher concentrations
Table 30.3: Other drugs potentially useful in multidrugresistant tuberculosis

Newer drugs
Diarylquinoline
R207910
TMC 207
Nitroimidazopyran
PA-824
Nitro-dihydroimidazo-oxazole
OPC 67683
Macrolides
Telithromycin
Oxazolidinones
Linezolid
PNU-100480
AZ 5847
Diamine
SQ109
Ring substituted imidazoles and other agents
Levamisole
Thalidomide
Pentoxyfylline
Interleukin-12 (IL-12)
Interferon- (INF- )
Imiquimod
Inhibitors of transforming growth factor
(TGB-) Transfer factor
Table 30.4: Classification of currently used antituberculosis

drugs (WHO, 2006)*
Group 1 - First-line oral anti-TB drugs
- Isoniazid
- Rifampicin
- Ethambutol
- Pyrazimamide
Group 2 - Injectable anti-TB drugs
- Streptomycin
- Kanamycin
- Amikacin
- Capreomycin
- Viomycin
Group 3 - Fluoroquinolones
- Ciprofloxacin
- Ofloxacin
- Levofloxacin
- Moxifloxacin
- Gatifloxacin
Group 4 - Oral bacteriostatic second-line anti-TB
drugs
- Ethionamide
- Prothionamide
- Cycloserine
- Terizidone
- Para-aminosalicylic acid
- Thiacetazone
*World Health Organization. Guidelines for the programmatic
management of drug resistant tuberculosis. WHO/HTM/TB
2006.361. Geneva, World Health Organization, 2006.
405
Chapter 30 Antituberculosis Drugs: First-line Agents

It has become customary to discuss anti-tuberculosis
drugs in terms of their effect on different physiologic
populations of mycobacteria:
Rapidly multiplying organisms in extra-cellular
environment of pulmonary cavities.
Intermittently multiplying organisms (semidormant)
in relatively hypoxic or acid environment of solid
caseous material.
Occasionally dividing organisms (dormant) in the
activated macrophages.
Drug resistant mutants.
WHO has classified the drugs in four groups Table
30.4.
Antituberculosis drugs vary in their ability to kill
actively metabolizing extracellular population (bactericidal
action), their action on semidormant bacilli (sterilizing
action) and in prevention of emergence of resistant strains
(Table 30.5).
Mitchison7 has proposed three prerequisites for an
antituberculosis drug; (i) Early bactericidal activity; (ii)
Sterilizing activity and (iii) Ability to prevent emergence
of resistance to the companion drug.

The early bactericidal activity (EBA) of an antituberculosis
agent is arbitrarily defined as the decrease during the
first 2 days of treatment in log10 colony forming units.
(Cfu) of M. tuberculosis in the sputum of pulmonary
tuberculosis patients. These patients have smear-positive
TB. Isoniazid has the highest early bactericidal activity.8,9
It reflects an agents ability to kill metabolically active
organisms present in the walls of tuberculosis cavities.
While rifampicin and pyrazinamide provide almost all
of the bactericidal activity, isoniazid is bactericidal only
during the first two days and thereafter prevents the
emergence of drug resistance.9a Although the EBA of
isoniazid is significantly enhanced by n-acetyltransferase2 (NAT 2) genotype, even in individuals who are
homozygous fast (ff) acetylators of isoniazid; a relatively
high EBA is still reached at doses that would usually be

used in clinical practice. 9b The rapid reduction in
infectiousness seen in TB patients is due to the use of
isoniazid.
Sterilizing Activity
Sterilizing activity is defined as the ability to remove so
called persisters once the large bulk of rapidly growing
organisms has been killed. There are two major
components of chemotherapy of tuberculosis.10 If there
is inability to destroy rapidly growing bacilli located
largely extracellularly, failure of treatment results.
However, if there is inability to eradicate the persisters,
the largely intracellular bacilli, relapse occurs subsequent
to treatment completion.
Persisters are those bacilli that have a lower metabolic
activity. These replicate much more slowly than bacilli
found in cavity linings. It was postulated that the efficacy
of rifampicin as a sterilizing agent was due to its activity
on persisters.11 Rifampicin and pyrazinamide have the
highest sterilizing activity followed by isoniazid, while
streptomycin, thiacetazone and ethambutol have weak
sterilizing activity.
Ability to Prevent Emergence of Resistance to the

Companion Drug
Prevention of the emergence of drug resistance is defined
as the ability of a drug to prevent selection of mutants
resistant to the companion drug. Rifampicin has the
highest activity to prevent emergence of resistance
against isoni-azid, followed by ethambutol and streptomycin
while pyrazinamide and thiacetazone have very low
activity (Table 30.5).
Isoniazid (INH)
Isonicotinic acid hydrazide (INH) was intro-duced in
clinical practice in 1952.12 It is selectively effective against
M. tuberculosis and is nearly a perfect chemotherapeutic
Table 30.5: Activity of some important antituberculosis drugs on different bacterial populations
Agent
Isoniazid
Rifampicin
Pyrazinamide
Streptomycin
Ethambutol
Bacterial Populations
*Active
(Extracellular)
* Semidormant
(Caseous)
** Dormant
(Caseous)
*** Resistant
(Mutants)
+++
+++
_
+++
++
++
+++
_
+
++
+++
++
+++
+++
_
++
+++
*-Bactericidal action ** Sterilizing action

*** - Prevention of emergence of resistance
Bactericidal drug active against intracellular organisms
Bacteriostatic/bactericidal against both intracellular and extracellular organisms
406
agent owing to its marked bactericidal and sterilizing

action, good oral absorption, relative safety and low cost.1
Antibacterial Activity
Isoniazid is only active against mycobacteria and is the
most widely used of the antituberculosis agents. In many
respects it is an ideal agent-bactericidal, relatively easily
administered, and inexpensive. The effect of isoniazid is
mainly against M. tuberculosis complex. Among the
various non-tuberculous atypical mycobacteria, only M.
kansasii is usually susceptible to isoniazid. Isoniazid is
bacteriostatic for resting bacilli but is bactericidal for
rapidly dividing bacilli. The minimal tuberculostatic
concentra-tion is 0.025 to 0.05 g/ml in broth and 0.1 to
0.2 g/ml in agar plates.13-15 Of all the antituber-culosis
drugs, isoniazid has the most potent early bactericidal
activity.8,16-18 The addition of other antituberculosis drugs
will not increase the early bactericidal activity.16 The
rapid reduction of infectiousness following initiation of
chemo-therapy is most likely due to the bactericidal
activity of isoniazid.19-21
The modern short-course chemotherapy aims at rapid
bactericidal and sterilizing action. Combination chemotherapy is employed because of the usual presence of
spontaneously resistant mutants to one drug, improper
chemotherapy leads to acquired drug resistance. The
frequency of natural resistance in a sample of wild type
mycobacteria is 3.5 10 6 for INH, 3.8 10 6 for
streptomycin, 3.1 108 for rifampicin and, 0.5 104 for
ethambutol.1,22 Children usually do not depict primary
resistance to antituberculosis drugs unless the source case is
suffering with resistant bacilli.
Mechanism of Action
The acid fastness of the mycobacterium is lost shortly
after treatment with isoniazid.23 Primarily isoniazid has
been shown to inhibit the biosynthesis of mycolic acids.24
There is a direct correlation between isoniazid uptake,
viability and mycolic acid biosynthesis.25,26 Isoniazid has
an inhibitory effect on the synthesis of saturated fatty
acids greater than 26 carbons and the synthesis of
monounsaturated long chain fatty acids in vivo.27,28
Isoniazid acts on the enzymatic steps (catalase-peroxidase
system) in the elongation of fatty acids, and the
biosynthesis of the very long fatty acid chains of mycolic
acids.29 Antimicrobial activity of INH has high levels of
selectivity for mycobacteria due to the unique mycolic
acids in their cell walls.
Catalase and peroxidase processed by a number of
mycobacteria play a critical role in INH sensitivity.30-32
These enzymes actively transport INH into the cells and
convert it into active metabolite. INH enters the organism
by diffusion and oxygen dependent active transport.
Under anerobic conditions the rate of uptake is reduced.
Postulated modes of action include inhibition of mycolic

acid synthesis, depletion of NAD (nicotine adenine
dinucleotide) caused by the incorporation of derivatives
of INH into NAD. INH is neither taken up, nor has any
effect on mycolic acid sythesis in the resistant organisms.
Further, there is correlation between resistance and
loss of catalase-peroxidase activity. 30,31 Isoniazidresistance strains could be sensitized to the drug by
transformation with the M. tuber-culosis katG encoded
catalase-peroxidase.33,34 Deletions and missence mutations
within katG gene are common in isoniazid-resistant clinical
isolates of M. tuberculosis.35,36
Based on these observations, currently iso-niazid is
classified as a prodrug which requires katG gene product
for activation by the catalase,29,37 targeting the last steps
in mycolic acidsynthesis.38 Although the exact mechanism
is not very clear the general mechanism of action is as
Mechanism of Resistance
Mutations in several genes (katG, inhA, ahpC, kasA and
ndh) have been identified which confer resistance to M.
tuberculosis. Two important mutations are located on the
katG gene,33 and the inhA gene.39 The inhA gene which is
considered as the primary drug target is generally
associated with low level of resistance. It is responsible
for approximately 25 percent of clinical isolates that
demonstrate resistance. Susceptibility to isoniazid is
dependent on the presence of the catalase-peroxidase
enzyme encoded by the katG gene. 36,40 Catalaseperoxidase is responsible for transforming the prodrug
INH (pharmacologically inactive-INH) to its activated
state (activated-INH). Mutations in kat G gene render
catalase-peroxidase inactive, which, in turn fails to
activate the prodrug INH. This causes high-level
isoniazid resistance to M. tuberculosis. The ahpC gene
Fig. 30.1: Proposed site of action of isoniazid
407
encodes the alkyl hydroperoxide reductase, and its

absence leads to isoniazid resistance.41 Approximately
60 to 70 percent of isoniazid resistant strains carry
mutations in one of the several genes involved in its
activation from prodrug (katG and possibly ahpC) or in
the drug target (inhA). Still, the mechanism of resistance
for one-third of isoniazid-resistance strains remains to
be elucidated. The maximum proportion of isoniazidresistant mutants able to grow during isoniazid
monotherapy of an isoniazid-susceptible strain is
estimated to be approximately 1 in 10.6,42-44
Pharmacokinetics
Following oral administration, INH is rapidly and
completely absorbed. Aluminium containing antacids
and food decrease the absorption from the gastrointestinal
tract.45 Therefore, it is best given on empty stomach. Peak
plasma concen-tration of 3 to 5 g/ml which is 60 to 100
times the MIC of the drug (0.05 g/ml), is achieved in 1
to 2 hrs after an oral dose of 5 mg/kg/day. However, in
children the peak ranges from 16 to 20 g/ml probably
due to a greater dosage of INH per unit of body weight.46
A study by Seth and Rao47 have demonstrated that with
the use of INH in the dosage of 10 mg/kg orally, peak
levels of 90 to 160 times of MIC were achieved. Therefore,
administration of higher dosages in children is not
justified.
After absorption, INH diffuses in all body cells and
fluids. Concentration in CSF is about 20 percent of that
in plasma, or maybe similar to plasma when meninges
are inflamed.48 The infected tissues, phagocytes, and
caseous material retain the drug for a longer time and in
higher concentrations.49 Although the drug readily
crosses the placenta and is secreted in breast milk, yet no
fetal or neonatal risks are involved.50,51
INH is metabolized in liver by both acetylation and
oxidation via the hepatic P-450 mixed oxidase drugdetoxifying cytochrome systems, the major metabolites
being acetyl isoniazid and isonicotinic acid. None of these
metabolites has any biological activity (Figs 30.2 and 30.3).2
The rate of acetylation of INH is genetically controlled.
Acetyl transferase is predominantly found in the liver
and the small intestine. In certain ethnic groups the rate
of rapid inactiva-tion is high. Thus, the Japanese, Koreans
and particularly the Eskimos have a prevalence of rapid
inactivation ranging from 50 to 95 percent.2 In South
Indian population it is as low as about 5 percent. INH
metabolite hydrazine plays an important role in the
hepatoxicity. Metabolism of INH leads to the production
of hydrazine via both direct and indirect pathways. In
both cases, the activity of an INH amidase is required to
hydrolyze an amide base. In experimental studies,
pretreatment with the amidase inhibitor (bis-p-nitrophenyl
phosphate), 30 minutes before injection of INH, inhibited
Fig. 30.2: Major pathway for isoniazid metabolism
Fig. 30.3: Pathway for isoniazid metabolism
the formation of INH derived hydrazine and decreased

hepatocellular damage.52 Significant effect on hepatic
microsomal cyto-chrome P-450 IAI/2 and cytochrome
P-450 2E1 activities suggest that their isozymes maybe
involved in the mechanism of the toxicity. After the initial
peak concentration which is similar in both slow and fast
acetylators, the steady state plasma concentration in the
latter is less than half of that in the former.3 The plasma
half-life (t ) in adult slow acetylators is 2.5 to 3 times
more as compared to the fast acetylators.53 Since it is the
peak level of the drug which is more important than the
sustained inhibitory concentration, the entire daily dose
given in both fast and slow acetylator types is not
different. However, in intermittent dosing regimens
(once weekly), controlled trials have shown that rapid
acetylators fare worse than slow acetylators as the drug
levels fall below the therapeutic concentration towards
the end of the week.54 INH-induced hepatotoxicity is
suggested to be dependent on the acetylation phenotype.
408
In 1975, Mitchell et al55 in their retrospective clinical study

showed that 86 percent of rapid acetylators had INHinduced hepatitis. On the basis of a parallel animal study,
that liver toxicity was ascribed to increased exposure in
rapid acetylators to a potent acylating agent formed by
microsomal activation of monoacetyl hydrazine. Subsequently, doubts were cast on the supposed risk of
hepatotoxicity among rapid acetylators by the demonstration that monoacetyl hydrazine is polymorphically
acetylated in man.56
According to another school of thought, the hepatotoxicity is more common in slow acetylators.57-59 The toxic
moiety according to these workers is a product of
oxidative metabolism (isoniazid hydrazine) rather than
of acetylation. In children acetylation phenotype plays
little or no role60,61 as only 3 to 10 percent of children
while on INH therapy experience transient elevation of
liver transaminases, a rate much lower than in adults.62,63
Seth et al64 have reported comparable levels of hepatic
enzymes in slow and rapid acetylators in children. In a
large population based study, there was no significant
difference in the incidence of INH-induced hepatotoxicity
by host acetylation rate status.65
INH is excreted in urine chiefly as metabolites within
twenty four hours of oral administration. Since only a
small portion of active drug is excreted in urine, mild
impairment of renal function does not necessitate the
dosage adjustment; however, in slow acetylators with
severe renal damage, the doses need to be halved.66
Adverse Effects
The total incidence of adverse effects is reported as 5.4
percent.66,67 These include skin rash (2%), fever (1.2%),
jaundice (0.6%) and peripheral neuritis (0.2%). Urticaria
and other hypersensitivity reactions occur in 1.2 percent
of cases. Hypersensitivity reactions, peripheral neuritis,
and the rare side effects related to CNS seen in adults,
are very rarely noticed in children.
Hepatotoxicity
It is reported to occur in 15 percent of adult patients,
however, in children the incidence is much lower (3-10%)
with serious jaundice occurring in only 0.6 percent of
the cases.67 Hepatotoxicity is age related, and is more
likely to occur in adolescents, in patients with severe
forms of the disease such as miliary tuberculosis and
meningitis.68,69 It is also associated with severe malnutrition.
For most children hepatotoxicity can be monitored using
clinical symptoms and signs. The routine biochemical
monitoring is not necessary when therapeutic dose of 5
mg/kg/day is being used. Hepatotoxicity is noticed
when higher doses are used (higher than 10 mg/kg/
day).57,70 Use of INH for chemopro-phylaxis even at 10
mg/kg/day resulted in elevation of transaminases in
only 7.5 percent of children.71

The incidence of hepatotoxicity in short-course
regimens and other regimens containing both INH and
rifampicin is reported to be approximately 4 times more
than that of regimens containing INH alone.72,73 A study
in adult patients taking INH and rifampicin revealed
hepatotoxicity in 5 percent of those given daily regimen
against 0 to 0.1 percent in those receiving thrice weekly
regimen.74 The appearance of jaundice is earlier when
both drugs are used together as compared to INH alone.
The increased toxicity is suggested to be due to
accelerated INH oxidation by rifampicin. However,
Girling75 on the basis of his studies concluded that risk
of hepatitis did not increase with addition of rifampicin
to INH therapy. Study by OBrien et al76 using 10 mg /
kg of INH and 15 mg/kg rifampicin demonstrated
hepatitis in only 3.3 percent of patients should hepatotoxicity
occur, it is observed generally with in the initial 2-3
months of therapy. A study conducted in adults
measuring the INH metabolites in urine after administration of both drugs showed insignificant changes
in the rate of hydrolysis.24 A large number of clinical
studies in 2500 adult patients in East Africa, Hong Kong
and Singapore using both drugs showed incidence of
jaundice in only 1 percent of cases. This is similar to that
encountered prior to the introduction of rifampicin.76-78
Hence, use of both the drugs together did not increase
the risk of hepatotoxicity.
Treatment of Hepatotoxicity
It has been observed that clinical and laboratory features
suggestive of hepatotoxicity maybe because of concomitant
viral hepatitis rather than due to antituberculosis
drugs.79,80
When the levels of transaminase (AST, ALT) enzymes
increase by 3 to 5 times of normal, temporary cessation
of both drugs is recommended.81 With clinically evident
hepatotoxicity, all drugs should be stopped and
combination of ethambutol and streptomycin be given,
till the liver functions are restored to normal. Seth82 has
recommended that rifampicin should be started in the
dose of 5 mg/kg when transaminases have decreased to
levels less than twice the normal while continuing
streptomycin and ethambutol. AST, ALT should be
estimated every week, if they are normal after a week,
rifampicin dose can be increased to 10 mg/kg and then
INH is reintroduced. At this stage, if the patient is having
serious type of tuberculosis such as TBM, miliary or
osteoarticular tuberculosis, pyrazinamide can be added
in the dose of 20 mg/kg with monitoring of AST and
ALT. The drugs can be continued even if the enzyme
levels are twice the normal. There is a need to stop INH
or pyrazinamide if the liver enzyme levels rise to more
than four times the normal. Regular monitoring of liver

functions is necessary with the altered treatment.
Adjustment of doses maybe required as hepatotoxicity
is dose related. INH should not be used more than 5 mg/
kg/day, even in the case of tuberculous meningitis in
daily regimen and 10 mg/kg in intermittent regimens.
Peripheral Neuritis
It is attributed to drug-induced pyridoxine deficiency and
is probably due to enhanced excretion of pyridoxine.2
Peripheral neuropathy is common in adults and is dose
and age dependent. Children are however, less prone to
have pyridoxine deficiency.83 In younger children,
pyridoxine levels maybe decreased, but clinical signs are
not apparent. Thus they rarely require the prophylactic
administration of pyridoxine, except those having
deficiency symptoms before therapy or have tuberculous
meningitis. Dose of pyridoxine is 5 to 10 mg/day in
children. It is also advisable to give pyridoxine with
isoniazid to women during pregnancy and to persons
who have a seizure disorder.
Central Nervous SystemSide Effects

INH may precipitate epilepsy, cerebellar ataxia, optic
neuritis and rarely psychotic changes in adults. These
reactions have responded to pyridoxine administration.
In a study by Sanfeliu et al84 done in Canada, hydrazine
was found to be the metabolite with the highest
neurotoxicity in mouse studies. INH also interferes with
niacin metabolism to a significant extent and
can cause neurological symptoms. Pellagra has been
produced due to exacerbation of niacin deficiency by INH
in undernourished individuals.84 Recently, Dompeling
et al85 have reported diplopia and strabismus, convergence
mimicking symptoms of tuberculous meningitis as side
effects of INH.85
409
Diagnosis
Severe isoniazid poisoning is characterized by the
presence of repetitive convulsions not responsive to usual
treatment and metabolic acidosis. Measurement of INH
serum levels are not useful for the clinical management
of INH overdose.
Chronic Toxicity
Hepatitis, peripheral neuropathy and hemolytic
anemia are manifestation of chronic toxicity. It produces
nausea, vomiting, restlessness, fever, toxic hepatitis, and
hemolytic anemia may be observed. At times psychosis
may occur.
Management
Acute Toxicity
Patients with INH overdose should always be admitted
to an emergency or intensive care unit. Treatment is as
follows:
Supportive Measures
Control of convulsions by short-acting barbiturate
(thiopental) or benzodiazepines (diazepam).
Protection of airway (intubation) and maintenance of
adequate ventilation (artificial ventilation) if
necessary.
Correction of hypotension by plasma expanders and/
or dopamine.
Rehydration and correction of metabolic acidosis
(sodium bicarbonate) and electrolyte abnormalities.
Antidote
ACUTE TOXICITY OF ISONIAZID
Convulsions should be treated with intravenous

pyridoxine (Approximately 1g of pyridoxine for each
gram of INH ingestion).
Main Risks and Target Organs
Elimination
CNS is the target organ of INH acute toxicity. It induces

generalized convulsions, coma, metabolic acidosis. Death
may occur from acute respiratory failure or hypotension.
Toxicity appears after 0.5 to 4 hours following ingestion.
Symptoms may include.
Slurred speech, hallucinations, coma
Generalized convulsions, status epilepticus
Respiratory failure, hypotension.
Severe metabolic acidosis, fever
Rhabdomyolysis
Gastrointestinal symptoms (nausea, vomiting) are
frequent prior to the onset of convulsions.
Gastric lavage and oral activated charcoal are indicated

with in 3 to 4 hours following ingestion. Ensure adequate
diuresis. The usefulness of forced diuresis is not
established. Hemodialysis may be considered in patients
unresponsive to supportive treatment, anticonvulsants
and intravenous pyridoxine.
Contraindications
Known severe adverse reactions or hypersensitivity due
to the drug. Previous hepatitis with INH. INH should
not be used in acute liver disease. INH may precipitate
porphyria.
410
Caution
Therapeutic Status
Convulsions may be precipitated in patients with

epilepsy.
Isoniazid is the most important drug for treating all types

of tuberculous infections. It is mostly used in combination
with other drugs preferably even in preventive therapy.
Daily dose is 5 mg/ kg/day and in intermittent regimens
it is to be given in a dose of 10 to 15 mg/kg thrice or
twice a week.
Miscellaneous
Dryness of mouth, epigastric distress, methemoglobinemia, tinnitus and urinary retention are rare side effects.
Patients with subclinical pyridoxine deficiency may show
anemia, rash and symptoms of neuropathy.
A drug-induced syndrome resembling lupus erythematosus (drug-induced lupus) has been reported.86 Toxic
dose may cause coma, seizures, acidosis and hyperglycemia.
Isoniazid crosses the placenta, but no significant
teratogenic effects have been reported even when used
during the first four months of pregnancy.86a
Pregnancy and Breastfeeding

Isoniazid is distributed into breast milk. An estimated
0.75 to 2.3 percent of the daily adult dose could be
ingested by the nursing infant. Problems in nursing
newborns have not been documented and breastfeeding
should not be discouraged. However, because isoniazid
concentrations are so low in breast milk, breastfeeding
cannot be relied upon for adequate tuberculosis
prophylaxis or therapy for nursing infants.12
Drug Interactions
Isoniazid is an inhibitor of oxidative and demethylation
metabolism, and also other cytochrome P-450 dependent
microsomal pathways.87 It is also a monoamine and
diamine oxidase inhibitor.88 Certain types of cheese rich
in monoamines may lead to hypersensitivity reactions.89
Effect of isoniazid are potentiated by paraaminosalicylic acid,90 insulin,91 carbamazepine92 and
theophylline.93 Effects of isoniazid are opposed by prednisolone94 and ketoconazole.95 Isoniazid potentiates the
effects of a large number of drugs. The acetaminophen
hepatotoxicity is increased by isoniazid.96,97 The action
of antiepileptics such as phenobarbitone, diphenylhydantoin, 98-100 carbamazepine, 101-104 ethosuximide105 and
valproic acid are enhanced.106-108 The interaction of isoniazid and antileptics increase the serum concentration
of both drugs. When these drugs are given concomitantly
the serum levels of antiepileptics should be monitored
and the antiepileptic doses decreased if necessary. The
effects of diazepam109 and triazolam,110 haloperidol111
and tricyclic antidepressants112,113 are potentiated by isoniazid. The anticoagulant action of warfarin114 and the
action of antineoplastic agent vincristine115 are enhanced.
RIFAMPICIN (RIFAMPIN)
Rifampicin is a semisynthetic derivative of rifamycin B
and is derived from Streptomyces mediterranei. 116
Rifampicin is a potent broad spectrum antibiotic effective
against mycobacteria, staphylococci, streptococci,
meningococci, clostridia and coliform organisms. Its
potent bactericidal and sterilizing activity against the
tubercle bacillus and suitability for oral administration
has made it a key drug for the treatment of tuberculosis.
Rifampicin has succeeded in reducing the duration of
treatment of tuberculosis from the former standard of 18
to 24 months to 6 to 9 months. Rifampicin is the most
potent antituberculosis drug in converting positive
sputum cultures to negative. This characteristic ability
of sterilization has been attributed to rifampicins ability
to affect dormant organisms.117 The minimum inhibitory
concentration of rifampicin in vitro is 0.005 to 0.02 g/
ml. The majority of other strains of mycobacteria are also
sensitive but to the higher concentration of the drug.
Primary drug resistance to rifampicin may occur in
less than 1 percent of cases which necessitates its
administration with other drugs.118,119
Mechanism of Action
Rifampicin inhibits DNA-dependent RNA polymerase
leading to suppression of initiation of chain formation in
RNA synthesis. The subunit of polymerase which is
involved in binding to DNA and initiation of RNA chain
has been shown to have specific binding sites for the drug.
As a result the initiation of RNA transcription is blocked
but the elongation is unaffected. Rifampicin resistance
occurs usually by a single mutation in the gene that
specifies subunit of RNA polymerase.10 It is bactericidal
for both intracellular and extracellular bacilli.
Mutations in the rpoB gene of M. tuberculosis are
responsible for most resistance,120 and have been found
in more than 97 percent isolates.121,122 Micro-organisms,
including mycobacteria, may develop resistance to
rifampicin rapidly in vitro as a one-step process, and one
of every 107 to 108 tubercular bacilli is resistant to the
drug. Mutations reduce binding of rifampicin to its target
polymerase of the mycobacterium therapy evading its
killing action. The maximum proportion of rifampicin-

resistant mutants able to grow during rifampicin
monotherapy of an isoniazid-susceptible strain is
estimated to be 1 to 108 approximately.123 Tuberculosis
caused by rifampicin-resistant mycobacteria has been
described in patients who had not received prior
chemotherapy but this is very rare.
Pharmacokinetics
After oral administration of rifampicin on an empty
stomach, the absorption is rapid and practically
complete. 124 Seth et al 125-127 carried out detailed
pharmacokinetic studies of rifampicin in different types
of tuberculosis under different drug regimens. Serum
half-life of rifampicin ranged from 3.03 to 3.81 hours,
whereas Cmax ranged from 3.38 to 3.88 ug/ml. Further, a
sustained serum concentration much above the MIC
of rifampicin was maintained even 24 hours after
administration of a single 12 mg/kg dose of the drug.
The mean t of rifampicin in children after initial dose is
2.9 hours but shortens to 2.5 hours on repeated dosing
because of its hepatic enzyme inducing action. Further,
when rifampicin was given in a dose of 10 mg/kg/day
to children suffering from pulmonary primary complex,
adequate serum levels of drug could be achieved that
were 50 times of MIC; and drug was found to be clinically
effective. Food interferes with the absorption of
rifampicin and results in a low plasma level and hence it
is advisable to give it atleast half an hour before
breakfast. 128 Further, it has been shown that the
pharmacokinetics is influenced by meals 129,130 but
depends upon the type of constituents of food.131
Carbohydrates and proteins seem to have virtually no
influence, while a fatty meal reduces serum concentration
considerably.131 The major differences in pharmacokinetics
following a meal include a reduced total amount
absorbed (area under the curve) and delayed achievement
of peak serum levels.132 It gives orange-red color to urine,
sweat, feces, saliva and tears.
Rifampicin is highly lipid soluble and penetrates well
into most of the tissues and is present in effective
concentration in all the organs and body fluids including
CSF. Rifampicin also reaches the caseous foci, phagocytes
and crosses the placenta. Breast milk, fat tissue, cavity
linings of lung, parenchyma and kidney achieve higher
tissue concentration of drug than the serum levels132 but
well above the minimum inhibitory concentrations are
achieved in pyogenic bone lesions and the pleura. Critical
concentration close to the minimum inhibitory concentration were measured in caseum and cerebrospinal fluid
in meningitis. In comparative studies, mean peak
rifampicin concentrations in the cerebrospinal fluid of
patients with tuberculous meningitis of 2.4 g/ml were
obtained 6 hours after administration of 600 mg
rifampicin, while a delayed mean peak of only 0.81 g/
411
ml was reached nine hours after drug ingestion in normal

subjects.132 The mean half-life in children after initial dose
is 2.9 hours but shortens to 2.5 hours on repeated dosing
because of its hepatic enzyme inducing action.133 The
half-life is increased by hepatic dysfunction and may be
decreased in slow INH-inactivator-patients concurrently
receiving INH.
Rifampicin is metabolized in liver by deacetylation
and undergoes enterohepatic circulation. The metabolite
retains full antibacterial activity. Approximately 60
percent of the drug and metabolites are excreted in feces.
Less than 30 percent of a dose is excreted in urine as
metabolites or as unaltered drug. Therefore, adjustment
of dosage is necessary in hepatic dysfunction, but not
required in cases of renal insufficiency.134
Adverse Effects
When given in therapeutic doses, rifampicin is well
tolerated and causes adverse effects in less than 4 percent
of patients. Common side effects are related to
gastrointestinal tract (GIT) and include nausea, vomiting
(1.5%), epigastric discomfort and diarrhea. Skin rash
(0.8%) and fever (0.5%) may also occur with its use in
adults.81 The incidence is more with higher doses and
with intermittent therapy. These side effects are
uncommon in children.
In general, adverse effects are divided in two broad
categories which include direct toxicity (GIT, liver) and
immune-mediated toxicity, autoimmune manifestations,
skin reactions etc.12
Hepatotoxicity
The incidence of hepatotoxicity is greater when higher
doses are used (> 15 mg / kg). Only 0.6 percent of patients
on rifampicin may develop jaundice. Patients with preexisting liver disease are at increased risk. Many patients
who develop slight elevation of serum transaminases
may not show symptoms despite continuous therapy,
therefore, discontinuation of therapy is not necessary.
Concurrent administration of INH may sometimes cause
serious but reversible hepatitis.134 It is usually associated
with excessive doses of INH.134 In children, however, if
the doses of INH and rifampicin are not exceeded beyond
5 mg/kg and 10 to 12 mg/kg respectively, toxic hepatitis
is rare as mentioned earlier.
Autoimmune Reactions
The immune-mediated reactions appear to be related to
the development of immune system recognition of
epitopes of rifampicin. Interrupted or intermittent
administration of rifampicin favours the development
of immune system recognition. Adverse reactions
associated with intermittent rifampicin include the flu
412
like syndrome and syndromes associated with

thrombocytopenia and purpura which are indications
for stoppage of the drug.2
High dose intermittent therapy or reinstitution of
rifampicin therapy after a drug free interval (either as a
part of a regimen or poor compliance) may lead to many
side effects that are due to the presence of rifampicin
antibodies in the circulation.135 In patients on once weekly
regimen of 25 mg/kg or more, influenza like syndrome
consisting of malaise, headache, fever and myalgias
maybe seen in 50 percent; some of them may experience
shortness of breath and wheezing also. It is advisable to
restart the therapy within 3 weeks of its stoppage in
reduced dosage in order to avoid hypersensitivity
reaction due to the persistence of circulating antibodies.75
With the use of 12 mg/kg dose, both in continuous and
intermittent therapy in children, these reactions are not
seen.
Other autoimmune reactions include respiratory shock
syndromes, acute hemolytic anemias and acute renal
failure. In case of acute hemolytic anemia or acute renal
failure, rifampicin should never be given again. Renal
failure is fortunately extremely rare and almost always
results in complete recovery of renal function.1,7
Cutaneous Syndrome
Flushing, itching with or without rash on face and scalp,
and sometimes watering of eyes occur within 2 to 3 hours
after a dose of rifampicin. These symptoms subside with
symptomatic treatment.135 These are also rare in children.
Rare Hypersensitivity Reactions

These may occur with intermittent therapy and include
eosinophilia, acute hemolytic anemia, and acute renal
failure. Thrombocytopenia, which is closely related to
the presence of circulating IgG and IgM antibodies, is
also reported. All these reactions are indications for
discontinuation of rifampicin therapy.136
Poisoning
Poisoning due to overdosage of rifampicin results in the
development of the so called red man syndrome which
maybe fatal.137 The skin and subsequently the sclera
become reddish orange in color. Nausea, vomiting,
abdominal pain and convulsions have been observed in
the few cases of overdosage described. Treatment is
essentially supportive and often needs gastric lavage.
to concentrate. Immunosuppression especially,

depression of T-cell mediated immunity, has been
reported, however, its clinical significance is not
known.138 The biliary excretion of bilirubin is reduced in
the initial period of treatment raising the serum levels,
however, it decreases after 2 to 3 weeks. The drug causes
red discoloration of urine, tears and sputum which is
harmless and serves as a check for drug compliance. Two
case reports show menstrual disturbances and
Addisonian crisis with its use.139,140 Theoretically, since
rifampicin crosses placenta and its teratogenicity is not
known, it is best to avoid rifampicin during pregnancy.
However, practically and paradoxically, the multidrug
regimen of isoniazid, rifampicin and ethambutol is
considered safe during pregnancy.
Limb defects have been observed in foetuses of
mothers taking rifampicin,140a but Snider et al140b failed
to detect increased incidence of teratogenicity among
mothers taking rifampicin during pregnancy. Presently,
rifampicin is considered to be an essential component
of antituberculosis treatment during pregnancy.140a,140c
Drug Interactions
Owing to its reported characteristic of being a powerful
inducer of hepatic drug metabolizing enzymes,
cytochrome P systems: CYP1A2, 2C9, 2C19 and 3A4,
rifampicin accelerates the metabolism and decrease the
half-life of drugs including glucocorticoids, oral
contraceptives, propranolol, metoprolol, quinidine,
digoxin, ketoconazole, fluconazole, cyclosporin, theophylline, barbiturates, clofazimine, sulfonylureas, oral
anticoagulants and digitalis.141
Appropriate increase in the dose of these drugs is
required to compensate for the increased metabolism. A
study from Chennai (Madras) showed enhanced renal
excretion of uric acid in patients receiving rifampicin and
pyrazinamide.142
Therapeutic Status
Rifampicin is a bactericidal and rapidly sterilizing drug
useful in pulmonary and extrapulmonary tuberculosis.
It is an important ingredient for all regimens used because
of its effectiveness, safety and oral administration. In
children it is used in doses of 10 mg/kg in daily dosage
regimens and in 12 to 15 mg/kg in intermittent dosage
schedules. It is never used alone in the treatment of
tuberculosis because of rapid development of resistance.
STREPTOMYCIN
Miscellaneous Side Effects
Side effects related to CNS are rare and include headache,
fatigue, drowsiness, dizziness, ataxia, generalized
numbness, muscular weakness, confusion and inability
Streptomycin belongs to the aminoglycoside group of

antibiotics and was the clinically effective drug which
became available a little after PAS for the treatment of
tuberculosis in 1947.
Streptomycin is a bactericidal drug with MIC as low as
0.4 g/ml. Most of the strains of M. tuberculosis are
sensitive to 10 g/ml. M. kansasii is frequently sensitive,
but other non-tuberculous mycobacteria are infrequently
susceptible. Its use has become limited because of its
toxicity, need for large doses that cannot be administered
orally but only parenterally, and rapid emergence of drug
resistant isolates.2,6 In addition, owing to its action
entirely on rapidly growing extracellular bacilli it
is unsuitable for sterilization of the lesion. In children
it needs to be used only in severe forms of tuberculosis
such as meningitis, miliary and osteoarticular tuberculosis for its action on the extracellular organisms.
Mechanism of Action
Streptomycin reacts with 30S-subunit of bacterial
ribosome thereby distorting the ribosome and preventing
normal interaction between codon of mRNA and
anticodon of tRNA, leading to miscoding of protein
synthesis. Leakage of low molecular weight substances
from the cells in vitro is suggestive of its action on cell wall
also.143
Bacterial resistance is due to the development of
ribosomes which are unable to bind to the antibiotics.
Resistance to streptomycin results for a limited number
of missence mutations in the rrs gene (16S rRNA) or in
rpsL gene (ribosomal protein S12).144 The maximum
proportion of streptomycin resistant mutants able to
grow during streptomycin monotherapy of an isoniazid
susceptible strain is approximately 1 in 10. 8,43 The
incidence of resistance increases with its longer duration
of therapy, hence not suitable beyond initial 2-4 months
of therapy.
Pharmacokinetics
Streptomycin is poorly absorbed from the gastrointestinal
tract. The salient features regarding the absorption of
aminoglycosides are that they need to be given
intravenously or intramuscularly145. Because of their size
and cationic charge, they do not cross most biological
membranes.2 The peak plasma concentration of 25 to 40
g/ml after intramuscular injection of 0.7 to 1 g dose is
achieved within 30 to 90 minutes.4 Streptomycin is poorly
distributed to extracellular fluids and CSF.2,45 However,
high concentrations are found in renal cortex, endolymph
and perilymph of the inner ear. Diffusion to pleural and
synovial fluids is slow but concentration equals the
plasma concentration are achieved after repeated doses.
Plasma half-life is about 2 to 3 hours which is prolonged
in patients with renal insufficiency, where the dose has
413
to be reduced. Deep intra-muscular injections will

prevent the discomfort of tender indurated masses at the
injection sites which will occur if the drug is injected into
the subcutaneous tissues.2 The excretion of streptomycin
is exclusively renal, by glomenular filtration.
Adverse Effects
Ototoxicity
Ototoxicity is the major toxic effect and is dose related.
Symptoms of vestibular toxicity such as vomiting,
tinnitus and vertigo are more common than hearing loss,
which, if occurs, is permanent. The dosage should be
reduced in patients with renal insufficiency. It should
not be given during pregnancy and to a child with ear
disease.81 Streptomycin induced ototoxicity has been
reported irrespective of period of gestation, therefore,
streptomycin should not be used during pregnancy. A
patient on streptomycin treatment should undergo
frequent monitoring of vestibular functions.
Renal Toxicity
Less severe renal toxicity than with other aminoglycosides
is known to occur with streptomycin.146 However, it
should be avoided in very young children and in patients
with renal insufficiency. If necessary, it should be used
in latter situation with half the loading dose. It is probable
that certain diuretics particularly loop diuretics may
potentiate its toxicity.147,148
Neuromuscular Blockade
In man, neuromuscular blockade is reported to occur
after intrapleural or intraperitoneal instillation of large
doses.149 However, it may also follow intramuscular
administrations. Most episodes of acute muscular
paralysis and apnea occur during anesthesia or with
other neuro-muscular blocking agents administered
simultaneously. Magnesium may potentiate the risk of
neuromuscular blockade while intravenous use of
calcium can overcome this toxic effect. Myasthenics are
at particular risk of neuromuscular blockade and the drug
must be preferably avoided in this group.
Miscellaneous
Peripheral neuritis, optic nerve dysfunction and
occasional hypersensitivity reactions characterized by
skin rash, urticaria, fever and anaphylaxis are also
reported.76
Drug Interactions
Ototoxicity of streptomycin is increased by furosemide147
and ethacrynic acid.148 Further, like other aminoglycosides
streptomycin has a neuromuscular blocking effect which
414
may lead to prolonged respiratory depression following

co-administration with curare-like drugs, such as
pancuronium,149 succinyl-choline or tubocurarine150
or non-depolarizing relaxants such as diallylnortroxiferine.151
Therapeutic Status
Since more effective and less toxic antituberculosis drugs
have become available, the use of streptomycin has
decreased. In tuberculous meningitis and in regimens
with 5 drugs to treat resistant cases the drug is still used
with good results. The recommended dose is 15 to 20
mg/kg/day to be given intramuscularly. Because of
difficulties associated with parenteral therapy and its
potential toxicity, streptomycin needs to be reserved for
serious and resistant cases requiring supervised therapy.
These drugs cross the placenta and use of streptomycin
is contraindicated during pregnancy as it is associated
with an increased incidence of fetal malformations as
compared with controls. Damage of the eighth cranial
nerve is the most frequent associated complication.
PYRAZINAMIDE
Mutations in pncA, a gene encoding pyrazinamidase,
cause resistance to pyrazinamide.158,159 Resistance against
pyrazinamide appears to develop very fast, if given as a
single effective agent.160
Pharmacokinetics
Pyrazinamide is well absorbed orally. After on oral intake
of 1500 mg of the drug, a peak level of 25 to 30 g/ml is
achieved after one to one and a half hour.161 It is widely
distributed in body tissues and fluids, and has one of the
best penetrations into CSF among the antituberculosis
drugs.162,163 Plasma half-life of the drug is 12 to 24 hours
which lends itself to once daily dosing.6 It is metabolized
in liver with about four percent of pyrazinamide excreted
unchanged in urine and about 30 percent as pyrazinoic
acid.164 It is only slightly influenced by ingestion of
antacids, but with a fatty meal Tmax is delayed and Cmax
slightly lowered, although these effects are unlikely to
bear clinical relevance.165 Absorption of pyrazinamide
is not influenced by food intake.
Like INH, pyrazinamide is a prodrug and a nicotinic acid

derivative. Studies in the early 1950s abandoned its use
due to hepatotoxic effect seen in 15 percent of the patients.
However, it was later found that larger doses (50 mg/
kg/ day) used for a longer period was the causative
factor. Hence, until 1970s pyrazinamide was used as a
second line agent.12 In doses of 20 to 35 mg /kg/day it
was no longer a hepatotoxic drug and does not add to
liver toxicity caused by INH and rifampicin. 75
Pyrazinamide is bactericidal with MIC of 12.5 g/ml,
against intracellular population of mycobacteria only at
an acidic pH.
Adverse Effects
Mechanism of Action
Gouty Arthralgia
Pyrazinamide is only active against M. tuberculosis, the

other mycobacteria such as M. bovis are naturally
resistant.152 Pyrazinamide is believed to be most effective
at an acidic pH.153 It acts specifically on dormant
intracellular organisms but is not active against rapidly
and intracellularly growing M. tuberculosis. 154,155
Pyrazinamide appears to exerts its effect after getting
converted into pyrazinoic acid inside the monocytes at
acidic pH.156 It is only the accumulation of pyrazinoic
acid through the action of amidase, pyrazinamidase by
susceptible M. tuberculosis which leads to its intracellular
bactericidal action.157 For the susceptibility to pyrazinamide,
presence of both a functional pyrazinamidase and
pyrazinamide transport system into M. tuberculosis have
been postulated as the prerequisites. The exact target is
not known, however, the NAD metabolic pathway has
been postulated as one of the potential targets.
Hepatitis
Hepatitis is commonly associated with the use of high
doses (40 to 45 mg / kg) of pyrazinamide. Studies
conducted with therapeutic doses of 30 to 35 mg/kg in
daily regimen or 45 mg/kg in thrice a week regimen did
not report hepatitis.67 A study from India did not show
hepatotoxicity in children treated with 30 mg/kg/day
dose of pyrazinamide.166 However, Kumar and Seth167
reported rise in both SGOT and SGPT without evident
jaundice in children with pulmonary primary complex.
The metabolite of pyrazinamide, pyrazinoic acid, is

suggested to interfere with excretion of uric acid by
decreasing its tubular secretion leading to increased urate
concentration in serum and clinical manifestations of
gout.83 It affects both small and large joints and mainly
involves the shoulder, knee and the finger joints.2 This
side effect is more common with daily regimen and
symptomatic treatment with aspirin is usually sufficient
without discontinuation of the therapy. Rarely
allopurinol might be needed. Although classical gout is
not seen, polyarthralgia which is related to elevated
serum uric acid levels is a common side effect.2
Miscellaneous Effects
Nausea, vomiting, photosensitivity and thrombocytopenia
are the rare side effects.
415
Drug Interactions
Allopurinol, increases plasma concentrations of

pyrazinoic acid which is directly responsible for the
inhibition of renal urate secretion. 168 Therefore,
pyrazinamide induced arthralgias are unresponsive to
allopurinol. Further, pyrazinamide might antagonize the
action of drugs that have a uricosuric effect such as acetylsalicylic acid, ascorbic acid, probenecid, and iodine
containing radiocontrast offering preparations.169,170
Most of the strains of M. tuberculosis and M. kansasii as

well as a number of strains of M. avium complex are
sensitive to ethambutol172 but the sensitivities of other
nontuberculous organisms are variable, and has no effect
on other bacteria. Ethambutol suppresses the growth of
most isoniazid and streptomycin resistant tubercle bacilli.
It may have bactericidal effect when given in the higher
dosage used in intermittent therapy.
Ethambutol is bactericidal on both extracellular and
intracellular tubercle bacilli.173 The MIC of ethambutol
for M. tuberculosis is from 0.95 to 7.5 g/ml in broth and
19 to 7.5 g/ml on agar.13
Ethambutol is less active than INH and rifampicin,
however, it suppresses the growth of all INH and
streptomycin sensitive as well as resistant mycobacteria.
Therapeutic Status
Due to faster sputum conversion rate, pyrazinamide is
an essential ingredient of six-months treatment regimen
administered usually in the first 2 months of therapy and
sometimes for a total period of 6 months, with the other
two or three drugs. As recommended by World Health
Organization (WHO) and International Union Against
Tuberculosis and Lung Disease (IUATLD), pyrazinamide
can be safely used in pregnancy.170a If pyrazinamide is
not included in the initial treatment regimen the
minimum duration of treatment is nine months. Benefits
of the use of pyrazinamidy in HIV-positive pregnant
women out weigh the undermined potential risks to the
fetus. Pyrazinamide is the third most important drug in
the treatment of tuberculosis.22
The relapse rate with pyrazinamide is very low
because of its unique property of killing the dormant
mycobacterial population. However, it is ineffective in
preventing drug resistance. Due to its excellent
penetration into the CSF, it is the most useful
antituberculosis agent for treating tuberculous meningitis.
Doses up to 30 mg/kg/day are well tolerated by children
without any side effects. Safe use of pyraminamide
during pregnancy is recommended by many European
countries and international agencies like International
Union Against Tuberculosis and Lung Disease (IUATLD)
however, its use during pregnancy is not recommended
in USA. It is because of lack of safety studies (teratogenecity) in the USA population.
ETHAMBUTOL
Ethambutol is a synthetic compound, with a selective
bacteriostatic action against rapidly growing cells of all
strains of mycobacteria. Ethambutol has become an
important companion drug in place of PAS or
thiacetazone in present day regimens.171 Ethambutol was
discovered as a new antituberculosis agent in 1961. Its in
vitro concentrations of 1-4 g/ml inhibited the growth
of M. tuberculosis H37 RV. In the heavy dose used (60100 mg/kg/day body weight) it resulted in toxic
amblyopia. However, these ocular disturbance improved
after stoppage of medicine.
Mechanism of Action
Ethambutol specifically inhibits the biosynthesis of the
mycobacterial cell wall by inhibiting the biosynthesis of
arabinogalactan, the major polysaccharide of the
mycobacterial cell wall. It inhibits the polymerization of
cell wall arabinogalactan and of lipoarabinomannan.174
Ethambutol indirectly inhibits mycolic acid synthesis, by
blocking arabinosyl transferases and thus limiting the
availability of arabinan for mycolic acids to attach to,175
and triggers a series of changes in the lipid metabolism
of mycobacteria, resulting in disaggregation of bacterial
clumps into smaller clusters.173 Ethambutol is suggested
to break the exclusion barrier, located in the M. avium
cell wall and thus significantly enables the activity of
other antituberculosis drugs, both intracellularly and
extracellularly.175 It suppresses the growth of both INHand streptomycin-resistant tubercle bacilli.
Bacterial resistance to ethambutol develops in vivo via
single amino acid changes in the embA gene when
ethambutol is given alone or in the absence of another
effective agent.176 The proportion of ethambutol resistant
mutants able to grow during ethambutol monotherapy
of an isoniazid-susceptible strain is estimated to be 1 in
108 tubercle bacilli.43 Resistance to ethambutol develops
very slowly in vitro.
Pharmacokinetics
Ethambutol is rapidly and almost completely absorbed
(75 to 80%) from the gastrointestinal tract following oral
administration. Serum concentration is maximal at about
2 to 4 hours.177,178 Following doses of 50 mg/kg body
weight and 25 mg/kg body weight daily, serum
concentrations achieved were 10 g/ml and 5 g/ml
respectively. Serum concentrations were proportional to
416
the dose. Less than 10 percent of the dose administrated

was present in the serum after 24 hours and there was,
little, if any evidence that ethambutol accumulates in the
tissues. From 90 to 94 percent of the administered drug
having been recovered from the urine and feces178 and
there was no evidence of accumu-lation of the drug over
more than 3 months. Within 6 hours, 28 percent of an
oral dose was excreted in urine.177 A recent study in
children using more sophisticated methodology 179
confirmed the initial observation that within 24 hours
three fourths of an ingested dose of ethambutol is
excreted unchanged in the urine; up to 15 percent is
excreted in the form of two metabolites, an aldehyde and
a dicarboxylic acid derivative. Renal clearance of
ethambutol is approximately 7 ml. min1 kg1; thus it is
evident that the drug is excreted by tubular secretion in
addition to glomerular filtration. About 20 percent of the
drug is excreted unchanged in feces. The Tmax tends to
be somewhat delayed in comparison to other drugs
(between 2 to 4 hours) and after a meal a lower Cmax is
found than when fasting (4.5 g/ml vs 3.8 g/ml after a
dose of 25 mg/kg). With the exception of central nervous
system, the tissue distribution of ethambutol has been
good and the concentration higher than those in the
serum or plasma has been found in several studies in
patients.180 It has poor penetration in uninflammed
meninges, however, good concentration is achieved in
CSF in patients with tuberculous meningitis. Renal failure
decreases body clearance and increases serum half-life,
hence dose adjustment in such patients is mandatory.
High fat meals alter the pharmacokinetics of ethambutol
somewhat but probably not importantly enough.179 The
concomitant concentration of ethambutol in abscess (pus)
was found to be considerably less than in concomitant
serum in two studies.181,182
Zhu et al179 have found the serum concentration in
children to be lower than that found in adults following
similar doses of ethambutol. Schmid et al184 used
ethambutol in 2634 children in a dose of 20 mg/kg and
increased this by 5 mg / kg in children aged <3 years
and decreased it by 5 mg/kg in patients aged >11 years.
By taking into account the serum concentrations of
ethambutol, they could avoid toxicity and achieve
therapeutic concentration in majority of children, without
experiencing any toxic damage, including eye, when
regular evaluation of eyes was done.
Adverse Effects
When used in therapeutic doses (15 mg/kg/day) the
incidence of adverse effects is only 2 percent.83 The major
side effects pertain to eye when high dose of the drug is
used with the incidence of 5 percent at 25 mg/kg and 15
percent at 50 mg/kg dose (dose effect relationship).
Ocular Toxicity
Ocular toxicity is the most important adverse drug event
of ethambutol, first reported in 1962.186 Subsequently a
large number of publications have reported this
toxicity.185,187-195 It has been suggested that binding of
ethambutol to zinc or copper maybe responsible for the
ocular toxicity.196,197 Two types of optic neuropathy, have
been reported for ethambutol.197,198 The most important
is the noninflammatory axial fiber disease involving
central fibers of the optic nerve, commonly known as
retrobulbar neuritis. Those with periaxial toxicity have a
defect in the peripheral isopters of their field of vision,
with little or no decrease in visual acuity and normal
redgreen color discrimination. The optic disc and fundus
are usually normal in both types of toxicity.
Retrobulbar neuritis can be unilateral or bilateral,
manifested first as decreased visual acuity, then redgreen color blindness, central scotomata, sometimes loss
of peripheral vision (gun barrel vision) occurring as early
as the 3rd week of treatment.199 The severity of visual
difficulty depends on the duration of ethambutol therapy
beyond the time the decreased visual activity first
manifests. These symptoms are usually reversible on
discontinuation of the therapy. 200 Usually, time to
recovery of visual impairment after withdrawl of
ethambutol is proportional to the severity of impairment
which in turn, is related to the duration of ethambutol
therapy. The color blindness may persist longer.
Continuation of therapy despite these symptoms may
lead to permanent blindness.
Seth et al185 have shown that children above the age
of 3 years are not at greater risk for developing
ethambutol induced optic damage as compared to adults.
They studied visual evoked responses (VERs) in 47
children aged 3 to 13 years with tuberculosis, treated with
ethambutol (20 mg/kg/day) as a part of the antitubercular
regimen. VERs were recorded by monocular whole field
stimulation, the stimulus being provided by a black and
white checker-board pattern reversed every 560 m/sec
and recorded before the commencement, 2, 4, 6, 9 and
12 months of therapy and between 3 to 6 months after
stopping the drug. In the first 6 months of therapy the
mean values of latency of VER ranged from 92.8 to
101.3m/sec in the 3 to <6 years age group and 88.5 to
100.3m/sec in children 6 to 13 years of age. Between 6 to
12 months of therapy, the mean values of latency were
between 93.3 to 101.5m/sec in the 3 to <6 years age group
and 96.0 to 101.5m/sec in the older group. Between 3 to 6
months after stopping therapy the means of latency
ranged from 92 to 96m/sec. The differences were not
statistically significant at any point of time (Fig. 30.4).
Similarly when amplitude was measured in the same two
age groups (3 to <6 and 6 to 13 years), it was comparable
(Fig. 30.5). It is necessary to monitor the vision before
Fig. 30.4: Effect of ethambutol therapy on latency of VER in

children aged 3 to 6 years and 6 to 13 years
417
regimens. It is a good substitute for PAS and thiacetazone

owing to its low toxicity in therapeutic doses and better
acceptance by the patients.203 In very young children (<3
years) its use has not been recommended.203 However,
as reported by Seth et al185 it does not cause retrobulbar
neuritis in children above 3 years of age in the dose of 20
mg/kg/day and therefore, it is not likely that ethambutol
will cause ocular damage in younger children (< 3 years)
as well. The difficulty of having cooperation from
children younger than 3 years can be overcome by doing
the test for ocular toxicity under general anesthesia.
Ethambutol is usually recommended even in the
intensive phase as a companion drug with INH,
rifampicin, streptomycin and pyraz-inamide even in very
young children with TBM and other serious forms of
tuberculosis such as tuberculous bronchopneumonia,
consolidation and disseminated disease.
Thiacetazone
Fig. 30.5: Effect of ethambutol therapy on the amplitude of VER in

children aged 3 to 6 years and 6 to 13 years
and during the treatment. Renal insufficiency causes an

increase in the serum concentration of the drug, thereby
causing an increased frequency of ocular toxicity.201
Dosage adjustment in patients with renal failure is
necessary.
Other Side Effects

These include pruritus, joint pains, gastrointestinal
upsets, malaise, headache, mental confusion, and
disorientation, while peripheral neuritis occurs in some
patients. Anaphylaxis is rarely seen after its administration.199 Urate excretion is reduced in 50 percent of
the patients but symptoms due to hyperuricemia are rare.
The untoward effect is possibly enhanced by INH and
pyridoxine. There is a case report of thrombocytopenia
noticed on the 6th day of therapy with ethambutol.202
Therapeutic Status
The drug is used as a companion drug with INH and
rifampicin in various short-course and long term
Thiacetazone is the cheapest antituberculosis drug.2 It is

a bacteriostatic drug with poor antituberculous activity
and is one of the oldest known antituberculosis agents,
discovered in Germany by Domagk and collaborators at
the Bayer laboratories in 1946. The use of thiacetazone
has decreased owing to its frequent side effects and low
potency. The renewed interest in the drug appeared after
it was used in East Africa in various pilot studies to
establish its optimum dosage. 204,205 Following these
reports, the WHO expert committee on tuberculosis in
its ninth report included it amongst the main drugs. In
combination with INH in a dose of 150 mg/day (2 mg/
kg) thiacetazone was widely used in developing
countries due to its low cost. It has been emphasized that
the drug is well tolerated in some communities and not
in other. An observation made in a comparison of
tubercle bacilli isolated from India and in the United
Kingdom showed that Indian strains were considerably
less susceptible to thiacetazone than the strains from
United Kingdom206 and this geographic variation was
subsequently confirmed.207-210 The susceptibility of
strains may vary even within the same country.211 The
response varies with immune status of the patient.212
Children, however, seem to tolerate thiacetazone very
well, rarely exfoliative dermatitis may occur.
Mechanism of Action and Pharmacokinetics

The mechanism of action of thiacetazone is not
clearly understood213 although it has been shown that
thiacetazone forms copper complex salts and it has been
postulated that these might represent the effective
compound.214 It is well absorbed when given orally. The
peak serum concentration is achieved in 4 hours (range 2 to
6 hours) after ingestion, with half-life of 12 hours. It is
excreted in urine in unchanged form within 24 hours.215-217
418
Adverse Effects
Major side effects are hepatic and mucocutaneous.
Hepatitis, exfoliative dermatitis, skin rashes and
stomatitis are the side effects to be looked for. Rarely
Stevens-Johnson syndrome has been reported.2 An ICMR
study from India reported jaundice in 4 cases, exfoliative
dermatitis in 6 and stomatitis with skin rashes in 7 cases
out of 640 adult patients put on thiacetazone.211 Nunn et
al218 administered thiacetazone (5 mg/kg) along with
usual dose of INH. In their study 1000 children, only one
child developed exfoliative dermatitis who recovered
with symptomatic management and withdrawal of the
drug. Thiacetazone is contraindicated in patients with
HIV infection. In one recent report, 22 of 111 HIV positive
patients developed cutaneous hypersensitivity reactions
that ranged from a maculopapular rash to toxic
epidermal necrolysis. Three of the 5 patients died.218
Miscellaneous
Nausea, vomiting, diarrhea, dizziness, vertigo, tinnitus,
ataxia, and even deafness maybe seen in some patients.
Signs of bone marrow depression have been noted rarely.
Drug Interaction
A cross resistance between ethionamide and thiacetazone
is reported.
Therapeutic Status
In combination with INH, thiacetazone is being used in
Africa, Latin America and Asia. It is economical, effective
and makes practical regimen in patients who cannot be
supervised frequently. The availability of single tablet
containing both INH and thiacetazone (300 mg + 150 mg
respectively) has helped in improving compliance.
However, this combination preparation has limited value
for pediatric use, for children require lesser dosage of

both isoniazid and thiacetazone.
The pharmacokinetics parameters and important
adverse effects and contraindication of individual drugs
and doses in continuous and intermittent regimens are
given in Tables 30.6 to 30.9.
FixedDose Drug Combination for Treatment of

Tuberculosis
Antituberculosis therapy (ATT) with multiple antimicrobials administered individually or as fixed dose
combinations (FDC) is the key to the control of
tuberculosis. Mathew219 has emphacized arguments in
favour of FDC include better patient compliance,
simplification of prescriptions, easier management of
drug supply, reduced cost of the program and less chance
of developing resistance.
Disadvantage is that the bioavailability of rifampicin
in FDC may be reduced owing to chemical reaction with
isoniazid in the acidic gastric pH. Further pyrazinamide
and ethambutol catalyze this reaction. Using FDC with
poor availability of rifampicin bioavailability can make
therapy inadequate and potential increased drug
resistance. A multinational study reported poor
bioavailability of rifampicin twice as common with FDC
in various ATT preparation from different countries
including India.
The other arguments against FDC are: (i) Younger
children may receive slightly higher dose than required;
(ii) Development of side effects may necessitate
omission/modification of the entire combination and (iii)
FDC may be more expensive than individual components
in terms of cost per tablet.
For these reasons although FDC are considered the
international standard for the treatment of tuberculosis,
WHO cautions that only preparations with proven
Table 30.6: Pharmacokinetic parameters of individual drugs

Drugs
Dose
(mg/kg)
Peak serum
conc #
(g / ml)
Urine
conc #
(g / ml)
Vd
(L / kg)
Normal
half-life
t (h)
Anuria
half-life
t (h)
Protein
bound
(%)
Excreted
unchanged
(%)
Isoniazid
3-5
Low
0.6
0.5-1.5+
Same
Low
<25
Rifampicin
10-12 (600)*
10-17
2-5
Same
60-90
<20
Streptomycin
20-30 (750-1000)
25-40
200-400
0.25
2.5
50-100
30
90-95
Pyrazinamide
25-30 (1000)*
45-60
60-100
12-24
>24
>20?
Ethambutol
15-25
High
1.5
3-4
18-20
20-30
60-80
Thiacetazone
3-5
12
2-3
33
# Conc. = concentration, + and ++ t half-life in rapid and slow acetylators respectively, ? Not known, Vd= volume of distribution
* Figures in parentheses is the maximum dose (mg)
419

Table 30.7: Adverse effects of antituberculosis drugs
Drug
Gastrointestinal
Hepatic
Renal
Neurological
Others
Isoniazid
Rare
Yes
(age related)
Rare
Peripheral
neuritis
Hypersensitive reactions,
may precipitate epilepsy.
Interaction with metabolism
of phenytoin sodium
Rifampicin
Yes
Yes
more with
intermittent
therapy
Rare
(immunemechanism)
No
Skin rash. Orange color of

urine and saliva,
immunosuppression,
pancytopenia, chills
fever, arthralgia and drug
interaction with other drugs
Streptomycin
No
No
Yes
(mild)
8th nerve
damage
Hypersensitivity (rash,
urticaria fever, anaphylaxis),
neuromuscular blockade,
dose related
peripheral neuritis
Ethambutol
No
No
No
Optic neuritis
(dose related)
Hyperuricemia , rash ,
pruritus, disorientation,
joint pain, headache ,
hypersensitive reactions
Pyrazinamide
Yes
Yes
No
No
Hyperuricemia, photosensitivity, fever dysuria,

malaise, arthralgia, and
rarely thrombocytopenia
Thiacetazone
Yes
Yes
No
No
Exfoliative dermatitis, rarely

vertigo, tinnitus, ataxia
Table 30.8: Drug dosage recommended for children and adults

Drug
Daily regimens
Intermittent regimens
Daily dose
(mg/kg)
Children
Isoniazid
5 (Po)
Rifampicin
10 (Po)
10
600
Streptomycin
15-20 (IM)
15
1000
Pyrazinamide
25 (Po)
1530
2000
Ethambutol
15 (Po)
1525
2500
Thiacetazone
2 (Po)
150
Po= Per oral route
Adults
Maximum
daily
dose (mg)
Twice weekly dose

(mg/kg)
Children
Adults
Maximum
daily
dose (mg)
300
10
15
900
15
10
600
25-30
25-30
1000
25-30
50-70
IM = Intramuscular
bioavailability should be used. In children though some

preparations are available but a large number of studies
on bioavailability have not been done. Seth et al (Chapter
32) have done a few studies on FDC syrup of isoniazid
and rifampicin and the combination with three drugs
isoniazid, rifampicin and pyrazinamide in the dispersible

tablet and syrup form.
Mathew has reviewed literature and that summarized
current based evidence does not support the presumed
superiority of FDC over separate administration.
420
Table 30.9: Contraindications for antituberculosis drugs
Isoniazid
Known hypersensitivity to isoniazid
Active hepatic disease
Rifampicin
Hypersensitivity to Rifampicins
Hepatic dysfunction
Pyrazinamide
Known hypersensitivity to pyrazinamide
Severe hepatic impairment
Gout
Streptomycin
Hypersensitivity
Auditory nerve impairment
Myasthenia gravis
Pregnancy
Ethambutol
Hypersensitivity
Pre-existing optic neuritis
Patients with creatinine clearance of less than
50 ml/min
HIGHLIGHTS
Centuries of human suffering and deaths from
tuberculosis led to widespread efforts to interrupt
its devastating effects.
Treatment of this dreaded disease evolved so much
that in a decade from 1944 to 1954 the prognosis of
an individual with tuberculosis changed from a
dismal outlook to the expectation of complete cure.
The early bactericidal activity of an antituberculosis
drugs reflects an agents ability to kill metabolically
active organisms present in the wall of the
tuberculous cavities.
While rifampicin and pyrazinamide provide almost
all of the bactericidal activity, isoniazid is
bactericidal only during first two days and there
after prevents the emergence of drug resistance.
Of all the antituberculous drugs, isoniazid has the
most potent early bactericidal activity.
Rifampicin is the most potent antituberculosis drug
in converting positive sputum culture to negative.
This characteristic ability of sterilization is attributed
to rifampicins ability to affect dormant organisms.
Rifampicin and pyrazinamide have the highest
sterilizing activity followed by isoniazid, while
streptomycin, thiacetazone and ethambutol have
weak sterilizing activity.
Rifampicin, has the highest activity to prevent
emergence of resistance against isoniazid, followed
by ethambutol and streptomycin while pyrazinamide
and thiacetazone have very low activity.
Ethambutol is less active that INH and rifampicin,

however, it suppresses the growth of all INH and,
streptomycin sensitive and resistant mycobacteria.
Children from 3 to 13 years given ethambutol 20
mg/kg/day as part of anti TB regimen, are not at
greater risk of developing ethambutolinduced optic
damage as compared to adults.
Role of streptomycin in the treatment of TB is
limited. In view of its toxicity and rapid emergence
of resistance, in children it needs to be used only in
severe forms of tuberculosis such as meningitis,
miliary and osteoarticular tuberculosis for its action
on extracellular organisms.
Although thiacetazone is the cheapest antituberculosis drug, its use has decreased owning to
its fatal though rare dermal side effects and low
potency. The Indian strains are considerably less
susceptible than in UK strain and Africa, hence not
used in India. Thiacetazone is contraindicated in
patients with HIV infection and the toxic reactions
range from cutaneous hypersensitivity reactions to
toxic epidermal necrolysis.
REFERENCES
1. Dubovsky H. Correspondence with a pioneer, Jurgen
Lehman (1898-1989), producer of the first effective
antituberculosis specific: S Afr Med J 1991;79:48-50.
2. William H, Chemotherapy of TuberculosisThe
Beginning. In Rom NW, Garays S (Eds): Tuberculosis,
1st edn. London: Stuart Little Brown and Company
1995;745-50.
3. Schraufnagel DE. Tuberculosis treatment for the
beginning of the next century. Int J Tuberc Lung Dis
1999;3:651-62.
4. Petri WA Jr. Antimicrobial agents: Drugs used in
chemotherapy of Tuberculosis, Mycobacterium avium
complex disease, and leprosy. In Bruton LL, Lazo JS,
Parker KL (Eds) in Goodman and Gilmans The
Pharmacological Basis of Therapeutics: McGraw-Hill,
New York 11th (edn) 2006;1203-23.
5. Alford RH. Antimycobacterial Agents. In Mandell GL,
Douglas RG Jr, Bennett JE (Eds): Principles and Practice
of Infectious Diseases, 3rd edn. New York, Churchill
Livingstone Inc 1990;350-60.
6. Antituberculosis Drugs in: Bennett PN, Brown MJ. (Eds)
Clinical Pharmacology, 9th edn. New Delhi by a division
of Reed Elsevier India Private Limited 2005;249-53.
6a. World Health Organization. Guidelines for the
programmatic management of drug-resistant
tuberculosis. WHO/HTM/TB. Geneva World Health
Organization 2006;361.
7. Mitchison DA. The action of antituberculosis drugs in
short-course chemotherapy. Tubercle 1985;66:219-25.
8. Donald PR, Sirgel FA, Botha FJ, et al. The early
bactericidal activity of isoniazid related to its dose size
in pulmonary tuberculosis. Am J Respir Crit Care Med
1997;156:885-900.

9. Hafner R, Cohn JA, Wright DJ, et al. DATRI 008 Study
Group. Early bactericidal activity of isoniazid in
pulmonary tuberculosis. Optimization of methodology.
Am J Respir Crit Care Med 1997; 156:918-23.
9a. Mitchison DA. Antimicrobial therapy of tuberculosis
justification for currently recommended treatment
regimens. Semin Respir Crit Care Med 2004;25:307-15
9b. Donald PR, Sirgel FA, Venter A, et al. The influence of
human N-acetyltransferase genotype on the early
bactericidal activity of isoniazid. Clin Infec Dis 2004; 39:
425-30.
10. Grosset J. New microbial aspects of the treatment of
tuberculosis. In: Luvara A, (Ed). Rifampicin. TB today:
from prevention of resistance to prevention of relapse.
A symposium held at the Forlanini Institute, Rome June
19, 1997. Amsterdam: Excerpta Medica 1977;1-11.
11. Fox W. The current status of shortcourse chemotherapy.
Tubercle 1979;60:177-90.
12. Ross. Drugs used in chemotherapy. In Modern Drug
Treatment of Tuberculosis, Indian Edition, Delhi: Oxford
University Press 1992;1-27.
13. Suo J, Chang CR, Lin T, et al. Minimal inhibitory
concentrations of isoniazid, rifampicin, etham-butol, and
streptomycin against Mycobacterium tuberculosis strains
isolated before treatment of patients in Taiwan. Am Rev
Respir Dis 1988;138:999-1001.
14. Inderlied CB, Salfinger M. Antimicrobial agents and
susceptibility tests: mycobacteria. In: Murray PR, Baron
EJ, Pfaller MA, Tenover FC, Yolken RH. (Eds). Manual
of Clinical Microbiology. Washington DC: ASM Press
1995;1385-1404.
15. Lee CN, Heifets B. Determination of minimal inhibitory
concentration of antituberculosis drugs by radiometric
and conventional methods. Am Rev Respir Dis
1987;136:349-52.
16. Jindani A, Aber VR, Edwards EA, et al. The early
17. Jindani A. The effect of single and multiple drugs on the
viable count of M. tuberculosis in the sputum of patients
with pulmonary tuberculosis during the early days of
treatment. Thesis, University of London, 1979.
18. Sirgel FA, Donald PR, Odhiambo J, et al. A multicenter
study of the early bactericidal activity of anti-tuberculosis
drugs. J Antimicrob Chemother 2000;45:859-70.
19. World Health Organization. A concurrent com-parison
of home and sanatorium treatment of pulmonary
tuberculosis in South India. Bull World Health Organ
1959;21:51-144.
20. Brooks SM, Lassiter NL, Young EC. A pilot study
concerning the infection risk of sputum-positive
tuberculous patients on chemotherapy. Am Rev Respir
Dis 1973;108:799-804.
21. Gunnels JJ, Bates JH, Swindoll H. Infectivity of sputumpositive tuberculous patients on chemotherapy. Am Rev
Respir Dis 1974;109:323-30.
22. Farrington M. General Pharmacology. In Bennett PN,
Brown MJ (Eds). Clinical Pharma-cology, 9th edn. New
Delhi Elsevier, a division of Reed Elsevier India Pvt. Ltd
2005;89-133.
421
23. Koch-Weser D, Ebert RH, Barclay WR, et al. Studies on

the metabolic significance of acid-fastness of tubercle
bacilli. J Lab Clin Med 1953; 42:828-9.
24. Winder FG, Collins PB. Inhibition by isoniazid of
synthesis of mycolic acid in Mycobacterium tuberculosis. J
Gen Microbiol 1970;63:41-8.
25. Takayama K, Wang L, David HL. Effect of isoniazid on
the in vivo mycolic acid synthesis, cell growth, and
viability of Mycobacterium tuberculosis. Antimicrob Agents
Chemother 1972;2:29-35.
26. Wang L, Takayama K. Relationship between the uptake
of isoniazid and its action on in vivo mycolic acid
synthesis. Antimicrob Agents Chemother 1972;2:438-41.
27. Takayama K, Schnoes HK, Armstrong EL, et al. Site of
inhibitory action of isoniazid in the synthesis of mycolic
acids in Mycobacterium tuberculosis. J Lipid Res
1975;16:308-17.
28. Davidson LA, Takayama K. Isoniazid inhibition of the
synthesis of monounsaturated long-chain fatty acids in
Mycobacterium tuberculosis H37Ra. Antimicrob Agents
Chemother 1979;16:104-5.
29. Sacchettini JC, Blanchard JS. The structure and function
of the isoniazid target in M. tuberculosis. Res Microbiol
1996;147:36-43.
30. Middlebrook G. Isoniazid-resistance and catalase activity
of tubercle bacilli. A preliminary report. Am Rev Tuberc
1954;69:471-2.
31. Winder F. Catalase and peroxidase in myco-bacteria.
Possible relationship to the mode of action of isoniazid.
32. Youati J. A review of the action of isoniazid. Am Rev
Respir Dis 1969;99:729-50.
33. Zhang Y, Heym B, Allen B, et al. The catalase-peroxidase
gene and isoniazid resistance of Mycobacterium tuberculosis.
Nature 1992;358:591-3.
34. Heym B, Zhang Y, Poulet S, et al. Characterization of the
katG gene encoding a catalase-peroxidase required for the
isoniazid susceptibility of Mycobacterium tuberculosis. J
Bacteriol 1993; 175:4255-9.
35. Stoeckle MY, Guan L, Riegler N, et al. Catalaseperoxidase gene sequences in isoniazid-sensitive and
resistant strains of Mycobacterium tuberculosis from New
York City. J Infect Dis 1993;168:1063-5.
36. Heym B, Alzari PM, Honore N, et al. Missense mutation
in the catalase-peroxidase gene, katG, are associated with
isoniazid resistance in Mycobacterium tuberculosis. Mol
Microbiol 1995; 15:235-45.
37. Somskovi A, Parsons LM, Salfinger M. The molecular
basis of resistance to isoniazid, rifampin, and
pyrazinamide in Mycobacterium tuberculosis. Respir Res
2001;2:164-8.
38. Zhang Y, Telenti A. Genetics of drugs resistance in
Mycobacterium tuberculosis. In:Hatfull GF, Jacobs WR, Jr.,
(Eds). Molecular genetics of mycobacteria. Washington
DC:ASM Press, 2000;235-54.
39. Banerjee A, Dubnau E, Quemard A, et al. inhA, a gene
encoding a target for isoniazid and ethionamide in
Mycobacterium tuberculosis. Science 1994;263:227-30.
40. Musser JM, Kapur V, Williams DL, et al. Characterization of the catalase-peroxidase gene (katG) and inhA
422
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
locus in isoniazid-resistant and suscep-tible strains of

Mycobacterium tuberculosis by automated DNA
sequencing:restricted array of mutations associated with
drug resistance. J Infect Dis 1996;173:196-202.
Heym B, Stavropoulos E, Honore N, et al. Effects of over
expression of the alkyl hydroperoxide reductase ahpC on
the virulence and isoniazid resistance of Mycobacterium
Canetti G, Grosset J. Teneur De souches sauvages De
Mycobacterium tuberculosis en variants resistants a 1
isoniazid et en variants resistants a la streptomycin sur
milieu de Loewenstein-Jensen. Ann Inst Pasteur
1961;101:28-46.
David HL. Probability distribution of drug-resistant
mutants in unselected populations of Mycobacterium
tuberculosis. Appl Microbiol 1970;20:810-4.
Mitchison DA. Drug resistance in mycobacteria. Br Med
Bull 1984;40:84-90.
Hurwitz A, Schlozman DL. Effect of antacids on
gastrointestinal absorption of isoniazid in rat and man.
Olaon Q, Pruitt AW, Dayton PG. Plasma concen-tration
of isoniazid in children with tuberculosis infection.
Pediatrics 1981;67:876-8.
Rao G. Clinico radiological and pharmacokinetic studies
of low dose isoniazid containing regimen in shortcourse
chemotherapy of pulmonary primary complex in
children Thesis submitted to the faculty of All India
Institute of Medical Sciences, New Delhi 1993.
Holdiness MR. Cerebrospinal fluid pharmaco-kinetics of
antituberculosis antibiotics. Clin Pharmacokinet
1985;10:532-4.
Robson IM, Sullivan PM. Antituberculosis drugs.
Pharmacol Rev 1963;15:169-223.
Good IT, Iseman MD, Davidson PT, et al. Tuberculosis
in association with pregnancy. Am J Obstet Gynecol
1981;140:492-8.
Snider DE, Layde PM, Johnson MW, et al. Treatment of
tuberculosis during pregnancy. Am Rev Resp Dis
1980;122:65-79.
Sarich TC, Adams SP, Petricca G, et al. Inhibition of
isoniazid-induced hepatotoxicity in rabbits by
pretreatment with an amidase inhibition. J Pharmacol
Exp Ther 1999;289:695-702.
Farrington M. Chemotherapy of bacterial infec-tions. In
Bennett PN, Brown MJ (Eds):Clinical Pharmacology, 9th
(edn). New Delhi, Reed Elsevier India Pvt Ltd 2005;24954.
Tuberculosis Chemotherapy Center, Chennai. WHO Bull
1970;43:143-205.
Mitchell IR, Thorgeirsson UP, Black M, et al. Increased
incidence of isoniazid hepatitis in rapid acetylators:
possible relation to hydrazine metabolites. Clin
Pharmacol Ther 1975;18:70-9.
Jenner P1. Ellard GA. Isoniazid related hepatotoxicity:A
study of the effect of rifampicin administration on the
metabolism of acetyl isoniazid in man. Tubercle
1989;70:93-101.
Gangadharam PRI. Isoniazid, rifampicin and
hepatotoxicity. Am Rev Resp Dis 1986;133:963-5.
58. Seth Vimlesh, Seth SD, Beotra A, et al. Comparison

between serum isonicotinic acid hydrazide (INH) levels
and urinary sulf-adimidine. (sulfamethazone acetylation
as predictors of INH acetylator status). Dev Pharmacol
Ther 1988;11:32-6.
59. Ohno M, Yamaguchi I, Yamamoto I, et al. Slow n-acetyl
transferase 2 genotype effects the incidence of isoniazid and
rifampicin induced hepatotoxicity. Int J Tuberc Lung Dis
2000;4:256-61.
60. Parthasarthy R, Sarma GR, Janardhanam B, et al. Hepatic
toxicity in South Indian patients during treatment of
tuberculosis with short course regimenscontaining
isoniazid, rifampicin and pyrazinamide. Tubercle
1986;67:99-108.
61. Martinez-Roig A, Cami J, Llorens Terol J, et al.
Acetylation phenotype and hepatotoxicity in the
treatment of tuberculosis in children. Pediatrics
1986;77:912-5.
62. Stein MT, Liang D. Clinical hepatotoxicity of isoniazid in
children. Pediatrics 1979;64:499-505.
63. OBrien RJ, Long MW, Cross FS, et al. Hepato-toxicity
from isoniazid and rifampicin among children treated
for tuberculosis. Pediatrics 1983;72:491-9.
64. Seth Vimlesh, Seth SD, Beotra A. Hepatotoxicity in relation
to the type of acetylator in children with tuberculosis. Indian
J Med Res 1985;89:306-9.
65. Gurumurthy P, Krishnamurthy MS, Nazareth O, et al.
Lack of relationship between hepatic toxicity and
acetylation phenotype in three thousand south Indian
patients during treatment with isoniazid with
tuberculosis. Am Rev Resp Dis 1984;129:58-61.
66. McCormack JG. Drug therapy of tuberculosis. Irish Med
J 1984;77:88-93.
67. Pitts FW. Tuberculosis: prevention and therapy. In Hook
EW, Mandell GL, Gwaltney IM Ir, Sande MA (Eds).
Current Concepts of Infectious Diseases New York:John
Wiley and Sons 1977;181-94.
68. Starke IR. Modern approach to the diagnosis and
treatment of tuberculosis in children. Pediatr Clin North
Am 1988;35:441-64.
69. Lit T IF, Cohen MI, McNamara H. Isoniazid hepatitis in
adolescents. J Pediatr 1976;89:133-5.
70. Donald PR, Schoeman IF, OKennedy A. Hepatic toxicity
during chemotherapy for severe tuberculous meningitis.
Am J Dis Child 1987;141:741-3.
71. Spyridis P, Sinaniotis C, Papadea R. et al. Isoniazid liver
injury during chemoprophylaxis in children. Arch Dis
Child 1979;54:6-7.
72. Tsagar Opoulonu Stinga H, Mataki-Emmanoui-lidon T,
Karida-Kavaliotis S, et al. Hepatotoxic reactions in
children with severe tuberculosis treated with isoniazidrifampicin. Pediatr Infect Dis J 1985;4:270-3.
73. Tuberculosis Research Center, Madras and National
Tuberculosis Institute, Bangalore. A controlled clinical
trial 3-and 5-months regimens in the treatment of
sputum-positive pulmonary tuberculosis in South India.
74. Hong Kong Chest Service/British Medical Research
Council:Controlled trial of four thrice-weekly regimens
and a daily regimen all given for 6 months for pulmonary
tuberculosis. Lancet 1981;i:171-4.

75. Girling DJ. The hepatic toxicity of regimens containing
1978;59:13-32.
76. OBrien RJ, et al. East African/British Medical Research
Councils controlled clinical trial of four short-course (6
month) regimens of chemotherapy for treatment of
pulmonary tuberculosis. Lancet 1984;i:237-40.
77. Singapore Tuberculosis Service/British Medical Research
Council. Clinical trial of 6-month regimens of
chemotherapy given intermittently in the continuation
phase in the treatment of pulmonary tuberculosis. Am
Rev Respir Dis 1985;132:374-8.
78. Tuberculosis:a persistent but treatable disease. WHO
Drug Information 1990;4:30-41.
79. Turktas H, Unsal M, Tulek H, et al. Hepatotoxicity of
antitubercular therapy (rifampicin, isoniazid and
pyrazinamide) or viral hepatitis. Tubercle Lung Dis
1994;75:58-60.
80. Kumar A, Misra PK, Mehrotra R, et al. Hepatotoxicity of
rifampicin and isoniazid:is it all drug induced hepatitis.
Am Rev Resp Dis 1991;143, 1350-2.
81. Girling DJ. Adverse effects of antituberculosis drugs.
Drugs 1982;23:56-74.
82. Seth Vimlesh. Clinicoimmunoradiological spectrum:
Management. In:Seth Vimlesh (Ed). Essential of
Tuberculosis in Children, New Delhi. Jaypee Brothers,
Medical Publisher P. Ltd. 1997;312-33.
83. Reed MD. Blumer IL. Clinical pharmacology of
antitubercular drugs. Pediatr Clin North Am 1983;30:17799.
84. Sanfeliu C, Wright JM, Kim SU. Neurotoxicity of isoniazid
and its metabolites in cultures of mouse dorsal root ganglion
neurons and hybrid neuronal cell lines. Neurotoxicology
1999;20:935-44.
85. Dompeling E, Schut E, Vles H, et al. Diplopia and
strabismus convergens mimicking symptoms of
tuberculous meningitis as side effects of isoniazid Eur J
Pediatr 2004;163:503-4.
86. Rothfield NF, Bierer WF, Garfield JW. Isoniazid induction
of antinuclear antibodies. Ann Intern Med 1978;88:6502.
86a. Warkany J. Antituberculosis drugs. Teratology 1997; 20:
133-37.
87. Baciewicz AM, Self TH. Isoniazid interactions. South Med
J 1985; 78: 714-8.
88. Kottegoda SR. Cheese, wine, and isoniazid. (Correspondence). Lancet 1985;2:1074.
89. Lejone JL, Gusmini D, Brochard P. Isoniazid and reaction
to cheese (Correspondence). Ann Intern Med 1979;91:793.
90. Boman G, Brog O, Hanngren A, et al. Pharmacokinetic
interactions between the tuberculostatic rifampicin,
paraamino salicylic acid and isoniazid. (Abstract). Acta
Pharmacol Toxicol (Copenh) 1970;28(Suppl 1):No. 4.
91. Grange JM, Winstanley PA, Vavies PDO. Clinically
significant drug interaction with antituberculosis agents.
Drug safety 1994;11:242-51.
92. Berkowitz FE, Henderson SL, Fajman N, et al. Acute liver
failure caused by isoniazid in a child receiving
carbamazepine. Int J Tuberc Lung Dis1998;2:603-6.
423
93. Hoglund P, Nilsson LG, Paulsen O. Interaction between

isoniazid and theophylline. Eur J Respir Dis 1987;70:
110-6.
94. Sarma GR, Kailasam S, Nair NGK, et al. Effect of
prednisolone and rifampin on isoniazid meta-bolism in
slow and rapid inactivators of isoniazid. Antimicrob
Agents Chemother 1980;18:661-6.
95. Engelhard D, Stutman HR, Marks MI. Interaction of
ketoconazole with rifampin and isoniazid. N Engl J Med
1984;311:1681-3.
96. Murphy R. Swartz R, Watkins PB. Severe actetominophen
toxicity in a patient receiving isoniazid. (Correspondence). Ann Intern Med 1990;113:799-800.
97. Moulding TS, Redeker AG, Kanel GC. Acetaminophen,
isoniazid, and hepatic toxicity. Ann Intern Med
1991;114:431.
98. Murray FJ. Outbreak of unexpected reactions among
epileptics taking isoniazid. Am Rev Respir Dis 1962;
86:729-32.
99. Kay L. Kampmann JP, Svendsen T, et al. Influence of
rifampicin and isoniazid on the kinetics of phenytoin. Br
J Clin Pharmac 1985;20:323-6.
100. Walubo A, Aboo A. Phenytoin toxicity due to concomitant
antituberculosis therapy. S Afr Med J 1995;85:1175-6.
101. Wright JM, Stokes EF, Sweeney VP. Isoniazid-induced
canbamazepine toxicity and vice versa. N Engl J Med
1982;307:1325-7.
102. Garcia B, Zaborras E, Areas V, et al. Interaction between
isoniazid and carbamazepine potentiated by cimetidine.
(Correspondence). Ann Pharma-cother 1992;26:841-2.
103. Pippenger CE. Clinically significant carbama-zepine drug
interactions:an overview. Epilepsia 2001;28(suppl 3):S71S76.
104. Hoyt Block S. Carbamazepine-isoniazid interaction.
Pediatrics 1982;69:494-5.
105. Van Wieringen A, Vrijlandt CM. Ethosuximide intoxication
caused by the interaction with isoniazid. Neurology
1983;33:1227-8.
106. Dockweiler U. Isoniazid-induced valproic-acid toxicity,
or vice versa. (Correspondence). Lancet 1987;2:152.
107. Patsalos PN, Duncan JS. Antiepileptic drugs. A review
of clinically significant interactions. Drug Safety
1993;9:156-84.
108. Jonville AP, Gauchez AS, Auttret E, et al. Interaction
between isoniazid and valproate:a case of valproate
overdosage. Eur J Clin Pharmacol 1991;40:197-8.
109. Ochs HR, Greenblatt DJ, Roberts GB, et al. Diazepam
interaction with antituberculosis drugs. Clin Pharmacol
Ther 1981;29:671-8.
110. Ochs HR, Greenblatt DJ, Knuchel M. Differential effect
of isoniazid on triazolam oxidation and oxazepam
conjugation. Br J Clin Pharmac 1983;16:743-6.
111. Takeda M, Nishinuma K, Yamashita S, et al. Serum
haloperidol levels of schizophrenics receiving treatment
for tuberculosis. Clin Neuropharmacol 1986;9:386-97.
112. Judd FK, Mijch AM, Cockram A, et al. Isoniazid and antidepressants:is it a cause for concern? Intern Clin
Psychopharmacol 1994;9:123-5.
424
113. Malck-Ahmadi P, Chavez M, Contreras SA.

Coadministration of isoniazid and antidepressant drugs.
(Correspondence). J Clin Psychiatry 1996;57:550.
114. Rosenthal AR, Self TH, Baker ED, et al. Interaction of
isoniazid and warfarin. JAMA 1977;238:2177.
115. Carrion C, Espinosa E, Herrero A, et al. Possible
vincristine-isoniazid interaction. (Corres pondence). Ann
Pharmacother 1995;29:201.
116. Sensi P. A family of new antibiotics, the rifamycins. Res
Prog Org Biol Chem 1964;1:338-421.
117. Maggi N. Pasqualucci CR, Ballotta R, et al. Rifampicin:a
new orally active rifamycin. Chemotherapia 1966;11:28592.
118. Dutt AK, Stead WW. Present chemotherapy for
tuberculosis. J Infect Dis 1982,146:698-704.
119. Ellard GA, Fourie PB. Rifampicin bioavail-ability:a
review of its pharmacology and the chemotherapeutic
necessity for ensuring optimal absorption. Int J Tuberc
Lung Dis 1999, 3 (11 suppl 3):S 301-8.
120. Miller LP, Crawford JT, Shinnick TM. The rpoB gene of
Mycobacterium tuberculosis. Antimicrob Agents
Chemother 1994;38:805-11.
121. Telenu A, Lowrie D, Matter L, et al. Detection of
rifampicin-resistance mutations in Mycobacterium
tuberculosis. Lancet 1993;341:647-50.
122. Cole ST. Rifamycin resistance in mycobacteria. Res
Microbiol 1996;147:48-52.
123. David HL. Probability distribution of drug-resistant
mutants in unselected populations of Mycobacte-rium
tuberculosis. Appl Microbiol 1970;20:810-4.
124. Acocella G. Clinical pharmacokinetics of rifam-picin. Clin
Pharmacokinet 1978, 3:108-27.
125. Seth Vimlesh, Seth SD, Beotra A, et al. Monitoring of
isoniazid and rifampin in childhood tuberculosis. Am
Rev Respir Dis1990;141:337.
126. Seth Vimlesh, Beotra A, Bagga A, Seth S. Drug therapy
in malnutrition. Indian Pediatr 1992;29: 1341-6.
127. Seth Vimlesh, Beotra A, Seth SD, et al. Serum
concentrations of rifampicin and isoniazid in tuberculosis.
128. Maggi N, Pasqualucci CR, Ballotta R, et al. Rifampicin: a
new orally active rifamycin. Chemotherapia 1996;20:3369.
129. Siegler DI, Burley DM, Bryant M, et al. Effect of meals on
rifampicin absorption. Lancet 1971;2: 197-8.
130. Peloquin CA, Namdar R, Singleton MD, et al.
Pharmacokinetics of rifampin under fasting conditions,
with food, and with antacids. Chest 1999;115:12-8.
131. Purohit SD, Sarkar SK, Gupta ML, et al. Dietary
constituents and rifampicin absorption. (Correspondence).Tubercle 1987;68:151-2.
132. Kenny MT, Strates B. Metabolism and pharma-cokinetics
of the antibiotic rifampin. Drug Metabolism Rev
1981;12:159-218.
133. McCracken GH Jr, Ginsburg CM, Zweighaft TC, et al.
Pharmacokinetic of rifampin in infants and children.
Relevance to prophylaxis against Hemophilus Influenzae
type b disease. Pediatrics 1980, 66:17-21.
134. Casteels Van Daele M, Igodt AL, Corbeel L, et al.
Hepatotoxicity of rifampicin and isoniazid in children. J
Pediatr 1975, 86:739-45.
135. Aquinas MA, Horstall WGL, Horsfal PAL, et al. Adverse

reactions to daily and intermittent rifampicin regimens
for pulmonary tuberculosis in Hong Kong. Br Med J 1972,
1:765-71.
136. Vanscoy RE, Wilkowske CJ. Antituberculous agents.
Mayo Clin Proc 1987;62:1129-36.
137. Bolan G, Laurie RE, Broome CV. Red man
syndrome:inadvertent administration of an excessive
dose of rifampin to children in a daycare center. Pediatrics
1986;77:633-5.
138. Gupta S, Grieco MH, Siegel I. Suppression of TIymphocyte rosettes by rifampicin. Ann Intern Med
1975;82:484-8.
139. Arora VK, Bali RC, Arora R. Rifampicin-induced
menstrual disturbances. Indian J Chest Dis Allied Sci
1987;29:63-4.
140. Wilkins EGL, Hnizdo E, Cope A. Addisonian crisis
induced by treatment with rifampicin. Tubercle
1989;70:69-73.
140a. Efferen LS. Tuberculosis during pregnancy. Curr Opin
Pulm Med 2007;13: 205-11.
140b. Snider DE Jr, Layde PM, Johnson MW, et al. Treatment
of tuberculosis during pregnancy. Am Rev Respir Dis
1980;145:494-8.
140c. Vallejo JG, Starke JR. Tuberculosis and pregnancy. Clin
Chest Med 1992; 13: 693-707.
141. Ohnhaus EE, Kirchhof B, Peheim E. Effect of enzyme
induction in plasma lipids using antipyrine,
phenobarbital and rifampicin. Clin Pharmacol Ther
1979;25:591-7.
142. Sarma GR, Acharyulu GS. Khannapiran M, et al. Role of
rifampicin in arthralgia induced by pyrazinamide.
Tubercle 1983;64, 93-100.
143. Winder FG. Mode of action of the anti myco-bacterial
and associated aspects of the molecular biology of the
mycobacteria. In:Ratledge C, Stanford (Eds). Biology of
mycobacteria, New York:Academic Press 1982;1:353-438.
144. Honore N, Cole ST, Streptomycin resistance in
mycobacteria. Antimicrob Agent Chemother 1994;38:23842.
145. Douglas JG, McLeod MJ. Pharmacokinetic factors in the
modern drug treatment of tuberculosis. Clin
Pharmacokinetics 199;37:127-46.
146. Hetman PS, Smith CR. Aminoglycoside nephro-toxicity
in humans. J Infect Dis 1983;(suppl 2):S284-S292.
147. Ohtani I, Ohtsuki K, Omata T, et al. Potentiation and its
mechanism of cochlear damage resulting from
furosemide and aminoglycoside antibiotics. J
Otorhinlaryngol Relat Spec 1981;40:53-63.
148. Mathog RH, Capps MJ. Ototoxic interactions of
ethacrynic acid and streptomycin. Ann Otol 1977;86:15863.
149. Giala MM, Paradelis AG. Two cases of prolonged
respiratory depression due to interaction of pancuronium
with colistin and streptomycin. (Correspondence). J
Antimicrob Chemother 1979;5:234-5.
150. Burkett L, Bikhazi GB, Thomas KC, et al. Mutual
potentitiation of the neuromuscular effects of antibiotics
and relaxants. Anesth Analg 1979;58:107-15.

151. Trubuhovich RV. Delayed reversal of diallylnortroxiferine after streptomycin. (Correspon-dence). Br
J Anaesth 1966;38:843-4.
152. Zierski M. Pharmakologie, Toxikologie und klinische
Anwendung von Pyrazinamid. Praxis Klin Pneumol
1981;35:1075-105.
153. Zhang Y, Scorpio A, Nikaido H, et al. Role of acid pH
and deficient efflux of pyrazinoic acid in unique
susceptibility of Mycobacterium tuberculosis to
pyrazinamide. J Bacteriol 1999;181:2044-9.
154. Nalin R, Potar M, David HL. Pyrazinamide is not
effective against intracellularly growing Mycobacterium
tuberculosis. Antimicrob Agents Chemother 1987;31:28691.
155. Restogi N, Potar MC, David HL. Pyrazinamide is not
effective against intracellularly growing Mycobacterium
tuberculosis. Antimicrob Agnets Chemother 1988;32:287.
156. Crowle AJ. Studies of antituberculosis chemo-therapy
with an in vitro model of human tuberculosis. Semin
Respir Infect 1986, 1:262-4.
157. Salfinger M, Crowle AJ, Barth Reller L. Pyrazina-mide
and pyrazinoic acid activity against tubercle bacilli in
cultured human macrophages and in BACTEC system. J
Infect Dis 1990;162:210-17.
158. Scorpio A, Zhang Y. Mutations in pncA, a gene encoding
pyrazinamidase/nicotinamidase, cause resistance to the
antituberculous drug pyrazinamide in tubercle bacillus.
Nature Med 1996;2:662-7.
159. Mestdagh M, Fonteyne PA, Realini L, et al. Relationship
between pyrazinamide, loss of pyrazinamidase activity,
and mutations in the pncA locus in multidurg-resistant
clinical isolates of Mycobacterium tuberculosis. Antimicrob
160. Yeager RL, Munroe WGC, Dessau FI. Pyrazina-mide
(Aldinamide) in the treatment of pulmonary tuberculosis.
Am Rev Tubere 1952;65:523-46.
161. Peloquin CA, Jaresko GS, Yong CL, et al. Population
pharmacokinetic modeling of isoniazid, rifampin, and
pyrazinamide. Antimicrob Agents Chemother
1997;41:2670.
162. Ellard GA, Humphries MI, Gabriel M. Penetration of
pyrazinamide into the cerebrospinal fluid in tuberculous
meningitis. Br Med J 1987;294:284-5.
163. Donald PR, Seifart H. Cerebrospinal fluid pyrazinamide
concentrations in children with tuberculous meningitis.
Pediatr infect Dis 1988;7:469-71.
164. Ellard GA. Absorption, metabolism and excretion of
pyrazinamide in man. Tubercle 1969;50:144-58.
165. Peloquin CA, Bulpitt AE, Jaresko GS, et al. Pharmacokinetics of pyrazinamide under fasting conditions, with
food, and with antacids. Pharmacotherapy 1998;18:
1205-11.
166. Pamra SP. Chemotherapy of pulmonary tuber-culosispresent state. Indian J Tuberc 1979;26:106-20.
167. Kumar Brijesh. To evaluate the efficacy and adverse
effects of two six-monthly short-course regimens for the
treatment of primary pulmonary complex in children.
MD Thesis submitted to AIIMS, New Delhi, 1987.
168. Lacroix C, Guyounnaud C, Chaou M, et al. Interaction
between allopurinol and pyrazinamide. Eur Respir J
1988;1:807-11.
425
169. Fox IH, Stein HB, Gershon SL. Effects of vitamins on the
renal handling of uric acid. Adv Exp Med Biol
1977;76B:30-5.
170. Manuel MA, Steele TH. Pyrazinamide suppression of the
uricosuric response to sodium chloride infusion. J Lab
Clin Med 1967;83:417-27.
170a World Health Organization. Treatment of tuberculosis
guidelines for national programs. Third edition WHO/
CDS/TB/2003. Geneva: World Health Organization;
2003.
171. Tripathy SP. Ethambutol plus isoniazid in the treatment
of tuberculosis. Bull Int Union Tuberc 1975;49:427.
172. Pablos Mendez, A, Raviglione MC, Lazlo A, et al. Global
surveillance for antituberculosis-drug resistance, 19941997. World Health Organization- International Union
against Tuberculosis and Lung Disease Working Group
on Anti-Tuberculosis Drug-Resistance surveillance. N
Engl J Med 1998;338:1641-9.
173. Crowle AJ, Sbarbaro JA, Judson FJ, et al. The effect of
ethambutol on tubercle bacilli within cultured human
macrophages. Am Rev Respir Dis 1985;32:742-5.
174. Mikusova K, Slayden RA, Besra GS, et al. Biogenesis of
the mycobacterial cell wall and the site of action of
ethambutol. Antimicrob Agents Chemother 1995;39:24849.
175. Rastogi N, David HL. Mode of action of antituberculosis
drugs and mechanisms of drug resistance in
Mycobacterium tuberculosis. Res Microbiol 1993;144:13343.
176. Belanger AE, Besra GS, Ford ME, et al. The embAB genes
of Mycobacterium avium encode an arabinosyl transferase
involved in cell wall arabinan biosynthesis that is a target
for the antimycobacterial drug ethambutol. Proc Natl
Acad Sci. USA. 1996;93:11919-24.
177. Place VA, Thomas JP. Clinical pharmacology of
ethambutol. Am Rev Respir Dis 1963;87:901-904.
178. Peets EA, Sweeney WM, Place VA, et al. The absorption,
excretion and metabolic fate of ethambutol in man. Am
Rev. Respir Dis; 1965; 91:51-8.
179. Zhu M, Burman WJ, Starke JR, et al. Pharma-cokinetics
of ethambutol in children and adults with tuberculosis.
180. Elliott H, Berning SE, Iseman MD, et al. Failure of drug
penetration and the acquisition of drug-resistance in
chronic tuberculous empyema. Tubercle Lung Dis
1995;76:463-7.
181. Tuli SM, Kumar K, Sen PC. Penetration of
antituberculosis drugs in clinical osteoarticular lesions.
Acta orthop scand 1977;48:362-8.
182. Kumar K. The penetration of drugs into the lesion of
spinal tuberculosis Int. Orthopeid 1992;16:67-8.
183. Benkert K, Blaha H, Petersen KF, et al. Tagesprofilc und
Profilveriaufsk ontrollen von Ethambutol bei kindern. Med
Klin 1974;69:1808-13.
184. Schmid P et al. Ethambutol und RifampicinVcrtraglichkeit und dosierung in Kindesalter. Padiat Prax
1981;25:207-9.
185. Seth Vimlesh, Khosla PK, Semwal OP, et al. Visual
evoked responses in tuberculosis children an ethambutol
treatment. Indian Pediatr 1991;28: 713-7.
426
186. Carr DE, Henkind P. Ocular manifestations of ethambutol.

Toxic amblyopia after administration of an experimental
antituberculosis drug. Arch Ophthalmol 1962;55:566-71.
187. Barron GJ, Tepper L, Lovine G. Ocular toxicity from
ethambutol. Am J Ophthalmol 1974;77:256-60.
188. Joubert PH, Strobele JG, Ogle CW, et al. Sub-clinical
impairment of colour vision in patients receiving
ethambutol. Br J Clin Pharmac 1986;21:213-6.
189. Citron KM, Thomas GO. Ocular toxicity from ethambutol.
(Editorial). Thorax1986;41:737-9.
190. Polak BCP, Leys M, van Lith GHM. Blue-yellow colour
vision changes as early symptoms of ethambutol
oculotoxicity. Ophthalmologica Basel 1985;191:223-6.
191. Chatterjee VKK, Buchanan DR, Friedmann AI, et al.
Ocular toxicity following ethambutol in standard dosage.
Br J Chest 1986;80:288-91.
192. Russo PA, Chaglasian MA. Toxic optic neuropathy
associated with ethambutol: implications for current
therapy. J Am Optometric Ass 1994;65:332-8.
193. Alvarez KL, Krop LC. Ethambutol-induced ocular
toxicity revisited. (Correspondence). Ann Apharmacother 1993;27:102-3.
194. Woung LC, Jou JR, Liaw SL. Visual function in recovered
ethambutol optic neuropathy. J Ocular Pharmacol Therap
1995;11:411-9.
195. Graham SM, Daley HM, Salaniponi FM, et al. Ethambutol
in tuberculosis:time to reconsider? Arch Dis Child
1998;79:274-8.
196. Cole A, May PM, Williams DR. Metal binding by
pharmaceuticals. Copper (I) and zinc(II) interactions
following ethambutol admini-stration. Agents Actions
1981;11:296-305.
197. Kozak SF, Inderlied CB, Hsu HY, et al. The role of copper
on ethambutols antimicrobial action and implications
for ethambutolinduced optic neuropathy. Deagn
Microbiol Infect Dis 1998;30:83-7.
198. Kahana LM. Toxic ocular effects of ethambutol. Can Med
Ass J 1987;137:213-6.
199. Vanscoy RE, Wilkowske CJ. Antituberculous agnets.
Mayo Clin Proc 1987;62:29-36.
200. Leibold JE. The ocular toxicity of ethambutol and its
relation to dose. Ann NY Acad Sci 1699;135:904-9.
201. Varghese A, Brater DC, Benet LZ, et al. Etham-butol
kinetics in patients with impaired renal function. Am Rev
Respir Dis 1986;134:34-8.
202. Prasad R, Mukerji PK. Ethambutol-induced thrombocytopenia. Tubercle 1989;70:211-2.
203. Recommendations from the Committee on Treatment of

Disease. Antituber-culosis regimens of chemotherapy.
Bull Int Union Against Tuberc Lung Dise 1988;63:60-4.
204. East African/British Medical Research Council Investigation. Tubercle 1960;41:399-423.
205. East African/British Medical Research Council Investigation. Tubercle 1963;44:301-33.
206. Thomas KL, Joseph S, Subbaiah TV, et al. Identification
of tubercle bacilli from Indian patients with pulmonary
tuberculosis. Bull World Health Organ 1961;25:747-58.
207. Mitchison DA, Lloyd J. Comparision of the sensitivity to
thiacetazone of tubercle bacilli from patients in Britain,
East Africa, South Indian and Hong Kong. Tubercle
1964;45:360-9.
208. Rist N. Thiacetazone sensitivity and resistance:
introductory remarks. Tubercle 1968;49 (Suppl): 36-8.
209. Mitchison DA. Natural sensitivity of M. tuberculosis to
thiacetazone. Tubercle 1968;49 (Suppl):38-46.
210. Grosset J, Rodrigues F, Benhassine M, et al. Sensitivity
to thiacetazone of strains of Myco-bacterium tuberculosis
isolated
in
Algiers:
Practical deductions. Tubercle 1968;49(Suppl): 48-51.
211. Gangadharam PRJ, Devaki V, Mohan K. Thiacetazone
sensitivity of Indian tubercle bacilli. Tubercle
1968;49(suppl):48-51.
212. Ellard GA, Dickinson 1M, Gammon PT, et al. Serum
concentrations and antituberculosis activity of
thiacetazone. Tubercle 1974;55:41-54.
213. Protivinsky R. Chemotherapeutics with tuber-culostatic
action. Antibiotics Chemother 1971; 17:101-21.
214. Liebermeister K. Zur Wirkung Der tuber-kulostatischen
Chemotherapeutika. eutsch Med Wschr 1950;75:621-2.
215. Wernitz W, Tornus H. Quantitative Conteben-studien. IV.
Mitteilung. Contebenblutspiegel beim Menschen. Zeitschr
Klin Med 1952;150:170-6.
216. Heilmeyer I, Heilmeyer L. Ueber Resorption und
Ausscheidug von TBI 698 (Conteben) nach peroraler
Belastung. Klin Wochenschr 1949;27: 790-1.
217. Jenner PJ, Ellard GA, Swai 08. A study of thiaceta-zone
blood levels and urinary excretion in man, using high
performance liquid chromatography. Lepr Rev
1984;55:121-8.
218. Nunn P, Kibuga D, Seth G, et al. Cutaneous hypersensitivity
reaction due to thiacetazone in HIV seropositive patients
treated for tuberculosis. Lancet 1991;337:627-30.
219. Mathew JL. Fixed-dose drug combination for treatment
of tuberculosis. Indian Pediatr 2009; 46: 877-80.
31
Second-line and Newer Agents
INTRODUCTION
The robustness of the available well-balanced chemotherapeutic regimens in the treatment of various forms
of tuberculosis and the considerable investment in terms
of time and cost to develop and assess the efficacy of
new drugs have precluded the development of new antituberculosis drugs in the last two decades. Further, the
decline in tuberculosis in developed countries and the
inability of developing countries to purchase expensive
drugs had resulted in only a low priority being given to
development of new antituberculosis drugs. However,
now because of the increasing incidence of tuberculosis
in HIV infected individuals, appearance of multidrug
resistant tubercle bacilli and the anticipated further
increase in the incidence of rifampicin (R) resistant
strains, there is increasing interest in the development
of newer agents in the developed countries. In India, the
situation is quite grim as indicated by a report from the
Tuberculosis Research Centre (TRC), Chennai.1 Of 3357
smear-positive pulmonary tuberculosis patients initiated
on antitubercular treatment in North Arcot district of
Tamil Nadu state between April 1986 and March 1988,
2306 (69%) were put on short-course chemotherapy (SCC)
and 1051 (31%) on standard chemotherapy (non SCC),
43 and 35% respectively completed 80% or more of their
treatment. Overall mortality was 28%. Of the remaining,
31% had active disease and were excreting bacilli with
65% of the cultures being resistant to isoniazid (H) and
12% to rifampicin. Combined resistance to H and R was
seen in 6% and to streptomycin (S) and H in 19%.
H resistance was significantly higher in those who had
been prescribed standard regimens and R resistance was
seen even in those who had not received the drug. In
Gujarat, among the institutionalized patients, an
alarming increase in acquired R resistance from 2.8% in
1980 to 37.3% in 1986 with 95% of the patients being
resistant to S, H or both was reported by Trivedi and
Desai.2 Among several reports documented from India,
the above cited ones reflect the ground reality of the
condition of tuberculosis patients in the community and
in the specialized institutions. Behera2a in a review article
about the drug resistance pattern all over the world,
reported that the new figures from Gujarat state, India
are the first reliable source of data on previously treated
cases in India and showed 17.2 % MDR-TB among this

group.
Before proceeding to the individual drug, (Table 31.1)
enumerates all the antituberculosis drugs as classified
by WHO.
SECOND-LINE AGENTS
The existing regimens, prescribed in the Revised
National Tuberculosis Control Program (RNTCP) of the
Government of India, are found to be robust in the
treatment of patients with no initial resistance or having
resistance to either H or S but extemely poor in the
treatment of patients with initial resistance to R as
confirmed by Mathew et al3 and Mitchison.4 It is also
known that resistance to R is always accompanied by
resistance to other antituberculosis drugs. In particular,
it has been noted that the prognosis in cases with initial
resistance to HR or SHR is poor irrespective of the
regimen prescribed even when they contain 4 or 5 drugs
including ethambutol (E). This makes it virtually
important to search for newer classes of drugs with
antitubercular activity especially against drugresistant
M. tuberculosis.
At present, there are a few classes of drugs which
show promise in the treatment of resistant tuberculosis
and they include thiomides, fluoroquinolones, such as
ciprofloxacin, ofloxacin, lomefloxacin, gatifloxacin, moxifloxacin and sparfloxacin, the newer rifamycin derivatives such as rifabutin (ansamycin) and rifapentine
combination drugs of betalactams with betalactamase
inhibitors such as sulbacin, augmentin and timentin,
tuberactinomycin (tuberactin with viomycin), aminoglycosides such as amikacin and capreomycin, and newer
macrolides such as clarithromycin, azithromycin and
some new drugs.
Thioamides
Following the discovery of the pyridine containing
isoniazid, numerous pyridine derivatives were tested,
and the activity of thioisonicotinamide against
M. tuberculosis was found by several groups. 5,6
Ethionamide was introduced by the group of Liberman
et al.7-8 Prothionamide is essentially similar to ethionamide
428
Table 31.1: Antituberculosis drugs grouped by World Health Organization
Group
Group 1
First-line oral agents
Group 2
Injectable agents
Group 3
Fluoroquinolones
Group 4: Oral bacteriostatic agents
Group 5: Agents with unclear

efficacy : Not recommended for
routine use.
Drugs
Isoniazid, rifampicin, ethambutol,
pyrazinamide
Aminoglycosides:
Streptomycin, kanamycin, amikacin
Polypeptides:
Capreomycin, viomycin, enviomycin
Ofloxacin, levofloxacin, moxifloxacin,
gatifloxacin
Thiomides:
ethionamide
prothionamide
Cycloserine, PAS; Thiacetazone.
Rifabutin
Clofazimine
Amoxycillin with clavulanic acid
Macrolides: Clarithromycin, Azithromycin
Linezolid.
PAS = Paraaminosalicylic acid
in its antibacterial effects and is generally considered to

be less unpleasant to take and hence less likely to replace
the latter.2
Antibacterial Activity and Mechanism of Action

Ethionamide is active against M. tuberculosis and to a
lesser extent against other mycobacteria.8 Like isoniazid,
ethionamide is also an inactive prodrug, and is activated
by a mycobacterial redux system. Ethionamide is
converted to a sulfoxide and thence to 2-ethyl4- aminopyridine. Although these products are not toxic
to mycobacteria, it is believed that a closely related
and transient intermediate is the active antibiotic. The
mechanism of action of ethionamide is, like isoniazid, at
the level of synthesis of mycolic acids and consequent
impairment of cell wall synthesis, 8 but lacks cross
resistance as it is active against resistant mutants of
INH. Thus, an additional site of action is suggested.
Ethionamide is a bacteriostatic drug at concentration
ranging from 0.6 to 2.5 g/ml. Resistance can develop
rapidly in vitro.
Ethionamide
Absorption
Ethionamide is essentially completely absorbed following
oral administration and is not subjected to any appreciable
first pass metabolism. The tablet may be administered
without regard to the timing of meals.
Pharmacological Properties
Pharmacodynamics
Ethionamide is bacteriostatic against M. tuberculosis at
therapeutic concentrations, but may be bactericidal at
higher concentration. It is also active against M. kansasii,
M. leprae and some strains of M. avium complex. With
monotherapy, drug resistance develops rapidly.
Pharmacokinetics
Ethionamide is completely absorbed following oral
administration. With single dose of oral administration
of ethionamide, Cmax is 2409 ng/ml (30.2%, the
corresponding value for (AUCo-inf) is 9161 ng (23.6%)
and AUCo-68941 nghr/ml (24.2%). The median range
value of Tmax is 0.75 (0.17-3.00) hours. Adenine
dinucleotide (NAD) are tight binding inhibitors of M.
tuberculosis. The crystal structures are inhibitors of M.
tuberculosis and M. leprae. These inhibited organisms
complexes provide the molecular details of target-drug
interactions. Knowledge of the precise structure and
mechanisms of action of these drugs provides insights
into designing new drugs that can overcome resistance
Table 31.2 gives the pharmacokinetic parameter of
ethionamide.
Plasma protein binding is approximately 30% and the
volume of distribution is 80 liters. Ethionamide
undergoes extensive hepatic metabolism into several
different metabolites, with only 1 of a given dose excreted
unchanged in urine. Ethionamide-sulfoxide is the major
metabolite, which has antibacterial activity. The plasma
half-life is approximately 2 to 3 hours.
Chapter 31 Antituberculosis Drugs: Second-line and Newer Agents

Table 31.2: Mean SD pharmacokinetic parameters of
ethionamide following single-dose administration of 250
mg film coated tablet to healthy volunteers
Cmax
mg/ml
Tmax
(hrs)
AUC
mg/hr/ml
2.16
(0.61)
1.02
(0.55)
7.67
(1.69)
Cmax for film-coated tablets was significantly higher

(2.16 g/ml) than sugar coated tablet.
Wang et al9 have emphasized that both ethionamide

(ETH) and prothionamide (PTH) are clinically effective in
the treatment of M. tuberculosis, M. leprae and M. avium
complex infections. Generally considered Second-line
drugs for tuberculosis, their use has significantly increased
due to increase in MDR and extensively drug resistant
tuberculosis. Using a cell-based activation method, it has
been shown that both thioamides form covalent adducts
with nicotinamide and adeninedinucleotide (NAD) and
are tight binding inhibitor of M. tuberculosis.
Distribution
Ethionamide is rapidly and widely distributed into body
tissues and fluids following administration of a sugar-coated
tablet with concentrations in plasma and various organs
being approximately equal. Significant concentrations are
also achieved in cerebrospinal (CSF) fluid.
Auclair et al10 demonstrated that pharmacokinetic
behavior of ethionamide (ETA) is not significantly
modified by the different conditions such as when the
drug is given with orange juice, food, or antacids. Mean
AUC ranged from 0.91 to 0.96 for the orange juice, food,
antacid treatments, indicating a minimal effect on relative
bioavailability. ETA can be administered with food if
tolerance is an issue.
Seifartabc 11 determined the cerebrospinal fluid
ethionamide concentrations in 18 children with raised
intracranial pressure with the dosage schedule of 15 mg/kg
used on 26 occasions. Spinal fluid ethionamide concentration
of 2.5 g/ml (minimum inhibitory concentration) was
exceeded in 27% times with the dose of 20 mg/kg. MIC of
2.5 g/ml was not achieved in 15% of cases. Hence, the use
of 20 mg/kg of ethionamide is recommended when the
presence of isoniazid resistant M. tuberculosis cannot be
excluded.
Elimination
The mean half-life was 1.92 (0.27) hours after administration of a 250 mg film coated tablet. Less than 1% of the
oral dose is excreted as ethionamide in urine.
Pharmaceutical form
It is a yellow circular deep biconvex film coated tablet
with plain surface on both sides. The tablet should not
429
be divided. It is a crystaline, non-hygroscopic compound

with a faint moderate to sulfide odor.
Indications
Ethionamide is indicated in combination with other
antituberculosis agents for the treatment of all forms of
tuberculosis caused by M. tuberculosis. It is only indicated
as a second-line antimycobacterial drug when resistance
to or toxicity from first-line drugs has developed.
Optimum dose for children

Optimum doses for children have not been established.
It can be used when the organisms are definitely resistant
to primary therapy and there is systemic dissemination
of the disease or other life threatening complications of
tuberculosis. A total daily pediatric dose is 10-20 mg/
kg. It can be either taken at a single occasion or split up
in two doses over the day to improve tolerability.
Hepatic and renal impairment

Ethionamide is almost completely metabolized in the
liver. Its use should be avoided in patients with severe
hepatic impairment. No data is available for mild to
moderate hepatic impairment. Very little eithionamide
is excreted by kidneys. Dose adjustment is not necessary
in patients with renal impairment.
Duration of therapy
The duration of antituberculous therapy depends upon
the regimen chosen, the patients clinical and
radiographical responses, smear and culture results and
susceptibility studies of M. tuberculosis isolates from the
patients or the suspected source case. If therapy is
interrupted, the treatment schedule should be extended
to a later completion date depending, e.g. on the length
of the interruption, the time during therapy (early or late)
or the patients status.
Contraindications
Hypersensitivity to ethionamide or to any of the
excipients
Severe hepatic impairment.
Special warnings and precautions for use

Resistance: There is rapid development of resistance
if ethionamide is used alone in the treatment of
tuberculosis. It is essential, therefore, to give a suitable
other antituberculosis drug or drugs, the choice best
made on the susceptibility testing. However, therapy
may be started depending upon the existing
susceptibility pattern
Liver Toxicity: Toxic hepatitis, obstructive jaundice,
acute hepatic necrosis, as well as modest elevations
of hepatic transaminase levels, bilirubin and alkaline
phosphatase with or without jaundice have been
described during ethionamide therapy
430
Neurological Effects: Psychotic disturbances, encephalopathy and optic neuritis, as well as pellagra-like
syndrome have been reported with ethionamide.
Administration of nicotinamide and pyridoxine
substitution have been able to improve the symptoms.
Therefore, current recommendation of administering
pyridoxine is made to prevent neurotoxic effects of
ethionamide.
Blood Glucose: Hypoglycemia is associated with
ethionamide treatment, glucose should be administered prior to and periodically throughout therapy.
In diabetes, in adults one has to be very cautious to
avoid fall in blood glucose level.
Hypothyroidism: Periodic monitoring of thyroid
functions is recommended as hypothyroidism with or
without goiter, has been reported with ethionamide.
Allergic Reactions: Ethionamide may cause severe
allergic hypersensitivity reactions with rash and fever.
If this occurs, ethionamide must be discontinued.
Visual disturbance are also caused sometimes and
hence ophthal moscopy is recommended before and
period ically during therapy.
Interactions
Hepatitis and jaundice are more common if
ethionamide is administered with rifampicin.
Coadministration must be avoided unless the benefits
outweigh the risks. If it is a must, patient must be
periodically assessed by liver function tests and
examined frequently for hepatic dysfunction clinically
Coadministration with isoniazid increases the serum
concentration of the latter in both slow and rapid
acetylators. If co-administration is a must, monitoring
of adverse effects such a peripheral neuritis,
hepatotoxicity and encephalopathy must be looked
for. Pyridoxine supplementation becomes mandatory.
A reversible pellagra-like encephalopathy has been
reported with ethionamide and cycloserine
coadministration. Again this is due to disturbance of
the pyridoxine metabolism.
Pregnancy and Lactation

Teratogenic effect has been demonstrated in rabbits and
rats. Some data indicate an excess of congenital
malformations when ethionamide is given to pregnant
women. Therefore, the drug should not be given to
pregnant women or those who are likely to become
pregnant.
In case of breast feeding, during ethionamide
treatment the baby should be monitored for side effects
of ethionamide.
Undesirable effects
Frequencies of undesirable effects is defined as follows:
Very common
Common
Uncommon
Rare
Very Rare
=
=
=
=
=
1/10
1/100, <1/10
1/1000, <1/100
1/10 000, < 1/1000
1/10 000
Nervous system disorders

Common: Headache, dizziness, drowsiness, asthenia,
paresthesia.
Gastrointestinal disorders
Very common: Epigastric discomfort, abdominal pain,

anorexia, nausea, vomiting, diarrhea.
Hepatobilliary Disorders
Very common: Elevated serum transminases.
Overdose
Ethionamide is not dialyzable.
FLUOROQUINOLONES
Fluoroquinolones (FQS) are important drugs used for
treatment of drug resistant tuberculosis. These are also
being considered as first line drugs to shorten the duration
of treatment of tuberculosis. Fluoroquinolones are
synthetic compounds structurally related to nalidixic acid
but with certain advantages of having wider spectrum of
activity, better absorption, longer half-life, better tissue
penetration and activity against a wide variety of
microorganisms. They inhibit the enzyme DNA gyrase
which is involved in DNA replication. The competing
actions of gyrase and topoisomerase. (the major relaxing
factor in bacteria) maintain the level of super-coiling within
a fixed range. The eukaryotic homologue of gyrase which
is topoisomerase II, in order of magnitude, is less sensitive
than gyrase to quinolones.12 Fluoroquinolones such as
ciprofloxacin, ofloxacin (O), norfloxacin, pefloxacin,
enoxacin, lomefloxacin, WQ 3034, gatifloxacin, sparfloxacin and moxifloxacin have, gained worldwide usage as
broad spectrum antimicrobials over the last decade.13 They
are active against mycobacteria and no cross-resistance
has been reported between fluoroquinolones and other
antitube rculosis drugs.14 Other tried fluoroquinolones
include lomefloxacin, defloxacin, 6-fluoro-8-methoxy
quinolone, AM 1155, levofloxacin and trovafl oxacin.
These have also been evaluated for their antituberculosis
action. 15-17Gatifloxacin, ofloxacin and ciprofloxacin
have comparable activities against M. tuberculosis.16
(Table 31.3).
It is important to remember that if resistance develops
to any of the fluoroquinolones, cross-resistance to all
members of fluoroquinolone family is the rule. Therefore,
the most active of the flouroquinolones (moxifloxacin,
gatifloxacin) should be used in combination with other
antituberculosis drugs.16a

Table 31.3: Classification of quinolones
Quinolone Generation
First generation
Second generation
Class I
Class II
Third generation
Fourth generation
Drug
Nalidixic acid
Lomefloxacin
Norfloxacin
Ofloxacin, Ciprofloxacin
Levofloxacin
Sparfloxacin
Gatifloxacin
Moxifloxacin
Trovafloxacin
Pharmacokinetics
The quinolones exhibit concentration-dependent bacterial
killing. Bactericidal activity becomes more pronounced as
the serum drug concentration increases to approximately
30 times the minimum inhibitory concentration (MIC).
Higher drug concentrations paradoxically inhibit RNA
and protein synthesis, thereby reducing bactericidal
activity. Quinolones have a post antibiotic effect of about
one to two hours. Quinolones are not synergistic when
used along with betalactams and aminolgycosides.
Absorption
Quinolones are well absorped following oral administration, with moderate to excellent bioavailability. Serum
drug levels achieved after oral administration are
comparable to those with intravenous dosing. This allows
an early transition from intravenous to oral therapy and
potential reduction of treatment costs.
Food does not impair the absorption of most
quinolones. They chelate with cations such as aluminum,
magnesium, calcium, iron and zinc. This interaction
results in significant reduction in absorption and
bioavailability, resulting in lower serum drug
concentrations. This causes less target-tissue penetration.
Distribution
Quinolones are distributed widely throughout the body.
Tissue penetration is higher than the concentration
achieved in plasma, stool, bile, prostate and lung tissue.
Intracellular concentration is exceptional in neutrophils
and macrophages. These drugs also penetrate well in
urine and kidneys, when renal clearance is the route of
drug elimination. Penetration in saliva, bone and
cerebrospinal fluid does not exceed serum drug levels.
Because of the latter, these agents are inadequate for firstline treatment of meningitis.
Elimination
Half-lives for quinolones vary from 1.5 to 16 hours. Hence,
these drugs are administered 12 to 24 hourly. The
431
quinolones are eliminated by both renal and nonrenal

route. Hence, dosages often need to be adjusted in patients
with impaired renal and hepatic function. The majority of
quinolones are excreted renally, however sparfloxacin,
moxifloxacin and trovafloxacin are excreted hepatically.
Classification of Quinolones
Antimycobacterial Activity
Singh M et al18 studied the efficacy of five fluoroquinolones namely, ofloxacin (OFX), ciprofloxacin (CIP),
sparfloxacin (SPX), gatifloxacin (GAT) and levofloxacin
(LEVX) for treatment of tuberculosis. The isolates of M.
tuberculosis were obtained from both treated and
untreated patients from Agra and Kanpur regions of
North India.
A total of 162 M. tuberculosis (MTB) isolates including
110 MTB isolates from untreated patients (Cat I) and 52
isolates from treated patients (Cat II) were tested for
sensitivity to FQS using standard minimum inhibitory
concentration (MIC) method on Lwenstein Jensen
medium. Ninetyseven percent of the isolates in Cat I were
sensitive to GAT, 89% to LEVX at 1 g/ml where as 92.7%
isolates were inhibited by OFL at 2 g/ml which
increased to 89% at 4 g/ml (higher than achievable peek
level). On the other hand, among the 52 isolates from
Cat II, 71.2 % were sensitive to GAT, 63.5% to LEVX at
1 g/ml concentration, 53.8 % to SPX at 0.5 g/ml
whereas 63.5% and 46.2% isolates were sensitive to OFL
and CIP at 2 g/ml respectively.
Singh et al18 showed that FQS were more effective in
Cat I cases whereas these drugs were comparatively less
effective in Cat II cases. The reasons being the prior use
of these drugs alone in the failing regimens of Cat II cases.
This results in higher resistance rates. This emphasizes
that drug susptibility testing (DST) must be done before
adding this drug to a failing regimen.
The detailed analysis was very useful in studying the
extent of resistance to various fluoroquinolones. Among
the 8 MDR isolates (from Cat I) GAT showed highest
activity inhibiting 78.5% at 1 g/ml concentration with
LEVX, 87.5% of the isolates were inhibited at higher
concentration (2 g/ml) of the drug which is still much
below the peak serum value.
Similarly 75% of isolates were sensitive to
CIP at 4 and 87.5% to SPX at 4 and 2 g/ml concentration
of the drugs respectively. These concentrations were
slightly higher than the peak concentrations i.e. 3.5 g/
ml for CIP and 1.4 g/ml for SPX. In isolates from treated
patients, GAT along with moxifloxacin was found to be
most effective fallowed by SPX, OFL, CIP and
lomifloxacin. In conclusion, fluoroquinolones hold
promising activity (97.2%), in inhibition for M. tuberculosis
isolates from untreated patients) in concentration lower
than the peak serum levels. FQS show better activity in
432
Cat I cases in comparison to Cat II. These drugs may be

useful in the treatment of tuberculosis including MDRTB, moxifloxacin shows promising results in vitro and
animal studies, need further researching.
Ciprofloxacin and Ofloxacin

They are the most extensively studied fluoroquinolones.18 When the activity of ciprofloxacin, ofloxacin,
pefloxacin, enoxacin and norfloxacin against fifty M.
tuberculosis strains sensitive to antituberculosis drugs was
compared, ciprofloxacin and ofloxacin were observed to
have the highest in vitro activity. In a study from
Tuberculosis Research Center (TRC) Chennai, it was
observed that there was no difference in the activity of
ciprofloxacin and ofloxacin in fifty two SHR sensitive and
fifty two SHR/HR resistant M. tuberculosis strains.19 None
of the strains showed MIC > 4 g/ml when the drugs
were incorporated into LJ medium. While the peak serum
level of ofloxacin attainable in normal dosage (Cmax 11
g/ml; half-life (7 hr) is far above its mean MIC, the
absorption of ciprofloxacin after oral administration is
poor (mean Cmax 2.4 g/ml) with a relatively lower
mean half-life (4.1 hr).20-22 Ciprofloxacin levels in
bronchial biopsy specimens exceed those in the serum,
indicating an accumulation of the compound in the lung
parenchyma23 and may inhibit all clinically important
species of mycobacteria including those showing primary
resistance to one or more primary antimycoba-cterial
drugs. In one study, ciprofloxacin was active against all
strains of M. tuberculosis sensitive to S, H, R and E, and
against almost all strains showing intermediate
sensitivity or resistance to one or more of these drugs at
a concentration of 3.2 g/ml.24,25 A study from TRC on
53 SHR/HR resistant strains of M. tuberculosis, reported
geometric mean MICs of 3.7 g/ml and 3.8 g/ml
respectively, for ciprofloxacin which are only slightly
lower than the peak serum concentration of 4 g/ml
obtained following oral doses of 500 to 750 mg of
ciprofloxacin.26
Resistance to fluoroquinolones arises rapidly and
cross-resistance among quinolones is the rule,23 but no
resistance has been reported between fluoroquinolones
and other antituberculosis drugs.14
In the case of ofloxacin, spontaneous resistance
appears to occur in about 1 in 106 organisms which is
similar to that for other drugs. Ofloxacin appears to have
an additive effect in combination with other
antituberculosis drugs. Resistance to ofloxacin appears
to occur in a two step pattern with two phenotypes of
resistance levels 5 g/ml and 10 g/ml respectively, and
no resistance levels beyond 100 g/ml.27 The most
common mode of resistance results from mutation in
the gyrA gene encoding the DNA gyrase,28 and enzyme.29
Quinolones should be used in combination with at least
two other antituberculosis drugs as resistance might
develop rapidly in a large proportion of patients 30

required for replication and gene transcription. In a study
conducted by the TRC, the early bactericidal activity
(EBA) of ofloxacin and sulbactam/ampicillin, alone and
in combination with R and H on log-phase and stationary
phase cultures of a drug sensitive isolate of M. tuberculosis
was studied in vitro.31 Ofloxacin had considerable early
bactericidal activity (EBA) activity against the log phase
culture and, at 5 g/ml, was as bactericidal as 1g/ml
of H or 1 g/ml of R. However, it had little bactericidal
activity against the stationary phase culture and was less
active than H or R alone. These results suggest that
ofloxacin may be most useful in the early stages of
treatment and in preventing the emergence of resistance
to other drugs but may not be effective as a sterilizing
drug to kill persisting bacilli in lesions. Kohno et al32 have
compared ofloxacin and ethambutol (E) in the primary
treatment of 124 patients with pulmonary tuberculosis
using 9 months regimens containing either O or E with
R and H. Culture conversion rates 3 months after starting
treatment were 98 and 94% for the O containing and the
E containing regimens respectively. By 6 months, all
patients in both groups were culture negative. This study
indicated that ofloxacin may be as effective as ethambutol
in the treatment of pulmonary tuberculosis when either
drug is combined with H and R. Thus, the reports
available to date indicate that against drug-resistant
M. tuberculosis, ofloxacin may be a better drug to use in
combination with any of the companion drugs still
available in comparison with other second-line drugs.
Adult dose of ofloxacin is 400 mg BD and that of
ciprofloxacin is 750 mg BD.19 In children, one can use 10
to 20 mg/kg/day in two divided doses along with
companion first-line antituberculosis drugs. The
experience with the use of quinolones in pediatric
tuberculosis is no longer limited.15 Tsukamura et al27
treated 22 patients with multidrug resistant tuberculosis
for 9 to 12 months with regimens containing 300 mg or
800 mg of ofloxacin and other drugs with favorable
outcome in thirteen patients. Ciprofloxacin in
combination with other antituberculosis drugs has also
been used successfully for the treatment of several cases
of multidrug-resistant tuberculosis in HIV negative
patients.
Lomefloxacin
The main advantage of lomefloxacin is its relatively long
serum elimination half-life (7-8 hr). The peak
concentration of lomefloxacin is 4.9 g/ml following a
single oral dose of 400 mg as compared to 10.7 g/ml
following 600 mg dose of ofloxacin and 2.9 g/ml
following 1000 mg dose of ciprofloxacin. 33 These
pharmacokinetic properties of lomefloxacin make it a
potential supplementary drug for intermittent treatment
regimens of tuberculosis. However, few studies have

been done so far to assess the in vitro activity of
lomefloxacin against M. tubercuslosis. In one of the few
reports available to date, when 90 M. tuberculosis strains
isolated from patients including those with AIDS were
tested for susceptibility to ciprofloxacin, ofloxacin and
lomefloxacin, the MIC ranges were 0.125 to 4 g/ml, 0.25
to 4 g/ml and 0.5 to 4 g/ml respectively.34 In a recent
study by the TRC, a total of 46 SHR/HR resistant M.
tuberculosis strains and 51 SHR susceptible M. tuberculosis
strains were tested for their susceptibility to lomefloxacin.
The results showed that, though lomefloxacin had poor
in vitro activity compared to ciprofloxacin and ofloxacin
with the MIC being generally higher (2 to 16 g/ml), it
is probably within the levels achieved in tissues and
macrophages. The findings of this study need to be
substantiated with more in vitro and in vivo studies to
clarify the role of lomefloxacin in antitubercular
treatment. In addition, lomefloxacin, because of its
pharmacokinetic property, of long serum elimination
half-life, seems an appropriate drug for the intermittent
treatment regimens of tuberculosis.
Sparfloxacin
The in vitro and in vivo activities of sparfloxacin have been
reported to be equal or better than those of ciprofloxacin
and ofloxacin. The MICs of ciprofloxacin, ofloxacin and
sparfloxacin in 6H12 broth for 10 M. tuberculosis strains
ranged from 0.25 to 0.5, 0.5 to 1 and 0.1 to 0.2 g/ml
respectively while in solid medium, they ranged from
0.51 g/ml for ciprofloxacin and ofloxacin, and 0.2 to 0.5
g/ml for sparfloxacin.35 However, more detailed in vivo
studies are required to assess its antimycobacterial
activity in adults and children.
Status of Fluoroquinolones in Treatment of Tuberculosis

The question arises, whether fluoroquinolones can
replace drugs lost to resistance and can they improve
the performance of conventional regimens versus drugsusceptible disease. The fluoroquinolones are by far the
most promising agents from both the angles mentioned
above. Wild strains of M. tuberculosis are predictably
susceptible in vitro to fluoroquinolones36 and various
fluoroquinolones have been demonstrated to be active in
marine models.37,38
The most potent of the currently available drugs in
descending in vitro activity are moxifloxacin, gatifloxacin,
levofloxacin, ofloxacin and ciprofloxacin.39-46 Considerable
experience in human disease documents the utility of
ciprofloxacin, ofloxacin and levofloxacin against TB
including MDR strains.47 The data from Indonesia, Hong
Kong and Turkey48 have indicated that the outcome of
treatment of MDR-TB was substantially better with in vitro
susceptibility to the fluoroquinolones.
While recent studies suggest that moxifloxacin is
particularly active, the long-term tolerability and safety
433
of third-generation fluoroquinolones like moxifloxacin

and gatifloxacin have not been established as they have
for ofloxacin and levofloxacin 49,50 and given the
unanticipated toxicity of such agents as temafloxacin,
trovafloxacin, sparfloxacin and grepafloxacin, this should
not be regarded lightly. Nonetheless, these drugs merit
careful study both as agents to augment conventional
therapy and as major drugs for MDR-TB.
Moxifloxacin
TB wonder drug that shortens treatment span to be
tested. India to be part of study to be conducted in 2400
patients.
India is likely to soon become a part of an international
trial to look at whether the drug moxifloxacin actually
increases cure rate and helps shorten the duration of
treatment for patients suffering from tuberculosis.
Moxifloxacin works by stopping the life cycle of a
harmful bacteria. It has been identified as a drug which
has the potential of shortening the duration of treatment
from to 4 months when used along with other first line
drugs.
The study will include 2400 fresh TB adult patients in
over 20 sites across the globe, India being one. Christian
Medical College (Vellore), Tuberculosis Research Center
(Chennai) and National Tuberculosis Institute (Bengaluru)
are being considered to be part of this consortium. This
study costing US $ 20 million would be financed by the
TB Alliance and Bill and Melinda and Gates foundation.
Reduction of treatment time to four months would mean
less exposure to drugs for the patient and less interaction
with health services reducing their workload.
The duration of the treatment makes adherence a
significant problem. Incomplete adherence can lead to
failure of cure or relapse. In view of the escalating number
of cases of TB globally, there is urgent need of regimens
of shorter duration. The study is going to be a double-blind
randomized controlled trial (neither the patient nor the
staff caring for them will know which combination they
are taking).
Summary of Adverse Effects and Drug Interactions

Incidence of adverse effects by ciprofloxacin is 14.8 %.
Major side effects are related to GIT, CNS and skin
including nausea, vomiting, diarrhea, headache,
restlessness, tremors, dizziness, insomnia, hallucinations
and seizures, skin rash and pruritus have been reported
in 9 % of cases.51 In children, the drug use is to be avoided,
because of recognition of drug-induced arthropathy
in juvenile laboratory animals. Initially fluoroquinolones
were only recommended in those who were over 17 years
of age due to fear of quinolones-induced arthropathy and
cartilage damage in this group. Recent safety studies have
employed MRI in the evaluation of children between 8
434
months to 13 years of age who had received ciprofloxacin

at a daily dose of 15 to 25 mg/day for 9 to 16 days, have
found no such bone or cartilage damage and follow-up
measurements done 2 years later detected no abnormality
in height.52 Transient increase in serum levels of hepatic
enzymes, blood urea and serum creatinine have been
noticed. Antacids delay absorption and probenecid is
reported to inhibit its renal excretion.15 It shows an
additive antimicrobial effect with other chemotherapeutic agents and delays the emergence of
resistance.53
mycobacteria, rifabutin is more active against

environmental species that are naturally resistant to
rifampicin, 57,58 including M. avium complex. 58-62
Although there is cross-resistance with rifampicin, it is also
active against a relative small subset of M. tuberculosis.60
This proportion is too small to make it generally a useful
drug in rifampicin-resistant disease.63 Treatment results
among patients with drug-susceptible M. tuberculosis are
similar to those obtained with rifampicin.64-66 However,
rifabutin is less active on extra cellular bacilli than
rifampicin.67
NEWER RIFAMYCIN DERIVATIVES
Pharmacokinetics
Rifampicin (R) has been one of the most efficacious firstline drugs in use in the treatment of tuberculosis for the
past two decades. However, it has a half-life of only about
1.5 to 5 hours. This is progressively shortened by about
40 % during the first 14 days of treatment by the action
of hepatic microsomal enzymes which accelerate the
deacetylation of the drug. Moreover, when R is given
once weekly as part of an intermittent regimen, the
dosage required may lead to a high incidence of serious
adverse reactions. The development of rifamycins with a
longer half-life giving sustained blood levels between
doses would overcome this problem and many novel
rifamycin molecules with long elimination half-life have
been designed with this aim. They include rifabutin and
rifapentine. Some of the properties of new rifamycins
relevant to their use in antituberculosis therapy are given
in Table 31.4.
Protein binding of rifabutin is only 25% of that of

rifapentin. Further, rifabutin is more lipid soluble, thus
tissue penetration is superior 68 resulting in tissue
rifabutin concentration several times higher than in the
serum (0.49 g/ml after 300 mg oral dose). This serum
level is approximately 10 times lower than that with the
same dose of rifampicin.68 Rifabutin has a serum halflife of 16 hours.69,70 This longer half-life may possibly
delay the emergence of resistance in patients who are
resistant to companion drugs and this may make it
particularly suitable for intermittent administration.
Rifabutin is extensively metabolized.68
Rifabutin (Ansamycin)
Rifabutin is a semisynthetic spiropiperidyl derivative of
rifamycins. 54 It is active against a wide range of
microorganisms, including gram-negative and grampositive bacteria, and mycobacteria. 55,56 Among
Drug Interactions
Rifabutin induces hepatic metabolism, but not as
extensively as rifampicin. 68 It does not affect the
pharmacokinetics of antiretroviral drugs that are excreted
in urine.71 It is a less potent inducer of the cytochrome
P-450 family, and thus causes fewer or less pronounced
clinically significant interactions than rifampicin. 71
Interactions of rifabutin with protease inhibitors are
generally less than with rifampicin,72,73 and it is the
rifamycin of choice for patients receiving highly active
Table 31.4: Comparison of some characteristics of rifamycins
MIC against
M. tuberculosis
(g/ml)
Rifampicin
resistant
M. tuberculosis
(% sensitivity)
Plasma t half-life
man (h)
Enzyme induction
Sensitivity against
M. avium complex (%)
Rifampicin
Rifampitin*
Rifapitin*
CGP
29861**
CGP
7040**
CGP
27557**
FC
22250**
0.3
0.08
0.04
0.04
0.08
0.04
ND
31
11
ND
12
10
40
30
20
++
35
++
69
69
85
92
50
ND
ND = Not done, *Initial clinical trials have been done, **Under investigation

antiretroviral therapy.
Resistance
As compared to rifampicin, resistance in subinhibitory
concentration of rifabutin is less rapidly acquired.
Further, like rifampicin, acquisition of resistance is
frequently accompanied by mutation in the rpoB gene are
susceptible to rifabutin.74 This difference is probably not
due to additional mechanism of resistance but is likely
that some of the mutations selected by rifampicin do not
sufficiently modify the rpoB structure so as to render this
protein resistant to rifabutin also.
Antimycobacterical Activity
Rifabutin has good in vitro activity against both rifampicin
sensitive and resistant strains. The activity is more than
rifampicin for sensitive strains (MIC 0.006 g/ml). In
animal models, rifabutin has been found to be effective
against M. tuberculosis with relatively high tissue levels
and long half-life. It has been found to be about 6 times
more active than rifampicin in experimental infection of
mice with M. tuberculosis or M. avium. The considerable
activity in murine disease may be indicative of high
intracellular concentrations in mouse macrophages. On
the other hand, caseating lesions in cavity walls containing
numerous acid fast bacilli, characteristic of human cavity
type of pulmonary tuberculosis, may contain lower
concentrations of the drug compared to the plasma. Thus,
in such human sites, rifabutin concentrations may not be
sufficiently high for effective antimycrobial activity. This
is also borne out by the results of a few clinical studies. In
one study, 22 patients with chronic pulmonary
tuberculosis harboring tubercle bacilli resistant to H, S and
R were treated with rifabutin.63 No evidence of sustained
benefit was observed in any patient. The results suggested
that rifabutin may not have a useful role in retreatment of
patients with multidrug resistant pulmonary tuberculosis
especially in cases of R resistance while it may possibly be
beneficial in patients who harbor R-susceptible strains. In
the same study, when 17 patients including 10 who had
earlier been treated with rifabutin, were retreated with
ofloxacin along with other companion drugs there was
good response in 10 including quiescence in 3. These
results suggest that ofloxacin may be a better drug to use
in treating patients with such drugresistant tuberculosis.
In another study, the efficacy of 4 different doses of
rifabutin (600, 300, 150 and 75 mg daily for 2 days), assessed
in terms of the early bactericidal activity (EBA) measured
as the fall in viable counts of M. tuberculosis in sputum
collections during 2 days, was compared to that of 3
different doses of R (600, 300 and 150 mg daily for 2 days)
and a single dose of H (300 mg daily for 2 days) in
435
previously untreated patients with smear-positive

pulmonary tuberculosis.75 Peak plasma concentrations of
rifabutin after initial doses were proportional to dose sizes
and were approximately 7 times lower than those after
the same doses of rifampicin. The EBA of rifabutin was
significantly different which may be due to the low plasma
concentrations of rifabutin that may not fully compensate
for its slightly greater antituberculosis activity in vitro. This
may be the reason why rifabutin appears to provide
clinically disappointing results even though it has very
good in vitro bactericidal activity against M. tuberculosis.
Rifapentine
Rifapentine is an RNA synthesis inhibitor like rifampicin
and shown to have antimycobacterial activities. It has 2
to 4 times the activity against a variety of clinical
mycobacterial isolates as compared to rifampicin. In
experimental tuberculosis and in vitro studies, it has been
found to be 10 times more potent than rifampicin against
M. tuberculosis, while against clinical isolates of M. avium
complex tested in vitro, it was found to be twice as potent
as rifampicin. Rifapentine is also bactericidal against
actively growing bacilli with a rate of killing similar to
that observed for rifampicin.76,77 It also has better tissue
penetration unlike rifampicin. The serum half-life is 14
to 18 hours 78-80 and is similar in adults and adolescents.
Intrapulmonary concentrations of rifapentine are below
those in serum.81 In contrast to rifampicin, higher peak
levels are achieved following food intake than after
fasting.79 Pharmacokinetics are not influenced in patients
of HIV.79 The main concern is that rifapentine has high
protein binding, which might require higher dosage than
used so far. In a study conducted by TRC, Chennai a
total of 103 M. tuberculosis strains were tested against
rifabutin and rifapentine. 82 All the 52 rifampicinsusceptible strains were susceptible to rifapentine as well
as rifabutin with a geometric mean MIC of 6 g/ml for
rifapentine and 1.3 g/ml for rifabutin as compared to
13.3 g/ml for rifampicin. All the 51 strains resistant to
rifampicin were also resistant to rifapentine while 11
(22%) were susceptible to rifabutin. The clinical efficacy
of rifapentine in the treatment of pulmonary tuberculosis
was assessed in a study of 267 patients.82 The results
suggest that twice weekly administration of rifapentine
is similar in effect to rifampicin given daily. Therefore, it
is a suitable drug for intermittent regimens. The usual
dose is currently 60 mg twice-weekly.76 However, higher
doses are now under investigation. Adverse events
are similar to rifampicin.76 Interaction expected most
likely to resemble those of rifampicin and so also the
mechanism of resistance. It has no activity against
rifampicin resistant strains.12
436
BETA-LACTAMS WITH BETALACTAMASE INHIBITORS

Mycobacteria produce beta-lactamase and are resistant
to beta-lactam antibiotics. A group of beta-lactams have
been recently developed which, though devoid of
antibacterial activity, are potent inhibitors of betalactamase enzyme present in M. tuberculosis. Beta-lactam
drugs penetrate poorly into mammalian cells. Recent
efforts on improving the intracellular concentration of betalactamase antibiotics include investigation on liposomal
encapsulation of these antibiotics. Liposome encapsulation of streptomycin and amikacin showed greater
bactericidal activity on intracellular bacteria in
macrophage culture in experimental models.83 This new
drug delivery system may be useful for beta-lactam
antibiotics. M. avium has much lower level of betalactamase activity than does M. tuberculosis. Amoxycillin
alone showed promising activity against these organisms
in vitro; certain cephalosporins which are beta-lactamase
stable, have shown moderate activity against M.
tuberculosis in vitro.84
Clavulanic acid, a beta-lactamase inhibitor, is more
active than the other inhibitors sulbactum and
tazobactum.85 Clavulanic acid combined with amoxycillin
as an oral preparation (Augmentin) and with ticarcillin as
a parenteral preparation (Timentin) increase the
antimycobacterial activity of these two agents. In vitro
studies have shown that Augmentin inhibits and kills most
strains of M. tuberculosis at a concentration of 4 to 8 g/ml
of amoxycillin and 2 to 4 g/ml of clavulanic acid.
Timentin inhibited all strains of M. tuberculosis at
<32 g/ml which is a clinically achievable concentration.86
Sulbactam is being used increasingly in combination with
ampicillin. Recently, at the TRC Chennai, the bactericidal
action of sulbactam/ampicillin (SA) alone and in
combination with R and H on log-phase and stationary
phase cultures of a drug sensitive isolate of M. tuberculosis
was studied in vitro.31 While SA was bactericidial against
log phase cultures, it had little bactericidal activity against
stationary phase cultures. In 2 or 3 drug combinations,
SA did not have any antagonistic effect on H, R or HR.
These results suggest that SA is more likely to be useful in
the early stages of treatment and in preventing the
emergence of resistance to other drugs but is unlikely to
be effective in killing persisting lesional bacilli. Another
recent study done in USA showed that ampicillin/
sulbactam combination was effective against intracellular
mycobacteria and could provide an effective alternative
therapy against infections caused by mycobacteria
resistant to other drugs.87 In an experimental study in mice,
its combination with clofazimine was found to be superior
to other combinations in eliminating infections due to M.
avium strains. Another good combination was ticarcillin
and clavulanic acid, which inhibited all strains of M.
tuberculosis at <32 g/ml a clinically achievable serum
concentration.86 It should be remembered, however, that
beta-lactam antibiotics penetrate poorly into mammalian

cells and this might limit their effectiveness in the
treatment of tuberculosis.12 More recently newer betalactam antibiotics including imipenem and meropenem
have also been shown to have in vitro antimycobacterial
activity.85 The most important drug event seen with betalactam antibiotics are hypersensitivity reactions, which
might be immediate (urticaria, laryngeal edema,
bronchospasm, hypotension, or local swelling), late
(morbilliform rashes, serum sickness, or urticaria), or other
than late reactions (toxic epidermal necrolysis, interstitial
nephritis, pulmonary infiltration, vasculitis, hemolytic
anemia, neutropenia, or thrombocytopenia).
TUBERACTINOMYCIN
Tuberactinomycin is a water soluble drug structurally
resembling viomycin. Tuberactino-mycin containing
regimens have been compared with viomycin-containing
regimens in Japan.88 The rate of sputum conversion by
culture after 6 months ranged from 73 to 80% for
tuberactino-mycincontaining regi-mens compared to 63%
for viomycin containing regimens. In advanced cases, it
was 67 to 76% for tuberactinomycin containing regimens
compared to 59% for viomy-cincontaining regimens.
Tuberactinom-ycin has been reported to be less toxic than
kanamycin and capreomycin.89 In a study conducted by
the TRC Chennai, crossresistance was not observed
between tuberactinomycin and S, H, E, R and
ethionamide. 82 However, 15 (54%) of 28 kanamycin
resistant strains were not susceptible to tuberactinomycin
at 25 g/ml. The results indicate that tuberactinomycin
may have limited use in the treatment of drug-resistant
tuberculosis. The use of tuberactinomycin has been largely
limited to East Asia, where it was found to be a useful
alternative to capreomycin in the treatment of multidrugresistant, aminoglycosideresistant tuberculosis.
MACROLIDES
These are a group of antimicrobial agents origi-nally
isolated from streptomyces species. Although
erythromycin has got limited activity against
mycobacteria, newer semisynthetic macrolides appear
to have promising activity.12,85 Roxithromycin has been
shown to lead to significant inhibition of intracellular
growth. This effect is potentiated by the addition of
amikacin or TNF or both. Clarithromycin and
azithromycin have been shown to reduce the bacillary
load in patients with disseminated Mycobacterium avium
infection and advanced AIDS.
Clarithromycin
Clarithromycin is a new semisynthetic macrolide
antibiotic. Clarithromycin has wide antibacterial
spectrum that includes mycobacteria. 91 More often

clarithromycin has been used as prophylactic agent or
against disease caused by M. avium complex.92 While in
vitro, it shows activity against M. tuberculosis complex in
human macrophages,93 such high concentrations are not
achieved in the serum or lung tissue of humans,94 and
hence not widely used in the treatment of tuberculosis.
When administered orally, it undergoes first pass
metabolism so that the bioavailability is 55%. It can also
be given intravenously. Clarithromycin is rapidly
absorbed and Cmax is achieved in two to three hours95
with serum elimination half-life of 2.5 to 5 hours. It is
metabolized to the active 14-hydroxyclarithromycin and
both reach high concentration in tissues, in part because
of intracellular uptake. Plasma protein binding is 80%.
Clarithromycin is extensively metabolized in the liver,
when it is both a substrate for and inhibitor of CYP3A.
Metabolites are excreted mainly in urine with a small
amount in feces via bile.
Interaction with Antiretroviral Drugs

Simultaneous coadministration of clarithromycin and
zidovudine reduces plasma concentrations of
zidovudine, but there is no reduction if the two drugs
are given two hours apart. If there is malabsorption, then
the two drugs must be given two hours apart.
Clarithromycin and ritonavir are both inhibitors of
CYP3A enzymes. Clarithromycin has little impact on
plasma concentrations of ritonavir. Coadministration of
clarithromycin with ritonavir result in complete
inhibition of the formation of the 14-hydroxymetabolite
of clarithromycin and an increase in clarithromycin AUC
of 77%. This is not important if the patient has normal
renal function but patients with compromised renal
function taking ritonavir, clarithromycin should be
reduced by 50% with creatinine clearance of 30 to 60 ml/
min and by 75% if creatinine clearance is less than 30 to
60 ml/min and the daily dose should not exceed 1 gm.
Simultaneous administration of clarithromycin and
didanosine resulted in statistically significant change in
didanosine pharmacokinetics. Efavirenz induces CYP3A4,
reduces clarithromycin concentration and increases
frequency of skin rashes. Nevirapine also reduces
clarithromycin concentration of the 14-hydroxy
metabolite, associated with an increased frequency of
skin rashes. Nevirapine also reduces clarithromycin
concentration. Azithromycin should, therefore, be
considered instead of clarithromycin in patients taking
efavirenz or nevirapine.
Although it undergoes extensive hepatic metabolism,
because of its predominant renal excretion, dose
adjustment may be required in patients with severe renal
impairment.65 Twice daily 500 mg clarithromycin in AIDS
patients was well tolerated, prevented M. avium complex
437
disease and reduced mortality.96 In the treatment of M.

avium complex disease, a twice daily dose of 1000 mg
has been given.97
Azithromycin
Azithromycin is semisynthetic derivative of erythromycin. It is rapidly absorbed after oral administration and
the bioavailability is 40%. It is widely distributed into
tissues and the tissue concentrations reach upto 100-fold
higher than plasma concentrations. The plasma concentrations fall slowly. It has got long elimination half-life
and hence can be given once daily or even as once weekly
dosing. It penetrates CSF poorly except when meninges
are inflamed. The metabolism of azithromycin is via
hepatic pathways other than CYP450 enzymes. It is
excreted mainly as unchanged drug in bile. It is a less
potent inhibitor of CYP3A than clarithromycin.
Interaction with Antiretrovirals

Coadministration of azithromycin and efavirenz does not
significantly effect the concentration of either drug.
Nelfinavir significantly increases the Cmax and AUC of
azithromycin by over 100% possibly via inhibition of
p-glycoprotein (P-gp). Azithromycin caused a small
decrease in nelfinavir concentrations, but no clinical
significance. Ritonavir is a potent inhibitor of Pgp and
may also increase azithromycin levels significantly.
Azithromycin has no significant impact on the Cmax
and AUC of zidovudine. Didanosine pharmacokinetics
are not affected by azithromycin and hence it can be safely
administered with these two antiretrovirals.
PHENAZINES
Clofazimine is a substituted iminophenazine bright
red dye that exerts a slow bactericidal effect on M. leprae.
It inhibits mycobacterial growth and binds preferentially to mycobacterial DNA causing inhibition of
transcription. Clofazimine is active in vitro against
M. leprae, M. tuberculosis, M. bovis, M. avium complex,
M. kansasii, M. scrofulaceum, M. simiae, M. marinum,
M. chelonei and M. fortuitum.98 Side effects include
discoloration of eyes and skin, GI upset, severe
abdominal pain and organ damage caused by crystal
deposition. It is likely that this drug will emerge as a
useful agent in the treatment of resistant and atypical
mycobacterial infections.
Lately a novel tetramethylpiperidine (TMP)
substituted phenazine (ATCC27294) has shown in vitro
activity against M. tuberculosis that is superior to both
clofazimine and rifampicin.98 These agents together with
clofazimine are significantly more active than clofazimine
alone against M. tuberculosis including multidrugresistant organisms. Using tuberculosis-infected
438
monocyte-derived macrophages, all of the TMP

substituted phenazines were found to possess
intracellular activity which was superior to both
clofazimine and rifampicin. In this experimental model
of intracellular bioactivity, the investigational compounds
inhibited bacterial growth at concentrations which were
approximately 10-fold lower than the corresponding
minimum inhibitory concentration values obtained using
in vitro sensitivity testing procedure. These results
demonstrate that the novel TMP phenazines are active
against multidrug-resistant M. tuberculosis strains and
particularly effective against intracellular mycobacteria.
The therapeutic efficacy of liposome encapsulated
clofazimine has been studied in mice and has been found
useful in the treatment of tuberculosis.99 It does not
penetrate CSF. It is likely to increase the plasma
concentration of drugs metabolized by CYP3A4
including protease inhibitors and etravirine.
Para-aminosalicylic Acid (PAS)

It is an antitubercular agent often administered with
isoniazid. The sodium salt of the drug is better tolerated
than the free acid.
Mechanism of Action
There are two mechanisms responsible for aminosalicylic
acids bacteriostatic action again M. tuberculosis.
1. Aminosalicylic acid inhibits folic acid synthesis
(without potentiation with antifolic compounds). The
binding of para-aminobenzoic acid, effectively
inhibits the synthesis of folic acid. As bacteria are
unable to use external sources of folic acid, cell growth
and multiplication slows.
2. Aminosalicylic acid may inhibit the synthesis of cell
well component of mycobacteria, thus reducing iron
uptake by M. tuberculosis.
Pharmacology
PAS is used for treatment of all forms of active
tuberculosis due to organisms sensitive to other
antituberculosis agents. It produces a prompt production
of a toxic inactive metabolite under acid conditions and
the short serum half-life of one hour for the free drug. It
is bacteriostatic against M. tuberculosis. It also inhibits the
onset of bacterial resistance to streptomycin and
isoniazid.
when administered with orange juice, food or antacid

treatment respectively. However, PAS is usually taken
with food because of the problem of gastritis it produces.
It is 50 to 60% protein bound.
CYCLOSERINE
Cycloserine is a broad-spectrum antibiotic and can be
isolated from Streptomyces orchidaceus, S. garyphalus, or S.
lavendulae. It was first isolated from a fermentation brew
in 1955 and later synthesized. Cycloserine is active against
M. tuberculosis and several species of grampositive
bacteria.100 Cycloserine is indicated in combination with
other antituberculosis drugs in the treatment of
tuberculosis after failure of the primary medications, i.e.
isoniazid, rifampicin, pyrazinamide, ethambutol and
streptomycin. It is also used in the treatment of atypical
mycobacterial infections, such as Mycobacterium avium
complex. Not all species or strains of a particular organism
may be susceptible to cycloserine.
Antibacterial Activity and Mechanism of Action

Cycloserine may be bactericidal or bacteriostatic
depending upon the concentration at the site of infection
and the susceptibility of the organism. The MIC of
cycloserine for M. tuberculosis ranges from 5 to 20g/ml
in vivo. There is no cross-resistance between cycloserine
and other tuberculostatic agents.
Cycloserine is an analog of the amino acid
D-alanine. It interferes with an early step in bacterial cell
wall synthesis101,102 by action of D-alanine racemase and
D-alanine synthase.
Pharmacokinetics
Cycloserine is rapidly and almost completely (70 to 90%)
absorbed from the gastrointestinal tract following oral
administration.Plasma concentration of 20 to 35 g/ml
is achieved after 20 mg/kg dose. It is widely distributed
to most body fluids including CSF, breast milk, lungs,
pleural and synovial fluids and crosses the placenta. CSF
concentration of cycloserine approach those found in the
serum. Upto 35% of cycloserine is metabolized. It is
excreted mainly in urine by glomerular filtration, 50%
excreted unchanged within 12 hours and 65 to 70%
excreted unchanged within 24 to 72 hours. It accumulates
in patients with impaired renal function and therefore,
the dose of cycloserine should be reduced to half in renal
failure.
Pharmacokinetic Parameters under Four Dosing

Conditions
Adverse Effects
Food significantly enhanced the Cmaxx of PAS 1.5-fold

and AUC (0-infinity) 1.7-fold, and doubled the time to
maximum concentration (Tmax), and the leastsquares
mean ratios (treatment) for Cmax were 0.90, 1.16 and 0.82
Most common side effects of cycloserine are neurologic

and psychiatric,103,104 although it has been used in the
treatment of psychiatric tuberculosis patients without
observation of major mental toxicity. Most frequently

observed adverse effects are vertigo and disorientation.
Psychotic states with a suicidal tendencies, delirium,
confusion, headache, convulsions, tremors, paranoid
reactions, catatonia and twitching has been reported.89
Cardiac depression, pareses, paresthesias, drug fever,
liver enzyme elevation and gastrointestinal disturbances were less frequently reported events. These effects
are dose related and usually disappear when the drug is
withdrawn. Stevens-Johnson syndrome has been
reported in HIV-infected patient. 105
Drug Interaction
Cycloserine interferes with elimination of phenytion
specially when taken with INH so that the dosage of
phenytoin must be reduced.106
Therapeutic Status
Cycloserine should be used only where microorganisms
are resistant to other drugs and must be given with other
effective antituberculosis drugs. Cycloserine is available
for oral administration. Dose ranges from 10 to 15 mg/
kg/day. Cycloserine is contraindicated in individuals
with a history of epilepsy.89 It may be valuable in
preventing appearance of resistance to ethionamide.1
AMINOGLYCOSIDES
The aminoglycoside group includes streptomycin,
kanamycin, amikacin, paromomycin, which are effective
antimycobactericidal antibiotics, in addition to
gentamicin, tobramycin, netilmycin and neomycin.
Aminoglycosides have concentration dependent
bactericidal activity. They bind to the 30S ribosome,
thereby inhibiting bacterial protein synthesis. Aminoglycosides are poorly absorbed orally but are well
absorbed from peritoneum, pleural cavity, joints, denuded
skin. Aminoglycoside are usually given IV. These are well
distributed into the extracellular fluid except for vitreous
humor, CSF, respiratory secretions and bile. For the
treatment of meningitis, therapeutic levels can only be
achieved if the drug is administered intraventricularly
for the treatment of meningitis. Aminoglycosides are
excreted by glomerular filtration and have a serum halflife of 2 to 3 hr the half-life increase exponentially as the
GRF falls. Streptomycin has been discussed with the firstline agents and amikacin, kanamycin and paromomycin
are discussed here.
Amikacin
Amikacin is an aminoglycoside. Amikacin has activity
particularly against gram-negative bacteria107 and is
active against M. tuberculosis.108 Amikacin has been found
to be more active against M. tuberculosis than other
439
aminoglycosides, and is frequently active against

streptomycin-resistant strains of M. tuberculosis.109 Crossresistance with other aminoglycosides may occur,
particularly frequent with kanamycin, and incomplete
with capreomycin.110 Amikacin appears to have little
early bactericidal activity, depending upon dose interval,
administered intramuscularly or intravenously. 111
Amikacin may lead to neuromuscular blockade, an effect
that may be reduced by lithium.112 Neurotoxicity might
be increased by muscle relaxants such as tubocurarine,
succinylcholine or decamethonium. Indomethacin may
interact with amikacin in newborns by increasing serum
levels to toxic concentration.113
Kanamycin
Kanamycin is also an aminoglycoside antibiotic. It is active
against a range of gram-negative bacteria and
mycobacteria including M. tuberculosis.114 Kanamycin, like
other aminoglycosides is not absorbed orally. After
intramuscular administration peak serum concentration
is achieved within an hour and the serum half-life is about
four to six hours.114 It is mainly excreted through kidneys,
and dose adjustment is required in patients with renal
failure. 114 Toxic effects include eighth cranial nerve
damage. Auditory toxicity is more pronounced than
vestibular toxicity, affecting up to 20% of patients after
three months, and upto 60% if kanamycin is administered
for six months. The other toxic effects include
neuromuscular blockade and renal toxicity. Resistance to
kana-mycin is through a single extrachromosomal plasmic
factor with multistep selection.115 Capreomycin resistant
strains are not usually resistant to kanamycin. The usual
dose of kanamycin is 15 mg/kg/day intramuscularly.
Paramomycin
This is an aminoglycoside antibiotic with in vitro activity
against M. tuberculosis.12,85 The potential of paromomycin
in the treatment of tuberculosis lies with the advantage
that there is little cross resistance with either streptomycin
or with amikacin/kanamycin. Its early bactericidal
activity indicates that it is at least as effective as
amikacin.107 Its toxicity, like that of neomycin, may
preclude its prolonged parenteral use. The drug should
prove to be useful in the treatment of both drug-resistant
and sensitive mycobacterial infection.
CAPREOMYCIN
Capreomycin is a polypeptide antibiotic. It is active
against various species of mycobacteria, including M.
tuberculosis.116 It is used for resistant or treatment failure
cases in combination with INH and ethambutol.117 No
cross resistance has been reported between capreomycin
440
and streptomycin.2 Cross resistance between kanamycin

and capreomycin is incomplete.118 Capreomycin is given
intramuscularly at dose range of 15 to 30 mg/kg, two to
three times a week for two to four months. Capreomycin
causes auditory, vestibular and renal toxicity.119 Rarely
hypokalemia has also been reported.119
The pharmacokinetic parameters and important
adverse effects and contraindications of individual drugs
and doses in continuous and intermittent regimens are
given in Tables 31.5 to 31.8.
MISCELLANEOUS AGENTS
Thalidomide
This drug has been shown to inhibit the in vitro release
of tumor necrosis factor (TNF) from stimulated
peripheral blood lymphocytes. TNF is a major cytokine
released in patients with tuberculosis and is believed to
be responsible for its toxic manifestations. In a patient
with tuber-culosis, thalidomide induces significant gain
in weight and inhibits TNF message in vivo.
Table 31.5: Pharmacokinetic parameters of individual drugs

Drugs
Dose
(mg/kg)
Peak serum
conc#
(g/ml)
Urine
conc#
(g/ml)
Vd
(L/kg)
Normal
half-life
t (h)
Anuria
half-life
t (h)
Protein
bound
(%)
Excreted
unchanged
(%)
Ethionamide
Cycloserine
Kanamycin
Capreomycin
Amikacin
Viomycin
15-20(1000)*
15-20(500)*
5-7.5
(1000)*
7.5
10-15
20
25-35
25
20-40
20-25
20-40
Low
High
>500
1000-2000
High
3000-5000
?
7
0.25
0.15
0.3
0.2
2
8-12
2.1
2-3
2.3
2-3
?
?
>48
50-100
>48
>48
?
?
<10
?
4
Low
?
50-70
95+
60-80
90-95
65-100
# Conc. = concentration, + and ++ t half-life in rapid and slow acetylators respectively, ? = Not known,
Vd = volume of distribution
* Figures in parentheses is the maximum dose (mg)
Table 31.6: Drug dosage recommended for children and adults
Daily regimens
Drug
Ethionamide
Cycloserine
Kanamycin
Capreomycin
Amikacin
Viomycin
Daily doses
(mg/kg)
Children
15-20 (Po)
10-15 (Po)
10-15 (Im)
15 (Im)
_
_
Po= Per oral route
Intermittent regiments
Adults
Maximum
daily
dose (mg)
Twice weekly
dose (mg/kg)
Children
Adults
Maximum
daily
dose(mg)
15-20
15-20
10-15
15-30
7.5 (Im)
10-15 (Im)
1000
1000
1000
1000
1000
1000
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
IM = Intramuscular
Table 31.7: Adverse effects of antituberculosis drugs
Drug
Gastrointestinal
Hepatic
Renal
Neurological
Others
Ethionamide
Yes
Rare
No
Peripheral
neuropathy
Cycloserine
No
No
No
Yes (dose
related)
seizures,
psychosis,
peripheral
neuritis
Gynecomastia, rash, alopecia,

generalized CNS effects like: headache,
depression, diplopia, blurred vision, tremors
Hypersensitivity rarely.
Monitoring of mental status of the
patients required
Amikacin
Capreomycin
Viomycin
Kanamycin
No
No
Yes
8th nerve
Hypersensitivity, neuromuscular blockade,

regular monitoring of vestibular functions
and audiometry required

Table 31.8: Antiretroviral drugs licensed
for use in HIV
1. Nucleoside reverse transcriptase inhibitors (NsRTIs):
Abacavir, didanosine, emtricitabine, lamivudine,
zidovudine
2. Nucleotide reverse transcriptase inhibitor: Tenofovir
3. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs): Efavirenz, etravirine, nevirapine.
4. Protease inhibitors (PIs): Atazanavir, darunavir,
fosamprenavir, indinavir, lopinavir, nelfinavir,
ritonavir, saquinavir, tipranavir
5. Entry inhibitors:
i. Fusion inhibitor: Enfurvirtide
ii. CCRs antagonist: Maraviroc
6. Integrase inhibitors: Raltegravir
Folate Antagonists
These group of drugs show promise in the treatment of
infection caused by mycobacteria other than tubercular
(MOTT) including M. fortuitum, M. marinum, M. chelonei
and possibly M. kansasii.12,85
Gangamicin
This is a vitamin K coenzyme analog found to be active
against M. tuberculosis and M. avium complex. It has been
shown to be effective in animal studies.12,85 Gangamicin has
been found to be active against both M. tuberculosis and
M. avium complex in vitro.
Dihydromycoplanecin A
This is a cyclic peptide antibiotic prepared by chemical
reduction of mycoplanecin A with in vitro activity against
M. tuberculosis, M. kansasii and M. bovis. However,
detailed studies are still needed.12,85
Fusidic Acid
This is a tetracycline triterpenoid antibiotic with in vivo
activity against M. tuberculosis and certain isolates of the
M. avium complex (MAC) but is still in investigational
stage.12,85
Streptolydigin
This is an antibiotic from Streptomyces lydicus that inhibits
the initiation of RNA synthesis and also the slow
elongation of the RNA chain and has also been tried for
the treatment of tuberculosis.5,81
441
response to mycobacterial infection.100 Agents showing

promise include interleukin-2 (IL-2), (interferon-gamma
(INF-), tumor necrosis factor (TNF), granulocyte monocyte colony stimutating factor (GM-CSF) and antigen
specific transfer factor.
IL-2 promotes the proliferation and differentiation of
helper T-cells, cytotoxic T cells, B cells and augments the
cytotoxic activity of NK cells and monocytes. Depressed
IL-2 generation and a decreased frequency of IL-2
responsive cells in the peripheral blood has been shown
in patients with tuberculosis.101 It appears that low dose
subcutaneous IL-2 may be useful in active tuberculosis
by enhancing the immune effect or response. INF-
enhances phagocytosis and immune function of
macrophages and also enhances intracellular killing.
More studies are required with regards to TNF.
Interferon alpha 2b is already under phase 2 trials in
adults with advanced intractable multi-drug resistant
tuberculosis.102
Vitamin D
Active metabolites of Vitamin D which is 1,25 (OH)2 Vit
D has been shown to activate peripheral blood monocytes
to kill mycobacteria.12,85
PHENOTHIAZINES
Chlorpromazine
This phenothiazine is an inhibitor of bacterial phospholipases. The reason for considering phenothiazines for
the treatment of tuberculosis arises from the fact that
pulmonary macrophages concentrate chlorpromazine
100-fold above of that achieved in plasma, concentration
that are active against mycobacteria in vitro103 and in
vivo.104 Chlorpromazine has a titrable ability to slow the
growth of intracellular tubercle bacilli in vitro105 It has been
shown in adults to be associated with clinical and
radiological improvement when administered to schizophrenics with tuberculosis.12,85
Trifluoperazine
This phenothiazine is a calmodulin antagonist and would
inhibit the growth of mycobacteria.106 It is known that
there is a calmodulin-like protein (CAMLP) in
mycobacteria which is needed for their proper growth
and its inhibition would suppress their normal
growth.12,85
NITROIMIDAZOPYRANS
Immunomodulation
This involves the use of agents that directly or indirectly
influence a specific immune function and enhance
various macrophage function and other aspects of host
Nitroimidazopyrans, a group of compounds have been

shown to possess antituberculosis activity. While the
earlier agents were shown to be mutagenic, newer
derivatives showed substantial activity against
442
M. tuberculosis. After activation by a mechanism

dependent on M. tuberculosis F-420 cofactor, nitroimidazopyran inhibited the synthesis of protein and cell
wall lipid107 inhibiting fatty acid and mycolic acid
synthesis. 108 The multidrug-resistant strains of
M. tuberculosis exhibited susceptibility to the new
nitroimidazopyran (PA-824). It indicates that there is no
cross resistance with current antituberculosis drugs,107
it might prove to be a useful agent in future.
OXAZOLIDINONES
Oxazolidinones are a class of protein synthesis inhibitors
and include linezolid and eperezolid.
Linezolid is active against gram positive and gram
negative organisms. Because of its unique mechanism of
action, linezolid is active against strains that are resistant
to multiple other agents. M. tuberculosis is moderately
susceptible with MIC of 2 g/ml.109
Linezolid inhibits protein synthesis by preventing
formation of 70 S ribosome complex that initiates protein
synthesis by binding to 23 S subunit of the 50 S subunit.
There is no cross resistance with other drug-classes.110,111
Linezolid is well absorbed after oral adminis-tration
and bioavailability is about 100% and dose for oral and
intravenous preparation is same. At present linezolid is
indicated in infections caused by multidrug-resistant
strains. No data is yet available in the treatment of MDR
tuberculosis.
Treatment of TB and HIV Together

In patients with HIV-related TB, the priority is to treat
TB, especially smear-positive PTB (on account of need
to stop TB transmission). However, patients with HIVrelated TB can have ART and anti-TB treatment at the
same time, if managed carefully, details discussed
elsewhere.
Table 31.9 enumerates the drugs licensed for use in
HIV and can have interaction with antituberculosis
drugs. Five classes of drugs are currently licensed for
the treatment of HIV.
Mechanism of Interaction with antiretroviral drugs

As most of the 2nd line drugs and newer agents will be
used in cases with resistant TB which is often associated
with HIV/AIDS, hence it is important to understand the
mechanism of interaction of these drugs with antiretroviral
drugs.
Pharmacokinetic interactions with antiretroviral drugs
may occur during absorption, distribution, metabolism and
elimination. Gastric pH, activity of transmembrane
transporters such as enterocyte P-glycoprotein (P-gp) and
drug metabolism by enterocyte cytochrome P450
(CYP450) enzymes may all influence the bioavailability of
antiretroviral drugs. Once absorbed, antiretroviral drugs

bind variably to plasma proteins (principally to albumin,
alph-1 acid glycoprotein).
Hepatic CYP450 enzymes are responsible for the
metabolism of a wide variety of drugs, NNRTIs and PI
are extensively metabolized by CYP450 and clinically
significant drug interactions are common. Efavirenz and
nevirapin are substrates for CYP450 and induce the
enzymes CYP2B6 and 3A4. Ritonavir is a potent inhibitor
of CYP3A4 used routinely to increase plasma
concentrations of other PIs. Ritonavir-boosted PIs may
therefore, lead to higher concentrations of other drugs
metabolized by CYP3A4 or other isoforms inhibited by
ritonavir (i.e. CYP2D6). In contrast, NsRTIs are not
metabolized by CYP450.
Ritonavir is an inducer of glucuronidation and has
been clearly shown to be responsible for significant
decreases in concentration of drugs.
Distribution of drugs is also mediated by plasma
membrane influx and effux transporters including P-gp
and multidrugs resistance protein (MRP). Three
transporters are present on many cell types including
intestinal epithelium, hepatocytes and kidney. They
control absorption, intracellular distribution, metabolism
and elimination of drug through biliary canals and active
tubular secretion. Table 31.9 gives the important
interactions of second-line agents and antiretrovirals.
THE NEW INVESTIGATIONAL DRUGS

Diarylquinoline TMC207
There appears to be a significant breakthrough in
discovering a new class of antimycobacterial drug. The
TMC207 is a diarylquinoline compound. TMC207 offers
a new mechanism of antituberculosis action by
specifically inhibiting mycobacterial ATP synthase. In
murine model and a few human TB-patient-studies with
multidrug-resistance have given very promising results.
In vitro TMC207 potently inhibits drug-sensitive and
drug-resistant M. tuberculosis isolates, and is bactericidal
against dormant (non-replicating) tubercle bacilli.120,121
In murine model, it is shown to be as active as the
combination of isoniazid, rifampicin and pyrazinamide,
whereas the addition of TMC207 to this triple drug
combination results in accelerated clearance of bacilli and
synergistic interaction with pyrazinamide. Similarly,
TMC207 enhances the antibacterial activity of secondline drug combination. It has acceptable adverse event
rates. In proof-of efficacy stage study, as compared with
placebo, addition of TBM207 to the standard drug
regimen of multidrug resistant tuberculosis resulted in
quicker a conversion to a negative sputum culture. After
treatment with 400 mg once daily produced a steady
plasma concentration of 3270 ng/ml.122,123
Antiretroviral
Use standard doses but measure concentration both NNRTIs and cycloserine
Monitor for psychiatric
morbidity with efavirenz
Use standard does but minitor renal
functions.
Clofazimine is a weak
inhibitor of CYP3A4. May
increase etavirine concentration
Use standard dose of clofazamine.

It is a weak inhibitor of CYP3A4, may
increase protease inhibitorconcentrations.
Use standard doses. Monitor

ECG if using efavirenz with
ofloxacin, levofloxacin
or gatifloxacin.
Azithromycin preferred to
clarithromycin in combination
with efavirenz or nevirapine.
NNRITs
Use standard dose but measure concentration of both PI and cycloserine.

Risk of convulsions with alcohol.
Avoid ritanavir liquid if possible.
Use standard dose but monitor
renal functions
Sparfloxacin and moxifloxacin are

metabolized by glucuronidation and
concentrations may be reduced by ritonavir,
atazanavir, might increase concentration
of sparfloxacin or moxifloxacin but
not clinically significant.
Use standard doses of ofloxacin,
levofloxacin or gatifloxacin, preferred
monitoring of ECG, when sparfloxacin
and moxifloxacin are used.
Clarithromycin can be used at
standard doses except in renal failure
with ritonavir when dose is to be reduced.
Cautious using azithromycin with
neltinavir or ritonavir. Use standard dose
but there is risk of toxicity of azithoromycin.
Protease inhibitors
Use standard dose
Risk of addition of additive toxicity

with tenofovir, use standard
dose but minitor renal function
Clarithromycin and
zidovudin should be given
separated by 1-2 hr.
Clarithromycin can be
safely given with didanosine
Azithromycin can be safely given
with ziduvudine and didanosive.
Use standard doses but measure
concentration of cycloserine
Use standard doses separate

in time from duffered
didanosine.
NRTIs
* Modified from Coyne KM et al. Pharmacology of second-line antituberculosis drugs and potential for interactions with antiretroviral agents. AIDS 2009; 23:437-46.
Narrow Spectrum
Amikacin
Aminoglycosides and
polypeptides
Aminoglycosides and
polypeptides
recommendations
PAS evidence
PASrecommendations
Clofazimine evidence.
Cycloserine
Macorolides
Recommendations
Fluoroquinolones
(Recommendations)
Broad spectrum
Fluoroquinolones
Second-line agent
Table 31.9: Second-line antituberculosis agents and antiretrovirals evidence for drug interactions and recommendations for use
443
444
Isatin Derivatives
REFERENCES
124
Fadl and Bin Jubir

have emphasized that there is
urgent need for anti-TB drugs with improved properties
such as enhanced activity against MDR strains, reduced
toxicity, shortened duration of therapy, rapid
mycobactericidal of action, ability to penetrate host cells;
and exert antimycobacterial effects in the intracellular
environment. Indoline-2,3 dione (Isatin) derivatives are
reported to show antitubercular activities. Isatin is a
versatile lead molecule for designing of potential
antitubercular agent.
Bonde et al125 synthesized a novel series of N-[2(substituted aryl)-3-chloro-4 oxoazetidin-1-yl]2-(pyrazin-2-xloxy) acetamide, 6- (substituted aryl)3-(pyrazin-2-yloxy) methyl) (1,2,4] Triazolol (3,4-b)
(1,3,4] thiadiazole and N-(6-(2-(pyrazin-2-xloxy)
acetyl] hydrazino] sylfonyl) 2-methyl-4-oxo-1,4dihydroquinazoline-3 (2H) yl] substituted aryl
sulfonamides. All synthesized compounds were
assayed in vitro for antimycobacterial activity against
the H37RV strain of M. tuberculosis. Minimum
inhibitory concentration (MIC) was determined for
the test compounds as well as for the reference
standards. The compounds which exhibited good
antimycobacterial activity contains the substituents
fluorine and methoxy. Compounds 28, 37 and 43
showed good antimycobacterial activity while
compound 51 showed a promising antimycobacterial
activity.
Protopopova etal 124,126 demonstrated compound SQ
109 with an MIC of 0.7-1.56 m (H3TRV, Erdaman
and drug-resistant strains of M. tuberculosis) is SI of
16.7 and 99% inhibition activity against intracellular
bacteria, demonstrated potency in vivo and limited
toxicity in vitro and in vivo, and was selected for
further development.
HIGHLIGHTS
Antituberculosis drugs as grouped by WHO has been given in a
tabular form.
All the second-line agents have been described in details
starting from their antibacterial activity, pharmacodynamics,
pharmacokinetics, adverse drug reactions and important
interactions.
Detailed description of fluoroquinolones have been given because
of their emergence as an important companion drug with
antituberculosis drugs for the management of resistant
tuberculosis and shortening of regimen for sensitive type of
tuberculosis.
Concomitant treatment of HIV and TB has been detailed and
important interactions between antiretroviral and antituberculosis
drugs have been detailed.
The new investigational drugs such as Diarylquinoline TMC 207
and isatin have been highlighted.
1. Datta M, Radhamani MP, Selvaraj R, etal. Critical

assessment of smear positive pulmonary tuberculosis
patients after chemotherapy under district tuberculosis
program. Tubercle Lung Dis 1993; 74:180.
2. Trivedi SS, Desai SG. Primary antituberculosis drug
resistance and acquired rifampicin resistance in India.
Tubercle 1988;69:37.
2a. Behera D. Anti-tuberculosis drug resistance in the world
Fourth Global Report The WHO/IUATLD.
3. Mathew R, Santha T, Parthasarathy R, et al. Response of
patients with initially drug-resistant organisms to
treatment with short-course chemotherapy. Indian J
Tuberc 1993;40:119.
4. Mitchison DA, Nunn AJ. Influence of initial drug
resistance on the response to shortcourse chemotherapy
of pulmonary tuberculosis. Am Rev Respir Dis
1986;133:423.
5. Gardner TS, Wenis E, Lee J. The synthesis of compounds
for the chemotherapy of tuberculosis. IV. The amide
function. J Org Chemistry 1954;19: 735-7.
6. Libermann D, Moyeux M, Rist N, et al. Sur la preparation
de nouveaux thioamides pyridiniques actifs dans la
tuberculose experimentale. C R Acad Sci Paris 1956;
124:2409-12.
7. Rist N, Grumbach F, Libermann D. Experiments
on the antituberculous activity of alphaethylthioisonicotinamide. Am Rev Respir Dis 1959;79:1-5.
8. Lucchesi ML Ethionamide activite, resistance, resistance
croisee. New York. Proceedings of the 20th Conference
of IUATLD, 1969;58-60.
9. Wang F, Lanley R, Gulten G, et al. Mechanism of
thioamide drug action against tuberculosis and leprosy
JEM 2007;204:73-8
10. Auclair B, Nix DE, Adam RD, et al. Pharma- cokinetics
of ethionamide administered under fasting conditions
or with orange juice, food or antacids. Antimicrobial agents
and chemotherapy 2000;45:810-14.
11. Seifartabc HI. Cerebrospinal fluid concentration of
ethionamide in children with tuberculous meningitis.
1989; 115: 483-86
12. Grosset JH. New approaches in antimy cobacterial
chemotherapy. Drugs Today 1988;24:291-301.
13. Tomioka H, Sato K, Kajitani H, et al. Comparative
antimicrobial activities of the newly synthesized
quinolone WQ3034, levofloxacin, sparfloxacin and
ciprofloxacin against Mycobacterium tuberculosis and
Mycobacterium avium complex, Antimicrob Agents
Chemother 2000;44:283-6.
14. Parenti F. New experimental drugs for the treatment of
tuberculosis. Rev Infect Dis 1989;11: 479.
15. Karl Drlica K, Muhammed M Malik, Jian Ying J, et al.
The fluoroquinolones as antituberculosis agents. In WN
Rom, Stuart Garey (Eds): Tuberculosis, 1st edn. London:
Little Brown and Company, 1995;745-50.
16. Vacher S, Pellegrin JL, Leblanc F, et al. Compa-rative
antimycobacterial activities of ofloxacin, ciprofloxacin and
grepafloxacin. J Antimicrob Chemother 1999;44:647-52.

16a. Ginsberg AS, Grosset JH, Bishai WR. Fluoroquinolones,
tuberculosis and resistance. Lancet Infect Dis 2003;3:43242.
17. Davies S, Spaham PD, Spencer RC. Comparative in vitro
activity of fluoroquinolones against mycobacteria. J
Antimicrob Chemother 1987;19: 605.
18. Singh M, Gupta P, et al. In vitro effect of fluoroquinolones
against Mycobacterium tuberculosis isolates from Agra and
Kanpur region in North India. Indian J Med Res 2009;
129: 542-7.
19. Venkataraman P, Paramasivan CN, Prabhakar R. In vitro
activity of ciprofloxacin and ofloxacin against South
Indian isolates of Mycobacterium tuberculosis. Indian J
Tuberc 1994;41:87.
20. Hooper DC, Wolfson, TS. The fluoroquinolones
pharmacology, clinical uses and toxicities in man.
Antimicrob Agents Chemother 1985;28:716.
21. Wise R, Lister D, McNulty CAM, et al. The comparative
pharmacokinetics of five quino-lones. J Antimicrob
Chemother 1986;18:71.
22. Mehra P, Agarwal KK. Ciprofloxacina new quinolone
antibiotic. Indian J Clin Pract 1990;1: 38.
23. Hyneybourne D, Wise R, Andrews JM. Ciprofloxacin
penetration into lungs. (Correspondence). Lancet 1987;
1:1040.
24. Martinis E, Legakis NJ. In vitro activity of ciprofloxacin
against clinical isolates of mycobacteria resistant to
Antimycobacterial drugs. J Antimicrob Chemother
1985;16:527.
25. Alangaden GJ, Manavathu EK, Vakulenko SB, et al.
Characterization of fluoroquinolone-resistant mutant
strains of Mycobacterium tuberculosis selected in the
laboratory and isolated from patients. Antimicrob Agents
Chemother 1995;39:1700-3.
activity of capreomycin and ciprofloxacin against South
Indian isolates of M. tuberculosis. Indian J Tuberc
1993;40:21.
27. Tsukamura M. In vitro antituberculosis activity of a new
antibacterial substance ofloxacin (DL8280). Am Rev
Respir Dis 1985;131:348.
28. Hopper DC. Quinolones. In: (Mandell GL, Bennett, JE,
and Dolin, R, (Eds). Mandell, Douglas, and Bennetts
Principles and Practice of Infectious Diseases, 5th ed.
Churchill Living- stone, Inc., Philadelphia, 2000;404:423.
29. Cambau E, Jarlier V. Resistance to quinolones in
mycobacteria. Res Microbiol 1996;147:52-9.
30. Berning SE. The role of fluoroquinolones in tuberculosis
today. Drugs 2001;61:9-18.
31. Daniel H, Paramasivan CN, Venkatesan P, et al.
Bactericidal action of ofloxacin, sulbactam/ampicilin,
rifampicin and isoniazid on logarithmic and stationary
phase cultures of M. tuberculosis. Antimicrob Agents
Chemother 1996;40:2296.
32. Kohno S, Koga H, Kaku M, et al. Prospective comparative
study of ofloxacin or ethambutol for the treatment of
pulmonary tuberculosis. Chest 1992;102:1815.
33. Kavi J, Stone J, Andrews JM, et al. Tissue penetration
and pharmacokinetics of lomefloxacin following multiple
doses. Eur J Clin Microbiol Infect Dis 1989;8:168.
445
34. Piersimoni C, Morbiducci V, Bornigia S, et al. In vitro

activity of the new quinolone lomefloxacin against
Mycobacterium tuberculosis. Am Rev Respir Dis
1992;146:1445.
35. Rastogi N, Goh KS. In vitro activity of the new
difluorinated quinolone sparfloxacin (AT-4140) against
Mycobacterium tuberculosis and further ehancement of its
extracellular activities by ethambutol. Antimicrob Agents
Chemother 1992;36:2843.
36. Heifets LB, Lindholm Levy PJ. Bacteriostatic and
bactericidal activity of ciprofloxacin and ofloxacin against
Mycobacterium tuberculosis and Mycobacterium avium
complex. Tubercle 1987;68:267-76.
37. Young LS, Berlin OGW, Inderlied CB. Activity of
ciprofloxacin and other fluorinated quinolones against
mycobacteria. Am J Med 1967;82:23-6.
38. Sirgel FA, Botha FJ, Parkin DP, et al. The early bactericidal
activity of ciprofloxacin in patients with pulmonary
tuberculosis. Am J Respir Crit Care Med 1997;156:901-5.
39. Hohl P, Salfinger M, Kafader FM. In vitro activity of the
new quinolone RO 23-6240 (AM-833) and the new
cephalosporins RO 15-8074 and RO 19-5247 (T-2525)
against Mycobacterium fortuitum and Mycobacterium
chelonae. Eur J Clin Microbiol 1987;6:487-8.
40. Tomioka H, Sato K, Akaki T, et al. Comparative in vitro
antimicrobial activities of the newly synthesized
quinolone HSR-903, sitafloxacin (DU-6859a), gatifloxacin
(AM-1155), and levofloxacin against Mycobacterium
tuberculosis and Mycobacterium avium complex.
Antimicrob Agents Chemother 1999;43:3001-4.
41. Peloquin CA, Berning SE, Huitt GA, et al. Levofloxacin for
drug-resistant Mycobacterium tuberculosis. (Correspondence).
Ann Pharma-cother 1998;32:268.
42. Ji B, Lounis N, Truffor-Pernot C, Grosset J. In vitro and in
vivo activities of levofloxacin against Mycobacterium
tuberculosis. Antimicrob Agents Chemother 1995;39:
1341-4.
43. Ji B, Lounis N, Truffor Pernot C, Grosset J. In vitro and in
vivo activities of moxifloxacin and clinafloxacin against
Mycobacterium tuberculosis. Antimicrob Agents
Chemother 1998;42:2066-9.
44. Piersimoni C, Morbiducci V, Bornigia S, et al. In vitro
activities of the new quinolone lomefloxacin against
Mycobacterium tuberculosis. Am Rev Respir Dis
1992;146:1445-7.
45. Gillespie SH, Billington O. Activity of moxifloxacin
against mycobacteria. J Antimicrob Chemother
1999;44:393-5.
46. Tsukamura M. Antituberculosis activity of ofloxacin (DL
8280) on experimenal tuberculosis in mice. Am Rev
Respir Dis 1985;132:915.
47. Mangunnegoro H, Hudoyo A. Efficacy of low-dose
ofloxacin in the treatment of multidrug-resistant
tuberculosis in Indonesia. Chemotherapy 1999; 45:19-25.
48. Alerge J, Fernandez de Sevilla T, Falco V, et al. Ofloxacin
in miliary tuberculosis. Eur Respir J 1990;3:238-9.
49. Kohno S, Koga H, Kaku M, et al. Prospective comparative
study of ofloxacin or ethambutol for the treatment of
pulmonary tuberculosis. Chest 1992;102:1815-8.
446
50. Casal M, Ruiz P, Herreras A. Study of the in vitro
susceptibility of M. tuberculosis of ofloxacin in Spain. Int
51. Gerald T. Salmenollosis. Harrisons Principles of Internal
Medicine, 14th edn. Faunwald, Issdbocher, Wilson,
Martin, Kasper, Hauser and Longo (Eds). New York:
McGraw Hill 1998;I:950-3.
52. Pradhan KM, Arora NK. Safety of ciprofloxacin therapy
in childhood magnetic resonance images, body flood
levels of fluoride and linear growth. Acta Pediatr
1995;84;555.
53. Sander S WE Jr. Efficacy safety and potential economic
benefits of oral ciprofloxacin in the treatment of
infections. Rev Infect Dis 1988;10:528-43.
54. Brogden RN, Fitton A. Rifabutin. A review of its
antimicrobial activity, pharmacokinetics properties and
therapeutic efficacy. Drugs 1994;47:983-1009.
55. OBrien RJ, Lyle MA, Snider DE. Rifabutin (ansamycin
LM 427): a new rifamycin-S derivative for the treatment
of mycobacterial diseases. Rev Infect Dis 1987;9:519-30.
56. Kunin CM. Antimicrobial activity of rifabutin. Clin Infect
Dis 1996;22:S8-S14.
57. Heifets LB, Iseman MD. Determination in vitro
susceptibility of mycobacteria to ansamycin. Am Rev
Respir Dis 1985;132:710-11.
58. Woodely CL, Kilburn JO. In vitro susceptibility of
Mycobacterium avium complex and Mycobacterium
tuberculosis strains to a spiropiperidyl rifamycin. Am Rev
Respir Dis 1982;126:587-97.
59. Gangadharam PRJ, Perumal VK, Jairam BT, et al. Activity
of rifabutin alone or in combination with clofazimine or
ethambutol or both against acute and chronic
experimental Mycobacterium intracellulare infections. Am
Rev Respir Dis 1987; 136:329-33.
60. Perumal VK, Gangadharam PRJ, Iseman MD. Effect or
rifabutin on the phagocytosis and intracellular growth
of Mycobacterium intracellular in mouse resident and
activated peritoneal and alveolar macrophages. Am Rev
Respir Dis 1987;136:334-7.
61. Perumal VK, Gangadharam PRJ, Heifets LB,
et al. Dynamic aspects of the in vitro chemotherapeutic
activity of ansamycin (rifabutin) on Mycobacterium
intracellulare. Am Rev Respir Dis 1985;132:1278-80.
62. OBrien RJ, Geiter LJ, Lyle MA. Rifabutin (ansamycin
LM427) for the treatment of pulmonary Mycobacterium
avium complex. Am Rev Respir Dis 1990;141:821-6.
63. Hong Kong Chest Service, British Medical Research
Council. A controlled study of rifabutin and an
uncontrolled study of ofloxacin in the retreatment of
patients with pulmonary tuberculosis resistant to
isoniazid, streptomycin and rifampicin. Tubercle Lung
Dis 1992;73:59-67.
64. McGregor MM, Olliaro P, Wolmarans L, et al. Efficacy
and safety of rifabutin in the treatment of patients with
newly diagnosed pulmonary tuberculosis. Am J Respir
Crit Care Med 1996; 154:1462-7.
65. Gonzalez Montaner LJ, Natal S, Yongchaiyud P, et al.
Rifabutin for the treatment of newly-diagnosed
pulmonary tuberculosis: a multinational, randomized,
comparative study versus rifampicin. Tubercle Lung Dis
1994;75:341-7.
66. Schwander S, Ruch-Gerdes S, Meteega A, et al. A pilot

study of antituberculosis combinations comparing
rifabutin with rifampicin in the treatment of HIV-1
associated tuberculosis. Tubercle Lung Dis 1995;76:
210-8.
67. Chan SL, Yew WW, Ma WK, et al. The early bactericidal
activity of rifabutin measured by sputum viable counts
in Hong Kong patients with pulmonary tuberculosis.
68. Blaschke TF, Skinner MH. The clinical pharmacokinetics
of rifabutin. Clin Infect Dis 1996; 22(suppl 1):S15-S22.
69. Fanfani A, Riva F, Sanflippo A, et al. Rifabutin: LM 427
Ansamycin. Farmitalia Carlo Elba, Milan; 1985.
70. OBrien RJ, Lyle MA, Snider DE Jr. Rifabutin (Ansamycin,
LM 427): A new rifamycin for the treatment of
mycobacterial diseases. Rev Infect Dis 1987;9:51.
71. Bendetti MS. Inducing properties of rifabutin, and effects
on the pharmacokinetics and metabolism of concomitant
drugs. Pharmacol Res 1995;32:177-87.
72. Narita M, Sgtambaugh JL, Hollender ES, et al. Use of
rifabutin with protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis. Clin
Infect Dis 2000;30:779-83.
73. Yang B, Koga H, Ohno H, et al. Relationship between
antimycobacterial activities of rifampicin, rifabutin and
KRM-1648 and rpoB mutation of Mycobacterium
tuberculosis. J Antimicrob Chemother 1998;42:621-8.
74. Sintchenko V, Chew WK, Jelfs PJ, et al. Mutation in the
rpoB gene and rifabutin susceptibility of multidrugresistant Mycobacterium tuberculosis strains isolated in
Australia. Pathology 1999;31: 257-60.
75. Chan SL, Yew WW, Ma WK, et al. The early bactericidal
activity of rifabutin measured by sputum viable counts
in Hong Kong patients with pulmonary tuberculosis.
Tubercle Lung Dis 1992;73: 33.
76. Truffot CH, Bismuth R, et al. The in vitro and in vivo
experimental activity of cyclopentyl rifamycin (MDL473)
on M. tuberculosis. 12th International Congress on
Chemotherapy. Florence 1981, Abstract 693
77. Yates MD, Collins CH. Comparison of the sensitivity of
mycobacteria to cyclopentyl rifamycin MDL 473 and
rifampicin. J Antimicrob Chemother 1982;10:147.
78. Jarvis B, Lamb HM. Rifapentine. Drugs 1998;56: 607-16.
79. Keung ACF, Owens RC, Jr., Eller MG, et al. Pharmacokinetics of rifapentine in subjects seropositive for the
human immunodeficiency virus: A phase I study.
80. Reith K, Keung A, Toren PC, et al. Disposition and
metabolism of 14C-rifapentine in health volunteers. Drug
Metabolism Disp 1998;26:732-8.
81. Conte JE, Jr., Golden JA, McQuitty M, et al. Single-dose
intrapulmonary pharmacokinetics of rifapentine in
normal subjects. Antimicrob Agents Chemother
2000;44:985-90.
activity of rifampicin, rifapentine and rifabutin against
South Indian isolates of Mycobacterium tuberculosis. Indian
J Tuberc 1993;40: 17.
83. Vladimirsky MK, Ledigina GA. Antibacterial activity of
liposome trapped streptomycin in mice infected with M.
tuberculosis Biomedicine 1982;36:375-80.

84. Heifets LB, Iseman MD, Cook JL, et al. Determination of
in vitro susceptibility of M. tuberculosis to cephalosporins
by radiometric and conventional methods. Antimicrob
Agents Chemoither 1985;27:11-5.
85. Guleria R. Newer drugs for the treatment of Tuberculosis.
Drug Alert 1996;5:2-13.
86. Casal MJ, Rodriguez FC, Luna MD, et al. In vitro
susceptibility of M. tuberculosis, M. africanum, M. bovis,
M. avium, M. fortuitum and M. chelonae to ticarcillin in
combination with clavulanic acid. Antimicrob Agents
Chemother 1987;31:132.
87. Sorg TB, Cynamon HC. Comparison of four beta
lactamase inhibitors combination with ampicillin against
Mycobacterium tuberculosis. J Antimicrob Chemother
1987;19:59.
88. Tsukamura M, Ichiyama S, Miyachi T. Superiority of
viomycin or streptomycin over ethambutol in initial
treatment of lung diseases caused by Mycobacterium avium
complex. Chest 1989;95: 1055.
89. Akiyoshi M, Sato K. On the ototoxicity of tuberactinomycin. Chemotherapy 1971;19:299.
90. Selvakumar N, Kumar V, Acharyulu GS, et al.
Susceptibility of South Indian strains of Myco-bacterium
tuberculosis to tuberactinomycin. Indian J Med Res
1992;95:101.
91. Luna Herrera J, Reddy VM, Daneluzzi D, et al.
Antituberculosis activity of clarithromycin. Antimicrob
92. Burman WJ, Reves RR, Rietmeijer CA, et al. A
retrospective comparison of clarithromycin versus
rifampin in combination treatment for disseminated
Mycobacterium avium complex disease in AIDS:
clarithromycin decreases transfusion requirements. Int J
93. Mor N, Esfandiari A. Synergistic activities of
clarithromycin and pyrazinamide against Mycobacterium
tuberculosis in human macrophages. Antimicrob Agents
Chemother 1997;41:2035-6.
94. Truffot-Pernot C, Lounis N, Grosset JH, Ji B. Clarithromycin
in inactive against Mycobacterium tuberculosis. Antimicrob
95. Rodvold KA. Clinical pharmacokinetics of
clarithromycin. Clin Pharmacokinetics 1999;37: 385-98.
96. Pierce M, Crampton S, Henry D, et al. A rando-mized
trial of clarithromycin as prophylaxis against
disseminated Mycobacterium avium complex infection in
patients with advanced acquired immunodeficiency
syndrome. N Engl J Med 1996;335:384-91.
97. Shafran SD, Singer J, Zarowny DP, et al. A comparison
of two regimens for the treatment of Mycobacterium
avium complex bacteremia in AIDS: Rifabutin,
ethambutol, and clarithromycin versus rifampin,
ethambutol, clofazimine, and ciprofloxacin. N Engl
J Med 1996;335:377-83.
98. Van Remburg, Joone GK, Sirgel FA, et al. In vitro
investigation of antimicrobial activities of novel
tetramethylpiperidine substituted phenazine against
mycobacterium tuberculosis. Chemotherapy 2000;46:
43-8.
447
99. Adams LB, Sinha I, Franzblau SG, et al. Effective treatment

of acute and chronic murine tuberculosis with liposome
encapsulated clofazimine. Antimicrob Agents Chemother
1999;43:1638-43.
100. Freerksen E, Kruger Thiemer E, Rosenfeld M. Cycloserin
(D-4-Amino-isoxazolidine-3-on). Antibiotica et
Chemotherapia 1959;6:303-96.
101. Ramaswami S, Musser JM. Molecular genetic basis of
antimicrobial agent resistance in Mycobacterium
tuberculosis:1998 update. Tubercle Lung Dis 1998;79:3-29.
102. David HL, Goldman DS, Takayama K. Inhibition of the
synthesis of wax D peptidoglycolilpid of Mycobacterium
tuberculosis by D-cycloserine. Infect Immun 1970;1:74-7.
103. Walker WC, Murdock JM. Cycloserine in the treatment
of pulmonary tuberculosis. A report on toxicity. Tubercle
1957;38:297-302.
104. Bucco T. Meligrana G, De Luca V. Neurotoxic effects of
cycloserine therapy in pulmonary tuberculosis of
adolescents and young adults. Scand J Respir Dis 1970;71
(Suppl):259-65.
105. Akula SK, Aruna AS, Johnson JE, et al. Cycloserine
induced Stevens Johnson syndrome in an AIDS patient
with multidrug-resistant tuberculosis. Int J Tuberc Lung
Dis 1997;1:187-90.
106. Perez-Stable EI, Hopewell PC. Current tuberculosis
treatment regimes. Clin Chest Med 1989;10:323-39.
107. Edson RS, Terrell CL. The aminoglycosides. Mayo Clin
Proc 1999;74:519-28.
108. Garcia Rodriguez JA, Martin Luengo F, Saenz Gonalez
MC. Activity of amikacin against Mycobacterium
tuberculosis. (Correspondence). J Antimicrob Chemother
1978;4:293-4.
109. Hoffner SE, Kallenius G. Susceptibility of streptomycinresistant Mycobacterium tuberculosis strains to amikacin.
Eur J Clin Microbiol 1988;7:188-90.
110. Allen BW, Mitchison DA, Chan YC, et al. Amikacin in
the treatment of pulmonary tuberculosis. Tubercle
1983;64:111-8.
111. Donald PR, Sirgel FA, Venter A, et al. The early
bactericidal activity of amikacin in pulmonary
112. Dehpour AR, Samadian T, Roushanzamir F. Interaction
of aminoglycoside antibiotics and lithium at the
neuromuscular junction. Drugs Exptl Clin Res
1992;18:383-7.
113. Zarfin Y, Koren G, Maresky D, et al. Possible
indomethacin-aminoglycoside interaction in preterm
infants. J Pediatr 1985;106:511-12.
114. Bunn PA. Kanamycin. Med Clin N Am 1970;54: 1245-57.
115. Alberghina M, Nicoletti G, Torrisi A. Genetic
determinants of aminoglycoside resistance in strains of
Mycobacterium tuberculosis. Chemotherapy 1973;19:
148-60.
116. Heifects L, Lindholm Levy P. Comparison of bactericidal
activities of streptomycin, amikacin, kanamycin, and
capreomycin against Mycobacterium avium and M.
tuberculosis Antimicrob Agents Chemother 1989;33:
1298-301.
448
117. Donomae I. The combined use of capreomycin and

ethambutol in retreatment of pulmonary tuberculosis.
118. McClatchy JK, Kanes W, Davidson PT, et al. Cross
resistance in M. tuberculosis to kanamycin, capreomycin
and viomycin. Tubercle 1977;58:29-34.
119. Aquinas M, Citron KM. Rifampicin, ethambutol and
capreomycin in pulmonary tuberculosis, previously
treated with both first and second line drugs; the
results of two years chemotherapy. Tubercle 1972;53:
153-65.
120. Andreos K, Verhasselt P, Guillemont J, et al. A
diarylquinolane drug active on ATP synthesis of M.
tuberculosis. Science 2005;307:223-7.
121. Koul A, Vranckx L, Dendouga N, et al. Diaryloquinolines are bactericidal mycobacteria as a result of
disturbed ATP homeostasis. J Biol Chem 2008;283:
25273-80.
122. Rustomjee R, Diacon AM, Aleen J, et al. Early bactericidal

activity and pharmacokinetics of diarylquinoline
TMC207 in treatment of pulmonary tuberculosis.
Antimicrobial Agents Chemother 2008;52:2831-35.
123. Perrin FM, Lipman MC, Mchugh TD, et al. Biomarkers
of treatment response in clinical trails of novel
antituberculosis agnets. Lancet Infect Dis 2007;7:481-90.
124. Fadl TA and Bin-Jubair FAS. Anti-tubercular activity of
Isatin derivatives. Int J Res Pharm Sci 2010;1:113-26.
125. Bonde CG, Peepliwal A, Gaikwad NJ. Synthesis and
antimycobacterical activity of azetidine-quinazoline and
triazalo-thiadiazole-containing pyrazines. Arch Pharm
(Weinheim) 2009; 342: 723-31.
126. Protopopova M, Hanrahan C, Nikonenko B,
et al. Identification of a new antitubercular drug candidate,
SQ 109, from a combinatorial library of 1,2 ethylencediamines Journal of antimicrobial chemotherapy 2005; 56:
968-74.
32
Pharmacokinetics
Vimlesh Seth, Alka Beotra, SD Seth, OP Semwal
INTRODUCTION
GENERAL ASPECTS
In Europe the companies that wish to develop a drug

for use in children, it is necessary to follow pediatric
investigation plan (PIP) as required by the European
Regulation on better medicines for children. Defining
the optimum dose of a drug is one of the most difficult
parts of the developmental process. In phase I clinical trials
to have standard pharmacokinetics/pharmacokinetic
pharmacodynamic, (PK/PD) approaches involve in
administration of either single or multiple doses of a
drug in healthy adults. Blood samples are taken at
specified time intervals from the participants. Drug is
subsequently assayed for its concentration and relevant
metabolites, age based on absorption and distribution
half-lives. These are the pharmacokinetic data and by
the pharmacodynamics, the effect of the drug at
different concentrations can be assessed.
These approaches if used for all new drugs in children
of each relevant age groups, present practical and ethical
challenges. For estimating the optimal dose or dose range
in pediatric population alternative methods can also be
used. These are allometric scaling, a population
pharmacokinetic (PK) approach and in silico modelling.
Scaling is a common tool which can be used to
extrapolate within species at different age periods
between animals and human beings. However, the factor
used for scaling differs. Though there is a nonlinear
relationship between dose and body weight, the latter is
the easiest to use. It is known for almost 60 years that
smaller species are more tolerant of drug treatment than
larger species. Body surface area (BSA) was subsequently
found to be more satisfactory index of drug requirement
as compared to body weight or age particularly during
infancy and childhood. In neonates BSA also overpredicts
clearance as it is the largest in them. In almost all species
including human, the log of basal metabolic rate plotted
against the log of body weight produce a straight line
with a slop of . Various theories exist for this
phenomenon. For scaling some PK parameters, this liner
slop is superior to body weight and BSA. These PK
parameters are plasma clearance, volume of distribution
and elimination half-life. This log relationship is used in
the allometric power model. However, none of these
parameter are ideal.
The treatment of tuberculosis is protracted and burdensome and its control is further complicated by the synergy
between tuberculosis and HIV/AIDS and by the
emergence of multidrug-resistant (MDR) strains of M.
tuberculosis. Even when many countries are engaged in
dealing with increasing occurence of MDR-TB (resistance
to isoniazid and rifampicin), a new trend in drugresistance has been emerging in some parts of the globe.
This is the appearance of extensively drug-resistant TB
(XDR-TB) which is the form that is resistant to anyone
of the fluoroquinolones and any of the second-line
antituberculosis injectable drugs (amikacin, kanamycin
or capreomycin) in addition to the resistance to isoniazid
and rifampicin (i.e. MDR-TB). Besides MDR-TB and XDRTB, other features also contribute to failure of TB-control
in many developing countries which are HIV
epidemic, collapse of public health infrastructure, war,
famine, population migration, increasing inequality and
poverty, and expensive drugs with dwindling
government support. In certain situations like poor drug
compliance (due to any reasons) and use of lowquality
or spurious antituberculosis drugs, suboptimal serum
concentrations are achieved which are associated with
worse treatment outcomes. It is important to maintain
high standards for drug-quality assurance as low quality
drugs often penetrate emerging markets, resulting in low
cure rates for patients and increased drug-resistance.
Considering all these aspects it is important to know in
details the kinetics of each of the antituberculosis drugs
in transit in the human body from the time of its
administration (oral or parenteral) to the elimination from
the body. Further, drug to drug interactions, drug to
pathogen, drug to food and drug to immune response
also play significant roles that may influence the
pharmacokinetics and pharmacodynamics of the drug
in question.
Serum Concentrations of the Antimycobacterial Drugs

Therapeutic drug monitoring (TDM) is the process of
adjusting drug dosages based on serum concentration
data or applied pharma-cokinetics, allows clinicians
to:
450
i. Quantify the relationships among drug doses.

ii. Serum concentrations.
iii. Therapeutic responses.
iv. Concentration-related adverse events.
The use of TDM in the dosing of antimycobacterial
drugs is relatively new. Optimal use of TDM requires a
complete model of the serum concentration response
curve for a drug. These curves are only partially described
for the antimycobacterial drugs. It is known that if a
patient fails to take a drug (serum concentrations of zero),
his treatment will fail. If they absorb isoniazid and
rifampicin normally, they are very likely to respond to
treatment. Somewhere between the normal serum
concentrations and zero, activities of isoniazid and
rifampicin wane. This dropoff in activity occurs even
more rapidly for ethambutol and the second-line
antituberculosis drugs. Further complicating, the
relationships between serum drug concentrations and
response is the fact that antituberculosis drug therapy
appears to have two distinct phases. First there is rapid
elimination of actively multiplying mycobacteria, known
as early bactericidal activity; and second there is the slow
elimination of semidormant organisms, and those in less
accessible areas, known as the sterilizing activity. It is
possible that the characteristics of a drug that are
important for one phase may be less important during
the subsequent phase. Thus, while high maximum serum
concentrates relative to the minimum inhibitory
concentrations (Cmax/MIC ratios) appear desirable early
on, they may be less critical later on. During the sterilizing
phase, it may be the ability of the drug to remain at the
site of infection for long periods of time, and its ability to
quickly inhibit or kill mycobacteria. Unfortunately, these
phenomena differ from patient to patient.
Altered pharmacokinetic profiles for antimicrobial
drugs in selected patient groups have been demonstrated,
e.g. AIDS patients display low serum concentration of
antimycobacterial drugs. This also occurs in patiens
with cystic fibrosis and diabetes mellitus due to
malabsroption. This drug malabsorption is responsible
for failure to drug therapy in 2 out of 5% of compliant
tuberculosis patients. TDM appears to be a useful tool
for identifying these patients early on and for adjusting
their doses before drug-resistance and or/clinical failure
occurs. TDM can be very cost-effective because it may
prevent the need for lengthy and expensive retreatment
and prevent additional cases of tuberculosis that occur
before treatment failures or relapses are identified. TDM
has certain limitations and is not a replacement of direct
supervision which is the key factor in DOTS therapy.
However, it can be particularly effective in guiding
therapy in second-line drugs. In the latter, effective
dosing against dose-related toxicities are very important.
When low serum concentrations are demonstrated with

normal dosing, higher doses are required even if they
exceed the so called maximum dose. Serious doserelated toxicities are relatively uncommon with the
antituberculosis drugs except cycloserine, ethambutol,
streptomycin and other aminoglycosides under conditions such as renal failure. TDM has been proved to be
beneficial in adults with HIV/AIDS and is a powerful
tool for optimizing drug therapy in patients with difficult
to treat mycobacteria.
Pharmacodynamics
The aim of antituberculosis treatment, as with any other
antibiotics, is to achieve adequate drug concentrations
at the site of infection for an appropriate length of time,
in order to ensure the eradication of the organisms and
optimize clinical success. This desired outcome1 depends
not only on the pharmacokinetics of the agent, but also
on the characteristic of the pathogen, e.g. microbicidal
susceptibility, and host related factors.
A new approach to this problem seeks to combine the
microbiologic activity with antibacterial pharmacokinetics
data into a discipline called pharmacodynamics. The best
pharmaco-dynamic parameter is the minimum effective
antimicrobial action in an area under the inhibitory titer
(AUC), which is calculated as the 24 hours serum AUC
divided by minimum inhibitory concentration (MIC) of
the pathogen. These two basic principles of pharmacokinetics and pharmacodynamics, in addition to,
microbicidal susceptibility of the organism are the rational
for combination chemotherapy applicable to mycobacterial infections.

The rate at which an antituberculosis drug kills, rapidly
metabolizing and multiplying bacilli during the first two
days of therapy is termed the early bactericidal activity
(EBA). EBA can be used to determine the lowest effective
dose of these drugs. This has been estimated for
practically all drugs, i.e. isoniazid, rifampicin, pyrazinamide streptomycin, and even ethambutol. EBA
reflects the ability of an agent to kill the metabolically
active bacilli in the walls of cavities. It might also reflect
the capacity of an agent to protect companion drugs
against resistance. Hence, in addition to the pharmacokinetics and pharmacodynamics of drugs, determination
of EBA is another important parameter to determine the
efficacy of an antituberculosis agent.
Pharmacokinetics
Pharmacokinetics is the study and characterization of the
timecourse of drug absorption, distribution, metabolism
and excretion, and the relationship of these processes to
Chapter 32 Antituberculosis Drugs: Pharmacokinetics

intensity and timecourse of therapeutic and toxicologic
effects of drugs. 2 Although, principles of pharmacokinetics are described in terms of mathematical
equations which are used to quantitatively predict the
nature of these processes, understanding of basic
pharmacokinetic principles and the use of plasma level
determinations can greatly help the physician in taking
deci-sions regarding drug, dosages. From the time, a drug
enters the body until it is eliminated, a number of kinetic
factors, which differ in infants and young children
from adults, may be responsible for the altered drug
response.3-6
First Order Kinetics

After drug administration, a drug crosses several
membranes by passive diffusion to reach its site of action.
In general, drugs in which the rate of transfer is
proportional to the amount of drug remaining to be
transferred is described by first order kinetics. It means
that a constant fraction of the drug in the body disappears
in each equal interval of time.4-6 Following a single intravenous dose, the plasma concentration of the drug is
found to fall exponentially. 7-10 Half-life is the time
required for 50% completion of this process.9 In first order
kinetics, the half-life is independent of the route of
administration, dose given and plasma concentration of
the drug and is directly related to the duration of its
pharmacological effect. A 93.7% of the drug is eliminated
in 4 half-lives. In the case of an exponentially eliminated
drug, a plot of the log of concentration against time gives
a straight line.6 Drug transfer can be considered to
proceed by first order kinetics when a semilogarithmic
plot of drug concentration versus time results in a straight
line (Fig. 32.1).
Most drugs are eliminated exponentially (first
order kinetics). For some drugs, e.g. phenytoin and
propranolol, the elimination is exponential at lower
451
dosage levels, but when the dose exceeds a certain critical

level the elimination mechanisms get saturated and then
a fixed quantity of the drug is eliminated per unit time.
This is called dose-dependent elimination or saturation
kinetics or zero order kinetics.10
Absorption
Absorption describes the rate at which a drug leaves its
site of administration and the extent to which it occurs.
The absorption from gastrointestinal tract becomes the
initial factor determining drug plasma concentration and
therapeutic effect. Absorption is influenced by
physiologic factors (e.g. rate of gastric emptying, GI
motility, food intake, etc.) which may vary greatly in the
neonate.11,12 Physicochemical properties of the drug (pKa,
molecular weight, lipid solubility) and manufacturing
techniques (particle size) also affect absorption.
Bioavailability
The bioavailability of a drug is defined as its rate and
extent of absorption. It is used to indicate the extent to
which a drug reaches its site of action. Bioavailability is
determined from blood level or urinary excretion data
after oral administration, with reference to similar data
after intravenous administration. The total area under
the drug level in blood or plasma versus time curve, i.e.
area under the curve (AUC), after a single dose, reflects
the amount of drug reaching the blood stream. For most
drugs, if we double the amount injected intravenously,
we double the AUC. It follows that if one compares the
AUC after oral administration with that obtained after
intravenous administration, one can determine the
fraction (F) of the oral dose available to the systemic
circulation. In other words,
F = (AUC)oral/(AUC)iv
If only 60% of an oral dose reaches the bloodstream,
then F = 0.60; if the entire dose is available, then F = 1.00.
The determination of bioavailability is a time consuming
and expensive procedure and needs to be carried out only
in the cases of drugs with a narrow therapeutic index.10
First Pass Effect
Fig. 32.1: Semi-logarithmic plot of drug concentration versus time
After oral administration, a drug must pass sequentially

from the gastrointestinal lumen, through the gut wall,
then through the liver before reaching the systemic
circulation. Since, the gut wall and liver are sites of drug
metabolism, a fraction of the amount absorbed may be
eliminated (metabolized) before reaching the blood
stream. Therefore, a drug may be completely absorbed
but incompletely available because part of the dose is
metabolized to other products during the drugs passage
from the gut lumen to the systemic circulation because
of first pass metabolism in the gut wall or liver. It results
in decreased oral drug bioavailability.
452
Distribution
The transfer of drug from blood to extravascular fluids
(i.e. extracellular and intracellular water) and tissues is
called distribution. Drug distribution is usually a rapid
and reversible process. After intravenous injection, drug
in the plasma exists in a distribution equilibrium with drug
in the erythrocytes, in other body fluids, and in tissues.
As a result of this, changes in the concentration of drug in
the plasma are indicative of changes in drug level in other
tissues including sites of pharmacologic effect
(bioreceptors). Figure 32.2 shows schematic representation
of drug absorption, distribution and elimination.
The moment a drug reaches the blood stream, it is
subject to both distribution and elimination. The rate
constants associated with distribution, however, are
usually much larger than those related to drug elimination.
Accordingly, drug distribution throughout the body is
usually complete while most of the dose is still in the body.
In fact, some drugs attain distribution equilibrium before
virtually any of the dose is eliminated. In such cases, the
body appears to have the characteristics of a single
compartment. But for most of the drugs, concentrations
in plasma measured shortly after intravenous injection
reveal a distinct distributive phase. This means that a
measurable fraction of the dose is eliminated before
attainment of distribution equilibrium. These drugs impart
the characteristics of a multicompartment system upon
the body. These compartments can often be classified as:
(i) the central compartment consisting of the plasma and
extracellular fluid and highly vascular tissue (usually the
red blood cells, lungs, liver, kidney), and (ii) a
compartment of poorly perfused tissue (fat, muscle, skin).
Elimination
Elimination processes are responsible for the physical or
biochemical removal of drug from the body. The transfer
of drug from the blood to the urine or other excretory
Fig. 32.2: Schematic representation of drug absorption,

distribution and elimination
compartments (i.e. bile, saliva and milk), and the

enzymatic or biochemical transformation (metabolism)
of drug in the tissues or plasma to metabolic products
are usually irreversible processes. Drugs are eliminated
from the body either unchanged or as metabolites. The
kidney is the most important organ for elimination of
drugs and their metabolites. Excretion of drugs in the
breast milk is important not because of the amounts
eliminated but because the excreted drugs are potential
sources of unwanted pharmacological effects in the
nursing infant.
In vivo drug metabolic studies are most useful for
estimating the clearance of a drug. It is a better index of
efficiency of drug elimination than the more commonly
used term half-life. Clearance is defined as the volume
of biological fluid that is irreversibly cleared per unit of
time. In general, drug elimination is impaired in
newborns, particularly, premature newborns. It improves
with age and tends to be more efficient in older infants
and children.
FACTORS RESPONSIBLE FOR ALTERED DRUG RESPONSE

IN CHILDREN
Dosing Guidelines
These are more complicated in children than those for
adults. Evidence indicates that children require and
tolerate larger mg/kg doses of many drugs than adults.
Estimates of the dose required for neonates, infants and
children should be given on the basis of the surface area
of the young patient, but often this is not done in
developing countries except for anticancer drugs and
drugs used in renal disease. The drugs are usually
dispensed as mg/kg dose or mg/kg/day divided into 3
to 4 doses. Calculations based on body surface area
indicate that in general, the average 3-month-old child
weighing 6 kg should receive twice the mg/kg dose given
to an adult, whereas the average 5-year-old child
weighing 20 kg should receive 1.5 times the mg/kg dose
given to adults.11 Hence, there is overdosing of drugs,
antituberculosis being one such group. Streptomycin
used to be given in the dose of 50 mg/kg/day IM, but
now it has been amply demonstrated that a dose given
as 20 mg/kg/kg, that too, for two weeks is enough. This
is because the drug acts on the rapidly multiplying
extracellular organisms, which are very few in
tuberculosis of children, except in adolescence. This
occurs in this age period of childhood (adult type of
pulmonary tuberculosis sputum, +ve, or severe
pulmonary with sputum, ve).
However, this concept does not hold true for
developing countries where a sizeable propor-tion of
children particularly preschoolers <5 years suffer from
grades II and III of malnutri-tion. Hence, the same dose

which is therapeutic and least toxic for children belonging
to western countries will not be right for developing
countries. The glaring example is isoniazid which was
given in the dose of 10 to 20 mg/kg to children
particularly who had serious type of tuberculosis, i.e.
neurotuberculosis. Pharmacokinetic studies on isoniazid
which will be described in the later part of the chapter, it
was demonstrated by Seth that a dose of 5 mg/kg is good
enough for having sufficient MIC, with good therapeutics
efficacy and least toxicity. Hence, in addition there are
ethnic factors which change the pharmacodynamics of
drugs, antituberculosis drugs being one such group.
The Requirement with Larger Doses in Children than in

Adults
Clinical pharmacokinetics are different in neonates as
compared to adults.12 It is related in part to the fact that
total body water (T-BW) and extracellular fluid (ECF)
make up a larger percentage of the total body weight in
children than in adults. Total body water decreases with
age, from 78% of the newborns body weight to 60% of
the adults weight.13 Differences in extracellular water
(ECW) are even greater. Extracellular water represents
about 45% of the body weight in the newborn but only
20% of the adults body weight.14 Inspite of this, in
newborns a fairly large proportion, i.e. about one-third
are low birth weight, appropriate for gestation, drugs
given using surface area basis will be higher and likely
to produce toxicity. Aggarwal et al14a have shown that
ciprofloxacin (not permitted in child and neonate) is used
increasingly in neonates for treating multidrug resistant
infection. The pharmacokinetics of this drug are
necessary in the newborn. By multiple dose
pharmacokinetics it was demonstrated that 10 mg/kg
I/V given 12 hourly is effective for neonatal sepsis but
higher doses are required for treating staphylococcal and
pseudomonas infection. Hence, one should not blindly
follow the dosage schedule which is given in western
books. Children in India, right from the newborn age
period to adolescence are lesser in weight except the ones
who belong to top 25 percentiles.
The Morphology and Functions of the Gastrointestinal

Tract
These vary almost continuously from birth till
senescence.15 The effect of food on drug absorption is
particularly important. Each drug must be considered
individually to see the effect on children.
Yaffe15 has summarized the following concepts:
i. The lower pH in children less than 3 years in
comparison to adults may influence the gut motility,
chemical stability of drug and the dissolution rate
453
of drug tablets as well as absorption of drugs. Acidic

and basic drugs are best absorbed in the stomach
and small intestine respectively. However, many
acidic drugs are absorbed more rapidly in the
duodenum than in the stomach, because of the larger
absorption area of duodenum. In the presence of a
poor mucosal development in neonates, pH is of
great importance.
ii. The bacteria colonizing the intestinal tract are of
importance in the hydrolysis of drug conjugates
excreted in the bile.
iii. Irregular gut motility and slower gastric emptying
time may not affect the degree of absorption but do
interfere with the achieve-ment of peak plasma
concentration of a drug.
In general, age related changes in drug distribution
tend to decrease the volume of distribution in adults,
compared with neonates for most water soluble drugs.
Drugs that are lipid soluble may have a lower volume of
distribution in neonates because of age related differences
in adipose tissue.
The most dramatic age related differences in drug
elimination often occur between the newborn and the
adult. Most of the enzymatic microsomal systems required
for drug metabolism are present at birth, but their titers are
usually lower than adult levels. In general, drugs subject to
biotransformation are eliminated more slowly in newborns than
in adults.16 Drug oxidation in the neonate is usually impaired, whereas drug conjugation presents a mixed
picture. Sulfate conjugation seems to be as efficient in
newborns as in adults, but conjugation with glucuronic
acid is considerably low, reaching adult levels only after
3 years of age.
VARIOUS FACTORS WHICH CHANGE

PHARMACOKINETICS
Drug Dose
For a drug to be effective, its serum concentra-tion must
exceed its minimum inhibitory concentration (MIC). Serum
rifampicin and isoniazid concentrations are a good basis
for evaluation of efficacy of a rational antituber-culosis
regimen. Unfortunately, in the pediatric population, the
recommended doses of the antituberculosis drugs are not
based upon well than designed pharmacokinetic studies
rather data generated in the western world, that too in
African countries on clinical observations. Animal studies
and those in adults have shown that the serum and tissue
concentrations achieved by oral administration of rifampicin
and isoniazid are much above their MIC.7 Olson et al17 and
Mount et al18 have demonstrated that the concentrations
achieved in children are higher because doses given on
weight basis are almost double as compared to adults.
454
Pharmacokinetics Characteristics of INH

Pharmacokinetic characteristics of INH have been
extensively studied in adults but data in respect of
children and especially younger children are limited.
Where such data are available cognizance has not been
taken of the genotype or of the trimodality of INH
elimination except a few studies by Seth et al19,20 have
demonstrated that considerable differences in exposure
to INH that exist between homozygous acetylators of
INH and heterozygous and homozygous fast acetylaters
in children described later in the chapter. Age
relationship analysis indicates that younger children
eliminate INH faster than older children. In a trimodel
model of INH elimination then is a significant age related
decline in the first order elimination rate constnt (k, h-1)
with age in all three genotypes. Further, the exposure of
the children to INH, as reflected by the first order
elimination rate constant, AUC for the period
2 to 5 hours after dosing, and INH concentrations at
different time intervals after dosing, is significantly less
than that of a group of adults drawn form the population
and receiving the same mg/kg body weight dose of INH.
Schaaf et al21 concluded that on the basis of NAT2
genotype, younger children eliminate INH faster than
older children and children as a group faster than adults.
Faster elimination has been ascribed to the relatively
greater mass of the liver in proportion to total body
weight and hence recommended the calculation of the
dose in relation to body surface area than body weight.
However, they had reservation of this recommendation
for use in the program conditions.
The normal range of INH concentration has been
given as 3-5 mg/L, and has been suggested that a 3 hours
concentration of 1.5 mg/L is desirable. In their study 35%
of the homozygous fast acetylators had a 2 hours INH
concentration of less than 3 mg/L and 45% did not reach
a 3-hour postdose concentration of 1.5 mg/L. From this
it seems that both homozygous and a significant
proportion of heterozygous fast acetylators will fail to
achieve the recommended concentrations.
For this, Schaaf et al21 justified the use of higher mg/
kg INH doses in children than adults. American
Academy of Pediatrics (AAPS) recommend an INH dose
of 10 to 15 mg/kg/day body weight. Many of the studies
including that is detailed below by Seth et al 19,20
demonstrated satisfactory clinical response with 5 mg/
kg of INH emanating from population in the North India.
The relative therapeutic disadvantage of heterozygote
fast acetylators will also be concealed by the synergistic
potential of a multidrug regimen. Under adverse
circumstances, such as failure of full compliance,
compromised absorption of INH itself or its companion
drug rifampicin. To be on the safe side, Schaafs and AAPS
recommendation suggested dose is at least 10 mg/kg.
Pharmacokinetics of Isoniazid in Isoniazid Resistant

Tuberculosis in Children
Isoniazid (INH) resistant and especially multidrug
resistant (MDR) tuberculosis (resistance to both INH and
rifampicin) poses an increasing problem for tuberculosis
control programs. This does not spare the children.
However, the value of using INH to which M. tuberculosis
shows an in vitro resistance especially to INH, in
treatment has been debated.
The critical concentration for high level INH
resistance is defined as >1.0 g/ml on Lowenstein Jensen
medium. The most critical concentration in liquid
medium, such as the BACTEC460 drug susceptibility test,
are 0.1 g/ml for low-level resistance and 0.4 g/ml
for high level resistance. However, concentration of INH
of more than 5 g/ml are readily attainable with high
dosages of INH in children. (15-20 mg/kg/day) and 5
g/ml serves as a practical measure of clinically relevant
high level resistance.
Children with drug resistant tuberculosis usually
have transmitted (new) resistance. Low-level INH
resistance is more common in adults with new (i.e. no
previous treatment) INH resistant tuberculosis than in
those previously treated for INH resistant tuberculosis.
As low level of INH resistance is more common implying
a potential therapeutic role of high dose INH (15-20 mg/
kg/day).
Treatment is difficult and the armamentarium of
second-line drugs is limited. This data is important for
better defining the most appropriate use of INH and to
prolong the usefulness of this key agent in case
management and tuberculosis control programs,
particularly in resource limited countries where the
availability of second line drugs is not easy. The far
reaching implication could be if appropriate, INH dosage
regimens could eradicate the partially resistant M.
tuberculosis organisms.
There was no difference in the level of INH resistance
between new and previously treated cases. This
emphasizes the importance of detailed history taking of
contact with infectious tuberculosis cases and the
possibility of exposure to drug-resistant organisms.
Schaaf et al21a have rightly emphasized in their study
is that drug susceptibility testing was not done at INH
concentrations of 0.4 g/ml, 1.0 g/ml and 2.0 g/ml
which would have given a better description of exact
minimal inhibitory concentration for INH in their
isolates.
In conclusion, whenever the minimal inhibitory
concentration of INH can be determined, treatment can
be individualized. When minimal inhibitory
concentration is below 1.0 g/ml or is unavailable, high
dose INH at 15 to 20 mg/kg/day could still possibly
455

value in the treatment of children with drug-resistant
tuberculosis, although, it should not replace any other
drug.
Paradoxical effect of Isoniazid on the Activity of

Rifampicin Pyrazinamide Combination in a Mouse
Model of Tuberculosis
Almeida et al23 concluded that the simplest and perhaps
the most reasonable response of the paradoxical effect of
isoniazid on the activity of rifampicinpyrazinamide
combination is that this antagonism is the price to pay
for having an excellent combined regimen that prevents
the selection of drug resistant mutants. INH has a crucial
role in the early bactericidal activity and prevents the
emergence of resistance to companion drug. However,
one can now imagine replacing INH in the initial phase
with moxifloxacin which exhibits no antagonism with
RIF.PZA combination. At the end of the initial phase
(1-2 weeks) INH could again be prescribed with
rifampicin. INH and RIF have a clear added effect. It is
emphasized that it is an experimental study and need a
lot of future research.
Review of Literature on Rifampicin Pharmacokinetics

Donald23a has summarized, in a tabular form, the
maximum serum concentration (Cmax) in relation to age
in children after administration of a single oral dose.
There are no significantly quotable studies for the age
group below 8 months singly. The rest of the age groups
studied are between 8 months and 14 years as below,
(Table 32.1).
The dose of RMP calculated for children according
to body weight and body surface area (Ansel and Stoklisa,
2001) is given in (Table 32.2).
Introduction to Rifampicin Pharmacokinetics

Rifampicin is a key drug in antituberculosis chemotherapy because it rapidly kills the majority of bacilli
in tuberculous lesions, prevents relapse and thus
enables 6 months shortcourse chemotherapy. Little is
known about the pharmacokinetics of rifampicin in
children. Schaff et al 24 evaluated the pharmacokinetics
of ritampicin in children with severe forms of
tuberculosis, both human immunodeficiency virus type1-infected and human immunodeficiency virusuninfected. The authors documented very low serum
RMP concentration in children of which the great
majority received the often recommended standard
dosage of 8 to 12 mg/kg body weight. There was a
trend for lower concentrations in HIV-infected
children on the first evaluation 1 month after
commencing treatment but this was not significant.
The evaluation after 4 months showed no difference

between the HIV-infected and HIV-uninfected
children. The highest value was reached when RMP
was administered in the suspension form. Peak
concentration of RMP varied from 3 to 5 g/ml. On
the basis of these the recommended dosage of RMP in
children under 6 year was 15 mg/kg body weight.
RMP concentration under 4 g/ml is considered low.
Schaafs study demonstrated that the calculated 2
hour-concentration was less than 4 g/ml. By 4 months
of treatment even with considerable improvement in
nutrition, the levels achieved were not different
implying that nutrition was not a significant factor for
achieving plasma RMP. It is concluded that low serum
RMP concentration in children with often recommended
dose of 8 to 12 mg/kg body may be of no consequence in
the management of less serious forms of childhood
tuberculosis, the recommended doses of 10 to 20 mg/kg
body by American Academy of Pediatrics is more
appropriate. Schaaf et al 11 further suggested AUC should
be calculated over 0 to 6, 0 to 12 or 0 to 8 hours.
Thee et al25 reported that recommended RMP dosages
in childhood tuberculosis led to lower serum levels as
compared to those recommend for adults attributed to
different pharmacokinetics and pharmacodynamic in
children. They recommend that in children it appears to
be more valid to recommend RMP dosage on the basis
of body surface area rather than body weight, leading to
higher dosages especially in younger children.
Thee et al12 conducted the studies between 2 and 14
years of age, a dosage of 10 mg/kg of RMP. The levels
were even lower when given with ethambutol. In adults,
after the standard dose of 600 mg RMP levels ranged
from 8 to 24 g/ml. Serum levels in the study by Thee et
al12 were even lower than the lower level reported in
adults.
As low drug concentrations reduce therapeutic
efficacy, higher doses than those recommended by WHO
(8-12 mg/kg body weight) might therefore, be necessary.
Table 32.2: The dose of RMP according to body weight
and body surface area in children
Weight
2
3
4
5
10
15
20
25
30
35
10 mg/kg
dose
Dose according
to BSA
BSA dose
as mg/kg
20
30
40
50
100
150
200
250
300
350
54
69
84
99
162
216
288
330
372
414
27
23
21
19.8
16.2
14.4
14.4
13.2
12.4
11.8
456
Table 32.1: Maximum serum concentration (Cmax) of rifampicin in relation to age after administration of a single oral dose
Author
Bergamnieted (1970)
Acocelle et at (1970)
Hussels et al (1973)
Cracken et al (1980)
Dose mg/kg
Age
20
10
10
10
10
10
10
10
10
10 Suspension
10 Suspension in apple sauce
10 Powder in apple sauce
The use of RMP in the suspension form resulted in a much

higher serum levels with the same dose (10 mg/kg) used
for prophylaxis in H. influenza infection. Peak serum
levels were attained after 2 hours of oral dose. The
absorption seems to be delayed in children as peak serum
concentration reaches at 4 hours. Elimination half-life is
on an average t of 2.9 hours in children given 10 mg/
kg dose.
Food seems to have been shown to significantly
reduce the absorption of RMP. The other factor
interfering with the absorption are gastric pH, emptying,
intestinal transit time, functional absorptive area,
metabolic capacity and carrier mechanisms or drug
transporters in the gastrointestinal tract, influence
gastrointestinal absorption. The most important of these
is intestinal absorptive area of the intestines in TB. In
addition to delayed absorption, in children only a
bioavailability of 50% is reached after oral administration.
It is well distributed through the body. As about 25% of
the drug is ionized at the physiological pH, while the
molecule as a whole is lipid soluble. Concentration of
RMP in the various tissues of the body is variable. RMP
is mainly metabolized in the liver by B-esterases,
however, it is a strong inducer of the cytochrome P450
system. Efficacy of RMP depends upon concentration
rather than time.
There is considerable intra-inter individual variation
in RMP serum levels. Uniform dosage of 10 mg/kg body
weight RMP does not appear to be appropriate and
especially not in children < 6 years of age. As these levels
were measured at the beginning of the study, the levels
would be lower during the course of therapy due to selfinduction of RMP metabolisation. In children the water
compartments at various ages are proportion to body
surface area (BSA), dosing according to BSA might be
more appropriate. An RMP dosage of 300 mg/m2 BSA
given to children resulted in the serum levels of 9.1 g/
ml in the age group of 3 months to 2.9 years. This is closer
to desired serum level of 10 g/ml. These calculations
8-12 months
8-11 months
4-18 months
2-<6 years
2-<6 years
6-10 years
6-10 years
10-14 years
10-14 years
6-58 months
6-58 months
6-58 months
n
14
14
12
7
7
11
11
9
9
21
12
5
Cmax g/ml
10.2
3.7
3.5
4.5
6.5
5.3
7.1
5.4
6.6
9.2
6.2
8.8
lead to a dosage of 15 mg/kg RMP to toddlers and young

children decreasing to 10 mg/kg at adolescence with the
combination therapy of HRZE. Minor hepatotoxic side
effects corresponding to RMP were found in 1.8% of the
children.
Peloquin et al 26 reported that changes in Cmax, Tmax,
and AUC0-oo can be avoided by giving rifamycin (RIF)
on an empty stomach. Most Tmax values are reached near
2 hours. The Optimal sampling time for the two sample
strategy is recommended by Peloquin et al.26 These are
3.1 hours and as late as 14.9 hours after the dose. Samples
drawn between 1 to 6 hrs post dose approached Cmax, 2
to 3 hours samples were closest.
Antacids did not affect the absorption. High-fat meal
had significant affects on the RIF, reducing Cmax (-36%)
and increasing Tmax (+103%). Food affects to a lesser
extent.
With a carbohydrate rich diet, there was a 15%
reduction in Cmax, 19% increase in Tmax and 4% reduction
in AUC. Studies on the rifampicin derivatives like
rifabutin showed that food had less of an affect on the
Cmax (-17%) than shown for rifampicin. Cmax (-36%) Tmax
(+80%) and AUC (-5%) of rifabution is similar to the
pharmacokinetics of RMP. Rifapentin, actually shows
improved absorption with food.
RIF is cleared predominantly through nonrenal
mechanisms, with only 10% of the drug being excreted
unchanged through the kidney. RIF is converted to 25desacetylrifampin and other, less abundant metabolites,
which are subsequently cleared by nonrenal mechanisms,
25-desacetylrifampin displays microbiological activity
approaching that of RIF, with displacement of serum
concentrations approximately 10% of those for RIF. RIF
is superior in its activity against M. tuberculosis as
compared to M. avium.
Pharmacokinetics of Pyrazinamide in Literature

Zhu et al29 reported concentration on time data analysed
using population methods in children. Pyrazinamide

concentrations increased linearly with increasing oral
doses. Median maximum serum concentration values
were 41.0 g/ml with daily dosing and 66.1 g/ml with
larger, twice weekly dosing. Incomplete (18%) or delayed
(30%) absorption was more common in children than in
adults (1% for each).
Thee et al30 estimated PZA serum levels alone or in
combination therapy with isoniazid and RMP. Serum
levels did not differ with age, in PZA monotherapy or in
combination therapy with a dosage of 30 mg/kg PZA,
efficient serum levels were reached. Because PZA is
uniformly distributed in the body, serum levels are
related to body weight and a dose of 30 mg/kg body
weight is appropriate in children.
Gumbo et al31 developed an invitro pharmacokineticpharmacodynamic model in which M. tuberculosis
replicating slowly at pH 5.8 was exposed to PZA by the
use of concentration time profiles encountered in
patients. Daily pyrazinamide dosing for 28 days
accurately achieved:
i. The PZA pharmacokinetics parameters.
ii. The lack of early bactericidal activity.
iii. A sterilizing effect rate of 0.10 log 10 CF /ml per
day starting on day 6 of therapy.
iv. A time to the emergence of resistance of the from 2
to 3 weeks of monotherapy encountered in patients
with tuberculosis.
The next dose scheduling studies were done. The
sterilizing effect was linked to the PZA ratio of the area
under the concentration time curve from 0 to 24 hr (AUC0) to the MIC (2=0.75 0.94). The currently used dosage
24
of PZA (15 30 mg/kg) achieved the AUC0-24 / MIC of
209.08 in the epithelial lining fluid (ELF) of only 15.1 to
53.3% of patients. Doses of > 60 mg/day performed better
but this dose is associated with hepatic toxicity. Gumbo
et als 31 preclinical PK PD model can be used to generate
data on the relationship between level of drug exposure,
time and sterilizing effects. Second standard mathematical
(PK-PD) models are used to describe the relationship
between the level of drug exposure, the level of microbial
killing, and suppression of resistance. PZA monotherapy
in patients has an early bactericidal effect of 0.05 0.18
log 10 CFU/ml per day, a time to start of slenderizing
effect of 4 days, sterilizing effect rate of 0.11 log 10 CFU/
ml per day, a time to the emergence of resistance of 2.5
to 3 weeks. Thus their invitro model achieved:
i. The PK parameters of PZA.
ii. The lack of early bactericidal activity.
iii. The daily rate of sterilization.
iv. The time to the emergence of resistance in patients
with TB.
This model has clinical relevance especially with PZA
and could be used to study sterilizing effect of old anti-
457
TB and new drugs. The development of shorter duration

of anti-TB regimens is the eradication of slowly
replicating bacilli (SRB) and non-replicating persistent
bacilli. If with the new drug, the bacilli are with in
macrophages, then a desirable property of the drug is
the capability of drug for intracellular penetration. If the
bacilli are extracellualr, the crucial property of the drug
has to be the capacity to achieve a high ELF concentration.
Relationship between PZA AUC/MIC as well as time
and both sterilizing activity and resistance suppression
is necessary to examine the likely success of different PZA
doses. The current recommended dose of 15 to 30 mg/
kg in children is more successful in achieving the
exposure associated with optimal sterilization in large
proportion of patients.
It is summarized that an invitro PK-PD model can be
used to examine the sterilizing effects of anti-TB drugs.
Microbial killing was linked to AUC/MIC, while
resistance suppression was liked to Tmic.
Graham et al32 evaluated the impact of age, nutritional
status, human immunodeficiency virus status to
characterize the pharmacokinetics of PZA. The children
were on three weekly regimen of antituberculosis drugs.
Serum drug levels were low for PZA in almost all the
cases. The maximum serum concentration (Cmax) failed
to reach the MIC for M. tuberculosis. The Cmax of PZA
was significantly lower in younger children (< 5 year)
than in older children. The Cmax was also lower in those
with human immunodeficiency virus infection and
children with severe malnutrition but the differences
were not statistically different.
Pharmacokinetic study has found poor absorption of
PZA in Malawian children. It was found that low levels
were found in intermittent therapy. Young child is at an
important risk factor for low level.
Sanchez and Maramba33 described therapeutic drugs
monitoring (TDM) as a process of adjusting drug dosages
on the basis of serum drug concentration for the purpose
of optimizing drug therapy. They used pyrazinamide
suspension for estimating pharmacokinetics.
Tmax of 2 hours, the mean serum concentration PZA
suspension is at 34.6 11.86 g/ml. The mean serum
trough level is 4.55 4.63 g/ml. There was no significant
difference between the three brands tested. Most serum
concentration of PZA suspension falls within the
established therapeutic ranges for PZA.
TDM requires the accurate timing of doses and blood
collection and avoidance of assay interferences.
Zhu et al34 reported that pharmacokinetic parameter
of PZA were independent of human immunodeficiency
virus status and patients demographics except for body
weight. Population elimination half-life values in
pediatric and adult patients were 3.5 and 6.0 hours,
458
respectively. Medium volume of distribution (L/kg) was

32% larger in children, and the median clearance (L/hr/
kg) was 106% larger in children with a resultant median
half-life 43% shorter in children. Absorption of P2A in
children was more incomplete or delayed.
Pharmacokinetics of Ethambutol in Children

In a review on ethambutol (EMB) in children a
recommendation for dosing regimen by Donald.35
reported that serum concentrations of EMB were
maximal at about 2 hours and were 10 g/ml and 5
g/ml following doses of 50 mg/kg body weight and
25 mg/kg daily. Serum concentration were proportional
to dose and less than 10% of the dose administered
was present in the serum after 24 hours and there was
no evidence in the serum of accumulation of the drug
over more than 3 months. Within 6 hours 28% of an
oral dose was excreted in urine. The great majority of
the drug (approximately 80%) is excreted unchanged
in the urine, that the T max tends to be somewhat
delayed in comparison to other drugs (between 2-4
hours). Following a meal, a lower Cmax is found than
when fasting (4.5 g/ml VS 3.8 g/ml after a dose of
25 mg/kg). Serum concentration in children are found
to be lower than those found in adults with similar
doses of EMB. Effective therapeutic concentrations are
achieved in the majority of children with the dosage
of 20 mg/kg, increased by 5 mg/kg in those aged < 3
year to decease it by 5 mg/kg in those aged > 11 year.
The review summarized after seeing the results of
pharmacokinetic in children that a dose of 25 mg/kg
is optimum.
Zhu et al38 by their studies on pharmacokinetics of
ethambutol (EMB) by concentration data analyzing
using non-compartmental and population pharmacokinetics methodsinferred that very low levels of
ethambutol serum concentrations are achieved with the
usual recommended doses. Very low Cmax (1 g/ml)
were common in children as was delayed absorption
(time to Cmax > 3 hrs) were common in children. Many
Cmax were at or below typical TB minimal inhibitory
concentration. Cmax values for HIV-positive patients
were 20% lower than HIV-negative patients were 20%
lower than HIV-negative patient with daily dose but
were similar with larger twice weekly doses.
Peloquin et al39 determined the pharma-cokinetics of PAS
under four dosing conditions in adults. Bioequivalence
testing was performed using the mean ratios of the
maximum concentration (Cmax) and AUC (0-infinty) of
PAS, with 90% confidence intervals. Compared with
fasting conditions, food increased Cmax 1.5-fold and AUC
(0-infinity) 1.7-folds, and doubled the time to least mean
sequere rates (treatment/reference) for Cmax were 0.90
(58% 139% CL), 1.16 (75% to 179% CI), and 0.82 (52%
127% CL) with orange juice, food, or antacid treatment

respectively. Corresponding ratios for AUC (0-infintiy)
were 1.05 (71% 158% CL), 1.52 (103% 224% CL), and
0.84 (57% 125% CL) respectively. It was concluded that
food significantly enhanced the absorption of PAS,
while orange juice and antacids had minor effects.
Zhu et al40 conducted that ethionamide (ETA) PK
parameters differed between TB patients and healthy
volunteers, possibly due to difference in the completeness
of absorption. Doses of atleast 500 mg appear to be
required to achieve serum concentrations above the
typical ETA MIC.
Zhu et al41 researched on the pharmacokinetics of
cycloserine and summarized that PK of cycloserine were
minimally affected by orange juice, antacids, whereas the
high-fat meal delayed absorption. Administering
cycloserine without a high fat meal avoids potential
alterations in the pattern of absorption. Dose given to
adults was 500 mg after a 12 hour fast with a high-fat
meal. The other companion drugs given was, (ETA),
clofazimine and PAS.
Nixa et al42 as a part of (four) drug regimen of
clofazimine, cycloserine, (ETA), PAS recorded the PK of
clofazimine for MDR-TB. It was inferred that administration
of clofazimine with a high fat meal provides the greatest
bioavailability, however, but it is associated with high
inter and intra subject variability. Both orange juice and
alumimiummagnesium antacid produced a reduction
in mean bioavailability of clofazimine.
Stambaugh et al 43 concluded that ofloxacin PK
parameters increased linearly with increasing oral dose.
Delayed absorption was seen atleast once in 29% of
patients. Ofloxacin elimination decreased with declining
renal functions and increasing age. Higher daily doses
were well tolerated and appeared to maximize the peak
concentration to Cmax, MIC.
PHARMACOKINETICS OF ANTITUBERCULAR DRUGS IN

RELATION TO VARIOUS FACTORS
Experience at AIIMS, New Delhi, India
Pharmacokinetics with the use of more than One
Antituberculosis Drugs
Seth et al44-46 conducted pharmacokinetic studies of and
isoniazid in the whole clinical spectrum of tuberculosis
in childrenpulmonary primary complex (PPC),
progressive primary disease (PPD) and tuberculous
meningitis (TBM). The used were 6HR; 2HRZ, 4HR; and
SHRZ, 1 HRZE, 4HRE, 3HE; and 2SHRZ, 4HRE,
3HE. Rifampicin (RIF) and isoniazid (INH) were
administered in a dose of 12 and 10 mg/kg respectively.

Isoniazid and rifampicin were given together in the form
of a syrup. Rest all the other drugs were given as
separate preparations. To have a general idea peak
levels of isoniazid and rifampicin were estimated and
compared with MIC. The peak levels and concentrations
achieved at 7 to 8 hours with these two drugs were much
above those required for therapeutic efficacy (MIC). The
levels were 50 to 250 times more for RIF and 35 to 60
times for INH. Keeping this in mind pharmacokinetics
of isoniazid were done using isoniazid in the dose of 5
mg/kg/day. Peak isoniazid levels were 40 times more
than MIC with the dose of 5 mg/kg/day. This is the
dose, i.e. 5 mg/kg/day recommended by WHO and
Disease (IUATLD).47-49 Peak rifampicin level using 10
mg/kg/day of this drug was 5.4 g/ml, which is 250
times the MIC. Hence, it seems that after more
pharmacokinetic studies with lower doses, one may be
able to reduce the dose of rifampicin further. In both
these studies, the same brand of drugs were used and
the study was blinded. The detailed pharmacokinetics
are described for individual drugs later in the chapter.
Severity of Disease
In relation to the severity of the disease, the peak levels of
rifampicin were maximum in TBM and minimum in PPC
when the child was given intermittent therapy. The
sampling was done after two days of therapy, i.e. the drug
was given on Sunday and Thursday and sampling was
done on Wednesday. It indicates that as far as pharmacokinetics is concerned effective levels are maintained even
during intermittent therapy. This is more cost effective
but the only disadvantage is that the mother needs to be
strongly motivated to bring the child to the center for
giving medicine under directly observed therapy (DOT).50
Nutrition
Nutritional deficiencies may result in an altered drug
response requiring readjustment of drug dosages. There
are limited studies on drug disposition in children with
protein energy malnutrition (PEM). Physicians need to
have practical guidelines regarding dosage and
frequency of administration of the commonly prescribed
drugs in malnourished children in whom reversible
structural and functional changes occur. As tuberculosis
and malnutrition often coexist, the knowledge of kinetics
of rifampicin and isoniazid in the malnourished patients
is important for successful therapy. Seth et al44-46 have
shown that peak serum concentration (Cmax) of both
isoniazid and rifampicin in undernourished and
malnourished children are higher than normal children.
The serum hal-flife of isoniazid and bioavailability of both
459
isoniazid and rifampicin were higher in undernourished

and malnourished patients when compared to the
normally nourished ones. Polasa et al51 and Polasa and
Krishnaswami52 have also reported higher Cmax, t and
AUC values for rifampicin in adults with undernutrition.
In kwashiorkor and marasmic kwashiorkor patients on
antituberculosis therapy, the potential hepatotoxic drugs
like isoniazid and hepatic enzyme inducer rifampicin
should be given in their lower range, i.e. 5 to 10 and 10
mg/kg/day respectively as there is fatty infiltration of
liver. In tuberculous meningitis, hepatotoxicity is quite
high even with low dosage, due to associated
malnutrition.53 Hence, drug dose and regimen should
be judiciously chosen. A study was conducted by Seth53a
in tuberculous meningitis using two regimens R1
2SHRZ, 4HRE, 3HE [2 months daily streptomycin (S),
isoniazid (H), rifampicin (R) and pyrazinamide (Z)
followed by 4 months of HRE, followed by 3 months of
HE] and R22SH2RZ, 4H2RE, 3H2E (2 months of daily
S, twice a week H and daily rifampicin and pyrazinamide, SR followed by 4 months of twice a week H and
daily R and E followed by 3 months of twice a week H
and daily E) to see the efficacy and hepatotoxicity. It
clearly indicated (Table 32.3) that in regimen 1 the
hepatotoxicity was fifty percent in children with severe
malnutrition. The dose of isoniazid used was 10 mg/
kg/day in regimen 1 and 20 mg twice a week in
regimen 2. It has been suggested that malnourished
children with tuberculosis who develop hepatotoxicity,
rifampicin should be discontinued, or alternatively, it
should be given in a dose of 12 mg/kg on alternate days
for initial 3 to 4 months followed by twice a week for 4
to 6 months.54
Fixed-Dose Formulation
Fixed-dose combination (FDC) of R, H and R, H, Z are
recent developments. Use of this simplifies combined
therapy in the form of syrup or dispersible tablets for
the administration of drugs and is easy to maintain
dosage as mg/kg of the regimen. These are effective and
have shown to have no higher degree of toxicity than
single drug administration. They avoid the risk of
inherent lapse in monotherapy which may result in the
emergence of drug resistance and minimize the risk
associated with prescription errors. A minor disadvantage is of having accustomed patients to one form
of medication in the initial phase, it is necessary to make
an adjustment to a different formulation in the second
phase. Unfortunately, fixed dose combination of drugs
have been marketed for which bioavailabity data are
inadequate. It is essential to use only those preparations
for which pharmacokinetic and pharmacodynamic
studies have been carried out and have shown that serum
drug concentrations are not altered by the combination.55
460
Table 32.3: Hepatotoxicity with respect to nutritional status in tuberculous meningitis
Nutritional status
No.
Normal
Undernourished
(Grade I + II)
Severe malnutrition
Regimen-1
Hepatotoxicity
Regimen-2
No.
Hepatotoxicity
Total cases
No.
Hepatotoxicity
Percentage
7
14
1
2
6
15
13
29
1
3
7.6
10.3
10
30
Regimen-1 = 2 SHRZ, 4HRE, 3HE; Regimen-2 = 2 SH2RZ, 4H2RE, 3H2E
In fact, this has led to a joint statement by the IUATLD

and the WHO pointing that antituberculosis fixed dose
combinations should be used only in National
Tuberculosis Programs if adequate bioavailability of
atleast the rifampicin component has been
demonstrated.56 In fact, combining rifampicin in the same
tablet with isoniazid with or without pyrazinamide has
been shown to affect the bioavailability of rifampicin. It
is known that many FDCs exist in the market which are
of inferior quality but are unknowingly being used
extensively in tuberculosis control programs in low
income countries with high incidence and prevalence of
tuberculosis. Advantages of such FDCs are the
simplification of procurement and prescribing practices
and the protection that they afford against the selection
of drugresistant mutants. In fact, some studies have
shown that up to 62 percent of the antituberculosis drugs
sold in the market are FDCs. 56 There is convincing
evidence that the rifampicin absorption from FDCs
manufactured under suboptimal conditions may be
significantly impaired and this appears to be especially
problematic with combined formulations of rifampicin,
isoniazid and pyrazinamide.57 Seth used combination of
(i) isoniazid and rifampicin, (ii) isoniazid, rifampicin and
pyrazinamide for pharmacokinetic studies, and the
bioavailability was not affected. The children were chosen
keeping the factors of nutrition and age similar. Table
32.4 shows the preparation of antituberculosis drugs
available in various combination of isoniazid+rifampicin
or isoniazid+ rifampicin and pyrazinamide.
Fixed-dose combination (FDC) tablets incorporate
two or more drugs within the same tablet. The use of 2drug combinations (e.g. rifampicin and isoniazid) is
widespread and there is increasing use of rifampicin,
isoniazid and pyrazinamide combinations.
Advantages of FDCs
When programs use FDCs, providers and patients
useless of single anti-TB drugs. This reduces the risk
of emergence of drug resistant organisms. In a
program using drugs supplied only in FDCs, in the event
of interruption of treatment and relapse, organisms will
remain sensitive to rifampicin and isoniazid
Table 32.4: Some preparations of antituberculosis drugs

available either as syrup or dispersible tablets as single
drug or in combination
Drugs
Syrup (mg/5ml)/DT(mg)
Isoniazid
Ipcazide
100
Isokin
100
Preparation of isoniazid + rifampicin
Bicox KT
H 100 +R 100
Binex KT
H 100 + R 150
Faminex KT
H 100 + R 150
Ipcacin KT
H 100 + R 100
Montonex KT
H 50 + R 100
Rcinex KT
H 100 + R 100
Rcinex 150DT
H 100 + R 150
RF-Kid
H 100 + R 100
Rifinex
H 50 + R 100
R-Zid
H 100 + R 100
Ticnex
H 50 + R 100
Xced 2
H 75 + R 100
Modified release form
Preparation of INH + rifampicin + pyrazinamide
Binex Z DT
H 50+R 100+Z 300
Caviter/Forte
H 80+R 120+Z 250
Rifacept 3
H 100+R 75+Z 250
RifaterH 80+R 120+Z 250
H= Isoniazid, R= Rifampicin, Z= Pyrazinamide
KT = Kid tablet, DT = Dispersible tablet
Physicians are more likely to prescribe an effective

regimen
The opportunity for inadvertent medication errors is
decreased
Many of the logistic problems which cause shortage
of individual drugs are eliminated (shortage of
individual drugs may result in either patients
receiving monotherapy, or changing of regimen, both
of which may increase the risks of resistance)
The procurement, management and handling of
drugs is simplified. In many national and district
programs, there are major problems with inadequate
and uncoordi-nated drug supplies, and the ordering,
shipping and storage of the individual drugs adds
enormously to the costs. If combination drugs are

used, there will only be one or two components to be
ordered, delivered and stored, with resulting savings
in costs and increased efficiency
The regimen is simpler for the patient, involves
consumption of fewer tablets, and promotes patient
adherence to treatment
The provision of rifampicin in FDCs may decrease
the unjustified use of rifampicin monotherapy for
infections other than TB.
Disadvantages of FDCs
The bioavailability of drugs, especially rifampicin, can
decrease when combined in FDCs. The decrease in
bioavailability is a particular problem with FDCs of
rifampicin and two other drugs. Many FDCs
currently available may result in subtherapeutic blood
levels of rifampicin. Bioavailability may vary among
batches of drugs, and following minor changes in the
manufacturing process. Therefore, programs must
monitor regularly the bioavailability of drugs,
especially isoniazid and rifampicin, in FDCs. WHO and
the IUATLD recommend the use of only those FDCs
for which human studies have demonstrated
satisfactory bioavailability of rifampicin
Currently, chemotherapy using FDCs is more costly.
From a program point of view, however, there will
be longterm savings as fewer patients develop drug
resistant disease and receive the more expensive
retreatment regimen. Prices may fall as the use of
FDCs becomes more widespread
Occasionally, it is necessary to adjust the dosages for
an individual patient, or to adjust the regimen when
serious side effects are experienced. Programs using
FDCs still require limited amounts of single drugs
for flexible prescribing by senior medical officers.
Selection of FDCs
The optimal formulation of FDCs chosen for a
program will depend upon the average weight of
patients, and regimens used (whether daily or
intermittent)
It is usually advisable to choose only one FDC for a
program, to avoid stock management problems and
confusion between different formulations
If a program uses FDCs of different formulations, then
the color and shape of the tablets for each formulation
should be different to avoid confusion.
Daily and Intermittent use of FDCs

Most adult TB patients fall within a certain weight band,
e.g. 45 to 55 kg. However, in children various weight
bands are required and hence require more attention.
The recommended number of tablets of FDCs for
patients falling within a certain weight band depends
461
on the weight band defined in each country and the

particular FDC formulations provided by the NTP.
Breastfeeding
Most antituberculosis drugs appear to be safe for use
during breastfeeding.58 These agents are secreted in
breast milk in relatively small concen-trations. No
adverse effects have been reported till date. The
percentage of the therapeutic dose of antituberculosis
agents that potentially may be delivered to the nursing
infant ranges from 0.05 to 28 percent. Currently,
isoniazid, rifampicin, ethambutol, streptomycin (first-line
agents), kanamycin and cycloserine (second-line agents)
are the only agents considered by the American Academy
of Pediatrics (AAP) to be compatible with breast
feeding.58 Unfortunately, there are still no clear data on
the safety of pyrazinamide, ethionamide and capreomycin
during breastfeeding.
Acetylator Status
The inactivation of isoniazid by acetylation shows a
genetic polymorphism. This was thought to be bimodal
but now it is considered as trimodal distribution of the
population into slow rapid and intermediate acetylators.
It has been suggested that rapid acetylators are more
susceptible to hepatotoxicity by isoniazid.59 Studies in
adults60 and children61 have demonstrated that acetylator
phenotype doesnot influence the incidence of isoniazid
induced hepatotoxicity. However, Parthasarthy et al62
have reported that the incidence of hepatitis is more in
slow acetylators of isoniazid than the rapid ones. Seth et
al63,64 have profiled the acetylation phenotype of North
Indian children and showed 73% to be slow acetylators.
Later, Seth et al65 designed a study to determine the
relationship of the acetylator phenotype with the
incidence of hepatotoxicity in North Indian children
suffering from pulmonary tuberculosis treated with
isoniazid and rifampicin. They reported that with the
dosage of isoniazid and rifampicin at 10 and 12 mg/kg/
day respectively there was no evidence of hepatotoxicity.
ISONIAZID
Isoniazid is well absorbed in the gastrointestinal tract and
readily distributed to all body cells and fluids. Although,
the drug readily crosses the placenta and is excreted in milk
yet no fetal or neonatal risks are involved.66 Peak serum
levels range from 6 to 20 g/ml in children17,18 as com-pared
to adults, where the values are usually lower and range
from 3 to 5 g/ml.7 Hence, the peak drug level is almost 20
to 80 times of the minimum inhibitory concentration and is
achieved in 1 to 2 hours after oral dose of 5 mg/kg in
adults.17,67 Since, the peak level is more important than the
sustained inhibitory concentration, the entire daily dose is
given once daily.68 The absorption of drug from the GI tract
462
is so complete that oral and parenteral doses produce

comparable plasma and tissue levels. The CSF concentration
of the drug in normal human volunteers is 20% of plasma
levels but in tuberculous meningitis higher concentrations
of up to 50% are achieved.69 The higher serum concentration
of isoniazid in children appears to be due to greater dosage
of isoniazid per unit of body weight. Hence, it seems that
there is probably no need to give such a high dosage of
isoniazid per unit of body weight. This misconception could
only be removed after having the pharmacokinetic data.
Seth et al44-46 and Beotra and Seth et al70 had undertaken
pharmacokinetic studies in different types of tuberculosis
in Indian children giving different drug regimens (Table
32.5 and Fig. 32.3). Serum isoniazid levels ranged from 4.38
to 8.17 g/ml at 1 hour (peak level) and from 0.33 to 0.84
g/ml at 0 hour (or 24 hr) in different disease and regimen
groups. These values are atleast 90 to 160 times of its MIC
at the peak concentration time (1 hour) and 7 to 17 times at
0 or 24 hours. The results of the present study and those of
Hobby71 and Naito et al 72 suggest that isoniazid
pharmacokinetic studies should be undertaken in children
with tuberculosis using isoniazid in much lower but
Fig. 32.3: Serum isoniazid concentrations (mean + SE) in different

types of tuberculosis
therapeutically effective dose. Hence, isoniazid was given

in a dose of 5 and 10 mg/kg/day to the children suffering
from pulmonary primary complex and those with TBM
respectively. Pharmacokinetic studies were done in both
groups. It was observed that adequate serum levels of
isoniazid around 40 times the MIC could be achieved with
the dose of 5 mg/kg/day. It was also observed that 5 mg/
kg dose was clinically as effective as 10 mg/kg dose.
Isoniazid along with rifampicin can be given as
intermittent therapy without compromising on treatment
efficacy. This cuts down the cost of the therapy which is
the main concern for poor drug compliance. The WHO
recommends that in twice weekly intermittent regimen,
the dosage of isoniazid should be kept in the range of 12
to 15 mg/kg body weight instead of 20 mg/kg, both in
adults and children.25 These dosage recommendations
are based on clinical impressions rather than inferences
drawn from well designed pharmacokinetic studies. No
published data regarding pharmacokinetics of isoniazid
in intermittent regimen in children with tuberculosis is
available in medical literature.
Seth et al 73 designed to investigate serum and
excretion kinetics of isoniazid and acetyl isoniazid in
pulmonary primary complex in the biweekly phase of
the intermittent regimen. The study provides an insight
into the pharmaco-kinetic aspect of INH as a constituent
drug of intermittent regimen in Indian children (Table
32.6 and Fig. 32.4). The peak serum isoniazid
concentration of 2.6 g/ml at 1 hour and that for acetyl
isoniazid of 5.5 g/ml at 5 hours in the biweekly phase
of the intermittent regimen was observed in the study.
The concentration of isoniazid was on an average 52 times
and a maximum of 88 times of its MIC when administered orally in the dose of 20 mg/kg/dose. The study
further shows that the concentration at 7 hours was 0.96
g/ml which is 19 times its MIC. Even at 72 hours (3
days), i.e. just before the administration of next due dose
of isoniazid, the concentration was sustained at 0.47 g/
ml which is 9 times higher than its MIC. It is thus clear
that an oral dose of 20 mg/kg of isoniazid in biweekly
phase of therapy is able to sustain a concentration which
is much above its MIC value.
Table 32.5: Pharmacokinetic parameters of isoniazid

Type of TB and regimen
PPC-6HR
PPD-2HRZ, 4HR
TBM
2SHRZ, 4HRE, 3HE
Cmax (g/ml) (mean)

4.38
8.17
5.38
Tmax (h) (mean)

1.0
1.0
1.0
T (h) (mean)
AUC0-7hr (g/ml/h)
4.98
4.20
4.55
34.1
57.5
43.8
Cmax = Maximum serum concentration, Tmax = Time to attain Cmax, T = Serum half-life, AUC = Area under the serum
concentration-time-curve. PPC = Pulmonary primary complex, PPD = Progressive primary disease, TBM = Tuberculous meningitis
463

The concept of acetylation status is defined as: A rapid
inactivator is one whose 6 hour serum level of active
isoniazid following a single test dose of 5 mg/kg is 0.2
g/ml or less while a slow inactivator is one whose 6
hour level is 0.8 g/ml or more after an equivalent dose.7
Schaaf et al 74 defined the pharmacokinetics of
isoniazid in children with tuberculosis in relation to Nacetyltransferase 2(NAT2) geno-type. The first order
elimination rate constant (k) and area under the
concentration curve (AUC) were calculated in 64 children
<13 years of age (median 3.8years) with respiratory
tuberculosis. Isoniazid concentrations were determined 2
to 5 hours after a 10 mg/kg/isoniazid dose. The NAT2
genotype was determined, 25 were classified as
homozygous slow (SS), 24 as heterozygous fast (FS) and
15 as homozygous fast (FF) acetylators. Younger children
elimate isoniazid faster than older children and, as a
group, faster than adults, and require a higher mg/kg/
body weights isoniazid dose to achieve serum
concentrations comparable to adults.
Excretion of isoniazid in urine is fairly good and
comparatively early as its maximum concen-tration is
seen between 3 and 6 hours and that of acetyl isoniazid
between 6 and 12 hours of the drug intake (Table 32.7
and Fig. 32.5). It suggests that in patients with normal
renal functions, isoniazid does not have the tendency to
accumulate in serum and, therefore, can be given safely
in prescribed doses irrespective of the status of acetylator
phenotype (rapid or slow) of the patients in general.
RIFAMPICIN
It is highly lipid soluble and it penetrates well into most
of the tissues and is present in effective concentrations in
all the organs and body fluids including CSF. It also
reaches in caseous foci, phagocytes and crosses the
placenta. Breast milk, fat tissue and the lungs contain
higher concentration of drug than serum.75 The mean t
in children after initial dose is 2.9 hours but shortens to
2.5 hours on repeated dosing because of its hepatic
enzyme inducing action.76 Seth et al44,45 carried out
detailed pharmaco-kinetic studies of rifampicin in
different types of tuberculosis with different drug
regimens (Table 32.8 and Fig. 32.6). Serum half-life of
rifampicin ranged from 3.03 to 3.81 hours, whereas Cmax
ranged from 3.38 to 3.88 g/ml. The results of these
studies show a sustained serum concentration much above
the MIC of rifampicin even 24 hours after administration
of single 12 mg/kg dose of the drug. Further, rifampicin
was given in a dose of 10 mg/kg/day to children
suffering from pulmonary primary complex and
pharmacokinetic studies of rifampicin were carried out.
Adequate serum levels of drug could be achieved that
Table 32.6: Isoniazid kinetics in serum in intermittent

regimen (2HR, 4 H2 R2 ) in pulmonary primary complex
Cmax*
Tmax
T*
AUC0-7h*
(g/ml)
2.6
(h)
1.0
(h)
4.5
(g/ml/h)
20.78
* = Mean values
Fig. 32.5: Urine total isoniazid and acetylisoniazid levels (mean SD)
in intermittent regimen (2HR, 4H2 R-2) in pulmonary primary complex
Table 32.7: Urine total isoniazid (INH) and acetyl isoniazid

(AcINH) levels by HPLC in intermittent regimen (2HR,
4H2R2) in pulmonary primary complex
Time interval (h) No. of samples
Fig. 32.4: Serum isoniazid and acetylisoniazid concentrations (mean

SD) in intermittent regimen (2HR, 4H2 R2 )
in pulmonary primary complex
0-3
3-6
6-12
12-24
9
9
9
9
Total urine level

(mg) mean SD
INH
AcINH
1.82 1.29
5.71 4.82
5.21 6.41
2.19 1.92
6.7 6.5
15.7 9.7
21.5 12.1
10.2 6.6
464
Fig. 32.6: Serum rifampicin concentrations (mean + SE)

in different types of tuberculosis in children
Table 32.8: Pharmacokinetic parameters of rifampicin

Type of
TB and
regimen
Cmax
(g/ml)
(mean)
PPC
6HR
PPD
2HRZ, 4HR
TBM
2SHRZ,
4HRE, 3HE
Tmax
(h)
T
(h)
(mean)
AUC0-7h
(g/ml/h)
(mean)
3.88
2.0
3.03
28.3
3.38
2.0
3.81
26.2
3.86
2.0
3.24
24.7
were 50 times of MIC and drug was found to be clinically

effective. Food interferes with the absorption of
rifampicin and results in a low plasma level and hence it
is advisable to give it atleast half an hour before
breakfast.58 Besides tuberculosis, rifamcipin is also used
for prophylaxis against H. influenzae type B infection in
infants and children.50
Jayram et al77 have demonstrated pharmaco-kineticspharmacodynamics of rifampicin in an aerosol infection
model of tuberculosis. They showed that, by the use of a
murine aerosol infection model with dose ranging and
dose fractionation over 6 days, the PD parameter that best
correlated with a reduction in bacterial counts.
PYRAZINAMIDE
The major limitation to the wider use of pyrazinamide as
an antituberculosis agent in humans in past was the high
incidence of hepatotoxity, especially with a dose of 40 to
50 mg/kg/day. When it was shown to be effective at a
lower dose of 30 mg/kg/day with a much lower incidence

of hepatotoxicity, pyrazinamide regained a prominent
place in the antituberculosis pharmacotherapeutics.
At a time when no data from a well-designed
pharmacokinetic study on pyrazinamide in children with
tuberculosis was available at the international level, a
pathbreaking effort was undertaken in detailed profiling
of pharmaco-kinetic aspects of pyrazinamide (serum and
urine kinetics) in Indian children having tuberculosis in
1985 in the departments of Pediatrics and Pharmacology
of AIIMS, New Delhi by Seth,78 Seth79 and Arya,80,81 and
this was to become a reference work subsequently for
others. Prior to the studies by Seth at al78 and Arya et
al80,81 except for serum concentrations versus time (Cmax,
Tmax), values for no other important pharmacokinetic
parameters were available in children and particularly
so in children with tuberculosis. In past values for various
pharmacokinetic parameters for children used to be
extrapolated either from studies in the adult healthy
volunteers, or adult tuberculosis patients. Considering
theses facts, this work assumes even more importance
in contributing newer data in pediatric population
suffering from tuberculosis. Comparative pharmacokinetic parameters of pyrazinamide following once a
day oral dose of 30 mg/kg/day in 40 progressive primary
disease (PPD) and 18 tuberculous meningitis (TBM)
children employing high performance liquid
chromatography (HPLC) is shown in Table 32.9.
Significantly higher mean serum concen-tration
(Cmax) were achieved in PPD (43.43 6.74g/ml) as
compared to TBM children (34.44 1.75g/ml) at Tmax
of 2.25 and 2.22 hours which are more than 2 times and
1.7 times the MIC of pyrazinamide (20g/ml) for M.
tuberculosis respectively. The mean serum concentration
even at 8 hours post-dose was 1.5 times the MIC in PPD
children (30.61 1.18g/ml) whereas it was nearly at
MIC in TBM children (19.44 0.80g/ml), thereby
showing adequate MIC coverage for a significantly
longer time for its antituberculosis action. However, at
24 hours the concentrations were sub-MIC (5.58 29g/
ml in PPD and 8.18 0.18 g/ml in TBM). The fact that
pyrazinamide concentration in cerebrospinal fluid equals
that in the serum, makes it a very potent and useful
antituberculosis drug in TBM. The mean T of 11.42
hours in TBM children was significantly prolonged than
in PPD children (7.78 hours). This prolonged elimination
in TBM children can be attributed to frequently
accompanying severe malnutrition in them affecting the
renal-elimination of the drug and also may be the severity
of the disease. Similarly, volume of distribution (Vd) of
10.33 litres was marginally less in TBM than 12.94 litres
in PPD children. The other pharmacokinetic parameters
i.e. clearance (CI), AUC0-24h and elimination-rate
constant calculated were comparable. Urine kinetics
showed a highly significant difference in the total amount

Table 32.9: Comparative pharmacokinetic parameters of
pyrazinamide (30 mg/kg/day oral dose) in Indian children
with PPD80 and TBM81: AIIMS experience
Pharmacokinetic
parameters
Cmax (g/ml)
Tmax (h)
T (h)
Vd (L)
C1 (L/h)
AUC0-24h (g/ml/h)
Kel (h1)
Mean (SD) values

PPD (n=40)
TBM (n=18)
43.43 (6.74)
2.25 (0.77)
7.78 (1.3)
12.94 (5.57)
1.16 (0.49)
496.11 (138.15)
0.09 (0.002)
35.44 (1.75)
2.22 (0.55)
11.42 (3.64)
10.33 (4.15)
0.77 (0.43)
409.19 (63.72)
Vd= volume of distribution, C1= clearance,

Kel= elimination rate constant
of pyrazinamide excreted in 24 hours in PPD (37.12 mg)

and TBM (65.12 mg) children. Even at 24 hours post
dose significant amount of the drugs was detectable in
urine in PPD (11.51 mg) and TBM (16.62 mg) children. A
study by Carlone et al 82 on mouse macrophages
harbouring tubercle bacilli exposed to 30 g/ml
concentration of pyrazinamide has shown the highest
rates of killing of 93 % for pyrazinamide and 92 % for
pyrazioic acid as compared to 59 % in the controls. It is
quite evident that serum pyrazinamide concentrations
so achieved are in tandem with the microbiological
parameter i.e. effective sterilizing actions. The kinetics
of pyrazinamide exhibited rapid absorption, a speedy
distribution and a longer elimination phase.79-81
Population Pharmacokinetics Modeling of pyrazinamide

in Children and Adults with Tuberculosis
Zhu et al83 demonstrated that pyrazinamide concentration
increased linearly with increasing oral dose. Median
maximum serum concentra-tion value were 41.0 g/ml
with daily dosing and 66.1 g/ml with large, twice weekly
dosing. Incomplete (18%) or delayed (30%) absorption was
more common in children than in adults. Human
immunodeficiency virus status and patient demography,
except for body weight, did not interfere with pharmacokinetic
parameters. Population elimination half-life values in
pediatric and adult patients were 3.5 and 6.0 hours,
respectively. Median volume of distribution (L/kg) was 32
% larger and median clearance (L/hr/kg) was 106% larger
in children. Compared with adults, absorption of
pyrazinamide in children is more likely to be incomplete
or delayed.
Streptomycin
The use of streptomycin has become limited because of
its toxicity, need for parenteral administration and
465
development of resistance. In addition, owing to its action

entirely on rapidly growing extracellular bacilli, it is
unsuitable for sterilization of the lesion. In children the
most prominent presentation is either pulmonary
primary complex (PPC) or the severest form such as
tuberculous meningitis (TBM) and miliary tuberculosis.
In both these situations, the role of streptomycin is
limited. In TBM it is used only for 15 days, that also in
the dose of 20 mg/kg/day IM to kill rapidly multiplying
extracellular bacilli, which are very few in the usual
manifestations of tuberculosis in children except which
occurs at adolescence. The latter is cavitary type like adult
tuberculosis.
Ethambutol
The drug is used as a companion drug with INH and
rifampicin in various short course and long-term
regimens. However, it is a second-line drug because of
its low efficacy and bacterio-static action. It is a good
substitute for PAS and thiacetazone owing to its low
toxicity at thera-peutic doses and better acceptance by
the patients. In very young children also it can be given
as ocular toxicity can be monitored by visual evoked
responses (VER) under general anesthesia. Seth et al84
periodically recorded VER in 49 children with
pulmonary tuberculosis above three years of age who
were given ethambutol as part of therapy to detect any
evidence of ethambutol-induced ocular toxicity. In all
patients both the latency and amplitude of the evoked
potentials were comparable with age and sex matched
controls. No change in color perception and visual
acuity was observed. Hence, it is suggested that ethambutol maybe given safely to children particu-larly those
with TBM, in a dose of 20 mg/kg /day. It has been
shown that ethambutol penetrates erythrocytes which
probably serves as a depot from where the drug is
released into circulation. 10 Ethambutol serum
concentrations have been determined by several
authors. It has been demonstrated that great majority
of the drug is excreted unchanged in urine
(approximately 80%). It has been observed that serum
concentrations in children tend to be lower than in
adults following similar doses of ethambutol. Hence, it
is suggested to use ethambutol in children at a dosage
of 20 mg/kg and to increase this by 5 mg/kg in those
aged <3 years and those aged >11 years. By this dosage
schedule in 2634 children there was no ocular toxicity
and effective therapeutic levels were achieved. As
recently as in 2004 Zhu et al83 found dose of 15 to 20
mg/kg/day quite sufficient for achieving a good
pharmacokinetic profile. Hence, this drug can be used
safely as a companion drug in the management of tuberculosis in children.
466
Pharmacokinetics of Ethambutol in Children and Adults

with Tuberculosis
Zhu et al in83 described ethambutol pharma-cokinetics
in children and adults with active tuberculosis. A
prospective, open labeled study was conducted in 56
adults and 14 children with active tuberculosis who
received ethambutol as a companion drug with other
antituberculosis drugs. Concentration data were
analyzed using noncompartmental and population
pharmaco-kinetic methods. Drug exposure increased
with dose, but less than proportionally at doses >3000
mg. Lower than expected maximum serum
concentrations Cmax (<2 g/ml) were common in adults
and very low Cmax (<1 g/ml) in children, as was delayed
absorption (time to Cmax >3 hr). Many Cmax values were
at or below typical TB minimal inhibitory concentration.
Cmax values for HIV-positive patients were 20 % lower
than HIV-negative patients with daily doses, but were
similar with larger twice weekly doses. Adult TB patients
often have lower than expected serum concentrations
whereas most pediatric TB patients have very low
ethambutol serum concentrations. Hence, higher doses
maybe indicated in children with proper therapeutic
monitoring.
Managing Antituberculosis Drug Therapy by

Therapeutic Drug Monitoring of Rifampicin and
Isoniazid
Therapeutic drug monitoring (TDM) is the process of
optimizing drug-dosages on the basis of serum drug
concentration monitoring to achieve a desired therapeutic
response or effect. TDM is useful when serum
concentrations show a better correlation with the
therapeutic effects or the incidence of adverse effects than
does the size of the dose alone. TDM requires the accurate
timing of doses and blood collection and the avoidance
of assay interference.
Gardiner and Marriott84b opine optimizing drug dose
using therapeutic drug monitoring (TDM) may be a better
approach than administering therapy as a standard dose.
Ninety patient episodes were accepted for study. The
rifampicin plasma concentration showed significant
scatter, with 46 % of rifampicin concentration below
normal range and 2 % above the normal range. Similarly
48 % isoniazid concentrations were below the lower
target of the normal range and 29 % were above the upper
limit. Hence, there is significant variably in
pharmacokinetic parameters with rifampicin and
isoniazid. Further, a substantial number of plasma
concentrations fell outside the suggested normal range
for both drugs. Isoniazid plasma concentrations were
significantly higher in female patients as compared to
males. Despite these abnormal results, the dose of

rifampicin and isoniazid was altered in only 17 % of
patients. The service was considered valuable by 83 % of
the responders to questionnaire. Due importance must
be given to TDM for these two drugs.
Jayant et al85 studied the utility of rifampicin blood
levels in the treatment and follow-up of active pulmonary
TB in patients who were slow to respond to routine directly
observed therapy. The patient was labelled as a slow
responder if even after three months, the patient improved
neither clinically, nor bacteriologically or radiographically.
The serum levels of rifampicin were found to be
subtherapeutic. With the increased dose of rifampicin to
900 mg/day, blood levels were still subtherapeutic.
However, these patients responded clinically,
radiographically and mycobacteriologically. Hence, slow
responders before being considered as failure to treatment,
should be given a trial with higher dose of rifampicin
without any change of dose of the other drugs.
Ethionamide Population Pharmacokinetics in Patients

with Tuberculosis
Zhu et al 86 in 2002 determined the population
pharmacokinetic (PK) parameters of ethiona-mide (ETA)
following multiple oral doses. ETA areas under the
concentration versus time curve (AUC) increased linearly
with increasing oral doses from 250 to 1000 mg.
Compared to the population pattern, delayed absorption
was seen at least once in 15 % of patients. ETA PK
parameter estimates were independent of age, weight,
height, gender and creatinine clearance. TB patients
appeared to have larger volumes of distribution (3.22 L/
kg) and clearance values (1.88L/kg) compared to
previously studied healthy volunteers. This resulted in
lower AUC values (3.95 g/ml/hrs) in TB patients. ETA
displayed a short elimination half-life (1.94 hr). ETA PK
parameters differ between TB patients and healthy
volunteers, possibly due to differences in the
completeness of absorption. Doses of at least 500 mg
appear to be required to achieve serum concentrations
above the typical ETA MIC.
Ofloxacin
Pharmacokinetics
Stambaugh et al 87 determined the population
pharmacokinetic (PK) parameters of ofloxacin as part of
their treatment. Delayed absorption was seen in 29 %.
Ofloxacin elimination decreased with increased oral dose,
increasing age and declining renal function. Higher daily
dose may offer pharmacodynamic advantages for the
treatment of TB.
HIGHLIGHTS
Why the knowledge of pharmacokinetics and
pharmacodynamics is important?
This determines the optimum, efficacious dose with
minimum toxicity
Knowledge of MIC for various organisms is known.
Pharmacokinetic studies help to determine the
optimum therapeutic dose for Indian children by
doing studies in Indian population
The knowledge available from western literature is
not suitable for Indian children e.g. isoniazid used
to be given in the dose of 20 mg/kg in TBM in
western counties. The same dose used here
produced marked hepatotoxicity in Indian children.
The reason being these dosages happen to be higher
for malnourished children, a condition commonly
associated with Indian children who develop
tuberculosis
Ethically, it is desirable that for any drug marketed
in another country, limited clinical trial should be
done in our country to look for pharmacokinetic and
safety profile, in addition to efficacy in Indian
children due to ethnic variation and associated
malnutrition of moderate to severe grade
Intermittent therapy is as good as continuous which
is being used in DOTS. Now if it can be logistically,
practical in developing countries with atleast 80 to
85 % coverage, it will be a boon
Limited information exists on the pharma-cokinetic
(PK)-pharmacodynamic (PD) relationships of antituberculosis drugs
There is concern about the marketing of substandard
FDC antituberculosis preparations on a wide scale.
Specific guidelines for industry seems to be
indicated
To overcome this problem, bioavailability testing of
atleast the rifampicin component only by a restricted
assay protocol of six sample times over 8 hours is
advocated, while in vitro procedures for other
activities in combination would suffice for
registration purposes
REFERENCES
1. Nuermberger E, Grosset J. Pharmacokinetic and pharmacodynamic issues in the treatment of mycobacterial
infections. Eur J Clin Microbial Infect Dis 2004;23:
243-55.
2. Gibaldi M. Introduction to pharmacokinetics. In
Biopharmaceutics and clinical pharmacokinetics, 4th edn.
Philadelphia: Lea and Febiger, 1991;113.
3. Morselli PL. Pediatric Clinical Pharmacology: routine
monitoring or clinical trials. In Gouveia, Tognoni, Van
der Klejn (Eds): Clinical Pharmacy and Clinical
Pharmacology. Amsterdam, Elsevier 1976;277-87.
467
4. Shirkey HC. Pediatric Clinical Pharmacology and

Therapeutics. In Avery, GS (Ed): Drug Treatment:
Principles and Practice of Clinical Pharmacology and
Therapeutics. London: Churchill Livingstone 1980;97157.
5. Roberts RJ. Principles of neonatal pharmacology. In Avery
ME, Taeush HW (Eds): Schaffers Diseases of the Newborn.
Philadelphia: W.B. Saunders 1984;950-68.
6. Yaffe SJ, Juchau MR. Pediatric pharmacology. Ann Rev
Pharmacol 1974;14:219-38.
7. Petri, Jr. WA. Antimicrobial Agents: Drugs used in the
chemotherapy of Tuberculosis, Mycobac-terium avium
complex disease and Leprosy. In Hardman, G, Limbird,
LeeL Goodman Gilman. (Eds): The Pharmacological Basis
of Therapeutics, 10th edn. New York: McGraw Hill,
International (edn) 2001;1273-94.
8. Nicolau DP. Predicitng antibacterial response from
pharmacodynamics and pharmacokinetic profiles.
Infection 2001;29 (suppl 2):11-5.
9. Satoskar RS, Bhandarkar SD, Ainapure SS. General
Considerations: general pharmacology. In RS Satoskar,
SD Bhandarkar, SS Ainapure (Eds): Satoskars
Pharmacology and Pharmaco-therapeutics. Mumbai:
Popular Prakashan, revised 16th edn 1999;1-57.
10. Schentag JJ, Gilliand KK, Paladino JA. What have we
learnt from pharmacokinetic and pharmacodynamics
theories. Clin Infect Dis 2001;32 (Suppl 1):539-46.
11. Wagner JG. Biopharmaceutics and relevant
pharmacokinetics, Washington, DC: Drug Intelligence
Publications 1971;1825.
12. Morselli PL. Clinical pharmacokinetics in neonates. Clin
Pharmacokinet 1976;81:1.
13. Diem K, Letner C (Eds): Documenta Geigy Scientific
Tables. 7th edn. Basel, Ciba Geigy Ltd 1970.
14. FrisHansen B. Body water compartments in children: changes
during growth and related changes in body composition.
Pediatrics 1961;28:169-73.
14a. Aggarwal P, Dutta S, Garg SK, et al. Multiple dose
pharmacokinetics of ciprofloxacin in preterm babies.
15. Yaffe SJ. Pediatric pharmacology: therapeutic principles
in practice. New York: Grune and Stratton 1980.
16. Rane A, Thompson G. Prenatal and neonatal drug
metabolism in man. Eur J Clin Pharmacol 1980;18:9.
17. Olson WA, Pruitt AW, Dayton PG. Plasma concentration
of isoniazid in children with tuberculosis infections.
Pediatr 1981;67:876.
18. Mount FW, Avastasiades AA, Schnak GA. Control study
of biologically active isoniazid in serum of children with
pulmonary tuberculosis. Am Rev Respir Dis 1961;83:173.
19. Seth Vimlesh, Seth SD, Beotra A, et al. Monitor-ing of
isoniazid and rifampin in childhood tuberculosis. Am
Rev Respir Dis 1990;141:337.
in malnutrition. Indian Pediatr 1992;29:1341-6.
21. Schaaf HS, Parkin DP, Seifart HI. Isonex
pharmacokinetics in children treated for respiratory
468
21a. Schaff HS, Victor TC, Engeke E, et al. Minimal inhibitory

concentration of isoniazid in Isoniazid resistant
mycobacterium tuberculosis isolates from children. Eur J Clin
Microbial Infect Dis DOI 10.1007/S10096-007-0257-9.
22. Mcilleron H, Willemse M, Werdy CJ, et al. Isoniazid
plasma concentration in a cohort of South African
children with tuberculosis. Implications for international
pediatric dosing guidelines. Int J Tuberc Lung Dis 2007;
11: 965-71.
23. Almeida D, Nuermberger E, Tasneen R, et al. Paradoxical
effect of isoniazid on the activity of rifampicinpyrazinamide combination in a mouse model of
tuberculosis. Antimicrobial agents and chemotherapy
2009; 53: 4178-84.
23a. Donald PR. A Literature review of the pharma-cokinetics
of rifampicin, isoniazid and pyrazinamide and
recommendation for the dosage to be used in children.
2008; April.
24. Schaaf HS, Willemse M, Cilliers K, et al. Rifampin
pharmacokinetics in children with an without
humanimmunodeficiency virus infection, hospitalized
for the management of severe forms of tuberculosis. BMC
Medicine 2009; 7: 19 doi: 10.1186/1741.
25. Thee S, Detjen A, Wahn U, et al. Rifampicin serum levels
in childhood tuberculosis. Int J Tuberc Lung Dis 2009;
13: 1106-11.
26. Peloquin CA, Pharma D, Roesanna N, et al.
Pharmacokinetics of rifampin under fasting condition
with food and other antacid. Chest 1999, 115: 12-8.
Downloaded from Chest Journal. Chest pubs.org by
guest on May 3, 2010.
27. Mehta JB, Shantaveerapa H, Ryland P, et al. Utility of
rifampicin blood levels in the treatment and follow-up
of active pulmonary tuberculosis in patients who were
slow to respond to directly observed therapy. Chest 2001;
120: 1520-4.
28. Ray J, Cardiner I, Marrio HD. Managing antituberculosis
drug therapy by therapeutic drug monitoring of
rifampicin and isoniazid. Intern Med J 2004; 34: 72-3.
29. Zhu M, Starke JR, Burman WJ, et al. Population
pharmacokinetics modeling of pyrazinamide in children
and adults with tuberculosis. Pharma-cotherapy 2002,
22(6). 10 do1. 10.5992 / Phco 22.9.686. 3407.
30. Thee S, Detjen A, Wahn U, et al. Pyrazinamide serum
levels in childhood tuberculosis. Clinical infectious
disease 2009; 48: 1547-53.
31. Gumbo T, Chandima S, Dona WS, et al. Pharmacokinetics
pharmacodynamics of pyrazinamide in a Nonal in vitro
model of tuberculosis for sterilizing effect, a paradigm
for faster assessment of new antituberculosis drugs.
Antomicrobial Agents and Chemotherapy 2009; 5: 31973204.
32. Graham SM, Bell DJ, Nyirongos S, et al. Low levels of
pyrazinamde and ethambutol in children with
tuberculosis and impact of age, nutritional status and
human immunodeficiency virus infection. Antimicrobials
Agents and Chemotherapy 2006; 50: 407-13.
33. Sanchez DO and Maramba CC. Serum concen-tration of

pyrazinamide suspension in children with tuberculosis. A
therapeutic drug monitoring. PIDSP Journal 2005;9:44.
34. Zhu M, Starke JR, Burman WJ, et al. Population
pharmacokinetic modeling of pyrazinamide in children
and adults with tuberculosis. Pharmacotherapy 2002; 22:
686-95.
35. Donald PR. Review of literature for determining
optimum dosage of ethambutol for children for WHO
2005.
36. Detjen A, Thee S, Quarcoo D, et al. Ethambutol (IMB) in
pediatric tuberculosis, aspects of ethambutol serum
concentration, efficacy and toxicity in children. Int J
Tuberc Lung Dis 2007; 11: 937.
37. Zhu M, Burman WJ, Starke JR, et al. Pharma-cokinetics
Int J Tuberc Lung Dis 2004; 8: 1360-7.
38. Zhu M, Burman WJ, Starke JR, et al. Pharmacokinetics
39. Peloquin CA, Zhu M, Adam RD, et al. Pharmacokientics
of paraaminosalicylic acid (PAS) granules under four
dosing condition. Pharma GKB, Accession ID: PA448382.
40. Zhu M, Namdar R, Stambaugh JJ, et al. Population
pharmacokinetics of ethionamide in patients with
tuberculosis. Tuberculosis (Edinb) 2002; 82: 91-6.
41. Zhu M, Nix DE, Adam RD, et al. Pharmacokinetics of
cycloserine under fasting conditions and with high-fat meal,
orange juice, and antacid pharmacotherapy 2001;8:891-7.
42. Nixa DE, Rodney D, Auclairc AB, et al. Pharmacokinetics
and relative bioavailability of clofazimine in relation to
food, orange juice, and antacids. DICP. The Annals of
Pharmacotherapy 1991; 25: 525-31.
43. Stambaugh JJ, Berning SE, Bulpitt AE, et al. Ofloxacin
pharmacokinetics in patients with tuberculosis. Int J
44. Seth Vimlesh, Seth SD, Beotra A, et al. Monitor-ing of
isoniazid and rifampicin in childhood tuberculosis. Am
Rev Respir Dis 1990;141:337.
in malnutrition. Indian Pediatr 1992;29:13416.
concentrations of rifampicin and isonia-zid in
tuberculosis. Indian Pediatr 1993;30:10918.
47. IUATLD. Tuberculosis in children: guidelines for
diagnosis, prevention and treatment. Bull Int Union
Against Tubere Lung Dis 1991;66:61-7.
48. WHO.TB/HIV: A clinical manual. WHO Geneva,
Switzerland. WHO/TB/96200;1996.
49. Enarson DA, Reder HL, Arradotter, T. et al. (Eds.)
Management of Tuberculosis: A Guide for Low Income
Countries. 5th. Paris IUATLD,2000.
Disease. Antituberculosis regimens of chemotherapy.
Recommendations from the Committee on Treatment.
Bull Int Union Tuberc Lung Dis 1988;63:60-4.

51. Polasa K, Murthy KR, Krishnaswamy K. Rifampicin
kinetics in undernutrition. Br J Clin Pharmacol
1984;17:481-4.
52. Polasa K, Krishnaswamy K. Rifampicin kinetics in
undernour-ished. Indian J Med Res 1986;83: 175-8.
53. Seth Vimlesh. Diagnosis and treatment of tuberculosis:
an overview in tuberculosis in children. Seth Vimlesh
(Ed): Indian Academy of Pediatrics, New Delhi 1991;852.
53a. Seth Rajeev. Continuous versus intermittent use of
isoniazid to determine the efficacy and hepatotoxicity of
two regimens in tuberculous meningitis in children.
Thesis submitted to All India Institute of Medical Science
New Delhi for MD Pediatrics 1987.
54. Udani PM. Tuberculosis. In Textbook of Pediatrics (vol1) 1st edn. New Delhi: Jaypee Brothers Medical
Publishers (Pvt.) Ltd 1991;1174-81.
55. Padgaonkar KA, Revankar SN, Bhatt AD, et al.
Comparative bioequivalence study of rifampicin and
isoniazid combination in healthy volunteers. Int J Tuberc
Lung Dis 1999;3:627-31.
56. Fourie PB , Spinaci S, with the IUATLD / WHO
statement. Structure required, roles and respon-sibilities
in maintaining laboratories for quality assurance of
antituberculosis fixed drug combinations in accordance
with the IUATLD / WHO statement. Int J Tuberc Lung
Dis 1999;3: S381-7.
57. Ellard GA , Fourie PB. Rifampicin bioavailibilty: a review
of its pharmacology and the chemo-therapeutic necessity
for ensuring optimal absorption. Int J Tuberc Lung Dis
1999;3:S 301-8.
58. Tran JH, Montakantikul P. The safety of antituberculosis
medications during breast feeding. J Hum Lact
1998;14:337-40.
59. Mitchell JR, Thorgeirsson UP, Black M, et al. Increased
incidence of isoniazid hepatitis in rapid acetylators:
possible relation to hydrazine metabolites. Clin
Pharmacol Ther 1975;18:70.
60. Gurumurthy P, Krishnamurthy MS, Nazareth O, et al.
Lack of relation-ship between hepatic toxicity and
acetyla-tor phenotype in three thousand south Indian
patients during treatment with isoniazid for tuberculosis.
Am Rev Respir Dis 1984,129:58.
61. Martinex-Roig A, Cami J, LlorensTerol J, et al. Acetylation
phenotype and hepatotoxicity in the treatment of
tuberculosis in children. Pediatric 1986;77:912.
62. Parthasarthy R, Raghupati Sarma G, et al. Hepatic toxicity
in South Indian patients during treatment of tuberculosis
with short-course regimens containing isoniazid,
rifampicin and pyarazinamide. Tubercle 1986;67:99.
63. Seth Vimlesh, Beotra A, Ray D. Acetylation phenotype
profile in North Indian children with pulmonary
tuberculosis. Indian Pediatr 1987; 24:1007.
64. Seth Vimlesh, Seth SD, Beotra A, et al. Compari-son
between serum isonicotinic acid hydrazide (INH) levels
and urinary sulfadimidine- (sulfamethazine) acetylation
as predictors of INH acetylator status.Dev Pharmacol
Ther 1988;11:326.
469
65. Seth Vimlesh, Beotra A. Hepatic function in relation to

acetylator phenotype in children treated with
antitubercular drugs. Indian Pediatr 1989;89:306-9.
66. Good JT, Iseman MD, Davidson PT, et al. Tuberculosis
in association with pregnancy. Am J Obstet Gynaecol
1981;140:492-8.
67. Reed MD, Blumer JL. Clinical pharmacology of
antituberculosis drugs. Ped Clin North Am 1983;30:177.
68. Gangadharam PRJ, Bhatia AL, Radhakrishna S, et al. Rate
of inactivation of isoniazid in South Indian patients with
pulmonary tuberculosis. Microbiological assay of
isoniazaid in serum following a standard intramuscular
dose. Bull WHO 1961;25:765.
69. General Pharmacology. In Clinical Phar-macology,
Bennett PN, Brown MJ (Eds): 9th edn. London: Churchill
Livingston, 2005,95 -6.
70. Beotra A, Seth Vimlesh, Mukhopadhyaya S, et al. Serum
rifampicin and isoniazid levels in children with
tubercular infections. Eur J Pharmacol 1990;183:23-89.
71. Hobby GL. Summation of experimental studies on the
action of rifampicin. Chest 1972;61:550-4.
72. Naito M, Mackawa N, Tsukuma S, et al. Studies on a
new antituberculous antibiotic rifampicin. Progress in
antimicrobial and anticancer chemotherapy. Proc 6th
International Congress Chemotherapeutics Tokyo, Vol I
Baltimore, University Park Press 1969;1058-61.
73. Seth Vimlesh, Seth SD, Beotra A, et al. Isoniazid and
acetylisoniazid kineticas in serum and urine in pulmonary
primary complex with intermittent regimen. Indian
Pediatr 1994;31:279-85.
74. Schaaf HS, Parkin DP, Seifast HI, et al. Isoniazid
pharmacokinetics in children treated for respi-ratory
tuberculosis. Arch Dis Child 2005;90:614-8.
75. Davidson PT, Goble M, Lester W. The antituber-culosis
efficacy of rifampicin in 136 patients. Chest 1972;61:5748.
76. McCracken GH, Ginsburg CM, Zweighaft TC, et al.
Pharma-cokinetics of rifampicin in infants and children:
relevance to prophylaxis against Haemophilus influenzae
Type B disease. Pediatrics 1980;66:17-21.
77. Jayram R, Gaonkar S, Kaur P, et al. Pharmaco-kineticspharmacodynamics of rifampin in an aerosol infection
model of tuberculosis. Anti-micro-b Agents Chemother
2003;47: 2118-24.
78. Arya D S. Pharmacokinetic studies of pyrazina-mide in
progressive primary disease and tubercular meningitis.
Thesis submitted to the faculty of All India Institute of
Medical Sciences, New Delhi 1985. Guided by Seth
Vimlesh and Seth SD.
79. Seth V, Seth SD, Arya DS, et al. Pharmacokinetics of
pyrazinamide in pulmonary tuberculosis in children.
Paper presented in Asia-Pacific Conference of Pediatrics,
New Delhi, February 9-13, 1994. Abstract 1994, FP 15-12,
Page 111.
80. Arya DS, Ojha SK, Semwal OP, et al. Pharmaco-kinetics
of pyrazinamide in children with primary progressive
disease of lungs. Indian J Med Res 2008;128:611-5.
81. Arya DS, Ojha SK. Pharmacokinetics of pyrazinamide in
pediatric patients of tuberculous meningitis. World J Med
Sc 2009; 4: 128-34.
470
82. Carlone NA, Acocella G, Cuffini AM, et al. Killing of
macrophageingested mycobacteria by rifampicin,
pyrazinamide, and pyrazinoic acid alone and in
combination. Am Rev Respir Dis 1985; 132: 1274-7.
83. Zhu M, Starke JR, Burman J, et al. Population
pharmacokinetic modeling of pyrazinamide in children
and adults with tuberculosis. Pharmacoetherapy
2002;22:686-95.
84. Seth Vimlesh, Khosla PK, Semwal OP, et al. Visual
evoked responses in tuberculous children on ethambutol
therapy. Indian Pediatr 1991;28: 713-7.
84a. Zhu M, Burman WJ, Starke JR, et al. Pharmaco-kinetics of
ethambutol in children and adults with tuberculosis. Int J
84b. Gardiner RJ, Marriott D. Managing antituber-culosis

drug therapy by therapeutic drug monitoring of
rifampicin and isoniazid. Intern Med J 2003;33:229-34.
85. Jayant B, Mehta MD, Harsha S, et al. Utility of rifampicin
blood levels in the treatment and follow up of active
pulmonary tuberculosis in patient who were slow to
respond to routine directly observed therapy. Chest
2001;120:1520-4.
86. Zhu M, Namdar R, Stambaugh JJ, et al. Population
pharmacokinetics of ethionamide in patients with
tuberculosis.Tuberculosis (Edn b) 2002;82:91-6.
87. Stambaugh JJ, Berning SE, Bulpitt AE, et al. Ofloxacin
population pharmacokinetics in patients with
tuberculosis. Int J Tubere lung Dis 2002,6: 503-9.
33
Pharmacogenetics of Tuberculosis
Manju Ghosh, Madhulika Kabra
WHAT IS PHARMACOGENETICS?
Pharmacogenetics
It is the study of the genetic basis for differences in response
to drugs, or more specifically the study of variations in
DNA sequence as related to drug response. 1
The concept of altered response based on genetic
background was recognized by Pythagoras as early as
510 BC, who observed that certain individuals developed
hemolytic anemia on consumption of fava beans.2 In 1914,
Sir Archibald Garrod, the pioneer of Inborn Errors of
Metabolism, expanded this observation, stating that
enzymes detoxified foreign agents so that they were
excreted harmlessly. However, some people lack these
enzymes and experience adverse effects.3 Hemolytic
anemia due to fava bean consumption was later
determined to occur in glucose-6-phosphate dehydrogenase deficient individuals. Thus Garrod laid the
groundwork for the study of pharmacogenetics well
ahead of his time.
Unusual drug responses, segregating in families have
been recognized for decades and were first documented
in 1950s,4-7 giving rise to the field of pharmacogenetics.
Inherited impairment in drug metabolism is a common
cause for adverse drug reactions. It is estimated that
genetics can account for 20 to 95 percent of variability in
drug disposition and effects.8 These interindividual
differences in drug response are due to sequence variants
in genes (polymor-phisms) encoding drug-metabolizing
enzymes, drug transporters, or drug receptors, and most
of these polymorphisms consist of single nucleotide
polymorphisms (SNPs).9 Recently developed genotyping
techniques permit an accurate and rapid detection of
common SNPs that are relevant to clinical response to
several drugs.
Pharmacogenomics
This is a broader aspect of pharmacogenetics involving
a genome-wide approach to elucidate the inherited basis
of differences between persons in the response to drugs.
It involves the study of genomic biomarkers that are
defined as a measurable DNA and/or RNA characteristic
that is an indicator of normal biologic processes,
pathogenic and/or response to therapeutic or other

interventions. 1
Following the sequencing of the human genome, 1.4
million SNPs were identified, of which 60,000 were in
the coding sequence of the genes. Some of these have
been associated with changes in the metabolism or effects
of medications and some are now being used to predict
clinical response. 4-6,10 The identification of common
polymorphisms across the human genome has expanded
our understanding of the mechanisms of variability in
drug action as a consequence of DNA polymorphisms,
or sets of polymorphisms, among individuals. This
approach defines the field of pharmacogenomics. This
knowledge would allow practitioners to integrate a
molecular understanding of disease with an individuals
genomic make-up to prescribe personalized, highly
effective and safe therapies.11
Originally, pharmacogenetic studies focused on
monogenic traits, involving genetic variation in
drug metabolism. However, contemporary studies
increasingly involve entire pathways encoding
proteins that influence both pharmacokineticsfactors
that influence the concentration of a drug reaching its
target(s)and pharmacodynamics, the drug target itself,
as well as genome-wide approaches. Pharmacogenomics is also increasingly moving across the
translational interface into the clinic and is being
incorporated into the drug development process. 12
Pharmacogenetics/Genomics of Tuberculosis
Single nucleotide polymorphisms of the genes encoding
drug-metabolizing enzymes are responsible for large
interindividual variability in drug metabolism. These
polymorphisms are a major cause of drug toxicity, drugdrug interactions, and lack of therapeutic effect. In the
past many years several polymorphisms of drugmetabolizing enzymes have been described and typing
tests have been developed for the in vivo evaluation of
enzyme activities (phenotyping) or for the detection of
mutations that cause impaired metabolism (genotyping).
These tests are currently being used to prevent adverse
drug reactions in patients who have inherited
impairment in drug metabolism.13
472
Although the causative agent of tuberculosis,

Mycobacterium tuberculosis, has been known for some 120
years, the disease continues to plague humanity. Applied
knowledge of pharmacogenetics and genomics of
Mycobacterium tuberculosis has greatly helped in
understanding the response to the important first-line
drugs like isoniazid, rifampicin, pyrazinamide and
ethambutol and the cause of emergence of multidrug
resistance at the molecular level. This knowledge has
helped in providing optimal therapy for mycobacterial
illness.
Isoniazid
Pharmacokinetics/Pharmacogenetics
Isoniazid (INH), considered the primary drug in the
treatment of TB, is still the most important drug
worldwide for treatment of all types of tuberculosis.
However, the response to treatment/drug toxicity to
INH therapy is all dependent on the rate at which the
drug is metabolized in the body. The main excretory
product of INH is the result of enzymatic acetylation
(acetylisoniazid) by liver N-acetyltransferases encoded
by an extremely polymorphic arylamine N-acetyltransferase 2 (NAT2) gene on chromosome 8p21.3-23.1.
Hereditary differences in N-acetylation activity among
individuals and in populations of diverse raciogeographic origin, have led to the phenotype
classification of humans as rapid and slow acetylators.14
Slow and rapid acetylators greatly differ in the occurrence
of side effects after the use of drugs that are acetylated.
The average concentration of active INH in the circulation
of fast acetylators is about 30 to 50 percent of that present
in persons who acetylate the drug slowly. In the general
population, the half-life of INH varies from 1 to 4 hours.
The mean half-life in fast acetylators is approximately 70
minutes, whereas 2 to 5 hours is characteristic of slow
acetylators.15 Acetylation polymorphism arises from the
allelic variations in human NAT2 gene, which results in
the production of NAT2 proteins with variable enzyme
activity or stability. Certain NAT2 traits may contribute
to the occurrence of adverse drug effects.16
NAT2 Gene Polymorphism

Presently 26 different NAT2 allelic variants that consist
of combinations of seven point mutations (SNPs) related
to impaired drug metabolism are known to occur in
humans. 17,18 The wild type allele is represented as
NAT2;17,18 each of the remaining 25 mutated alleles
possess a characteristic combination of 1 to 4 nucleotide
substitutions that occur at defined positions within the
870 bp of the coding sequence. 19 Most genotyping
methodologies for NAT2 polymorphism analyze

genomic DNA by allele- specific mutation amplification
by PCR and restriction fragment length polymorphism
analysis 20 and newly developed genotyping kits based
on real time PCR and use of fluorescent hybridization
probes.21 The seven major SNPs located in the coding
region of the NAT2 gene constitute diverse allelic
variants, having variable effect on enzyme activity
depending whether co-segregating in a dominant or
recessive manner. Mutations located at nucleotide
positions 191, 282, 341, 590 and 857 are related to slow
acetylation. Therefore, any alleleic variant that contains
one or more of these mutations will affect the acetylation
status.22
Extensive studies of the allele frequencies in various
racial backgrounds, indicate that analysis of a few
appropriate SNPs can give high predictive capacity. For
instance, SNPs at nucleotide position 341, 481 and 803
are at extreme linkage disequilibrium, hence analysis of
just one of them would predict 60 percent of defective
alleles in the Caucasians. Adding analysis of SNP 282,
located on a different allele, would increase predictive
capacity to 97 percent.23 In the Asian population, study
of 2 SNPs, 282 and 341 would enable a phenotype
prediction of approximately 100 percent.22 Molecular
genotyping studies of the NAT2 gene in 166 unrelated
individuals belonging to eight Dravidian communities
in South India revealed very high prevalence of
nucleotide substitutions at 282T and 803G, which per se
alone or in combination did not alter acetylator status of
the enzyme, but when present in combination with 341C,
590A or 857A polymorphisms, resulted in slow acetylator
genotypes. The slow acetylator phenotype was found to
be 74 percent in this Indian study.20
Geographical Variation of Slow and Rapid Acetylator

Phenotypes
Significant racial variation of the acetylation status has
been observed worldwide. Fast acetylation was found in
Eskimos, Japanese and Chinese,24 while American and
west European Caucasians showed slow acetylation status
ranging between 53 to 62 percent.25 Studies in the Asian
population showed variable status of acetylators from slow
acetylators at 73 percent in Hongkong to 58 percent in
Singapore, in contrast to the fast acetylators in the Japanese
and Chinese races ranging between 92 percent and 80
percent respectively.26,27 Studies from India indicated an
average of high percentage of slow acetylators in our
population. Given the complex ethnic diversity of the
Indian population, considerable variation in the
proportion of slow acetylators was observed in different
studies from North and South India.28,20 It has been
reported by Seth et al,29 that almost two-third of North
Indian children are slow acetylators while one-third are
Chapter 33 Pharmacogenetics of Tuberculosis

rapid acetylators. Hepatic functions in relation to
acetylator phenotype in children with antitubercular drugs
were investigated by Seth et al.30 Estimation of the levels
of SGOT and SGPT determined before therapy and at
monthly intervals for the first three months, and then three
monthly for one year, did not indicate any biochemical
toxicity as an evidence of hepatic derangement in relation
to the type of acetylator. They further elucidated that mild
degree of malnutrition does not predispose the child to
more hepatotoxicity.
Acetylator Status and Side Effects of INH

Peripheral neuropathy is the most frequently observed
side effect in slow acetylator adults receiving the
intermittent high dose regimen of INH.31 Conversely,
rapid acetylators are more likely to have treatment failure
with biweekly doses of INH. Hepatotoxicity has been
reported more commonly in Indian patients on INH,
where majority are slow acetylators28-31 in adults. Seth
et al30 did not find so in children in their longitudinal
study. In addition to the above side effects, slow
acetylators on INH may develop drug-induced lupus.28
Idiosyncratic reactions to other drugs like sulonamides, carbamazepine, diphenylhydantoin, warfarin and
alcohol should be anticipated in slow acetylators taking
INH.32,33
Hepatotoxicity
Anti-TB drug (ATD)-related hepatotoxicity is a
worldwide serious medical problem among TB patients.
Apart from acting on the bacteria, isoniazid, the principal
ATD, is also metabolized by human enzymes to generate
toxic chemicals that might cause hepatotoxicity. It has
been proposed that the production and elimination of
the toxic metabolites depends on the activities of several
enzymes, such as N-acetyltransferase 2 (NAT2),
cytochrome P450 oxidase (CYP2E1) and glutathione Stransferase (GSTM1). There is now evidence that DNA
sequence variations or polymorphisms at these loci
(NAT2, CYP2E1 and GSTM1) could modulate the
activities of these enzymes and, hence, the risk of
hepatotoxicity. Since the prevalence of polymorphisms
is different in worldwide populations, the risk of ATD
hepatotoxicity varies in the populations. Thus, the
knowledge of polymorphisms at these loci, prior to
medication, may be useful in evaluating risk and
controlling ATD hepatotoxicity.34
INH Resistance
In addition to genetic polymorphism of the human NAT2
gene, response to INH therapy may be further
compromised by genetic resistance to the drug by the
Mycobacterium tuberculosis. INH resistant mutants
arise spontaneously at a rate of 105-106 organisms. This
is attributed to mutations in atleast five different
473
mycobacterial genes, namely, katG, ahpC, kasA, ndH

and inhA. Most of the INH resistant strains have amino
acid changes in catalase peroxidase gene (katG) or inhA,
which codes for an enzyme important for mycolic acid
biosynthesis. Because mycolic acids are unique to
mycobacteria, this explains the high degree of selectivity
of the antimicrobial activity of isoniazid.35
Recent studies36 have demonstrated the presence of
arylamine N-transferase, homologous to the human
NAT2 enzyme, in Mycobacterium tuberculosis. This
intriguing finding has important implications in
modulating response to INH therapy. It may be,
therefore, important to investigate NAT in M. tuberculosis
for polymorphisms. Preliminary investigations suggest
that NAT in different clinical M. tuberculosis isolates is
also polymorphic.36
Rifampicin
Rifampicin, a semi-synthetic derivative of Streptomyces
mediterranei, is considered the most important and potent
antituberculous agent. It is active against a wide spectrum
of other organisms.
Mechanism of Action
Rifampicin has both intracellular and extracellular
bactericidal activity by blocking RNA synthesis by
specifically binding and inhibiting DNA-dependent RNA
polymerase. Details discussed elsewhere.
Bacterial Resistance
Mycobacteria may develop resistance to rifampicin
rapidly in vitro, and one in 107-108 tubercle bacilli may
show resistance to rifampicin. At the molecular level this
is due to spontaneous point mutations that alter the beta
subunit of the RNA polymerase (rpoB) gene. Studies
have shown that 96 percent of rifampicin resistant strains
have a missence mutation within a 91bp central core of
the gene.37
Pyrazinamide (PZA)
A derivative of nicotinic acid, is an important bactericidal
drug used in the short-course therapy of TB.
Mechanism of Action
PZA is similar to INH in its narrow spectrum of
antibacterial activity essentially restricted to M.
tuberculosis only. The drug is bactericidal to only slowly
metabolizing bacilli in acidic environment of phagocytes
and caseous granulomas. It is active only at pH < 6. It is
considered a pro drug as it is converted into the active
drug by the tubercle bacillus into its active form,
pyrazinoic acid. The target for this compound is a fatty
acid synthase gene.38
474
Resistance
Susceptibility testing for PZA is difficult to demonstrate
because of the requirement of acid pH for the activity of
the drug to be converted to its active form pyrazinoic
acid by the bacterial enzyme pyrazinamidase. Resistance
to this drug is due to mutations in the Mycobacterial
pncA gene, coding for pyrazinamidase, resulting in its
loss of activity. It has been established that more than 90
percent of the isolates with MICs of > 100 g/ml have
mutations in the pncA gene.39
Ethambutol
Ethambutol is a water soluble compound that is active
only against mycobacteria. Among the 1st line drugs,
ethambutol is the least potent and administered with
rifampicin in cases intolerant or resistant to INH.
Mechanism of Action
Ethambutol is a bacteriostatic drug and acts by inhibition
of the bacterial arabinosyl transferase enzyme that
mediates the polymerization of arabinose to
arabinogalactan in the cell wall.
Resistance
Mycobacterial resistance to ethambutol is known to be due
to missense mutations present in the embB gene that codes
for arabinosyl transferase. Amino acid substitutions at
positions 306 and 406 were found in 77.6 and 95.5 percent
of resistant isolates respectively in a study.40
Molecular Diagnosis of MDR Tuberculosis

Expeditious diagnosis of drug susceptibility and
resistance in Mycobacterium tuberculosis is difficult and
time consuming by conventional methods. The genetic
mapping of the mycobacterial genes and identification
of the gene mutations causing specific resistance to the
antimycobacterial drugs, have led to development of high
throughput micro-array based techniques that can
analyze hundreds of samples at a time on a biochip, and
have results within 12 hours.41
More recently, researchers have developed a
Pyrosequencing assay for rapid detection of SNPs in the
mycobacterium genes associated with resistance to
particular drugs. Pyrosequencing is a real time sequencing
method able to rapidly detect mutations in a large number
of samples. Pyrosequencing assay method was used for
rapid screening of rifampicin, isoniazid and ethambutol
resistant strains of M. tuberculosis based on characterization
of resistance-associated hot mutations. Thus mutations at
codon 526 and 531 of the rpoB gene, codon 315 of the katG
gene, and codon 306 and 406 of the embB gene can be
determined with great accuracy and speed, identifying

majority of cases resistant to rifampicin, isoniazid and
ethambutol.42,43
HIGHLIGHTS
Genomics will introduce a new dimension in drug
research.
Gene expression analysis and genetic polymorphisms
are important for determining incidence of adverse
drug reactions and drug resistance.
A detailed knowledge of the genetic basis of
individual response is of major clinical and economic
importance and can provide the basis for a rational
approach to drug prescription.
REFERENCES
1. EMEA/ CHMP/ ICH/ 437986. Definitions for genomic
bio-markers, pharmacogenomics, pharmacogenetics,
genomic data and sample coding categories 2006.
2. Weber WW. Populations and genetic polymorphisms.
Mol Diagn 1999;4:299-307.
3. Scriver CR and Childs B. In: Garrods Inborn Factors and
Disease (a reprinted edition of the original book of assays).
Oxford University Press, New York 1989.
4. Kallow W. Familial incidence of low pseudo cholinesterase
level. Lancet 1956;2:576.
5. Carson PE, Flanagan CL, Ickes CE, et al. Enzymatic
deficiency in primaquin sensitive erythrocytes. Science
1956;124:484-5.
6. Hughes HB, Biehl JP, Jones AP, et al. Metabolism of
isoniazid in man is related to occurrence of peripheral
neuritis. Am Rev Tuberc 1954;70:266-73.
7. Evans DAP, Manley KA, Mckusick VA, et al. Genetic
control of isoniazid in man. Br Med J 1960;2:485-91.
8. Kallow W, Tang BK, Endrenyi I, et al. Hypothesis:
Comparisons of inter- and intra-individual variations
can substitute twin studies in drug research.
Pharmacogenetics 1998;8:283-9.
9. Evans WE, Reiling MV. Pharmacogenomics: translating
functional genomics into rational therapeutics. Science
1999;286:29-39.
10. Yates CR, Krynetski EY, Loennechen T, et al. Molecular
diagnosis of thiopurine S-methyl transferase deficiency:
genetic basis for azathiopurine and mercaptopurine
intolerance. Ann Intern Med 1997;126:608-14.
11. Evans WE, Mcleod HL. Pharmacogenomicsdrug
disposition, drug targets, and side effects. N Engl J Med
2003;348:538-49.
12. Weinshilboum RM, Wang L. Pharmacogenetics and
Pharmacogenomics: Development, Science and
Translation. Ann Rev Genomics and Human Genetics
2006;7:223-45.
13. OKane DJ, Weinshilboum RM, Mayer TP.
Pharmacogenomics and reducing the frequency of
adverse drug events. Pharmacogenomics 2003;4:1-4.
14. Blum M, Grant DM, Mcbride W, et al. Human arylamine
N-acetyltransferase genes: isolation, chromosomal
Chapter 33 Pharmacogenetics of Tuberculosis
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
localization, and functional expression. DNA Cell Biol

1990;9:193-203.
Petri WA, Jr. Chemotherapy of Tuberculosis,
Mycobacterium avium complex disease and leprosy. In:
Goodman and Gillman, (Eds) The Pharmacological
Basis of Therapeutics. 11th Edn McGraw-Hill 2006;
1203-23.
Clark DW. Genetically determined variability in
acetylation and oxidation. Therapeutic implications.
Drugs 1985;29:342-75.
NAT2gene homepage-http:/www.Louisville. edu/
medschool pharmacology/NAT2.html.
Vatsis KP, Weber WW, Bell DA, et al. Nomenclatures
for N-acetyltransferases. Pharmacogenetics 1995;5:1-17.
Mrozikiewicz PM, Cascorbi I, Brockmoller J, et al.
Determination and allelic allocation of seven nucleotide
transitions within the arylamine N-acetyltransferase gene
in Polish population. Clin Pharmacol Ther 1996;59:
376-83.
Anitha A, Bannerjee M. Arylamine N-acetyltransferase
2 polymorphism in the ethnic population of South India.
Int J Mol Med 2003; 11:125-31.
Brans R, Iaizane D, Annika Khan, et al. NAcetyltransferase 2 Genotyping: An accurate and feasible
approach for simultaneous detection of the most common
NAT2 allele. Clin Chem 2004;50:1264-6.
Lin JJ, Han CY, Lin BK, et al. Slow acetylator mutations
in the human polymorphic N-acetyltransferase gene in
786 Asians, Blacks, Hispanics and Whites: Application
to metabolic epidemiology. Am J Hum Genet 1003; 52:
827-34.
Cascorbi I, Dracoulis N, Brockmoller J, et al. Arylamine
N-acetyltransferase mutations and their alleleic linkage
in unrelated Caucasians individuals: correlation with
their phenotypic activity. Am J Hum Genet 1995;57:58192.
Ellard GA. Variations between individuals and
populations in the acetylation of isoniazid and its
significance for the treatment of pulmonary tuberculosis.
Clin Pharmacol Ther 1976;19:610-25.
Hilderbrand M, Seifert W. Determination of acetylator
phenotype in Caucasians with caffeine. Eur J Pharmacol
Ther 1989;37:525-6.
Mashimo M, Suzuki T, Abe M, et al. Molecular
Genotyping of N-acetylation polymorphism to predict
phenotype. Hum Genet 1992;90:130-43.
Rothman N, Hayes RB, Caporaso N, et al. Correlation
between N-acetyltransferase activity and NAT2 genotype
in Chinese males. Pharmacogenetics 1993;3:250-5.
Pande JN, Singh SPN, Khilnani GC, et al. Risk factors for
hepatotoxicity from anti-tuberculosis drugs: A case control
study. Thorax 1996;50:132-6.
475
29. Seth Vimlesh, Beotra A, Ray D. Acetylation phenotype

profile in north Indian children with pulmonary
tuberculosis. Indian Pediatr 1987;24: 1007-11.
antitubercular drugs. Indian J Med Res 1989; 89:306-9.
31. Parthasarathy R, Sarma GR, Janardhanam B, et al.
Hepatotoxicity in South Indian patients during treatment
of tuberculosis with Short-course regimens containing
1986;67:99-108.
32. Snider DE Jr. Pyridoxine supplementation during
isoniazid therapy. Tubercle 1980;61:191-6.
33. Spielberg SP. N-acetyltransferases; pharmacogenetics and
clinical consequences of polymorphic drug metabolism.
J Pharmacokinet Biopharm 1996;24:509-19.
34. Roy PD, Majumdar M, Roy B. Pharmacogenomics of antitubercular drugs related to hepatotoxicity. Pharmacogenomics 2008; 9:311-21.
35. Bannerjee A, Dubnau E, Quemard A, et al. inhA, a gene
36. Sim E, Payton M, Noble M and Minchin R. An update on
genetics, structural and functional studies of arylamine
Nacetyltransferases in eucaryotes and procaryotes. Hum
Mol Gen 2000;9:review 2435-41.
37. Musser JM. Antimicrobial agent resistance in
mycobacteria: Molecular genetic insights. Clin Microbiol
Rev 1995;8:496-8.
38. Zim Hong O, Cox JS, Weleh JT, et al. Pyrazinamide
inhibits the eukaryotic-like fatty acid synthetase I (FASI)
of Mycobacterium tuberculosis. Nat Med 2000;6:1043-7.
39. Blanchard JS. Molecular mechanisms of drug resistance
in Mycobacterium tuberculosis. Am Rev Biochem
1996;65:215-39.
40. Parsons LM, Salfinger M, Clobridge A, et al. Phenotype
and molecular characterization of Mycobacterium tuberculosis
isolates resistant to both isoniazid and ethambutol.
41. Gryadunov D, Mikhailovich V, Lapa S, et al. Evaluation
of hybridization on oligonucleotide microarray for
analysis of drug resistant Mycobacterium tuberculosis. Clin
Microbiol Infect 2005;11:531-9.
42. Isola D, Pardini M, Varaine F, et al. A pyrosequencing
assay for rapid recognition of SNPs in Mycobacterium
tuberculosis embB306 region. J Microbiol Methods
2005;62:113-20.
43. Zhao JR, Bai YJ, Wang Y, et al. Development of a
pyrosequencing approach for rapid screening of
rifampicin, isoniazid and ethambutol-resistant
Mycobacterium tuberculosis. Int J Tuberc Lung Dis
2005;9:328-32.
34
Management of Tuberculosis
The management of tuberculosis has evolved over

centuries. In pre-chemotherapy era it was mainly based
on rest, good food and fresh air. In chemotherapy era
one of the first drugs discovered to be effective in
tuberculosis was streptomycin around 1940s. It had a
dramatic effect on the symptoms of tuberculosis.
However, since it was used alone, 80 percent of the
organisms became streptomycin resistant in 3 months.
Discovery of para-aminosalicylic acid (PAS) in 1949 and
isoniazid in 1952 led to the use of all 3 drugs together
and prevention of resistance. The drugs were given for
18 to 24 months for adequate therapy. With discovery of
rifampicin in 1960, the combination of isoniazid,
rifampicin and streptomycin was able to reduce the
duration of therapy to 9 months. Pyrazinamide was then
discovered to have effect on special subgroup of
mycobacterium which exists in the acidic pH
intracellularly. It is high sterilizing activity resulted in
being able to shorten chemotherapy to 6 months.
COMMONLY USED DRUGS

The drugs used for treatment of tuberculosis in children
along with their doses are given in Table 34.1.
DRUG REGIMENS
The drug regimens used for treatment of various forms
of tuberculosis can be divided into two phases. In the
initial intensive phase 3 to 5 drugs are given to the child.
In the second maintenance phase 2 to 3 drugs are
prescribed for a period of 4 to 10 months, usually four
months for milder form such as pulmonary primary
complex and for a longer duration for severe form of TB.
Selection of antituberculosis regimen depend on the
type of tubercular disease. WHO has described
standardized treatment categories for adults with
tubercular disease in Directly Observed Therapy Shortcourse (DOTS). The major problem in inclusion of
children in DOTS is difficulty in demonstration of AFB
on sputum-smear and classification of different clinical
manifestations according to categories described for
adults. There have been efforts to develop classification
of different types of childhood TB into 4 categories similar
to those for adults. A classification was developed and
evaluated in the tuberculosis clinic of All India Institute
of Medical Sciences, New Delhi, India1 a tertiary care
hospital.1 It is to be noted that the regimens used were
all continuous unlike intermittent in DOTS. The reason
Table 34.1: Doses and important side effects of antituberculosis drugs

Drugs
Isoniazid
Rifampicin
Doses (mg/kg/day)
5
10
Streptomycin
10-30
Ethambutol
15-25
Pyrazinamide
25-35
Thiacetazone
**Ethionamide
3-5
15-20
Cycloserine
15-20
Side effects
Hepatotoxicity, hypersensitivity rash, fever, optic neuritis, psychosis, seizures
Nausea, vomiting, hepatotoxicity, flu like syndrome, blood dyscrasia, arthralgia,
wheezing
Ototoxicity: Vestibular or hearing loss, rash, fever, arthralgia, neuromuscular blockade,
peripheral neuritis, anaphylaxis
Hypersensitivity reactionrash, fever, joint pain, optic neuritis, GI upset, confusion,
dizziness
GI upset, hepatotoxicity, hyperuricemia, photosensitivity, dysuria, malaise, arthralgia,
fever, thrombocytopenia
*GI upset, hepatotoxicity, exfoliative dermatitis, vertigo, tinnitus, ataxia
GI upset, hepatotoxicity, peripheral neuropathy, gynecomastia, rash, alopecia,
headache, depression, diplopia, blurred vision, tremors
Seizures, psychosis, peripheral neuritis
*GI = Gastrointestinal
** The other drugs for resistant tuberculosis are discussed elsewhere.
Practically not used now due to dermal hypersensitivity reaction.
477
Chapter 34 Management of Tuberculosis

is that the infrastructure required for DOTS is neither
available to practicing pediatricians nor to the
pediatricians in medical colleges. It is not possible to
accommodate all children under the DOTS, as they come
from different areas which may not be under the
delineated zones. Though fairly large number of
adolescent children may be covered under DOTS, the
others will have to resort to continuous therapy. Recently
a consensus statement jointly prepared by Indian
Academy of Pediatrics and Revised National Tuberculosis Control Program (RNTCP) has also proposed a
classification of different types of tuberculosis in children
of three categories2 now under two categories (discussed
elsewhere). Table 34.2 gives standardized categories
given by WHO along with suggested clinical condition1
and antituberculosis drugs regimens in children. These
are modified continuous, more popular with pediatricians
in medical colleges and those in practice.
Patients not improving or deteriorating despite
administration of 5 drugs (as per Category II) for at least
3 months are labeled as multidrug-resistant tuberculosis.
The drugs used for this category of patients are described
in detail elsewhere.
The continuous regimens used at AIIMS in the pediatric
TB clinic are:
Category I 2 HRZE, 4 HR or
2 SHRZ 4 HR
Category II 2 SHRZE, 1 HRZE
Category III 2 HRZ, 4 HR (Table 34.2)
These regimens were given to a total of 541 children
(boys 58% and girls 42%) with TB disease over a period
of five years (2000-2005). The data was statistically
analyzed by bivariate analysis followed by multivariate
analysis using STATA 70 software. Age range was 2
months to 15 years. History of contact with TB patients
in the family was present in 42%. Table 34.3 gives in

details in the clinical profile and treatment outcome.
Cure rates ranged from 80 to 100%. In cavitary and
disseminated types only 66% of the patients got cured.
In tubercular lymphadenitis, in almost 15% treatment had
to be extended and in about 5% of the cases regimen had
to be changed.
Factors Associated with Failure of Therapy

1. AFB positivity at diagnosis
2. Nonreceipt of BCG vaccination at birth or later.
3. Extrapulmonary tuberculosis
AFB Positivity Diagnosis

AFB positivity at the time of diagnosis indicates either
the disease was extensive or drug resistant. At AIIMS, (a
tertiary care center) AFB positivity was found more
commonly in lymph node tuberculosis. Seven percent of
children required change of regimen. MDR-TB was more
common in lymph node tuberculosis, for which regimen
had to be changed.
BCG
BCG has not been studied systematically in relation to
outcome of tuberculosis in children. It has been
demonstrated experimentally that in mice prior
immunization enhances macrophage phagocytosis and
CD4 T-helper cell activity to contain mycobacterial
dissemination. A meta-analysis found overall protective
effect of BCG as 50% against TB infections. BCG as is
commonly interpreted limits the hematogenous spread
and thus facilitates cure.
Table 34.2: Standard WHO clinical categories and suggested clinical conditions
of tuberculosis in children at AIIMS TB clinic
Categories
As suggested by
WHO for adults
in children
Suggested
regimens
Category I
New sputum positive

Pulmonary TB
2 HRZE
4 HR
or
2 SHRZ
4 HR
Category II
Relapse
Treatment failure
Sputum negative pulmonary with
limited parenchymal involvement
Extrapulmonary TB (less severe forms)
PPD, TBL
Pleural effusion
Abdominal TB
Osteoarticular TB
Genitourinary TB
CNS TB
Relapse
Treatment failure
Category III
Single lymph node

Small effusion
Skin TB, PPC
PPCPulmonary Primary Complex, PPDProgressive Primary Disease,

TBLTubercular Lymphadenitis, CNS TBCentral Nervous System Tuberculosis
2 SHRZE
1 HRZE
7 HRE
2 HRZ
4 HR
478
Type of TB
Table 34.3: Clinical profile and outcome of treatment of childhood tuberculosis

Total
Cured
Extension of
Change of regimen
No.
%
treatment
Primary pulmonary
Progressive primary disease
Cavitary tuberculosis*
Miliary tuberculosis
Pleural effusion
Tubercular lymphadenitis
Abdominal tuberculosis
Osteoarticular tuberculosis
Tuberculoma brain
Tubercular meningitis
Disseminated tuberculosis*
Pericardial tuberculosis
Genitourinary tuberculosis
Total
* Cure rate only 66%
98
155
3
11
30
153
19
22
10
4
30
3
3
98
138
2
9
26
124
17
18
8
4
20
3
2
541
469
One of the chances of higher failure in extrapulmonary
tuberculosis may be false perception of non-response/
failure as in lymph node tuberculosis. Earlier studies in
nineties have reported that affected lymph nodes may
enlarge when patients are receiving appropriate therapy
or after the end of treatment, without any evidence of
bacteriological relapse. Children with non-resolution of
lymph node or reappearance of new nodes on treatment
should only be labeled as failure if they have systemic
manifestations (weight loss, fever) along with evidence
of tuberculosis (granuloma/AFB) on FNAC. Resistant
TB can only be diagnosed if there is demonstration of
AFB in aspiration or biopsy material of lymph nodes and
provided the patients have taken the primary regimen
with appropriate compliance. At AIIMS, in the TB clinic,
medicines are given to the patient as per regimen for a
period of 2 weeks in the intensive phase and every month
in the continuation phase. On each visit it is only enquired
from the parents or caretaker whether the medicine have
been given as prescribed. Empty blister packs are taken
and counted to ensure whether patient has been
compliant.
CATEGORIES AND DRUGS

REGIMEN UNDER DOTS
The basis for assigning a category to a particular type of
tuberculosis under DOTS is as follows:
Category I
All freshly diagnosed serious cases of tuberculosis are
included in category I. In addition, patients with joint
tuberculosis are also included in category I, because it
may have long-term sequelae, if treated inadequately
100
89
66
81
86
81
89
81
80
100
66
100
66
9
15
1
2
4
22
2
3
0
0
10
0
1
1
2
0
0
0
7
0
1
2
0
0
0
0
69
13
producing handicaps later in life. The drug regimen for

this category is 2H3 R3 Z3 E3, 4 H3 R3 under DOTS.
Category II
Children who received full antituberculosis treatment in
past and were declared cured and presented again with
tuberculosis disease (relapse cases) are included in
category II. Patients who are diagnosed to have
tuberculosis in the past and received irregular treatment
for the same without improvement or deteriorated
(suspected resistance) are also placed in category II. A
child who failed to respond or deteriorated (clinical/
radiographic evidence + bacteriology) after 12 weeks of
intensive phase with good compliance is defined as
treatment failure and is placed in category II. Patients
who have interrupted treatment for two months or more,
and return with active TB as judged on clinical and
radiological assessment (treatment after interruption) are
also classified in category II. The regimen for this category
is 2S3 H3 R3 Z3 E3/1 H3 R3 Z3 E3/5H3 R3 E3.
Category III
Patients with primary pulmonary complex (PPC), single
lymph node tuberculosis, minimal pleural effusion and
isolated skin tuberculosis are included in category III.
The suggested regimen for this category is 2H3 R3 Z3, 4H3
R3 .
CORTICOSTEROIDS IN TUBERCULOSIS
Corticosteroids have been used as an adjunct to
antituberculosis therapy. It may be useful to mention that
although corticosteroids are helpful in decreasing
morbidity due to TB but it is advised that these should
not be used indiscriminately. There is unequivocal
evidence of benefit of systemic steroids in CNS tuberculosis.3
479

Corticosteroids should be routinely used in HIV-negative
people with tuberculous meningitis to reduce death and
disabling residual neurological deficit amongst survivors.
However, there is not enough evidence to support or
refute a similar conclusion for those who are HIV positive.
Children with bronchial obstruction due to tuberculosis
may benefit with systemic steroids but the evidence is
restricted to a single randomized controlled trial.4
Therefore steroids cannot be recommended routinely and
should be used after weighing benefits and harm to the
patients in such situations. There are no strong evidence
for use of steroids in pleural effusion,5 may be used if
there is massive pleural effusion. Other conditions may
be miliary TB, pericardial tuberculosis.6 Systemic steroids
did not prevent appearance of new nodes during
antituberculosis treatment.7 Prednisolone is the preferred
steroid preparation. The dose is 1 to 2 mg/kg/day for 2
to 4 weeks and then gradual tapering over next 4 to 6
weeks.
MONITORING OF TREATMENT
Adherence to treatment and completion of assigned
regimen is the key to success of treatment of tuberculosis.
Compliance of drugs is assessed by asking the patient
directly, about the color of urine which would indicate
whether the child is taking rifampicin. Each visit must
be utilized to provide health education and reinforce the
need for treatment for full period. [Patients are given
drugs which are provided by a Non-Government
Organization (NGO) for pediatric TB clinic at AIIMS].
Interrupted Treatment
Whenever the treatment is interrupted for more than 2
weeks, the child should be reassessed clinically and
radiologically. Wherever possible, bacteriological
examination should be performed. A suggested guideline
for treatment after interruption of therapy is given in
Table 34.4.
S.
No.
Duration of
therapy
1.
Up to 4 weeks
2.
4-7 weeks
3.
> 8 weeks
Response to antituberculosis treatment can be

monitored by (i) Clinical improvement; (ii) Radiological
clearance; (iii) Clearance of mycobacterium and; (iv)
Nonspecific laboratory tests.8
Clinical Improvement
Majority of the patients show clinical improvement in
symptoms and signs within a few weeks. Patients on
antituberculosis drugs should be followed every week
in the 1st month of intensive phase and then twice
monthly in the intensive phase. On each clinical visit
improvement in fever, cough, appetite and subjective
well-being is assessed by asking the parents or the child
(if he is old enough). The child should be examined for
weight gain, reduction in lymph node size, improvement
in chest findings and presence of side effect of
medications.
Majority of the patients show clinical improvement
in symptoms and signs within a few weeks. In the
presence of poor response or worsening of symptoms and
signs, the initial basis of diagnosis of tuberculosis is
checked again. The patient should be assessed for
compliance to drugs, other associated problems and/or
resistant tuberculosis and managed accordingly.
The clinical criteria used for monitoring are weight
gain, resolution in symptoms and signs which is the most
common outcome in treated patients. In a study on lymph
node tuberculosis, nearly 10-12 percent patients showed
appearance of fresh nodes or increase in size of existing
nodes. Few patients had residual nodes at the end of
treatment (9 RHE). Some of these nodes increased in size
or fistula was formed later on. However, these changes
were not associated with a bacteriological relapse. Hence,
the study noted no advantage in further prolongation of
treatment.9
Follow-up should be continued every 2 to 4 weeks
for the duration of treatment in the continuation phase.
After the treatment is over, follow-up every 3 to 6 months
for next 2 years is desirable.10a

Duration of
Decision
interruption
<2 weeks
>2 weeks
<2 weeks
>2-8 weeks
>8 weeks
<2 weeks
>2 weeks:
Not active disease
>2 weeks:
Active disease
*Continuous regimens as suggested in Table 34.3.

Reassess and start appropriate regimen
Extend intensive phase by 1 month
Reassess and start appropriate regimen
Resume therapy
Resume therapy
Resume therapy
Category of treatment
(continuous)*
Category II therapy
Category I
480
Radiological Improvement
Clinical improvement precedes radiological clearance of
lesion on X-ray film of chest (CXR). Frequency of doing
CXR in children with pulmonary tuberculosis is not clear.
In view of limited resources, the reasonable approach
would be to obtain CXR after 8 weeks of treatment, and
if it shows significant improvement, further follow-up
should be based on clinical criteria. In patients who show
increase or little change in radiological features coupled
with delayed clinical response, it is suggested to extend
the intensive phase by one more month. Further X-ray
films should be done after 4 weeks. If patient is better, he
should be put on continuation phase, else he should be,
investigated for failure of treatment and drug resistance.
On the degree of the radiological clearance of the
lesion, the response to therapy is graded as:11
Complete clearance
Moderate to significant clearance (1/2 to 2/3
clearance)
Mild clearance (1/3 decrease in size)
Static lesion
No clearance or appearance of new lesions.
If a patient has achieved complete or moderate to
significant clearance there is no need to continue
antituberculosis drugs beyond the duration of regimen
selected for the patient.12 One should not attempt to treat
till complete radiological clearance as the improvement
in X-ray may continue to occur even after stoppage of
treatment.13,14
Persistent Abnormal Shadows on

CXR in Follow-up
Abnormal shadows maybe due to evolving calcification
in lymph nodes, segmental/sub-segmental collapse or
residual bronchiectasis. In these patients it is difficult to
assess the activity of disease by CXR alone. If the patient
is clinically asymptomatic, the assigned antituberculosis
drugs regimen is completed and stopped. The patients
should be followed up regularly and CXR repeated after
6 months. Persistence of static shadows on CXR without
clinical deterioration indicates inactivity of disease. In
some patients occurrence of posttuberculous
bronchiectasis or bronchial hyperactivity, etc. may lead
to situation where clinical signs and symptoms of cough,
expectoration, etc. persist along with radiological
shadows even though TB may have responded to
treatment.14
Bacteriological Criteria
Childhood tuberculosis is often a paucibacillary disease.
It is difficult to demonstrate Mycobacterium tuberculosis
in sputum/gastric lavage/aspiration from lymph nodes

and in biopsy specimens in over 50 percent of patients
even in best centers. However, observing the disappearance of bacilli on treatment is as important as
attempt to isolate the bacilli for diagnosis even among
children. This is particularly true for cases with
pulmonary progressive primary disease or lymph nodes
with necrosis and fistula formation as these are more
likely to yield acid fast bacilli. WHO recommends that
monitoring by AFB isolation is important and all cases
must undergo AFB tests at the end of intensive phase of
treatment to detect conversion to negative status among
those who were initially positive and detect early failures
in those who were AFB negative. Further bacteriological
tests are done at least once more before stopping
treatment to establish true cure.15
Sputum examination, gastric aspirate or induced
sputum examination may be used for AFB demonstration.
Nonspecific Test for Monitoring

Although an elevated erythrocyte sedimentation rate
(ESR) maybe expected in children with tuberculosis, a
recent study found that one-third of children with TB
had a normal ESR at the time of diagnosis, suggesting
little value in using ESR as a diagnostic and monitoring
test for childhood tuberculosis.16
MONITORING FOR SIDE EFFECTS

The child should be examined for side effects on each
visit. The common side effects of antituberculosis drugs
are given in Table 34.1. The important side effects that
have clinical implication include hepatotoxicity, ocular
toxicity, and skin hypersensitivity reactions. It has been
observed that children tolerate anti-TB drugs at currently
recommended doses very well, incidence of serious
toxicity is very low. Occasional fatal hepatotoxic events
are described in children.17 Monitoring for adverse effects
will need to be improved if increased doses are to be
used in children especially in regions where comorbidities are common.18
Hepatotoxicity
Hepatotoxicity is the major fear when the combination
of isoniazid (INH), rifampicin (RIF) and pyrazinamide
(PZA) is administered during intensive phase of
treatment. The factors held responsible for hepatotoxicity
include acetylator phenotype, doses of antituberculosis
drugs, nutritional status of the patient and severity of
the disease.2,10
It has been observed that acetylator phenotype does
not cause hepatotoxicity due to INH.14,17 The chances of

hepatotoxicity increase if higher doses or combination
of INH, RIF, PZA are used.18,19 Children with severe
disease like tubercular meningitis, miliary tuberculosis,
etc. are at a greater risk of developing antituberculosis
drugs-induced hepatotoxicity.20,21 Similarly, children
with pre-existing liver dysfunction, viral hepatitis and
malnutrition particularly grade III are predisposed to
antituberculosis drugs-induced hepatotoxicity.
Monitoring of transaminases may pickup antituberculosis drug-induced hepatotoxicity early.
However, most experts prefer to substitute laboratory
monitoring with routine questions about appetite,
nausea, vomiting, appearance of jaundice, pain abdomen
and subjective well-being. The patient may be examined
for jaundice, hepatomegaly and weight gain. In case
nausea, vomiting, abdominal pain or jaundice occur,22
the patient can be counseled to stop INH and contact the
clinician immediately.
Laboratory investigations including transaminases,
serum bilirubin, and alkaline phosphatase may be done
if antituberculosis drugs-induced hepatotoxicity is
suspected on clinical ground. In certain high-risk cases
like pre-existing liver disease, routine monitoring is
recommended.23 Investigations for viral hepatitis, should
be carried out as the hepatitis maybe because of viral
infection rather than due to antituberculosis drugs.24,25
If a child on antituberculosis drugs develops clinically
evident jaundice or rise in blood transaminases more than
five times the normal, the INH, RIF and PZA should be
stopped. Rifampicin alone causes true hepatotoxic
reaction, though uncommonly, can perhaps potentiate
hepatotoxicity due to other drugs like INH. However, if
the picture is that of cholestatic jaundice, i.e. increased
bilirubin with minimal increase in transaminase levels,
rifampicin is most likely the culprit.26 Isoniazid, rifampicin
and pyrazinamide should be stopped. The patient should
be started on streptomycin and ethambutol if the disease
is life-threatening. The transaminases are repeated every
week. When the transaminase levels decrease to less than
two times the normal, the child can be started on
rifampicin, isoniazid and pyrazinamide in sequence.
Initially half the dose, then the full dose. It is preferable to
add or modify the dose one at a time with monitoring of
transaminases weekly. However, in severe disease, 2 to 3
changes (i.e. increasing the dose/adding new drug) can
be made at a time with frequent monitoring of liver
enzymes.10
Ocular Toxicity
Ocular toxicity due to ethambutol may occur in up to 5
percent of patients if the doses are between 25 to 50 mg/
kg/day. The toxicity results in reversible optic neuritis,
blurred vision, scotoma and alteration in color vision.
481
However, it is rare in doses of 15 mg/kg/day.27,28 It has

been shown that children above the age of 3 years are
not at a great risk for developing ethambutol induced
optic damage.29 In young children if ethambutol toxicity
is suspected they need careful monitoring by
electroretinogram (ERG) in consultation with an eye
specialist. However, in the older patients, regular
monitoring of color vision maybe sufficient. If ocular
toxicity is suspected, the drug should be discontinued.
Ethambutol toxicity is dose related and in recommended
doses (15-25 mg/kg) it is safe and can be used in younger
children. 30-34 Seth at al 31 have demonstrated by
measuring visual evoked responses in children that these
functions can be measured in children above 3 years of
age. They further reported no ocular toxicity in this dosage.
Peripheral Neuritis
Clinically manifest peripheral neuritis in children on INH
therapy due to pyridoxine deficiency is very rare.33 The
patients who are predisposed for development of
peripheral neuritis include children who do not eat dairy
and animal products, malnourished and HIV
infected.35,36 If at all it occurs, it manifests as pins and
needles sensation in hands and feet. These children
should be treated with pyridoxine 25 to 50 mg/day.9
Adverse reactions due to antituberculosis drugs such
as Stevens-Johnson syndrome, psychosis and other
hypersensitivity reactions are very rare in children in
usual doses. If they occur, the most probable offending
drug is withdrawn. Most of the other side effects are
minor and self limiting and treated symptomatically.
Thiacetazone is not recommended for use in tuberculosis
of children because Stevens-Johnson syndrome is more
likely to occur when there is associated HIV/AIDS
infection.
HIGHLIGHTS
It is feasible to classify children with tuberculosis in
different categories for different antituberculosis
regimens.
Children should be followed up at least every 4 weeks
to judge the response to treatment, early detection of
treatment failure and side effects of medication.
Clinical parameters are main indicators of
improvement.
For pulmonary tuberculosis, X-ray film may be
repeated after 8 weeks of starting the treatment, and
thereafter, only if warranted clinically earlier, and
the 2nd film at the end of therapy.
Important toxic effects of ATT include hepatotoxicity.
Ocular toxicity and hypersensitivity reactions are
rare.
482
Hepatotoxicity is managed by stopping INH, RIF
and PZA with weekly monitoring of transaminases,
the drugs can be restarted gradually starting with
rifampicin.
Rare indications for withholding antituberculosis
drugs include hypersensitivity reactions, such as
Stevens-Johnson syndrome and psychosis.
REFERENCES
1. Kabra SK, Lodha R, Seth Vimlesh. Category based
treatment of tuberculosis in children. Indian Pediatr 2004;
41:927-37.
2. Chauhan LS, Arora VK. Management of pediatric
tuberculosis under the Revised National Tuberculosis
Control Program (RNTCP). Indian Pediatr 2004;41:9016.
3. Prasad K, Singh MB. Corticosteroids for managing
tuberculous meningitis. Cochrane Database Syst Rev
2008;(1):CD002244.
4. Toppet M, Malfroot A, Derde MP, et al. Corticosteroids
in primary tuberculosis with bronchial obstruction. Arch
Dis Childhood 1990;65:1222-6.
5. Galarza I, Cafiete C, Granados A, et al. Randomised trial
of corticosteroids in the treatment of tuberculous
pleurisy. Thorax 1995;50:1305-7.
6. Strang JIG, Nunn AJ, Johnson DA, et al. Management of
tuberculous constrictive pericarditis and tuberculous
pericardial effusion in Transkei: results 10 years followup. Q J Med 2004;97:525-35.
7. Hawkey CR, Yap T, Pereira J, et al. Characterization and
management of paradoxical upgrading reactions in HIVuninfected patients with lymph node tuberculosis. Clinic
Infec Diseases 2005;40:1368-71.
8. Kabra SK, Ratageri VH. Tuberculosis in children:
Monitoring of treatment and management of side effects.
Paediatr Today 1999;2:81-4.
9. Starke JR, Smith MHD. Tuberculosis. In: Feigin RD,
Cherry JP, Dammeler GJ, Kaplan SL (Eds): Textbook of
pediatric infectious diseases (5th edn). Philadelphia: WB
Saunders 2004; 1337-70.
10. Seth Vimlesh. Clinico-immunoradiological spectrum:
Management. In: Seth Vimlesh (Ed): Essentials of
tuberculosis in children (1st edn). New Delhi: Jaypee
Brothers, Medical Publishers 1997;312-33.
10a. Seth Vimlesh, Kabra SK, Seth Rachna. Clinicoimmunological profile: Indian scenario. In Seth Vimlesh,
Kabra SK (Ed): Essentials of tuberculosis In children (3rd
edn). New Delhi: Jaypee Brothers Medical Publishers
2006;95-105.
11. Mukhopadhyaya S, Gupta AK. Imaging in Childhood
Tuberculosis. In: Seth Vimlesh, Puri RK, Sachdev HPS
(Eds): Tuberculosis in Children. Indian Academy of
Pediatrics 1991;95-132.
12. Ramachandran P, Kripasankar AS, Duraipandian M.
Short-course chemotherapy in pulmonary tuberculosis
in children. Ind J Tub 1998;45:83-7.
13. Starke JR. Current concepts of epidemiology, diagnosis
and treatment of childhood tuberculosis in the United
States. Ind Pediatr 1991;28:335-55.
14. Seth Vimlesh, Jain RC. Drug resistant tuberculosis. In:

Sachdev HPS, Choudhary P (Eds): Frontiers in Pediatrics
(1st edn). New Delhi: Jaypee Brothers Medical Publishers
1996;139-56.
15. Treatment of Tuberculosis: Guidelines for National
Programs. Geneva: World Health Organization 1993.
16. Marri MR, Kirkpatrick MB. Erythrocyte sedimentation
rate in childhood tuberculosis: Is it still worthwhile? Int
17. Centers for Disease Control and Prevention (CDC).
Severe isoniazid-associated liver injuries among persons
being treated for latent tuberculosis infection-United
States, 2004-2008. MMWR Morb Mortal Wkly Rep
2010;59:24-5.
18. Frydenberg AR, Graham SM. Toxicity of first-line drugs
for treatment of tuberculosis in children: review. Trop
Med Int Health 2009; 14:1329-37.
19. Rugmini PS, Mehta S. Hepatotoxicity of isoniazid and
rifampicin in children. Indian Pediatr 1984;21:119-26.
20. Tsagaropoulou-Stinga H, Mataki-Emmanouilidou T,
Korida-Kavalioti S, et al. Hepatotoxicity reactions in
children with severe tuberculosis treated with isoniazidrifampicin. Pediatr Infect Dis J 1985;4:270-3.
antitubercular drugs. Indian J Med Res 1989;89:306-9.
22. Rahajoe NN, Rahajoe N, Boedman L, et al. The treatment
of TBM in children with a combination of isoniazid,
rifampicin and streptomycin: A preliminary report.
Tubercle 1979;60:245-50.
23. Seth Vimlesh, Arya DS, Seth SD, et al. Pharmacokinetic
of pyrazinamide in pulmonary tuberculosis in children.
In: Choudhary P, Puri RK, Sachdeva HPS (Eds): Scientific
abstract of the 8th Asian Congress of Pediatrics and XXXI
National Congress of Indian Academy of Pediatrics. New
Delhi: Jaypee Brothers Medical Publishers 1994;111.
24. Byrd RB, Hom BR, Solomn DA, et al. Toxic effects of
isoniazid in tuberculosis chemotherapy role of
biochemical monitoring in 1000 patients. JAMA
1979;241:1239-41.
25. Starke JR. Tuberculosis in children. Diagnosis and
treatment. Annals Nestle 1997;55:10-23.
26. Turktas H, Unsal M, Tulek M, et al. Hepatotoxicity of
antituberculosis therapy (rifampicin, isoniazid and
pyrazinamide) or viral hepatitis. Tubercle Lung Dis
1994;75:58-60.
27. Kumar R, Mishra PK, Mehrotra R, et al. Hepato-toxicity
of rifampicin and isoniazid: Is all drug induced hepatitis?
Am Rev Respr Dis 1991;143: 1350-2.
28. OBrien RJ. Hepatotoxic reaction to antituberculous
drugs: adjustments to therapeutic regimens. JAMA 1991;
265:23-33.
29. Reed MD, Blumer JL. Clinical pharmacology
of antituberculosis drugs. Pediatr Clin North Am
1983;30:177-99.
30. Grahm SM, Daley HM, Banerjee A, et al. Ethambutol in
tuberculosis: Time to reconsider. Arch Dis Child
1998;79:274-8.
31. Seth Vimlesh, Khosla PK, Semwal OP, et al. Visual evoked
responses in tuberculosis in children on ethambutol
therapy. Indian Pediatr 1991;28:713-7.

32. Thee S, Detjen A, Quarcoo D, et al. Ethambutol in
paediatric tuberculosis: aspects of ethambutol serum
concentration, efficacy and toxicity in children. Int J
33. Donald PR, Maher D, Maritz JS, et al. Ethambutol dosage
for the treatment of children: literature review and
recommendations. Int J Tuberc Lung Dis 2006; 10:1318-30.
34. Trbucq A. Should ethambutol be recommended
for routine treatment of tuberculosis in children? A
483
review of the literature. Int J Tuberc Lung Dis 1997;

1: 12-7.
35. Pellock JM, Howell J, Kendig EL Jr, et al. Pyridoxine
deficiency in children treated with isoniazid. Chest
1985;87:658-61.
36. Cilliers K, Labadarios D, Schaaf HS, et al. Pyridoxal-5phosphate plasma concentrations in children receiving
tuberculosis chemotherapy including isoniazid. Acta
Paediatr 2010;Feb 8.
35
Consensus Statement on Childhood

Tuberculosis2010 IAP Working
Group on Tuberculosis
YK Amdekar
Justification: Revised National Tuberculosis Control

Program (RNTCP) has focused on adults with smear
positivitya tool not so well used in children with
tuberculosis.
There is a need to redefine standardization of
diagnosis and management protocols for childhood
tuberculosis.
Process: Indian Academy of Pediatrics (IAP)
constituted a working group to develop consensus
statement on childhood tuberculosis (TB). Members of
the group were given individual responsibilities to review
the existing literature on different aspects of the childhood
TB. The group deliberated and developed a consensus
which was circulated to all the members for review.
Efforts were made to ensure that the recommendations
are standardized.
Objectives: To produce recommendations and
standard protocols for reasonably accurate diagnosis and
rational treatment of tuberculosis in children.
Recommendations: Fever and/or cough >2 weeks with
loss of weight and recent contact with an infectious case
should arouse suspicion of TB. Chest X-ray and trial with
broad-spectrum antibiotic for 7 to 10 days is justified. In
case of clinical and radiological nonresponse, Mantoux
test and sputum or gastric aspirate for AFB
is recommended. If AFB is positive, diagnosis is
confirmed. If AFB is negative but chest X-ray
is suggestive and Mantoux test is positive, it is a probable
case. If these tests are negative, alternate diagnosis must
be sought and referral made to an expert. Ideally, it is
recommended to use 1TU of PPD for Mantoux test but 2
or 5 TU may be acceptable (but less preferred). Cut-off
point of 10 mm for natural infection may be used for test
done with 1, 2 or 5 TU. There is no linear relation of
reaction to tuberculin strength and so no more than 5 TU
should be used. BCG test is not recommended. Diagnosis
must not be made without an attempt to look for AFB in
gastric aspirate or sputum, as it is possible to get AFB
even in primary complex. ELISA and PCR tests for TB
are not recommended. There is no place for trial of
antitubercular therapy.
Lymphnode enlargement >2 cm with or without

typical findings suggestive of TB and failure of antibiotic
response demands FNAC for histopathology and
bacteriology. Clinical suspicion of tubercular meningitis
(TBM) should be confirmed by CSF examination and CT
scan though none of these investigations are confirmatory
and hence should not be considered in isolation. CSF tests
for TB antibody and PCR are not recommended for
routine use. Diagnosis of abdominal TB is made on
circumstantial evidence and there are no standard
guidelines.
For treatment, disease is divided into three categories.
The Category I and III are recommended for different
types of new cases, i.e. those who have received treatment
for not more than 4 weeks. Category III includes primary
pulmonary complex, one site peripheral lymphadenitis
and pleural effusion, while all other forms of TB are
included in Category I that corresponds to smear positive
TB in adults. This is because AFB is often found in many
Category I disease in children. Category II includes
defaulters, relapses and failure cases irrespective of the
site of disease.
Standard protocol is followed for each of these
categories. Intermittent thrice weekly therapy with higher
dose has been found to be equally effective as daily
therapy and so is recommended in DOTSDirectly
Observed Therapy Short-term. Compliance of treatment
must be ensured. Repeat chest X-ray is ideal at the end of
therapy. Liver function tests are not routinely
recommended. Recommendations are also made for
special situations such as MDR-TB, TB and HIV and
neonate born to a mother suffering from TB.
Tuberculosis is a single major infectious disease
causing significant morbidity and mortality amongst all
humans including children. Three sets of guidelines
related to the management of childhood tuberculosis have
been produced by the various consensus groups of the
IAP since 1997,1-3 with the last one coming out in 2004.3
Cases were classified into three categories, as per WHO
and Revised National Tuberculosis Control Program
(RNTCP) guidelines. These guidelines also addressed the
Reproduced with permission from Indian Pediatrics 2010;27:41-55.
Chapter 35 Consensus Statement on Childhood Tuberculosis
485
issue of intermittent therapy and direct observation of

therapy.
OBJECTIVES
In consonance with the decision of Indian Academy of
Pediatrics to standardize and update the protocols for
diagnosis and treatment of childhood tuberculosis, a
meeting of IAP Working Group was held in Mumbai on
26th and 27th April 2008. Members of the Group were
given individual responsibilities to review the existing
literature on different aspects of the childhood TB and
present the review to the Group. The Group deliberated
in the light of presentations made by the members, based
on literature reviewed, and developed a consensus for
the topics covered.
The deliberations were than written as a draft
document and circulated to all the members for review.
The Group also informally interacted with the different
national and international bodies that were also working
on developing guidelines for TB management to
incorporate the latest changes that were in the offing.
Efforts were made to ensure that the recommendations
are standardized for reasonably accurate diagnosis and
rational treatment of childhood TB.
RECOMMENDATIONS
Pulmonary Tuberculosis When to Suspect?
Figure 35.1 depicts the diagnostic algorithm for
pulmonary tuberculosis in a child.
Fever and/or cough of recent onset lasting for >2
weeks should arouse suspicion of tuberculosis. It is
important to document fever and not depend merely on
impression. Fever can be of any type and the oftendescribed evening rise of temperature is neither specific
to this etiology nor commonly present. Cough can be dry
or moist and may be severe. Cough persisting beyond 2
weeks, particularly as an only symptom in an otherwise
healthy child can be due to viral infection and is often
not due to TB. Such children, therefore, do not always
warrant investigations. Recurrent symptoms with normal
intervening period are less likely to be due to
tuberculosis. Recent loss of appetite may be relevant but
unexplained recent loss of weight can be an important
pointer to the suspicion of tuberculosis. A static weight/
not growing well are not significant pointers to this
disease. History of contact with an infectious TB patient
(smear positive) should always prompt detailed
examination for likelihood of the disease. However, in a
symptomatic child, contact with a person with any form
of active tuberculosis within last two years may be
significant.
Diagnosis is also more likely in presence of risk factors
such as recent history of measles or whooping cough and
Fig. 35.1: Algorithm for diagnosis of tuberculosis in children
immunocompromised state including steroid therapy.

Persistent lower respiratory infection not responding to
antibiotic therapy may point to a probable diagnosis of
tuberculosis. Significant superficial lymphadenopathy
must be specially looked for, as it may often coexist.
For a clinically suspected case, further investigations
are necessary. Diagnosis of tuberculosis should never be
made only on clinical features. The above mentioned
features in isolation or in combination should only make
you suspect TB. Therapeutic trial with anti-TB drugs is
therefore, not recommended and instead every attempt
must be made to prove the diagnosis.
Tuberculin Test
The standard tuberculin test recommended for use is the
Mantouxs test. Commercially available tuberculin in the
country are 1, 2 and 5 Tuberculin Unit (TU) PPD (RT23
486
equivalent). It is important to raise a wheal of about 6

mm after the intra-dermal injection and the test is read
48 to 72 hours after an injection. Ballpoint or palpatory
methods are used to read the induration.
The width of reaction (induration) in the horizontal
plane is noted for interpretation. (see annexure for details)
Mantouxs test or PPD skin test is considered positive if
the induration is 10 mm or more. This cut-off was
recommended using a 1 TU PPD RT23.
Currently the laboratories more often use 5 TU PPD
(RT23 equivalent) or sometimes even some other higher
strengths or types of PPD are used. The standard cut-off
of 10 mm can actually not be justified for any higher
strength of PPD used. The reaction evoked is not
dependent on the amount of antigen given but also does
not have a linear relationship with the increasing
strengths. Therefore, the current practice may actually
lead to an increase in false positive reactions using the
10-mm cut-off with the higher strength of PPD. The
Group recommends that the 10-mm cut-off may be
continued to use for strengths of PPD only up to 5TU.
Efforts should be made to use only 1 TU PPD to decrease
the false positives4 and in no case strength higher than 5
TU should be used. Degree of reaction, including necrosis
and ulceration, may not necessarily differentiate infected
from diseased. Prior BCG vaccine has minimal influence
on PPD reaction.5,6
If the patient returns for reading beyond 72 hours but
by 7th day, a positive test can still be read. A repeat test
may be needed, if there is no induration and the suspect
presents beyond the stipulated time for reading. Repeat
tuberculin test when required should preferably be done
on the other arm. The reading of the same should be
interpreted as in any other individual.
BCG Test
BCG test is not recommended in diagnosis of
tuberculosis.7
Chest Radiograph
Chest radiograph merely localizes the site of pathology
and not etiology. There are no pathognomonic
radiological signs of tuberculosis. In relevant clinical
setting, certain radiological lesions may strongly suggest
tuberculosis and they include miliary, hilar or
paratracheal lymphadenopathy with or without
parenchymal involvement and fibrocaceous cavitatory
lesions. Rarely chest X-ray may be normal, such cases
should be referred to an appropriate center for further
detailed investigations, if the clinical suspicion is high.
In clinical practice, nonresolving chest shadows
despite adequate antibiotic therapy in a symptomatic
child raises the possibility of tuberculosis. It is worth
mentioning that all persistent radiological lesions are not
necessarily due to TB. Asymptomatic patients may have

persistent shadows due to parenchymal scarring, pleural
thickening, and healed fibroatelectatic changes. On the
other hand, a child with bronchiectasis or an interstitial
lung disease may have presence of nonresolving
shadows with persistent symptoms.
Ultrasonography of chest is helpful to assess pleural
fluid collection; although decubitus chest X-ray film may
also reveal similar information. CT scan is rarely
necessary and is not cost and radiation effective. Chest
CT scan, however, may offer an opportunity for CT
guided biopsy for tissue diagnosis.
Bacteriology
Demonstration of AFB from any body fluid or tissue is
the gold standard of diagnosis of tuberculosis. Such a
proof is often lacking in childhood tuberculosis because
of difficulty in collection of sputum and due to
paucibacillary primary disease in children. However,
studies do report that the yield of a positive test in
advanced cases may be as high as in adults.
Few studies have reported as high as 33%
bacteriological positivity even in primary disease such
as hilar adenopathy.8,9 Therefore, every attempt must be
made to bacteriologically prove the diagnosis in every
case of suspected tuberculosis.
Early morning gastric aspirate is a preferred specimen
for most young children with suspected TB for detecting
AFB or isolating M. tuberculosis. The child is kept fasting
for about 6 hours (at night) and an appropriate size intragastric tube is passed in the morning. Initially the aspirate
is drawn from the stomach and then a further washing
with 15 to 30 ml saline is taken. The contents so recovered
are then immediately transferred to the laboratory. This
specimen can also be collected as an ambulatory
procedure after 4 to 6 hours fasting.10 Sputum collection
is possible in older children with extensive and cavitatory
disease, particularly if the patient has a wet cough.
Induction of sputum by 3% nebulized hypertonic saline
can be tried in older children (after the age of 4 months).
The patient is pretreated with nebulized bronchodilators
prior to induction. Following saline nebulization, chest
physiotherapy is done to loosen up the secretion and the
samples are collected from the throat or nasopharynx.11
Whichever method one chooses to use, one needs to
collect at least two, preferably three, samples.
Where the facilities are limited, these tests may be
prioritized and at least be done in all children with wet
cough or children who have definite parenchymal lesion
on chest skiagram. Experience with bronchoscopy and
BAL as a diagnostic tool is limited but it is often needed
when evaluating a persistent pneumonia. TB remains an
important cause of persistent pneumonia in our
country.12

Ziehl-Neelsen stain can reveal AFB only if sample
contains >10,000 bacilli per ml. Different culture methods
are used, such as LJ medium, Radiometric (BACTEC) and
Nonradiometric (MGIT) can be used for confirming
diagnosis in paucibacillary state. The newer methods are
capable of giving faster results and may be used if
available. Mycobacterial culture assumes special
significance in case of suspected drug resistance.
Serodiagnostic Tests
As mycobacterial antigens overlap in different stages of
infection and disease, there are no specific antigens that
can confirm natural infection or active disease. Besides,
antigen tests vary widely and are often negative in
paucibacillary disease. Antibody tests share similar
problems for interpretation and in addition cannot
differentiate natural infection from BCG vaccine induced
infection and active disease from old healed disease.
Thus, both antigen and antibody TB ELISA tests are
poorly sensitive and specific and are not recommended
for diagnosis of tuberculosis.13
Interferon Gamma Release Assays (IGRAs)

A newer generation of tests which measure the
production of interferon gamma by the peripheral
mononuclear cells have been developed to identify the
patients with TB disease or latent infection. These use
two antigens, early secretion antigen target (ESAT 6) and
culture filtrate protein 10 (CFP 10), which are specifically
present only in Mycobacterium tuberculosis and not in other
mycobateria or the BCG vaccine strain. These tests
though have a principle similar to skin test but do away
with the need for a repeat visit by the patient for reading
purposes.14 QuantiFERON Gold and T spot are two of
the commercially available IGRAs. These are being used
in place of the skin test in low prevalence countries to
detect latent TB infection. However, these expensive tests
do not differentiate the TB infection from disease. Its exact
utility in high burden situation is still not clear.15,16
TB Lymphadenitis
Clinical correlate of diagnosis includes progressive
enlargement of lymph node for more than 2 weeks, firm,
minimally tender or not tender, fluctuating, further may
get matted and develop chronic sinus formation.
Mantoux test is mostly positive in a significant
proportion. Fine needle aspiration cytology (FNAC) is
usually adequate for accurate diagnosis and it correlates
well with biopsy in >90% of cases.18,19 Histopathology,
typically, shows necrosis and epitheloid granuloma. It
is important to look for AFB in FNAC specimen and it
may be positive in 20 to 70% of patients. When FNAC is
inconclusive, biopsy is necessary for confirmation of
diagnosis. In children lymphadenopathy is common due
to recurrent tonsillitis and URIs as well. Reactive
lymphadenitis may closely clinically mimic tuberculosis
but do not warrant anti-TB drugs. Hence anti-TB drugs
should not be given unless the diagnosis of TB is
confirmed by FNAC or histopathology (Fig. 35.2).
Pleural Effusion
If chest X-ray is suggestive of pleural effusion, pleural
aspiration should be performed for biochemical,
cytological and smear examination by ZN stain to
confirm the diagnosis. Typically, a tubercular effusion
fluid is straw colored (pus, if aspirated, is very rarely
PCR Test
Nucleic acid amplification tests using polymerase chain
reaction (PCR) cannot differentiate living from dead
bacilli and so continues to be positive even after
successful treatment. PCR is positive in 95 to 100% of
culture positive cases but only in 50 to 60% of culture
negative cases. It may be false positive in 1 to 30% of
cases. Thus no decisions can be made only on the basis
of PCR tests and hence these tests are not recommended
in clinical practice.17
487
Fig. 35.2: Diagnostic algorithm for tubercular lymphadenitis
488
due to TB etiology) has large numbers of cells (in

hundreds; predominantly mononuclear), with high
proteins (>3 g/dl). Adenosinedeaminase (ADA) levels
over 60 IU/l may be suggestive of tuberculous pleural
effusion but is not diagnostic of TB.20,21 Pleural biopsy
may be performed, where facilities are available,
particularly when the fluid aspirate findings are
inconclusive.
Tubercular Meningitis (TBM)

Children with TBM present with a rather longer (>1
week) duration of fever, with vague CNS symptoms such
as behavior changes, irritability, drowsiness, headache,
vomiting and seizures. Physical examination reveals
typically global encephalopathy with focal deficits,
hydro-cephalus and movement disorder. Risk factors for
TBM include age <5 years, contact with an adult suffering
from tuberculosis, PEM grade III and IV, and HIV
infection.
Typically CSF is clear, usually does not show very
high cell count (under 500 cells/cumm) with
lymphocytosis. Biochemical investigations reveal
increased proteins and mild reduction in glucose. The
typical CSF picture may, however, not always be seen.
Furthermore, the typical CSF picture described above can
also be mimicked by partially treated pyogenic
meningitis. In such a situation, CSF can be repeated after
48 to 72 hours of treatment with a fresh set of broad
spectrum potent antibiotics to evaluate change in clinical
status as well as in CSF. During this time, efforts are made
to establish the diagnosis by collecting more evidence
using PPD, chest skiagrams, and bacteriological
diagnosis from appropriate samples including CSF.
Many a time concomitant TB lesions elsewhere in the
body (say, pulmonary) coexist and can clinch the
diagnosis. Mycobacterial culture from CSF should also
be attempted but CSF culture has poor sensitivity (16%)
though specificity is high (90%).
Neuroimaging is an important diagnostic modality.
It may reveal one or more of the following findings: basal
meningeal enhancement; hydrocephalus with or without
periventricular ooze; tuberculoma(s); or infarcts may be
seen in different areas, especially in basal ganglia.
Normal CT scan does not rule out TBM and in case of
strong clinical suspicion of diagnosis, a repeat follow-up
CT scan after few days may show newly developing
lesions. CSF abnormalities in TBM may take variable time
up to few months to return to normal. Besides routine
CSF examination. CSF adenosinedeaminase (ADA) is
high in TBM. Various studies have a cut-off point
between 7 and 11.3 IU/L for diagnosis. This may offer
supportive evidence in favor of TBM but should not be
taken in isolation.22 CSF antigen and PCR tests are neither
routinely available nor reproducible. They are, therefore,

not recommended. CSF antibody tests have poor
sensitivity and specificity and hence are not useful.
Tuberculoma
Often seen in older children, it may present as a focal
seizure in supratentorial cortical lesion or with symptoms
and signs of raised intracranial tension with multiple
localizing signs and hydrocephalus in posterior fossa
lesion. It may sometimes also be seen as a part of TB
meningitis.
Differentiation from other ring lesions, especially
neurocysticercosis (NCC) is difficult in cortical lesion. A
ring enhancing lesion is not pathognomonic of
tuberculoma. A larger lesion >20 mm, disc lesion or ring
lesion with thicker rim with central nodule favors
tuberculoma while multiple, smaller, thin rim with
epicentric nodule favor NCC. MR spectroscopy may help
in diagnosis of tuberculoma as it shows lipid peak.
It may present as localized disease such as mesenteric
lymphadenopathy, intestinal disease, peritoneal
involvement or systemic disseminated disease presenting
as hepatosplenomegaly. Large matted lymph node mass
may be clinically evident and ultrasound guided biopsy
may help in confirming the diagnosis.
There are no standard guidelines for sonography
diagnosis of abdominal tuberculosis. However,
corroborative evidence includes: echogenic thickened
mesentery with lymph nodes >15 mm in size; dilated
and matted bowel loops; thickened omentum, and
ascites.23 Barium follow-through examination may be
suggestive of intestinal disease but is not confirmatory.
Exudative peritoneal disease presents as ascites that is
often clinically evident. The ascetic tap should always
be done in such situations and the fluid tapped is an
exudate, typically showing lymphocytic predominant
cellular response with high proteins (>3g/dl).
Treatment of Tuberculosis
Basis of Pharmacotherapy
Choice of anti-TB drugs is based on several determinants
such as bacillary and metabolic subpopulation, bacillary
load, drug resistant strains, lag period of bacterial
population, pharmacokinetic profile and pathological
factors. There are different types of bacillary population
in every case of tuberculosis and hence drugs are
selected in a combination to attack entire (extracellular
and intracellular, slow and rapidly growing) bacillary
population for successful chemotherapy. Isoniazid

(INH) and rifampicin (RMP) kill the fast growing bacilli,
pyrazinamide (PZA) take care of intracellular organisms
in acidic medium while extracellular slow growing
bacilli are best killed by RMP. Thus every case of
tuberculosis must be treated at least with these three
drugs. The chances of naturally occurring mutants are
higher if the bacillary load is more and therefore, such
cases need more drugs in intensive therapy, say as in
smear positive cases.
As dividing time of TB bacilli is about 21 hours, all
the drugs are administered in such a way that they
achieve peak concentration all at one time so as to hit
bacilli hard. The drug concentration is poor in caseum
and sequestrated tissue, so these should be removed
surgically wherever feasible.
Mycobacterium tuberculosis when exposed to certain
concentration of most currently used anti-TB drugs in
vitro shows an inhibition of growth for 1 to several days.
This suggests that the drugs can be effective even when
used on an intermittent basis as a continuous high serum
level of these drugs is not needed. This forms the basis
of intermittent therapy. While RCTs in children using
thrice weekly regime are awaited, RCTs from adults as
well as observational studies including programatic data
in all age groups have shown that intermittent thrice a
week therapy with higher dose is as effective as daily
therapy with conventional dose and is an effective
alternative.24 However, intermittent therapy is not safe
when self-administered, as there is no margin for any
error in taking medications. The directly observed
therapy under DOTS takes care of the adherence issues
and therefore uses thrice a week intermittent therapy.
Antitubercular Therapy
The appropriate management of tuberculosis requires
assessment of the patient correctly with respect to the
site of disease, bacteriological status, treatment type of
patient and the severity of disease. These definitions are
detailed in Table 35.1. After appropriately defining the
disease, the patient is then categorized to receive
appropriate anti-TB therapy (Table 35.2). The drug
dosages are given in Table 35.3.
The Group agreed to include all children with
extensive pulmonary lesions (anything beyond the
primary pulmonary complex) under Category I because
of the evidence and experience that a significant
proportion of these turn out to be smear positive when
diligent efforts are made. It is only milder forms of the
disease, also more likely to be paucibacillary, such as
primary complex (mediastinal or hilar lymphadenitis
with or without a parenchymal lesion, single site
peripheral lymphadenitis and unilateral pleural effusion
that are treated as Category III.25
489
In case of delayed response to assigned therapy,

intensive phase may be prolonged by one more month
in Category I and II. Similarly, continuation phase may
have to be prolonged by 3 months for TB meningitis,
miliary and spinal TB. There are studies to suggest that
6 months therapy may be adequate in these situations
as well. Yet, the group felt that the prolongation of the
continuation phase is justified in these situations as (a)
the lesions may take longer to sterilize in such
pathology, and (b) due to the risk of serious morbidity
associated with relapse.
Category II therapy utilizes all the first line drugs as
it is used to treat relapsers, treatment defaulters and
treatment failures who are more likely to have drug
resistance. It is generally considered to add two drugs to
the failed regime till culture and drug sensitivity reports
are available. However, this categorization can also mean
addition of a single drug Streptomycin to a failed
regime (say a Category I failure). Evidence suggests that
most common drug resistance is limited to first line drugs
singly or in combination and the multidrug resistance
with bacilli resistant to at least INH and rifampicin is
relatively uncommon (<5%). Therefore, except for
multidrug resistance, this regime would work well for
most. Complete adherence to therapy being the key to
achieving cure and decreasing the chances of
development of resistance, this is imperative that the
treating pediatrician makes all efforts to ensure
compliance. DOTS provide a great opportunity for the
same. Patients who are nonresponsive to a wellsupervised Category II are likely to have MDR-TB and
should therefore be referred to an appropriate facility.
The above definition, categorization and duration of
therapy should be used for every child with TB whether
the patient is under individual care or under the program.
This protocol should form the current standard of care
and should override all earlier recommendations.
Steroids in Tuberculosis
Definite indications for concomitant steroid therapy
include TBM and pericarditis. Steroids are routinely not
indicated in lymphadenitis and pleural effusion. They
may be used in endobronchial tuberculosis or mediastinal
compression syndrome due to tuberculosis, pleurisy with
severe distress and miliary disease with alveolocapillary
block. Predinsone 2 to 4 mg/kg/day or its equivalent is
used for 2 to 4 weeks and then tapered over next 2 weeks.
Fixed Drug Combination (FDC)

These combinations contain 2 or more drugs in a single
formulation and therefore simplify the prescription of
490
Table 35.1: Definitions for categorizing for treatment of pediatric TB
A. Case definitions for site
Pulmonary: Refers to disease involving lung parenchyma.
Extrapulmonary: Refers to disease involving sites other than lung parenchyma
Both pulmonary and extrapulmonary constitutes
Pulmonary extrapulmonary involving several sites is defined by most severe site.
B. Case definitions for severity
Pulmonary TB
Severe Pulmonary TB
All other except PPC, e.g.
Progressive primary disease
Fibrocavitatory disease
Miliary
Extrapulmonary TB
Severe extra Pulmonary TB Meningitis, Spinal or Bone or
Peripheral joints
Bilateral or extensive pleural effusion
Intestinal
Genitourinary
Peritonitis
Pericarditis
Adrenal glands
Less severe Pulmonary TB

Primary Pulmonary Complex (PPC)
Less severe extra pulmonary TB

Single Lymph node site
Unilateral pleural effusion
C. Case definition for bacteriology

Smear positive: Sputum / Gastric aspirate /BAL/any other tissue or fluid
Any sample positive for acid-fast bacilli on staining
Smear Negative: None positive
D. Type of patient as per history of previous ATT
New case
Relapse
Treatment failure
Treatment after default
:
:
:
:
A patient who has had no previous ATT or for less than 4 weeks.
Patient declared cured/completed therapy in past and has evidence of recurrence.
Patient who fails to respond/deteriorates after 12 weeks of compliant intensive phase.
A patient who has taken treatment for at least 4 weeks and comes after interruption of treatment
for 2 months and has active disease.
drugs. More importantly, they limit the risk of drugresistant tuberculosis arising as a result of inappropriate
drug selection due to prescription errors or due to
omission of some drugs by the patient. FDC is patient
friendly but there are some relevant issues about them.
Bioavailability of liquid formulations is not dependable.
One of the problem with FDC is that it is fixed and
makes titration of individual drug dosage difficult. While
the combination of rifampicin and INH as a single
formulation are still well accepted, the bioavailability of
individual components, particularly rifampicin, may be
affected in other 3 or 4 drugs FDC formulations. It is
reported that in most situations, blood levels of the drugs
are inadequate because of poor drug quality rather than
poor absorption. 26 Currently, there are several
formulations available with varying combinations with
confusing and similar sounding brand names. This could
make the prescription not simplified but error prone.
FDCs from standard manufacturers with proven
bioavailability should only be used.
CURRENT TRENDS IN CHEMOTHERAPY OF TB UNDER

REVISED NATIONAL TB
Control Program (RNTCP)27,28
TB is considered a global emergency and in countries
like India, despite effective chemotherapy, control has
not been achieved due to poor therapeutic practices.
The emerging threat of poorly treatable rifampicin
resistant TB warrants that the first line drugs be
used appropriately to give them longevity in the
armamentarium. RNTCP has evolved to take care of
these problems by using DOTS strategy. This includes
quality diagnosis by sputum microscopy, supervised
drug therapy (thrice weekly visits in intensive phase
followed by weekly visit to the clinic during
continuation phase when one dose is administered
under supervision and two doses are given to the patient
to be taken at home subsequently), regular drug supply,
patient tracking (progress to be monitored till end of
491

Table 35.2: Treatment categories and regimens for childhood tuberculosis
Category of treatment
Category I
Type of patients
Category II
Category III
Intensive phase
Continuation phase
New smear-positive pulmonary

Tuberculosis (PTB)
New smear-negative severe
forms of PTB
New severe forms* of
extrapulmonary TB
Smear-positive relapse, treatment
failure or treatment after default
Cases who are smear negative but
considered to have relapse,
treatment failure or defaulted
Less severe forms of
pulmonary TB*
Less severe forms of
extrapulmonary TB*
HRZE (2 mo)
HR (4 mo)
SHRZE (2 mo)+
HRZE (1 mo)
HRE (5 mo)
HRZ (2 mo)
HR (4 mo)
H = INH, R = Rifampicin, Z = Pyrazinamide, E = Ethambutol, S = Streptomycin

*Refer Table 35.1 for details of severity
In patients with TB meningitis on Category I treatment, the four drugs used during the intensive phase can either be HRZE or
HRZS. The present evidence suggests that ethambutol can be used in children.
Continuation phase of treatment in TB meningitis, miliary and spinal TB with neurological complications should be given for 6-7
months, extending the total duration of treatment to 8-9 months.
Under Revised National Tuberculosis Program (RNTCP) all patients shall be covered under directly observed intermittent (thrice
weekly) therapy. While the supervised therapy is considered the most optimal treatment, this very same combination of drugs can
also be used on a daily basis, for a similar duration, in case the treatment is being given unsupervised. It is important to ensure
completion of treatment in every case put on treatment to prevent emergence of resistance, particularly to rifampicin.
Table 35.3: Antituberculous drugs, dosages and adverse effects

Drug (symbol)
Daily dosages per

Kg body weight
Maximum per
day dose (daily
regime)
Intermittent
thrice weekly
dosage as under
RNTCP per Kg
body weight
Maximum per
day dose
(intermittent
regime)
Streptomycin (S)
Rifampicin (R)
15-20 mg
10 mg
1000 mg
600 mg
20 mg
15 mg
1000 mg
600 mg
Isoniazid (H)
5-10 mg
300 mg
15 mg
600 mg
Pyrazinamide (Z)
30-35 mg
2000 mg
35 mg
2000 mg
Ethambutol (E)
20 mg
1000 mg
30 mg
1200 mg
therapy) and administrative and political commitment.

Each patient on diagnosis has an entire box of drugs
allocated with his name on it, though not handed over,
to ensure supervised uninterrupted therapy. The Indian
program is the first program in the world to provide
pediatric patients weight wise boxes for childhood TB
cases and the pediatricians should help their patients
in using these facilities.
Major side
effects
tinnitus
hepatotoxicity
gastritis, flu
like illness
peripheral
neuropathy,
hepatoxicity,
arthralgia,
hepatotoxicity,
oculotoxicity
Chemoprophylaxis
It is estimated that in developing countries the annual
risk of tuberculosis infection in children is 2 to 5%.29 The
estimated lifetime risk of developing tuberculosis disease
for a young child infected with Mycobacterium tuberculosis
as indicated by positive tuberculin test is about 10%.30
About 5% of those infected are likely to develop
disease in the first year after infection and another 5% in
492
rest of their lifetime. These rates increase in HIV infected

individuals. Nearly 8 to 20% of the deaths caused by
tuberculosis occurring in children.31 The age of the child
at acquisition of tuberculosis infection has a great effect
on the occurrence of tuberculosis disease.
Approximately 40% of infected children less than 1
year of age if left untreated develop radiologically
significant lymphadenopathy or segmental lesions
compared with 24% of children from 1 to 10 years and
16% of children from 11 to 15 years of age.32
Six months of chemopropylaxis is recommended for
all under 6 years age contacts of an infectious case,
irrespective of their BCG or nutritional status. PPD
positive children over 6 years of age and who do not
have any evidence of active disease but are planned for
immunosuppressive therapy (e.g. children with
nephrotic syndrome, acute leukemias, etc) may also be
given the benefit of chemoprophylaxis. While there is
evidence that HR combination can make the prophylaxis
shorter (3 months) but the group does not recommend
this due to the risk of misuse of rifampicin.
Follow-up During and After Completion of Treatment

With correct evaluation of type of patient, site and
severity of disease and compliant treatment, one can
anticipate clinical and radiological improvement over a
standard time frame. Symptoms of active disease such
as fever, cough and loss of appetite usually disappear
within 2 to 4 weeks. Weight gain is evident only if active
disease had resulted in loss of weight. Children often do
not loose significant weight and so would not show
weight gain even after successful treatment.
The present evidence does not suggest any cost
benefits of repeating X-ray chest at the end of intensive
phase, if the clinical improvement is on expected lines.
Few patients who have persistence of symptoms on
therapy will need investigations for bacteriological and
radiological response. They should be given the benefit
of extension of intensive phase by 4 weeks provided the
alternative diagnosis and comorbidities are ruled out.
At the end of stipulated therapy, patient must be
shown to have achieved cure by demonstrating negative
bacteriology. A chest radiograph at the end of treatment
is desirable to document the radiological status. This may
be helpful to diagnose any subsequent disease in this
high-risk group.
Repeat chest X-ray may sometimes be considered
early in case of unanticipated clinical progress. In the
presence of clinical improvement but radiological
persistence of lesion, it is best to wait for radiological
clearance over time, as it may not signify active disease.
The patient should be followed up every 3 months for at
least one more year for a possible relapse.
Paradoxical upgrading reaction (PUR)worsening

of lesion on treatment or appearance of new lesion is often
seen in TB irrespective of their HIV coinfection. Immune
reconstitution syndrome occurs in HIV infected
individuals on treatment with HAART.
Routine monitoring of liver transaminases in patients
on ATT is not recommended though hepatitis is the
commonest serious drug toxicity seen. As the anti-TB
drugs are hepatic enzyme inducers, asymptomatic
biochemical derange-ment without increase in billirubin
level may be tolerated till the enzymes remain up to 5
times the normal range. However, if patient develops
jaundice or other signs of liver dysfunction during
therapy, its prudent to stop ATT immediately
irrespective of enzyme levels. The drugs are withheld
till the serum bilirubin becomes normal and the enzymes
also start touching the normal range. Although many
patients with drug-induced hepatotoxicity can be
successfully rechallenged, this is best done in a place
where liver function can be carefully monitored. The
drugs should be reintroduced in sequential order starting
with rifampicin, followed by isoniazid and then
pyrazinamide. We add the first drug and reassess for its
impact on liver enzymes. If the enzymes remain within
the acceptable range, then only the subsequent drugs are
added in the given sequence every 5 to 7 days. Some
experts prefer building up the doses of each of the
drug; starting with half the dose and then increasing
to full dose after 3 to 4 days, and then adding the next
drug in half the dose and continuing the same way till
all the drugs are reintroduced. Drugs causing severe
intolerance on reintroduction are best avoided and
substituted with other drugs. If the period without drugs
is likely to be prolonged, and the patient is sick and
requires treatment, at least two other drugs (e.g.
streptomycin, ethambutol, floroquinolones) should be
given until it is determined whether the offending drug
can be resumed. All patients who require alteration from
the standard regimen should be referred to experienced
pediatricians.
Efforts should be made to ensure drug adherence in
every patient. If the patient is under non-DOTS treatment,
then the treating pediatrician should monitor adherence
to therapy and follow-up. At each visit a pill count or
prescription review should be done with the patient or
the caregiver. It is very important to realize that the
emergence of multidrug resistant TB (MDR-TB) is always
a man made problem and failure of the patient to
complete the prescribed course completely and
adequately is one of the major reasons. When you have
a patient who has returned after a break in therapy,
further management becomes difficult. Table 35.4 details
the guidelines for treatment after a period of interruption
in therapy. Whenever treatment is interrupted for more
493
Table 35.4: Managing patients with interruptions in treatment

Duration of therapy
Duration of interruption
Up to 4 weeks
4-8 weeks
>8 weeks
<2 weeks
>2 weeks
<2 weeks
2-8 weeks
>8 weeks
<2 weeks
>2 weeks.
Decision
Review
activity
than 2 weeks, the child should be reassessed clinically

and radiologically, with bacteriological examination,
wherever possible. In all such cases the resumption of
treatment must be preceded by evaluation for activity
and investigating the causes for nonadherence. The
pediatrician should not merely restart the treatment but
also enable the completion of treatment by addressing
issues related to nonadherence in the first instance.
Addressing issues like side effects of the therapy (real or
perceived), cost involved as well as educating about the
need for a complete treatment even after the symptoms
abate may help adherence. Both the child as well as the
caregivers must be involved in decision making for reinitiating treatment.
Special Situations
When to Suspect MDR-TB
It may be suspected prior to starting therapy in case of
contact with proven MDR-TB. It is also likely in a child
who has had one or more courses of ATT in the past or
had been noncompliant with prescribed therapy.
Persistence of positive sputum or symptoms
after extended intensive phase (3 months) in spite
of compliant therapy should alarm you to the possibility
of drug resistant TB and all necessary cultures should
be sent while the patient is put on Category II
therapy. The patients who are nonresponsive to a wellsupervised Category II regime are likely to have MDRTB and should therefore be referred to an appropriate
facility.
Multibacillary lesions are more likely to be drug
resistant than paucibacillary. HIV infection by itself does
not predispose to MDR-TB but the MDR-TB prevalence
is higher in such cases due to several factors.
Malabsorption of anti-TB drugs in such patients may lead
to suboptimal concentration of drugs in spite of
compliance. Due to frequent hospital visits, they may also
come in contact with MDR-TB.
The treatment of MDR-TB should only be done by
experts. The details of the management of MDR-TB in
children are beyond the scope of this consensus
guidelines.
Resume original regime

Reassess and start treatment again
Extend intensive phase by 1 month more
Category II if diagnosis is still TB
Continue same treatment if; no active disease.
Category II therapy for active diseases.
When to Consider HIV Testing

Clinical markers of HIV infection such as oral thrush,
chronic diarrhea, clubbing of nails, herpes infection,
failure to thrive obviously demand HIV testing. Beside
these, history of HIV infection in parents and past history
of blood transfusion justifies HIV testing. In case,
tuberculosis in a child does not respond as anticipated
to compliant treatment, HIV infection may be one of the
causes. HIV testing may be considered especially if there
is no other cause for poor response to treatment.
MANAGEMENT OF A NEONATE BORN TO A MOTHER

WITH TUBERCULOSIS
Prophylactic INH is recommended for newborns born
to mother with tuberculosis after ruling out congenital
tuberculosis. Modern chemotherapy is so efficacious that
separation of the mother and infant is no longer
considered mandatory, once the mothers therapy is
started. Separation should occur only if the mother is ill
enough to require hospitalization, if she has been or is
expected to become nonadherent to her treatment, or if
she is infected with a drug resistant strain of M.
tuberculosis. INH therapy should be continued in the
infant at least until the mother has been shown to be
noninfectious (culture negative) for 3 months. The infant
should receive INH for a total of 6 to 9 months.
Vaccination with BCG appears to decrease the risk of
tuberculosis in exposed infants, but the effect is variable.
The mother can continue to breastfeed the baby. The ATT
excreted in the milk has no therapeutic or adverse effect
on the baby. Appropriate cough hygiene should be
observed by the mother.
GAPS IN KNOWLEDGE
The group strongly identified the following key research
areas which can provide answers to some of the
unresolved issues.
1. Feasibility and utility of induced sputum in children.
2. Tuberculin test and redefining cutoff values for
diagnosis of infection with the different strengths and
formulations available.
494
3. Role of GA in ambulatory setting.

4. Role of Interferon gamma release assays in diagnosis
and assessment of activity in children.
5. Possibility of shorter duration of ATT for CNS/ renal
and bone and joint TB by RCTs.
Finally, in conclusion we submit that the current
guidelines have been developed keeping in mind the
earlier guidelines of IAP, the national program guidelines
and the International standard for TB care. We hope that
guidelines henceforth will form the basis of childhood
TB management in the country in both public and private
sectors.
ACKNOWLEDGMENTS
YK Amdekar, Varinder Singh, Sushil K Kabra and GR
Sethi Following members attended the meeting(s): YK
Amdekar: Convenor; Varinder Singh, GR Sethi, Sushil
Kabra, Mahesh Babu, D Vijayasekaran, Joseph Mathews,
RK Agarwal; President IAP 2008, Panna Choudhury:
President elect IAP 2008; and Rohit Agarwal: Secretary
General IAP 2008.
Funding: The meeting of the group was facilitated by
an academic grant from M/s Lupin Pharma.
Conflict of interest: None of the members of the group
have reported any conflict of interest in the current work
due to their existing or past association with the industry
and other stakeholders (if any).
REFERENCES
1. IAP Working Group. Treatment of childhood
tuberculosis: Consensus statement of IAP working group.
2. IAP Working Group. Consensus statement of IAP
Working Group: Status report on diagnosis of childhood
tuberculosis. Indian Pediatr 2004; 41:146-55.
3. Management of Pediatric Tuberculosis under the Revised
National Tuberculosis Control Program (RNTCP). A joint
statement of the Central TB Division, Directorate General
of Health Services, Ministry of Health and Family
Welfare, and experts from Indian Academy of Pediatrics.
4. Chadha VK. Tuberculin test. Indian J Pediatr 2001;68:53-8.
5. Araujo Z, de Waard JH, de Larrea CF, et al. The effect of
Bacille Calmette-Gurin vaccine on tuberculin reactivity
in indigenous children from communities with high
prevalence of tuberculosis. Vaccine 2008;16:26:5575-81.
6. Wang L, Turner MO, Elwood RK, et al. A meta-analysis
of the effect of bacille Calmette Gurin vaccination on
tuberculin skin test measurements. Thorax 2002;57:804-9.
7. Singla M, Sahai V, Sodhi S, et al. BCG skin reaction in
mantoux negative healthy children. BMC Infect Dis 2005;
5: 19-20.
diagnosis of pulmonary tuberculosis in children. Tuber
Lung Dis 1995;76:295-9.

Pediatr 2000;37:947-51.
10. Lobato MN, Loeffler AM, Furst K, et al. Detection of
Mycobacterium tuberculosis in gastric aspirates collected
from children: Hospitalization is not necessary. Pediatrics
1998;102:e40.
Pediatr 2000;37:947-51.
13. Ichhpujani RL, Agarwal SP, Chauhan LS. Diagnostic
needs and status of new diagnostic tools for tuberculosis.
In: Agarwal SP, Chauhan LS (Eds). Tuberculosis control
in India. Directorate General of Health Services, Ministry
of Health and Family Welfare, Government of India. New
Delhi 2005;165-78.
14. Dheda K, Udwadia ZF, Hugget JF. Utility of antigen
specific interferon gamma assay for the management of
tuberculosis Curr Opin Pulm Med 2005;11:195-202.
15. Bianchi L, Galli L, Moriondo M, et al. Interferon-gamma
release assay improves the diagnosis of tuberculosis in
children. Pediatr Infect Dis J 2009;28:510-4.
16. Kampmann B, Whittaker E, Williams A, et al. Interferon
gamma release assays do not identify more children with
active TB than TST. Eur Respir J 2009;33:1374-82.
childhood tuberculosis. Indian J Med Res 2004;120:38797.
18. Verma K, Kapila K. Aspiration cytology for diagnosis of
tuberculosisperspectives in India. Indian J Pediatr
2002;69 Suppl 1:S39-43.
19. Sharma M, Agarwal S, Wadhwa N, et al. Spectrum of
cytomorphology of tuberculous lymphadenitis and
changes during anti-tubercular treatment. Cytopathology
2007;18:180-3.
20. El Jahiri Y, Chellak S, Garcia C, et al. The usefulness of
adenosine deaminase determination in biological fluids
for tuberculosis diagnosis Ann Biol Clin 2006:64;117-24.
21. Kaur A, Basha A, Ranjan M, et al. Poor diagnostic value
of adenosine deaminase in pleural, peritoneal and
cerebrospinal fluids in tuberculosis. Indian J Med Res
1992;95:270-7.
22. Gambhir IS, Mehta M, Singh DS, et al. Evaluation of CSFadenosine deaminase activity in tubercular meningitis. J
Assoc Physicians India 1999;47:192-4.
abdominal tuberculosis: Sonographic findings in patients
with early disease AJR 1995;165:1391-5.
24. Mwandumba HC, Squire SB. Fully intermittent dosing
with drugs for treating tuberculosis in adults. Cochrane
Database Syst Rev 2001;(4):CD000970
25. Kabra SK, Lodha R. Seth V. Category based treatment of
tuberculosis in children Indian Pediatr 2004;41:927-37.

26. Blomberg B, Spinaci S, Fourie B, et al. The rationale for
recommending fixed-dose combination tablets for
treatment of tuberculosis. Bull WHO 2001;79:61-8.
27. Kumar P. Journey of tuberculosis control movement in
India: National tuberculosis control program to revised
national tuberculosis control program Indian J Tuberc
2005;S2:63-71.
28. Kelkar-Khambate A, Klelmann K, Pawar S, et al. Indias
Revised National Tuberculosis Control Program:
Looking beyond detection and cure. Int J Tuberc Lung
Dis 2008;12:87-92.
495
29. Chugh S. Paediatric tuberculosis and DOTS strategy

under RNTCP. J Indian Med Assoc 2008;106:799-802.
30. Enarson DA. The International Union Against
Tuberculosis and Lung Disease Model National
Tuberculosis Programmes. Tuber Lung Dis 1995;76:95-9.
31. Comstock GW, Livesay VT, Woolpert SF. The prognosis
of a positive tuberculin reaction in childhood and
adolescence. Am J Epidemiol 1974;99:131-8.
32. Munoz FM, Starke JR. Tuberculosis in children. In:
Reichman LB, Hershfield ES, editors. Tuberculosis: A
Comprehensive International Approach: NewYork.
Marcell Dekker Inc 2000;553-95.
ANNEXURE
Tuberculin Test
Purified protein derivative (PPD) solution must be kept
refrigerated at 2 to 8C and to avoid fluctuations in
temperature, never store in the refrigerator door. The vial
should be discarded if it has been open for more than 30
days or the expiration date has passed. Select a well-lit
area for administering the test.
Administration of Skin Test

The patients forearm is exposed with the palm-side-up
and slightly flexed at the elbow. The injection is to be
given about 2 to 4 inches below the elbow avoiding areas
of skin with veins, sores, rashes, scars, or excess hair.
Using standard precautions for injection safety.
The injection site is cleaned with alcohol swab, using
circular motion beginning in the center and working the
way outward.
The 1 ml tuberculin syringe is loaded with PPD just
prior to administration ensuring that all air and excess
solution is expelled from the syringe, leaving exactly 0.1
ml of tuberculin solution in the syringe.
The skin is stretched taut over the injection site to
provide a surface that is easy for the needle to penetrate.
The syringe is held between thumb and index finger with
the needle bevel facing up and the syringe parallel to the
forearm. With the needle against the patients skin, the
needle is inserted slowly at a 5 to 15 angle, just below
the surface of the skin (one should be able to see the bevel
of the needle just below the skin surface). Once the bevel
of the needle has fully entered just beneath the superficial
most part of the skin, the stretched skin is released
holding the syringe in place. The tuberculin solution is
then injected slowly forming a 6 to 10 mm wheal (pale,
raised area with distinct edges; has orange peel
appearance and does not disappear immediately). If no
wheal forms or if it is less than 6 mm in diameter, the test
should be repeated about 2 inches from the original site
or on the opposite arm.
After a successful injection the needle is removed

without massaging or pressing the area. Sometimes there
may be minor bleeding which can be dabbed with a 2x2
gauze pad or cotton ball till oozing of blood stops. There
is no need to cover the site with an adhesive bandage.
The patient can get mild itching, swelling, or irritation
which is normal and usually goes away within 1 week.
The patient is advised to avoid scratching the site,
keeping the site clean and dry and is also advised to
return within 48 to 72 hours for reading of the test result.
Reading the Mantoux Tuberculin Skin Test

The site of injection on the forearm of the patient is
located. The fingernails of the reader should be short and
should not extend beyond the fingertip. The induration
may not always be visible, Therefore palpation of the
area with fingertips to determine induration at the
injection site is needed. The area is touched lightly with
the pads of fingertips and the fingertips are lightly swept
in 2-inch diameters from the injection site in all four
directions to locate the edges of the induration.
Alternatively, one can use a zig-zag feather-like touch to
palpate the area for margins of induration. Some times a
margin of induration may be confused with a margin of
muscle on the forearm. In such a case a repeat palpation
with the patients arm raised to a 45 angle is done.
Once the outer edge of the induration is reached rest
one fingertip firmly against the induration margin on one
side before marking the margin. The fingertip should
remain in contact with the skin at all times. A ball point
pen is used to mark the margin lightly with a fine dot at
the widest edge of the induration. The procedure is
reported on the opposite margin on the other side of the
induration. It is ensured that the induration was marked
correctly by a repeat palpation. If needed, the dots are
altered on repeat measurement.
Alternatively, the induration may be detected by the
Ball point method. In this technique, a medium-point
496
ballpoint pen is used to draw a line starting 1 to 2 cm

away from the skin reaction and moving toward its
center. When the pen reaches the margin of the
induration, an increased resistance to further movement
is felt and the pen is lifted. The procedure is repeated on
the opposite side of the skin reaction. The distance
between the ends of the opposing lines at the margins of
the induration is measured.
Usually, a millimeter ruler is used to measure the
widest diameter of the induration perpendicular to the
long axis of the forearm. Only the margins of the
induration are relevant for measurement and the redness
should not be measured. Reactions to the tuberculin skin

test at the injection site vary and if there is blistering, the
induration should be palpated gently as it may be painful.
Sometimes the margins are not equally clear all the way
around the induration but it is still necessary to mark
the margins on each side of the induration. For irregular
margins of induration, mark and measure the longest
diameter across the forearm. The exact measurement in
millimeters of induration should be recorded and not the
interpretation of the results as positive or negative along
with the date and time the test was read. If there is no
induration, this measurement should be recorded as 0
mm of induration.
36
in Children
36.1 DRUG-RESISTANT TUBERCULOSIS

HS Schaaf, PR Donald
THE DEVELOPMENT OF DRUG-RESISTANCE AND

DISCOVERY OF BASIC PRINCIPLES OF DRUG-RESISTANT
TUBERCULOSIS
Streptomycin (SM) and para-aminosalicylic acid (PAS)
were the first antituberculosis drugs to be discovered in
the early 1940s. Although PAS was the first used in
treating a patient, SM was the drug with the most
promise, showing the best clinical response. Resistance
of Mycobacterium tuberculosis (M. tuberculosis) emerged
soon after in vivo and in vitro exposure to SM.1
The finding that a small number of tubercle bacilli
were resistant to SM in the sputa of patients who had
tuberculosis but had not received any previous
chemotherapy. They also had probably not been in
contact with other patients who previously had
chemotherapy with SM. This led to the conclusion that
any large number of tubercle bacilli may be expected to
contain organisms which are relatively resistant to SM
without having been exposed to the drug.2 This was
confirmed by the presence of naturally resistant
organisms in stock cultures of the control M. tuberculosis
strain H37RV.3,4 SM-resistance gradually increased (both
number of resistant organisms and degree of resistance)
in patients within 4 weeks of starting monotherapy but
only became predominantly resistant at 6 to 13 weeks.2
SM did not cause resistance, but caused selective growth
of the resistant organisms. Once the organism was
resistant to SM, resistance remained.5,6 In these early days
it was already concluded that SM-resistance was an
inherited genetic change, a conclusion which later proved
to be correct.2
British Medical Research Council (MRC) studies with
SM monotherapy for TB showed that therapeutic results
were related to the degree of drug-resistance that
developed. In 35 of 41 patients in whom data was
available, resistance was >10 to 2000 times that of the
original strain of the patients or control (H37RV) strain.
The researchers concluded that emergence of SMresistance may be prevented by adding another drug to
SM treatment. SM-resistance develops within 2 to 3

months of SM treatment in patients with cavitary
pulmonary TB and further treatment with SM is unlikely
to be effective. Hence SM-resistant strains could be a
public health risk.7 They also found that patients with
cavitary pulmonory TB were far more likely than
noncavitary pulmonary TB patients to develop resistance,
which was due to higher bacillary load and therefore
more naturally resistant mutant strains in cavitary
disease.8,9
The first documented cases of transmission of SMresistant M. tuberculosis occurred in 3 health care workers.
In 1949, a nurse working with SM treated patients
contracted TB and the M. tuberculosis strain recovered
from her sputum was resistant to 1000 g/ml on original
isolation.10 Two further cases of primary (i.e. no previous
treatment with antituberculosis drugs) SM-resistant
pulmonary TB in health care workers were described
during the same year.11,12 These cases highlighted the
public health risk of drug-resistant TB.
The first child known to present with drug-resistant
TB was an 11-week-old infant diagnosed with SMresistant miliary TB in 1948. 13 The mother was
diagnosed with TB when the infant was aged 2 weeks
and they were immediately separated. Neither of them
had received previous SM-treatment. Primary SMresistance could not be confirmed because no isolate
was obtained from the mother. This case confirmed the
desirability of doing drug-susceptibility tests on all
diagnostic cultures obtained from new TB patients.
Early Solutions to Prevent Development of

Drug-resistance
Drug-resistance was perceived as an important problem
and possible solutions were sought, one of which was to
use more than one drug in the treatment of TB. Patients
receiving PAS also showed considerable improvement
compared to a placebo control group.14 Further studies
showed that PAS and SM had a synergistic effect when
498
given together, if the strain was not resistant to SM,15,16

and this regimen showed a substantial reduction in the
development of drug-resistance in the treatment of
pulmonary TB.17,18 However, a high dose of PAS was
needed, causing severe gastrointestinal adverse effects,
which eventually led to abandonment of PAS in most
regimens. An interesting observation was that resistance
to PAS took much longer to develop than with SM
(22-26 weeks).16,19
New Drugs and Further Problems

Thomas et al20 documented the first case of primary
polydrug-resistant TB with resistance to both SM and
PAS (Box 36.1.1). In 1952, isoniazid (INH) was introduced
for the treatment of TB. In the series of Thomas et al20
two patients developed resistance to INH while on a twodrug regimen (including INH), but the strain was already
resistant to one drug before treatment started. Adding
one drug to a failing regimen was then already confirmed
to be bad practice.
Several other antituberculosis agents were developed
during the period mid-1940s to mid-1960s, including
rifampicin (RMP), the last official current first-line
antituberculosis drug discovered in 1965.21 Despite the fact
that it was clearly shown early on that a combination of
drugs was needed to prevent the development of drugresistance to a drug, every drug was used as monotherapy
Box 36.1.1: Definitions in drug-resistant tuberculosis
Monodrug-resistance: M. tuberculosis isolate resistant to one
first-line antituberculosis drug
Polydrug-resistance: M. tuberculosis isolate resistant to two or
more first-line antituberculosis drugs, but not both isoniazid
and rifampicin (previously called multiple drug-resistance)
Multidrug-resistance: M. tuberculosis isolate resistant to at
least isoniazid and rifampicin
Extensive drug-resistance: M. tuberculosis isolate resistant to
at least isoniazid, rifampicin, the fluoroquinolones and
a second-line injectable drug (amikacin, kanamycin or
capreomycin)
Pre-extensive drug-resistance: M. tuberculosis isolate resistant
to at least isoniazid and rifampicin plus resistance either to
the fluoroquinolones or a second-line injectable drug (amikacin,
kanamycin or capreomycin). Not an official definition, but
mentioned in articles
Primary drug-resistance: Resistance found in patients not
previously treated for tuberculosis
New drug-resistance: No previous antituberculosis treatment
or previous treatment for < 1 month. Often used instead of
primary drug-resistance
Acquired drug-resistance: Resistance that developed in patients
previously treated for tuberculosis
Previously treated drug-resistance: Previously treated for TB
for > 1 monthoften used istead of acquired drug-resistance.
in treatment studies and in every case drug-resistance

developed, often within one month of starting single drug
therapy.
Important lessons on the development of drugresistance became clear from well performed studies by the
British Medical Research Council (MRC). Antituberculosis
drugs should not be used alone in the treatment of
pulmonary tuberculosis; Treatment regimens should
include 2 drugs to which the organism is susceptible,
implying that drug susceptibility tests should be done at
diagnosis before starting treatment. If this was not done,
inadvertent monotherapy can result, which will lead to
resistance developing to that drug as well, and; Taking a
history of previous antituberculosis treatment before compiling a
treatment regimen could be of great value as culture and drug
susceptibility test (DST) results are not always available. A
history of previous treatment with any (single) drug or
contact with a previously treated source case with known
DST results may be a guide in making the correct choice of
treatment.22,23
Bacillary Populations and Drug-resistance

Resistance is a phenomenon linked to large bacillary load.
The largest number of bacilli are found in pulmonary TB
cavities (approximately 107 to 109 bacilli), while those
found in caseous foci, such as in some forms of
extrapulmonary TB or primary TB in children, usually
do not exceed 102 to 104 bacilli.24 Wild type strains of M.
tuberculosis do contain a few resistant mutants for almost
all drugs among 106 bacilli.24 Spontaneous mutations
vary in number for different drugs with rifampicin the
highest at about 1 in 108, INH at 1 in 106 and ethambutol
at 1 in 104 bacilli. Second-line drugs usually have a higher
spontaneous mutation rate than first-line drugs, which
makes it even more important to use an adequate
combination of drugs to prevent the development of
further drug-resistance.
Both the bacillary load and the possible presence of
resistant mutants have important treatment implications.
In latent TB infection, with low numbers of bacilli, there is
an almost negligible chance of eliciting resistance by using
INH as single drug preventive treatment.24 An important
question at the time was whether an intensive phase of
treatment with multiple antituberculosis drugs and a
continuation phase with fewer drugs for a longer period
would be sufficient treatment and still prevent emergence
of resistance.24 The rationale behind this was that the
majority of the bacilli are killed with the initial multidrug
treatment, and the low number of remaining bacilli would
have a low-risk for the development of resistance during
the continuation phase. This principle was confirmed in
the first International Union against TB trial and is now
current treatment practice.25
Chapter 36 Drug-resistant Tuberculosis in Children
Early Epidemiology and Drug-resistance Surveillance

In several large, mostly hospital-based, surveys in the
United States in the early 1950s the incidence of primary
drug-resistance was low (1.6-2.6% for SM and INH).26,27
However, in previously treated patients, today a well
recognized risk factor for drug-resistant TB, SMresistance was 20.4%.26 Several experts thought that
primary drug-resistance was not a public health risk
except maybe in institutions, because multidrug
treatment regimens would reduce the number of drugresistant cases developing.28,29 However, in the United
Kingdom (UK) the prevalence of primary drug-resistance
to one or more of the commonly used drugs was 5.1%
(95% confidence interval: 4.1-6.5%) with SM-resistance
at 2.3%, PAS at 2.2%, and INH at 0.7%, which experts
interpreted as a possible public health problem of
importance.30 This led to the introduction of three-drug
regimens for tuberculosis treatment 19561959 in the
UK.30 Drug-resistance was already a worldwide problem
in 1957, with primary drug-resistance at 6.5% and
acquired (previously treated tuberculosis) at 42% in a
hospital-based study covering several countries.31 With
the development of multidrug treatment regimens and
especially short-course chemotherapy after the discovery
that RMP and pyrazinamide (PZA) were good sterilizing
drugs, scientific interest in drug-resistant TB waned
despite warnings from eminent TB researchers such as
Canetti.24
Infectiousness of Drug-resistant
M. Tuberculosis Strains
The infectiousness and the risk of developing disease
after infection with INH-resistant and therefore probably
also multidrug-resistant (MDR) strains of M. tuberculosis
has long been a point of discussion. MDR-TB is defined
as resistant to the two most potent anti-TB drugs viz.
isoniazid (H) and rifampicin (R). Some investigators
found these strains to be less infectious than drugsusceptible strains, but in practice new (no previous
antituberculosis treatment or treatment for <1 month)
INH-resistant TB in children soon followed the development of INH-resistant TB in adults in the early 1950s.
The prevalence of INH-resistant TB in children and adults
identified from the same area was approximately the
same and the rapid rise of drug-resistant TB among
adults in New York City during 1985-95 was soon
followed by a similar trend in children.32,33 In a landmark
study Snider et al found that the infection rate amongst
children was similar or higher in children in contact with
isoniazid-resistant source cases compared to drugsusceptible source cases.34 A study from South Africa
confirmed this finding with similar infection rates in
childhood contacts of adults with drug-susceptible (48%
infection) and MDR pulmonary TB (64% infection).35
499
Steiner et al 36 investigated transmission by comparing

DST results found in adult-child contact pairs. They
confirmed a high rate of concordance with 14 of 15
INH-resistant strains (93%) from adult-child pairs and
20 of 29 (69%) adult-child pairs with any drug-resistance
showing identical DST results.36 This was followed many
years later by a study from South Africa showing that 18
of 22 MDR strains (82%) obtained from adult-child pairs
had identical DSTs.37 Transmission was confirmed in a
prospective study by identical restriction fragment length
polymorphism (RFLP) analyses in 5 of 6 adult-child pair
M. tuberculosis isolates in a prospective study.38
Cause of Drug-resistance
Although M. tuberculosis organisms have spontaneous
natural mutations causing resistance to individual drugs,
drug-resistant TB is mainly a man-made disease. Poor
management of drug-susceptible or drug-resistant TB
cases will lead to development of resistance or further
resistance, for example, prescribing poor regimens (e.g.
adding a single drug to a failing regimen or prescribing
a weak combination of drugs), interruption of treatment
because of drug supplies not being available, using drugs
with poor bioavailability of components such as
rifampicin and poor adherence to antituberculosis
treatment by patients and health systems.
Once patients (mainly adults) have developed drugresistant TB, poor management of cases may lead to
transmission of drug-resistant M. tuberculosis strains
(primary or new drug-resistance). In many high-burden
TB countries new TB cases are diagnosed by sputum
smear microscopy only:
i. Measures should be in place to identify drugresistant cases early by doing culture and DST on
sputum of patients who have a known drugresistant source case.
ii. Patients not responding to treatment (smear or
culture-positive at 2 to 3 months or at end of
treatment, latter called treatment failure).
iii. Any patient with relapse or retreatment TB and, as
recently recommended by the WHO.
iv. Patients with HIV infection.39
Poor infection control measures especially in health
care settings but also in other institutions such as prisons
are a further preventable cause of transmission of drugresistant TB.
Epidemiology of Drug-resistant Tuberculosis

Despite effective antituberculosis treatment regimens, a
dramatic worldwide increase in the incidence of TB
occurred during the late 1980s. This was mainly due
to the growing epidemic of HIV infection, now known
as the most potent facilitator of TB disease after infection.
Outbreaks of MDR-TB with high mortality, originally
500
described in HIV-infected persons, were responsible for

refocusing the attention of developed countries on TB.40
Drug-resistant TB has always been a global problem and
developing countries had higher rates of primary
and acquired resistance than developed countries.41
MDR-TB was, however, mainly a problem in countries
making use of the more expensive RMP-containing shortcourse chemotherapy regimens. This was reflected in
data from several global reviews of drug-resistance
surveillance.42-44
The increase in MDR-TB led to drastic measures
including second-line drug regimens for MDR-TB,
upgrading of TB health services including directly
observed therapy, and improved infection control
measures in developed countries, effectively reducing the
numbers of MDR-TB in these countries. However,
worldwide MDR-TB numbers have increased. In the 2006
worldwide WHO survey (data from 116 countries) of
drug-resistant TB, it was estimated that any resistance
occurred in approximately 20.0%, INH resistance in
13.3% and MDR-TB in 5.3% of all TB cases annually.
The total number of MDR cases were estimated at
approximately 490,000 per year. Fifty percent of these
MDR-TB cases are from China and India with the Russian
Federation contributing a further 7%.39
In 2006, the term extensive drug-resistant (XDR)TB was coined and the definition finalized, i.e. M.
tuberculosis isolate resistant to at least isoniazid,
rifampicin, the fluoroquinolones and a second-line
injectable drug (amikacin, kanamycin or capreomycin).
Although extensively resistant cases were known to
occur long before 2006, focus was placed on this
condition following a 98% mortality in 53 mainly HIVinfected patients in KwaZulu-Natal, South Africa.45
This led to a worldwide search for XDR-TB patients
and according to WHO, XDR-TB cases have already
been diagnosed in all regions of the world with
between 2 and 19% of MDR-TB strains in 49 countries
having XDR-TB.39
The incidence or prevalence of drug-resistant TB in
children is not well documented, as a microbiological
diagnosis of TB in children is more difficult. However,
Steiner et al published several 4-year surveys of drugresistance in children from a New York hospital from
1960 to 1992, showing an increase in the prevalence of
resistance and the development of MDR-TB after the
introduction of RMP.32,33 A number of mainly hospitalbased surveys of drug-resistant TB in children from
several countries have been published in the past two
decades. In South Africa, follow-up surveys in one region
showed a rising trend in MDR-TB in children.46 More
studies are needed in children, because drug-resistance
in isolates obtained from children are a good indicator
of currently circulating strains in the community.
Molecular epidemiology has added a new dimension

to tuberculosis. RFLP analysis is used to confirm
transmission 38 and spoligotyping has been used to
identify strains of M. tuberculosis to see whether any
particular strain is more often associated with drugresistant tuberculosis. The W-Beijing strain and in some
instances the Haarlem strain have been implicated in
drug-resistant TB although this has not been a constant
finding.47
Human Immunodeficiency Virus and

Drug-resistant TB
Although HIV infection was associated with an increase
in drug-resistance in some studies, mainly from
developing countries, this was not the case in several
other studies, specifically from Africa, where the
incidence of HIV is extremely high. A large childhood
survey also found no significant difference between HIVinfected and HIV-uninfected children with drug-resistant
TB.46 Monoresistance to RMP is generally rare,42,48 but
recently it was noted that mono-resistance to RMP was
on the increase and RFLP analysis found the strains to
be of independent origin.48 Most of these strains were
obtained from HIV-infected patients, and one of the
possible explanations was selective malabsorption of
RMP in some HIV-infected patients, or poor protection
of RMP by low levels of INH in patients who are fast
acetylators of INH receiving once or twice a week
therapy.
Diagnosis of Drug-resistant Tuberculosis in Children

The diagnosis of drug-resistant tuberculosis is primarily
a microbiological diagnosis, confirmed only if the M.
tuberculosis organism can be retrieved from the patient
and DST or genetic mutation analysis done on the
isolate. Child contacts of infectious pulmonary TB cases
with microbiologically confirmed drug-resistant TB
most likely will be infected with the same strain and
therefore, if they develop TB, will have probable drugresistant TB. 37,38,49 Drug-resistant TB should also be
suspected in children if, disease becomes worse on
adherent first-line antituberculosis treatment. This is
particularly so amongst those having contact with adult
TB cases, with unknown DST results, who failed TB
treatment. Further there is history of previous TB
treatment or an adult has died while on TB treatment.
Such children need cultures and DST done. According
to the WHO 2008 guidance for drug-resistant TB update,
all HIV-infected TB patients should also have culture
and DST done.39
Drug-resistant TB is not a clinical or radiological
diagnosis, as several studies50,51 showed no difference
between clinical findings or radiological features in drug-

susceptible and drug-resistant cases. Other than
obtaining specimens for culture of M. tuberculosis from
every possible source in a child with suspected drugresistant TB, the most important part of the evaluation is
the history of contact with infectious TB cases and previous
TB treatment in both the child and the source case, as this is
important information in building a treatment regimen for
the child. Schaaf et al50 have emphasized that previous
antituberculosis treatment in the child is a risk factor for
drug-resistant TB, not because the child developed drugresistance because of poor management but because
drug-resistant TB was initially missed due to an
incomplete history of contact or culture and DST was
not initially done.46,52
Confirmatory Tests for Drug-resistant TB

The conventional way of diagnosing drug-resistance is
by culture and DST. Conventional methods such as
indirect proportion method on solid media (agar plate
or Lwenstein-Jensen media) are less expensive but slow
and can take up to 6 weeks. Culture is first done and
culture growth is then subcultured on drug-containing
and drug-free media. Growth of >1% on the drugcontaining medium confirms drug-resistance to that drug
at the specific concentration of the drug used in the
culture medium. Lately, more rapid DST methods using
semi-automated radiometric (e.g. BACTEC 460 TB
system) or automated fluorescence [e.g. BACTEC MGIT
(Mycobacterial Growth Indicator Tube) 960 system]
liquid broth are more often used. These systems are much
more expensive, but can give results within 10 to 14 days
after a positive culture has been obtained. Because of the
risk of infectiousness and the risk of acquiring further
drug-resistance with incorrect treatment regimens, there
is a strong drive for development of more rapid
diagnostic methods for drug-resistance. Currently under
investigation is the Microscopic Observed Drug
Susceptibility (MODS) assay, where culture and DST is
performed at the same time. Daily examination of wells
for mycobacterial growth by inverted microscopic
observation, may give both confirmatory culture result
and DST results within 7 to 10 days.53 This method is
being field tested and holds much promise.
Genotypic evaluation tests used either for detection
of M. tuberculosis directly from clinical samples or for
identification of mycobacteria from culture, currently
hold the biggest promise in the diagnosis of drugresistant TB. The major advantages of the nucleic-acid
based assays are speed and ease of interpretation. The
tests are still expensive and laboratory infrastructure is
needed. The GenoType MDR-TB Plus (Hain Lifesciences,
Nehren, Germany) is probably the best known of
these tests. The kit can be used to detect M. tuberculosis
directly from clinical samples, or for identification of
501
mycobacteria from culture. The underlying principle

involves multiplex amplification of extracted mycobacterial DNA by PCR, with subsequent hybridization
of the biotin labelled amplicons to oligonucleotide probes
bound to a membrane strip (also called line-probe tests).
This test can at the same time identify the majority of
RMP and INH resistanceidentification is done by
evaluation of the resultant banding pattern. The kits
have been shown to have excellent correlation with
conventional methods, usually over 95%.54
Management of Drug-resistant Tuberculosis

The basic principles of the management of adult and
childhood drug-resistant TB are the same. However,
because children often have paucibacillary disease, some
aspects of management may differ. Fewer drugs and
shorter duration of treatment may be sufficient in
children with early primary disease. Children will more
often receive drug-resistant treatment without it being
microbiologically confirmed because of known contact
with an adult drug-resistant TB case. Some of the
important principles are as follows:55
Never add one drug to a failing regimen
Give directly observed treatment with daily treatment only
(not intermittent treatment)
Be guided by the adult source cases isolate DST result
if no M. tuberculosis isolate is obtained from the child
If resistance to INH and/or RMP is found, do secondline DST
Give 3 or preferably more drugs to which the isolate
from patient or adult source case is susceptible or
when there is no history of previous antituberculosis
drug therapy
Use drugs from the different drug groups (as defined
by WHOsee Table 36.1.1) and be aware of possible
cross-resistance between drugs
Support the caregivers by counseling about adverse
effects, treatment duration and importance of
adherence at every follow-up visit
Clinical, radiological and culture response to
treatment should be carefully monitored
Although the optimal duration of treatment for MDR
and XDR-TB is not known, a minimum of 18 months
after the first negative culture is usually recommended. In children with early primary disease this
could probably be less.
Treatment of INH-Monoresistant TB
If INH resistance is diagnosed before the onset of
treatment and the child has primary disease, a 2-month
intensive phase of rifampicin (RMP), ethambutol (EMB)
and pyrazinamide (PZA) and a 7-month continuation
phase of RMP and EMB should be sufficient. However,
502
Table 36.1.1: Drug groups for MDR and XDR-TB treatment regimens
Drug Group
Drug name
Daily dosage
(mg/kg)
Maximum dose
(mg)
Group 1: Oral first-line drugs

to which the organism shows
in vitro susceptibility by DST
Ethambutol
Pyrazinamide
20-25
25-35
2000
2000
Group 2: Second-line injectable

agents (streptomycin is first-line
drugnot for use in MDR/XDR-TB
Amikacin
Kanamycin
Capreomycin
15-22.5
15-30
15-30
1000
1000
1000
Ofloxacin
Levofloxacin
Moxifloxacin
15-20
7.5-10
7.5-10
800
750
400
c
Group 4: Second-line oral
bacteriostatic agents
Ethionamide
(or prothionamide)
Cycloserine
(or terizidone)
Para-aminosalicylic
acid (PAS)
15-20
15-20
10-20
10-20
150
1000
1000
1000
1000
12g
High-dose INH
Linezolid
Amoxicillin/clavulanate
Clarithromycin
Thiacetazone
Imipenem/cilastatin
15-20
10-12 twice daily
30-40 amoxicillin
7.5-15 twice daily
3-4 (only IV)
400
600 twice daily
Group 3: Fluoroquinolones
Group 5: Drugs of unclear

use in drug-rsistant TB treatment
500 twice daily

150
Cannot rely on DSTuse as additional drug if DST result susceptible or not done.
Choose one drug in each of these groups; amikacin preferred to kanamycin in children.
c
Choose one or more of these drugs to make up total of 4 new drugs.
d
Consider use of these drugs if insufficient drugs to build an acceptable regimen with previous groups. Linezolid dosage for
TB is still uncertain. Thiacetazone should NOT be used in HIV-infected patients.
b
once this treatment regimen fails or the INH resistance

is diagnosed long after the start of therapy, 2 or more
drugs, preferably including a fluoroquinolone should
be added as further resistance could have developed.
The continuation phase should also be prolonged.
Treatment of RMP-Monoresistant TB
First and foremost is to determine whether there is no
contact history of MDR-TB and to ensure that DST results
are correct. Many experts will still treat these patients as
MDR-TB, with the addition of INH, ethambutol, a
fluoroquinolone, pyrazinamide with/without an
aminoglycoside. Some second-line drugs may have to
be added taking into account the extent or type of disease
for 12 to 18 months.
Treatment of Polydrug-resistant TB39

All available oral first-line drugs (group 1, Table 36.1.1)
together with other preferably bactericidal drugs (groups
2 and 3) to make up a minimum of 3 active drugs required
in case with minimal disease. Four active drugs

(additional drugs from group 4) need to be given in
advanced disease. The duration of treatment is 12 to 18
months depending on extent of disease whether RMP or
PZA susceptibility remains. Either of these latter drugs
is given throughout the treatment course.
Treatment of MDR and XDR-TB

If either the child or the source case had previous
treatment with pyrazinamide and/or ethambutol for >1
month, the remaining first-line drugs (group 1, Table
36.1.1) could be used if DST shows susceptibility.
However, because of unreliability of the DST for these
drugs, they would count only as additional drugs. In
children with early primary (not extensive or disseminated) TB, 3 bactericidal drugs should be sufficient,
more extensive disease, four or more active drugs should
be included in the regimenone drug each from groups
2 and 3, and one or more drugs from group 4. If these
groups are not sufficient to build an acceptable regimen
of 4 active drugs, drugs from group 5 could be added.39

INH at a high-dose, especially when given in
combination with ethionamide, may be beneficial
depending on which mutation causes INH resistance, the
child may have low-level INH resistance, but could then
be resistant to ethionamide. Studies have shown lowlevel INH resistance in 80% children with INH-resistant
TB.56 Further, in an adult randomized controlled trial,
the addition of high-dose INH to a MDR-TB treatment
regimen, compared with normal dose (5 mg/kg daily)
or no INH, found earlier sputum conversion and
improvement in chest radiographs in the high-dose INH
study group.57
Treatment duration for MDR and XDR-TB in children
should also be 18 months after the first negative culture,
as in adults, with cultures being done at least monthly
until it becomes negative. Thereafter cultures could be
done 2-monthly until the end of treatment. Early primary
[hilar adenopathy or contained primary pulmonary
(Ghon) focus] MDR-TB could probably be treated for 12
months only.
Role of Surgery in the Management of MDR

and XDR-TB
The role of surgery remains controversial. Some
conditions, such as lymph node obstruction of airways,
draining of pericardial effusion, insertion of ventriculoperitoneal shunt for non-communicating obstructive
503
hydrocephalus and some other, need surgery the same

as for drug-susceptible cases.
Resectional (pulmonary) surgery has proven to be a
useful component of the management of MDR-TB in
adults infected with strains resistant to most drugs.58,59
Surgery remains an important adjunct to medical therapy
especially in cases not responding to adherent adequate
MDR-TB treatment regimens, with mainly localized
disease and the remaining lung tissue should be relatively
free of disease. These procedures are not without
complications, and stump breakdown with bronchopleural fistulas, empyemas, bleeding and even death may
occur, therefore, patients should be carefully selected.
Adverse Effects of Second-line Antituberculosis Drugs

Second-line antituberculosis drugs are generally more
toxic than first-line drugs. Although children have less
adverse effects than adults treated with the same drugs,
they need to be monitored carefully, as it is more difficult
to assess adverse effects in children than in adults.
Important adverse effects to monitor and how to monitor
these are summarized in Table 36.1.2. Adverse effects
should be treated as soon as possible, because it could
lead to serious irreversible problems such as hearing loss
and peripheral neuropathy, but it could also lead to poor
adherence to treatment if not adequately managed.
Table 36.1.2: Important adverse effects of second-line drugs and how to monitor them
Second-line drug
Adverse effect
Tests to monitor
Amikacin
Kanamycin
Capreomycin
Ototoxicity
Nephrotoxicity
Hearing test (audiology)

Serum creatinine and
potassium levels
Fluoroquinolones
Gastrointestinal disturbance
Insomnia
Arthralgia
Clinical observation
Serum uric acid if used with
pyrazinamide
Ethionamide
(or prothionamide)
Hepatotoxicity
Hypothyroidism
Jaundiceserum alanine
transferase and billirubin
Thyroid stimulating hormone
levels and free T4
Cycloserine (or terizidone)
Psychosis, Convulsions,
Paresthesia, Depression
Para-aminosalicylic acid (PAS)
Hypothyroidism
Thyroid stimulating hormone
levels and free T4
Linezolid
Myelosuppression
Lactic acidosis
Peripheral neuropathy
Pancreatitis
Full blood counts

Serum lactate level
504
Outcome of MDR -TB in Children

Treatment of MDR and XDR-TB patients is often initially
administered in hospital firstly, because they may have
extensive disease secondly, because primary health care
clinics often do not want to administer daily injections to
children. Further, the source cases poor adherence to
treatment, who could be the mother or caregiver, causes
doubt whether the child will actually be taken for daily
directly observed therapy. It is also important to do followup cultures to determine the final duration of treatment.
Obtaining specimens for culture of M. tuberculosis from
children is quite difficult and health care workers are often
reluctant to take gastric aspirates or induced sputum
specimens at clinic level. We usually admit children for
the time that they receive second-line injectable drugs and,
if social circumstances and the clinical condition of the
child permit, the rest of the treatment is given at primary
health care level as daily directly observed therapy.
However, in a study from Peru, the majority of the children
managed for MDR-TB were not admitted to hospital but
treated in the community by directly observed therapy
with cure or probable cure in 36 of 38 cases.60 A South
African study of 39 culture-confirmed childhood MDRTB cases also had good outcome with only 4 (10%) deaths
and a majority of children clinically cured.37 More data
are needed to compare cure rates of HIV-infected and HIVuninfected children, with MDR-TB and specific types of
TB. In general, MDR tuberculous meningitis has a very
high mortality.
Management of Child Contacts of Infectious

Drug-resistant Cases
In general, all children in close (usually household)
contact with an infectious TB case should be screened
for TB and active TB disease excluded. Once TB disease
has been excluded, WHO guidelines recommend that all
children less than 5 years of age and all HIV-infected
children irrespective of age should receive preventive
therapy (chemoprophylaxis).61 However, in case of drugresistant contacts, no randomized controlled trials for
chemoprophylaxis have been conducted. As long as there
is no resistance to INH, INH for 6 to 9 months remains
the preferred regimen. In case of MDR-TB, WHO

recommends INH chemoprophylaxis only, not to prevent
MDR-TB but in case the child may have been infected by
a drug-susceptible source case.49 Several failures of INH
or INH/RMP combination chemoprophylaxis for MDRTB contacts have been documented.62
In INH-resistant contacts, RMP as monotherapy for
4 months has been shown to be effective and is currently
recommended by the American Academy of Pediatrics.63
In case of MDR-TB contacts, the situation is more
complex and there is no universally accepted regimen.
WHO does not recommend using second-line drugs for
chemoprophylaxis of MDR-TB contacts and recommends
only regular follow-up of these children for a minimum
of two years.49 However, one study has shown that giving
a combination of two drugs to which the source cases
isolate is susceptible or nave prevents the development
of disease in high-risk child contacts.64 This is also the
current recommendation of the American Aademy of
Pediatrics. 63 We prefer a combination of a fluoroquinolone, ethambutol (if DST shows susceptibility) or
ethionamide plus high-dose INH for 6 months in highrisk cases.
There is no effective chemoprophylaxis for XDR-TB
contacts. Regular follow-up as for MDR-TB contacts is
the only option, with early treatment once disease occurs.
Infection Control Measures

No discussion about drug-resistant TB can be complete
without mentioning the importance of good infection
control measures. Children with acid-fast bacilli sputum
smear-positive or cavitary pulmonary TB are most likely
infectious and should be isolated until they are at least
smear-negative. In the developing world good ventilation is the most important and most easily implemented
measure for infection control other than diagnosing and
treating infectious cases early and effectively. In case of
children presenting with possible TB, it should be
remembered that the adult accompanying the child may
be the source case, therefore, it is important that a history
of TB from the adult should be obtained or they should
be screened if they are symptomatic to prevent possible
transmission of disease in the health care setting.
36.2 MULTIDRUG-RESISTANT TUBERCULOSIS

Multidrug-resistant (MDR) TB is defined when

M. tuberculosis isolates are resistant to both isoniazid and
rifampicin with or without resistance to other drugs.
Isoniazid and rifampicin are the most important drugs
in the management of TB. Resistance to either isoniazid
or rifampicin can be treated with other first-line

antituberculosis drugs. However, multidrug-resistant TB
(MDR-TB) demands treatment with second-line drugs
that have limited sterilizing capacity, are less effective and
more toxic.

The management of MDR-TB in adults has been
extensively documented, relatively little is known about
its diagnosis and management in children. Soon after
streptomycin was introduced for the treatment of
tuberculosis, it became apparent that initial success was
frequently followed by relapse and the emergence of a
population of streptomycin resistant M. tuberculosis. As
more antituberculous drugs became available, it was
discovered that this problem could be prevented by using
drugs in combination.
The phenomenon of drug-resistance in Mycobacterium
tuberculosis was observed as early as 60 years ago,
however, the current threat is due to the emergence of
strains resistance to the two most potent anti-TB drugs
viz., isoniazid (H) and rifampicin (R). The response of
patients with MDR-TB to treatment is poor and the
mortality rate is usually high. Since these patients need
to be treated with expensive and toxic second-line drugs,
and may require hospitalization to manage their toxic
reactions and other complications, they require a sizeable
proportion of health care resources. Further, an alarming
increase in infection due to the human immunodeficiency
virus (HIV) has aggravated this situation and it is
believed that, as of now, about 3 to 5 million people in
India are infected with HIV. There is a grave concern in
India regarding the increase in HIV-associated TB and
the emergence of MDR-TB both in terms of magnitude
and severity of TB epidemic.
It is now known that any population of M. tuberculosis
will contain a small number of resistant organisms,
irrespective of previous exposure to the drugs in
question. These are the result of constant but relatively
low rate of mutation. As the number of organisms are
low in the lesions of children, resistant mutants are less
likely to be found, unless the child has been infected by
a resistant strain.
There is some evidence that isoniazid resistant
(catalase-negative) organisms are less pathogenic than
isoniazid-sensitive (catalase-positive) organisms in
experimental animals, however, there is no doubt that
resistant organisms can cause human disease. Such
infection can be transmitted to children and can cause
disseminated forms of tuberculosis such as tuberculous
meningitis.
When to Suspect Drug-resistance?

Drug-resistance should be suspected whenever:
Therapeutic progress is not maintained.
Whenever bacterial relapse occurs during course of
treatment.
Recurrence occurs in patients previously treated for
tuberculosis and their contacts including children.
Once there is strong possibility of drugresistance complicating therapy, all treatment should be
505
re-evaluated, culture and sensitivity studies should be

undertaken using rapid methods for identification of AFB
on smear and culture. In children emphasis has to be on
repeated examination of gastric lavage and induced
sputum specimen, fine needle aspiration (FNA) material
in nonresolving lymphadenitis. Additional drugs should
not be added piecemeal to the existing regimen as this
will lead to reduction of choice of drugs for use in an
effective alternative therapeutic regime.
Definition of Drug-resistance
Drug-resistance in mycobacteria is defined as a decrease
in sensitivity to a sufficient degree to be reasonably
certain that the strain concerned is different from a
sample of wild strains of human type that have never
come in contact with the drugs.
Multidrug-resistant TB (MDR-TB) is caused by
bacteria that are resistant to the most effective anti-TB
drugs (isoniazid and rifampicin). MDR-TB results from
either primary infection or may develop in the course of
a patients treatment.
Extensively drug-resistant TB (XDR-TB) is a form
of TB caused by bacteria that are resistant to isoniazid
and rifampicin (i.e. MDR-TB) as well as any fluoroquinolone and any of the second-line anti-TB injectable
drugs (amikacin, kanamycin or capreomycin).
Types of Drug-resistance
Drug-resistance in TB may be broadly classified as primary
or acquired. When drug-resistance is demonstrated in a
patient who has not received anti-TB treatment previously,
it is termed primary resistance. Acquired resistance is that
which occurs as a result of specific previous treatment.
The level of primary resistance in the community is
considered to reflect the efficacy of control measures in
the past, while the level of acquired resistance is a measure
of on-going TB control measures. However, the World
Health Organization (WHO) and the International Union
Against Tuberculosis and Lung Disease (IUATLD), in the
light of discussions in several international fora, have
replaced the term primary resistance by the term drugresistance among new cases and acquired resistance by
the term drug-resistance among previously treated
cases. For more details see Chapter 36.1.
Cause of Drug-resistance
The emergence of drug-resistance in M. tuberculoses has
been associated with a variety of management, health
provider and patient-related factors, these include:
(i) deficient or deteriorating TB control programs
resulting in inadequate administration of effective
treatment; (ii) poor case holding, administration of
506
substandard drugs, inadequate or irregular drug supply

and lack of supervision; (iii) ignorance of health care
workers in epidemiology, treatment and control of
disease; (iv) improper prescription of regimens; (v)
interruption of chemotherapy due to side effects; (vi)
nonadherence of patients to the prescribed drug therapy;
(vii) availability of anti-TB drugs across the counter,
without prescription; (viii) massive bacillary load; (ix)
illiteracy and low socioeconomic status of the patients;
(x) the epidemic of HIV infection; (xi) laboratory delays
in identification and susceptibility testing of M.
tuberculosis isolates; (xii) use of nonstandardized
laboratory techniques, poor quality drug powders and
lack of quality control measures; and (xiii) use of anti-TB
drugs for indications other than tuberculosis.
Isoniazid, the most powerful antimycobacterial drug
available, ensures early sputum conversion and thus
helps in reducing the transmission of TB. Rifampicin, by
its mycobactericidal and sterilizing activities is crucial
for preventing relapses. Thus, for the management of
tuberculosis, these two drugs are most important. If there
is resistance to one of them, the disease still can be
managed with other first-line drugs. If there is resistance
to both isoniazid and rifampicin, MDR-TB requires
treatment with second-line drugs. These drugs have
limited sterilizing capacity and are not suitable for shortcourse treatment. Thus, the problem of transmission is
crucial to the occurrence of disease in children, is of grave
concern when there is contact of a child with MDR
tuberculosis in the family resulting in primary resistant
infection. MDR-TB has important implication both for
individual patient and tuberculosis control program.
The modern era of tuberculosis recently has been
characterized by a rise in the number of cases of infection
with multidrug-resistant (MDR) M. tuberculosis. This has
also led to outbreaks and individual cases that are only
marginally treatable and often fatal. World Health
Organization (WHO) on World Tuberculosis Day in 1993
declared tuberculosis as a global emergency. This was
prompted firstly, by the resurgence of tuberculosis in the
west in the mid-1980s and, secondly, by the outbreak of
MDR-TB in many countries, including USA in the late
1980s and early 1990s.1 MDR-TB has been described as
the third epidemic, complicating the epidemic of HIV.
The conditions that have led to the resurgence of
tuberculosis have also contributed to an increasing
incidence of resistant forms of tuberculosis in the
developed and developing world. The resurgence of
tuberculosis in the USA has been more striking for
children than for the adults. Although the incidence of
new cases increased by 20% from 1987 to 1992, the
incidence of new cases in children less than fifteen years
of age increased to 40% in 1993.2
EPIDEMIOLOGY
The emergence of MDR-TB in the United States attracted
attention in the 1990s. Till then drug-resistance was
considered to be only a potential problem. WHO and
Disease (IUATLD) conducted three rounds of survey
between 1996-2002. The third round included new data
from 77 settings or countries that were collected between
1999 and 2002. In the third survey it was found that
among new cases, the prevalence of MDR-TB (Median,
1.1%) ranged from 0% in eight countries to 14.2% in
Kazakhistan (51 of 359 patients) and Israel (36 of 253
patients). Among previously treated cases the median
prevalence of MDR-TB was 7.0%. The prevalence of
MDR-TB was exceptionally high in all countries from the
former Soviet Union surveyed, including Estonia,
Kazakhistan, Lativ, Lithuania the Russian Federation,
and Uzbekistan. High prevalence of MDR-TB were also
found among new cases in China, Ecuador, and Israel.
Central Europe and Africa, in contrast reported the
lowest median levels of drug-resistance. A recent
estimate of global prevalence in 184 countries suggest
that an estimated 458,000 new cases of MDR-TB occurred
world wide in 2003, with 276,000 of those, i.e. (60%) from
high-burden countries. Poor or worsening TB control,
immigration of patients from areas of higher resistance,
outbreak of drug-resistant disease and variation in the methods
of surveillance are some of the factors which could be responsible
for increases in the prevalence of resistance.
Global Situation
A review by WHO of a series of 63 surveys of drugresistance carried out worldwide between 1985 and 1994
led to the conclusion that the new epidemic maybe
global.3,4 The highest rates of MDR-TB were from Nepal
(48%), Gujarat state (India) (34%), New York City (USA)
(30%), Bolivia (15%) and South Korea (15%). Subsequently, between 1994 and 1997, WHO and the IUATLD
conducted drug-resistance surveillance for the four firstline antituberculosis drugs namely isoniazid, rifampicin,
streptomycin and ethambutol, through extensive
network of reference laboratories in 35 countries
including India. The prevalence of primary multidrugresistance was 1.4%. It was further reported that India
accounts for almost a third of the worldwide burden of
tuberculosis and the combined prevalence of multidrugresistance to the tune of 13.3%. Although tuberculosis
remains endemic in many parts of Asia, primary drugresistance has dramatically declined in Korea, having
shown a fall from 31% in 1960 to 15% in 1990, reflecting
improved tuberculosis control measures.5
In the recently released WHO report, it is estimated
that in 2008, 390,000 to 510,000 cases of MDR-TB emerged

globally (best estimate, 440,000 cases).6 Among all
incident TB cases globally, 3.6% [95% confidence interval
(CI): 3.04.4] were estimated to have MDR-TB. Almost
50% of MDR-TB cases worldwide were estimated to occur
in China and India. While the TB case populations of
China and India may have proportions of MDR-TB lower
than Eastern European and Central Asian countries, the
sheer sizes of the two countries TB case populations
result in the highest estimated numbers of MDR-TB cases
emerging annually in these two countries: approximately
100,000 cases each. In 2008, MDR-TB caused an estimated
150,000 deaths globally.
The Russian Federation, which was able to provide
high-quality continuous surveillance data from 12 of its
oblasts and republics, reported proportions of 23.8 to
28.3% MDR-TB among new TB cases in three of its oblasts
in the northwest part of the country.6
A 4 years prospective study in the Western Cape
province of South Africa evaluated 149 child contacts of 80
adult MDR pulmonary TB cases. Culture for
M. tuberculosis was obtained from both the adult source cases
as well as the child contacts. Isolates were compared by
drug susceptibility pattern and restriction fragment length
polymorphism (RFLP) analysis. Six adult-child pairs with
cultures positive for M. tuberculosis were identified. Drug
susceptibility pattern and RFLP analysis were identical for
five adult-child pairs. One child, with no other known
source case, had a strain different from that of the identified
source case, but the MDR-M. tuberculosis strain with which
he was infected was prevalent in the community he resided.
This study confirms that most of the childhood contacts of
adults with MDR-TB are likely to be infected by these MDR
source cases despite their exposure to other drug-susceptible
adults with TB in some instances. Child contacts of adults
with MDR-TB should be treated according to the drug
susceptibility patterns of M. tuberculosis strains of the likely
source cases unless their own strains susceptibility testing
indicates otherwise. Contact tracing remains of fundamental
importance in identifying children at risk.7 In Western Cape
province of South Africa, initial isoniazid (INH) resistance
and MDR among adults was 3.9 and 1.1%, respectively,
during 1992-1993.7 In a report of 306 of 338 children with
cultures positive of M. tuberculosis the incidence of INH
resistance was 5.6% and MDR 1% in children aged < 5 years
in South Africa.8
Initial Drug-resistance in India

The Indian Council of Medical Research (ICMR) undertook drug-resistance studies during 1965-67 in nine urban
areas of the country. However, this exercise was not a
surveillance study and did not use strict sampling
techniques, the centers being selected more for logistic
considerations than for epidemiological reasons. Sputum
specimens collected from all patients attending chest
507
clinics were tested for drug susceptibility to streptomycin,

isoniazid, para-aminosalicylic acid (PAS) and thiacetazone.
The first study was on patients who had denied any history
of previous treatment, while in the second study, patients
with and without previous chemotherapy were included.
The results showed that in the first study resistance to
isoniazid ranged from 11 to 20%, to streptomycin from 8
to 20% and to both drugs from 4 to 11%. The second study
showed resistance to isoniazid in the range of 15 to 69%,
to streptomycin from 12 to 63% and to both drugs from 5
to 58%. Further, the level of drug-resistance was proportional to the duration of previous treatment.9
A decade later, a study at the Chest Clinic of
Government Stanley Hospital (GCI-SH), Chennai
(formerly Madras) yielded results similar to those in
earlier ICMR surveys, indicating that the prevalence of
initial drug-resistance had not risen during the span of
ten years. However, both the above studies were
undertaken in the pre-rifampicin period and are not of
relevance in the present setting.
During the 1980s, though the levels of initial drugresistance to isoniazid and streptomycin in 11 reports
were similar to those in the earlier studies, rifampicin
resistance was observed in all centers studied except
Gujarat. The level of MDR-TB in all centers (except
Wardha) was observed to be less than 5%. The reason
for the emergence to rifampicin-resistance during this
period may be the introduction of short-course chemotherapy (SCC) regimens containing rifampicin. Further,
a higher level of initial drug-resistance to isoniazid
(32.9%) was observed among the rural population in
Kolar compared to the urban patients, contradicting a
Korean study, where a much higher level of initial
resistance was seen among urban patients, attributed to
easy access to the antituberculosis drugs. There was also
an increase in the proportion of initial drug-resistance to
rifampicin (4.4%) encountered in this rural population
in Karnataka.
In the early 1990s, a retrospective study done at New
Delhi showed a high level of initial drug-resistance to
isoniazid (18.5%) and a low level of resistance to
rifampicin.10
Data on the prevalence of drug-resistance from the
Army Hospital, Pune showed a very low level of initial
resistance to isoniazid and the authors have explained
that this lower level of drug-resistance in this population
could be due to the minimal chance of indiscriminate
exposure of anti-TB agents prior to reporting to the
hospital. However, it should be emphasized that several
of these reports, except those from the Tuberculosis
Research Center (Chennai) TRC, National Tuberculosis
Institute (Bengaluru) (NTI) and the Armed Forces
Group, may have inherent limitations due to flaws in
508
methodology and hence need to be interpreted with

caution.
The ICMR and the TRC, Chennai, have conducted
drug-resistance studies in different parts of the country.
These have been supplemented by various other drugresistance surveys.9-13 A study conducted at the New
Delhi Tuberculosis Center showed initial resistance to
isoniazid and rifampicin at 18.5% and 0.6% respectively
and acquired resistance as 50.7% and 33.0% respectively.10 A referral hospital based study in Mumbai
recently reported primary drug-resistance to isoniazid
as 45%, to rifampicin as 27%, to ethambutol as 9% and to
streptomycin as 54%.11 Secondary resistance to isoniazid
was reported as 68%, to rifampicin as 60%, to ethambutol
as 8% and to streptomycin as 36%. Thirty percent cases
showed multidrug-resistance to isoniazid and rifampicin.
The estimated overall prevalence of primary drugresistance in adults has been reported to be 20 to 30% for
INH and 2 to 3% for rifampicin. Acquired drug-resistance
is much higher at 50 to 60% for INH, 20 to 30% for
rifampicin and 15 to 20% for streptomycin.12
In the recent WHO report6 it is estimated that the %
MDR among new TB cases (95% CI) is 2.3 (1.82.8), while
that among previously treated cases is 17.2 (14.919.5).
In a recently published representative state-wise survey
in the state of Gujarat (2005 population: 56 million), of
1571 isolates from new patients, 1236 (78.7%) were
susceptible to all first-line drugs, 173 (11%) had INH
resistance and MDR-TB was found in 37 (2.4%, 95%CI
1.6-3.1).13,14 Of 1047 isolates from previously treated
patients, 564 (54%) were susceptible to all first-line drugs,
387 (37%) had INH resistance and MDR-TB was found
in 182 (17.4%, 95% CI 15.0-19.7%). Among 216 MDR-TB
isolates, 52 (24%) were ofloxacin (OFX) resistant; seven
cases of extensively drug-resistant TB (XDR-TB) were
found, all of whom were previously treated cases.
In a study from Uttar Pradesh, a total of 686 M.
tuberculosis isolates were obtained from 1162 patients, of
which 318 were from untreated subjects and 368 were
from patients who were treated for tuberculosis in the
past.15 Prevalence of MDR was 19.8 percent, initial and
acquired being 13.2 and 25.5 percent respectively.
There is a paucity of reports of drug-resistance in
children due to comparatively few centers where facilities
for culture and drug sensitivity exist. Therefore, much
of drug-resistance has been presumed clinically when
patients do not improve or the symptoms return after
initial improvement. There are large number of patients
carrying resistant strains of M. tuberculosis and since the
disease in children is just a reflection of the disease in
adults, similar conclusions can be drawn.
The diagnosis of pediatric MDR-TB is often extremely
delayed due to reliance on the adult case definition and
should be changed to prevent progressive, chronic illness
in such children. Programmatic changes could facilitate

earlier diagnosis and treatment of pediatric MDR-TB and
in other DOTS-Plus Programs.16
Mechanism and Transmission of Drug-resistance

Drug-resistance in M. tuberculosis occurs by random,
single step, spontaneous mutation at a low but
predictable frequency, in large bacterial populations.
The probability of incidence of drug-resistant mutants
is 10-8 for rifampicin, while for isoniazid and some of
the other commonly used drugs it is 10-6. Therefore, the
probability for resistance to both isoniazid and
rifampicin to develop is 10-14, which is much larger than
the number of organisms present in a medium sized
cavity in a patient with open pulmonary TB.
Although for several years, drug-resistant strains of
M. tuberculosis were considered to be less infectious
than the drug susceptible ones, recent studies have
demonstrated that the drug-resistant mutants are equally
infectious and can cause severe disease in an individual
exposed to the same.
Microbiological Basis
Several types of mycobacterial drug-resistance have been
defined.
Natural Resistance
Natural resistance is defined as resistance to a drug when
a strain has never been previously exposed to the drug,
e.g. Mycobacterium bovis is naturally resistant to
pyrazinamide.
Primary Drug-resistance
Primary drug-resistance is when the patient is infected
with drug-resistant population without having received
prior treatment. The infection is transmitted from a
person with drug-resistant tuberculosis.
Acquired or Secondary Drug-resistance

Acquired or secondary drug-resistance is when the
patient harbors organisms which were initially drug
susceptible, and the resistance has developed during the
course of treatment. This could be due to poor compliance
or a faulty treatment plan.
Wild Type Resistance

Wild type resistance is when in a large population of
drug susceptible mycobacterium, individual organisms
are resistant to a single drug. This results from
spontaneous mutations in the mycobacterial chromosome. Table 36.2.1 gives the frequency of spontaneous
mutation to various drugs.

Table 36.2.1: Frequency of spontaneous mutation
against different drugs
Drug
INH, Streptomycin
Rifampicin
Ethambutol
Incidence of spontaneous
mutation
1-5 10-6
10-8
10-4
Since resistance to the various antituberculosis drugs

occurs independently, chances that the organism have
wild type resistance to two drugs is very rare, e.g. for
INH and RIF is 10-6 and 10-8 respectively and together
10.-14 A tubercular cavity containing 107 to 109 bacilli will,
therefore, have no organism which is resistant to two
drugs. Similarly, closed caseous lesion in children, having
105 to 107 bacilli will have no resistant organism.
Resistant tuberculosis in children is usually of the
primary type caused by exposure to a case of resistant
tuberculosis. Because they have a lower bacillary burden
they are less likely to develop acquired resistance, even
if suboptimally treated.17
However, Karande et al18 described a 12-year-old boy
in Mumbai with secondary multidrug-resistant TB. He
had received multiple courses of inadequate treatment
with various anti-TB treatment regimens for 9 years. The
TB gradually progressed in severity and was disseminated with the bacterial load increasing sufficiently for
multidrug-resistant TB to develop.
Genetic Basis
Drug-resistance appears to be chromosomal in origin,
caused by specific mutations that occur in independent
genes. This type of drug-resistance is not transferable
from one organism to another and is not linked between
antimicrobial drugs, however, the bacilli may show crossresistance to drugs with similar structure. 19,20 The
molecular mechanism of rifampicin resistance in most
M. tuberculosis is a missense mutation in the gene (rpoB)
encoding the beta unit of the RNA polymerase.21 Some
strains of M. tuberculosis that are resistant to INH have
reduced catalase-peroxidase activity. A specific gene
(katG) controls this activity. A complete absence of katG
from the chromosome has been detected in some strain
of INH resistant M. tuberculosis.22,23 Another gene (inhA)
is also thought to be involved in INH resistance. 24
Mutations in the 16S ribosomal RNA gene are associated
with resistance to streptomycin.25,26 With the emergence
of MDR strains of M. tuberculosis resistance has also been
observed to quinolones with a missense mutation at the
area of gyrA.27
Chromosomally borne mutations occur spontaneously in M. tuberculosis only at a predictable rate as
described earlier. A characteristic feature of these mutations is that they are unlinked.
509
Table 36.2.2: Antituberculosis drug and the genes

involved in their resistance
Drug
Group 1
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
Group 2
Streptomycin
Capreomycin
Group 3
Fluoroquinolones
Genes involved in drugs resistance

Enoyl acyl carrier protein (acp),
reductase (inhA)
Catalase-peroxidase (katG)
Alkyl hydroperoxide reductase
(ahpC)
Oxidative stress regulator (oxyR)
B-Ketocyl acyl carrier protein
synthase (kasA)
RNA polymerase subunit B (rpoB)
Pyrazinamidase (pncA)
Arbinosyl transferase (emb A, emb B,
and emb C)
Ribosomal protein submit 12 (rpsL)
16s ribosomal RNA (rrs)
Aminoglycoside
phosphotransferase gene (strA)
Haemolysin (tlyA)
DNA gyrase (gyr A and gyr B)
The genes involved in drug-resistance is given in

Table 36.2.2.
Potential Causes of Drug-resistance

Patient-related Factors
Nonadherence to treatment is the single most important
factor for emergence of drug-resistance. 28,29 Nonadherence to a single drug is more dangerous than failure
in taking all the drugs. The adherence to treatment may
be particularly difficult for children. Children with
tuberculosis are generally not very ill, and convincing
them or their parents to take several medications for
many months maybe difficult. Moreover, tuberculosis in
children is often associated with socially disadvantaged
households which further compromises adherence to
treatment.30
The most effective means to prevent acquired drugresistance is the use of directly observed therapy (DOT),
whereby a health care worker or other second party is
directly involved in the administration of each dose of
medication to the patient.
Physician-related Factors
Many cases of drug-resistant tuberculosis have resulted
from inadequate management by the physician. The
most common errors are addition of a single drug in a
510
failing regimen (thereby creating serious resistance for

several drugs), an inadequate initial regimen, failure to
recognize primary or acquired resistance, inability to
and deal with nonadherence with prescribed treatment,
and inappropriate single-drug therapy.31
Multiple inappropriate prescriptions for treatment of
tuberculosis by physicians may be promoting drugresistant tuberculosis. A study of 100 prescriptions in
Mumbai reveled 80 different anti-TB regimens; most were
both inappropriate and expensive.32
Detection of Drug-resistance
The conventional methods of culture, identification and
drug susceptibility testing of the isolated organism
require a minimum of 10 to 12 weeks. Although most
widely used, the long waiting period in obtaining the
results by these methods may delay the initiation of
proper treatment, resulting in the patient transmitting
drug-resistant infection in the community. The use of
direct sensitivity tests, especially to isoniazid and
rifampicin has resulted in a saving of at least 4 weeks in
obtaining the resistance status. However, this method is
not very useful in smear negative and paucibacillary
specimens.
Several newer methods including molecular
diagnostics have resulted in cutting down the time
interval between collection of the specimen and
availability of results in 2 to 3 weeks or even less.
However, these methods require considerable technical
expertise and impose financial constraints in a routine
laboratory set up in the developing nations.
Clinical Features of Resistant Tuberculosis

The spectrum of disease caused by drug-resistant
organisms is similar to that caused by drug susceptible
bacilli.16 Children with drug-resistant primary tuberculosis tend to have typical radiological patterns
including hilar adenopathy, segmental lesion and
collapse consolidation and those with reactivation
disease tend to have apical cavities.16,33 The incidence of
extrapulmonary tuberculosis appears to be similar
among children infected with MDR bacilli and drug
susceptible strains.12 When tuberculosis exists with HIV,
the disease pattern is no different from that seen in HIV
seronegative children.
In a recent study of 39 culture confirmed MDR-TB
from South Africa primary tuberculosis was observed in
26 (67%) and adult type of tuberculosis was documented
in 11 (28%) children. Remaining children had extrapulmonary tuberculosis including CNS tuberculosis.34
In CNS tuberculosis only 8% had meningitis and 13%
had granuloma.
Diagnosis
Since the clinical presentation of both, drug-resistant and
drug-susceptible tuberculosis is the same, the only certain
way of diagnosing resistant tuberculosis is by isolating
the infective strain and assessing its susceptibility pattern.
But AFB isolation from children with tuberculosis except
in miliary or cavitary disease is low (25-44%), even in
the most advanced centers.35 Adult contacts of children
should be assessed for history of prior antituberculosis
therapy with persistent sputum-positivity. Since this is
a pointer towards drug-resistance, children with such
adult contacts should be watched for any lack of response
or deterioration on treatment.
Diagnosis of drug-resistance is further confounded
by certain peculiarities of tuberculosis disease. The
resolution of radiographic abnormalities of chest can take
months or years after successful treatment. Also, posttuberculous bronchial hyper-reactivity, bronchiectasis
and other residual lesions can cause symptoms with
persistence of radiological shadows. About 15 to 20% of
patients with susceptible organisms continue to have
lymph nodes of considerable size even after complete
therapy. They may disappear gradually or persist or
fluctuate intermittently. In such cases, histopathology
may show persistence of sterile granuloma, however, no
AFB will be isolated except in cases of relapse or drug
failure. Also, tuberculomas of brain may increase in
number as well as size even on successful treatment and
ultimately heal over a period of months to years. A
patient can have recurrence of seizures during the healing
phase, but such symptoms do not necessarily imply a
relapse or resistance to antituberculosis therapy.
The diagnosis of MDR-TB is often delayed due to
various reasons. In a recent report of 39 children with
MDR-TB average delay in starting appropriate MDR
treatment after TB diagnosis was a median of 2 days, if
MDR-TB source cases were taken into account, but 246
days if the drug susceptibility pattern of the source case
was not considered. There was a delay of 283 days in the
absence of a known tuberculosis source case. Correlation
between the drug susceptibility results of the childs and
adult source cases isolates was 68%.34 Observations of
this study suggest that there is need to change the
definition of MDR-TB in children. If a child has an adult
patient with documented MDR-TB he can be considered
to be suffering from MDR-TB. He should be started on
appropriate treatment after taking appropriate samples
for culture and sensitivity for M. tuberculosis. Similarly,
a patient who fails to improve after appropriate
antituberculosis drugs with good compliance, it is likely
that he maybe suffering from drug-resistant tuberculosis.
The child should be referred to specialized center dealing
with drug-resistant tuberculosis cases. The primary care

physician should not start the child on regimen for drugresistant tuberculosis.
Predictors of Drug-resistance in Children

Patterns of drug-resistance among children with
tuberculosis tend to reflect those found among adults in
the same population.33,34 Predictors of drug-resistance
in children are:
Residence in country or area with high rates of drugresistance
Previous antituberculosis therapy
HIV infection in the child or the adult source case
Known contact with adult patient with MDR-TB.
Laboratory Diagnosis of Drug-resistant Tuberculosis

Various methods are used for drug susceptibility tests.36They include the conventional and the newer tests
utilizing phenotype and genotypic resistance testing.
39
Direct Methods
The clinical material is inoculated directly onto drug-free
and drug-containing media, thereby, allowing simultaneous isolation and susceptibility testing. They are
generally performed for smear-positive material only.
The results of this method may be more accurate as they
are representative of entire bacterial population present.
Results are available in 3 to 6 weeks time. The methods
used are 7H10 media, gradient plate method or L-J
media.
Indirect Method
Colonies from a pure culture isolate are subcultured into
a broth media and then plated on drug-free and drugcontaining solid media. The colony selected may not be
truly representative of the entire bacterial population.
Now modified proportion method is used, i.e. evaluation
is done as proportion of growth permitted on drug
containing media compared to drug free media.
Resistance is present when 1% or more growth occurs
on drug containing media compared with drug free
media. This test can be performed on smear-negative but
culture-positive cases. But it takes a long time and cannot
be used for pyrazinamide (PZA) susceptibility testing.
Rapid Method
BACTEC system: This automated radiometric system can
significantly shorten the time for mycobacterial detection
and susceptibility testing.36 This method consists of
growing M. tuberculosis in liquid media containing
14
C-fatty acid substrate with and without critical
concentration of drugs. As the bacilli grow, they release
14
CO2. The instrument quantitates this in growth index
511
units. This method is rapid (average time taken is 9.3

days), uses liquid media in which drug concentrations
remain stable and even susceptibility to PZA can be
estimated. But this method is expensive and cannot be
used for reserve drugs, e.g. cycloserine, ethionamide.
Luciferase phage system: In this system the mycobacteria
are infected with a phage carrying the enzyme luciferase,
which is responsible for the glow of the firefly. When the
infected M. tuberculosis carrying the enzyme is grown in
culture containing the drug, to which the substrate
luciferin is added, light is produced if the M. tuberculosis
strain is resistant to the drug in the medium. If the strain
is sensitive to the drug, it is killed and there is no
luciferase in the system and no light is produced.39 The
test is both highly sensitive and specific.
Polymerase chain reaction (PCR): Single stranded
conformation polymorphism has made possible the rapid
identification of rifampicin resistant M. tuberculosis.40,41
Results are available within 24 hours. The analogous
setting for isoniazid resistance is less favorable, since
more than one gene maybe involved in isoniazid
resistance.22,23 Restriction fragment length polymorphism
(RFLP) using insertion element IS986/IS6110 based DNA
probe has been used with success in epidemiological
studies in MDR-TB outbreaks.42
Slide culture sensitivity systems: This system which can
provide results in 7 days is particularly useful for guiding
the treatment of smear-positive patients. In this method
smear-positive sputum is spread on slides and incubated
without prior decontamination in a selective lyzed
human blood medium. Drug concentrations and
definitions of resistance are suggested for tests against
first and second-line antituberculosis drugs. They need
further evaluation in clinical settings in developing
countries.43
Using these methods the time spent in awaiting
reports is cut down to 2 to 3 weeks. However, there are
financial and technological constraints in applying these
methods in developing countries. Since, in most
developing countries, the diagnosis of drug-resistant
tuberculosis is often made without isolation of AFB from
the child, all other possible confounding alternatives
must be carefully excluded before starting treatment with
reserve drugs. Also, attempts should be made to isolate
the bacteria by all possible modalities, i.e. induced
sputum (3% hypertonic saline), concentrated smears,
bronchoalveolar lavage or direct fine needle aspirates of
the involved areas such as lymph nodes.
MANAGEMENT OF PATIENTS WHO HAVE

DRUG-RESISTANT DISEASE
Microbial resistance to antimycobacterial drugs may be
either initial or secondary. Initial resistance occurs in
512
patients who are not known to have had previous

antimycobacterial treatment. Risk factors for initial
resistance include exposure to a patient who has drugresistant tuberculosis, being from a country with a high
prevalence of drug-resistance, and greater than 4%
primary resistance to isoniazid in the community.
Secondary resistance occurs in patients who have been
treated in the past. The frequency of both types of
resistance is to a large extent determined by the adequacy
of tuberculosis treatment programs. Poor treatment
programs enable resistant organisms to emerge,
producing secondary resistance in inadequately treated
patients. These organisms are then transmitted and, when
disease occurs, the infected person has primary
resistant disease.
In the past primary isoniazid resistance rates in most
areas of the United States were < 4%; thus, two-and
three-drug regimens for tuberculosis were considered
adequate. Community rates of primary isoniazid
resistance < 4% may be an indication that an initial
regimen of fewer than four drugs is acceptable.
However, continued surveillance of drug susceptibility
patterns is necessary to ensure that low rates of primary
drug-resistance continue.
Recently, pockets of tuberculosis caused by organisms
that are resistant to both isoniazid and rifampicin have
been described. Resistance to both of these potent agents
considerably complicates patient management, making a
successful outcome much less likely than if susceptibility
to one or the other of these two agents were maintained.
The basic principle of managing patients whose
organisms are resistant to one or more drugs is
administration of at least two agents to which there is
demonstrated susceptibility.
Unfortunately, good data are not available on the
relative effectiveness of various regimens and the
necessary duration of treatment for patients with
organisms resistant to both isoniazid and rifampicin.
Moreover, many such patients will have resistance to
other first-line drugs (e.g. ethambutol and streptomycin)
when drug-resistance is discovered. Because of the poor
outcome in such cases, it is preferable to give at least
three new drugs to which the organism is susceptible.
This regimen should be continued at least until
bacteriologic sputum conversion is documented,
followed by at least 12 months of two-drug therapy.
Often, a total of 24 months of therapy is given
empirically. Finally, surgery appears to offer considerable benefit and significantly improved cure rate for
those patients in whom the bulk of disease can be
resected.
To summarize in the management of drug-resistance
whenever possible, obtain expert opinion and advice
when it appears likely that a patient harbors drugresistant organisms.44
1. Take a careful history of previous treatment, or in the

case of child, the previous treatment of possible index
cases; susceptibility testing may have been carried out
on the index cases.
2. If possible, obtain material for culture and sensitivity
testing and if the clinical situation permits await the
results before altering or starting any regimen.
3. Where resistance to isoniazid and rifampicin (MDR)
is suspected or found, at least three and preferably
five drugs to which the patient has not previously
been exposed should be used. Ethionamide,
ofloxacin, ethambutol, possibly pyrazinamide and
an aminoglycoside (amikacin or kanamycin) is a
suggested combination. This regimen is continued
to smear conversion after which ethambutol and
ofloxacin or another bacteriostatic agent should be
continued for a further 18 months.
4. The use of second-line drugs carries the risk of an
increased incidence of side-effects which may be both
unpleasant and potentially dangerous. Patients,
therefore, require careful observation and continual
encouragement to persevere with treatment. This may
be the patients last chance for survival.
Relationship of Development of Resistance to a

Particular Drug with the Clinical Response
1. Resistance to rifampicin is of particularly ominous
significance as this drug is especially valuable for the
sterilization of lesions and in preventing the
emergence of resistance during therapy.
2. The most common form of resistance is that against
isoniazid, with a small number of patients harboring
organisms resistant to both isoniazid and rifampicin.
This is referred to multidrug-resistance (MDR).
3. If a patient harbors organisms resistant to isoniazid
and is being treated with a regimen containing
isoniazid, rifampicin and pyrazinamide, as is the case
in primary complex will be effectively receiving
pyrazinamide and rifampicin only. Pyrazinamide
although effective in the sterilization of lesions, is less
effective in preventing the development of resistance.
It is, therefore, particularly important that rifampicin
should be used in properly designed regimens
under supervision, in fixed combination with other
antituberculosis drugs, so that there is no chance of
monotherapy.
Management of Multidrug-resistant (MDR)

Tuberculosis
The treatment of MDR tuberculosis is a challenge since
it involves the use of second-line reserve drugs which
are not only more expensive and toxic, but also less
effective than standard first-line drugs. Second-line
513
Table 36.2.3: Drugs useful in the treatment of MDR-TB

Drugs
Daily dosage
Aminoglycosides
Streptomycin
Kanamycin
Amikacin
Capreomycin
15 mg/kg (750-1,000 mg)

15 mg/kg (750-1,000 mg)
15 mg/kg (750-1,000 mg)
15 mg/kg (750-1,000 mg)
Thioamides
Ethionamide
Prothionamide
10-20 mg/kg (500-750 mg)

10-20 mg/kg (500-750 mg)
Pyrazinamide
Adverse drug reactions

Pain at injection site
Ototoxicity (vertigo and deafness), nephrotoxicity
hemolytic anemia, aplastic anemia, agranulocytosis,
Thrombocytopenia, and lupoid reactions
Hypokalemia, hypocalcemia and hypomagnesemia,
and occasionally hepatotoxicity; may potentiate the
effect of neuromuscular blocking agents administered
during anesthesia
Epigastric discomfort, anorexia, nausea, metallic
taste and sulfurous belching, vomiting, excessive
salivation; psychotic reactions including hallucinations and depression: hypoglycemia, hypothyroidism,
and goiter; hepatotoxicity, gynecomastia, menstrual
disturbance, impotence, acne, headache, and
peripheral neuropathy; tolerance varies with
ethnicity; usually well tolerated in Africa and Asia
20-30 mg/kg
(1, 200-1,600 mg)
Hepatotoxicity, GI intolerance, hyperuricemia, and

arthralgias
Fluroquinolones
Ofloxacin
Levofloxacin
Uncommon, GI intolerance (e.g. Dizziness, headache,

mood changes, and rarely convulsions)
7.5-15 mg/kg (600-800 mg)
500-1000 mg
Ethambutol
15-20 mg/kg
(1,000-1,200 mg)
Dose-dependent optic neuritis,* and peripheral

neuritis;
Cycloserine
|| Terizodone
15-20 mg/kg (500-750 mg)

15-20 mg/kg (600 mg)
Dizzness, slurred speech, and convulsions;

Headache, tremor, insomnia, confusion, depression;
and altered behavior; suicide risk generalized
hypersensitivity reaction or hepatitis.
Para-aminosalicylic acid
150 mg/kg (10-12 g)
GI disturbance (e.g. anorexia, nausea, vomiting,

abdominal discomfort, and diarrhea); general skin or
other hypersensitivity, and hepatic dysfunction;
hypokalemia; hypothyroidism and goiter; best
avoided in renal failure as it may exacerbate acidosis;
sodium salt should not be given when a restricted
sodium intake is indicated
Chemical structure resembles thiacetazone, with which there is frequent and partial cross-resistance. However, strains that
are resistant to thiacetazone are often sensitive to thioamides, but the reverse is seldom the case. Therapy is more acceptable
if the drug is administered with orange juice or milk ingestion, or at bedtime to avoid nausea.
|| Terizidone is a combination of two molecules of cycloscrine.
* Optic neuritis is not a problem as researched by Seth Vimlesh.50
drugs include aminoglycosides, thioamides, fluoroquinolones, cycloserine and para-aminosalicylic acid

(PAS). They are enumerated in Table 36.2.3.
Principles of Treatment of MDR-TB

MDR-TB should always be treated in consultation with
a clinician who has experience in treating the disease.
Patients should be treated with at least 2 or preferably
3 to 4 medications, to which the strain of the patient
or source case is known or likely to be susceptible.
Aminoglycoside or capreomycin should be one of the

medicines as studies have indicated that its use is a
predictor of culture conversions and survival.45
Use bactericidal drugs as far as possible.
Treatment should be given for at least 12 months after
M. tuberculosis cultures have converted to negative.
In children with HIV infection or cavitary lesions it is
extended to 24 months.46
Intermittent regimens are not recommended.47
If patients M. tuberculosis culture remains positive
after 4 to 5 months of treatment it should be tested
514
for susceptibility to first-and second-line drugs. If this

is not available as in most centers in our country
at least two new drugs should be added while
continuing original medication. If available, and
patient is clinically stable it is preferable to wait for
susceptibility studies and add drugs accordingly.
If patient develops an adverse drug reaction, the
offending drug can be removed and the rest of the
regimen continued. Alternatively, a new medication
can be substituted. In general the first-line drugs are
well tolerated by children but adverse effects with
second-line drugs are higher. Children taking secondline drugs need to be closely monitored and liver
enzymes, renal functions and hearing tests done
periodically.
Treatment of Drug-resistant Tuberculosis Disease

Even under ideal conditions, M. tuberculosis is isolated
from sputum or gastric aspirate of only 50% of children
with pulmonary tuberculosis, while culture yields from
other anatomic sites are lower. For this reason, the
clinician needs to be aware of the resistance pattern in
the community. Also, since the vast majority of resistance
in children is primary, susceptibility information can
come from the M. tuberculosis isolate that is obtained from
the adult who transmitted the infection.
Children with Tuberculosis Disease with Known Adult

Patients with MDR Tuberculosis
All children with MDR tuberculosis need an individualized treatment regimen (ITR). For children with known
adult contacts and the sensitivity of M. tuberculosis is
known, following principle maybe followed for ITR.
Children first should receive any oral first-line agents to
which the isolate (from adult contact) is sensitive.
Second, all regimens should include an injectable agent
for a minimum of six months after culture conversion,
and an oral quinolone for the duration of therapy.
Children who do not yet have five drugs in their regimen should receive additional second-line drugs
(ethionamide, cycloserine or PAS). If a strain is highly
resistant and the childs regimen still contains less than
five drugs, additional agents with known antituberculosis activity (e.g. amoxicillin/clavulanate, linezolid,
clarithromycin) can be added.48
Children with Tuberculosis Disease

without Known Contact
These are children who fail to respond to appropriate
antituberculosis treatment. The treatment failure maybe
due to several reasons including inappropriate regimen,
poor adherence or wrong diagnosis. In this group it is
recommended that the diagnosis of TB should be
ascertained again, appropriate specimen should be

collected for demonstration of M tuberculosis and category
2 treatment be started (2 SHRZE 1 HRZE 5 HRE). The
family should be counseled to achieve 100% compliance.
Children who are already on category 2 regimen and do
not show improvement even after 3 months of intensive
phase may be considered for treatment regimen for MDRTB in a TB Hospital which is equipped for this under
WHO program of treating MDR tuberculosis.
Treatment of Drug-resistant Infection

All children with infection caused by an MDR strain of
M. tuberculosis should be treated. A difficult issue is
treatment of children who have had recent (< 3 months)
close exposure to an adult with MDR-TB but whose
Mantoux test is negative. In a similar situation but when
the adult has drug susceptible disease the child is given
INH and the Mantoux is repeated 3 months after
exposure has ended. Because of toxicity of drugs used
for MDR-TB the risk benefit has to be evaluated.49 But,
since children less than 2 years have risk of rapidly
developing life-threatening tuberculosis, they should be
treated. If the Mantoux test remains negative 3 months
after exposure has ended, the treatment can be stopped.2
Also, any child having any immunocompromising
condition, i.e. AIDS should be treated. For other details
refer to Chapter 36.1.
Another suggested approach to design a treatment
regimen for MDR-TB is given in Figure 36.2.1.
Monitoring of Treatment
It is recommended that children getting treatment of
MDR-TB should receive supervised treatment to ensure
100% adherence. The person giving medications should
observe for side-effects daily and report to doctor
regularly. Sputum/gastric aspirate should be done every
month and treatment is continued for 18 to 24 months
till 12 consecutive cultures are negative.48
In the pediatric tuberculosis clinic at All India Institute
of Medical Sciences all children who fail to respond to
category 2 regimen (drugs are used daily and not
intermittent) for 3 months are admitted in-hospital,
diagnosis is ascertained again, sputum/gastric aspirates,
bronchoscopic lavage, FNAC aspirate from lymph nodes
are sent for M. tuberculosis culture and child is started on
individualized treatment regimen (ITR) (as described
above). Child is observed for at least two to three weeks
in hospital for drug toxicity and parents are counseled
about adherence. After three week of observation child
is followed up every 2 to 4 weeks till therapy is
completed. After completing the therapy child is
followed every 3 month for at least 2 years.
515
Fig. 36.2.1: Suggested approach to designing a treatment regimen for MDR-TB
Improvement in the result of bacteriologic tests

(sputum/gastric lavage, etc.) is the main marker of
response but decreased fever, cough, sputum and gain
in weight are important indirect evidences of success of
chemotherapy. Radiological improvement may lag
behind other changes.
In general, the first-line drugs are well tolerated by
children, and monitoring for adverse reactions by
laboratory testing is unnecessary. While children usually
tolerate the second-line drugs better than adults do, the
rates of adverse reactions among children are much higher
than for the first-line drugs. Children taking ethionamide
frequently develop gastrointestinal disturbances and
rarely hepatitis. Aminoglycosides can cause renal toxicity
and eighth cranial nerve dysfunction. Cycloserine, though,
generally well tolerated can rarely affect central nervous
system and cause personality disturbances. Ethambutol
is reported to cause optic neuritis and children taking this
drug should have visual testing but it is not true as has
been demonstrated by Seth et al.50 Monitoring of liver and
renal functions and hearing tests are needed periodically.
Role of Surgery
Resectional surgery is a useful component of treatment
of MDR-TB in adults infected with bacilli which are
resistant to most drugs and sensitive to only one or two

weak drugs.51 Surgery remains a crucial adjunct to
medical therapy for the treatment of MDR-TB and
medically failure lesions. Proper selection of the patients
and early decision for surgical intervention can achieve
a high success rate and can salvage the lung parenchyma
in this difficult group of patients. Resectional surgery
has a role in patients with predominantly unilateral or
localized disease with adequate respiratory reserve and
in whom chemotherapy alone has failed. Surgery is
usually considered when following criteria are met:
i. An adequate chemotherapeutic regimen including both
first and second-line antituberculosis medication have
failed to cure.
ii. The extent of disease is limited enough to necessitate
only a lobectomy or pneumonectomy.
iii. The remaining lung tissue is relatively devoid of
tuberculosis.
Role of Immunotherapy
Immunotherapy with M. vaccae vaccine has been used
in small trials in adult patients. Results of these trials
have shown some benefit.52 A series of small trials in
Argentina, India, Nigeria, Romania, South Africa and
Vietnam have pioneered the way forward, disclosing
geographic variability, with South Africa as the only
516
country where almost no effects were recorded.

Together the studies have shown that a single dose may
not be sufficient. These studies have confirmed the
mode of action of M. vaccae to be regulation of cellmediated immunity with enhancement of Th1 and
down-regulation of Th 2. Benefits have been shown in
faster bacteriological conversion, reduction in ESR,
recovery of body weight and resolution of radiological
opacities, leading to better recovery from the disease
even when given to patients receiving directly observed
therapy, short-course (DOTS). There are currently no
reports of immunotherapy in pediatric drug-resistant
cases.
Cytokine Therapy
The other agents investigated include aerosolized
INF-, granulocytemacrophage colony stimulating
factoraerosolized IFN-, and low dose recombinant
human interleukin-2 as an adjunctive treatment for
patients with MDR-TB.
A number of other nonspecific immunopotentiating
agents are listed in Table 36.2.4.
Table 36.2.4: Other agents used in the treatment
of MDR-TB
Thalidomide
Pentoxifylline
Levamisole
Transfer factor
Inhibitors of transforming growth factor [TGF-]
Interlukin-12 [1L-12]
Interferon- [IFN- ]
Imiquimod (an oral agent that stimulates the production
of interferon-)
Newer Drugs
Even though the need for newer drugs to combat MDRTB exists, there are no drugs showing promise. In the
recent past there have been few reports qouting the value
of agents like imipenem, amoxicillin-clavulanic acid,
interferon gamma via aerosol, newer rifamycins
(rifabutin, rifamycin, rifatazil) and recombinant human
interleukin 2.53 A recently investigated group of compounds which appears encouraging is oxazolidinones.54
Table 36.2.5 gives the list of some of the older drugs
and newer drugs with potential of being anti-TB agent.
Concept of DOTS Plus

In spite of introduction of highly effective therapy for
tuberculosis in the form of DOTS (Directly observed
therapy, short-course) treatment failure continues. Strict
implementation of DOTS removes the onus of adherence
Table 36.2.5: Some of the older drugs and newer drugs

with potential of being an anti-TB agent at various stages
of development
Drugs
Older drugs
Rifamaycin derivatives
Rifapentine
Rifabutin
Fluoroquinolones
Ofloxacin
Sparfloxacin
Levofloxacin
Moxifloxacin
Gatifloxacin
Newer drugs
Diarylquinoline
R 207910/TMC 207
Nitroimidazopyran
PA-824
Nitro-dihydroimidazo-oxazole
OPC 67683
Pyrrole
LL3858, LL3522
Macrolides
Clarithromycin
Telithromycin
Oxazolidinones
Linezolid
PNU100480
Diamine
SQ 109
Ring-substituted imidazoles
from the patient. DOTS regime uses isoniazid and

rifampicin as the basis of the short-course chemotherapy.
Patients with MDR-TB are infected with strains resistant
to at least isoniazid and rifampicin, thus, the failure of
DOTS in MDR-TB. To combat this problem, in 1997 WHO
Global Tuberculosis Program, CDC, IUATLD got
together in an effort to expand DOTS in manner that
would take into account MDR-TB. In early 1999, the
WHO formally announced the establishment of a
working group to plan the implementation of pilot DOTS
Plus interventions.55
Two basic approaches to DOTS Plus have been
proposed: individualized treatment regimens and
standardized regimens incorporating second and thirdline drugs.
In individualized treatment regimens (ITRS), the
regimen is designed as per the resistance pattern of the
strain infecting each patient. ITRS is unlikely to fail since
inadvertent monotherapy would not occur, but they
require intensive laboratory facilities. It has limited
applicability in resource poor countries.
517
Standardized approach can be of two types. Firstly,

uniform throughout the world and, secondly, adapted
to local epidemiology according to common resistance
patterns identified in a given population. The advantage
of such a regime is its lower cost, less laboratory work
and less technical expertise required to administer it.
As we know, the way towards tuberculosis
elimination is by effectively treating all cases. DOTS
was envisioned as the most effective means of doing
it, but with the advent of MDR-TB it is failing.
Furthermore, if rifampicin and isoniazid based regimes
are used for patients resistant to these medications, it
not only is a waste of resources, but also serves as a
means of acquiring resistance to ethambutol, pyrazinamide and streptomycin. In such a scenario, where drug
susceptible and drug-resistance disease coexist, DOTS
plus needs to be evaluated. When treating children
with MDR-TB, the treating expert will have to be
guided by the drug susceptibility studies of their adult
infectious source.
limited number of highly specialized centers, at least one

in each state, which have ready access to an RNTCP
accredited culture and DST laboratory, with qualified
staff available to manage patients, using standardized
second-line drug regimens given under daily DOT and
standardized follow-up protocols, and have systems in
place to deliver ambulatory DOT after an initial short
period of inpatients care to stabilize the patients on the
second-line drug regimen, and with a logistics system
and standardized information system in place.
Following months of preparatory activity, DOTS-Plus
activities under RNCTP have been initiated in the states
of Gujarat and Maharashtra for the last few months. On
the 29th of August 2007, Gujarat became the first state in
the country to initiate MDR-TB patients on treatment
under RNTCP with its Category IV regimen. On this date,
14 confirmed MDR-TB patients were initiated on
treatment under RNTCP in Gujarat.
Similar provision will be extended to other states in
the phased manner.
RNTCP Launches Category IV Treatment (DOTS-Plus

Treatment) for Multidrug-resistant Tuberculosis
Patients in Gujarat on the 29th of August 2007
Prevention
The emergence of resistance to drugs used to treat

tuberculosis (TB), and particularly multidrug-resistance
TB (MDR-TB), has become a significant public health
problem in a number of countries and an obstacle of
effective TB control. To address this issue, the Revised
National Tuberculosis Control Program (RNTCP) has
initiated DOTS-Plus activities under the program for the
appropriate management of MDR-TB patients and to
prevent any further propagation and dissemination of
MDR-TB.
The RNTCP views the treatment of MDR-TB patients
as a standard of care issue. Recognizing that the
diagnosis and treatment of MDR-TB cases is complex,
RNTCP has developed national guidelines based on
the WHO recommended international DOTS-Plus
guidelines. These guidelines promote full integration of
DOTS and DOTS-Plus activities under the RNCCP, so
that patients with MDR-TB are both correctly identified
and properly managed under the guidelines set out in
this document.
The diagnosis of MDR-TB will be made at a network
of at least 24 RNTCP state level Intermediate Reference
Laboratories (IRLs) accredited to perform culture and
drug sensitivity testing (DST). RNCTP has initiated the
establishment of the IRL network in a phased manner at
National Tuberculosis Institute (NTI), Bengaluru
(formerly Bangalore) LRS Institute, New Delhi; and
JALMA, Agra. The treatment of MDR-TB patients is
planned to being at DOTS-Plus sites established in a
The prevention of drug-resistant tuberculosis depends on

effective use of the principles of tuberculosis control. The
timely identification and adequate treatment of patients
who have MDR-TB infection and disease is of foremost
importance in preventing further spread. The integrity of
public health system which has the responsibly, do tracing
of source case through contact investigation of children of
an adult with MDR tuberculosis. All patients with
tuberculosis should be treated by clinicians who have some
expertise in TB treatment. Drug regimens should be
adequate and simple errors avoided.
HIGHLIGHTS
We are living in a time in which a series of MDR-TB
epidemics are progressing unchallenged.
In a complex epidemic where drug-susceptible and
drug-resistant disease coexist, DOTS which relies on
fixed-dose, short-course chemotherapy may not be
effective in preventing the progression of this
epidemic.
Some drug regimens have been highlighted for the
treatment of latent MDR-TB or the disease in a child
with MDR-TB by literature search.
There is an urgent need to seriously consider the
application of DOTS-Plus to the National Tuberculosis
Programs already committed to DOTS. This has
already been started in India including children. This
has been possible with International cooperation for
clinical and laboratory support and financing and
drug supply.
518
REFERENCES
1. Youmans GP, Williston EH, Feldman WH, et al. Increase
in resistance of tubercle bacilli to streptomycin: A
preliminary report. Proc Mayo Clin 1946;21:126-7.
2. Pyle MM. Relative numbers of resistant tubercle bacilli
in sputa of patients before and during treatment with
streptomycin. Proc Mayo Clin 1947;22:465-73.
3. Vennesland K, Ebert RH, Bloch RG. The demonstration of
naturally-occurring streptomycin-resistant variants in the
human strain of tubercle bacillus H-37RV. Science 1947;
106:476-7.
4. Yegian D, Vanderlinde RJ. A quantitative analysis of the
resistance of mycobacteria to streptomycin. J Bacteriol
1948;56:177-86.
5. Middlebrook G, Yegian D. Certain effects of streptomycin
on mycobacteria in vitro. Am Rev Tuberc 1946;54:553-8.
6. Karlson AG, Feldman WH, Hinshaw HC. Persistence of
resistance of tubercle bacilli to streptomycin during
passage through guinea pigs. Proc Soc Exper Biol & Med
1947;64:6-7.
7. British Medical Research Council. Streptomycin
treatment of pulmonary tuberculosis. Br Med J 1948;2:
769-82.
8. Howard WL, Maresh F, Mueller EE, et al. The role of
pulmonary cavitation in the development of bacterial
resistance to streptomycin. Am Rev Tuberc 1949;59:
391-401.
9. Howlett KS Jr, OConnor JB, Sadusk JF Jr, et al. Sensitivity
of tubercle bacilli to streptomycin. Am Rev Tuberc
1949;59:402-14.
10. Shamaskin A. Comments on bacterial resistance to
streptomycin. Dis Chest 1949;15:303-5.
11. Brennan AJ, Wichelhausen RH. Streptomycin-resistant
tubercle bacilli: Isolation of resistant organisms from
pleural fluid prior to institution of streptomycin therapy.
JAMA 1949;140:1275.
12. Furtos NC, Doane EA. Transmission of streptomycinresistant tubercle bacilli in man. JAMA 1949;140:1274-5.
13. Tinne JE, Henderson JL. Primary streptomycin-resistant
tuberculosis in a newborn child. Lancet 1950;259:901-04.
14. Therapeutic Trials Committee of the Swedish National
Association Against Tuberculosis. Para-aminosalicylic
acid treatment in pulmonary tuberculosis. Am Rev
Tuberc 1950; 61:597-612.
15. Vennesland K, Ebert RH, Bloch RG. In vitro effect of
streptomycin and para-aminosalicylic acid (PAS) on the
growth of tubercle bacilli. Proc Soc Exp Biol 1948;68:
250-5.
16. Karlson AG, Pfuetze KH, Carr DT, et al. The effect
of combined therapy with streptomycin, paraaminosalicylic acid and promin on the emergence of
streptomycin-resistant strains of tubercle bacilli: A
preliminary report. Proc Mayo Clin 1949;24:85-9.
17. British Medical Research Council. Treatment of
pulmonary tuberculosis with para-aminosalicylic acid
and streptomycin: Preliminary report. Br Med J
1949;2:1521.
18. British Medical Research Council. Treatment of pulmonary

tuberculosis with streptomycin and para-aminosalicylic
acid. Br Med J 1950;2:1073-85.
19. Carstensen B. Para-aminosalicylic acid (PAS) in
pulmonary and extrapulmonary tuberculosis. Am Rev
Tuberc 1950;61:613-20.
20. Thomas OF, Borthwick WM, Horne NW, et al. Infection
with drug-resistant tubercle bacilli. Lancet 1954;1:
1308-10.
21. Maggi N, Pasqualucci CR, Ballotta R, et al: A new orally
active rifamycin. Chemotherapia 1966;11:285-92.
22. British Medical Research Council. Isoniazid in the
treatment of pulmonary tuberculosis. Br Med J 1953;1:
521-36.
23. British Medical Research Council. Emergence of bacterial
resistance in pulmonary tuberculosis under treatment
with isoniazid, streptomycin plus PAS, and streptomycin
plus isoniazid. Lancet 1953;2:217-23.
24. Canetti G. Present aspects of bacterial resistance in
25. Bignall JR, Rist N. An international investigation of the
efficacy of chemotherapy in previously untreated
patients with pulmonary tuberculosis. A trial directed
by the Committee on Treatment and the Committee on
Bacteriology and Immunology of the International
Union against Tuberculosis. Bull Int Union Tuberc
1964;34:79-191.
26. Cummings MM, Livings DG. The prevalence of streptomycin-resistant tubercle bacilli in 5,526 consecutive
hospital admissions. In: Transactions of the 13th
Conference on the Chemotherapy of Tuberculosis. Edited
by the Veterans Administration Area Medical Office, St
Louis,Missouri, and the Department of Medicine and
Surgery, Washington, DC: Government Printing Office
1954:222-4.
27. Chaves AD, Robins AB, Abeles H, et al. The prevalence
of streptomycin- and isoniazid-resistant strains of
Mycobacterium tuberculosis in patients with newly
discovered and untreated active pulmonary tuberculosis.
Am Rev Tuberc 1955;72:143-50.
28. Editorial. Streptomycin-resistant tubercle bacilli as a
public-health hazard. N Engl J Med 1954; 251:584-5.
29. Beck F. Infection with drug-resistant tubercle bacilli. Am
Rev Tuberc 1955;72:151-7.
30. Fox W, Wiener A, Mitchison DA, et al. The prevalence of
drug-resistant tubercle bacilli in untreated patients with
pulmonary tuberculosis: A national survey, 1955-1956.
Tubercle 1957;38: 71-84.
31. Crofton J. Tuberculosis undefeated. Br Med J 1960;2:
679-87.
32. Steiner M, Cosio A. Primary tuberculosis in children.
Incidence of primary drug-resistant disease in 332
children observed between the years 1961 and 1964 at
the Kings County Medical Center Brooklyn. N Engl J
Med 1966;274:755-9.
33. Steiner P, Rao M. Drug-resistant tuberculosis in children.
34. Snider DE Jr, Kelly GD, Cauthen GM, et al. Infection and
disease among contacts of tuberculosis cases with drugresistant and drug-susceptible bacilli. Am Rev Respir Dis
1985;132: 125-32.

35. Schaaf HS, Gie RP, Donald PR, et al. Evaluation of young
children in household contact with adult multidrugresistant pulmonary tuberculosis cases. Pediatr Infect Dis
J 1999;18: 494-500.
36. Steiner P, Rao M, Mitchell M, et al. Primary drug-resistant
tuberculosis in children: Correlation of drug-susceptibility
patterns of matched patient and source case strains of
Mycobacterium tuberculosis. Am J Dis Child 1985; 139:7802.
37. Schaaf HS, Shean K, Donald PR. Culture-confirmed
multidrug-resistant tuberculosis in children: Diagnostic
delay, clinical features, response to treatment and
outcome. Arch Dis Child 2003;88:1106-11.
38. Schaaf HS, Van Rie A, Gie RP, et al. Transmission of
2000;19:695-9.
39. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis.
Emergency update. WHO, Geneva, Switzerland 2008.
WHO/HTM/TB/2008:402.
40. Nolan CM. Multidrug-resistant tuberculosis in the USA:
The end of the beginning. (editorial) Tuberc Lung Dis
1996;77:293-4.
41. Horne NW. Drug-resistant tuberculosis: A review of the
world situation. Tubercle 1969; 50(suppl):2-12.
42. Cohn DL, Bustreo F, Raviglione MC. Drug-resistant
tuberculosis: Review of the worldwide situation and the
WHO/IUATLD global surveillance project. Clin Infect
Dis 1997; 24(Suppl 1):S121-S30.
43. Pablos-Mndez A, Raviglione MC, Laszlo A, et al for the
WHO-IUATLD Working Group on Anti-Tuberculosis
Drug-resistance Surveillance. Global surveillance for
antituberculosis-drug-resistance, 1994-1997. N Engl J
Med 1998;338: 1641-9.
44. Espinal MA, Laszlo A, Simonsen L, et al. Global trends
in resistance to antituberculosis drugs. N Engl J Med
2001;344:1294-1303.
45. Ghandi NR, Moll A, Sturm AW, et al. Extensively drugresistant tuberculosis as a cause of death in patients
coinfected with tuberculosis and HIV in a rural area in
South Africa. Lancet 2006;368:1575-80.
46. Schaaf HS, Marais BJ, Hesseling AC, Donald PR, et al.
Surveillance of antituberculosis drug-resistance amongst
children from the Western Cape Province of South
Africaan upward trend. Am J Public Health 2009 Feb
5. [Epub ahead of print].
47. Marais BJ, Victor TC, Hesseling AC, et al. Beijing and
Haarlem genotypes are over-represented among children
with drug-resistant tuberculosis in the Western Cape
Province of South Africa. J Clin Microbiol 2006;44:353943.
48. Lutfey M, Della-Latta P, Kapur V, et al. Independent
origin of mono-rifampin-resistant Mycobacterium
tuberculosis in patients with AIDS. Am J Respir Crit Care
Med 1996;153:837-40.
49. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO,
Geneva, Switzerland 2006. WHO/HTM/TB/2006:361.
50. Schaaf HS, Gie RP, Donald PR, et al. Primary drugresistant tuberculosis in children. Int J Tuberc Lung Dis
2000;4:1149-55.
519
51. Steiner P, Rao M, Victoria MS, et al. A continuing study

of primary drug-resistant tuberculosis among children
observed at the Kings County Hospital Medical Center
between the years 1961 and 1980. Am Rev Respir Dis
1983;128:425-8.
52. Schaaf HS, Marais BJ, Donald PR, et al. Childhood drugresistant tuberculosis in the Western Cape Province of
South Africa. Acta Paediatrica 2006;95:523-8.
53. Oberhelman RA, Soto-Castellares G, Caviedes L, et al.
Improved recovery of Mycobacterium tuberculosis from
children using the microscopic observation drug
susceptibility method. Pediatrics 2006;118:100-6.
54. Barnard M, Albert H, Coetzee G, et al. Rapid molecular
screening for multidrug-resistant tuberculosis in a highvolume public health laboratory in South Africa. Am J
Respir Crit Care Med. 2008;177:787-92.
55. Schaaf HS. Drug-resistant tuberculosis in children. S Afr
Med J 2007;97 (Part 2):995-7.
56. Schaaf HS, Victor TC, Engelke E, et al. Minimal inhibitory
concentration of isoniazid in isoniazid-resistant
Mycobacterium tuberculosis isolates from children. Eur J
Clin Microbiol Infect Dis 2007;26:203-5.
57. Katiyar SK, Bihari S, Prakash S, et al. A randomized
controlled trial of high-dose isoniazid adjuvant therapy
for multidrug-resistant tuberculosis. Int J Tuberc Lung
Dis 2008;12:139-45.
58. Takeda S, Maeda H, Hayakawa M, et al. Current surgical
intervention for pulmonary tuberculosis. Ann Thorac
Surg 2005;79:959-63.
59. Mohsen T, Zeid AA, Haj-Yahia S. Lobectomy or
pneumonectomy for multidrug-resistant tuberculosis can
be performed with acceptable morbidity and mortality:
A seven-year review of a single institutions experience.
J Thorac Cardiovasc Surg 2007;134:194-8.
60. Drobac P, Mukherjee JS, Joseph JK, et al. Communitybased therapy for children with multidrug-resistant
tuberculosis. Pediatrics 2006;117:2022-9.
Tuberculosis Programmes on the management of
tuberculosis in children. WHO, Geneva, Switzerland
WHO/HTM/TB/2006:371.
62. Sneag DB, Schaaf HS, Cotton MF, et al. Failure of
chemoprophylaxis with standard anti-tuberculosis
agents in child contacts of multidrug-resistant tuberculosis cases. Pediatr Infect Dis J 2007;26:1142-6.
63. American Academy of Pediatrics. Tuberculosis. In:
Pickering LJ, Baker CJ, Long SS, McMilan JA, eds. Red
Book: 2006 Report of the Committee on infectious
Diseases. 27th (edn). Elk Grove Village, IL: American
Academy of Pediatrics 2006:678-04.
64. Schaaf HS, Gie RP, Donald PR, et al. Evaluation of young
children in contact with adult multidrug-resistant
pulmonary tuberculosis: a 30-month follow-up. Pediatrics
2002;109:765-71.
Multidrug-Resistant Tuberculosis
1. Kochi A. The global tuberculosis situation and the new
control strategy of the World Health Organization. Bull
World Health Organization 2001;79:71-5.
520
2. Swanson DS, Starke JR. Drug-resistant tuber-culosis in
pediatrics. Pediatr Clin North Am 1995;42:326-39.
3. Cohn DL, Bustreo F, Raviglione MC. Drug-resistant
tuberculosis: Review of the worldwide situation and the
WHO/IUATLD Global Surveillance Project. International Union Against Tuberculosis and Lung Disease.
Clin Infect Dis 1997;24 (Suppl 1):S-121-30.
4. PablosMandez A, Biokin N, Riedes L, et al. Global
surveillance for antituberculosis drug-resistance 19941997. World Health Organization, International Union
against Tuberculosis and Lung Disease Working Group
on Anti-tuberculosis Drug Resistace Surveillance. N Eng
J Med 1998;338:1641-8.
5. Nunn P, Feller M. Surveillance of resistance to antituberculosis drugs in developing countries. Tuberc Lung Dis
1994;75:163-7.
6. World Health Organization. Multidrug and extensively
drug-resistant TB (M/XDR-TB). Global Report on
Surveillance and Response. Geneva 2010.
7. Schaaf HS, Van Rie A, Gie RP, et al. Transmission of
2000;19:695-9.
8. Schaaf HS, Gie RP, Beyers N, et al. Primary drug-resistant
tuberculosis in children. Int J Tuberc Lung Dis 2000;4:
1149-55.
9. ICMR: Prevalence of drug-resistance in patients with
pulmonary tuberculosis presenting for the first time with
symptoms at chest clinics in India. Findings in urban
clinics among patients giving no history of previous
chemotherapy. Indian J Med Res 1968;56:1617-30.
10. Jain NK, Nagpaul DR, Bhakta SU, et al. Enquiry into the
extent of initial and acquired drug-resistance to
antituberculosis drugs in Delhi, India. Tuberc Lung Dis
1995;76(Suppl 2):96-9.
11. Varaiya A, Gogate A. Drug-resistance to first-line of
antitubercular regimen (A preliminary report). Indian J
Pub Health 1998;42:126-30.
12. Amdekar YK. Multidrug-resistant tuberculosis. Indian
Pediatr 1998,35:715-8.
13. Trivedi SS, Desai SC. Primary antituberculosis drugresistance and acquired rifampicin resistance in Gujrat,
India. Tubercle 1988;69:37-42.
14. Ramachandran R, Nalini S, Chandrasekar V, et al.
Surveillance of drug-resistant tuberculosis in the state of
Gujarat, India. Int J Tuberc Lung Dis 2009;13:1154-60.
15. Jain A, Mondal R, Prasad R, et al. Prevalence of
multidrug-resistant Mycobacterium tuberculosis in
Lucknow, Uttar Pradesh. Indian J Med Res 2008; 128:
300-6.
16. Mukherjee JS, Joseph JK, Rich ML, et al. Clinical and
programmatic considerations in the treatment of MDRTB in children: A series of 16 patients from Lima, Peru.
17. Steiner P, Rao M. Drug-resistant tuberculosis in children.
18. Karande S, Kelkar A, Jagiasi A, et al. Acquired multidrugresistant tuberculosis in an immuno-competent
adolescent. Pediatr Infect Dis J 2002;21:577-8.
19. Steiner P, Portugualeza C. Tuberculous meningitis. A
review of 25 cases observed between the years 1965 and
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
1970 at the Kings County Medical Center of Brooklyn

with special reference to the problem with infection with
primary drug-resistant strains of M.tuberculosis. Am Rev
Resp Dis 1973;197:22-9.
McClatchy Jk, Kanes W, Davidson PT, et al. Crossresistance in tuberculosis to kanamycin, capreopycin.
Tubercle 1977;8:29-34.
Kapur V, Li L L, Jordanescu S, et al. Character-ization by
automated DNA sequencing of mutations in the gene
(rpoB) encoding the RNA polymerase (B sub unit) in
rifampicin-resistant Mycobacterium tuberculosis strains
from New York City and Texas. J Clin Microbiol 1994;
32:1095-8.
Zhang Y, Garbe T, Young D. Transformation with KatG
restores isoniazid-sensitivity in Mycobacterium tuberculosis
isolates resistant to a range of drug concentrations. Mol
Microbiol 1993;83:521-4.
Zhang Y, Heum B, Allen B, et al. The catalase- peroxidase
gene and isoniazid resistance of Mycobacterium tuberculosis
. Nature 1992; 358:591-3.
Banerjee A, Dubnau E, Quemar W D, et al. inhA, a gene
Douglass J, Steyn LM. A ribosomal gene mutation in
streptomycin-resistant Mycobacterium tuberculosis isolates.
J Infect Dis 1993;167:1505-6.
Finken M, Kirschner P, Meier A, et al. Molecular basis of
streptomycin resistance in Mycobacterium tuberculosis:
Alterations of the ribosomal proteins S12 gene and point
mutations within a functional 16S ribosomal RNA
pseudoknot. Mol Microbiol 1993;9:1239-46.
Takiff H, Salazar L, Guerrero C, et al. Clonning and
nucleotide sequence of Mycobacterium tuberculosis gyr A
and gyr B genes, and detection of quinolone resistance
mutations. Antimicrob Agents Chemother 1994;38:
773-8.
Iseman MD, Madsen LA. Drug-resistant tuberculosis.
Jacobs RF. Multiple drug-resistant tuberculosis. Clin
Infect Dis 1994;19:1-10.
Center for Disease Control Atlanta. A strategic plan for
the elimination of tuberculosis in the United States.
MMWR 1989;38(Suppl 3):1-25.
Mahmoudi A, Iseman MD. Pitfalls in the case of patients
with tuberculosis. Common errors and their association
with the acquisition of drug-resistance. JAMA 1993;270:
65-8.
Uplekar MW, Shepard DS.Treatment of tuberculosis by
private general practioners in India. Tubercle 1991;72:28490.
Steiner P, Rao M, Mitchell M. Primary drug-resistant
tuberculosis in children: Correlation of drug susceptibility
patterns of matched patient and source case strains of
Mycobacterium tuber-culosis. Am J Dis Child 1985;139:
780-2.
Schaaf HS, Shean K, Donald PR. Culture confirmed
multidrug-resistant tuberculosis: Diagnostic delay,
clinical features, and outcome. Arch Dis Child 2003;88:
1106-11.
Abadco D, Steimer P. Gastric lavage is better than
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.

Infer Dis J 1992;11:735-8.
Globe M. Drug-resistant tuberculosis. Semin Respir Infect
1986;1:220-32.
Heifets LB, Good RC. Current laboratory methods for
the diagnosis of Tuberculosis. In Bloom B (Ed):
Tuberculosis pathogenesis, protection and control.
Washington DC, American Society for Microbiology
1994;85-110.
Heifets LB. Qualitative and quantitative drug susceptibility tests in mycobacteriology. Am Rev Respir Dis
1988;137:1217.
Jacobs WR Jr, Barlelta RG, Udani R, et al. Rapid
assessment of drug susceptibilities of Mycobacte-rium
tuberculosis by means of luciferase reporter phages.
Science 1993;260:819-22.
Sharma M, Altamirano M, Parsad HK, et al. Characterization by single strand conformation, Polymorphism
of mutation in the rpoB gene of rifampicin-resistant
Mycobacterium tuberculosis in strains from Vancouver,
Mexico City and New Delhi. J Assoc Physcians of India
2000;48:565-7.
De Beenhouwer H, Lhiang Z, Jannes G, et al. Rapid
detection of rifampicin resistance in sputum and biopsy
specimens from tuberculosis patients by PCR and line
probe assay. Tuber Lung Dis 1995;76:425-30.
Mazurele GH, Cave MD, Eisenach KD, et al. Chromosomal DNA finger print pattern produced with IS 6110
as strain specific marker for epidemiology study of
tuberculosis. J Clin Microbiol 1991;29:2030-3.
Dickinson JM, Allen BW, Mitchison DA, Slide culture
sensitivity tests. Tubercle 1998;70:115-21.
Croften J, Chaulet P, Maher D, et al. Guidelines for the
management of drug-resistant tuberculosis. Geneva:
World Health Organization, 1997;Also available from:
URL: http#www.who. Int/gtb/publications/gmdrt.
Frieden TR, Sherman LF, Maw KL, et al. A multiinstitutional outbreak of highly drug-resistant tuberculosis: Epidemiology and clinical outcomes. JAMA
1996;276:1229-35.
Iseman MD.Treatment of multidrug-resistant tuberculosis.N Engl J Med 1993;329:784-91.
Mitchinson DA, Nunn AJ. Influence of initial drugresistance on the response to short-course chemotherapy
of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:
423-30.
Mukherjee JS, Rich ML, Socci AR, et al. Programs and
principles in treatment of multidrug-resistant tuberculosis. Lancet 2004;363:474-81.
Schaaf HS, Gie Robert P, Kennedy M, et al Evaluation
of young children with adult multidrug-resistant
pulmonary tuberculosis: A 30 month follow-up.
50.
51.
52.
53.
54.
55.
521
Pediatrics 2002;109:765-71; This information has been

cited as the current information up to Dec.6. 2004 by
American Academy of Pediatrics.
Seth Vimlesh, Khosla PK, Semwal OP, et al. Visual
evoked responses in children having tuberculosis on
ethambutol treatment. Indian Pediatr 1991;28:713-7.
Takeda S, Maeda H, Hayakawa M, et al. Current surgical
intervention for pulmonary tuberculosis. Ann Thorac
Surg 2005;79:959-63.
Stanford J, Stanford C, Grange J. Immunotherapy with
Mycobacterium vaccae in the treatment of tuberculosis.
Front Biosci 2004;1;9:1701-19.
Telanti T, Iseman MD. Drug-resistant tuberculosis. What
do we do now? Drugs 2000;59:171-9.
Sharma SK, Mohan A. Multidrug-resistant tuberculosis:
A menace that threatens to destabilize tuberculosis
control. Chest 2006; 130:261-72.
Epsinal M (Ed) Report on multidrug-resistant tuberculosis:
Basis for the development of an evidence-based casemanagement strategy for MDR-TB within WHOs DOTS
strategy. Proceedings of 1998; Meetings and Protocol
recommendationsGeneva: World Health Organization.
SUGGESTED READING
1. John TJ. Extensively drug-resistant tuberculosis in India.
Indian J Med Res 2010;313:109-10.
2. Dheda K. Extensively drug-resistant mycobacterium
tuberculosis: What are these up to in India? Indian J Med
Res 2009;130:357-8.
3. Resistant tuberculosis-cure for extreme TB strain found
Times of India April 8 2009.
4. Schaaf HS, Victor TC, Enllke E, et al. Minimum inhibitory
concentration of isoniazid in isoniazid-resistant
mycobacterium tuberculosis isolates from children. Eur J
Clin Microbial Infect Dis DOI 10 1007/S 10096-007-02579 springer-verlag 2007.
5. Maris BJ, Victor TC, Hessling AC, et al. Beijing and
Haearlim genotypes are over represented among children
with drug-resistant tuberculosis in the western cape
province of South Africa. Journal of Clinical Microbiology
2006;44:3539-43.
6. Multidrug-resistant and extensively drug-resistant
extensively drug-resistant TB in India. Consensus
statement on the problem, prevention, management and
control. From the consultative meeting of national experts
organized by the TB Research Center, ICMR, Govt of
India on 14-15 September 2007 at Chennai.
7. Sharma SK, George N, Kadhiravan T, et al. Prevalence
of extensively drug-resistant tuberculosis among patients
with multidrug-resistant tuberculosis a retrospective
hospital-based study. Indian J Med Res 2009;130:392-5.
37
Organization of Pediatric
Tuberculosis and HIV Clinic
Vimlesh Seth
INTRODUCTION
Inspite of a National Tuberculosis Control Program in
India since 1962 with modifications, off and on, the
problem of tuberculosis still exists in epidemic proportion.
Since the beginning, emphasis has been on the
management in adults both in diagnostic parameters and
use of various drug regimens for treatment. The basic
assumption was that children acquire infection from adults
and hence the transmission should be reduced by treating
adults. Further the disease is paucibacillary and dose not
contribute to transmission which is a myth. The children
have been completely neglected. Now it is realized that
the children who acquire latent tuberculosis from an
infectious adult, if neither develop mild pulmonary nor
disease serious manifestations such as TBM or miliary TB
in infancy, they keep on harboring the bacilli. This group
at a later age, i.e. near adolescence can develop endogenous
(cavitary) tuberculosis. Hence, they are a source of
transmission of TB. Now the importance of latent
tuberculosis has been recognized, though action being
taken to manage it is far from satisfactory in the National
Program atleast in India. An adult patient with
tuberculosis in household will transmit the infection to all
children in the house and young children are at risk of
developing disease within a year. Chemoprophylaxis
given to these children may prevent development of illness
in near as well as later in life. Because of nonspecific clinical
features and difficulty in documenting M. tuberculosis,
diagnosis is delayed or children may present with severe
and life threatening illness like miliary, disseminated
disease such as bronchopneumonia and serious forms of
extrapulmonary tuberculosis like tubercular meningitis.
BCG which is included in the Universal Program of
Immunization for children only prevents dissemination
but not transmission. In the school age period and before
adolescence, the major manifestations are tuberculous
lymphadenitis, pulmonary tuberculosis and its local
complications, skeletal and abdominal tuberculosis. Lobar
pneumonia with complication of collapse consolidation
can lead to bronchiectasis, if not properly treated. Pleural
effusion also can lead to collapse and subsequent
bronchiectasis. In the adolescent age group of 12 years and
above, manifestations are like adults, cavitary lesions with
extensive bacillary load. Even when the disease develops

endogenously, it is a severe pulmonary disease like adults.
Till recently in the National program, emphasis has
been on directly observed treatment short-course (DOTS)
therapy based on the principle of sputum-positivity or
severe lung disease in sputum negative adults. Now
India is the first country to adopt DOTS for children.
Though still there are some lacunae discussed elsewhere
by the program managers themselves.
Over the years, there has been complete dichotomy
in both the diagnostic criteria and treatment regimens
used for children by Pediatricians and Program managers
of National Tuberculosis Control Program (NTP) and
now Revised National Tuberculosis Control Program
(RNTCP). The current concept of blanket use of
intermittent therapy regimens for children advocated in
RNTCP is not very palatable to Pediatricians. The
children have not been given the due attention they
deserve both for diagnosis and treatment. It is only since
2004, for the management of tuberculosis in children,
there is an attempt to involve Medical Colleges, again
under the departments of Internal Medicine. The
involvement of Pediatric departments has not been
ensured. Lately with the insistence of the members of
Indian Academy of Pediatrics, a workshop was held in
2009 in Mumbai. The outcome of which is the publication
of guidelines for management of tuberculosis in children
in (detailed in another chapter) totality barring a few
specific conditions like MDR-TB, organ specific TB and
congenital TB. Hence there is hope that some benefit will
be ensured for children. The Government of India with
the help of WHO has opened a DOTS center in every
medical college. To make use of this facility, the Pediatric
departments of all medical colleges should have a
Pediatric TB clinic like all the other super specialties such
as neurology, neonatology, oncology and so on.
Uptill now in all the conferences organized by
Tuberculosis managers and TB Hospitals, and TB
Association, Pediatrics is represented just in the form of
one or two lectures by pediatricians who have worked
in the field of tuberculosis in children, or a panel
discussion at the most. In isolation, the pediatricians have
been holding various regional workshops on the subject.
The pediatricians are very conscious of the problem more
Chapter 37 Organization of Pediatric Tuberculosis and HIV Clinic

so with increasing incidence of HIV/AIDS and MDR-TB
in adults, a constant threat for childern. There is a TB
chapter in the Indian Academy of Pediatrics. Two
consensus statements, one on diagnosis and the other
on treatment have been published in Indian Pediatrics.1,2
The latter have been published in the 3rd edition of book
in the form of separate chapter. The latest has been
published in Indian Pediatrics 2010 of has been
reproduced in this book. Hence now is the time to set up
a proper Pediatric TB Clinic in each Pediatric Department.
All India Institute of Medical Sciences (Pediatric
department) has been running a separate Pediatric TB
clinic for almost five decades. In the beginning the
proforma used was difficult to analyze. Now there is a
well designed patient case record form (previously called
precoded proforma). The latter ensures better case
records, which can be objectively analyzed. The junior
residents are compelled to fill up these proformas and
there is a check list for follow-up visits. Each case is
worked up by a junior resident but drug regimen is
decided by the faculty member along with senior resident
depending upon the system involved and severity of
disease. (See annexures I, II and III).
It is recommended by the adult TB experts that all
children with any type of tuberculosis should be treated
with DOTS. (Table 37.1)
To assist in calculating required dosages and
administration of anti-TB drugs for children, medication
should be made available in the form of combipacks in
patient-wise boxes, linked to the childs weight. These
are now available from DOT center but need some
modifications. Try to involve a DOT provider from the
DOT center so that two purposes are taken care off i) the
children will get medicine and ii) the information as per
DOTS criteria will be collected.
For details of treatment of children under Revised
National Tuberculosis Control Program, specific
guidelines have been made by a group of renowned
Pediatricians of Indian Academy of Pediatrics, TB experts
and members of Central TB Division of Ministry of
Health. However, it is neither feasible and practical nor
right to put all the children under DOTS because the kind
of infrastructure required for this is neither available for
all types of TB nor for all children. For uniformity of
treatment regimen, it is suggested that all children should
be categorized as DOTS and if it is not feasible to send
the patients to DOTS center, they should receive same
regimen except that it will be daily inplace of intermittent
523
regimen. Even if a patient is being treated under DOTS

it is responsibility of treating Pediatrician to follow up
the patient every 4 weeks and monitor for improvement
in symptoms and weight gain, contact tracing, etc.
It is important to have separate tuberculosis clinic for
children immaterial of who is treating. Pediatric
Department of each medical college must have one in
like the other superspeciality, clinics. Seth Vimlesh has
given the following guidelines how to go about it:-
STARTING TUBERCULOSIS CLINIC FOR CHILDREN

Minimum infrastructure
A separate day, with involvement of atleast one
faculty member and junior and senior residents of,
his unit equipments for measuring weight and height
of infants and children, facility for CXR, (a committed
radiologist for review of xrays) USG, mantoux test,
basic microbiology services for smear and culture.
These facilities are available in every medical college.
Involvement of the microbiologist like radiologist is
mandatory to ensure that all efforts have been made
to look for AFB on smear and culture.
Personnel
A pediatrician who is interested in tuberculosis, nurse
(for doing gastric aspirates and induced sputum,
manoux test, dispensing medications, counseling for
good adherence), medical social worker (counseling),
DOT worker from the DOT center for dispensing
medicines, psychologist (for special conunselling for
HIV).
Methods
For starting pediatric TB clinic following steps should
be followed.
Step 1
Fix a day for clinic. Depending on the number of patient,
number of clinics can be fixed per week. It is important
that it should be at least once a week.
Step 2
Prepare a case record form for diagnosis, treatment and
follow up of childhood TB. (Annexure I, II, III, IV) To
have uniformity as per WHO guidelines, similar table
has been designed by Seth et al. for continous therapy
which is given Table 37.2.
1. Consensus statement recommendation of Indian Academy of Pediatrics, 1997: Inidan-Pediatr 1997;34:

1093-6.
2. Diagnosis of childhood tuberculosis. Consensus statement of Indian Academy of Pediatrics working Group-Indian Pediatr
2004;41:146-55.
524
Table 37.1: Treatment categories and regimens as per DOTS
Treatment category
Type of patients
IP
CP
Category I
New sputum smear-positive PTB,

Seriously ill* sputum smear-negative PTB,
Seriously ill EPTB
Sputum smear-positive relapse,
Sputum smear-positive treatment failure,
Sputum smear-positive treatment after default
Sp utum smear-negative and EPTB not seriously ill**
2H3R3Z3E3***
4H3R3
2S3H3R3Z3E3/
1H3R3Z3E3
5H3R3E3
2H3R3Z3
4H3R3
Category II
Category III
TBTuberculosis, CATCategory, HIsoniazid, RRifampicin, ZPyrazinamide, EEthambutol, SStreptomycin, PTBPulmonary TB, EPTB
Extrapulmonary TB, IPIntensive Phase, CPContinuation Phase.
*Seriously ill sputum smear-negative PTB includes all forms PTB other than primary complex. Seriously ill EPTB includes TB meningitis
(TBM), disseminated/miliary TB, TB pericarditis, TB peritonitis and intestinal TB, bilateral or extensive pleurisy, spinal TB, with or without
neurological complications, genito-urinary tract TB, bone and joint TB.
**Not seriously ill EPTB includes lymph node TB and unilateral pleural effusion.
***Prefix indicates month and subscript indicates thrice weekly.
Step 3
Screening of Patients to be Registered for TB Clinic
Prepare a case record form for HIV clinic (Annexure V)

that include history, examination, and followup
information.
This must be done by the senior resistant who has got

some knowledge about TB and faculty incharge knows
what is expected of him. The patients registered must
have the benefit of treatment in the Pediatric TB clinic.
The senior resident sees that at least the basic
investigations of Mantoux and X-ray chest and family
survey have been done. This would be able to find the
adult who is diseased in the family. If all this is available,
then only the case is registered. Senior resident must
known how and what medicines will be dispensed to
the patient. For this purpose one DOT worker should be
posted for the pediatric TB clinic out of the strength of
those with internal medicine. This will help both in the
proper screening and dispensing of medicines at the
clinic. Besides DOTS, for pediatric TB clinic at AIIMS,
the medicines are provided by a Non-Governmental
Organization (NGO) with limited budget. Hence only
select cases are registered, e.g. pulmonary and nave case
of peripheral lymphadenitis so that full treatment is
ensured. Few cases of resistant TB detected at AIIMS are
also looked after in the clinic on ambulatory basis after
initial stabilization in the isolation bed of the pediatric
ward. They are usually of peripheral lymphadenitis.
Step 4
Prepare treatment and follow up guidelines. Hand out
of chapter 29 and 34 on principles of treatment and
management of TB in children are given to the residents
on the 1st day of their posting in the Pediatric TB clinic
so that they understand and revise their essential
knowledge about the disease in pediatrics. They are
explained by the faculty incharge about how to fill the
case record form explaining the importance of filling
them accurately and completely. Each case is discussed
with the faculty incharge and the decision to which
category of treatment will be administered is taken. Those
who can be put on DOTS should be done so and
medicines procured by DOT worker who is involved and
made responsible to report to the faculty in the clinic
about the case.
Step 5
Ensure that on the day of TB clinic one responsible person
is available to take care of patients attending the clinic. It
is important that some of the staff including doctors is
present in clinic. It is important that the person sitting in
the clinic is interested in TB. If a child or parents sees
same doctor each time in clinic, they will come to clinic
regularly. This helps both in capacity building for the
clinical and better follow up of the patient. To ensure
this at AIIMS, junior resident is made to work up the
case and present to the senior resident who in turn along
with junior resident discusses it with the faculty.
INSTRUCTIONS FOR RESIDENT DOCTOR

A written protocol should be available for the doctors
attending the clinic. It is desirable that all residents must
have the latest booklet on RNTCP published by Central
TB Division of Ministry of Health and Family Welfare,
New Delhi. These can be procured from Deputy Director
General of Central TB Division of Ministry of Health. This
booklet is revised from time to time and the latest should
be collected for the residents. This will help the residents

to have the latest insight about RNTCP in India. The
regimens under non-DOTS program as used at AIIMS
pediatric TB clinic are given in (Table 37.2).
Duration of interruption of treatment and suggested
regimens are given in Table 37.3.
Dosages of antituberculosis drugs in daily and
intermittent regimen is given in (Table 37.4).
FLOW OF PATIENTS IN TB CLINIC

Diagnosis and Referral to TB Clinic
It is important that a written protocol for diagnosis of TB
is circulated to all the doctors in the hospital particularly
Pediatric surgery department who after initial treatment
of TB lymphadenitis refer the children to Pediatric TB
Clinic mainly for the procurement of antituberculosis
drugs. This is discourged and such cases are only advised
proper regimen and sent back to the parent department.
Based on clinical findings, laboratory results and protocol
cases are defined as suspect TB, probable TB and
confirmed TB. It should be made mandatory to send all
the patients with probable and confirmed TB to TB clinic.
To have uniformity, it is desirable that unless it is an
emergency, all the patients are referred to TB clinic
without starting ATT.
NEW CASES
Registration of Patients in Tuberculosis Clinic
A doctor (senior resident doctor) shall screen all the
referred patients for registration. He/she will
recommend registration of all the patients who have
probable or confirmed TB. If diagnosis of tuberculosis is
in doubt or the investigations are not complete, the
resident doctor shall fill appropriate investigation forms
and give only symptomatic treatment and ask them to
come on next visit for registration.
Work-up
New cases once registered should be worked up by a
junior resident in a designated room and all the history
and examination findings should be filled up on patient
case record forms (Annexure I, II, III). The case is then
presented to the senior resident and then faculty in charge
and diagnosis made and appropriate regimen advised.
Case Record Form (Annexure IV) has been designed
for other medical college to send their data to the tertiary
care center like All India Institute of Medical Sciences
(AIIMS). The latter should make a concerted effort to have
a research project funded from either Indian Council of
Medical Research of Government of India (GOI) or
Table 37.2: Clinical categories of WHO and, the suggested conditions in children accordingly followed
drug regimens in pediatric TB clinic in children
Categories
Category I
Category II
Category III
525
Suggested by
WHO for adults
in children
Suggested
regimens
New sputum positive Pulmonary

TB (PTB)
New smear-negative PTB
with extensive parenchymal
involvement
New cases of severe forms of
extrapulmonary TB.
Relapse
Treatment failure
Sputum negative pulmonary
with limited parenchymal
involvement Extrapulmonary
TB (less severe forms)
PPD, TBL
Massive pleural effusion
Abdominal TB
Osteoarticular TB
Genitourinary TB
CNS TB
Pericardial TB
Relapse
Treatment failure
2HRZE
4HR*
Single lymph node

Small effusion
Skin TB
PPC
2SHRZE
1HRZE
5HRE
2HRZ
4HR
PPCPulmonary Primary Complex, PPDProgressive Primary Disease,

TBLTubercular Lymphadenitis, CNS TBCentral Nervous System Tuberculosis,
2HRZE 4HR-2 months of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampicin,
2 SHRZE 1 HRZE 5HRE first two months daily isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin followed by one month
of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by 5 months of isoniazid, rifampicin and ethambutol,
2HRZ 4HR2 months of isoniazid, rifampicin and pyrazinamide, followed by 4 months of isoniazid and rifampicin.
*10 HR in cases of osteoarticular and CNS tuberculosis.
526
S. No.
Duration of therapy
Duration of interruption
Decision
1.
Upto 4 weeks
2.
4-7 weeks
3.
>8 weeks
<2 weeks
>2 weeks
<2 weeks
>2-8 weeks
>8 weeks
>2 weeks: Not active disease
>2 weeks: Active disease

Reassess and restart appropriate regimen
Extend intensive phase by 1 month
Category II therapy*
Resume therapy
Category II
4-7 2.
* DOTS and Non-DOTS category of treatment keeping in mind the original regimen on which the patient was started.
PS: Whenever the treatment is interrupted for more than 2 weeks, the child should be reassessed clinically and radiologically, wherever
possible bacteriological examination should be performed, by gastric lavage in younger children and induced sputum or spontancously
collected sputum. Technique of induction of sputum is described in chapter on pulmonary tuberculosis.
Department of Biotechnology (GOI) to employ personnel

for collating this as National Data Base. AIIMS should
hold a meeting involving representatives of 5 zones of
India, Center, North, West, East and South. In each of
these centers one medical college should be designated
to collect data as suggested in the chapter research
agenda. This will provide national data base of pediatric
TB with uniform criteria of diagnosis, management of
TB in children.
Initial Evaluation Sheet to be Filled by DOT Worker on
All Old Patients whether on DOT on non DOT therapy and
to be checked by senior resident
1. Improvement in symptoms
Fever
Yes/no
Days to
Number of days
defervescence
Anorexia
Improving/Improved/
unchanged
LN size
Increased/same/
decreased
Cough
Increased/same/
decreased
2. Weight
kg
3. Height
cm
4. Compliance
Color of urine
INH test* (urine)
No. of sachets (empty)
5. Self reported adverse effects
a.
b.
6. Cost incurred on drugs in the previous months.
7. Source of medicine DOT center, NGO, purchased
from market.
8. Any other family member fallen sick.
Social scientist will then decide either to send the
patient for further evaluation by the resident doctor or
send the patient to collect the medicines for next two
weeks if he is in the continuation phase and during
intensive phase he should be instructed to come on

alternate days to collect medicines. The referral to the
resident doctor is required for the following:
i. All patients in first two months of treatment where
full workup is still awaited, or where symptom relief
is not adequately documented.
ii. Doubtful or poor compliance.
iii. Self reported adverse effects or new symptoms.
iv. No weight gain on 2 successive visits.
v. Completion of treatment duration prior to stopping
treatment.
vi. Every two months for need to decide if
X-ray is indicated.
The referral to the drug collection center is done if
a. Patient is doing well,
b. Compliance is documented to be normal.
c. No new adverse effect.
CHECK LIST FOR THE SENIOR RESIDENT DOCTOR ON

FOLLOW-UP VISIT
First He/She should check the Case Record form of
Annexure I, II, III
1. Mantoux of siblings less than 5 years preferably 10
years.
2. X-ray of siblings, parents, grand parents and servant,
if any.
3. Enter family survey X-ray reports.
Table 37.4: Dosage of drug in daily intermittent
regimen (mg/kg/day)
Medicine
Isoniazid
Pyrazinamide
Rifampicin
Ethambutol
Streptomycin I/M
Ciproflox. when used
Daily
Intermittent
5
30
10
20
25
20
10
50
10
30

4. Check drugs compliance and scheduled attendance
in clinic.
5. Record symptoms.
6. Follow-up proforma to be filled every month for 1st
3 months then 3 monthly.
7. Hemogram (Absolute Eosinophil count).
8. Category based diagnosis
i. Pulmonary specify the type PPC, PPD, cavitary,
pronchopnevmonia, collapse consolidation,
disseminated.
ii. Lymph Nodes.
iii. Neurotuberculosis.
iv. Bone Tuberculosis.
v. Abdominal Tuberculosis.
9. Category-based treatment.
10. Check compliance
Status of symptoms
Weight gain
Compliance of the Regimen.
1. = 100% drug dosage intake
2. = 80 to 100% drug dosage intake
6. = <50% drug dosage intake
The resident doctor should also explain the drugs to
patients/attendants and check whether the social worker
has done it properly. Should give requisition forms for
family survey and Mantoux test of children (sibs) below
5 years in all the patients. The resident doctor should
direct the patients for drugs to other room where the drug
are given at least for fifteen days. Under DOTS the drugs
should be given as per advise recommended in DOTS.
Responsibility of the Senior Resident Doctor

1.
2.
3.
4.
Evaluation of patients, referred for registration.

Evaluate completeness of the case record forms.
Evaluation of all patients in 1st 3 months of treatment.
Supervise treatment or research protocols.
Drug Collection Center

All patients maybe dispensed drugs for fifteen days in
the 1st three months and then every one month by the
dispenser (DOT worker). The dispenser should explain
by demonstrating the drug bottle/strip and the amount
to be consumed. He/she should ask the attendant of the
patient to make 15/30 sachets of the dispensed drugs
(one for each day) and physically check these before the
patient is sent back. In case one or more of these drugs
have to be bought from the open market, the attendant
should be encouraged to procure that drug and then
527
make these sachets in the clinic premises. The patient

should be clearly explained the importance of procuring
the drug which is not available.
Old Patients
All patients started on antituberculosis therapy should
first be examined by senior resident doctor who evaluates
the child for improvement in symptoms, drug
compliance, weight, height gain and any adverse effects.
The evaluation procedure for that is as follows:
Initial evaluation sheet to be filled by social worker
with the involvement of DOT worker.
1. Improvement in symptoms
Fever
Yes/no
Days to
Number of days
defervescence
Anorexia
Improving/Improved/
unchanged
LN size
Increased/same/
decreased
Cough
Increased/same/
decreased
2. Weight
kg
3. Height
cm
4. Compliance
Color of urine
INH test (urine)
No. of sachets (empty)
5. Self reported adverse effects
a.
b.
She should also evaluate socioeconomic impact of
disease by asking:
6. Cost incurred on drugs in the previous months?
7. Any other family member fallen sick?
Resident should then Decide

1. To either send the patient for further evaluation by
the consultant doctor or assess the patient to collect
medicines for next 2 weeks. The referral to the
consultant doctor is required for:
i. All patient in first three months of Rx, where full
workup is still awaited, or where symptom relief
is not adequately documented.
ii. Doubtful or poor compliance.
iii. Self reported adverse effects or new symptoms.
iv. Failure to gain weight on 2 successive visits.
v. Completion of treatment duration prior to
stopping treatment.
vi. The X-ray done after the intensive phase and then
at the end of treatment.
If no problem send the patient to the drug
collection center as the:
528
a. Patients is doing well,

b. Compliance is documented to be normal
c. No new adverse effects seen.
2. Consultant doctor should see the child at the end of
continuation phase of the regimen. All patients started
on antituberculosis drugs should be followed every
2 to 4 weeks till the regimen is over. After that, every
6 months for two visits and then every year for 4 visits,
for a total of 3 years.
3. On each visit a detailed clinical symptomatology, i.e.
fever, cough, appetite should be assessed. A detailed
physical examination for weight gain, toxicity of
antituberculosis drugs should be done. All findings
should be entered at appropriate place in the file.
4. Repeat X-ray films Repeat X-ray should be done at
the end of intensive phase or earlier if there is no
improvement. X-ray film should be done at the end
of therapy and then every year for 3 to 4 years.
All X-ray film shall be kept in the envelops along with
the requisition slip and the files with X-ray maybe handed
over to staff helping in dispensing the medicines. X-ray
should be reviewed every week of new cases and old
cases with the radiologist who is particularly interested
in Pediatric Imaging.
Other Investigations
A base line LFTs of patients with severe malnutrition,
progressive primary disease, disseminated tuberculosis,
suspected viral hepatitis, drug toxicity should be carried
out. The same shall be repeated only if hepatotoxicity
occurs.
Change in Regimen
The antituberculosis drug regimen decided at the time
of registration shall be continued. Any change if indicated
shall be only after discussion with consultant doctor of
tuberculosis clinic.
Suggested workup plan for lymph node tuberculosis
1. Presence of systemic symptoms.
2. Mantoux test positive in mm.
3. LN group involved Cervical
Axillary
Inguinal
4. FNAC
Necrosis
AFB
Granuloma
Solid Media
5. Culture Mycobact, method
Liquid Media
Sensitivity
6. BCG
Yes/No
7. Rx regimen.
8. Any increase in size on Rx.

9. LN size at the end of 6 months in (cm).
10. LN size increase during follow-up:
11. Chest X-ray finding (describe).
Health Education by social worker to parents and
child care taker. It should be done as per the following
proforma:- This should be computer typed in big font
and a poster formed and hanged at the entry of TB clinic.
1. Tuberculosis (TB) is a common disease in India and
may occur in all age groups including very young
children.
2. TB is caused by a bacterium named Mycobacterium
tuberculosis.
3. Large number of these bacteria are added to
surrounding air by a person suffering from
tuberculosis when he/she coughs. These bacteria
enter in the lung of healthy people through air.
Once the bacteria in the lungs of an individual they
may produce disease irrespective of the caste,
religion, sex or age of person. The chance of disease
is more in children, elderly and malnourished.
4. TB can affect all the organs of body including lungs,
intestine, brain, bones, etc. the spread of disease in
the body is more common in children because of less
resistance, thus it is a serious disease in children.
5. Unlike adults, TB in children may not manifest with
specific symptoms (i.e. cough, blood in sputum). In
children the symptoms may be fever, cough, not
gaining weight, or weight loss and decreased
appetite.
6. TB is curable. The treatment is longer. The number of
medications and duration of treatment depends on
the type of disease. It is decided by the doctor.
7. If treatment of TB is taken irregularly (i.e. less doses,
less duration) the disease may recur and may not
respond to routine drugs. This is called resistant
tuberculosis.
8. Treatment of resistant tuberculosis is difficult and
very expensive. Hence for prevention of resistance
regular treatment as advised by doctor should be
taken.
9. TB is not a hereditary disease as it is caused by a
bacteria. However, it may occur in multiple members
of a family because of infectious nature of disease.
10. The spread of TB can be prevented by observing
certain precautions such as early diagnosis of disease,
the patient should like regular treatment, patient
should cough with a cloth covering his mouth and
proper disposal of sputum of the patient.
11. BCG vaccination at birth provides protection against
severe form of tuberculosis.
12. Children suffering from tuberculosis do not need
isolation. They should be treated with drugs and
nutritious diet at home.
529
ANNEXURE I
CASE RECORD FORM
PEDIATRIC T.B. CLINIC
Date of Registration ______________
1. T.B. Clinic No.

Year
No.
Name :_____________________________ 3. Age in months

Postal Address:______________________ 4. Sex
1. Male
2. Female
____________________________________
____________________________________
5-6
Fever
7-8
Cough
9-10
Weight Loss/
1. Yes 2. No
Duration in months
Not gaining weight

11-12
Loss of appetite
13-14
Lymph nodes enlarged
15-16
Contact with TB
patient at home
Family History
17. 1. Positive
2. Negative
18-21 Mother
22-25 Father
26-29 Sibling
30-33 Sibling
Present
1. Yes
2. No
Past
1. Yes
2. No
If yes
How many month
ago
Type of TB
1. Pulmonary
2. Lymph node
3. Abdominal
4. Other (specify)
530
34-37 Sibling
38-41 Grandmother
42-45 Grandfather
Others
Immunization
46-48
BCG
1. Given
2. Not Given
1. Scar positive Age at BCG vaccination

2. Scar negative in months (*)
* 00 month = at birth or within the first month

Physical Examination
49. Weight (kg)
50. Nutritional status (Grade)
Percentile (NCHS)
Percentile (KN Aggarwal)
1. Normal
2. PEM grade 1
3. PEM grade 2
4. PEM grade 3
5. PEM grade 4
51-52
Height in cms
Percentile (NCHS)
Percentile (KN Aggarwal)
Lymph Nodes
53-59 Cervical
1. Ant cerv.
2. Post cerv.
3. Subocc.
Present
1. Yes
2. No
3. Bilat
Site
Gr. of
1. Right LN
2. Left
3. Bilat
Size
in cms
1. <1
2. 1-2
3. 2-3
4. >3
Number Consistency
1. Sing. 1. Soft 1. Matt. Mob.
2. Mult. 2. Firm 2. Matt. Fix.
3. Fluc. 3. Disc. Mob
4. Hard 4. Disc. Fix
Sinus
1. Yes
2. No
531
4. Subman
5. Sub ment.
6. Jug dig.
7. Superf.
8. Deep
60-68. Axillary
1. Central
2. Apical
3. Lateral
* Sing Single; Mult Multiple; Fluc Fluctuant; Matt Matted; Mob Mobile; Fix Fixed; Ant Anterior; Post Posterior;
Cerv Cervical; Subocc Suboccipital; Subman Submandibular; Submen Submental; Jug dig Jugulodigastric; Superf
Superficial
532
69-77. Inguinal
78-86. Other
87-88. Liver
Enlarged
Cms below costal margin
1. Yes
2. No
89-90. Spleen
91.
Chest
1. Clear
5. Decreased air entry
2. Loc. crepts
3. Gen. crepts
4. Bronchial breathing
6. Rhonchi
7. Others (specify)
Investigations
92. Mantoux test
(measurement in mm)
(Horizontal)
(Vertical)
93. Hemoglobin gms/dl

94. Total leukocyte count (x 103/cumm)
95,96,97,98.
Differential leukocyte counts
Polymorphs
99. AST
Lymphocytes
Monocytes
ALT
Absolute eosinophilic Count (x 102)
100. Gastric Lavage

Smear
Induced Sputum
Smear
Eosinophils
Sputum
Smear
Positive (1)
Positive (1)
Positive (1)
Negative (2)
Negative (2)
Negative (2)
Culture
Culture
Culture
Positive (1)
Positive (1)
Positive (1)
Negative (2)
Negative (2)
Negative (2)
Smear: Lab Technique Used for Gastric Lavage

Culture: Lab Technique Used for Sputum
SGOT Aspartate Transaminase
SGPT Alanine Transaminase
Loc. crepts Local crepitations

Gen. crepts General crepitations

1. X-ray film of chest
1. Normal
4. (2+3)
7. Pleural effusion
Calcification/Fibrosis
2. Parenchymal lesion 3. Lymph nodes

5. Lobar consolidation 6. Collapse-Consolidation
8. Bronchopneumonia 9. Miliary
2. Fine needle aspiration cytology (Histopathology report)/Biopsy

1. Necrosis
2. Granuloma
3. AFB
3. CNS Tuberculosis
1. Yes
2. No
(if yes, fill following, if no go to next)

Type of CNS TB
1. Tuberculoma
CSF
2. TBM
3. Other specify
Proteins
mg/dl
Sugar
Cells
Cells
(per cubic ml)
Lymph%
Polys
Smear for AFB

Culture for AFB
CT Scan
1. Basal exudates
2. Hydrocephalous 3. Tubercles
4. Infarct
5. Other-specify
Other investigation specify

MRI describe the findings
4. Abdominal Tuberculosis
1. Yes
2. No
If yes, fill following if no go to next type of abdominal tuberculosis

1. Ascitic
2. Intestinal
Ascitic fluid
3. Lymph node
1. Done
4. Other specify
2. Not done
(if 1 fill following, if 2 go to next)

Protein
gms/dl
Sugar
Cells
(per cubic ml)
Ultrasound abdomen
1. Abnormal
If abnormal describe the findings.
*For other organ involvement
AFB smear
(Present 1, Absent 2)
2. Normal
533
534
5. Osteoarticular TB*
1. Osteomyelitis, 2. Arthritis
If Arthritis, Joints involved
1. Knee, 2. Hip, 3. Ankle, 4. Others
1. Yes 2. No
6. Renal Tuberculosis *
Urine AFB smear
Culture
Ultrasound abdomen
CT abdomen.
1. Yes 2. No
1. Yes 2. No
1. Yes 2. No
* After recording preliminary findings as mentioned, refer the child to orthopedic department and Pediatric Nephrology
clinic respectively.
X-ray Review Report of Patient

S. No.
Date
Sr. No. of X-ray
Findings
Parenchymal/Pleural/Nodal
535
536
FAMILY SURVEY
S. No...........................................
X-ray No./Date...........................................
Findings ....................................
Father ................................................................................................................................
Mother ..............................................................................................................................
Siblings:
Tuberculin (mx) Test
Age (Years)
Sex
2.
3.
4.
5.
Other relatives:
Grandmother
Grandfather
Male 1
Female 2
1.
Treatment Sheet
Treatment Required
Name of Medicine
Intensive phase
I. INH
II. Rifampicin
III. Pyrazinamide
IV. Ethambutol
V. Streptomycin
VI. Others
Maintenance phase
I. INH
II. Rifampicin
III.Pyrazinamide
IV. Others
Out Patient
Duration
(months)
In Patient
Dosage (mg/kg) Category assigned:
DOTS/nonDOTS
ANNEXURE II
Check List for the Resident Doctor on Follow-up Visit
1. Mantoux of siblings less than 5 years preferably 10 years.
2. X-ray of siblings, parents, grand parents and servant, if any
3. Enter family survey X-ray reports.
4. Check drugs compliance and scheduled attendance in clinic.
5. Record symptoms.
6. Follow-up, case record form CRF to be filled every month for 1st 3 months then 3 monthly.
7. Hemogram (Absolute eosinophilic count).
8. Category based diagnosis.
i.
ii.
iii.
iv.
v.
Lungs.
Lymph Nodes.
Neurotuberculosis.
Bone tuberculosis.
Abdominal tuberculosis.
9. Category based treatment.

10. Check compliance.
Status of symptoms
Weight gain
Compliance of the Regimen.
1. = 100% drug dosage intake
6. = <50% drug dosage intake
*CRF Case record form
537
538
ANNEXURE III
FOLLOW-UP SCHEDULE FOR PEDIATRIC TB CLINIC
Name:.................................................................. Date:..................................................................
1-2. T.B. Clinic No.
year of enrollment
No.
Year
3. Follow-up No.
4. Scheduled or Nonscheduled visit
1. Sch.
2. Nonsch.
5. Weight (Kg)
6. Nutritional status
1.
2.
3.
4.
5.
Normal
PEM grade 1
PEM grade 2
PEM grade 3
PEM grade 4
7-8. Height in cms

Lymph nodes (TBL)
Present Site
Gr. of
1. Yes
1. Right LN
2. No
2. Left
3. Bilat
9-15 Cervical
1. Ant cerv.
2. Post cerv.
3. Subocc.
4. Subman
5. Sub ment.
6. Jug dig.
7. Superf.
8. Deep
Percentile (NCHS)
Size
in cms
1. <1
2. 1-2
3. 2-3
4. >3
Number
1. Sing.
2. Mult.
Consistency
Sinus
1. Soft 1. Matt. Mob. 1. Yes
2. Firm 2. Matt. Fix.
2. No
3. Fluc. 3. Disc. Mob
4. Hard 4. Disc. Fix

16-23 Axillary
as a group
24-31 Inguinal
as a group
32-39 Other
(spec.)
40-41 Liver
Enlarged
Cms below costal margin
1. Yes
2. No.
42-43 Spleen
44.
Chest
45.
Write the site in the rectangle
1. Clear
2. Loc. Crepts
3. Gen. Crepts
4. Bronchial breathing
Investigations
46.
AST
ALT
47. Gastric Lavage/Sputum/Induced sputum

Smear
Smear
Positive (1)
Positive (1)
Negative (2)
Negative (2)
Culture ............................................... Culture
Positive (1)
Positive (1)
Negative (2)
Negative (2)
SGOT Aspartate Transaminase

SGOT Alanine Transaminase
Smear: Lab Technique Used for Gastric Lavage
Culture: Lab Technique Used for Sputum
48.X-ray film of chest
5. Decreased air entry

6. Rhonchi
7. Others (specify)
539
540
1. PPC
1. Normal
3. Nodal (N)
2. Parenchymal (infiltrative lesion (P))

4. P + N
2. PPD
1. Consolidation
4. Pleural effusion
2. Cavity
5.Bronchopneumonia
3. PPL (Post Primary Lesion)

1. Calcification
2. Fibrosis
48. Type of Clearance in X-ray Chest film
1. Complete clearance
3. Mild clearance (1/3 clearance)
5. Deterioration
3. Collapse with nodes

6. Miliary
3. (1 + 2)
2. Moderate to significant ( to 2/3 clearance)

4. No change
49. Tubercular lymphadenitis

Reduction in size
1. 1/3
2. 1/2
3. 2/3
4. Complete
5. No change
Size of Gland
50. Fine needle aspiration cytology (FNAC)/Biopsy
Histopathology report
*Similar case record forms can be designed for other systems for follow-up.
For AFB
Smear
Culture
1. Positive
2. Negative
51-52. Treatment
DOTS equivalent category continuous therapy
1. Cat I
2. Cat II
3. Cat III
DOTS as under RNTCP
1. Cat I
2. Cat II
3. Cat III
53-54. Regimen
Non-DOTS but equivalent category
a. PPC Cat III of DOTS
b. PPD Cat I of DOTS
c. Tubercular Lymphadenitis Cat I of DOTS
d. Symptomatic Mantoux +ve any age
Asymptomatic Mantoux +ve <5 years
Post Primary Lesion (calcification or
Fibrosis)
e. Multidrug Resistant Tuberculosis
Individualize the regimen
3 HR
3 HR
No ATT
ANNEXURE IV
CHILDHOOD TUBERCULOSIS NATIONAL DATABASE
National code
Name the medical college with state
Center code
Name of Medical College....................................................................................
With complete address........................................................................................
Name...........................................................
Age
Sex
(Months)
1M, 2F
1. Presenting complaints and their duration:

1 Yes 2 No
Duration (Months)
Fever
Cough
Loss of appetite
Weight loss
Not gaining weight
Other Specify
2. Contact with TB patient
1 Yes 2 No
(if yes, fill following, if no go to next column)

TB at present
Type of TB
(1 Yes, 2 No)
1 Pulmonary, 2 Lymph node

3 CNS, 4 Abdominal 5 Others
Mother
Father
*TB at present include treatment for TB in last 2 years
*TB in past
Duration of
TB month
Type
1. Renal
2. Bone
541
542
Sibs
Grand Mother
Grand Father
Neighbors
Relatives
3. BCG vaccine 1 Yes 2 No

If yes fill following, otherwise go to next
Age at vaccination (months)
Scar (+) (1), () (2)
4. Weight
(kgs)
Height
(cms)
5. Mantoux test
(mm)
Vertical
Horizontal
PPD used (type and strength)........................................................................................

6. Hb
gm/dl
DLC%
TLC
P
7. CXR
(More than 1 response maybe present)
1 Normal 2. Adenopathy 3. Infiltration 4. Consolidation 5. Bronchopneumonia
6. Miliary 7. Cavity 8. Pleural effusion 9. Others-Specify
8. Serology: done (1) or not (2)
(If yes what antigen used) .............................................................................................
9. Diagnosis:
Pulmonary TB, Yes 1 No 2
(If yes, fill following, if no go to next)

Type of pulmonary TB
1. Normal
4. Consolidations
2. Adenopathy
5. Bronchopneumonia
3. Infiltration
6. Miliary
7. Cavity
8. Pleural effusion
9. Other Specify
10. Gastric lavage
Positive
Negative
Not done
11. Sputum smear
Positive
Negative
Not done
Positive
Negative
Not done
culture
12. Pleural fluid
Proteins (gm%)
TLC
P
(Per cubic ml)

L
2. Lymph Node Tuberculosis Yes 1 No 2

Group of lymph nodes involved
1. Cervical
2. Axillary
3. Inguinal 4. Other Specify
Fine needle aspiration cytology of Lymphnode

1. Necrosis 2. Granuloma
3. AFB
4. Not done 5. Other specify
Biopsy of Lymph node
1. Necrosis 2. Granuloma
3. Abdominal Tuberculosis
3. AFB
4. Not done 5. Other specify
Yes 1 No 2

Type of abdominal tuberculosis
1. Ascitic
2. Intestinal
Ultrasound abdomen
Ascitic fluid
3. Lymph nodes
4. Other specify
1. Abnormal
1. Done
2. Normal
2. Not done
Protein (mg/dl)
Sugar
Polys
Lympho
AFB Smear
Present (1)
Culture
Absent (2)
4. CNS Tuberculosis
Yes 1 No 2
cells (cu mm)

cells (cu ml)
543
544
Type of CNS TB
1. Tuberculoma
CSF
2. TBM
Proteins
(mg/dl)
3. Other specify
Sugar
(mg/dl)
Cells
Lymph%
cells (per cubic ml)
Cells
Polys%
CT Scan
1. Basal exudates
2. Hydrocephalus
Other investigation specify
MRI describe the findings
5. Osteoarticular TB
3. Tubercles
4. Infarct
5. Other-specify
1 Yes 2 No
1. Osteomyelitis, 2. Arthritis
If Arthritis Joints involved
1. Knee,
2. Hip,
3. Ankle, others
6. Renal Tuberculosis
Urine AFB smear
Culture
Ultrasound abdomen*
1 Yes 2 No
1 Yes 2 No
1. Yes 2 No
CT abdomen
7. Other TB
Treatment Required
Out Patient
Name of Medicine
Duration
Intensive phase
*INH
Rifampicin
Pyrazinamide
Ethambutol
Streptomycin
* Describe findings of each investigation
In Patient
Dosage (mg/kg) Category DOTS/Non-DOTS
545
Others
Maintenance phase
Duration
INH
Rifampicin
Pyrazinamide
Others
* Give the dosage in mgs/kg used.
Dosage (mg/kg)
Non-DOTS
The case record form given above for National Data Base can be modified by the faculty member incharge of TB
clinic in the Pediatric Department of Medical College as per details used at Pediatric TB clinic at All India Institute of
Medical Sciences, New Delhi.
These forms are to be filled by the individual Medical college for each patient and then centrally collected and
Data can be analysed by National Institute of Medical Statistics, Indian Council of Medical Research. It can be
546
submitted as a project by Pediatric Department (faculty incharge of TB clinic) to Indian Council of Medical Research
and Department of Biotechnology as mentioned earlier for funding for data analysis.
ANNEXURE V
CASE RECORD FORM
PEDIATRIC HIV CLINIC
1. HIV Clinic No.
No.
Year
Name...............................................................
3. Sex: M/F
Date of Registration.....................................
4. Age: in months
1 Male 2 Female
Address Postal ...........................................................................................................................................
...........................................................................................................................................
5-6 Age at first symptom:
Months
Years
7-8
Months
Years
Age at diagnosis:
9-11 Per capita income:

12 Family history
1. Positive
2. Negative
Age
(yrs)
Occupation
13-18
Father
HIV status
1. Known
2. Unknown
H/O promiscuitry
Blood transfusion
(When, Where)
Symptoms
1. Present
2. Absent
Medication
1. Anti-TB
2. Antiretroviral
3. Others
19-23
Mother
24-29
Sibling
30-35
36. Knowledge of disease/awareness in parents:
Present-
Yes, Absent No.

Yes 1
No 2
37. 1. Nature
2. Transmission
3. Outcome
4. Prevention
38. Mode of diagnosis of /1index case screening /2 referred / 3 clinical suspicion
4. Diagnostic test: ELISA
39. Mode of infection in index case
a. Perinatal Parental promiscuity,
b. Blood transfusion
c. Unknown
40-50 Presenting symptoms
40-41
1. Asymptomatic
42-43
2. Pyrexia of unknown origin
44-45
3. Failure to thrive / with loss
46-47
4. Oral thrush
48-49
5. Anemia
Duration (months)
Age at onset (months)
547
548
50-51.6. Development
Number of Episodes
57-62 7. Pneumonia
1
52-53 -
Nature
54-56 -
1. Consolidaton
2. Bronchopneumonia
Severity
Mild
57-59 -
Duration
(Days)
60 -
<5
Moderate
Severe
6-10
>10
Investigation
Describe
Therapy
Describe
62Response
Describe
63-64 8. Diarrhea
Nature
Duration
(days, months)
61 -
65-67 Past History

1. Contact with tuberculosis
2. Breast feeding
3. Blood transfusion/patenteral therapy
68-69 Immunization status
1. Routine
2. Hepatitis B/H. influenzae / Pneumococcus
70-75 Nutritional intake
1. Calories / Proteins
76.
Others
77.
Examination
78-82 Anthropometry
Parameter
Weight
Height
Percentile

Wt. For Ht.
Head circumference
Nutritional status
83 Development = Describe as per age
84-92
General physical
1. Fever
2. Pallor
3. Cyanosis
4. Parotid enlargement
5. Clubbing
6. Lymphadenopathy
7. Oral thush
8. Skin rash
9. Fundus (chorioretinits/tubercles)
Respiratory system
93-96
1. Respiratory Rate
2. Recessions
3. Shape
4. Air Entry and adventitious sounds
97-100
CVS
1. Pulse rate
2. JVP
3. BP
4. Precordium
1-2 Abdomen
1. Liver
2. Spleen
3-4 CNS
Diagnosis & Staging
Yes / No
Comments
549
550
Summary of Problem
1. Investigation
5-19
Date
1st Visit
2nd Visit
Hemoglobin (g/dl)
TLC (/mm3)
DLC
Absolute eosinophil
PBS
ESR (mm/1st hr)
Serum Na/K/C1
Urine Na /K/Cr
OT/PT/SAP
Ca/Po4
Creatinine/BUN
Blood Sugar
USG abdomen
Others
20. Tuberculin Status
21-24Chest X-ray
Normal / abnormal
Infiltrates
Hilar / Perihilar / Alveolar / Intersitial
Bronchiectasis
25 Family survey
a. Positive
b. Negative
26-27 Gastric aspirates for AFB

a. Positive
b. Negative
28 CECT chest
Describe
29 SaO2/ABG
Culture
a. Positive
b. Negative
30 Stool parasites
a = present
b= absent
3rd Visit
4th Visit

31
ECHO
32
Others
33
Treatment (Check List)
34
1. Nutrition
35
2. Counseling
36
3. Immunization
37-40 4. Prophylaxis
PCP
Tuberculosis
Bacterial infection
Fungus
41 5
Antiretroviral therapy
42 6
Others
551
552
39.
Follow-up 3 sheets
Date New Complaints
Compliance /side effects
Caloric
intake
Wt/Ht
& Wt
Physical
Investigation
Examination
PS. This case record form can be modified according to the place of clinic by the faculty member incharge.
SECTION 7
PREVENTION AND CONTROL

OF TUBERCULOSIS
Bacillus Calmette-Guerin (BCG)
Bacillus Calmette-Guerin (BCG) Vaccination
BCG VaccinationFrequently Asked Questions
Latent Tuberculosis
Latent Tuberculosis Infection in Children and
Adolescents
Symptoms-based Screening of Child
Tuberculosis ContactsImproved Feasibility
in Resource Limited Settings
Tuberculosis Control Program in Children:

Lacunae and Experiences
Prospective of Prevention, Diagnosis and

Management of Tuberculosis in the
National Program
Frequently Asked Questions about Tuberculosis
Ethical Issues and Concerns about Tuberculosis

Research in Children
Tuberculosis in Children Research Priorities
38
Bacillus Calmette-Guerin (BCG)
38.1 BACILLUS CALMETTE-GUERIN (BCG) VACCINATION

INTRODUCTION
The epidemiological data available to date demonstrate
that the spread of tuberculosis (TB) is a global health
emergency. The continuous spread of the TB pandemic
justifies a need for the accelerated development of safe,
more effective and affordable vaccine with old and new
therapeutic strategies. The currently available vaccine,1
the only one available against tuberculosis was developed
more than 100 years ago. Several variants of the vaccine
based on different attenuated strains of M. bovis (BCGPasteur, Tokyo, Glaxo Smith Kline Biologicals, Tice, etc.)
are being used as part of childhood immunization
programs in many parts of the world, supported by WHO
and UNICEF. Over the past years, BCG has been shown
to be safe and inexpensive. However, it has been
established that BCG vaccine is not able to prevent
infection with wild type M. tuberculosis in children,
although they are still effective in preventing meningitis
and miliary tuberculosis in 80 percent of vaccinated
children.2 This protective efficacy varies significantly in
different geographical locations and different
populations. There are additional safety concerns related
to BCG vaccines in populations with high prevalence of
HIV. In recent years, no vaccine other than BCG has been
the subject of such extensive reviews and controversies
regarding its efficacy for protection against tuberculosis.3,4
NEED FOR BCG VACCINATION

The incidence of tuberculosis is on the rise in India in
spite of the National Tuberculosis Control Program by
the Government of India, even with the help of
International agencies. The occurrence of multidrugresistant tuberculosis in adults is a great threat for same
type of tuberculosis in children. The increase in the
incidence of tuberculosis in children cannot be decreased
by chemotherapy alone in adults, immunoprophylaxis
with BCG need continuous researching for the availability
of more efficacious vaccine.
There are hardly any studies in India where the

immune parameters of cell mediated immunity have
been estimated to assess the level of its efficacy. Seth et
al5-8 have done a number of studies for evaluation of cell
mediated immunity by leukocyte migration inhibition
index by LMIT in children who have had BCG at birth,
its relation to nutritional status, correlating the cell
mediated immunity by tuberculin test and LMIT. It has
been further estimated by them, is that how long does
the protecting response remains. Further, it has been
illustrated by their studies that in preterm, low birth
weight newborns, the BCG vaccination needs to be given
at the age, when the baby would have born as full term.8
It has been shown that the immunological response
declines in a year or so, CD4 subset of T cells which
regulate the immune responses to M. tuberculosis by being
directly cytotoxic for monocytes pulsed with
mycobacterial antigens also decrease. These cells cross
inflamed endothelial surfaces to reach the sites
of mycobacterial infection. It has been shown
experimentally in mice that infection by M. tuberculosis
substantially enhances the depletion of CD4 subset of T
cells.9 Orme10 has further demonstrated the IFN- an
essential component of host defense against mycobacteria
which is responsible for the activation of macrophages
and stimulation of their antimycobacterial properties is
increased after BCG vaccination.
Notwithstanding these controversies, BCG vaccine
continues to occupy an important place in the Universal
Program of Immunization in developing countries.
Although it has been in use since 1921, the efficacy of the
vaccine continues to be debated.9,10
History
Ever since, Kochs discovery of the tubercle bacillus in
1882, numerous workers tried to attenuate the bacillus
in the hope of producing a vaccine for the prevention of
tuberculosis. In Lille, Albert Calmette and Camille Guerin
were also trying to attenuate a highly virulent strain of
556
Section 7 Prevention and Control of Tuberculosis
tubercle bacillus of bovine origin isolated by Nocard of

Alfort from tuberculous mastitis in a heifer. In 1908, these
scientists observed that addition of beef bile divided the
aggregates of tubercle bacilli almost to single units. They
soon prepared a suitable culture medium incorporating
pieces of potato cooked at 70 C in beef bile containing 5
percent glycerine. As the bacilli multiplied in this medium
they were repeatedly subcultured every three weeks. Over
the next few months the culture lost its characteristic
appearance and the bacilli lost their virulence first for the
calf followed by guinea pigs. In 1921, after a total of 231
transplants, the strain proved to be completely harmless
even in highly susceptible guinea pigs, yet its antigenicity
was unimpaired. This strain was named bacillus Calmette
and Guerin (BCG). In 1924, Calmette declared the bacillus
incapable of reverting to virulent form.
Mechanism of Protection of TB Disease by BCG

Despite routine vaccination with Mycobacterium bovis
bacillus Calmette-Gurin (BCG) soon after birth,
tuberculosis in babies and adults remains epidemic in
South Africa. The immune responses of the nave
newborn child and how are they affected by vaccination
with BCG are as yet not fully understood. Immunity
during pregnancy and in healthy human newborns may
be skewed toward type 2 cytokine production; however,
it is type 1 cytokines that are required for protection
against M. tuberculosis infection. To better understand
neonatal cytokine responses prior to and following
exposure to mycobacteria, Watkins et al11 collected cord
blood and peripheral blood samples and evaluated the
cytokine response following ex vivo incubation with BCG.
Gamma interferon (IFN-), interleukin 10 (IL-10), IL-12,
and low levels of IL-13 and IL-5 but no IL-4 were secreted
into the culture supernatant of cord blood mononuclear
cells. Intracellular staining showed that IL-10 and IL-12
were produced by monocytes and that IFN- was
produced by natural killer (NK) cells but not by CD4(+)
or CD8(+) T cells. In contrast, in the peripheral blood
samples collected from babies 13 weeks post-BCG
vaccination, IFN- was detected within CD4(+) and
CD8(+) T cells. Taken together, the data suggest a central
role for Th1 cytokines in nave as well as BCG-vaccinated
neonates in the protective immune response to
tuberculosis. NK cell-derived IFN-gamma produced in
nave neonates likely plays a key protective role via
monocyte activation and the priming of a subsequent
adaptive Th1 response.11
The BCG Strain Family

Until the introduction of freeze-drying in Japan in 1943,12
the only means of maintaining a viable strain was through
subculturing. With the distribution of the vaccine strain

to multiple laboratories in the world, each using slightly
different technique for strain maintenance, it is not
surprising that the BCG family shows large diversity.13
The first freeze-dried French strain (1949) from the
Pasteur Institute in Paris was strain 1173-P2, from which
the Glaxo and Danish strains descended.14
Recent work based on molecular characterization of
the various substrains points to various mutations that
have occurred at different points in time15-17 and indicates
that the various BCG substrains are morphologically and
genetically different from each other.
The original strain of BCG was replaced by a variant
while it was being maintained by serial transfer on
artificial culture media at the Pasteur Institute. Since
then it has been maintained by many different
laboratories, using many different methods. As a result,
the BCG strains used today are not bacteriologically
identical. Three parent strains (Glaxo, Tokyo, and
Copenhagen) account for more than 90 percent of
the vaccine used in the world today. 18 In 1966, a
WHO Expert Committee on Biological standardization
adopted a series of recommendations for the production
of BCG vaccine. It states that the vaccine should be
freeze-dried, and that the vaccine strain should be
maintained by the seed-lot-system whereby no vaccine
is produced from a seed more than 12 passages removed
from a primary freeze-dried lot.19 This eliminated the
possibility of more attenuated variants in later BCG
vaccine lots.
Safety Record of BCG Vaccination

A large review has shown BCG to be one of the safest
vaccines. The demarcation between a normal reaction and
an adverse reaction is not always clear.20,21 The normal
reaction is a red indurated area measuring 5 to 15 mm in
transverse diameter. A crust is formed around this
induration, which is soft at the center for three to four
weeks. At six to ten weeks, the crust falls off, leaving a
flat scar measuring three to seven millimeters.22 Regional
lymphadenopathy in the absence of erythema or vesicle
formation should also be considered a normal reaction
to the vaccine.23 Complications include cutaneous lesions
and regional suppurative lymphadenitis; more severe
localized or multiple lesions (such as musculoskeletal
lesions); 24-26 and non-fatal and fatal complications
resulting from hypersensitivity reactions or
mycobacterial dissemination. 20,21,27-34 The risk of
complications varies with the type of vaccine and with
the age at vaccination. The risk of osteomyelitis ranged
from 0.01 to 50 per 1 million vaccinations, that of multiple
or generalized lesions from 0.01 to 2 and that of fatal cases
Chapter 38 Bacillus Calmette-Guerin (BCG)

from 0.01 to 1 per million vaccinated individuals.20,21 The
lowest complication rates were reported with the Tokyo
strain, and the highest with the Gothenburg strain
produced in Denmark.25,35
In a prospective study in South Africa among 10000
neonates receiving the Copenhagen strain intradermally
at birth, at six weeks post vaccination, the vaccination
scar had healed in more than 95 percent of children, 1.5
percent had no vaccination scar, and in 3 percent, adverse
events were noted.35a All adverse events were local
(oozing, abscesses, rarely combined with lymphadenopathy).
Tabatabaie et al36 reported osteomyelitis due to BCG
vaccine in a six-month-old immunocompetent boy who
had received BCG at birth but developed multiple
abscesses in the left subaxillary region and swelling and
wound infection on the left arm. Radiograph revealed
osteolytic lesions in the left humerus. A biopsy from the
site revealed chronic granulomatous lesion positive for
M. bovis on tissues culture. Hence, the diagnosis of
osteomyelitis due to BCG vaccination was confirmed. The
child was put on 4 drugs in the intensive phase 2SHRE
and three drugs 10HRE in the continuation phase which
lasted for ten months.
Hematogenous spread of BCG vaccination may result
in osteomyelitis, but this is a rare complication.
Symptoms resulting in pediatric orthopedic referral may
be vague and present as late as 30 months following
vaccination. These can be osteitis and septic fulminant
osteomyelitis. The lesion can be distant to the site of
injection but usually on the same side of vaccination. In
a complication such as osteomyelitis, the child must be
thoroughly investigated for humoral and cell-mediated
immunity. Timely diagnosis of BCG osteomyelitis is
important since therapy is effective if instituted early in
the course of disease. The diagnosis can be delayed due
to late development of symptoms because the early
course is often benign. Chest X-ray does not reveal any
specific diagnostic lesions.
557
of BCG vaccination must be asked it there are symptoms

and signs on the left upper arm.
BCG vaccine is considered safe, however, some
complications may occur such as abscess at the site of
inoculation, ulceration at the vaccination site, and
regional lymphadenitis. Some vaccine strains have been
responsible for osteomyelitis in 1 case per million doses
administered. A meta-analysis of published literature
between 1950 to 70 indicated the frequency of
osteomyelitis after BCG vaccination as 1 in 80 000 in some
European countries. The lesions are localized in the
metaphysis or epiphysis of long bones.
Risk of osteomyelitis due to BCG vaccination in
immunodeficiency patients is much higher and is
associated with fatal disseminated infection.
Because BCG is a live vaccine, concerns were raised
early on about the safety of its use in persons infected
with HIV, 37-39 and several case reports about
disseminated mycobacteriosis40-46 and mycobacterial
meningitis due to BCG40,42,47 have been published. A
study among mother-child pairs with and without HIV
infection has shown that children of mothers with HIV
infection who also had HIV infection themselves had a
slightly increased risk of suppurative lymphadenitis, but
the manifestations were mild and easily manageable.48
Apparently, living BCG can persist for decades and cause
localized 49 or disseminated 50 complications after
acquisition of immunosuppression. Nevertheless, most
of these case reports appear to be isolated events,
although it has been argued that disseminated disease
attributable to BCG vaccination in HIV-infected children
might be exceedingly difficult to diagnose.51 However,
a study in Zambia among HIV-symptomatic children
with a median age of 15 months, showed that
mycobacteremia due to BCG must be exceedingly rare.52
A recommendation by WHO states that no principal
changes in BCG vaccine policy are warranted unless
children present with symptomatic HIV infection,53 a
statement that has not been challenged.54,55
Treatment of BCG Osteomyelitis

It consists of:
1. Antituberculosis therapy
2. Surgical intervention
The advantages of surgical intervention are two-fold,
(i) one can get a specimen for bacteriologic confirmation
both by smear and culture. (ii) Healing process is quicker.
Osteomyelitis due to BCG vaccination has a benign
course. Hence, if osteomyelitis does not respond to
appropriate and adequate antibiotic therapy, its etiology
in a baby (neonate or infant) more often the former is
likely to be due to BCG vaccination complication. History
Indications and Recommendations for the Use of BCG

Vaccination
Approximately 100 million children now receive BCG
every year.55 The number of doses produced in the year
2000, in descending order, were the Copenhagen 1331
strain, D2PB302, Tokyo 172, Sofia SL 222, Pasteur 1173,
Glaxo 1077.55
While there have been wide variations in the
protection afforded by BCG vaccination in different trials,
the evidence is overwhelming that BCG provides
protection against tuberculosis, especially against
558
tuberculous meningitis and death from disseminated

tuberculosis in children. Where it worked, its protective
effect waned over time, to disappear after 15 to 20 years.
The evidence for protection against bacteriologically
confirmed tuberculosis in adults has been less consistent.
Several low-prevalence countries are reviewing their
policies, usually shifting from universal vaccination to
vaccination of infants in high-risk groups only. In a
recently published report from Netherlands, it is
demonstrated that in the absence of vaccination, the
annual risk of developing severe TB for a children
belonging to high risk group was 3/100 000, while BCG
vaccination reduces this risk by 73 percent. This study
estimated that about 9000 children would need to be
vaccinated to prevent 1 case. Vaccinating children from
high-incidence countries would then cost about Euro
4,500 per discounted disability-adjusted life year averted.
The authors in this study conclude that current Dutch
BCG strategy, as well as the proposed inclusion of
immigrant children from Turkey, Surinam and former
Yugoslavia, is on average cost-effective.56
BCG Vaccine Production in India

In India, the BCG vaccine laboratory was started in
Chennai in 1948 for the production of BCG vaccine for
use in India and also for supply to some neighboring
countries. Since 1966, Danish strain 1331 is being used
for preparation of both the liquid and freeze-dried
vaccine.
For preparing the liquid and freeze-dried BCG vaccine,
the Guindy (BCG) Laboratory in Chennai used the method
followed at the State Serum Institute, Copenhagen, i.e.
using Sauton potato medium for maintaining the BCG
strain. The prepared vaccine is tested for purity by ZiehlNeelsen smear for acid fast bacilli, and by culture on
nutrient broth, thioglycollate medium and Sabourauds
agar medium. Total bacterial count and the number of
culturable particles in the preparation are estimated.
Biological tests are carried out in guinea pigs to estimate
the degree of virulence, allergenicity and safety. In
addition to the above tests, in the case of freeze-dried
vaccine, tests are carried out to estimate residual moisture
and heat stability. Both types of vaccines are to be stored
at 2 to 4C temperature, protected from light. Under these
conditions of storage, the liquid vaccine can be used for
four weeks from the date of manufacture while the freezedried-vaccine can be used for three months.
Constitution
Previously BCG vaccine was available in both the liquid
form and the freeze-dried form, however, now only the
freeze-dried vaccine is used in all countries. The
attenuated Calmette Guerin strain of bovine M.

tuberculosis is present in a concentration of 0.1 to 0.4
million viable bacilli per dose of vaccine. The WHO
recommends the Danish 1331 strain for the production
of BCG vaccine, which has been used by the BCG
Laboratory, Guindy, Chennai since 1966. Quality control
is ensured by the International Reference Center at
Copenhagen.
Storage
If stored at subzero temperatures (20 C) the vaccine
remains potent for two years. The undiluted vaccine can
be stored in the middle compartment of the refrigerator
(2 to 4C) without loss of potency upto six months. At
the peripheral level, at 2 to 8 C, it is good enough for
use up to one week. Strict attention should be paid to
maintenance of the cold chain and it should be
transported in thermos flasks with ice to the outreach
immunization clinics. As the vaccine deteriorates on
exposure to light it is usually supplied in dark colored
ampoules and wrapped in black paper/cloth.57
Reconstitution
Ampoules of freeze dried BCG vaccine are long and
sealed under vacuum. Thus they have to be opened
carefully by gradually filing at the junction of the neck
and the body of the ampoule so that air does not rush in,
causing spillage. The vaccine is then reconstituted by
dissolving in normal saline as distilled water acts as an
irritant.58 The diluent should always be kept with the
vaccine in the main compartment of the refrigerator/cold
box/vaccine carrier to ensure that it is cold enough when
one needs it. Reconstituted BCG vaccine should be used
within three hours. It can be prevented from
contamination by proper hand washing and sterilization
of equipment, and using separate needles for each child.57
Dosage
The standard dose of BCG vaccine is 0.1 mg in 0.1 ml
volume. Some experts recommend a dose of 0.05 ml to
newborns aged less than 4 weeks as they fear a higher
incidence of regional lymphadenitis with the
administration of full dose.58 In controlled trials, the
incidence of lymphadenitis was 1.3 percent as compared
to 1 percent with a lower dose. However, doubts on the
efficacy of the lower dose exist. Hence the same dose (0.1
mg) should be given at all ages.59
Optimal Age of Vaccination

The use of BCG started in early 1950s under the mass
BCG campaign. It was later included in the Expanded

Program of Immunization (EPI) and is currently given
to infants under the Universal Program of Immunization
(UPI). Most studies have shown good sensitization when
BCG has been given at birth.59-62 A randomized clinical
trial has shown that delaying BCG vaccination from birth
to 10 weeks of age enhances the quantitative and
qualitative BCG-specific T cell response, when measured
at 1 year of age.63 However, since it is difficult to get
children back for immunization and BCG immunization
at birth shows an adequate cell mediated immune
response (CMIR),8 it is preferable to give BCG at birth.
Thus it is recommended that BCG be given either at birth
or at the time of earliest contact with the child, preferably
before the child is one year of age.
Mussi-Pinhata et al 64 determined the effect of
intrauterine growth retardation (IUGR) on the response
of BCG vaccination. The infants were evaluated using
post-vaccination skin tests to PPD and tuberculin
lymphocyte transformation tests. They found similar rate
of response to the BCG in the term babies who were small
for gestational age and term babies having weight
appropriate for gestational age. Thus, the presence of
IUGR should not be a reason for delaying BCG
vaccination. Similarly, it has been found to be equally
effective in preterm infants >34 weeks of age.65
Administration
Conventionally BCG is given by intradermal route in the
left upper arm region. The vaccine is reconstituted as
described earlier. No special preparation of the skin is
necessary before its administration; cleaning with sterile
water is enough. BCG is usually administered in a single
dose as part of the immunization schedule.
Sequence of Events
When 0.1 ml of the vaccine is injected intradermally it
raises a wheal 8 mm in diameter over the injection site.
Hair follicles are seen as small pits on the wheal
produced. Failure to observe this means that either the
volume actually injected was inadequate. (e.g. because
of leakage from the syringe) or that the injection was
given too deep. The latter should be avoided because it
will produce a subcutaneous abscess that heals only
slowly and often produces an ugly, retracted scar. The
wheal is absorbed in 20 to 30 minutes. No rubbing or hot
fomentation at the injection site is recommended.
Nothing is visible at the site of injection for some days.
By the 3rd or 4th week induration is felt at the vaccination
site that becomes a lump of 6 to 10 mm by the 6th week.
This is not painful but is tender to touch. This lump would
soften with pus formation and discharge, leaving a tiny
ulcer that heals by itself. This cycle of ulceration and
559
healing may repeat 2 to 3 times over a period of 2 to 3

months. Healing is usually complete by 10 to 12 weeks
and the site is marked by a small pigmented scar of 5 to
7 mm in size.66
Vaccine assessment in groups of school children has
shown that for the usual vaccines the mean diameter of
the scar is 5 to 7 mm, with a standard deviation of not
more than 2 mm. If no scar is observed during the
months following vaccination, it may be concluded that
BCG was not given properly and the dose be repeated.
Variations in the number of culturable particles in the
vaccine only slightly influence the size of the local lesion.
The latter, therefore, is related to the technique of the
vaccination rather than of the quality of the vaccine.
Contraindications to BCG Vaccination

BCG should not be given to persons:
i. Whose immunologic responses are impaired because
of congenital immuno-deficiency, HIV disease,
leukemia, lymphoma or other malignancies.
ii. Whose immunologic responses have been
suppressed by steroids, immunosuppressant drugs,
alkylating agents, antimetabolites or radiation.
It is best to avoid BCG for a period of 4 to 6 weeks
following a viral infection (e.g. measles, chicken pox,
hepatitis B) since all viral infection affect the immune
response of an individual. It is also advisable to postpone
BCG for at least three months in a child who has received
immuno-globulins.18 BCG vaccine can be administered
safely with all other childhood vaccines. Even in HIV
infected newborns BCG vaccine does not appear to
adversely affect the immune response to the other
childhood vaccinations given simultaneously.19
Efficacy and Effectiveness of BCG Vaccination

Efficacy is the extent to which an intervention produces
a beneficial result under ideal conditions. The best setting
to address efficacy is thus prospectively, in a controlled
clinical trial. In contrast, effectiveness takes the various
constraints into account that are found in the field in the
actual routine delivery of the intervention. Effectiveness
is often ascertained retrospectively, such as in casecontrol studies. Efficacy (in clinical trials) and
effectiveness (in case-control studies) have been
ascertained in various settings. The principle underlying
the design of prospective and retrospective studies
should be well understood. These trials were
supplemented by community trials and contact studies.
The variation in estimates of protection ranged widely,
from harm (more cases among the vaccinated than among
controls) to a high level of protection.
560
Because BCG vaccination is given early in life, the

protection afforded is limited in time, and its effect on
bacteriologically confirmed tuberculosis in adults is
inconsistent, it cannot be expected to have a great impact
on the epidemiology of tuberculosis.67-69
It seems inappropriate to conclude from metaanalyses
that BCG provides some average protection.70,71 The
observed range in protection is real and remains largely
unexplained.
In light of the evidence, WHO recommends its use in
newborn children or as early in life as possible.72,73 This
is still a sound policy for those countries in the world
where tuberculosis is highly prevalent, and tuberculous
meningitis is frequent, disabling and has fatal occurrence
because it is diagnosed late. It fails to address the role of
BCG where tuberculosis in children has become a rare
occurrence.
The IUATLD has developed recommendations on
criteria for the discontinuation of mass BCG vaccination.74
Three key issues enter into the decision making process
on the discontinuation of BCG vaccination.
The first is the extent of protection BCG actually
imparts in a given location. In the USA, the low efficacy
of BCG vaccination in Georgia, Georgia-Alabama, and
Puerto Rico had an important impact on the decision not
to routinely utilize BCG vaccination. As such prospective
studies are usually beyond the realm of resource
availability, effectiveness might alternatively be studied
utilizing the case-control or contact study approach.
The second is the frequency of serious forms of
tuberculosis in children (meningitis, disseminated forms)
weighed against the frequency of adverse reactions from
the vaccine itself. This has been best studied in Sweden
where the frequency of serious adverse reactions from
BCG vaccination (osteoarticular and disseminated
mycobacteriosis due to BCG) out-weighed the incidence
of cases that the vaccine was intended to prevent.35 BCG
vaccination may become noncosteffective as the
frequency of childhood tuberculosis decreases, so that
an increasing number of children need to be vaccinated
to prevent one case.
The third consideration is the value attached to the
preservation of the utility of the interpretation of
tuberculin skin test results. BCG vaccination induces
tuberculin sensitivity and complicates the interpretation
of tuberculin skin testing results. In industrialized
countries with an elimination strategy in mind, the
tuberculin skin test is an important means of identifying
persons with tuberculous infection at a high-risk of
progression to tuberculosis who would benefit from
preventive chemotherapy.
WHO discourages revaccination because there is no
evidence of its usefulness.75 Lack of evidence is, however,
not synonymous with lack of efficacy. Revaccination at

school entry is likely to be inefficient (even if it were
efficacious), because it falls into the period in life when
the risk of tuberculosis is lowest.
Finally, concerning HIV infection, the WHO has
concluded after careful review of available data, that BCG
vaccination schemes do not need to be altered unless
HIV infection is symptomatic (AIDS).51 This, too, seems
to be a reasonable recommendation given the lack of
evidence of an increased frequency of serious adverse
events in BCG-vaccinated children who also have
acquired HIV infection from their mother. However, it
appears that HIV infection lowers the protective effect
against extrapul-monary tuberculosis.76 In industrialized
countries, where the need for BCG vaccination is
generally lower, it is usually recommended not to give
BCG vaccination to individuals known to have HIV
infection.77
The freeze-dried vaccine should be kept refrigerated
and protected from light, and diluted only immediately
before vaccination. In most countries, BCG vaccine is
given by the intradermal route, generally by injection
with a 25 or 26 gauge needle, in the deltoid insertion
region on the left side.78 Most manufacturers (including
all those who provide vaccine for UNICEF, the largest
purchaser in the world) recommend a 0.05 ml dose for
infants, and the double dose for children.
Difficulties have arisen for decision makers about the
value of vaccinating health care workers at increased risk
of infection with M. tuberculosis, particularly in settings
where multidrug-resistant tuberculosis is common. The
uncertainty stems from the scarcity of data on protection
against tuberculosis among adults, and the generally low
level of protection (or none at all) among adults in clinical
trials. While decision analyses appear to favor the use of
BCG vaccination in such settings.79 Such a conclusion has
been disputed, largely based on the argument that it
deprives those vaccinated from ever learning whether they
have acquired tuberculous infection or not (loss of
specificity of the tuberculin test).80 Nevertheless, in areas
where BCG has been demonstrated to provide appreciable
protection against tuberculosis among adults, where there
is a high-risk for health care workers of becoming infected,
and where multidrug-resistant tuberculosis is common, a
BCG vaccination policy for health care workers might
deserve consideration. Where these conditions are not met,
nonvaccination of health care workers might be more
appropriate.
In summary, barring a better alternative, BCG
vaccination remains a useful adjunct for the individual
protection against disabling and lethal forms of childhood
tuberculosis in most parts of the world where tuberculosis
remains highly prevalent. It cannot be expected, however,

to have great impact on the epidemiologic situation of
tuberculosis.68,69
The efficacy of BCG vaccination is best ascertained in
a prospective clinical trial, while an estimate of its
effectiveness in routine application might be obtained
through retrospective studies, such as case-control, contact,
or case-population studies, although possible confounding
effects cannot be controlled so easily.
Briefly, clinical trials are a prospective ascertainment
of cases occurring among the exposed. Clinical trials thus
start with looking at the exposure (BCG vaccination given
or not) and then ascertain the outcome (tuberculosis) in
a group of individuals, preferably randomly assigned to
exposure.81These are population-based studies and the
denominator is the number of person-years of
observation. The measures are incidence rates among the
exposed and unexposed and the summary measure is
the relative risk (the risk among the exposed divided by
the risk among the unexposed). Vaccine efficacy (in per
cent) is calculated as (1 - relative risk) 100.732. The 95
percent confidence intervals were calculated (or
recalculated, where appropriate) using the formula
proposed by Orenstein in his review on assessment of
vaccine efficacy,82 unless adjusted or stratified summary
estimates were provided by the authors.
To defray the costs incurred in clinical trials and to
obtain results more quickly, it was proposed to ascertain
the effectiveness of BCG vaccination by means of
retrospective case-control studies.83 Briefly, case-control
studies start with looking at the outcome (tuberculosis)
and then ascertain exposure (BCG vaccination given or
not) in a group of patients with the outcome, compared
to an appropriately selected control group of persons
without the outcome. 84 A relative risk cannot be
calculated as this measurement is confined to populationbased studies. The measurement of risk in a case-control
study is the odds ratio (or relative odds). For rare diseases,
the odds ratio approximates the relative risk in a clinical
trial.
The advantages and disadvantages in the use of the
case-control approach are linked to its being
observational, having subjects selected on the basis of
disease status, and using controls from the population
from which the cases emanated.85 The advantages of casecontrol studies include avoidance of ethical problems
arising in situations where there is already evidence that
the vaccine is better than placebo; allowing much faster
conduct than randomized trials; and requiring a much
smaller number of subjects. They are thus substantially
cheaper to conduct than randomized clinical trials.85
The most challenging difficulty in the design of casecontrol studies is the selection of appropriate controls in
that they have to be selected in such a way that they are
561
comparable to cases in every respect except for the outcome.

Selection bias resulting from a failure to ensure this
comparability may thus invalidate any findings.
The results of some of these case-control studies are
summarized below. Vaccine effectiveness (in per cent)
from a case-control study is estimated as (1 - odds ratio)
x 100.82 For unmatched case-control studies, the 95
percent confidence intervals were calculated (or
recalculated where appropriate) using Woolfs method.84
For matched and adjusted analyses, the confidence
interval published by the authors of the study was
chosen. If not stated for matched studies, the confidence
interval around the crude odds ratio was calculated as
above.
Efficacy of BCG Vaccination

AS Pulickal 85a has quoted a number of studies
demonstrating scar formation in > 90% after BCG
vaccination. The fact that needs to be pointed out is
Pulickal85a has not highlighted that these studies were
done using Copenhagen 1331 BCG vaccine where as in
India BCG vaccine is manufactured in Guindy
Laboratory Chennai. This might be the underlying cause
of less percentage of children retaining scar after BCG
vaccination by school age. Further in the studies quoted
by Pulickal1-4 the scar formation was evaluated in the
neonatal period itself and not at school age. By school
age, scar formed immediately in the neonatal period does
disappear but the cell-mediated immunity measured in
vitro by T cell functions does remain.
Prospective and Retrospective Studies on BCG

Vaccination
In one of the first clinical trials with a methodo-logically
fairly acceptable design (systematic alternate allocation),
BCG was given to children exposed to a parent with
tuberculosis and compared to a similar group who did not
receive the vaccine.86 The impact on fatality was dramatic,
with 82 percent reduction in the risk. Nevertheless,
suspicion about the efficacy of BCG vaccination persisted,
particularly in the United States,87 but also in the United
Kingdom,88 largely because the design of many studies was
dubious at best.
One of the most conspicuous differences observed in
the protection afforded by BCG reveals that age at
vaccination is important. Of further crucial importance
is the type of tuberculosis that is targeted for protection
by vaccination.
In the following summary of the best-known studies
in the English literature, the studies are identified as being
prospective or retrospective. For each of these two study
types five classes were examined:
562
Protection against disseminated and meningeal

tuberculosis, and against death from tuberculosis.
Protection afforded to children by vaccination of
newborns or infants.
Protection afforded by vaccinating children beyond
the age of one year.
Protection afforded by vaccinating adolescents or
adults.
Protection afforded by vaccinating people of various
ages.
Protection Conferred by BCG Vaccination Against

Disseminated and Meningeal Tuberculosis, and Against
Death from Tuberculosis
Eight major prospective studies have looked into the
protection afforded by BCG vaccination against death
from tuberculosis. 86,89-95 All of these studies were
conducted before the advent of curative chemotherapy.
Four of the studies showed a point estimate of the
protective efficacy of 80 % and above, and one afforded
no protection. The confidence interval was wide in all
studies, because the number of events was small.
Several retrospective studies (including two using
two different control groups) examined the protection
against disseminated and meningeal tuberculosis.96,97-105
The protective effectiveness was usually in excess of 80%
and in no case did the 95% confidence interval include zero.
It may be concluded from these studies that BCG
affords very good protection against death from
tuberculosis, and against disseminated and meningeal
tuberculosis.
Protection Conferred by BCG Vaccination of Newborns

and Infants
Three prospective studies looked into the protective
efficacy of BCG given to newborns or infants against all
forms of tuberculosis or morbidity.93,94,106 The point
estimate of the efficacy was between 50 and 80 percent.
Several retrospective studies examined the effectiveness
of newborn or infant vaccina-tion.98,99,104,107-113 The level of
protection in these studies varies widely, but frequently
above 50%. Noteworthy is the study from Zambia, which
stratified effectiveness estimates by HIV status, 111
showing that HIV-infected children had no protection
as compared to 60% protection among HIV-negative
children.
Protection Conferred by BCG Vaccination of Children

Over One Year of Age
Only six protective studies of BCG vaccination of older
children are available.114-119 All six showed a very low
level of protection of less than 30 percent. In Chingleput,

south India, where BCG gave little or no protection, there
was a tendency to provide some protection in children
below the age of 15 years, but a similar tendency towards
harm (more cases in the vaccinated than the
nonvaccinated) in older persons.116
Three retrospective studies among children also
showed very variable levels of protection, from 16 to 74
percent.101,120,121
These studies seem to show that vaccination of older
children does not offer protection against tuberculosis
that is as reliable as vaccination at an earlier age.
Protection Conferred by BCG Vaccination Among

Adolescents and Adults
Six prospective studies have examined the protection of
BCG vaccination against tuberculosis among adolescents
or adults.114-117-119,122,123 The study in Ulleval, Norway, was
the first ever conducted prospective study. It does,
however, not live up to current requirements for a
controlled trial, as student nurses with a negative
tuberculin skin test at entry could choose whether to be
vaccinated or not. In this context, the study conducted in
England (where M. microti, not BCG was used) remains
the only study of high standard that has shown a very
high level of protection, of close to 80 percent, in this age
group.124-129 The other studies show little or no protection,
with a tendency to reveal a potentially harmful effect in
India.114-117,130 In England, protection appeared to last for
about 10 years before dropping rapidly.129 In contrast, in
Chingleput, where there was no overall protection,
vaccination appeared to confer harm (more cases than in
the control group) in the first five years and minimal
protection subsequently.131
These studies seem to indicate that vaccination of
adolescents or adults is rarely a useful intervention.
Protection Conferred by BCG Vaccination Across Various

Age Groups
Of the seven clinical trials studying protective efficacy
across a wide range of age groups, with a preponderance
of persons other than infants, two showed a high level of
protection, of around 80 percent, while all of the others
showed little or no protection.89,114-119
These observations reconfirm that utilization of BCG
vaccination in age groups other than infants is rarely an
effective intervention.
One retrospective study from the Gambia reported
that 35 patients among 200 without a BCG scar died
during chemotherapy, while none of 85 with a BCG scar
did so. 92 While considerable attention was paid to
adjustment for potential confounding factors (yet the
563

affect remained), the authors were still cautious in
concluding that BCG vaccination reduces case fatality
from pulmonary tuberculosis.
infectious cases, therefore, makes it possible to investigate

the protective effect of BCG vaccination in an efficient
manner. By comparing the incidence of the disease in
the vaccinated and in the unvaccinated groups the
efficacy of BCG vaccination can be estimated. The
disadvantage of active case finding is that the type of
tuberculosis can not be studied precisely as treatment is
started at the earliest. The results of contact studies are
shown in Table 38.2.142-144
In a meta-analysis conducted by Colditz and
coworkers145 in 1995, based on the available literature, it
was concluded that BCG vaccine reduces the risk of
acquiring tuberculosis by 50 percent irrespective of the
study design or the form of tuberculosis. Although, the
protection from tuberculosis deaths, meningitis and
disseminated disease was found to be higher than for
total tuberculosis cases but the authors attributed this to
lower diagnostic error in identifying severe forms of
tuberculosis.
A recent publication from Ireland reports that in 2007,
an outbreak of tuberculosis occurred in a toddler
population attending two child care centers in Cork,
Ireland. Of 268 children exposed, 18 were eventually
diagnosed with active tuberculosis. 24 percent of the
exposed children had been previously vaccinated with
BCG, and no case of active disease was found in this
group (p = 0.016), suggesting a profound protective effect
of BCG in this population.146
Controlled Trials
The protective efficacy of BCG varies substantially.
Several well planned large scale controlled trials have
been conducted in various parts of the world including
India.131-135 These show that the range of protection
offered by BCG varies enormously from no protection
to 85 percent protective efficacy. The report of the
Chennai Tuberculosis Prevention Trial conducted in the
Chingleput District of Western Chennai has been widely
misinterpreted as showing that BCG offers no protection
against tuberculosis under any epidemiological
condition. However, since extrapulmonary forms of
tuberculosis and children under 10 years of age were not
included in the assessment, the results of this study
cannot be extrapolated on to the pediatric population.
Case-control Studies
The protective effect of BCG vaccination is calculated
from the vaccination converge among cases and
comparable controls. The Table 38.1 shows the results of
various case control studies for which BCG product was
used. There is lot of variation in the results. The highest
protection was observed in the studies in Brazil and India.
These studies have shown that highest levels of
protection were against the types related to the
hematogenous spread of the bacillus, e.g. meningeal and
miliary tuberculosis (Table 38.1).
How Do We Explain the Variable Results with BCG

Vaccine?
Several hypotheses have been put forward to explain the
variability in results of the field trials with BCG vaccine.147
None has emerged as the obvious solution and it seems
more reasonable to accept that several mechanisms may
be involved. A few of these hypotheses are discussed
below:
Contact Studies
A young child in contact with an infectious adult in the
family runs a high-risk of developing tuberculosis within
only a few months from the time the infectious case is
detected. Examination of child contacts of newly detected
Country
(vaccine used)
Table 38.1: Case-control studies on the efficacy of BCG vaccination of the newborn
Age group
No. of cases
No. of controls
Efficacy (%)
(observed months)
Brazil136
(Rio de Janeiro strain)
Brazil137
(Rio de Janeiro strain)
Burma138
(Japan BCG Lab)
Canada139
(Connaught Lab)
England140
(Glaxo Lab)
Chennai141
(Japan BCG Lab)
012
45
90
82
05
73
604
8284
05
311
1536
38
018
71
213
60
01
111
555
49
05
107
321
564

Table 38.2: Contact studies on the efficacy of BCG vaccination against tuberculosis in children
No. of contacts
No. of cases among contacts
Efficacy (%)
Country
(Vaccine used)
Vaccinated
Unvaccinated
Vaccinated
Thailand
(Merieux)
1253
253
Togo158
(Glaxo lab)
875
Korea159
(Paris seed lot)
806
157
Unvaccinated
(95% C.I.)
218
66
53 (3864)
546
62
113
62 (5070)
417
45
84
75 (6282)
Hypotheses About the Variation in the Efficacy of BCG

Vaccination
While the overall evidence is clearly in favor of a
protective effect of BCG vaccination, the observed
variations are large in both prospective and retrospective
studies. A number of hypotheses have been formulated
to address these discrepancies. Smith148 and Smith and
Fine149 have comprehensively reviewed the evidence,
and the following outline is guided by, and draws heavily
on, their assessment.
The principal hypotheses to explain the variations
observed in the protection offered by BCG include:
Differences in methodological stringency
Differences in vaccine strains
Differences in vaccine dose
Differences in virulence of M. tuberculosis strains
Differences in risk attributable to exogenous
reinfection tuberculosis
Differences in genetic make-up of vaccinees
Differences in nutritional status of vaccinees
Differences in prevalence of infection with
environmental mycobacteria
Other factors.
Differences in Methodology in Conducting Study

The most relevant trial showing no protection against
bacteriologically confirmed tuberculosis, conducted in
Chingleput, India, was judged to be of high scientific
quality by a WHO expert committee specifically charged
to ascertain the trials validity.70 It must be kept in mind
that the range of protection cannot be taken at face value,
but must also be seen in the context of what the study in
question sought to address. BCG trials (be they
prospective or retrospective) ascertained protection
against various outcomes such as morbid state
(tuberculosis or death from tuberculosis) and site of
disease, e.g. pulmonary, extrapulmonary single site, and
disseminated tuberculosis, taking into account such
things as bacteriologic certainty of the case, age of the
patients, and time elapsed since vaccination. What seems
apparent from the studies is the tendency of BCG to
provide its greatest protection within the few years
following vaccination, against death from tuberculosis,

disseminated disease manifestations, and bacteriologically unconfirmed tuberculosis. In summarizing these
effects, BCG is generally most effective against serious
forms of tuberculosis occurring shortly after infection
acquired at an early age. Thus, any evaluation of the
protective efficacy of BCG vaccination should be
stratified according to these variables.
Differences in Vaccine Strains

The available BCG vaccine strains differ widely in
phenotype and geno-type.150,151 It has been proposed152
that differences in vaccine strains may account for
observed variations in vaccine efficacy. In the rabbit
model, not all BCG (and M. microti) strains provided the
same level of protection. However, the most powerful
argument against this hypothesis arises from the
Chingleput study, where two vaccine strains were used
that had documented high efficacy in other settings but
were not shown to be efficacious in Chingleput.
Furthermore, one of the studies (a case-control study
from Indonesia) cited for evidence of differential
effectiveness of strains, examined successive vaccination
policies, and was thus by necessity a nonconcurrent study
which additionally failed to adjust for time elapsed since
vaccination.153
The recent delineation of genetic differences between
BCG vaccine strains has renewed interest in the influence
of the vaccine strain on the protective efficacy against
tuberculosis. Although there is good evidence to support
the notion that the induced immune response and
protection afforded against tuberculosis differs between
BCG vaccine strains, currently, there are insufficient data
to favour or recommend one particular strain. Identifying
BCG strains with superior protection would have a
dramatic effect on tuberculosis control at a population
level: a small increment in protection provided by BCG
immunization will prevent large numbers of cases of
severe tuberculosis and deaths, particularly in children.154
Differences in Vaccine Dose

BCG has been administered through various routes,
initially orally, then parenterally. The latter administration

may have been given intradermally or transdermally via
multipuncture devices. The dosage reaching the target
thus may well have varied. Nevertheless, the following
observations seem to contradict the argument of an
influence of differential dosage effect. Three controlled
clinical trials with low efficacy used multipuncture
administration, and one with high efficacy did not differ
in their efficacy. Furthermore, the trial in Chingleput
specifically considered in its design the possibility of
deterioration (vaccine potency in the field, and allocated
vaccinees also to two arms receiving a ten-fold difference
in dose, but with no difference in effect.
Differences in Virulence of M. Tuberculosis Strains

That not all tubercle bacilli are equally virulent has been
demonstrated repeatedly both for M. bovis BCG and M.
tuberculosis in general, and for isoniazid-resistant strains
in particular.
The hypothesis that the relative frequency of more or
less virulent tubercle bacilli affects the observed
protective efficacy of BCG vaccination is based on the
argument that tubercle bacilli of lower virulence might
also cause tuberculin skin test reactions of smaller size.
Such persons then might be classified as non-reactors,
i.e. persons not infected with tubercle bacilli, thus
becoming eligible for vaccination. Vaccination of actually
infected persons may thus mask any protective effect of
BCG vaccination, as vaccination is not expected to
provide protection against those who are already
infected.
The argument fails to account for the fact that BCG
provided no protection at all in some trials. Depending
on the proportion of individuals who had escaped
infection with environmental mycobacteria at the point
of BCG vaccination, masking of protection by BCG
vaccination would be expected to be incomplete.
Differences in Risk Attributable to Exogenous Reinfection Tuberculosis

BCG vaccination is expected to provide protection against
tuberculosis resulting from infection acquired subsequent
to vaccination. It is not expected to provide greater
protection than a naturally acquired primary infection.
Protection conferred by a primary infection against
disease from re-infection is incomplete. Thus, the
protective efficacy of BCG might be increasingly masked
as the contributory fraction of cases attributable to reinfection increases. Thus, following this argument, the
protection afforded by BCG is expected to be lower where
the risk of infection with M. tuberculosis (and thus reinfection) is high.
565
This is not borne out by observations. The annual risk

of infection in the United Kingdom decreased
considerably over time, yet the level of protection
afforded by BCG remained high and virtually
unchanged.
Differences in Genetic Make-up of Vaccinees

Because differences in protection from BCG among males
and females were observed in at least one study, other
genetic factors may also play a role in the differential
protection conferred by BCG. Nevertheless, the finding
that BCG gave virtually no protection to children in
Chingleput, but high protection in children from the
Indian sub-continent living in the United Kingdom
would tend to disfavor this hypothesis.
Differences in Nutritional Status of Vaccinees

As nutritional status affects the functioning of the cellular
immune system, it might be expected that poor
nutritional status would adversely affect the protective
efficacy of BCG vaccination. However, BCG provided
very high protection against tuberculosis death among
poorly nourished North American Indian children, even
somewhat higher than among well-nourished British
adolescents, a finding that would tend to contradict this
hypothesis. Studies conducted by Seth et al 5-8 also
demonstrated that mild to moderate degree of
malnutrition did not affect the induction of cell mediated
immune response in children after BCG.
Difference in the Burden of Mycobaterial Infection in

Community
A study from low burden countries (Norway and
Sweden) demonstrated the protective effect of newborn
BCG vaccination in nativeborn 0 to 14-year-olds in
Finland, and of adolescent BCG vaccination in 15 to 29
year-olds in Norway. The Norwegian BCG vaccination
program conferred 61 to 64% protection to 15 to 29-yearolds; however, 21699 to 25125 vaccinations were needed
to prevent one case.155
BCG Vaccine and Tuberculin Surveys

Chadha et al155a conducted a study in selected villages
in three defined zones of India for comparison of
prevalence of tuberculous infection among children with
and without bacille Calmette-Guerin (BCG) scar. The age
group was 1 to 9 years and tuberculin testing was done
using 1TU-PPD RT 23 with Tween 80. In the age group
of 1 to 4 years, the estimated prevalence of infection
among those with BCG scar was considerably higher than
566
in those without BCG scar. The difference was small in

those aged 5 to 9 years.
Tuberculin surveys may be conducted irrespective of
BCG scar status among children aged 5 to 9 years, when
BCG vaccination is given using Danish 1331 strain during
infancy under the expanded program of immunization.
Chadha et al155b qualitatively estimated the size of
tuberculin reaction in children who were vaccinated with
Danish BCG at birth in the age group of 1 to 9 years. 45
to 60% of the BCG vaccinated children evoked reaction
< 5 mm in size and 70 to 80% had reaction <10 mm. The
study also revealed that a proportion of children did have
reaction between 10 to 14 mm and 15 to 19 mm. 19 mm
was the upper limit of induration. Hence, it is
recommended that among scar positive BCG given
children a reaction > 20 mm in size must be considered
due to infection with tubercle bacilli irrespective of BCG
vaccination. Chadha et al 155b in the same research
protocol on protective efficacy of BCG in children did
case control analysis. It was a little surprise to found to a
little surprise that though the protective efficacy of BCG
against extrapulmonary TB was observed to be higher
than pulmonary TB, it was not statistically significant.
In AIIMS data on the extent of BCG positivity was almost
30 percent in proven case of TBM (unpublished work).
This does not make a case for stoppage of BCG
vaccination but does alert us about the need of a new
vaccine. These two papers emphasize that the size of the
reaction should also be considered along with other
diagnostic tests and the cutoff for clinical use in India
may need to be modified, based on these recent
observations.
Differences in Prevalence of Infection with

Environmental Mycobacteria
BCG vaccination has been used not only for protection
against tuberculosis, but also against leprosy, often with
more success than in the prevention of tuberculosis. It is
thus apparent that different mycobacterial species (in this
case M. tuberculosis, M. bovis BCG, M. microti, and
M. leprae) produce a modification of the immunologic
response to infection with another mycobacterial species.
It is thus postulated that infection with one species of
mycobacterium triggers a cellular immune response
prepared to act more swiftly in the killing of mycobacteria
of another species acquired during a subsequent
infection. This is most apparent from the (limited)
protection provided by infection with nontuberculous
mycobacteria against super infection with tubercle bacilli,
and the apparently similar effect of M. bovis BCG under
certain circumstances. That BCG can also afford protection
against leprosy would indicate that cross-protection is not
limited to closely related mycobacterial species.
It has been postulated that different mycobacterial

species induce different immunologic responses, some
beneficially increasing protection against superinfection
with another mycobacterial infection, while others may
increase susceptibility to progression to clinically overt
disease. In experimental models, protection afforded by
vaccination with M. bovis BCG, M.fortuitum, M. avium,
M. kansasii, and M. scrofulaceum (then called Gause strain)
against M. tuberculosis was examined in the guinea pig.
All environmental mycobacteria used in this study
provided some protection, but with a wide variation, yet
none provided as high a level of protection as BCG
vaccination. It has, therefore, been postulated that the
low protection afforded by BCG in Georgia as compared
to the high protection observed in Britain maybe
attributable to a differential prevalence of infection with
environmental mycobacteria. 156 Edwards and
colleagues 157 demonstrated similar protection by
vaccinating with M. avium complex against M. tuberculosis
isolated in Chingleput as with the Danish BCG strain.
Orme and Collins158 demonstrated that airborne infection
with M. avium in mice was as effective as intravenous
BCG in protection against a challenge with virulent
tubercle bacilli. Brown and colleagues159 administered
M. vaccae in drinking water to mice, subsequently
challenged them with BCG and measured the
proliferative response of spleen cells. The results showed
that, depending on the timing of the exposure of the mice
to M. vaccae before BCG vaccination, M. vaccae could
enhance, mask or interfere with the expression of
sensitization by BCG.
If environmental mycobacteria do indeed provide
protection against M. tuberculosis, and infection with them
occurs before the administration of BCG, then the effect
of the latter will be at least partially masked.153 This may
explain the larger protection conferred by BCG given
earlier in life than if given later as demonstrated in
Chingleput.135
Furthermore, the risk of tuberculosis would be
expected to be greater in initially tuberculin negative
persons than in individuals with small tuberculin skin
test reaction sizes (more likely attributable to infection
with environmental than tubercle bacilli).
In Puerto Rico, protection from BCG was lower in
rural areas, where nonspecific sensitivity was higher than
in urban areas, where protection from BCG was higher.
However, in Chingleput, the rate of tuberculosis among
persons with a reaction size of more than nine millimeters
to a sensitive produced from M. avium complex (PPD-B)
was identical to that among those with zero to nine
millimeters reaction sizes.116
In the United Kingdom, the risk of tuberculosis was
higher among initially tuberculin skin test negative

adolescents than among those reacting to 100 tuberculin
units only, but the risk decreased over time. The
protection afforded against tuberculosis by a tuberculin
skin test reaction that can be elicited only by this large
dose of tuberculin is remarkably similar (but smaller) to
that imparted by BCG vaccination.
In the Karonga, Malawi trial, the risk of tuberculosis
during follow-up was lowest among those with an initial
tuberculin skin test reaction size of 6 to 10 mm. After
adjustment for age and sex, the risk was also lower
among those with reactions of one to five millimeters
than among nonreactors.
That different species of mycobacteria seem to act on
the immune system has also been demonstrated by
observations from Sweden. After the cessation of mass
BCG vaccination, there was a large increase in peripheral
lymphadenitis due to environmental mycobacteria.
Similarly, in the Czech Republic, the incidence of
lymphadenitis among children due to M. avium following
cessation of BCG vaccination was 3.6, compared to 0.2
per 100,000 person-years among children vaccinated on
the insistence of their parents, suggesting a protection of
95 percent (95% confidence interval 88 to 98%) from BCG
against lymphadenitis due to M. avium.
While not all findings are consistent with the
hypothesis that environmental mycobacteria may mask
the protection that BCG can confer in their absence, it
may explain to a considerable extent certain variations
in observed efficacy.
Infection with Nontuberculous Mycobacteria

Infection with nontuberculous mycobacteria is the oldest
and one of the most popular hypothesis till date.
According to this hypothesis, infection with certain
nontuberculous mycobacteria prevalent in the
environment provides some protection against
tuberculosis. This naturally acquired infection can mask
any protection that may result from BCG vaccination.
This hypothesis is supported by animal experiments 150
and by the fact that the trials showing lowest BCG efficacy
were in the areas where the infection with nontuberculous
mycobacteria is common; such as southeastern regions
of United States and South India. However, Comstock
and coworkers,134 in their study on Puerto Rican children,
were unable to find evidence of lowered protection after
BCG vaccination among those with intermediate level
of tuberculin sensitivity (thought to be attributed to
nontuberculous mycobacteria infection).
Explanation of this varying protective effect following
nontuberculous mycobacterial infection comes from
another hypothesis according to which exposure to
nontuberculous mycobacteria results into two types of
immune responses; Koch type(Th-2) and Listeria
567
type(Th-1). Koch response is a delayed hypersensitivity

response which increases the susceptibility to develop
disease by rendering tissues more sensitive to destruction
by TNF following infection, with M. tuberculosis whereas,
Listeria type of response correlates with the appearance
of macrophage activating lymphocytes and provides
immunity against tuberculosis. Different species of
nontuberculous mycobacteria produce varying levels of
these responses, e.g. Mycobacterium vaccae produces
Listeria type response while Mycobacterium scrofulaceum
produces Koch type response, thus explaining the
variable results seen in the trials conducted in different
geographical locations.
Other Factors
It has been suggested that infestation with parasites, in
particular with helminths, may affect the human T cell
immune responses to mycobacterial antigens. Treatment
of helminths resulted in significant improvement of T
cell proliferation and interferon-gamma production. This
could explain to some extent the reduced efficacy of BCG
in countries in the world where helminthic infestation is
common.
Differences Between BCG Vaccine Used

Differences in the potency and immunogenicity of the
vaccine strains also may contribute to the variability in
the efficacy of BCG; however, few data support this
hypothesis. In Chingleput trial the recipients were
randomized to receive either a low dose or a high dose
of French or Danish vaccine and no difference in the
results were noticed.131
Differences in the Natural History of Infection and

Disease
These series of explanations include suggestions that
variation in the efficacy could be related to the differences
in M. tuberculosis or to differences in the pathogenesis of
the disease. It has been found that a higher proportion of
strains of M. tuberculosis from the Chingleput area are of
low virulence in guinea pigs than is found elsewhere in
the world. Hence, it has been suggested that this might
explain the low protection imparted by BCG in this region.
However, laboratory data, which shows that the protection
can be influenced by the challenging strain of M.
tuberculosis, has failed to show evidence for poor protection
against the low virulent south Indian strain.
Another explanation suggested is that protection
against tuberculosis by BCG is a function of relative
importance of the disease due to endogenous
reactivation versus exogenous reinfection. Since the
action of BCG is to protect against the disease due to
568
hematogenous spread of infection, protection is expected

to be better against the serious types of tuberculosis like
miliary and meningitis than against pulmonary TB. These
findings seems to be responsible for variations in results
many studies. Based on the same reasoning it is
postulated that BCG would protect better against
endogenous than exogenous pulmonary disease; thus the
low protection observed in the south Indian study was
due to high-risk of reinfection in that community. A high
proportion of tuberculosis in south India is of exogenous
type has been inferred from the high prevalence of
infection as elicited by tuberculin sensitivity, and low
risk of the disease subsequent to primary infection as
assessed by the tuberculin conversion.160
Variation in Host Parameters

Host genetics also have been suggested to play a role in
the efficacy of BCG vaccine. However, no statistically
significant differences have been found between racial
groups in field trials to confirm that genetic variability is
an important factor in the development of immunity
following vaccination.
Chronic dietary protein deficiency in children has been
demonstrated to impair the retention of cell-mediated
immune response following BCG vaccination.5-7 It was
considered that this would lead to decreased protection
from tuberculosis, however, data from human trials is
lacking to support nutrition as a cause of variable efficacy
from BCG vaccination.
Age at vaccination has also been considered to be a
variable affecting BCGs efficacy; it was greater when
vaccine was given early in life. In the meta-analysis by
Colditz and coworkers145 the protection from BCG was
85 percent when given at birth and it decreased to 52
percent for those vaccinated after 20 years of age.
Methodological Differences in the Trials

Finally, the different study methodologies used in the
controlled trials have been blamed for the variable results.
The major source of bias in the trials was in detection of
tuberculosis; e.g. detection of disease by chest X-ray of
only symptomatic persons could result in biased
estimation of BCG efficacy. Besides, the trials varied
widely in their statistical precision, estimated by
calculating 95 percent confidence interval for each
efficacy value. In general the trials with narrower
confidence intervals, considered to be more precise
estimate of vaccines efficacy, have shown better
protection with BCG.164
A recent study in school children suggested that BCG
vaccination was associated with a reduction of M.
tuberculosis infection diagnosed by gamma interferon
release assay testing in children during an outbreak

suggesting difference in technique of assessment may
alter the outcome.165
BCG and Disease Outcome

In a retrospective analysis of factors determining outcome
of treatment of tuberculosis reported non receipt of BCG
during infancy as one of the significant factors responsible
for adverse outcome (OR=1.73, 95% CI 1.02- 2.91). The other
factors were AFB positivity and extra pulmonary
tuberculosis miliary and meningeal followed by lymph
node disease with MDR-bacilli. The beneficial effect of BCG
in treatment outcome of TB needs to be confirmed by a
prospective study.166
Other Antituberculosis Vaccines

Vole Vaccine
The earliest studies of alternative to BCG as a living
attenuated vaccine compared the potency of BCG to
that of the vole bacillus, a strain of mycobacteria isolated
from naturally infected meadow mice (voles).
Experimentally it was shown that the vaccination with
the vole vaccine protected as well, as BCG.
R1 Rv
It is derived
M. tuberculosis.
from
attenuated
strain
of
H37Ra
Another mutant strain derived from M. tuberculosis,
affords equal protection as compared BCG Paris.
INH Resistant Vaccine

Routinely available BCG vaccine is INH susceptible. Thus
if the child who has had a close contact with a case and
needs to be given ATT prophylaxis with INH, the
protective effect of the vaccine if given recently will be
nullified. However, the INH resistant vaccine will
maintain its protective effect inspite of the coadministration of INH.
Correlation of BCG Scar with Induction of Cell Mediated

Immune Response (CMIR)
It has been seen by Seth et al7 by in vitro estimation of
CMIR after BCG vaccination that almost 12 to 15 percent
of neonates do not develop scar but have positive CMIR.
The absence of scar is more conspicuous among those
who were given BCG immediately after delivery. The
frequency of tuberculin reactions do not vary in children

with and without a scar. Mallol et al 161 and
Sedaghation162 had similar observations.
Should the Children be Revaccinated?

Sakha et al167 evaluated the immunogenicity of neonatal
BCG-vaccination in 150 children by skin test using Purified
Protein Derivative (PPD) who received BCG during
neonatal period and had a scar even at the age of 7 to 8
years. They tested children with 0.1 ml of 5-unit of PPD
solution. The diameter of indurated area resulted from
PPD-test after 72 h was less than 5 mm in 95.33% and 5 to
9 mm in 4.66 percent of children. There was no case with
induration of 10 mm or more. Every child who developed
an induration area of 5 mm or more by PPD test, had a
BCG scar with the diameter of 5 mm or more. There was a
statistically meaningful direct correlation between size of
neonatal-BCG scar and diameter of induration after PPDtest (r = 0.21 and p = 0.008). This study shows that reactivity
to PPD test (and probably immunity against tuberculosis)
decreases as age increases. Authors recommended that
there is need to repeat BCG-vaccination in children at the
age of entering primary school.
It is or has been the policy in many countries to
revaccinate with BCG at school entry or later in life. There
is no evidence that this increases protection against
tuberculosis, but in Northern Malawi, it has been shown
to considerably increase protection against leprosy. Revaccination schemes often fall into the lowest tuberculosis
risk period in life (age 5 to 14 years) and target a
population where protection from BCG vaccination is
dubious or variable at best.
It has been observed that both natural and BCG
induced tuberculin sensitivity tend to wane in the course
of time.163 This waning could also be associated with
some degree of loss of protection against exogenous
super-infection. Seth et al7 showed that only 26.3 percent
children were Mantoux positive after 3 to 6 years of BCG
vaccination compared to 35.7 percent at 1<3 year group.
Theoretically these observations would point towards
considering revaccination in children at a later age.
However, WHO discourages BCG revaccination on the
basis of lack of evidence for additional protection to that
from the first vaccination.157
A recent report on revaccination of BCG at 19 months
of age in Africa observed no survival benefits of
revaccination with BCG. In this study there was increased
mortality for sometime necessitating premature stoppage
of trial.168
Adverse Reactions
Various untoward reaction with BCG vaccine are listed
in Table 38.3.
569
Table 38.3: Untoward reactions with BCG vaccination

Loco-regional complications
Simple local reactions swelling and pain at the site of
injection
Ulcer, abscess
Temporary swelling of regional lymph nodes
Regional suppurative lymphadenitis
Complications of dissemination
Otitis
Retropharyngeal abscesses
Cutaneous lesions
Metastatic subcutaneous or intramuscular abscesses
Lesions of bones, joints and synovia
Renal and urogenital lesions
Mesenteric adenitis
Generalized lymphadenitis/ Hepatosplenomegaly
Generalized disseminated disease
Post-BCG syndromes
Local chronic cutaneous lesions (Keloids, histiocytoma)
Acute cutaneous eruptions (erythema nodosum, rashes)
Ocular lesions-phylectanular conjunctivitis
The most frequent adverse reactions after BCG

vaccination are regional lymphadenitis, injection site
abscess, osteitis and osteomyelitis.169,170 The incidence of
lymphadenitis varies in different studies. Most cases tend
to occur by 5th month of vaccination. In a prospective
survey of 2 million infants vaccinated between 1979 and
1981 in six European countries the risk of lymphadenitis
was detected to be 2.5 per lakh.59 Several factors contribute
to the occurrence of lymphadenitis; the vaccine strain, the
total number of viable and nonviable bacilli, the dose of
the BCG, and the age at vaccination.18 When given in
preschool or school age children the incidence of
lymphadenitis was found to be 5 to 10 times less than when
the vaccine was given in neonatal period.
Children with severe combined immune deficiency
and HIV infection are at risk of developing disseminated
BCG disease.171
Management of Adverse Reactions due to BCG

Vaccination
Children with lymphadenitis due to BCG were randomly
allocated to receive either isoniazid or no treatment. There
was no difference in the duration of lymphadenitis
between the two groups, nor did isoniazid prevent the
occurrence of suppuration. Similarly, children with
abscess formation were randomly assigned to receive
either isoniazid or erythromycin (serving as placebo). The
response in each treatment group was the same. In
another study, comparing excision, excision plus
isoniazid, and isoniazid alone compared to a control
group without intervention; no significant differences
were observed between the various interventions, and
570
in particular, isoniazid offered no advantage.

Nonsuppurative lymphadenitis is a normal reaction, and
is best left without antibiotic treatment.
Patients with suppurative lymphadenitis following
BCG vaccination were randomly assigned to treatment
with simple needle aspiration, introducing the needle
subcutaneously two to three centimeters distant from the
node, versus no treatment. Regression was significantly
faster in the treated than in the non-treated group, and
spontaneous drainage was less frequent.
For osteoarticular mycobacteriosis due to BCG,
combination therapy is indicated, but results were not
always favorable (both in terms of sequelae and relapses)
in a case series from Sweden.
A standard course of treatment (as for clinically
manifest tuberculosis) is also indicated in disseminated
mycobacteriosis due to BCG. As this is a rare
complication, however, treatment regimens have not
been amenable to formal study. In treatment, it should
be kept in mind that BCG is, like its parent organism, M.
bovis, naturally resistant to pyrazinamide.
Opinions differ on the optimal management of the
BCG adenitis. In most cases, it tends to resolve with time,
though some cases tend to be indolent or suppurate and
form fistulous tracts. Though there are no statistically
proved trials but erythromycin given for two weeks has
been shown to have beneficial effect in resolution of
indolent lymphadenitis.172 However, its use is not
recommended any more. Caglayan and coworkers164
found that when lymphadenitis develops rapidly (within
2 months) after vaccination chances of its suppuration
are higher. They recommend total surgical excision in
such instances to prevent spontaneous drainage and
chronic suppuration. WHO suggests that drainage and
direct instillation of an antituberculosis drug into the
lesion should be considered for adherent and fistulous
lymph nodes but usually it is not done. Systemic
treatment with antituberculosis drug is ineffective.172
Osteitis also can occur after the vaccination with BCG
but its incidence is much less than the lymphadenitis. It
usually involves the epiphysis of the long bones
particularly the lower limbs. Antituberculosis drugs
coupled in some cases with surgical curettage and
debridement, usually results in the healing of skeletal
lesions.173
The most dreaded complication of BCG vaccination
is disseminated BCG disease. It is most frequently seen
in children with concomitant immunodeficiency and is
usually fatal. Most cases of BCG-itis occur within
6 months of vaccination. Treatment is similar to treatment
of active tuberculosis except that pyrazinamide is not
used, as all strains of BCG are resistant to this
antituberculosis drug.
BCG Vaccination and HIV Infection

In HIV-infected children increased frequency of
complications following BCG vaccination have been
reported.174,175 One study has shown a relatively high rate
(10%) of post BCG lymphadenitis among the HIV infected
children, however, the study did not include noninfected
children as control group.176 Also there are some case
reports of disseminated BCG disease developing in
infants following BCG vaccination.177,178 However, in a
controlled trial infants born to HIV infected mothers had
no additional complications though their PPD reactivity
after the vaccine was much lower compared to the infants
born to HIV negative mothers (33 to 83%).179
In a systematic review of BCG related disease in HIV
infected children including 16 studies reported a total of
49 cases of disseminated BCG disease. Majority (41 cases)
were reported from Cape Town Province of South Africa.
The review concludes that HIV-infected infants are at
risk of BCG disease, but the degree of increased risk
remains uncertain. Improved laboratory-based
surveiliance and more incidence data of confirmed cases
are urgently needed. Improved population-based studies
in areas outside sub-Saharan Africa are also required to
inform vaccination policy. Improved knowledge of the
potential efficacy of BCG for HIV-infected and HIVexposed infants in TB-endemic communities is critical
to the risk-benefit analysis needed to change policy.180
Hesseling et al180a performed an analysis of isolates
of M. tuberculosis complex for the determination of the
prevalence of bacilli Calmette-Guerin (BCG) disease
among human immunodeficiency virus (HIV) infected
children. Specification was done with polymerase chain
reaction;183 isolates from mycobacterial cultures for 49
HIV infected patients were analyzed. The Danish M.
bovis BCG strain was isolated from 5 patients. No case of
Tokyo M. bovis BCG strain was detected responsible for
disease.
All patients were asymptomatic at birth, <12 months
of age, and severely immunodeficient at presentation.
Four patients had regional adenitis ipsilateral to the
vaccination site, and 2 had pulmonary BCG disease.
Characteristics of BCG disease
Ipsilateral axillary adenitis to BCG vaccination site

Hepatosplenomegaly
Intraabdominal lymphadenopathy
Symptomatology
- Failure to thrive
- Oral candidiasis
- Generalised lymphadenopathy
- History of TB contact.

Investigations
- Tuberculin skin test ve
- Decrease in CD 4+ cells, medinstinal lymphadenopathy with persistent lobar consolidation,
bronchopneumonic opacification, pneumatocele,
bronchiectasis, diffuse alveolar opacifications or even
mliary.
- All children were asymptomatic at birth and given
BCG vaccination.
All patients with BCG related disease were infants
after change in the vaccine policy in July 2000, when the
recommendations of the Health Department of South
Africa were changed from a percutaneous vaccine with
the Tokyo M. Bovis BCG strain. Young symptomatic HIVinfected children are at risk of developing BCG related
disease. The children who acquired HIV infection
through vertical transmission, progress rapidly to
symptomatic HIV disease. They have also a high risk of
BCG related disease. It is quite possible to have dual
infection with M. tuberculosis and M. bovis BCG. This is
highly relevant in setting such as India where the
prevalence of tuberculosis and HIV is high and there
routine BCG immunization is a part of universal program
of immunization. One inference from this seems to be
logical that if an infant develops ipsilateral axillary
adenitis after BCG vaccination, she or he must be
screened for HIV along with the mother and father.
Before this one must ensure that after BCG vaccination
an intradermal papule was raised and BCG was not
accidentally given intracutaneously by not so an expert
vaccinator. The mycobacterial isolate form such infants
is usually resistant to INH, rifampicin and pyrazinamide.
Ethical Considerations
The collection of gastric aspirates and other body fluids
for culture of M. tuberculosis complex forms part of
routine clinical practice for children in whom tuberculosis
is suspected. The collection of mycobacterial isolates in
a sample bank was approved by the institutional review
board of Stellenbosch University (Cape Town, South
Africa). HIV testing for these patients was done in the
course of routine clinical management; informed consent
was obtained, and pre- and post counseling were
available. HIV-infected children were identified from a
confidential database maintained by the pediatric
infectious diseases unit (PIDU) at Stellenbosch
University, which is accessible to attending physicians
only. Standard procedures to maintain patient
confidentiality was maintained through coding of
mycobacterial cultures and patients personal
information and through blinding of laboratory staff
571
dosing isolation and information about patient. After

PCR speciation of M. tuberculosis complex was
performed, the results were linked to patients personal
information. Maximum effort was made to trace these
patients through repeat telephone calls and home visits.
Informed consent was obtained before clinical
information was studied. This study proposal was
approved by the institutional review board (IRB) of
Stellenbosch University.
Treatment of BCG Vaccination Induced Disease in HIV

Infected Children
Recommended treatment is INH +RIF + PZA (2 months)
then RIF + ETH + Ethionamide + ofloxacin + Amikacin.
Treatment has to be individualized. Sensitivity testing
of the isolate by BECTEC (rapid method) becomes
mandatory. Treatment needs to be done at a specialized
center rather by a pediatrician who has got expertise both
in treating HIV and tuberculosis disease. Outcome is
quite poor. Response to antituberculosis (ATT) therapy
is ascribed to a number of host factors such of HIV-related
gastrointestinal disease with inadequate absorption.
Surgical excision of large axillary lymphondes may
be necessary for local containment of regional disease.
M. bovis species are generally resistant to
pyrazinamide, and there is a possibility of resistance
to other drugs as well.
Danish BCG strain poses a risk for localized and
disseminated disease in infants who are infected with
HIV infection through vertical transmission, even if they
are asymptomatic at birth. It is also reporetd that Infection
with HIV severely impairs the BCG-specific T cell
response during the first year of life. BCG may, therefore
provide little, if any, vaccine-induced benefit in HIVinfected infants. Considering the significant risk of
BCGosis, these data strongly support not to give BCG to
HIV-infected infants.181
Given the paucity of data suggesting serious effects
of BCG vaccination on the HIV infected, WHO
recommends BCG vaccination for all asymptomatic HIV
infected children particularly those residing in the
developing countries. WHO does not recommend BCG
vaccination for those with symptomatic HIV infection
or for persons known or suspected to be HIV infected
but have minimal risk of infection with M. tuberculosis.182
BCG as a Diagnostic ModalityThe BCG Test

The importance of BCG as a diagnostic modality is out
now from the armamentarium of TB diagnostics. In his
classical paper on BCG test in tuberculosis Udani et al183
described it in detail.
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BCG test has the major drawback that once it is given,

the tuberculin test cannot be reliably used in near future
to judge the difference between infection and TB disease.
Hence, the use of BCG test is not recommended.
Immunologically it does not stand to scientic reason
because the antigen load is much more and includes all
components of tuberculous bacillus.
Effects of BCG Other Than Those Directed Against

Tuberculosis
BCG has been shown to be protective against leprosy in
some situations while not in others. It has also been shown
to be effective against M. ulcerans, albeit with an apparently
very shortlived protection. BCG as vaccine, is also being
tried for prevention of leprosy. A recent doubleblind study
in Malawi by the Karonga Prevention Trial Group (1996)186
showed that initial BCG vaccination afforded 50%
protection against leprosy and a second vaccination added
appreciable (another 50%) protection without providing
any protection against tuberculosis. Curihas et al186a has
shown that here is clear evidence that BCG protects against
leprosy, but cross-immunity with environmental
mycobacteria can interfere with vaccination protection.
The study was designed to estimate the vaccine
effectiveness of neonatal BCG against leprosy in Amazan
region in Brazil. This research indicated that neonatal BCG
vaccination in Brazilian Amazan elicited protection of 74%
against all forms of leprosy cases. Secondly, highest
protection was observed (93%) for multibaciliary cases. It
is inferred that the study provides evidence that BCG
vaccine may have an important and overloaded impact
on the occurrence and transmission of leprosy particularly
at an age when there is high incidence of leprosy.
The best known indications for BCG against other
than mycobacterial diseases are its use as an
immunotherapeutic agent in the treatment of superficial
bladder cancer and nephritic syndrome in developing
countries and, to a lesser extent in, malignant melanoma.
It has also been suggested that BCG reduces the risk of
atopy and asthma, and reductions in the risk of intestinal
nematodes in children and HIV-infected patients have
been reported.
Newer Vaccines
Scientists are excited about the prospects of a new
vaccine, after tests on mice and guinea pigs as it appears
to be more effective than the BCG vaccine which is
currently used.
The points new to this vaccine are:
1. Rather than trying to make changes in the current
vaccine, researchers used a weakened version of the
bacterium that causes TB in people.
2. The researchers found a gene in the organism that

helps adude immune system detection, and removed
it from the bacterium.
3. It was found that vaccine extended the lives of mice
and guinea pigs and stimulated stronger immune
responses compared to the existing vaccine.
4. The scientists believe that if the results continue to be
positive, human studies may be possible in two to
three years.
It is said that TB, a bacterial infection that usually
attacks the lungs, kills about 1.6 million people a year
globally. The increasing resistance of the TB organism to
drug treatment makes creation of a truly effective vaccine
even more crucial.
The existing BCG vaccine in the use for almost a
century despite its limited effectiveness is based on a live
attenuated strain of bacterium that causes TB in the cattle.
In the new vaccine, use is made of a weakened version
of the bacterium that causes TB in human beings. The
basis being similar to other vaccines by trying to make
the bodys own immune system stronger and have better
defenses to fight off invaders like disease causing
bacteria. The researchers have found a gene in the
organism that helps it edude immune system detection
and removed it from the bacterium. This helps the vaccine
used in mice and guinea pigs whose life was extended
and a stronger immune response was elicited as
compared to the existing BCG vaccine. However, a major
limitation is that it is still probably too infectious to give
it to humans. It is only partially attenuated for virulence.
Removal of additional genes may make the vaccine safer.
Global Aspect
The TB organisms is present roughly in a third of the
worlds population. Most infections remain latent but can
become active when the immune system is weakened,
for example when the same person gets HIV infection in
case of children viral infection like measles. The existing
BCG vaccine protects young children from tuberculosis
but not the adolescents and adults against the type of
disease present in them.
TB can be treated effectively with drugs in many
cases, but drugs have to be given for upto six months
making treatment difficult and expensive. Many poorer
parts of the world lack the medical infrastructure to
deliver this kind of treatment, so many experts feel an
effective vaccine, could be a highly valuable tool in
combating the disease.
A new generation of TB vaccines is presently under
development, mostly targeting the induction of cellmediated immunity by stimulation of CD4+/CD8+ Tcell. All the modern vaccination strategies are being

explored, including recombinant BCG vaccines,
recombinant subunit vaccines, DNA vaccines, attenuated
M. tuberculosis, viral vectors and saprophytes, as well as
combined vaccine approaches.
Various antigens such as MTB8.4, ESAT-6, MPT63,
MPT64, MPT83, PstS-1, MTB39, hsp60, and hsp70 have
been tested in animal models and found to have some
efficacy.187,88 In addition, there have been efforts to
deliver multiple antigens of M. tuberculosis by using
recombinant poxviruses and Salmonella as the vaccine
carriers.189,190 Different adjuvants have been used for
these vaccines to improve the immunological response.
There are also efforts to develop new attenuated
vaccines based on M. tuberculosis and also improve the
BCG vaccine. Several vaccine candidates have been
shown to be effective in preventing virulent TB infection
in animal models. Immunization using a recombinant
Ag85B protein, produced promising results by
preventing infection in lungs, spleen and increasing the
survival time of vaccinated animals. Other vaccine
approaches, based on DNA expression of Ag85, alone or
in combination with a modified vaccines Ankara (MVA)
vectors expression of the same antigen have also
produced encouraging results in preventing TB infection
in animal models. Additional research is under way to
modulate immunogenicity of candidate vaccines by
addition of cytokines. Among these studies, evaluating
adjuvant effects of granulocyte macrophage-colony
stimulating factor (GM-CSF) on BCG-based vaccines and
IL-12 on DNA vaccines are showing promising results.
At least seven candidate TB vaccines and their
combinations have entered human clinical trials and are
aimed at replacing or improving existing vaccination and
treatment strategies for TB. Attenuated M. tuberculosis
and a combination of BCG+rAg85A have been proposed
to replace BCG for vaccination in children. Several
vaccine strategies, using either a live vaccine vector
expressing Ag85A, heat inactivated M. vaccae or fusion TB
protein, are currently being evaluated for their capacity to
prevent TB infection. Other vaccine approaches are aiming
at boosting BCG efficacy in adults or enhancing TB
chemotherapy efficacy.
The Korean TB vaccine research program, under the
responsibility of five national clinical research centers, is
pursuing various types of vaccine approaches, including;
recombinant BCG (Korean Institute of Tuberculosis), CFP
and Triton-X soluble proteins (Choongnam university),
DNA vaccines, adenovirus vector and IL-12 (Pohang
university); DNA vaccines and cytokines (Seoul National
University); gene knock out in mycobacteria
(Youngnam university) peptides, recombinant proteins
and recombinant BCG (Yonsea University).
573
AERAS-402 is a novel TB vaccine designed to boost

immunity primed by BCG, is the only licensed vaccine.
A study on safety and immunogenicity of AERAS-402 in
healthy M. tuberculosis uninfected BCG vaccinated adults
from a TB endemic region of South Africa reported that
AERAS-402 is safe and immunogenic in healthy adults.
The immunity induced by the vaccine appears promising;
polyfunctional T cells are thought to be important
for protection against intracellular pathogens like
M. tuberculosis. AERAS-402 induced a robust and
durable CD8 T cell response, which appears extremely
promising.191
MVA-85A, in development by Oxford-Emergent
Tuberculosis Consortium Ltd and the EU-funded
research program TB-VAC, is a live attenuated viral
vaccine expressing the immunodominant tuberculosis
(TB) antigen 85A, and is intended for use in a heterologous
prime-boost strategy to prevent TB. MVA-85A is highly
immunogenic in both animals and humans, eliciting
strong polyfunctional CD4+ T-cell responses when
administered as a boost following BCG vaccination or
when administered to individuals previously exposed
to TB. Animal studies have demonstrated trends toward
reduced pathology and bacillary burden for animals
vaccinated with BCG prime followed by MVA-85A boost
compared with BCG alone; however, these positive
effects appear to be modest, and interpretation is limited
by the small number of animals tested. The vaccine has an
excellent safety profile in BCG-nave, previously BCGvaccinated and TB-exposed adults, as well as in BCGvaccinated adolescents and children. At the time of
publication, MVA-85A was in a more advanced stage of
clinical development than other novel TB vaccine
candidates, with a large-scale, proof of concept phase IIb
clinical trial underway for the determination of safety,
immunogenicity and prevention of TB in infants.192
HIGHLIGHTS
Given the higher incidence of tuberculosis in most
developing countries and the inability to control the
spread of infection through prompt diagnosis and
effective treatment of the infectious patients, WHO
continues to recommend BCG vaccination for
children on a worldwide basis.
In the countries with high prevalence of tuberculosis
the vaccine should be given to the infants as soon as
possible after birth.
In the countries with low prevalence of tuberculosis
policy regarding BCG vaccination should be adapted
to the changing situations, taking in account both local
and global epidemiological trends.
Due attention should continue to be paid to the quality
of BCG vaccine, its handling, technique of application,
574
the training of the personnel and the coverage of the

eligible population.
BCG vaccination rather than being considered in
isolation as means of tuberculosis control, should
form part of a comprehensive control program that
includes case detection and treatment.
Besides, research is needed for develop-ing a more

efficacious vaccine that would deliver uniform results
in all settings.
Government of Delhi, Directorate of Family Welfare
has given the following instruction sheet for BCG
vaccination (Annexure).
ANNEXURE
INSTRUCTION SHEET FOR BCG IMMUNIZATION SECTION
DOs
DONts
1. Maintain prescribed cold chain.

2. Check the label and expiry date of vaccine before use.
3. Ensure the hand wash with soap and water before
starting immunization.
4. Use the vaccine specific diluent for reconstitution.
5. Use the reconstituted BCG vaccine within four hours.
6. Use a separate sterilized needle and syringe for each
child. However, if changes of syringe are not possible,
it can be used for ten children and then replaced with
fresh disposable at sterilione.
7. Discard all opened vials of the vaccine at the end of
the day.
8. Ensure that enough vaccine is available for the next
session.
1. Vaccine should not be exposed to directed sunlight

and care should be taken to conduct immunization
session in a properly shade site.
2. Do not store any vaccine in the door of the
refrigerator.
3. Do not send any target child back without
vaccination.
4. Never use distilled/boiled water.
5. Do not constitute more than one vial of one antigen
(vaccine) at a time.
6. Do not freeze.
7. Do not store any vaccine in the door of the
refrigerator.
Government of Delhi
Directorate of Family Welfare
Malkaganj, Delhi
38.2 BCG VACCINATIONFREQUENTLY ASKED QUESTIONS

Vimlesh Seth
Q 1. What does BCG stand for and how was it

invented?
BCG stands for bacilius Calmette-Guerin. It was prepared
by Calmette and Guerin by repeated subcultures of
Mycobacterium bovis on ox bile medium. Prior to its
discovery, numerous investigators had tried to submit
the tubercle bacilli to attenuate it, in order to produce a
vaccine for the prevention of tuberculosis. In Lille
(France), Albert Calmette (a bacteriologist) and Camille
Guerin (a veterinarian) were working on the same with
a highly virulent strain of tubercle bacilli of bovine origin,
isolated a few years earlier by Nocard of Alfort from
tuberculous mastitis in a helfer. In 1908, these workers
observed that addition of beef bile, acting like a soap,
melted the fatty surface of the bacilli and made possible
the dissociation of the aggregates and their division
almost to single units. The bacilli were then cultured and
transplanted every three weeks for thirteen years (a total
of 231 transplants). In 1921 the strain proved to be

harmless even in highly susceptible guinea pigs; yet its
antigenic properties were unimpaired. They called this
bacillus Calmette and Guerin (BCG). In 1924, Calmette
declared the bacillus incapable of reverting to virulent
form. In 1928, the League of Nations declared the BCG
strains as harmless in animals and man. Since then
millions of infants and children have been BCG
vaccinated all over the world.
Q 2. Why should BCG vaccine be given at left upper

arm only? Some parents insist that it should be given
at gluteal region to avoid visible scar at the upper arm.
Can BCG be given at sites other than left upper arm?
It is a convention to give it on left upper arm, so that for
take up of the vaccine, one is sure where to look for the
scar.
BCG vaccine should not be given at gluteal region,

because the regional lymphadenitis, there would prove
to be more problematic. In any case, the scar of BCG is
very small and produces no cosmetic problems. In some
of the cases, it may even fade away completely.
Q 3. Why BCG ampoules are dark colored and so long

in size while other vaccines (DPT, DT, Measles, MMR)
are supplied in clear ampoules or vials?
BCG ampoules, are dark colored because the vaccine
deteriorates on exposure to light. A black paper is also
usually supplied with each pack of BCG ampoules, to
achieve the same objective.
Q 4. Are any special precautions necessary while

opening a BCG ampoule and why?
Ampoules of freeze dried BCG Vaccine are sealed under
vacuum and there is no air or very little air in the
ampoule. Thus, they have to be opened carefully to avoid
rushing in of air and spilling of powder.
The neck of the ampoule should not be crushed or
broken suddenly by a metallic object. It should always
be cut gradually at the junction of the neck and the body
of the ampoule, by a cutter (file) so that air goes in slowly
into the ampoule, and the powder is not spilled.
Q 5. BCG ampoules are supplied without any

information regarding its dilution. Does this mean that
any diluent can be used for its dilution?
No, freeze dried BCG vaccine has to be reconstituted by
dissolving it with normal saline as distilled water acts as
an irritant to the skin. The diluent should always be kept
with the vaccine in the main compartment of the
refrigerator or in the cold box or in the vaccine carrier. It
will ensure that it is cold enough when one needs it.
Q 6. For how long is the reconstituted dissolved

vaccine potent?
Reconstituted BCG vaccine should be used within 3
hours.
Q 7. Why do the manufacturers produce BCG in

ampoules only? Would it not be better if it is supplied
in vials to avoid contamination of the diluted vaccine?
Once diluted, BCG has to be used within 3 hrs. so the
question of keeping it safe for a longer period in a vial
does not arise.
Q 8. How can the diluted vaccine be prevented from

contamination?
575
Contamination can be prevented as follows:

i. Separate needle must be used for each child.
ii. Reconstitution of ampoule should be done after
washing hands.
iii. It is far better to use disposable syringes and needles
rather than boiled syringes and needles.
Q 9. In which compartment of the refrigerator should

BCG be stored (undiluted and diluted) to maintain
potency?
Diluted vaccine is not to be retained for more than 3 to 4
hours, hence during this period it should be kept in the
vaccine carrier containing ice. However, undiluted
vaccine should be stored in the middle of the main
compartment. The temperature in this compartment is 2
to 4 C and at this temperature freeze dried vaccine can
be stored for upto 6 months. There is no need to put this
vaccine in a freezer.
Q 10. An authentic study was conducted in Chingleput

regarding the efficacy of BCG way back in 1980. It
proved its ineffectiveness in preventing pulmonary
tuberculosis. But all the vaccination schedules still
recommend BCG immunization.
Reports from the Tuberculosis Prevention Trial
Chingleput, have been widely interpreted to show that
BCG offers no protection against tuberculosis under any
epidemiological conditions. This is not true as:
i. The efficacy of BCG was assessed solely by the
incidence of sputum positive pulmonary
tuberculosis (secondary or adult type).
ii. Extrapulmonary forms of tuberculosis, occurring in
the study populations were not recorded
iii. Children under 10 years of age although vaccinated,
were not included in the assessment lasting for seven
and a half years.
iv. The report was written only seven and a half years
after the beginning of the study and this period is
not sufficient to study the natural history of
tubercular infection.
The study had only shown the ineffectiveness of BCG
vaccine to prevent adult type of tuberculosis and it is
not justified to extrapolate these results to infants and
children.
One must remember that even natural infection with
tuberculosis does not protect against secondary type of
tuberculosis and hence it would be futile to expect BCG
(which provides much lesser immunity than natural
infection) to do so.
The basic mechanism by which BCG acts, is by
interfering with the silent bacillemia which follows after
576
the very first exposures to human strain of tuberculous

bacteria and hence, it is most likely to be effective against
hematogenous forms of primary tuberculosis. Other
studies have shown that the incidence of hematogenous
types of tuberculosis (the fatal form of tuberculosis) in
infants and children is definitely lower in BCG vaccinated
children. Also some more studies from Thailand and
Hongkong, done after Chingleput trial have also shown
that the incidence of tuberculosis is lower in BCG
vaccinated contacts of open case of tuberculosis. It is for
all these reasons that BCG vaccine is still included in all
immunization schedules.
Q 11. In several countries of the world (USA, UK)

routine BCG is not given, still they have a low incidence
of tuberculosis. Does this not mean that BCG has no
role in eradicating tuberculosis?
Yes, it is a fact that BCG is not given in UK and USA as a
routine. It is because these countries have a very low
incidence of tuberculosis and hence routine vaccination
is not indicated in these countries. This is in conformity
with the basic principle that vaccination is not required
wherever the chances of natural infections are very low.
This cannot be interpreted to show that BCG is not helpful
in controlling tuberculosis.
Q 13. There is a lot of confusion regarding the optimal

age of vaccination. Some recommend at birth, while
many others recommend at the age of one month.
Recently, it is being recommended to be given between
3 and 9 months of age. Please clarify.
Although some studies have shown a slightly higher
tuberculin conversion rate when BCG is given at 3 months
of age, most studies have shown good sensitization even
when BCG was given at birth. Therefore, the current
practice of giving BCG at birth is to be continued especially
in view of the high endemicity of the disease in our
country, and because it is so much easier to get the children
at birth rather than at 1 or 3 months on a nation wide scale.
If BCG has been missed at birth, then it should be given at
the earliest contact, preferably before 9 months of age.
Q 14. BCG at birth may not produce any immunity. Is

this true?
This is not true. It has been shown that cell mediated
immune response (CMIR) could be induced in a
comparable proportion of cases at birth (78.2%) and at 3
months of age (72.5%). It is, therefore, considered that
new borns are capable of evoking CMIR at birth and the
practice of giving BCG at birth should be continued.
Q 12. In UK, the BCG vaccine is given only at 12 to 13

year of age, while in India we give it at birth. Why is it
so?
Q 15. Can preterm babies be vaccinated at birth? If so,

is there any point (gestational age) below which
vaccination is contraindicated?
BCG vaccination policy chosen for a particular area

depends on its epidemiologic picture as suggested by
WHO, ICMR study group. Thus, in areas of high
prevalence, BCG should be given as early in life as
possible, as the chances of a child acquiring infection early
in life is very high. Thus, it is in early life only that the
vaccine will have the greatest impact on serious sequelae
of primary infection. In general, where more than 5% of
children aged 10 to 14 years have been infected, BCG
should be given at birth; where the rate is more than 2%
but less than 5% it should be given at school entry; and
in places where less than 2% of children are infected at
10 to 14 years, BCG could be given at 12 to 13 years, thus
affording maximum protection over the years of puberty.
UK falls in the last category.
It seems that maximum BCG efficacy is seen within 1
to 2 years of vaccination and hence giving it just prior to
the age when natural infection is most likely to occur in a
given population is the most cost effective way of giving
vaccine.
BCG has been found to be effective in preterm infants

also. A tuberculin conversion rate is 83% in a group of
preterm, appropriate for gestational age newborns (3236 wks). However, small for gestational age babies have
a poor tuberculin conversion following BCG vaccination.
Q 16. Similarly, is there any cut off point regarding birth

weight and BCG vaccination?
No specific references are available, but probably
appropriate for gestational age 32 to 36 weeks newborns,
may be treated as a cut off. Babies above 2000 gm can be
easily vaccinated but it may be advisable to wait for some
time for babies with lesser birth weight.
Q 17. I am unable to give intradermal injection. Can I

give it by subcutaneous or intramuscular route? Can
BCG be given orally?
No. BCG can not be given by subcutaneous or
intramuscular route. Small abscesses are most likely to
occur if the vaccine is given subcutaneously and the

efficacy would be reduced. The vaccine cannot be given
orally.
At present, there is no substitute for intradermal
injection for BCG and the technique must be mastered
by all those who wish to give-BCG vaccination. 26 gauge
needle should be used for giving intradermal injection.
Q 18. How should the skin be cleaned before giving

BCG? Can spirit be used for this purpose?
No special preparation of the skin is necessary before
giving BCG vaccination, i.e. washing with disinfectants
like alcohol, dettol, etc. is not to be done. In fact, their
use is contraindicated as they may destroy vaccine
bacillus and thus affect the immune response adversely.
Cleaning with sterile water is enough.
Q 19. The method of using the same needle (after

flaming) for BCG intradermal injection should be
recommended or not? Can same syringe with only
change of needles be advocated?
In mass campaigns, the needle is often passed through a
heated flame for its sterilization. The organisms contained
in the length of the needle are killed. This practice is to
be strongly condemned and use of separate disposable
needles must be adhered to for every case. The same
syringe can however be used.
Q 20. How do I Know that BCG has been given

intradermally?
Raising a wheal over the injection site is a sure sign of
intradermal injection. When an intradermal injection is
given, hair follicles are seen as small pits on the wheal
produced. This wheal should be clearly seen for all
intradermal injections. When correct volume (0.1 ml) of
vaccine is injected the wheal produced has a diameter of
about 8 mm.
Q 21. What is the dose of BCG vaccine? Does it vary

with the age or weight of the child?
The standard dose of BCG vaccine is 0.1 mg in 0.1 ml
volume, irrespective of age and weight of the child. The
recommendation of reduced dose (0.05 mg in 0.05 ml) in
the first month of life is without any scientific explanation.
A fear has been expressed by some workers that the rates
of regional lymphadenitis are higher when higher dose
(0.1 mg) is given in infants. In controlled trials the
incidence was 1.3% as compared to 1% with low dose
(not a significant difference). Further, one is not sure of
the efficacy of the lower dose of vaccine. Hence, the same
dose (i.e. 0.1mg) should be given at all.
577
Q 22. Is rubbing at injection site of BCG, recommended

soon after administration?
No, it is not desirable to disperse the bacteria contained
in the vaccine from the intradermal site, otherwise the
efficacy would be compromised. The wheal produced
by BCG is not painful and would settle down in 20 to 30
minutes.
Q 23. I have given BCG today. What should I tell the

mother who asked me whether she can bathe the child
today?
Since, the wheal settles in 20 to 30 minutes after
vaccination, the mother can bathe the child the same day.
Q 24. Should hot fomentation be done at the Injection

site?
Though direct references are not available (in the case of
BCG), actions and substances which increase local
vascularity (such as rubbing, histamine, hyaluronidase,
etc.) diminish the immune response. The same might
hold true for fomentation and hence, it is not
recommended.
Q 25. Do I need to given any other instructions to a

mother of a baby who has received BCG today?
It is advisable to explain the expected reactions of
vaccination to the mother in simplified language. The
raised area will be absorbed in 20 to 30 minutes and
would disappear and nothing will be seen at the site of
injection for some days. By about the 3rd or 4th week, an
area of hardness will be felt at the site of vaccination,
which will become a lump of 6 to 10 mm by about the
6th week. It is generally not painful but may be tender to
touch. The lump sometimes softens with pus formation
which may discharge, leaving a tiny ulcer which heals
by itself. After 10 to 12 weeks all that is visible, is a tiny
scar, 5 to 7 mm size, with a little pigmentation at the site.
The process of healing and ulceration may repeat 2 to 3
times over a period of 2 to 3 months.
Q 26. Accidentally, I have injected 0.4 ml instead of 0.1

ml of BCG vaccine. What complications are anticipated?
Practically it is impossible to give 0.4 ml of BCG
intradermally. If it has been injected, it has probably gone
subcutaneous. The chances of local complications like
abscess formation and suppurative lymphadenitis,
increase with higher doses of BCG and with
subcutaneous injection. It would be preferable to wait
for any complication to occur, and then if required, to
give INH therapy for 3 to 6 months. It may not be
578
advisable to give INH right at the time of overdose of

injection, as it may interfere with the viability of injected
bacilli and hence may interfere with the immune
response.
In office practice, it is preferable to do Mantoux testing

before giving BCG in all age groups except in children
below 1 year of age in whom BCG can be given without
Mantoux testing.
Q 27. How long after BCG inoculation does Mantoux

test become positive?
Q 32. National Tuberculosis Control Program

recommends giving BCG even in older children without
prior Mantoux testing. This is contrary to what I was
taught. What is your opinion?
Taking responses of 5 to 6 mm as converted in the case

of newborns, 90% of the conversions will have occurred
by six weeks, and 95% by 12 weeks.
Q 28. There is no indication of BCG take up even after 8

weeks of inoculation. Is there any recommendation for
repeating BCG vaccination? If so, how long after this first
BCG?
If no reaction is seen at the local site even after 12 weeks,
it is an indication that BCG has not taken up. In such
cases, BCG should be given again.
Q 29. Should Mantoux test be done in such a case

before giving the second dose of BCG?
Yes, it would be preferable to give a Mantoux test in such
children. If no reaction ( 5mm) is seen with 1TU
tuberculin even after 12 weeks of vaccination, then only
the BCG vaccine may be given. Although it should be
remembered that absence of reaction of Mantoux test
does not necessarily mean that a hypersensitivity or
immunity to tuberculosis has not been set up. In fact
many of these children (i.e. Mx negative even after BCG)
show a positive reaction to more sensitive tests of cell
mediated immunity like phytohemaglutinin blast
transformation (PHA) or lymphocyte migration
inhibition test (LMIT).
Q 30. If there is no take up (reaction) after BCG

vaccination, then what are the reasons for it? Is the
vaccine not potent or the technique faulty?
Either of the factors, i.e. the potency of BCG and faulty
technique, may be operative when no reaction of BCG is
obtained. If the instructions regarding storage, transport,
etc. are not followed meticulously, the vaccine may be
inactivated. If the vaccine is given subcutaneously, it may
not evoke adequate cell mediated immune response, and
also if adequate dose is not given the vaccine may not
take up. Apart from potency of BCG and the technique,
certain host factors (like malnutrition, a recent attack of
measles, etc.) may also interfere with uptake of BCG.
Q 31. Should Mantoux test be done prior to BCG

vaccination in older children. Till what age BCG can be
given without performing a Mantoux test?
In a tuberculin test survey done over a period of 5 years,

it was realized that in mass immunization program, as
also in large number of children attending outpatient
services, the drop out rate is 51% for follow up if we
decide to do BCG vaccination after tuberculin testing.
Thus, there was enormous waste of hospital time.
Tuberculin test could not be read in 51% cases. Thus, such
a procedure though ideal, would be futile and impractical
at the field level. Since the studies were conducted in 0
to 14 years age group, no cut off point for tuberculin test
prior to BCG is recommended, in the national health
program.
Direct BCG vaccination of even previously exposed
(Mx+ve) children does not cause any adverse reactions
except an accelerated reaction and hence is quite safe.
Q 33. A newborn is born to a mother who is an open

case of tuberculosis (TB). How can he be protected from
TB. Can such a mother breast feed her child? Can BCG
and antituberculosis treatment (ATT) be given
together?
A rational approach would consist of:
i. Treatment of the mother, and
ii. Protection of the newborn.
i. Treatment of the mother: The mother of such a
newborn has to be treated intensively with 3 to 4
drugs. There is no need to isolate the infant from
the mother. It has been demonstrated that INH
administered to newborns prevented infection even
when the infants remained with their mothers,
suffering from open tuberculosis. Breast feeding is
not contraindicated as the infection does not spread
through breast milk and would be preferable over
bottle feeding as in any other child. None of the
antituberculosis drugs are excreted in sufficient
amounts in breast milk to cause any toxicity to the
newborn.
ii. Protection of the newborns: All the newborns born
to infectious mothers, should be put on INH (10 mg/
kg) prophylaxis after excluding congenital
tuberculosis. They should be observed clinically
over the next three months, it any symptom like

failure to thrive, fever, etc. develop, the child should
be screened for tuberculosis and treated for the same
with 3 to 4 drugs depending upon the type of TB
the new born develops. If the child remains healthy,
a Mantoux test should be given at three months. If
it is negative, BCG is given and INH is stopped. But
if Mantoux at three months is positive, child is
investigated for tuberculosis and treated
appropriately with 2 to 3 drugs as per
recommendations of WHO.
Q 34. A child has already been treated for tuberculosis.

Does this child need BCG?
The fundamental purpose of BCG is to give a nonpathogenic primary infection, using a measured dose of
an attenuated bovine mycobacterium. The primary
infection induces tuberculin hypersensitivity and
increase defence mechanisms so that if the recipient is
later exposed to reinfection with a pathogenic strain of
mycobacteria, that infection will not cause a clinical
disease or if it does, then it will be localized. In other
world, once tuberculized naturally, the child already has
primary infection and hence would not need BCG.
Q 35. Is this not ideal to give BCG to all children who

are Mantoux positive to protect them from flaring up
of tuberculosis. In other worlds can BCG protect against
recrudescence type of secondary tuberculosis?
Mantoux positivity indicates that the person has been
exposed to tuberculosis and has acquired at least primary
infection (clinical or subclinical). Thus, going by the
analogy mentioned in previous question, the role
expected to be filled by BCG has already been achieved.
There is thus no need of BCG to such children. BCG
prevents bacteremia following primary infection with M.
tuberculosis.
There is no evidence till now that it can help in
preventing recrudescence type of tuberculosis. Further,
BCG in a Mantoux positive child tends to produce an
accelerated reaction with an increased incidence of local
lymphadenitis.
Q 36. Can BCG vaccine be given along with measles

vaccine?
Ideally different live vaccines should not be given at the
same time. A period of 4 to 6 weeks should elapse before
the next vaccination is given.
It is preferable not to give these two vaccines together,
Measles vaccine is known to depress cell medicated
immunity. This may, therefore interfere with the uptake
579
of BCG. A six weeks gap should be there between measles

vaccine and BCG.
Q 37. Which vaccines can be given concurrently with

BCG and which vaccines should not be given
simultaneously with BCG?
BCG can be given with OPV or DPT at the same time.
Measles and MMR should not be given with BCG.
Q 38. I try to avoid giving two injections to children on

one visit. For example a two months old child is brought
to me for vaccination. I give BCG at first visit and tell
them to come after few days for DPT and Polio
vaccination. Parents accept this practice do you agree
with me?
There is no harm in giving DPT and Polio on the same
day as BCG, but if for some reason, they are not given on
the same day, then a gap of least 4 weeks must elapse
between two vaccinations. A lesser gap will interfere with
the uptake of both BCG, DPT and Polio.
Q 39. An ulcer has formed at BCG inoculation site. It is

not healing even after eight weeks. Which antibiotics
(local/parenteral) do you recommend to treat this
condition? What is the suggested management?
Ulcer formation at BCG inoculation site is a normal
phenomenon. The phenomenon of healing and ulceration
may repeat 2 to 3 times over a period of 8 to 12 weeks.
Nothing needs to be done for this. Antibiotics are not
needed unless there is evidence of secondary infection
like cellulitis or abscess formation. In these cases
erythromycin would be the drug of choice.
Q 40. Can ATT be tried in this case of nonhealing Ulcer?

ATT is not required for the so called non healing ulcer.
Almost all of these ulcers would heal spontaneously within
4 to 5 months of vaccination.
Q 41. Following BCG, an axillary lymph node has

formed. What should be done?
Local lymph node enlargement is also a normal
component of BCG uptake, suggesting formation of a
primary complex. Nothing needs to be done for this if
the lymph node is less than 1.5 cm in size and is not
suppurating. If it shows signs of suppuration, excision
may be required in an occasional case where a sinus
formation is threatened.
Q 42. Can neck glands also enlarge in response to BCG

infection?
580
Yes, if BCG vaccination is given high up on the shoulder,

the bacilli reach the nodes in supraclavicular or anterior
triangle of the neck.
Q 43. I get a chest X-ray done on a four year old child to

rule out tuberculosis. Left axilla shows calcified glands.
Can this be due to BCG vaccination given in infancy or
this may be due to tuberculosis?
Calcified left axillary gland is generally due to BCG
vaccination. Primary infection of the lung leads to either
hilar or paratracheal calcification.
Q 44. A two year old child has been brought with history
of definite BCG vaccination at birth but there is no scar.
What should be done?
Absence of scar, despite definite BCG vaccine, in a two year
old child suggests that the child had failed to react to the
vaccination. Although theoretically, a scar once formed can
also disappear but it is too early to do so by 2 years.
Revaccination should be considered if the child does not
react to a test dose of tuberculin ( 6 mm to 1TU).
Q 45. In a eight years old child, there is no BCG scar.

According to the parents a scar was present initially any
how it has faded. Is it possible? If so, does it mean that
the immunity has also decreased? What should be done
in such a case?
Yes, BCG scars are known to disappear over a period of
time, but the disappearance of scar is not synonymous
with either decrease of hypersensitivity or immunity.
Nevertheless revaccination should be done if a child does
not react to test dose of tuberculin ( 6 mm to 1TU).
Q 46. A five year old child with a positive BCG scar, is

being investigated for tuberculosis. His Mantoux test is
negative and the rest of the investigations are also
normal. Having excluded tuberculosis, do I need give
BCG to this child again as his Mantoux is negative?
Opinion on this may differ. It is well known that LMIT
may still be positive when the Mantoux has become
negative, thus suggesting that hypersensitivity to BCG
still persists. There is no need to give BCG.
Q 47. Can BCG be administered concurrently with

Mantoux test at the same sitting? Is Mantoux reaction
affected by BCG administration?
Yes, they can be given but there is no justification for
such a procedure. Mantoux given on the same day as
BCG is not going to be affected by it. Mantoux test
becomes positive only after 6 to 8 weeks of BCG

administration.
Q 48. BCG is used by some in the diagnosis of

tuberculosis. Do you recommend such a practice?
No. It is absolutely not required.
Q 49. I gave BCG to a nine months old child who

developed measles after 10 days of inoculation. What
should be done?
Isoniazide chemoprophylaxis in a dose of 10 mg/kg/
day during risk period (for 12 weeks following measles
infection) is to be administered to children who develop
measles or whooping cough within 4 to 6 weeks of BCG
administration, to prevent possible dissemination.
It will be advisable to ensure Mantoux conversion in
such children as BCG may not take up in such
circumstances.
Q 50. Can BCG be given to children who are on long

term steroids or chemotherapy (i.e. compromised
hosts)?
No. They are at increased risk of disseminated
tuberculosis if BCG is given. A minimum period of 6 to 8
weeks must elapse after stopping steroids before giving
BCG.
Q 51. Can BCG be given to a child who has received

immunoglobulin 10 days back?
It is best avoided for another four weeks.
Although it is generally agreed that cell mediated
immunity is the major component of immune reaction
with BCG, recently it has been shown that even humoral
immunity also plays an important part in preventing
tubercular infection. Therefore, it is theoretically possible
that BCG may be affected after immunoglobulin
administration. It would be advisable therefore, to
postpone BCG for 4 to 6 weeks. If given earlier, it should
be ensured that BCG has been successfully taken up by
demonstrating a Mantoux conversion.
Q 52. Can BCG be given to children with congenital

infections (TORCH)?
BCG efficacy has been in doubt in low birth weight
neonates with severe intrauterine growth retardation
who weigh less than 3rd percentile for their gestational
age. These factors and accompanying secondary
immunosuppression are often found co-existing in
children with congenital infections. Immunization would
depend on the presence/absence and interplay/severity

of these factors and in general BCG should be avoided
in these neonates.
Q 53. Can BCG be given to a child with hepatitis B

infection?
In general, all viral infections have an effect on the immune
response of an individual which may differ from virus to
virus. BCG status in all these infections has not been worked
out. Hence, it is best to avoid BCG for a period of 4 to 6
weeks following a viral infection. An exception to this
statement would be hepatitis B. BCG is a nonspecific
stimulator of cell mediated immunity and therefore BCG
vaccination may be helpful as an immunomodulator in
chronic hepatitis B infection.
Q 54. Can BCG be given to a child with chicken pox

whose skin lesions have already dried up?
There is no definite data on this. It is not known whether
there are any immunological changes following chicken
pox infection but like all other viral infections, it will be
preferable to wait for 4 to 6 weeks.
Q 55. How soon BCG be given to a child after an attack

of measles?
BCG can be given anytime after 12 weeks of measles
infection.
Q 56. Can BCG cause tuberculous disease? If so, under

what conditions?
BCG can cause tuberculous disease dissemination in
following conditions:
i. Immunodeficiency states.
ii. Incubation period of another infection particularly
measles.
iii. HIV infected children
Q 57. Why BCG cannot be made available in single dose

ampoules?
Single dose ampoules will not be cost effective in
countries like India where mass BCG vaccination strategy
is implemented. Also, since the same syringe can be used
with change of needles for different children, waste
incurred is hardly any.
The size of BCG ampoule has been made for mass
campaigns. In office, practice wastage can be minimized
if a separate day (once in a week/fortnight/month) is
fixed for BCG vaccination. Of course, if would be still
better if smaller ampoules can be provided for office
practice.
581
Q 58. As per government instructions, no child should

be denied any vaccination and ampoule of vaccine is
to be opened even for a single child. What are your
comments? Will it not lead to a lot of wastage?
Cost of a wasted ampoule will always be less than that
of a full course of antituberculosis therapy which might
be needed if immunization is withheld and the child
develops active disease.
Q 59. What is the status of new BCG vaccine?

Scientists are excited about the prospects of a new
vaccine. After tests on mice and guinea pigs it appears
to be more effective than the currently used BCG vaccine.
The points new to this vaccine are:
1. Rather than trying to make changes in the current
vaccine, researchers used a weakened version of the
bacterium that causes TB in people.
2. The researchers found a gene in the organism that
helps immune system detection. They removed it
from the bacterium.
3. It was found that vaccine extended the lives of mice
and guinea pigs and stimulated stronger immune
responses compared to the existing vaccine.
4. The scientists believe if the results continue to be
positive, human studies may be possible in two to
three years.
It is said that TB, a bacterial infection that usually
attacks the lungs, kills about 1.6 million people a year
globally. The increasing resistance of the TB organism to
drug treatment makes creation of a truly effective vaccine
even more crucial.
The existing BCG vaccine is in the use for almost a
century despite its limited effectiveness. It is based on a
live attenuated strain of bacterium that causes TB in the
cattle. In the new vaccine, use is made of a weakened
version of the bacterium that causes TB in human beings.
The basis being similar to other vaccines by trying to
make the bodys own immune system stronger and have
better defenses to fight off invaders like disease causing
bacteria. The researchers found a gene in the organism
that helps it edude immune system detection and
removed it from the bacterium. That helps the vaccine
using this live weakened version of the organism, induce
a strong immune response.
The new vaccine was tested in mice and guinea pigs
whose life was extended and a stronger immune response
was elicited as compared to the existing BCG vaccine.
However, a major limitation is that it is still probably
too infectious to be given it to humans. It is only partially
attenuated for virulence. Removal of additional genes
may make the vaccine safer.
582
Global Aspect
The TB organisms infect roughly a third of the worlds
population. Most infections remain latent but can become
active when the immune system is weakened, for
example, when the same person gets HIV infection. 10
million people have TB. The existing BCG vaccine
protects young children from tuberculosis but not the
adolescents and adults against the type of disease
prevalent in them.
TB can be treated effectively with drugs in many
cases, but drugs have to be given for upto six months
making treatment difficult and expensive. Many poorer
parts of the world lack the medical infrastructure to
deliver this kind of treatment. So many experts feel an
effective vaccine could be a highly valuable tool in
combating the disease.
REFERENCES
38.1 BCG VAccination
1. Proceedings of the Fourth Global Vaccine Research
Forum. World Helath Organization. Department of
Vaccines and Biologicals CH-1211 Geneva 27,
Switzerland 2004.
2. Seth Vimlesh, Kabra SK, Jain Y, et al. BCG revisited.
3. Paramasivan CN, Herbert D, Prabhakar R. BCG: Do we
have an alternative? ICMR Bulletin 1995;25, No. 3.
4. Fine PEM. Variation in protection by BCG: implications
of and for heterologous immunity. Lancet 1995;346:133945.
5. Seth Vimlesh, Kukreja N, Sundaram KR, et al. In vivo
correlation of cell mediated immune reponse after BCG
in preschool children in relation to their nutritional status.
6. Seth Vimlesh, Kukreja N, Sundaram KR, et al. Cell
mediaed immune response in children in relation to their
nutritional status. Delayed hypersensitivity after BCG in
preschool status. Indian J Med Res 1982;74:392-8.
7. Seth Vimlesh, Kukerja N, Sundram KR, et al. Waning of
cell mediated immune response in preschool children
8. Kathipari K, Seth Vimlesh, Sinclair S, et al. Cell mediated
immune response after BCG as a determinant of optimum
age of vaccination in newborns. Indian J Med Res
1982;76:508-11.
9. Flory CM, Hubbard RD, Collins FM. Effects of in vivo T
lymphocyte subset depletion on myco-bacterial infection
in mice. J Leukoc Biol 1992;52:225-9.
10. Orme I. Beyond BCG: The potential for a more effective
TB vaccine. Mol Med Today 1997;5:487-92.
11. Watkins ML, Semple PL, Abel B, et al. Exposure of cord
blood to Mycobacterium bovis BCG induces an innate
response but not a T-cell cytokine response. Clin Vaccine
Immunol 2008; 15:1666-73.
12. Hishimoto T. The vaccination, theory and practice. BCG.
Tokyo: International Medical Foundation Japan1975.
13. Osborn TW. Changes in BCG strain. Tubercle 1983;64:1.

14. Gheorghiu M, Augier J, Lagrange PH. Maintenance and
control of the French BCG strain 1173-P2 (primary and
secondary seedlots). Bull Inst Pasteur 1983;81:281-8.
15. Behr MA, Small PM. A historical and molecular
phylogeny of BCG stains. Vaccine 1999;17:915-22.
16. Oettinger T, Jorgensen M, Ladefoged A, et al.
Development of the Mycobacterium bovis BCG vaccine:
review of the historical and biochemical evidence for a
genealogical tree. Tubercle Lung Dis 1999;79:243-50.
17. Behr MA, Schroeder BG, Brinkman JB, et al. A point
mutation in the mma3 gene is responsible for impaired
methoxymycolic acid production in Mycobacterium bovis
BCG strains obtained after 1927. J Bacteriol 2000;182:33949.
18. American Academy of Pediatrics, committee on
infectious diseases. Report of the committee on infectious
disease 22nd ed. Elk Grove Village 1991;11:AAP.
19. Rigder RW, Oxtoby MJ, Mvula M, et al. Safety and
immunogenicity of BCG, DPT and oral polio vaccines in
newborn children in Zarie infected with HIV type. I J
Pediatr 1993;122:697-702.
20. Lotte A, Wasz-Hockert O, Poisson N, et al. BCG
complications. Estimates of the risks among vaccinated
subjects and statistical analysis of their main
characteristics. Adv Tuberc Res 1984;21:107-93.
21. Lotte A, Wasz-Hockert O, Poisson N, et al. A
bibliography of the complications of BCG vaccination.
A comprehensive list of the World literature since the
introduction of BCG up to July 1982, supplemented by
over 100 personal communications. Adv Tuberc Res
1984;21:194-245.
22. FitzGerald JM. Management of adverse reactions to
bacille Calmette-Guerin vaccine. Clin Infect Dis
2000;31(suppl):S75-S76.
23. Lotte A, Wasz-Hockert O, Poisson N, et al. Second
IUATLD study on complications induced by intradermal
BCG-vaccination. Bull Int Union Tuberc Lung Dis
1988;63:47-59.
24. Bottiger M, Romanus V, De Verdier C, et al. Osteitis and
other complications caused by generalized BCG-itis.
Experiences in Sweden. Acta Paediatr Scand 1982;71:4718.
25. Schopfer K, Matter L, Brunner C, et al. BCG osteomyelitis.
Case report and review. Helv Paediat Acta 1982;37:7381.
26. Kroger L, Korppi M, Brander E, et al. Osteitis caused by
bacille Calmette-Guerin vaccination: a retrospective
analysis of 222 cases. J Infect Dis 1995;172:574-6.
27. Horwitz O, Meyer J. The safety record of BCG vaccination
and untoward reaction observed after vaccination. Adv
Tuberc Res 1957;8:245-71.
28. Tardieu M, Truffort-Pernot C, Carriere JP, et al. Tuberculous
meningitis due to BCG in two previously healthy children.
Lancet 1988;1:440-1.
29. Abramowsky C, Gonzalez B, Sorensen RU. Disseminated
bacillus Calmette-Guerin infections in patients with
primary immunodeficiencies. Am J Clin Pathol
1993;100:52-6.

30. Stone MM, Vannier AM, Storch SK, et al. Brief report:
meningitis due to iatrogenic BCG infection in two
immunocompromised children. N Engl J Med
1995;333:561-3.
31. Gonzalez B, Moreno S, Budach R, et al. Clinical
presentation of bacillus Calmette-Guerin infections in
patients with immunodeficiency syndromes. Pediatr
Infect Dis J 1989;8:201-6.
32. Jouanguy E, Altare F, Lamhamedi S, et al. Interferongamma-receptor deficiency in an infant with fatal bacille
Calmette-Guerin infection. N Engl J Med 1996;335:195661.
33. Casanova JL, Blanche S, Emile JF, et al. Idiopathic
disseminated bacillus Calmette-Guerin infection: a
French national retrospective study. Pediatrics
1996;98:774-8.
34. Talbot EA, Perkins MD, Fagundes M, et al. Disseminated
bacille Calmette-Guerin disease after vaccination: case
report and review. Clin Infect Dis 1997;24:1139-46.
35. Romanus V. The impact of BCG vaccination on
mycobacterial disease among children born in Sweden
between 1969 and 1993. Smitts-kyddsinstitutet,
Stockholm;1995.
35a. Jeena PM, Chhagan MK, Topley J, et al. Safety of the
intradermal Copenhagen 1331 BCG vaccine in neonates
in Durban, South Africa. Bull World Health Organ
2001;79:337-43.
36. Tabatabai P, Mahjoub F, Mehdizadeh M, et al.
Osteomyelitis due to BCG vaccination. Indian Pediatr
2008; 45: 930-2.
37. Nousbaum JB, Garre M, Boles JM, et al. Deux
manifestations inhabituelles dune infection par le virus
LAV-HTLV III: BCGite et varieclle pulmonaire. Rev
Pneucol Clin 1986;42:310-1.
38. von Reyn CF, Mann JM, Clements CJ. Human
immunodeficiency virus infection and routine childhood
immunization. Lancet 1987;2:669-71.
39. Weltman AC, Rose DN. The safety of bacilli bacille
Calmette-Guerin vaccination in HIV infection and AIDS.
AIDS 1993;7:149-57.
40. Houde C, Dery P. Mycobacterium bovis sepsis in an infant
with human immunodeficiency virus infection. Pediatr
Infect Dis 1988;7:810-1.
41. Boudes P, Sobel A, Deforges L, et al. Disseminated
Mycobacterium bovis infection for BCG vaccination and
HIV infection. (Correspondence). JAMA 1989;262:2386.
42. Ninane J, Grymonprez A, Burtonboy G, et al.
Disseminated BCG in HIV infection. Arch Dis Child
1988;63:1268-9.
43. Lallemant-Le Coeur S, Lallemant M, Cheynier D, et al.
bacille Calmette-Guerin immunization in infants born
to HIV-1-seropostive mothers. AIDS 1991;5:195-9.
44. Besnard M, Sauvion S, Offredo C, et al. bacille CalmetteGuerin infection after vaccination of human
Dis 1993;12:993-7.
45. Rosenfeldt V, Paerregaard A, Valerius NH. Disseminated
infection with bacille Calmette-Guerin in a child with
advanced HIV disease. Scand J Infect Dis 1997;29:526-7.
583
46. Romanus V, Fasth A, Tordai P, et al. Adverse reactions

in healthy and immunocompromised children under six
years of age vaccinated with the Danish BCG vaccine,
strain Copenhagen 1331: implication for the vaccination
policy in Sweden. Acta Paediatr 1993;82:1043-52.
47. van Deutekom H, Smulders YM, Roozendaal KJ, et al.
bacille Calmette-Guerin (BCG) meningitis in an AIDS
patient 12 years after vaccination with BCG.
(Correspondence). Clin Infect Dis 1996;22: 870-1.
48. OBrien KL, Ruff AJ, Louis MA, et al. bacille CalmetteGuerin complications in children born to HIV-1-infected
women with a review of the literature. Pediatrics
1995;95:414-8.
49. Ninane J, Grymonprez A, Burtanboy G, et al.
Disseminated BCG in HIV infection. Arch Dis child
1988;63:1268-9.
50. Armbruster C, Junker W, Vetter N, et al. Disseminated
bacille Calmette-Guerin infection in an AIDS patient 30
years after BCG vaccination. (Correspondence). J Infect
Dis 1990;162:1216.
51. Reichman LB. Why hasnt BCG prove dangerous in HIVinfected patients? JAMA 1989;261:32-46.
52. Waddell RD, Lishimpi K, Fordham von Reyn C, et al.
Bacteremia due to Mycobacterium tuber-culosis or M. bovis,
bacille Calmette-Guerin (BCG) among HIV-positive
children and adults in Zambia. AIDS 2001;15:55-60.
53. World Health Organization. Special Programme on AIDS
and Expanded Programme on Immuni-zation Joint
Statement. Consultation on human immunodeficiency
virus (HIV) and routine childhood immunization. WHO
Wkly Epidem Rec 1987;62:297-9.
54. Milstine JB, Gibson JJ. Quality control of BCG vaccine by
WHO: a review of factors that may influence vaccine
effectiveness and safety. Bull World Health Organ
1990;68:93-108.
55. World Health Organization. BCG in immunization
programmes. Wkly Epiderm Rec 2001;76:33-9.
56. Altes HK, Dijkstra F, Lugnr A, et al. Targeted BCG
vaccination against severe tuberculosis in low-prevalence
settings: epidemiologic and economic assessment.
Epidemiology 2009;20: 62-8.
57. Seth Vimlesh. BCG Vaccine. In: Immunisation in Practice.
Mittal SK, 1st (edn). Kukreja S (Eds). Indian Academy of
Pediatrics Delhi Branch1989;1740.
58. Park JE, Park K. Text Book of Preventive and Social
Medicine, 12th edn. Jabalpur, Banarasidas Bhanot
Publishers1994;25.
59. Lotte A, WaszHockert O, Porsson N, et al. Second
IUATLD study on complications induced by intradermal
BCGvaccination. Bull Int Union Tuberc Lung Dis
1988;63:47-59.
60. Aronson JD, Aronson CF, Taylor HC. A twenty-year
appraisal of BCG vaccination in the control of
Tuberculosis. Arch Intern Med 1958;101: 881-93.
61. Chandra P, Hari Lal KT. Factors affecting efficacy of BCG
vaccination. Indian Pediatr 1977;14: 535-40.
62. Tendam HG, Hitze KL. Does BCG vaccination protect
the newborn and young infants? Bull World Health Org
1980;58:37-42.
584

63. Kagina BM, Abel B, Bowmaker M, et al. Delaying BCG
vaccination from birth to 10 weeks of age may result in
an enhanced memory CD4 T cell response. Vaccine.
2009;7:488-95.
64. Mussi-Pinhata MM, Goncalves AL, Foss NT. BCG
vaccination of full term infants with chronic intrauterine
malnutrition: influence of immunization age on
development of postvaccination, delayed tuberculin
hyper-sensitivity. Bull WHO 1993;71:1-5.
65. Thayyil-Sudhan S, Kumar A, Singh M, et al. Safety and
effectiveness of the BCG vaccination in preterm babies.
66. Rosenthal SR. Routes and methods of administration
Littleton, MA: (Ed). In BCG vaccine: Tuberculosis
Cancer. Littleton, MA: PSG Publishing, 1980;146-75.
67. Odent M. Future of BCG. (Correspondence). Lancet
1999;354:21-70.
68. Styblo K, Meijer J. Impact of BCG vaccination programs
in children and young adult on the tuberculosis problem.
Tubercle 1976;57:17-43.
69. Rouillon A, Waaler H. BCG vaccination and
epidemiological situation. Adv Tuberc Res 1976;19:64126.
70. Colditz GA, Berwer TF, Berkey CS, et al. Efficacy of BCG
vaccine in the prevention of tuberculosis. Meta-analysis
of the published literature. JAMA 1994;271:698-702.
71. Colditz GA, Berkey CS, Mosteller F, et al. The efficacy of
bacillus Calmette-Guerin vaccination of newborns and
infants in the prevention of tuberculosis: meta-analyses
of the published literature. Pediatrics 1995;96:29-35.
72. World Health Organization. Vaccination against
tuberculosis. Report of an ICMR/WHO Scientific Group.
Tech Rep Ser 1980;651:1-21.
73. World Health Organization. BCG vaccination policies.
Report of a WHO Study Group. Tech Rep Ser 1980;652:117.
Disease. Criteria for discontinuation of vaccination
programs using bacille Calmette-Guerin (BCG) in
countries with a low prevalence of tuberculosis. A
statement of the International Union Against
Tuberculosis and Lung Disease. Tubercle Lung Dis
1994;75:179-80.
75. World Health Organization. Global Tuberculosis
Program and Global Program on Vaccines. Statement on
BCG revaccination for the prevention of tuberculosis.
WHO Wkly Epidem Rec 1995;70:229-31.
76. Arbelaez MP, Nelson KE, Munoz A. BCG vaccine
effectiveness on preventing tuberculosis and its
interaction with human immunodeficiency virus
infection. Int J Epidemiol 2000;29:1085-91.
77. Centers of Disease Control and Prevention. The role of
BCG vaccine in the prevention and control of tuberculosis
in the United States: a joint statement by the Advisory
Council for the Elimination of Tuberculosis and the
Advisory Committee on Immunization Practices. Morb
Mortal Wkly Rep 1996;45(No. RR4):1-18.
78. Fine PEM, Carneiro IAM, Milstien JB, et al. Issues relating
to the use of BCG in immunization programs. A
79.
80.
81.
82.
83.
84.
85.
85a.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
discussion document. WHO/VandB/-99.23: Geneva:

WHO,1999;1-42.
Greenberg PD, Lax KG, Schechter CB. Tuber-culosis in
house staff. A decision analysis comparing the tuberculin
screening strategy with the BCG vaccination. Am Rev
Respire Dis 1991;143:490-5.
Reichman LB, Jordan TJ, Greenberg PD. Decision analysis
comparing the tuberculin screening strategy with BCG
vaccine. (Correspondence). Am Rev Respir Dis
1992;145:732-3.
Rothman KJ, Greeland S. Modern epidemiology. 2nd.
Philadelphia: Alippincott Reven Publishers, 1998;1-738.
Orenstein WA, Bernier RH, Dondero TJ, et al. Field
evaluation of vaccine efficacy. Bull World Health Organ
1985;63:1055-68.
Smith PG. Retrospective assessment of the effectiveness
of BCG vaccination against tuber-culosis using the casecontrol method. Tubercle 1982;63:23-35.
Schlesselman JJ. Case-control studies. Design, conduct,
analysis, 1st edn. New York: Oxford University Press,
1982;1-354.
Rodrigues LC, Smith PG. Use of the case-control
approach in vaccine evaluation: efficacy and adverse
effects. Epidemiol Rev 1999;21:56-72.
Pullical AS, Fernadex GVJ. Comparison of the prevalence
of tuberculosis infection in BCG vaccinated versus non
vaccinated school age children. Indian Pediar 2007; 44:
344-7.
Aronson JD, Dannenberg AM. Effect of vaccina-tion with
BCG on tuberculosis in infancy and in childhood.
Correlation of reaction to tuberculin tests, roentgenologic
diagnosis and mortality. Am J Dis Child 1935; 50:111730.
Feldberg GD. Disease and class. Tuberculosis and the
shaping of modern North American Society. 1st edn. New
Jersey: Rutgers University Press, 1995;1-214.
Dormandy T. The white death. 1st edn. London and Rio
Grande: The Hambledon Press, 1999; 1-433.
Aronson JD, Palmer CE. BCG vaccination among
American Indians. Publ Health Rep 1946;61:802-20.
Townsend JG, Aronson JD, Saylor R, Parr I. Tuberculosis
control among the North American Indians. Am Rev
Tuberc 1942; 45: 41-2.
Aronson JD, Aronson CF, Taylor HC. A twenty-year
appraisal for BCG vaccination in the control of
tuberculosis. Arch Intern Med 1958;101:881-93.
Aronson JD. Protective vaccination against tuberculosis
with special reference to BCG vaccination. Am Rev
Tuberc 1948;58:255-81.
Rosenthal SR, Loewinsohn E, Graham ML, et al. BCG
vaccination against tuberculosis in Chicago. A twentyyear study statistically analyzed. Pediatrics 1961;28:62441.
Ferguson RG, Simes AB. BCG vaccination of Indian
infants in Saskatchewan. Tubercle 1949;30:5-11.
Levine MI, Sackett MF. Results of BCG immuni-zation
in New York City. Am Rev Tuberc 1946;53: 17-32.
Wunsch Filho V, de Castilho EA, Rodrigues LC, et al.
Effectiveness of BCG vaccination against tuberculosis
meningitis: a case-control study in Sao Paulo, Brazil. Bull
World Health Organ 1990;68: 69-74.

97. Wunsch-Filho V, Moncau JEC, Nakao N. Methodo-logical
consideration in case-control studies to evaluate BCG
vaccine effectiveness. Int J Epidemiol 1988;17:629-34.
98. Miceli I, De Kantor IN, Colaiacovo D, et al. Evaluation of
the effectiveness of BCG vaccination using the casecontrol method in Buenos Aires, Argentina. Int J
Epidemiol 1988;17:629-34.
99. Murtagh K. Efficacy of BCG. (Correspondence). Lancet
1980;1:423.
100. Zodpey SP, Maldhure BR, Dehankar AG, et al.
Effectiveness of bacille Calmette-Guerin (BCG)
vaccination against extra-pulmonary tuberculosis: a casecontrol study. J Commun Dis 1996;28:77-84.
101. Chavalittamrong B, Chearskul S, Tuchinda M. Protective
value of BCG vaccination in children in Bangkok,
Thailand. Pediatr Pulmonol 1986;2: 202-5.
102. Sharma RS, Srivastava DK, Asunkanta Singh A, et al.
Epidemiological evaluation of BCG vaccine efficacy in
Delhi 1989. J Com Dis 1989;21:200-6.
103. Camargos PAM, Guimaraes MDC, Antunes CMF. Risk
assessment for acquiring tuberculosis meningitis among
children not vaccinated with BCG: a case-control study.
Int J Epidemiol 1988;17:193-7.
104. Myint TT, Win H, Aye HH, et al. Case-control study on
evaluation of BCG vaccination of newborn in Rangoon,
Burma. Ann Trop Pediatr 1987;7:159-66.
105. Rosenthal SR, Loewinsohn E, Graham ML, et al. BCG
vaccination in tuberculous households. Am Rev Respir
Dis 1961;84:690-704.
106. Sirinavin S, Chotpitayasunondh T, Suwanjutha S, et al.
Protective efficacy of neonatal bacillus Calmette-Guerin
vaccination against tuberculosis. Pediatr Infect Dis
1991;10:259-65.
107. AI-Kassimi FA, AI-Hajjaj MS, AI-Orainey IO, et al. Does
the protective effect of neonatal BCG correlate with
vaccine-induced tuberculin reaction? Am J Respir Crit
Care Med 1995;152:1575-8.
108. Lanckriet C, Levy-Bruhl D, Bingonon E, et al. Efficacy of
BCG vaccination of the newborn: evaluation by a followup study of contacts in Bangui. Int J Epidemiol
1995;24:1042-9.
109. Packe GE, Innes JA. Protective effects of BCG vaccination
in infant Asians: a case-control study. Arch Dis Child
1988;63:277-81.
110. Young TK, Hershifield ES. A case-control study to
evaluate the effectiveness of mass neonatal BCG
vaccination among Canadian Indians. Am Public Health
1986;76:783-6.
111. Bhat GJ, Diwan VK, Chintu C, et al. HIV, BCG and TB in
children: a case control study in Lusaka, Zambia. J Trop
Pediatr 1993;39:219-23.
112. Rodrigues LC, Gill ON, Smith PG. BCG vaccina-tion in
the first year of life protects children of Indian
subcontinent ethnic origin against tuber-culosis in
England. J Epidemiol Comm Health 1991;4578-80.
113. Smith PG. Evaluating interventions against tropical
diseases. Int J Epidemiol 1987;16:159-66.
114. Tuberculosis Prevention Trial. Trial of BCG vaccines in
South India for tuberculosis prevention: first report. Bull
World Health Organ 1979;57:819-27.
585
115. Baily GVJ, Narain R, Mayurnath S, et al. Trial of BCG

Tuberculosis Prevention Trial, Madras. Indian J Med Res
1980;72(suppl):1-74.
116. Tuberculosis Research Centre (ICMR) Chennai. Fifteen
year follow-up of trial of BCG vaccines in South India
for tuberculosis prevention. Indian J Med Res
1999;110:56-69.
117. Comstock GW, Livesay VT, Woolpert SF. Evalua-tion of
BCG vaccination among Puerto Rican children. Am J
Public Health 1974;64:283-91.
118. Frimodt-Moller J, Thomas J, Parthasarthy R.
Observations on the protective effect of BCG vaccination
in a South Indian rural population. Bull World Health
Organ 1964;30:545-74.
119. Frimodt-Moller J, Acharyulu GS, Pillai KK. Observations
on the protective effect of BCG vaccination in a South Indian
rural population: fourth report. Bull Int Union Tuberc
1973;48:40-9.
120. Shapiro C, Cook N, Evans D, et al. A case-control study
of BCG and childhood tuberculosis in Cali, Colombia.
Int J Epidemiol 1985;14:441-6.
121. Capewell S, Leitch AG. The value of contact procedure
for tuberculosis in Edinburgh. Br J Dis Chest 1984;78:31729.
122. Heimbeck J. Sur La vaccination vreventive de la
tuberculose par injection souscutanee de BCG chez les
eleves-infirmieres de 1hopital Ulleval, a Oslo (Norvege).
Ann Inst Pasteur 1929; 43: 1229-32.
123. Heimbeck J. BCG vaccination in nurses. Tubercle
1948;29:84-5.
124. DArcy Hart P, Pollock TM, Sutherland I. C. Assessment
of the first results of the Medical Research Councils trial
of tuberculosis vaccines in adolescents in Great Britain.
Adv Tuberc Res 1957;8:171-89.
125. British Medical Research Association. BCG and vole
bacillus vaccines in the prevention of tuberculosis in
adolescents. First (progress) report to the Medical
Research Council by their Tuberculosis Vaccines Clinical
Trials Committee. BMJ 1956;1:1-15.
adolescents. Second report to the Medical Research
Council by their Tuberculosis Vaccines Clinical Trials
Committee. BMJ 1959;2:379-96.
adolescents and early adult life. Third report to the
Medical Research Council by their Tuberculosis Vaccines
Clinical Trials Committee. BMJ 1963;1:973-8.
128. Tuberculosis Vaccines Clinical Trials Committee. BCG
and vole bacillus vaccines in the prevention of
tuberculosis in adolescents and early adult life. Fourth
report to the Medical Research Council by Tuberculosis
Vaccines Clinical Trials Committee. Bull World Health
Organ 1972;46:371-85.
129. D/Arcy Hart P, Sutherland I. BCG and vole bacillus
vaccines in the prevention of tuberculosis in adolescence
and early adult life. Final report to the Medical Research
Council. BMJ 1977;2:293-5.
586
130. Karonga Prevention Trial Group. Randomize controlled

trial of single BCG, repeated BCG, or combined BCG and
Killed Mycobacterium leprae vaccine for prevention of
leprosy and tuberculosis in Malawi. Lancet 1996;348:1724.
131. Tuberculosis prevention trial, Chennai. Trial of BCG
132. Stein SC, Aronson JD. Occurrence of pulmonary lesions
in BCG vaccinated and unvaccinated persons. Am Rev
Tuberc 1953;68:6957-12.
133. Hart PD, Sutherland I. BCG and vole bacillus vaccines
in the prevention of tuberculosis in adolescence and early
adult life. BMJ 1977;2:293-5.
134. Comstock GW, Livesay VT, Woolpert SF. Evalua-tion of
BCG vaccination among Puerto Rican children. Am J
Public Health 1974;64:283-91.
135. Frimodt-Motler J, Acharyulu GS, Kesava Pillai K.
Observations on the protective effect of BCG vaccination
in a South Indian rural population: 4th report. Bull Int
Union Tubercle Lung Dis 1973;48:40-9.
136. Camaros PAM. Guinareas MDS, Antunes CM. Risk
assessment for acquiring meningitis tuberculosis among
children not vaccinated with BCG - A case Control study.
Int J Epidemiol 1988;17:193.
137. Wunsch Filho V, de Castilho EA, Rodrigues LC, et al.
Effectiveness of BCG vaccination against tuberculous
meningitis - a case control study in Sao Paulo, Brazil.
Bull World Health Org 1990;68:69.
138. Myint TT, Win H, Aye OHH, et al. Case control study on
evaluation of BCG vaccination of newborn - in
Rangoon, Burma. Ann Trop Pediatr 1987;7:159.
139. Young TK, Herhfield ES. A case control study to evaluate
the effectiveness of mass neonatal BCG vaccination
among Canadian Indians. Am J Public Health
1981;76:783.
140. Packe GE, Inner JA. Protective effect of BCG vaccination
in infant Asians - a case control study. Arch Dis Child
1988;68:277.
141. Thilothammal N, Runyan DK, Banu K, et al. Does BCG
vaccine prevent tuberculous meniingitis in children. Arch
Dis Child 1996; 74:144-7.
142. Padungchan S, Konjanart S, Kasiratta S, et al. The
effectiveness of BCG vaccination of the newborn against
childhood tuberculosis in Bangkok. Bull WHO
1986;67:269.
143. Tidjani O, Amedome A, Ten Dam HG. The protective
effect of BCG vaccination
of the newborn against
childhood tuberculosis in an African Community.
Tubercle 1986;67:269.
144. Jin BW, Hong YP, Kim SJ. A contact study to evaluate
the BCG vaccination programme in Seoul. Tubercle
1989;70:241.
145. Colditz GA, Brewer T, Berkey C, et al. Efficacy of BCG
vaccination of the newborns and infants in the
prevention of tuberculosis; Meta-analysis of
published literature. Pediatrics 1995;96:29-35.
146. Gaensbauer JT, Vandaleur M, ONeil M, et al. BCG
protects toddlers during a tuberculosis outbreak. Arch
Dis Child. 2009;94:392-3.
147. Fine PEM. BCG vaccination against tuberculosis and

leprosy. Br Med Bull 1988;44:691-703.
148. Smith MHD. Tuberculosis in adolescence characteristics
recognition and management Clinical Pediatrics 1967;6:915.
149. Smith PG, Fine PEM. BCG vaccination in Devise PDO
(Ed), clinical tuberculosis, 2nd ed. London: Chapman and
Hall, Chapter 22.1998;417-31.
150. Osborn TW. Changes in BCG strains. Tubercle 1983;64:1.
151. Grrange JM, Gibson J, Osborn TW, et al. What is BCG?
Tubercle 1983;64:12939.
152. Comstock GW. Identification of an effective vaccine
against tuberculosis. Am Rev Respir Dis 1988;138:47980.
153. Sutrisna B, Utomo P, Komalarini S, et al. Penelitan
efectifitas vaksin BCG can beberapa factor lainnya pada
anak yang menderita TBC berat di 3 rumah sakit di
Jakarta 1981-182. Medika 1983;9:143-50.
154. Ritz N, Hanekom WA, Robins-Browne R, et al. Influence
of BCG vaccine strain on the immune response and
protection against tuberculosis. FEMS Microbiol Rev
2008;32:821-41.
155. Brantsaeter AB, Romanus V, Andersen PH, et al. Evidence
of protective effect of BCG vaccination in persons at low
risk of tuberculosis in Nordic Countries. Int J Tuberc Lung
Dis 2009;13:440-5.
155a. Chadha VK, Jaganntha PS, Kumar P. Can BCG vaccinated
children be included in tuberculin surveys to estimate
the annual risk of infection in India? Tuberc Lung Dis
2004;8:1437-42.
155b. Chadha VK, Jaganath PS and P Kumar. Tuberculin
sensitivity among children vaccinated with BCG under
universal immunization program. Indian J Pediatr 2004;
71:1063-8.
155c. Chadha VK, Suryanarayana LT, Suryanarayan HV.
Protective effect of BCG among children vaccinated
under universal immunization program. Indian J of
pediatr 2004;71:1083-4.
156. Palmer CE, Long MW. Effects of infection with atypical
mycobacteria on BCG vaccine and tuberculosis. Am Rev
Respir Dis 1966;94:553-68.
157. Edward ML, Goodrich JM, Muller D, et al. Infection with
Mycobacterium avium intracellulare and the protective
effects of Bacille Calmette Guerin. J Infect Dis
1982;145:733-44.
158. Orme I, Collins FM. Efficacy of M. bovis BCG vaccination
in mice undergoing prior pulmonary infection with
atypical mycobacteria. Infec Immun 1984;44:28-32.
159. Brown CA, Brown IN, Swinburne S. The effect of oral M.
vaccae on subsequent responses of mice to BCG
sensitization. Tubercle 1985;66:251-60.
160. Clemens JD, Chuong JJR, Feinstein AR. The BCG
controversy: a methodological and statistical reappraisal.
JAMA 1983;249:2362-9.
161. Mallol J, Girardi G, Quezada A, et al. Tuberculin reaction
in healthy infants
vaccinated with BCG at birth. Rev
Chil Pediatr 1990;61:252-7.
162. Sedaghation MR, Shana AI. Evaluation of BCG at birth
in United Arab Emirates. Tubercle 1990;71:177-80.
163. World Health Organization. Global tuberculosis
Programme and Global Programme on Vaccines.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
180a.
181.
Statement on BCG revaccination for the prevention of

tuberculosis. Wkly Epidemiol Rec 1995;70:223-31.
Caglayan S, Yenin O, Karyan K, et al. Is medical therapy
effective for regional lymphadenitis following BCG
vaccination? Am J Dis Child 1987;141:1213-4.
Eisenhut M, Paranjothy S, Abubakar I, et al. BCG
vaccination reduces risk of infection with Mycobacterium
tuberculosis as detected by gamma interferon release
assay. Vaccine 2009; 27:6116-20.
with treatment failure in childhood tuberculosis. Indian
Pediatr 2008;45:769-71.
Sakha K, Behbahan AG. Immunogenicity of neonatal
BCG vaccination in children entering primary school. Pak
J Biol Sci 2008;11:930-3.
Roth AE, Benn CS, Ravn H, et al. Effect of revaccination
with BCG in early childhood on mortality: randomised
trial in Guinea-Bissau. BMJ 010;340:c671.
Jou R, Huang WL, Su WJTokyo-172 BCG vaccination
complications, Taiwan. Emerg Infect Dis 2009;15:1525-6.
Saifudheen K, Anoop TM, Mini PN, et al. Primary
tubercular osteomyelitis of the sternum. Int J Infect Dis.
2010;14:e164-6.
Sadeghi-Shabestari M, Rezaei N. Disseminated bacille
Calmette-Gurin in Iranian children with severe
combined immunodeficiency. Int J Infect Dis.
2009;13:e420-3.
WHO. BCG vaccination of newborn. Rationale and
guidelines for country programmes. WHO/TB/86.147.
Geneva: WHO, 1986.
Pettola H, Salini I, Vahvenen V, et al. BCG vaccination
as a cause of vaccination of osteomye-litis and
subcutaneous abscess. Arch Dis Child 1984;54:157-161.
Sirisanthana V. Complications of bacille Calmette-Guerin
(BCG) vaccine in HIV-infected children. J Infect Dis
Antimicrob Agents 1995;12:63-7.
Edwards KM, Kernodle DS. Possible hazards of routine
bacille Calmette-Guerin immunization in human
Dis J 1996;9:836-8.
Beregre P. BCG vaccination and AIDS. Bull Int Union
Ninane J, Gremonprez A, Burtonboy G, et al.
Disseminated BCG in HIV infection. Arch Dis Child
1988;63:1268-9.
Honde C, Dery P. Mm bovis sepsis in an infant with HIV
infection. Pediatr Infect Dis J 1988;7:810-12.
Lallemant le Coeur S, Lallemant M, Chenyier D. BCG
immunization in infants born to HIV-1 seropositive
mothers. AIDS 1991;5:195-9.
Azzopardi P, Bennett CM, Graham SM, et al. bacille
Calmette-Gurin vaccine-related disease in HIV-infected
children: a systematic review. Int J Tuberc Lung Dis
2009;13:1331-44.
Hesseling AC, Schaaf HS, Haneban WA, et al. Danish
BCG vaccine-induced
disease
in
human
immunodeficiency virus infected children. Clinical
Infectious Disease 2003;37:1226-33.
Mansoor N, Scriba TJ, de Kock M, et al. HIV-1 infection
in infants severely impairs the immune response induced
182.
183.
184.
185.
185a.
186.
187.
188.
189.
190.
191.
192.
587
by Bacille Calmette-Gurin vaccine. J Infect Dis

2009;199:982-90.
WHO/IULTLD. Tuberculosis and AIDS. Statement on
AIDS and tuberculosis. Bull Int Union Tubercle Lung Dis
1989;64:8-11.
Udani PM, Pasrikh UC, Shah PM, et al. BCG test in
tuberculosis. Indian Pediatr 1971;8:143-50.
Goeman A, Ertan U, Kiper N, et al. Is the BCG test of
diagnostic value in tuberculosis. Tubercle Lung Dis
1994;75:54-7.
Sonmez E, Yakinei C, Aladag M, et al. Diagnosis
of tuberculosis; PPD or BCG test. J Trop Pediatr
1998;44:40-2.
Curihas SS, Rodrigues LC, Pedrosa V, et al. Neonatal BCG
protection agsint leprosy. Lepr Rev 2004;75:357-66.
Karonga Prevention Trial Group. Randomised controlled
trial of single BCG, repeated BCG, or combined BCG
and killed Mycobac-terium leprae vaccine for prevention
of leprosy and tuberculosis in Malawi. Lancet
1996;348:17-24.
Morris S, Kelley C, Howard A, et al. The immunogenicity
of single and
combination DNA vaccines against
tuberculosis. Vaccine 2000;18:2155-63.
Horwitz MA, Lee BW, Dillon BJ, et al. Protective
immunity against tuberculosis induced by vaccination
with major extracellular proteins of Mycobacterium
tuberculosis. Proc Natl Acad Sci USA. 1995;92:1530-4.
Zhu X, Venkataprasad N, Ivanyi J, et al. Vaccination with
recombinant vacciniaviruses protects mice against
Mycobacterium tuberculosis infection. Immunology
1997;92:6-9.
Mollenkopf HJ, Groine-Triebkorn D, Andersen P, et al.
Protective efficacy against tuberculosis of ESAT-6
secreted by a live Salmonella typhimurium vaccine carrier
strain and expressed by naked DNA. Vaccine
2001;19;4028-35.
Abel B, Tameris M, Mansoor N, et al. The Novel TB
Vaccine, AERAS-402, Induces Robust and polyfunctional
CD4 and CD8 T Cells in adults. Am J Respir Crit Care
Med. 2010 Feb 18. [Epub ahead of print]
Nicol MP, Grobler LA. MVA-85A, a novel candidate
booster vaccine for the prevention of tuberculosis in
children and adults. Curr Opin Mol Ther 2010;12:124-34.
SUGGESTED READING
1. Alyasin S, Katibeh P, Asadi S. The relationship between
tuberculin response, BCG vaccine scar and asthma. Iran
J Allergy Asthma Immunol 2009;8:205-10.
2. Arrcola MC, Vidal YL. A second generation anti TB
vaccine is long overdue. Annals of Clinical Microbiol and
Antimicrobials 2004;3:10-20.
3. Barouni AS, Augusto C, Queiroz MVNP, et al. BCG
lymphadenopathy detected in a BCG-Vaccinated infant.
Braz L Med Biol Res 2004;37:697-700.
4. Bowerman RJ. Tuberculin skin testing in BCG vaccinated
population of adults and children at high-risk for
tuberculosis in Taiwan. Int J Tubere Lung Dis 2004;8:122833.
5. Dawar M, Clark M, Deeks SL, et al. A fresh look at an
old vaccine: dose BCG have a role in 21st Century
588
6.
7.
8.
9.
Canada. Int J Circumpolar Health 2004;63 Suppli 2:

230-6.
Derrick SC, Repique C, Philop S, et al. Immuni-zation
with a DNA vaccine cocktail protects mice lacking CD4
cells against an aerogenic infection with mycobacterium
tuberculosis. Infection and Immunity 2004;72:1685-92.
Haile M, Kallenius G. Recent development in tuberculosis
vaccines. Curr Opin Infect Dis 2005;18:211-5.
Hatherill M, Mahomed H, Hanekom W. Novel vaccine
prime and selective BCG boost: A new tuberculosis
vaccine strategy for infants of HIV-infected mothers.
Vaccine. 2010 May 11.
Hesseling AC, Schaaf HS, Hanekom WA, et al. Danish
Bacille Calmette Guerin Vaccine induced disease in HIV
10.
11.
12.
13.
infected children. Clinical Infectious Diseases

2003;37:1226-33.
Roth AE, Benn CS, Ravn H, et al. Effect of revaccination
with BCG in early childhood on mortality: randomised
trial in Guinea-Bissau. BMJ. 2010;340:c671.
Sartono E, Lisse IM, Terveer EM, van de Sande PJ, Whittle
H, Fisker AB, Roth A, Aaby P, Yazdanbakhsh M, Benn
CS. Oral polio vaccine influences the immune response
to BCG vaccination. A natural experiment. PLoS One.
2010; 5:e10328.
Van-Dunem JC, de Alencar LC, Rodrigues LC, et al.
Sensitivity and specificity of BCG scar reading among
HIV-infected children. Vaccine. 2010;28:2067-9.
Vargas MH, ernal-Alcantara DA, Vaca MA, et al. Effect of
BCG vaccination in asthmatic school children. Pediatr
Allergy Immunol 2004;15:415-20.
39
Latent Tuberculosis
39.1 LATENT TUBERCULOSIS IN CHILDREN AND ADOLESCENTS

Vimlesh Seth, J Cunningham, S Kuhn
INTRODUCTION
Tuberculosis continues to be the worlds most important
infectious cause of morbidity and mortality among adults.
Nearly 1.6 million people develop TB disease each year,
and an estimated one million die each year. Despite this
enormous global burden, case detection rates are low
posing serious hurdles for TB control.
DEFINITION
Latent tuberculosis infection is the currently accepted
term for the stage of M. tuberculosis infection that is
asymptomatic, dormant and noncontagious; the patient
is not sick in any way and has a normal chest X-ray. A
positive tuberculin skin test is the only evidence of latent
tuberculosis infection. This stage may continue for the
patients entire life time or, in a matter of few weeks to 6
years, may progress to the stage of active disease called
tuberculosis. The latter can affect the lung or the other
parts of the body (lymph nodes, miliary, meningeal, bone
and joint) and may be contagious to others. Treatment of
latent tuberculosis infection, previously called preventive
treatment or chemoprophylaxis aims to prevent the future
development of active disease. The Mantoux test
recommended for screening for risk of tuberculosis
should be an essential function of primary health care
for all children.
Highlights of Tuberculosis Screening

Recommendations
Screening for risk of tuberculosis exposure by clinical
history taking or tuberculosis risk questionnaire is an
essential part of routine well-child care
Tuberculin skin test for infants and children at high
risk of exposure to tuberculosis
Continuing risk, test annually or every 2 to 3 years,
depending upon type of risk
No further risk. Retest only if risk recurs
No tuberculin skin test in infants who are not at risk

or in infants and children who are at low risk of
infection
Use only Mantoux test.
Infants and children identified as having latent
tuberculosis infection should receive treatment
(isoniazid (INH) for 9 months).
The pediatric age group is an important one in the
cycle of transmission of M. tuberculosis, for both the
individual and the community. Young children with
tuberculosis infection are more likely than adults to
develop serious forms of disease. Thus, children
constitute a high risk group deserving special attention.
Unfortunately, exposure at an early age to infectious
tuberculosis is common in most developing countries,
and there are many children with subclinical infection.
These children join the nearly 2 billion people in the world
who are infected with the tubercle bacillus. Over time,
more and more new cases arise from this ever-increasing
pool, with each new case representing another opportunity for continued tuberculosis (TB) transmission.1
Among the interventions which can curtail the spread
of tuberculosis is preventive chemotherapy or
chemoprophylaxis. These terms are often a source of
confusion for patients and providers, as the majority of
candidates are infected with TB and the role for therapy
is secondary rather than primary prevention.
In an effort to most accurately describe this intervention,
the American Thoracic Society (ATS) supports the
replacement of both these terms with treatment of latent
tuberculosis infection (LTBI).2
While case detection and cure of active disease are
critical in reducing transmission, treatment of LTBI
intervenes at an earlier point in the cycle, preventing the
development of tuberculosis in those who were
previously infected. This strategy of TB control has
received far more attention in developed countries where
programs can focus on TB elimination and are not sinking
beneath the case load seen in many developing countries.
Thus, international guidelines (International Union
590
Against Tuberculosis and Lung Disease [IUATLD],

World Health Organization [WHO]) concentrate on
strategies for case-finding, holding and treatment of active
TB disease while strategies to manage LTBI are generated
from organizations in low prevalence countries such as
the American Academy of Pediatrics,3 Canadian Lung
Association,4 and the British Thoracic Society.5 The
variation in strategies across these groups reflects a lack
of available and/or consistent evidence and programspecific characteristics, priorities and resources. This
chapter will attempt to summarize the rationale behind
these recommendations particularly as they pertain to
the pediatric population including those in high
prevalence countries. The first challenge in addressing
latent tuberculosis infection is making the diagnosis.
Tuberculin skin testing is currently the most commonly
used tool for diagnosing LTBI. This method has serious
flaws and ultimately cannot exclude the presence of TB.
Clinical history and chest X-ray may assist interpretation.
The value of this test and the conditions that challenge
its utility will be discussed. New technology is emerging,6
but is not likely to be accessible to resource-poor countries
in the near future.
Isoniazid has a leading role to play in the treatment
of LTBI. Since its introduction in 1952, it has proven to be
a safe, and effective agent in the treatment of tuberculosis.
Both the WHO and IUATLD recommend isoniazid for
the treatment of LTBI in young children who are
household contacts of infectious cases and for PPDtuberculin positive persons with HIV infection. 7,8
However, despite its low cost and ease of administration,
the intervention has not been widely accepted or
implemented outside North America. However, there is
renewed interest in treatment of LTBI in both high and
low prevalence countries as a result of the impact of HIV
infection on tuberculosis epidemiology.9 Other antituberculous medications and combinations have also
been recommended for treatment of both drug
susceptible and resistant LTBI.2
Risk of Latent Tuberculosis Infection in Children Living

in Households with Tuberculosis Patients
9a
Nguyen et al supports the importance of contact tracing

in remote settings with high prevalence TB setting. The
following suggestions are made:
Study Procedure
Study should be performed in a stipulated period say for
three months using a pretested questionnaire. Study
participants are interviewed for medical history,
vaccination, number of missed days of treatment, degree
and duration of contact, characteristics of the household
and distance to health centers, knowledge of the
transmission of the disease and practices related to cough
and spitting.
Physical examination of the study participants is
performed. It includes presence of BCG scar in contacts
and investigation for clinical signs of TB patients. Patients
nutritional status is to be assessed by body mass index
(BMI) weight (kg)/(height m)2. Adults are considered
under weight if BMI is < 18.5 and severely underweight
if BMI < 16.
Laboratory Procedures
ZiehlNeelsen staining of three sputum samples for
the presence of AFB
TST with ITu injection of 0.1 ml of PPD
Villagers with clinical signs or symptoms of TB to be
X-rayed
Patients and their family receive counseling
Consent is to be taken from parents or care taker of
the child
Ethics committee approval to be taken.
Definitions
LTBI is defined as a positive TST in the absence of TB
disease. The latter is suspected if the interviewers report
cough (chronic) (longer than 3 weeks), weight loss, night
sweats and fever or if signs of extrapulmonary TB are
present.
Compliance
If a patient had taken medicines for more than 90%, he/
she is labeled as compliant.
Degree of Contact
It is defined as close if patients and children usually share
the same meal or the same bed, live in the same room.
Duration of contact is the reported time period from the
onset of disease to the beginning of directly observed
therapy (DOT).
Risk of Latent TB Infection

Unlike adults who have 10 to 15% chance of developing
the disease in their life time, contact children are at highest
risk of developing overt disease. It is likely that up to
50% of infants will develop the disease within 3 to 9
months of infection and 25% of children during 1 to 6
year of age, 15% at adolescence with in 1 to 2 years of
infection. Targeting 0 to 5 year age group has been
recommended particularly for those Nations that are
unable to implement full scale contact investigation.
Contact Tracing
Contact tracing in high incident countries is generally
given a low priority. A recent review suggests that this
Chapter 39 Latent Tuberculosis

strategy merits revision. Contact tracing is a means to
improve early case detection, prevent further propagation
of drug resistance and is a cost-effective method for early
identification of secondary cases to decrease transmission
of M. tuberculosis to meet case-detection target rates of
Clark9b has summarized the pitfalls in contact tracing
and early diagnosis of TB. Effective contact tracing and
screening remain essential to prevent secondary cases and
are specially important for child contacts, given their
greater susceptibility to disseminated disease and the
difficulty in diagnosis in this age group.
Tuberculosis is easily missed in children. A
combination of contact history, tuberculin testing and
radiology aid in diagnosis. Clark9b describes the following
three cases of serious tuberculosis disease which illustrate
their vulnerability to the disease and problems that can
be encountered with apparently straight forward contact
tracing procedures.
Case 1
A 5-month Asian girl who had been vaccinated for
tuberculosis was seen as a contact of her grand mother.
The latter had fully sensitive pulmonary tuberculosis. The
child was well at this time and after one negative heef
test, was given BCG vaccination and discharged.
Six weeks later the child presented with fever, poor
feeding and vomiting. On referral to the hospital, she was
found to be pale, unwell and tachypneic with widespread
crepitations on auscultation but no hepatosplenomegaly.
X-ray chest showed miliary shadows and a small opacity
in the right mid zone. Miliary tuberculosis was diagnosed.
A 9 month course of triple antituberculosis therapy cured
her.
Case 2
A 6-year-old white girl was screened as a contact of an
aunt who had fully sensitive smear-positive pulmonary
tuberculosis. Two heef test six weeks apart gave negative
results, she was given BCG vaccination. Two weeks later
she presented with history of cough, headache, weight
loss and fever. A chest X-ray film showed right middle
lobe consolidation. Family history was not traced and
initially the child was treated for bacterial pneumonia.
She did not improve after two weeks of antibiotic
therapy. Repeat X-ray showed right hilar adenopathy
with right middle and lower lobe consolidation. The
family history was then ascertained and she was put on
only two drugs, isoniazid and rifampicin. She relapsed
after one month of treatment with complete right middle
to lower lobe collapse on chest X-ray film. Then she was
referred to specialized center. A Mantoux test (1 unit)
was positive at 10 25 mm induration, bronchoalveolar
lavage showed plentiful acid fast bacilli. Pyrazinamide
591
and prednisolone in the dose of 25 mg and 2 mg/kg

respectively were added with intensive physiotherapy
this resulted in expansion of both lungs. Although as a
late sequelae, the child developed bronchiectasis.
Case 3
A 10-month-old male child had both an uncle and aunt
with a fully sensitive smear-positive pulmonary
tuberculosis. On screening X-ray chest and heef test were
negative. Two further heef tests one after 8 week and the
other after 8 weeks of BCG were also negative. Prophylactic isoniazid (10 mg/kg) was given for 4.5 months. The
child developed a painless lump over hip joint after 13
months, hip radiograph showed a lytic lesion in the neck
of the right femur from which sterile pus was evacuated.
Culture of the mycobacteria was not requested and the
family history of tuberculosis not ascertained.
The lesion of the hip worsened in spite of being in
hips-pica and three months therapy with flouroquinolones and cloxacillin. At this time a Mantoux test
(10 TU) produced a positive result of 17 17 mm induration. Chest X-ray, renal ultrasound showed no
abnormality.
Tuberculosis was diagnosed from the contact history,
the clinical findings, about the positive tuberculin test
with good compliance of treatment for one year with
excellent result. There is no limp and normal limb growth.
There is resolution of lytic lesion.
This is inferred that in spite of screening, these three
children developed serious form of tuberculosis. In
contrast to adults, tuberculosis is usually a primary
disease in children. Early diagnosis is, therefore, very
important but difficult and at best, only 30 to 50% of cases
are confirmed by culture. Conventionally, two of the
following five criteria are required to make a diagnosis,
a positive tuberculin test; positive radiology: a history of
contact with tuberculosis; compatible clinical symptoms;
positive histology or culture. The tuberculin test, and
contact history are more important for the diagnosis in
children as compared to adults. Close contacts of smearpositive cases, aged under 2 (previously 5) year old,
require prophylaxis with isoniazid for 6 months. Shorter
courses of monotherpay are less effective.
The children should be treated by doctors with
experience in childhood tuberculosis, who are aware of
these differences and of the diagnostic criteria for the age
group. It is recommended that all children should have
chest radiography irrespective of the result of tuberculin
test.
The Tuberculosis Spectrum

Latent TB is defined solely by evidence of immunological
sensitization by mycobacterial proteins in the absence of
clinical signs and symptoms of active disease.9c TST was
592
the only method used till recently to define sensitization.

Drawback of TST is that PPD contains cross reactive
antigens that are present in nonpathogenic mycobacteria,
resulting in false positive test in those immunized with
bacille Calmette-Guerine. Recent TST conversion has got
the major disadvantage of being negative in disseminated
TB and those with HIV. More specific tests of sensitization
are those rely on the in vitro release of interferon-
(IFN-) in response to specific M. tuberculosis antigens.
Characterization of Subpopulation in Latent TB

The hypothesis is that latent TB is a reservoir of organisms
that are encased in caseous lesions under hypoxic
conditions, where as active TB is typified by bacilli
replicating aerobically at the margin of liquefied cavities.
Immunological Basis of New Diagnostics in Latent

Tuberculosis Infection in Adults and Children
Latorre et al9d evaluated the quantitative T-cell response
after specific M. tuberculosis antigen stimulation in active
tuberculosis (TB) and latent TB infection (LTBI) patients.
In adults the median number of T-cells after RDI antigen
stimulation was significantly higher in active TB patients
than in LTBI patient. In children the number of responder
T-cells against the specific antigen stimulation was higher
in active TB patients than in LTBI patients, though the
difference was not significant. The authors summarized
that in patients with suspected clinical TB, although there
is over lapping in the number of responder T-cells
between both groups, a T-cell count above the described
threshold could suggest active TB, especially in patients
with a high probability of active TB and low probability
of having LTBI. The results are consistent with the current
evidence that T-cell response may indicate mycobacterial
burden and disease activity.
Skin TST Status Prelude to Development of Latent TB

Hussain et al 9e suggested that TST conversion is
associated with early increase in IFN- and IL-10
responses and precedes latency by several months post
exposure.
Lucas et al10 conducted a first large-scale prospective
study to investigate the clinical utility of currently available
immunological tests for latent tuberculosis infection (LTBI)
in resettled refugee children. There is lack of evidence
regarding the optimal diagnostic test for LTBI from
sufficiently powered cohort studies of children particularly
those <5 year old. These data are essential to balance the
need for treatment of LTBI against unnecessary
intervention and over treatment in this vulnerable
population. It was meant to test the claimed superiority of
T-SPOT. TB assay over the QFT-GT assay. Despite
reasonable concordance of positive results between the
IGRAs, there were a number of discordant positive results.

These tests with both IGRAs may be indicated when the
clinical suspicion of M. tuberculosis infection is high. What
can be concluded is that by IGRAs one would be able to
demonstrate TB in children less than 12 months of age.
In QFT-GT, there is probably an inadequate T-cell
response to mitogen. The latter was attributed to
helminthic infection in which there is polarization of
circulating T-cells towards T-helper 2 (Th2) responses,
resulting in impaired Th1 responses, increased regulatory
T-cell activity and lower IFN- responses. There is
production of immunoglobulin E (IgE) antibodies due to
parasitic infections, which can result in monocyte
production, immunosuppressant factors such as
prostaglandin E2 which inhibit T-cell proliferation. On
basis of this data the authors suggested that a strategy
that uses TST as a screening test followed by a
confirmatory IGRA for positive cases as suggested by UK
National Institute for Health and Clinical Excellence
(NICE) guidelines is inferior to solely IGRA based
approach.
Hence, it is suggested that IGRAs are the preferred
screening tool for LTBI in refugee children. QFT-GT
performance is compromised by inderminante results
where as the T-SPOT. TB performance is compromised by
the high number of failed tests specially in younger
children. This study highlights the need for continued
research to improve reliability of LTBI diagnosis in children
from high incidence countries.
Advantage of T-SPOT.TB Over Tuberculin Skin Test in

Prediction of TB Disease
Leung CC et al10a demonstrated the better performance
of T-SPOT.TB over tuberculin test in patients with silicosis
in adults. A positive T-SPOT.TB test significantly
predicted the subsequent development of active TB
(relative risk 4.50, 95% CL: 1.03-19.68) and culture/
histology-confirmed TB. (relative risk 7.80, 95% CL; 1.0259-63). T-SPOT.TB performs better than TST in the
targeted screening of LTBI among silicosis patients.
Advances in Latent TB Diagnosis:

Interferon-Gamma Release Assays
Until recently the diagnosis of latent TB infection (LTBI)
depended solely on the tuberculin skin test (TST). The
biggest advance in recent times has been the development
to T-cell-based interferon-gamma release assays
(IGRAs).10b These are in-vitro blood tests that are based
on interferon gamma release after stimulation by TB
specific antigens (e.g. ESAT-6, and CFP-10). Two IGRAs
are now commercially availablethe quantiFERON-TB
Gold in-Tube Assay (Cellestis Ltd. Carnegie, Victoria,
Australia) and the T-SPOT.TB assay (Oxford Immunotec
Limited, Abingdon, Oxon, UK). IGRAs have very high

specificity and are unaffected by prior BCG vaccination
or sensitization to nontuberculous mycobacteria. The
sensitivity of IGRAs in active TB is 75 to 90 % and are
more specific than TST in immunocompromised patients.
Their use is rapidly expanding in low incidence countries,
even though they cannot distinguish between latent and
active TB. Also there is limited data on their ability to
predict the development of active TB. Despite their
limitations these can be of use in special groups such as
young children, immunocompromised persons,
individuals with smear-negative and extrapulmonary
disease.
Several studies are undergoing in developing
countries to have strong evidence for making policy
decisions.
Yoshiyama et al10c reported that TB incidence among
QFT-G-positive contacts was higher than among QFT-Gnegative contacts. Andersen et al11 have suggested that the
development of highly specific IGRAs has enabled the
accurate identification of TB infection, but it has not been
possible so far to translate this into a better or earlier
identification of contagious disease. A prognostic marker
that enables targeted treatment of populations in high
endemic regions that are in the process of developing
contagious TB would greatly contribute to the control of
this global epidemic. They have suggested that instead of
using IGRAs only in binary mode (infected and non infected)
based on a cutoff value, the magnitude or conversion of an
IGRA response might enable the identification of individuals
who, although still asymptomatic are in the process of
developing active TB. The issues to be resolved are:
Can an incipient disease cutoff value for IGRAs can
be established so that a single measurement of the
IFN- response to ESAT-6 and CFP-10 can simplify
the clinicians decision to treat an M. tuberculosis
infected but asymptomatic individual? Or alternatively

is it on the basis of conversion that a decision can be
made
Does the specificity and/or cytokine profile of the
immune response to the pathogen change over time
to include latency antigens? Can responses that are
characteristic of the different stages of infection be
identified? However, these issues involve
interpretation of the results from existing technologies,
not the invention of new tools. Although the
observation that IFN- produced in response to
specific antigens increases with increasing bacterial
load seems simple enough to apply. Ultimately, the
utility of this approach can be determined only by
testing the hypothesis in large-scale cohort studies.
These are the challenges ahead.
For screening of latent tuberculosis, assays based on
interferon- (IFN-) are an exciting new development. Its
usefulness in adults have been quite extensively tried,
but the data in children is limited. National Institute for
Health and Clinical Excellence (NICE) guidelines
recommend their use for screening pediatric tuberculosis
(TB) contacts. Under NICE guidelines, patients with
positive Mantoux results (or in whom Mantoux testing is
unreliable) undergo IFN- testing. Table 39.1.1 gives the
NICE guidelines used by authors.12
The following flow chart used in relation to BCG and
Mantoux status helps in diagnosing latent TB (Fig. 39.1).
With the use of NICE guidelines 85% fewer children
would have been given chemoprophylaxis for LTBI after
contact with TB. This would make significant reduction in
prescribing, decreasing costs and unnecessary treatment
for children. Trial of treatment in a suspect of latent or TB
disease is often a part of the diagnosis in children.
Indeterminate results are more often in younger children
Table 39.1.1: NICE guidelines for screening of pediatric tuberculosis contacts

Parameter
NICE Guidelines
Indications for giving three

drug therapy
< 2 Years
- Mantoux positive and abnormal CXR,
+ clinical evidence of TB.
> 2 Years
- Mantoux positive + IFN- positive + CXR + clinical evidence.
- Mantoux ve (smear positive contact)
- IFN- +ve + clinical evidence
Criteria for diagnosing latent

tuberculosis infection (LTBI)
- Mantoux +ve, + IFN- positive

+ no clinical evidence of TB
+ no prior BCG vaccination
- Mantoux negative (smear positive contact) IFN- positive + no clinical
evidence
- Evidence of TB scars on CXR, no history of adequate treatment
Criteria for giving BCG
593
No prior BCG, Mantoux < 6mm < 2 year + IFN- negative
594
Fig. 39.1.1: Diagnosis of latent TB
due to inherent immunosuppression. The Mantoux test is

well recognized as having good sensitivity and specificity
for TB disease in high prevalence population but not in
those with low prevalence.
IFN- tests are as sensitive and specific as Mantoux tests
in adults. There is less data available in children, although
an ELISPOT IFN- test has shown 83% sensitivity for
children in South Africa with 73% in HIV-positive children.
IFN- results do correlate better with risk factors and
degree of exposure in contacts of MTB than the TST does.
A recent study in high TB prevalence area suggested that
the TST correlated better than IFN- test with recent
exposure.
Treating LTBI on the basis of TST results decreases
the risk of active TB by 60%. The potential decrease in
false positive Mantoux results with the introduction of
IFN- tests will significantly decrease the amount of LTBI
treatment given to children in contact with TB.
With in NICE guidelines, there is reliance on the
superiority of QFT over Mantoux test. However, as there
is no gold standard to determine the absolute sensitivity
and specificity of QFT in LTBI, it has limitation in the
diagnosis of LTBI. It is recommended to use the clinical
judgment to interpret results to ensure the best
management outcome for the child.
Menzies et al13 have emphasized by metanalysis of new
tests for diagnosis of latent tuberculosis. The most consistent
finding in this review is the high specificity of IGRA, which
is unaffected by BCG vaccination in all populations. This
reflects that the antigens used in these assays are neither
present in BCG nor in certain nontuberculous
Mycobacteria. It was inferred that the results of tuberculin
skin test varied with the age at which BCG was
administered. In earlier review of 24 studies, involving

240243 children, false positive results (>10 mm) of
tuberculin skin test attributable to BCG vaccination
occurred in 6.3% persons and only in 1% of those who
were tested after more than 10 year. In the same review of
12 studies involving 12728 persons who were vaccinated
at 2 years of age or older, BCG was responsible for false
positive in 40% of all persons and 20% of those who were
vaccinated after 10 or more years.
In spite of such a big cohort the authors recommend
further research as follows:
1. Independent studies need to be done to see the
reproducibility of the test. To estimate variability,
repeated assays should be performed on the same
sample by the same technician, by different
technicians in the same laboratory or in different
laboratories.
2. To estimate biological variability repeated tests should
be done in unexposed and under treated persons at
intervals ranging from days to years. This information
is crucial to distinguish random variability from
conversions attributable to new TB infection and to
study the effect of treatment on IGRA response.
3. Tuberculin test and IGRA should be compared in HIV
+ve and ve cases along with the other children with
immune suppression due to other cause, such as those
on long-term steroid therapy or are severely
malnourished.
4. Further it is recommended that large scale cohort studies
are needed that estimate risk for progression to active
disease in persons who have had both the tuberculin
and IGRA tests. It will be important to see those with
discordant results for the development of active disease.
595

Tuberculosis being a public health challenge its
control requires the use of efficient diagnostic tools. M.
tuberculosis (MTB) requires a strong immune response
upon infection, a phenomenon measured by the old
tuberculin skin test (TST). However, this test has many
limitations and a high rate of these in BCG vaccinated
subjects. Recent studies have identified several MTBantigens for diagnostic use, including the ESAT-6 and
CFP-10 proteins. Based on these antigens, one of the most
significant advance is the development of diagnostic
armamentorium for TB. These include the assays based
on IFN-determination IGRAs. The principle of these is
that T-cells of infected individuals produce IFN-gamma
on encountering MTB antigen in vitro.13a
The two-step approach (first using TST followed by
IGRA for confirmation) is the most favored strategy for
IGRAuse in the general population while the use of
IGRA alone is suggested in particular clinical settings
and/or patient groups.
APPROACH TO LATENT TUBERCULOSIS INFECTION

Diagnosis
It is unclear whether the TST size cut-offs are

appropriate for highly endemic countries as these
guidelines have been based on studies of nonendemic
populations. However, models have been formulated
which can illustrate the predictive value of a positive or
negative test at different cut-offs as a function of
prevalence of TB infection.10b
A new method of testing has been developed which
detects interferon-gamma (IFN-) responses in whole
blood samples to M. antigens. While the first commercialized test detected responses to tuberculin purified
protein derivative (PPD),6 a recent version utilizes
antigens that are more specific to M. tuberculosis.14 The
latter has been approved by the FDA in the United States,
and has a specificity and sensitivity that exceeds that of
the TST.14 While, it is not influenced by BCG vaccination
status,15 sensitivity appears to be less in those who are
immune-suppressed.16 Unless the methodology can be
adapted to a resource-poor setting, the technology
required will preclude routine use in most highlyendemic countries.
Considerations for Selected Populations
Earlier, Tuberculin skin testing (TST) was the only

commonly available tool for diagnosing LTBI. A detailed
discussion of the TST is found elsewhere in this text.
Immunization with BCG or infection with nontuberculous Mycobacteria can result in a falsely positive TST,
limiting the specificity of the test. This is particularly
problematic for the diagnosis of LTBI where by definition
there are no clinical and no/minimal radiologic findings
to support M. tuberculosis infection. As a result,
interpretation of the test is guided by a prior risk of
infection and/or progression to active disease if the
individual is infected. The greater the high risk, the
smaller the reaction size required to qualify as TST
positive (Table 39.1.2).
TB Programs with Limited Resources

As only 5 to 10% of those infected with M. tuberculosis
will ever develop active disease, it is neither feasible nor
cost effective to skin test everyone. However, in countries
with sufficient financial resources and tuberculosis
program infrastructure, screening for latent infection in
those at high-risk of progression to active disease is an
appropriate part of disease control.2,17 In the resourcepoor setting, the WHO recommends that TST is done as
part of the assessment of children who are household
contacts of smearpositive pulmonary TB cases to identify
those with active disease.7 If tuberculosis disease is
excluded, WHO recommends that all children up to
Table 39.1.2: Criteria for positive tuberculin skin test (TST) in children and adolescents
Tuberculin skin test result (mm)
> 5*
> 10
> 15
Close contact of active TB case
High-risk of dissemination
(age = 5 years, various medical
conditions)
Age = 5 years and no

known risk factors
Immunosuppressed (e.g. HIV)

Active TB disease
High-risk of exposure
(resident in, migrant from,
or traveller to a high prevalence
area; exposure to high-risk adult
* Although North American authorities state that TST results should be interpreted irrespective of BCG immunization
status, some endemic countries use a minimum cut-off of 10 mm for a positive result.
In areas where atypical mycobacteria infections are prevalent.
Age cut-off varies from < 4 (AAP) to = 5 years (WHO, IUATLD, Canadian Thoracic Society).
Adapted from American Academy of Pediatrics. Red Book: 2003 Report of the Committee on Infectious Diseases (Ref. 3).
596
5 years receive prophylaxis. Breastfed children of

smearpositive mothers are considered as the highest risk
of all and require close follow-up. In settings where the
annual risk of TB infection is high, the risk of activating
latent disease must be weighed against the risk of
reinfection following treatment. However, the high-risk
of progression to severe disease, particularly for children
under 5, supports this approach for the pediatric age
group if resources allow.18
Recipients of BCG
In disease endemic countries, the majority receive
primary prevention through BCG vaccination during
infancy. Although BCG administration usually results in
a positive TST, the size of the reaction wanes with time.19
The relative merits of its use vis a vis TST are discussed
elsewhere in this text. Most authorities agree that a
positive TST result should be attributed to LTBI rather
than BCG if there are factors present such as a history of
contact with active TB, a family history of TB, residence
or migration from a region of high prevalence, increasing
time since BCG (> 5 years), and TST reaction > 15 mm3.
One or more of these factors are likely to apply to children
tested in resource-poor countries. Ultimately it is
important to remember that the TST result is only one
piece of information used to make a clinical decision about
treatment.
HIV Infection
The HIV epidemic has lead to a dramatic rise in the
number of adults developing active tuberculosis.
Although the impact on the TB incidence in children is
not as well documented, the relationship with HIV
appears to be a negative one in many respects. It has been
shown that LTBI in adults with HIV has a higher risk
of progression compared to HIV-negative individuals,

with an annual risk of disease of 5 to 10 %20. Therefore, it
comes as no surprise that in high-prevalence countries,
TB is a common disease in HIV-infected children.21 A
study in Zaire demonstrated the risk of tuberculosis in
HIV-infected women of child bearing age was three times
higher as compared to HIV-uninfected.22 Moreover, a
subnormal response to BCG compared to infants of HIVnegative mothers suggests an abnormality in immune
function that may also place them at increased risk of
tuberculosis.23 Older children with parents who are HIVinfected are also at increased risk since progression of
HIV disease has a negative impact on the financial wellbeing of the family. This in turn leads to poverty,
malnutrition, and overcrowding which are all factors that
increase the risk of exposure to TB.24
The high rate of progression to disease justifies the
low threshold to treat HIV-infected children for LTBI.
Given the high frequency of atypical and smear-negative
disease in this population,25 the distinction between latent
infection and disease in HIV infected children can be
difficult, particularly where diagnostic facilities are
limited. Minimum investigations include a careful
examination, TST, and CXR. While case-finding and
successful treatment of TB cases remains the highest
priority for tuberculosis programs in the setting of limited
resources, it has been suggested that preventive therapy
of individuals with dual HIV-TB infection may also
contribute to TB control. While the public health impact
of such a policy has been questioned,26 there is no doubt
regarding the benefit to the individual and probably even
more so for a young child than an adult. Regardless of
the decisions made by individual National TB programs
for HIV-infected individuals, it is clear that an integrated
approach between HIV/AIDS and TB control programs
is beneficial27 (Table 39.1.3).
Table 39.1.3: General recommendations for treatment of LTBI in children according to

tuberculosis program resources
Limited resources
Moderate resources
TST negative
TST positive
Age < 5 years or

immunocompromised
Treat for LTBI
Start treatment for LTBI,

repeat TST in 8-12 weeks.
If +ve, investigate for active
TB vs LTBI and treat
accordingly. If ve, stop
therapy unless immunecompromised
Investigate for LTBI vs active

disease. Treat according to
diagnosis.
Age > 5 years and not

Immunocompromised
Withhold
treatment
No treatment
Investigate for LTBI vs active

disease. Treatment of LTBI
depends on extent of resources
(See text)
Adapted from references 3, 4, 7, 8, and 16
TREATMENT OF LATENT TUBERCULOSIS INFECTION

Antimycobacterial Agents
Isoniazid
Isoniazid is the most widely used of the antituberculosis
agents. Initially, experimental studies were conducted in
the guinea-pig model using a daily dose of 5 mg/kg. This
regimen demonstrated the efficacy of isoniazid to prevent
active tuberculosis following infection.28 Subsequently,
a number of human studies, conducted in both industrialized and developing countries, have shown that
isoniazid is an effective agent in treatment of LTBI. A
single agent is sufficient to eradicate the infection given
by the relatively small population of Mycobacteria. For
latent tuberculosis recommended by Blumberg et al28a is
continuous 9 months isoniazid therapy. Randomized,
placebo-controlled trials around the world demonstrated
a protective efficacy of about 90% incompliant patients,
most of whom received isoniazid daily for a year.29
It was also found that as long as isoniazid was continued,
even if taken irregularly, a protective benefit was present.
Prolonged therapy has a negative impact on
compliance, therefore, shorter durations of treatment
have been investigated. While LTBI studies in Alaska
demonstrated maximal benefit was achieved by 6 to 12
months of therapy,30 subgroup analyses of adult trials
concluded that the maximal benefit of isoniazid is likely
to be achieved by 9 months.31 In an IUATLD study, adults
with stable fiberotic lesions on CXR were randomized to
3, 6, or 12 months courses of isoniazid or to placebo.
Tuberculosis cases were reduced by one-third, two-thirds
and ~90% respectively compared to placebo. Although
efficacy was lower for 6 compared to 12 months, hepatic
toxicity was also less, therefore, six months of INH is
considered as an acceptable regimen in adults.32 The
recommendations of major advisory groups for the
treatment of LTBI in HIV-uninfected children are 6
(WHO, IUATLD) to 9 (American Academy of Pediatric,
American Thoracic Society) months of isoniazid.
American organizations continue to recommend a
treatment duration of 9 months given the lack of data on
shorter-courses in the young, their very low rate of serious
adverse effects due to INH, and the greater lifetime risk
for reactivation disease.33 The Canadian Lung Association
recommends 6 to 9 months, but emphasizes the need for
good compliance if 6 months is given.4 Daily therapy is
the preferred schedule, but intermittent regimens (two
or three days per week) are acceptable alternatives if
provided as directly observed therapy (DOT).4,33
Rifampicin-Containing Regimens
Alternate antimyicobacterial agents have been explored,
principally in adults, due to concerns about multidrug
597
resistance, compliance with long treatment courses, and

adverse effects of INH. Rifampicin (RIF) is bactericidal
for slow-metabolizing, intracellular bacilli,34,35 which may
be particularly advantageous for treatment of infection
without disease. In addition it has a lower rate of
spontaneous mutations. Studies in HIV-negative adults
with silicosis have demonstrated efficacy with rifampicin
alone.36 Data for children remains limited, although a 6
months course has been studied in 157 adolescents with
no failures noted.37 Adverse effects such as anorexia,
nausea, fatigue and rash were not uncommon, occurring
in about one-quarter of teenagers studied, although < 5%
discontinued medication. Based on these data, rifampicin
for 6 to 9 months4,33 has been reserved as an alternate to
INH if there is intolerance or contraindications to its use,
or high-risk of an INH-resistant but RIF-susceptible
isolates. Rifampicin-containing combinations have also
been used in an effort to reduce the duration of therapy
and potentially improve compliance as a result. Shortcourses of multidrug therapy have been found highly
efficacious for smear/culturenegative pulmonary disease,
including both two and three months courses of isoniazid,
rifampicin, pyrazinamide and streptomycin.38 While
streptomycin is not likely to be of sufficient benefit to
offset the risk of adverse effects and noncompliance39 in
the treatment of LTBI, both isoniazid and pyrazinamide
have been studied in combination with rifampicin.
INH and RIF have been given in twice weekly doses
for 6 months as directly observed therapy in adult
Canadian aboriginal patients with LTBI and compared
with daily self-administered isoniazid for 12 months.
Although the rate of adverse effects was about three times
higher in the combination group, their completion rates
were much higher (82 vs. 19%) and rate of tuberculosis
was only one-tenth that of the monotherapy group.40 A
meta-analysis examined data from 5 studies of adult
patients with LTBI comparing RIF + INH for 3 months to
INH monotherapy for 6 to 12 months. The authors
concluded that the two approaches were equivalent in
terms of efficacy, proportion of severe adverse effects and
mortality.41
In the recently published guidelines of the Indian
Academy of Pediatrics, six months of chemoprophylaxis
(INH) is recommended for all under 6 years of age
contacts of an infectious case, irrespective of their BCG
or nutritional status. PPD positive children over 6 years
of age and who do not have any evidence of active disease
but are planned for immunosuppressive therapy (e.g.
children with nephrotic syndrome, acute leukemias, etc.)
may also be given the benefit of chemoprophylaxis. While
there is evidence that HR combination can make the
prophylaxis shorter (3 months) but the group does not
recommend this due to the risk of misuse of rifampicin.42
Pediatric support for short-course INH plus RIF
therapy is limited to observational data in a district of
598
England with a high incidence of TB. Starting in the early

1980s dual therapy for pediatric LTBI was introduced
and the duration gradually reduced from 9 to 3 months.
The reduction in pediatric cases noted after a program of
treatment for LTBI was instituted in 1981 has been
sustained in spite of the decreasing duration of therapy.
Although the results suggest that this approach may be
useful in children, the sample size and study design limit
the conclusiveness of the findings.43 In the details of these
studies it is claimed to be the largest programmatic
experience using rifampicin-based treatment of LTBI from
Blackburn, England, where children at increased risk of
TB have been treated daily with rifampicin/isoniazid
since 1981. During 1981-86, the treatment duration was
shortened from 9 to 3 months, and the proportion of
Pediatric TB case-patients as a percentage of all reported
cases decreased from 25 to 4%. It is not a controlled clinical
trial but the data suggested that this intervention has been
highly effective in reducing the rate of childhood TB in
this city. Thus this regimen is currently recommended
for the treatment of both adults and children with LTBI
in the United Kingdom.43,44
Rifampicin has also been combined with
pyrazinamide for a short 2 months course in adults with
LTBI. After efficacy and safety in HIV-infected
adolescents and adults was shown in a large trial
published in 2000,45 the combination was included as an
option in American recommendations. However, reports
of severe hepatotoxicity and some deaths in HIVuninfected persons were subsequently published and the
recommendations revised as a result.46,47 Although twice
weekly regimens for two and three months appear
promising, sample sizes were small and the comparison
groups used only 6 months of INH, therefore, it cannot
be recommended as an unequivocal regimen.48, 49
Increased rates of hepatitis in HIV-uninfected individuals
using this combination has been confirmed in other
geographic regions as well.50 Liver abnormalities have
not been related to underlying liver disease, alcohol use,
or viral hepatitis.51 Therefore, although the higher
completion rates are attractive, caution is advised both
for the HIV-infected using protease inhibitors or NNRTIs
as well as HIV-negative individuals. US guidelines for
HIV-negative adults suggest it to be considered for
contacts of isoniazid-resistant but rifampicin-susceptible
cases only.52-54 There is no data on the use of this
combination in children and its use is not recommended
at this time by major pediatric guidelines.33
Non-isoniazid/Rifamycin Combinations
Treatment of LTBI for contacts of isoniazid and
rifampicin-resistant cases is problematic, given that
treatment with 2 or more active drugs is desirable. A
combination of pyrazinamide and ethambutol for 9 to 12
months has been recommended if the isolate is susceptible

to both.55 (Table 39.4) Although traditionally ethambutol
has been avoided for children < 6 years, recent reports
suggest a dose of 15 mg/kg/day is safe and does not
require routine eye examinations.56 Seth et al57 evaluated
the visual evoked responses (VER) in children with
tuberculosis above the age of three years on ethambutol
therapy as one of the drug in the regimens these children
were on. The VER; both Amplitude and Latency were
evaluated before therapy, during therapy at, 3, 6, 9 and
12 months and 6 months after stoppage of ethambutol.
The study revealed no ocular toxicity. There is quite
extensive data now on the safety of use of ethambutol in
children.
New Therapy
Newer Rifamycins such as
Rifapentine and Rifabutin
These are highly active against M. tuberculosis with a long
half-life that has the advantage of potentially widely
spaced intermittent dosing. The optimal dose is being
studied, 58 but weekly administration appears to be
acceptable for rifapentine as part of a multidrug treatment
regimen for active disease. However, treatment failures
with once weekly rifapentine/isoniazid exceed those who
use twice-weekly isoniazid/rifampicin, and appears to
be related to low concentrations of isoniazid.59 Relapse
rates with rifabutin appear to be no different than those
with rifampicin in HIV-infected patients treated for active
TB.60 No specific data are available for treatment of LTBI
with rifapentine or rifabutin, but the latter is considered
an alternate drug to rifampicin, e.g. in some HIV-infected
patients as it has fewer interactions with antiretroviral
drugs. However, drug interactions are complex due to
effects on CYP450 and guidelines must be carefully
considered. There is no information on use of these agents
in children and, therefore, they are not considered options
for treatment of disease or LTBI at this time.
Fluoroquinolones
There are another drug class of interest in the treatment of
tuberculosis. While levofloxacin and ofloxacin are the most
commonly used at this time, newer agents such as
moxifloxacin and gatifloxacin are also being studied and
appear to have greater in vitro activity.61 Fluoroquinolones
have traditionally been avoided in young children due to
animal data suggesting deleterious effects on growing
cartilage. However, a review of human data suggests this
is not a concern, at least with ciprofloxacin and probably
levofloxacin.62 Nevertheless clinical studies of this class of
drugs are necessary to determine their relative safety and
utility in treating LTBI.
See Table 39.1.5
Rifampicin+
isoniazid
10-20
(600)
10-20
(300)
10-20
(600)
20-40
(900)
Dose
mg/kg (max)
Daily
Twice
weekly*
Duration
(months)
6
(9-12 if HIV+)
6-9
(9-12 if HIV+)
Daily
* All intermittent therapy should be administered under DOT.

Adapted from references 3,4
Ref. 3American Academy of Pediatrics recommendations, Red Book; 2003.
Ref. 4Canadian Lung Association5th edition Government of Canada; 2002.
Other
combinations
Multidrug resistant
cases
Intolerant to isoniazid;
Suspected/known
resistance to isoniazid
and pyrazinamide
intolerance
Rifampicin
Rifampicin+
pyrazinamide
Low risk of resistance
Indications
Isoniazid
Drug
9
(9-12 if HIV+)
9
(9-12 if HIV+)
Twice
weekly
Not recommended due

to adverse effects in
HIVadults and
lack of pediatric data.
Should be individualized
according to susceptibilities
of index case and discussed with a
pediatrician and TB expert.
Limited published data

on use. Not used
Routinely in nonendemic
countries. See text.
Contraindicated if using
protease inhibitors or
nonnucleoside reverse
transcriptase inhibitors
(HIV+).
Pyridoxine (vitamin B6)

if malnourished or
breastfed.
Comments
Table 39.1.4: Therapy for treatment of latent tuberculosis infection in children
599
600

Table 39.1.5: Indian Academy of Pediatrics working group
recommendations for preventive therapy in childhood
tuberculosis*
Indication for therapy
Treatment regimen
Asymptomatic TST
positive <3 years
Daily isoniazid
and rifampicin
for 6 months
Asymptomatic TST
positive <5 years with
grades III or
IV malnutrition
TST positive, recent

converter/no signs
(healed lesion-normal
CXR or calcification/fibrosis
Children <3 years with

household TB contact
Children <5 years,

grade III or IV malnutrition
with household TB contact
Indian Pediatr 1997;37:1093-6

See Table 39.1.4 for drug doses.
Use of Combination of Rifampicin and PZA

in Treating Latent TB
Tortazada et al68 have recommended that rifampicin and
pyrazinamide combination should only be considered for
treating latent tuberculosis when other regimens are
unsuitable and intensive monitoring of liver function is
feasible. Treatment interruption due to hepatotoxicity (ALT
and AST > 5 times of upper limit of normal) was observed
in 10% of contacts in 2RZ group and in 2.5% of the 6H group.
Idh et al69 assessed the kinetics of the QFN and initial
tuberculin test (TST) in relation to severity of disease in
tuberculosis (TB) endemic area. The TST, QFN, CD4+ cells
count and clinical symptoms (TB score) mere assessed
and followed up during treatment from baseline to 7
months of treatment, there was a significant decrease in
QFN activity (93.8% to 62.8% in HIVve 70.3% to 33.3%
in HIV-/TB patients) down to a level of control group of
blood donors (51.2%). QFN activity is significantly
reduced at the end of treatment against active TB to the
background level of healthy blood donors and the
agreement between TST of QFN is poor including
correlation to the severity of disease.
Discovery of Drugs Against Latent TB

The most ambitious objectives for anti-TB drug discovery
are to identify new drugs that effectively eradicate latent
TB infection and reduce chemotherapy of active disease
to 2 weeks. For this there is a need to kill those
subpopulations of M. tuberculosis that are not eliminated
efficiently with current antibiotics.
A project to study fundamental biology and drug

development strategies for latent tuberculosis (TB) was
initiated in 2005 as a part of a program to tackle grand
challenges in global health. The project was funded jointly
by the Bill and Melinda Gates Foundation and the
Welcome Trust, brought eight academic groups from four
continents with industrial expertise provided by Novartis
Institute for Tropical Diseases (NITD). The project focused
in particular the role of hypoxia in latent TB. They
organized three groups:
1. To characterize TB lesion in freshly resected lung
tissues in humans and nonhuman primates with
active and latent TB.
2. The second component is directed towards drugs
discovery.
3. The final component addresses strategies for the
evaluation of drugs with activity against hypoxic M.
tuberculosis by using positron emission tomography
(PET) and computed tomography (CT) imaging to
monitor the effect of drugs on individual lesions in a
nonhuman primate model.
Assessment of Drug Activity Against Latent TB

There are interesting data showing that the IFN- response
to M. tuberculosis antigens approximately halves during
drug treatment of latent TB. This decrease may mark
successful treatment with the chemotherapeutic
reduction in the number of bacteria corresponding to a
reduced necessity to mount an immune response. There
was an initial doubling of IFN- response at 1 month
possibly due to an increase in the antigen release
following bacillary death.
Lee et al70 have investigated the role of QFT-GIT
reversion on rifampicin prophylaxis in TB contacts. They
found that QFT-GIT reversions were achieved in 41.9%
of subjects (31/74) after 4 months of rifampicin treatment.
The serial test results suggest the possibility that the QFTGIT test may be useful to monitor the response to
rifampicin prophylaxis. However, the authors have
emphasized that further controlled studied with more
participants and long-term follow-up are required to
clarify these issues.
Toxicity
In order to be practically and ethically acceptable,
preventive therapies should have a low level of toxicity.
Motivating patients to undergo treatment in the semblance
of health is a challenging task. Multiple clinic visits, lengthy
waiting times and other operational factors complicate the
diagnostic process and a prolonged treatment course
further jeopardizes adherence. While a 5 to 10% lifetime
risk of progression to active disease has significant public
health implications, this must be weighed carefully against
the individuals risk of serious drug toxicity.

Although hepatic toxicity was not initially recognized
when isoniazid was first recommended in North America
in the mid-1960s, subsequent reports noted an association
with elevated hepatic transaminases as well as clinical
hepatotoxicity and several deaths.49,63,64 Risk of hepatic
toxicity is about 1%, but increases with age and alcohol
consumption.29,65 Hepatic failure due to isoniazid has
been rarely reported in the pediatric age group66 and
elevation of liver enzymes is also extremely uncommon.
Caution should be exercised in the presence of a past history
of adverse effects with isoniazid, concurrent medications
with potential hepatotoxicity, underlying liver disease, or
a prior diagnosis of hepatitis.33 Routine liver tests should
only be used in these patients as well as HIV-infected
and pregnant or postpartum adolescents. Otherwise
monthly monitoring for signs and symptoms of adverse
effects is considered sufficient.
Isoniazid neurotoxicity including peripheral neuritis,
optic neuritis, encephalopathy, seizures and other
symptoms is also uncommon in children. This results
from interference with niacin metabolism due to
isoniazid-induced pyridoxine (vitamin B6) deficiency.
While this is unusual in industrialized countries, it is an
important consideration for breastfeeding infants and
children at risk of malnutrition and dietary deficiency of
vitamin B6.67 Where the standard of health and nutrition
in a community is low, supplementary vitamin B6 is
recommended.71
Various adverse effects including gastrointestinal upset,
skin eruptions, hepatitis and rarely, thrombocytopenia are
associated with rifamycin therapy. In the Hong Kong study
of treatment of LTBI, monotherapy with rifampicin was not
associated with increased adverse reactions. Rifampicin
alone may be less hepatotoxic than isoniazid, but elevations
in hepatic transaminases and hepatotoxic reactions have
been noted when it is combined with either pyrazinamide72
or isoniazid.36
Drug Resistance
The treatment of LTBI is now complicated by the
emergence of drug resistant M. tuberculosis. The global
project on antituberculosis drug resistance surveillance
(DRS) reports rates of MDR-TB ranging up to 14% in
several Eastern European and Central Asian countries.73
Isoniazid treatment of LTBI has not been shown to
increase the risk of isoniazid-resistant tuberculosis
compared to controls if active disease is carefully
excluded.29 Individuals at increased risk for drug resistant
tuberculosis infection include those who are: (i) contacts
of a person with prior treatment for active TB; (ii) contacts
of someone with drug resistant contagious TB disease;
(iii) residents of areas where prevalence of drug-resistant
MTB is high; (iv) contacts of a source case with
601
smear-+ve or culture +ve disease after 2 months of

appropriate antituberculosis therapy.
Published data on treatment of MDR-LTBI in
children is very limited. A follow-up of preschool
children exposed to adults with MDR-TB in South Africa
compared 2 or more drugs based on the source cases
susceptibility pattern for 6 months to no therapy.
Untreated children were four times more likely to
progress to active disease (20% vs 5%).74 However, treatment duration and definitions of disease may have
negatively influenced the latter response rate.
No definitive data exists for the treatment of contacts
exposed to drug resistant TB, and there is disagreement
among experts about the optimal approach to MDR-TB
infection.75 Rifampicin and pyrazinamide combination
therapy or a longer course of rifampicin monotherapy is
recommended for contacts of isoniazid resistant cases. A
watch and wait approach is advocated by some for
immunocompetent adults exposed to MDR-TB, but for
those at higher risksuch as young children-tailor-made
regimens based on susceptibility pattern of the index-case
are suggested.76 Pyrazinamide plus ethambutol for 9 to
12 months is the combination suggested in American
guidelines for adults patients with MDR-LTBI,54 but if
the isolate is not susceptible to one or both of these, at
least 2 second line drugs to which the organism is sensitive
should be used.77 Although concerns about monitoring
for ocular toxicity in children have traditionally limited
the use of ethambutol, a review of the literature suggests
that ethambutol is considered safe in children of all ages at
a dose of 15 mg/kg.56 Even in young infants ethambutol
therapy can be monitored by recording visual evoked
responses (VER) as reported by Seth et al57 but at few
centers only and not as a routine.
Compliance
A major obstacle to the successful treatment of LTBI is
patient compliance. Reports indicate that compliance with
isoniazid in treating LTBI varies widely, although children
are slightly better than adult patients in one study
encompassing all age groups.78 Certainly this is suggested
by the 1990 findings of the Centers for Disease Control
(CDC), Atlanta, in which 63% of people overall completed
their course of preventive therapy, increasing to 76% when
only those < 15 years were considered. This suggests that
children may benefit from the greater attention some
parents pay to the well-being of their offspring than
themselves.
Unfortunately while efficacy increases with time, the
reverse is true for adherence.32 How does one convince
parents of the benefits of a prolonged course of
medication in a child who is not clinically ill, even if the
medication, e.g. isoniazid is relatively free of side effects?
602
Determinants of compliance to treatment of LTBI are

complex and not well understood.79 Motivation through
education and incentives are two means of addressing
this problem that have been studied.80,81 One New York
study in prisoners was able to demonstrate a significant
improvement in completion of preventive therapy as a
result of such efforts.82,83 Providers need to consider
other needs of the parents, i.e. travel costs, time away
from other children and work responsibilities. Even
drug dosages can be a further limiting factor, as
intermittent regimens involve the use of larger doses
which may be more difficult to administer to small
children.
Directly observed therapy (DOT) has been increasingly used as a major component of comprehensive
tuberculosis services to improve compliance. Ingestion
of each dose of medication is observed, which appears to
increase completion of therapy compared to selfadministered programs85 and may also be more cost
effective.86
HIGHLIGHTS
Children should be identified for treatment of
LTBI on the basis of risk factors determined
by epidemiologic factors and TST reaction.
Interpretation of this may vary with the use of BCG,
prevalence of nonmycobacterial infections, HIVinfection and malnutrition
Even in the absence of availability of skin test,
exposure history alone will determine the need for
treatment for presumed LTBI
Children < 5 years
Those infected with HIV
Treatment of LTBI in children should be undertaken
at least with 6 to 9 months of isoniazid
Rifampicin containing regimen maybe required in
situation of exposure to drug resistance
Future efforts in tuberculosis research should
include investigations and use of more than one drug
with shorter-treatment regimens.
39.2 SYMPTOMS-BASED SCREENING OF CHILD TUBERCULOSIS

CONTACTSIMPROVED FEASIBILITY IN RESOURCE LIMITED SETTINGS
Alexey Kruk, Robert P Gie, H Simon Schaff, Ben J Marais
INTRODUCTION
Preventing and treating tuberculosis (TB) in children is
often a low priority in TB-endemic countries.1 Although,
child TB cases are rarely recorded with accuracy, children
contribute substantially to the global TB disease burden.2
It is estimated that of the 8.3 million new TB cases
diagnosed in the year 2000, out of 884. These 019 (11%)
were children. 3 In high-income countries child TB
constitutes 2 to 7% of all TB cases and is mainly found
among immigrant populations; in low-income countries
child TB exists in close association with conditions of
poverty and constitutes 15 to 20% of all TB cases.3-6 An
autopsy study from Zambia found TB to be leading
respiratory cause of death among human
immunodeficiency virus (HIV)-infected and uninfected
children.7 In South Africa TB has been reported as the
third most common cause of death in HIV-infected
children admitted to hospital with a clinical diagnosis of
acute severe pneumonia,8 a community-based survey
recorded a child TB incidence of 407/100 000/year (in
children <13 years of age).9
The World Health Organization (WHO) and most
National TB Programs (NTPs) advise that all children less
than 5 years of age who are in close contact with a sputum

smearpositive source case should be screened for TB
diseae.10 These recommendations are motivated by the
increased risk of developing TB and the potential severity
of disease observed in young children.11 Once TB disease
has been excluded in these vulnerable children,
preventive chemotherapy should be provided to
eliminate the chance of developing latent infection and
to prevent progression to TB disease. The best-studied
preventive chemotherapy regimen, isoniazid (INH)
monotherapy for 6 to 9 months, reduces the risk of
developing TB disease in exposed children by at least twothirds and probably by more than 90% with good
adherence.12-14
Screening of child TB contacts has huge potential to
reduce the burden of pediatric TB worldwide. Although it
is universally recommended, it is rarely practiced in
resourcelimited settings.15 This discrepancy mainly results
from resource constraints that limit the availability of
tuberculin skin testing and chest radiography, often
regarded as prerequisite tests for adequate contact
screening.16,17 Lacking the capacity to perform mandatory screening tests, clinics in resource limited settings
rarely even attempt to provide preventive chemotherapy

to TB exposed children. WHO Guidance for National
Tuberculosis Programs on the Management of
Tuberculosis in Children no longer regard the tuberculin
skin test (TST) and/or chest radiograph (CXR) as
mandatory screening tests for all children in settings where
these tests are not readily available (Fig. 39.2.1).10 Although
access to preventive chemotherapy should be greatlyimproved by employing simple symptom-based screening,
the safety and feasibility of this approach have not been
evaluated in prospective studies. A single retrospective
study for South Africa demonstrated that symptom-based
screening may be useful to identify the subset of children
who require further investigation to exclude TB disease.
This would allow the majority of vulnerable contacts who
are asymptomatic at the time of screening to access
preventive chemotherapy without delay.18 However,
concerns have been raised regarding the safety of this
simplified approach. The study was aimed to evaluate the
safety and feasibility of applying a symptom-based
approach to exclude TB disease among children in
household contact with an adult TB index case.
A prospective observational study was conducted
from January 2004 through December 2004 in Cape Town,
South Africa. Children were recruited at 3 local clinics
served by Tygerberg Childrens Hospital as the referral
center. The study area is a well-established
epidemiological field site within a predominantly
colored community (people of mixed ethnicity) that
experience a high TB incidence (adult TB incidence 845/
100,000), 9 with a relatively low prevalence of HIV
infection19 (<10% of adult TB patients tested during 2004).
Local clinics provide general primary health care services
and coordinate the diagnosis and treatment of TB
patients, free of charge. Adult TB cases are identified by
Fig. 39.2.1: Suggested approach to contact management when chest

radiography and tuberculin skin testing are not readily available. Adapted
from the World Health Organization Guidance10
603
passive case finding and managed according to the

directly observed therapy, short-course (DOTS) strategy.
A TB source case was defined as an adult (> 15 years of
age) with pulmonary TB; diagnosed on sputum smear
and/or culture. Child household contacts were defined as
children less than 5 years of age living and sleeping in the
same house, or group of clustered houses on the same plot,
as a newly diagnosed TB source case. In accordance with
the South African National Tuberculosis Program (NTP)
guidelines,20 all children younger than 5 years in household
contact with a TB source case were assessed by
documenting symptoms suspicious of TB, as well as
tuberculin skin test (TST) an chest radiograph (CXR)
results. Children diagnosed with TB disease received
standard TB treatment as directly observed therapy (DOT);
2 months of 3 drugs (INH, rifampicin (RMP), and
pyrazinamide (PZA) followed by 4 months of 2 drugs
(INH, RMP), unless they were exposed to an index case
with known drug-resistant TB in which case individualized
treatment was provided. The treating clinician acted
independently from the research clinician. According to
current WHO recommendations,10 children without TB
disease received unsupervised INH monotherapy for 6
months, with monthly collection of tablets from the clinic.
All children in household contact with a newly
diagnosed tuberculosis (TB) source case (routinely
entered into the local TB register) were identified and
invited to the clinic for evaluation, during a home-visit
by the study social worker. At evaluation, study nurses
enquired about the presence of current symptoms (fever,
cough, wheeze, reduced playfulness/unusual fatigue, or
weight loss), performed a TST and arranged for a CXR to
be taken. Nurses recorded current symptoms using a
standard data capture document, irrespective of their
duration or character. This approach must be differentiated from the strict emphasis on well-defined symptoms
that have been promoted for symptom-based diagnosis.21,22 In TB-endemic areas, the presence of a persistent
non-remitting cough or wheeze for more than 2-4 weeks,
together with reduced playfulness/unusual fatigue and
documented failure to thrive provides good diagnostic
accuracy in immune-competent children.21,22 However,
for screening purposes the specificity of the test is less
relevant, but excellent negative predictive value is
essential to ensure optimal safety.
A Mantoux TST, using intradermal injection of 2
tuberculin units of purified protein derivative (PPD RT
23, Statens Serum Institute, Copenhagen, Denmark), was
performed on the volar aspect of the left forearm. The
transverse diameter of induration was measured in
millimeter after 48 to 72 hours; an induration of > 10 mm
(> 5 mm in HIV-infected children) provided a proxy for
M. tuberculosis infection. The diagnosis of TB disease was
primarily made on radiologic grounds. Chest radiographs
were read by the same expert who was blinded to all
604
clinical information; both anteroposterior and lateral

CXRs were performed. Findings were documented on a
standard report form and categorized as certain TB, or
certain not TB. All CXRs judged to be certain TB by
the first reader were read by a second independent expert.
Radiologically certain TB was defined as agreement
between both independent experts. TB disease manifestations were classified according to a recently proposed
radiologic classification of childhood intrathoracic TB.23
Written informed consent was obtained from the
parent/guardian in the home language of the patient. HIV
testing was not routinely performed, as the HIV
prevalence among children in this community is low.
Nevertheless, all children with symptoms suspicious of
HIV infection, known HIV exposure or a diagnosis of TB
disease were offered an HIV test, together with routine
pre-and post-test counseling. A rapid test was used to
screen for HIV infection (Determine HIV raid test,
Abbott, Tokyo, Japan); no confirmatory tests was required, as none of the children had a positive raid test. The
Western Cape Provincial Tuberculosis Program, the NTP
and the City of Cape Town Health Department were
consulted and their consent obtained. The University of
Stellenbosch Ethics Committee approved the study.
Data were entered into an Excel spreadsheet.
Descriptive analyses were done using SPSS (version 14,
SPSS Inc., Chicago, IL). The sensitivity, specificity and
negative predictive value (NPV) of using any current
symptom to screen for active TB were calculated.
Symptom frequencies recorded in those treated for TB
compared to those not treated for TB were compared
using the chi-squared test.
During the study period 357 adult TB cases [245
(68.6%) sputum smearpositive; 201 (56.3%) male, 218
(61.1% 15-40 years of age)] were identified; 195 (54.4%)
cases were sputum smear- and/or culture-positive cases
and in household contact with children aged less than 5
years; representing 187 households with 271 children (on
average 1.45 children < 5 years/household). Complete
information (symptoms, TST and CXR) was available in
252/271 (93.0%) children; included in the analysis. The
mean age of the children was 30 months (range 1-60
months). Of the child TB contacts included in the analysis,
240/252 (95.2%) were in contact with a sputum smearpositive and 12 (4.8%) with a sputum smearnegative
culture-positive source case. In total 136/252 (54.0%)
children had a positive TST, with a mean positive
induration of 18 mm (Table 39.2.1).
TB treatment was administered to 33 (13.1%) children;
25 (75.8%) were less than 3 years of age, 32 (97.0%) had
positive TST and 24 (72.7%) had a rapid HIV screening
test; all tested negative. Table 39.2.2 reflects the TB disease
manifestations recorded in the 27 children categorized
as certain TB; the majority (22/27, 81.5%) had
uncomplicated hilar adenopathy. The treating clinician
Table 39.2.1: Demographics of children in household

contact with an adult TB source case
Characteristics
Number (%)
Adult TB source cases (n = 197)

Sputum smear-positive
Sputum smear-negative
culture-positive
183 (93.8)
12 (6.2)
Household contacts
< 5 years of age (n = 271)
Children with complete data set
(symptoms, TST* and CXR)
252 (93.0)
Children included in the analysis

(n = 252)
Male
Age categories
Age < 1 year
Age 1-2 years
Age 3-5 years
54 (21.4)
106 (42.1)
92 (36.5)
TST* results
TST positive ( 10 mm induration)
136 (54.0)
TB treatment
Isoniazid (INH) preventive
chemotherapy
No preventive therapy (received
INH within the preceding year)
Treated for TB disease
141 (56.0)
217 (86.1)
2 (0.8)
33 (13.1)
* TSTTuberculin skin test
Table 39.2.2: Radiographic disease manifestations

recorded in child TB contacts
TB disease manifestation
Number (%)
Not TB
Uncertain TB
Treated as TB*
Certain TB
211 (83.7)
14 (6.0)
6/14 (42.9)
27 (10.7)
Certain TB n = 27
Uncomplicated lymph node disease
Complicated lymph node disease
- parenchymal consolidation
- airway compression
Lung cavity
Pleural effusion
22 (81.5)
2 (7.4)
1(3.7)
1(3.7)
1(3.7)
* The treating clinician initiated TB treatment in 6 children with

uncertain TB all had positive TST (mean 19 mm) and had
either suggestive symptoms or were less than 3 years of age.
initiated TB treatment in 6 children with uncertain TB;

all had a positive TST (mean 19 mm) and 4 had suggestive
symptoms, their average age was less than 3 years (35
months). None of the other children with uncertain TB
developed symptoms suspicious of TB while on
preventive therapy.
605

Table 39.2.3: Comparing symptoms reported in child TB contacts treated for TB versus those not treated for TB
Symptoms
Total
N=252(%)
Treated for TB
N=33(%)
Not treated for TB

N=219(%)
Odds Ratio
(95%C1#)
Cough
Fever
Weight loss*
Fatigue
Any symptom
62 (24.6)
14 (5.6)
19 (7.5)
16 (6.3)
76 (30.2)
18 (54.5)
6 (18.2)
10 (30.3)
6 (18.2)
25 (75.8)
44 (20.1)
8 (3.7)
9 (4.1)
10 (4.6)
51 (23.3)
4.8 (2.1-10.9)
5.9 (1.7-20.6)
10.1(4.8-59.5)
4.6 (1.4-15.4)
10.3 (4.1-26.6)
# 95% C195% Confidence Interval

* Weight loss Weight loss of flattening of growth trajectory documented on the road to health card
Table 39.2.4: The value of symptom-based screening to exclude TB disease in child TB contacts: calculations done
using different case definitions for TB disease
Different case definitions
Case definition 1
All children treated for TB
Case definition 2
All children with Certain TB on chest radiograph
Case definition 3#
All children with Certain TB on chest radiograph,
excluding those with asymptomatic hilar adenopathy
Sensitivity (%)
Specificity (%)
NPV (%)
25/33 (75.8)
168/219 (76.7)
168/176 (95.5)
22/27 (81.5)
170/225 (75.6)
170/175 (97.1)
22/22 (100)
175/230 (76.1)
175/175 (100)
NPV*negative predictive value

#
This case definition demonstrates that the only cases missed by symptom-based screening were children with uncomplicated
hilar adenopathy on chest radiography, which indicates recent primary infection
Symptoms recorded at the time of screening are

reflected in Table 39.2.3. Children completely asymptomatic were 176 (69.8%). Subjective weight loss was reported
in 43 (16.7%) children, but failure to thrive was documented
on the road to health card in only 19 (7.4%) cases; 10 of
whom were treated for TB. Among those not treated for
TB, worm infestation with iron deficiency anemia and/or
food insecurity were regarded as the most common causes
of failure to thrive, as children responded well to deworming and food supplementation. A cough was the most
common symptom recorded in those treated for TB, being
present in 18/33 (54.5%), but it was present in 44/244
(19.6%) children not treated for TB as well; 21 had perihilar streakiness indicative of possible viral infection and
2 had symptoms and signs suggestive of bacterial
pneumonia.
Of the children treated for TB, 25/33 (75.5%) reported
symptoms at the time of screening. All 5 children with
radiographic signs other than uncomplicated hilar
adenopathy were symptomatic, 3 with airway compression
reported cough and fever (2 had documented weight loss
as well), 1 with pleural effusion reported fever and fatigue,
1 with parenchymal cavitation reported cough, fatigue and
weight loss. On CXR the 8 asymptomatic children all had
uncomplicated hilar adenopathy, 6 with certain TB and
2 with uncertain TB; 5 were less than 3 years of age.
Table 39.2.4 indicates the diagnostic value of symptombased screening to exclude TB disease in children TB
contacts. The negative predictive value of symptom-based
screening varied according to the case definition used,
95.6% when using all treated for TB, 97.2% when only
children with radiologic certain TB were included, and
100% if the case definition excluded those with
asymptomatic uncomplicated hilar adenopathy.
Nurses reported that symptom-based screening was
quick and easy to perform. TST requires refrigeration of
the PPD, a diabetic needled syringe and appropriate
expertise on the part of the study nurse to place and
interpret the test result correctly. Performing a TST is time
consuming, especially when taking into consideration the
need to record the result at a second visit 2-3 days later.
CXR was done at the local day and/or referral hospital.
It places a considerable additional workload on radiography services, particularly at the local day hospital, as
evidenced by the fact that their annual stock of child
radiograph negative was depleted within 3 months.
Although, it was not accurately quantified, parents/
caregivers spent a considerable amount of time to get the
required tests done, especially when they were dependent
on public transport.
This prospective community-based study demonstrates that screening for TB disease is feasible using a
606
symptom-based approach. Employing a simplified

approach has particular relevance in TB-endemic settings
with limited resources, where TST and CXR are not
readily available. In our study more than two thirds of
child TB contacts were completely asymptomatic at the
time of screening and would have required no further
tests to exclude TB disease. Although 8/33 (24.2%)
children treated for TB during the study were completely
asymptomatic, all these children had uncomplicated hilar
adenopathy detected on CXR only. The natural history
of TB in children demonstrates that transient hilar
adenopathy is a common finding following recent
primary infection. According to the pre-chemotherapy
literature only a small percentage of these children are
likely to develop progressive disease, which would be
accompanied by clinical symptoms.11 This suggests that
asymptomatic hilar adenopathy is a natural component
of the primary (Ghon) complex, reflecting recent M.
tuberculosis infection rather than active TB disease.11,12,23
By convention asymptomatic hilar adenopathy is
currently treated as TB disease in most countries. The
current study was unable to evaluate the risk of providing
INH monotherapy to children with asymptomatic hilar
adenopathy, as all these children received full TB
treatment. However, early experience with INH monotherapy (the US Public Health trials of the 1950s and
1960s) demonstrated that preventive chemotherapy
should be sufficient in these cases.12 From a public health
perspective it is important to balance the minimum
potential risk experienced by children with asymptomatic
hilar adenopathy receiving INH monotherapy, with the
high disease risk of not providing any preventive therapy
to TB exposed children, due to an inability to screening
for TB disease. Insistence that TST and CXR are
mandatory screening tests, severely limits the access
of child TB contacts to preventive chemotherapy,
especially in resource-limited settings where children are
most likely to be exposed to TB at a young and vulnerable
age.17 The most important benefit demonstrated is the
fact that less than one third of child TB contacts reported
symptoms that required additional investigation to
exclude TB disease. This implies that the majority of
young and vulnerable children can receive preventive
chemotherapy without delay, the excellent negative
predictive value achieved (up to 100% with the exclusion
of asymptomatic hilar adenopathy) also indicates that
symptom-based screening seems to be safe.
In addition, any child who develops symptoms
suggestive of TB, even after the provisional preventive
chemotherapy, should be evaluated to exclude TB
disease. This provides a safety net for those children in
whom INH monotherapy may be ineffective. Another
concern that is frequently mentioned is the risk of
encouraging the development and spread of INH
resistance. While this may be valid concern in adults who
receive INH monotherapy without adequately ruling out
TB disease, it is less of a concern in children. Children

tend to develop pauci-bacillary disease, which reduces
the likelihood of transmission and the risk of acquiring
drug resistance. Asymptomatic children would have even
lower bacillary loads, posing a negligible risk of acquiring
INH resistance. A positive TST result provides proof of
M. tuberculosis infection, but it is less reliable in very
young, malnourished and/or immune compromised
children and may take up to 3 months to convert.24 Its
main clinical applications would be to identify latent TB
infection (LTBI) in vulnerable groups (e.g. in oncology
patient prior to the initiation of chemotherapy) and to
provide supportive evidence for a TB case definition in
symptomatic children. Due to delayed TST conversion
TB infection can only be reliably excluded in immune
competent children 3 months after TB exposure ended,
which explains why the American Thoracic Society (ATS)
guidelines utilize the 3 months TST result to guide early
termination of preventive chemotherapy.25 In resourcelimited settings where TST is not routinely available, the
benefit versus cost (including nursing time, patient time,
transport costs, and inappropriate management due to
misinterpretation) should be carefully considered. It seems
important to prioritize CXR access as the diagnostic test
of preference to exclude TB disease in symptomatic
children;15,26 the yield in this group of children was high
(22/76, 28.9%). In the absence of objective diagnostic tests
to confirm TB disease, symptom-based diagnosis may be
considered, but this requires a strong emphasis on careful
symptom definition for improved diagnostic
accuracy.21,22
The reality in most TB-endemic areas is that curative
TB services are already overburdened and clinics cannot
spare the resources required to screen and treat child TB
contact. Implementing a simple symptom-based approach
makes screening far more feasible. Feasibility may be
further improved by restricting the focus to those children
who stand to benefit most from the provision of preventive chemotherapy. The natural history of disease
demonstrated that very young (<3 year of age) and/or
immune-compromised children are at highest risk to
develop TB disease following exposure.11 In our study,
16/22 (72.7%) children who met the case definition of TB
disease were less than 3 year of age, including all the
children with complicated disease. Although, TB disease
should be excluded in any child with symptoms
suspicious of TB, restricting the provision of preventive
chemotherapy to those at highest risk following TB
exposure (<3 years and/or immune-compromised) will
drastically reduce the additional load on already
overburdened health care services; 36.5% of child TB
contacts in this study were older than 3 years of age.
Due to its cross sectional design we are unable to
comment with certainty on the safety of symptom-based
screening, however, ongoing disease surveillance
continued in 2 of the 3 study clinics. Only 2 children who

received preventive chemotherapy presented with TB
disease during the following year; both were less than 3
years of age and reported poor adherence to preventive
chemotherapy, only collecting tablets once. Additional
study limitation include potential recall bias and reporter
subjectivity, these influences were limited by the focus
on current symptoms and the use of standardized datacapture forms that were completed prior to TST and CXR
evaluation. Investigator bias was further limited by the
fact that radiographs were reviewed by independent
experts blinded to all clinical information.
None of the children in this study were known to be
HIV-infected, which limits our ability to reflect on this
group. It seems reasonable to expect that the complete
absence of symptoms would still exclude TB disease,
although a smaller percentage of HIV-infected children is
expected to be completely asymptomatic at any point in
time. In addition, we cannot comment on the safety of using
INH monotherapy in HIV-infected children with
asymptomatic hilar adenopathy. WHO advises routine
HIV testing of all children with symptoms suspicious of
TB in countries with a high HIV prevalence; this
recommendation should be included in national TB
guidelines as well.10
We collected limited source case information, but
previous studies from Africa described an increased
transmission risk depending on sputum smear grading
and if the source case is the mother/primary care giver
of the child.15,27 Data were collected by well-trained
research nurses and it is uncertain if the findings would
be similar in routine clinical care, however, symptom
enquiry relied on five simple questions and responses
were captured on a standardized data capture sheet that
would be easy to implement. A remaining challenge
is poor adherence to unsupervised preventive
chemotherapy.28,29 The development of short-course
regimens and the implementation of other measures to
improve adherence to preventive chemotherapy requires
further evaluation.12,27-30
The finding of the study support current WHO
recommendations that encourage symptom-based screening
of child TB contacts in TB-endemic areas with limited
resources; most importantly, strategies with improved
feasibility should improve access to preventive chemotherapy
for those children at greatest risk to develop TB disease.
HIGHLIGHTS
National Tuberculosis (TB) Programs in TB-endemic
countries rarely implement active tracing and
screening of child TB contacts, mainly due to
resource constraints
It is important to evaluate the safety and feasibility
of applying a simple symptom-based approach to
screen child TB contacts for active disease
607
All children < 5 years old in household contact with

an adult TB source case should be assessed by
documenting current symptoms, tuberculin skin test
and chest radiograph results
Current WHO recommendations, demonstrating
that symptom-based screening of child TB contacts
should improve feasibility in resource-limited
settings and seems to be safe.
REFERENCES
Latent Tuberculosis in Children and Adolescents
1. Curtis AB, Ridzon R, Vogel R, et al. Extensive
transmission of M. tuberculosis from a child. N Engl J Med
1999;341:1491-5.
2. American Thoracic Society and Centers for Disease
Control and Prevention. Targeted Tuberculin Testing and
Treatment of Latent Tuberculosis Infection. Am J Respir
Crit Care Med 2000;161:S221-47.
3. American Academy of Pediatrics. Tuberculosis. In:
Pickering L, (Ed). Red Book: 2003; Report of the
Committee on Infectious Diseases. Elk Gove Village, IL;
2003;642-60.
4. Canadian Lung Association/Canadian Thoracic Society,
Health Canada. Canadian Tuberculosis Standards. 5th ed.
Government of Canada, 2000.
5. Joint Tuberculosis Committee of the British Thoracic
Society. Control and prevention of tuberculosis in the
United Kingdom: Code of Practice 2000; Thorax
2000;55:887-901.
6. Mazurek GH, Villarino ME. Guidelines for using the
QuantiFERON-TB test for diagnosing latent Mycobacterium
tuberculosis infection. MMWR 2003; 52[RR-2]: 15-8
7. Treatment of tuberculosis: Guidelines for national
programmes (3rd edn). Geneva: World Health
Organization, 2003.
8. Enarson DA, Rieder HL, Arnadottir T, et al. IUATLD.
Management of tuberculosis. A guide for low-income
countries (5th edn). Paris 2000; IUATLD, 2000.
9. Borgdorff MW, Floyd K, Broekmans JF. Interven-tions to
reduce tuberculosis mortality and transmission in lowand middle-income countries. Bull WHO 2002;80:217-27.
9a. Nguyen TH, Odermatt P, Sleasak G, et al. Risk of
latenttuberculosis infection in children living in
households with tuberculosis patients a cross sectioned
survey in remote northern Lao peoples democratic
republic. MBC Infectious Disease 2009;9:96-105.
9b. Clark JE. Lessons of the week. Pitfalls in contact tracing
and early diagnosis of childhood tuberculosis. BMS 1996;
313: 221-2.
9c. Barry 3rd CE, Boshaff HI, Dortois V, et al. The spectrum
of latent tuberculosis rethinking the biology and
intervention strategy. Nature reviews Microbiology/
AOP, published online 26 t h October, 2009;
do1:10.1038/nrmicro 2236.
9d. Latorre I, Souza-Galvao MD, Ruizmanzano J, et al.
Quantitative evaluation of T- cell response after specific
antigen stimulation in active and latent tuberculosis
infection in adults and children. Diagnostic microbiology
608
9e.
10.
10a.
10b.
10c.
11.
12.
13.
13a.
14.
15.
16.
17.
18.
19.
20.
and infectious disease do1:10.1016/J. diagmicrobio.

2009.07.015.
Hussain R, Talat N, Shahid F, et al. Biomarker changes
associated with tuberculin skin test (TST) conversion: A
two-year longitudinal follow up study in exposed
household contacts. PLOS one/ www.plosone.org.oct
2009, volume 4 / issue10/e7444.
Lucas M, Nicol P, Mckinnon E, et al. A prospective largescale study of methods for the detection of latent M.
tuberculosis infection in refugee children. Thorac 2010; 65:
442-8.
Leung CC, Yam WC, Yew WW, et al. T-spot. TB
outperforms tuberculin skin test in predicting tuberculosis
disease. Korean J Lab Med 2010; 30: 171-7.
Pai M and OBrien MD. New diagnostics for latent and
active tuberculosis: state of the art and future prospects.
Semin Respir Crit Care Med 2008; 29: 560-8.
Yoshiyama T, Harada N, Higuchi K, et al. use of the
QuantiFERON-TB Gold test for screening tuberculosis
contacts and predicting active disease. Resprology 2010;
15: 220-40.
Andresen P, Doherty TM, Pai M, et al. The prognosis of
latent tuberculosis. Can disease be predicted? Trends Mol
Med 2007; 30: 8.
Tayler REB, Corrt AS, Clark JE. Potential effect of NICE
tuberculosis screening. Arch Dis Child 2008; 93: 200-03.
Menzies D, Pai M and Comstock G. Meta-analysis: New
tests for diagnosis of latent tuberculosis infections. Areas
of uncertainty and recommendations for research. Ann
Int Med 2007; 146: 340-54
Armicosanate M, Ciccozzi M, Markova R. Rational use of
immunodiagnostic tools for tuberculosis infection:
guidelines and cost effectiveness studies. New Microbiol
2010; 33: 93-107.
Mori T, Sakatani M, Yamagishi F, et al. Specific detection
of tuberculosis infection. Am J Respir Crit Care Med
2004;170:59-64.
Brock I, Weldingh K, Lillebaek T, et al. Comparison of
tuberculin skin test and new specific blood test in
tuberculosis contacts. Am J Respir Crit Care Med
2004;170:65-9.
Ferrara G, Losi M, Meacci M, et al. Routine hospital use
of a commercial whole blood interferon-gamma assay
for tuberculosis infection. Am J Respir Crit Care Med Jun
16, 2005; personal communication.
Hoeppner V, Marciniuk D, Hershfield E. Treatment of
tuberculosis disease and infection. In: Long R, (Ed).
Canadian Tuberculosis Standards. Canadian Lung
Association and Health Canada, 2000:83-109.
Comstock GW. Prevention of tuberculosis among
tuberculin reactors: Maximizing benefits, minimizing
risks. JAMA 1986;256:2729-30.
Seth Vimlesh, Kukreja N, Sundaram KR, et al. Waning of
cell-mediated immune response in preschool children
Selwyn PA, Hertel D, Lewis VA, et al. A pros-pective
study of the risk of tuberculosis among intravenous
drug users with human immuno-deficiency virus
infection. New England Journal of Medicine 1989;320:
545-50.
21. Shah SR, Tullu MS, Kamat JR. Clinical profile of pediatric
HIV infection from India. Archives of Medical Research
2005;36:24-31.
22. Braun MM, Badi N, Ryder RW, et al. A retros-pective
cohort study of the risk of tuberculosis among women of
childbearing age with HIV infection in Zaire. Am Rev
Respir Dis 1991;143: 501-4.
23. Msellati P, Dabis F, Lepage P, et al. BCG Vaccination and
pediatric HIV infection - Rwanda 1988-90. Morbidity and
Mortality Weekly 1991; 40:833-4.
24. Datta M, Swaminathan S. Global aspects of tuberculosis
in children. Pediatr Respir Rev 2001; 2:91-6.
25. Barnes PF, Block AB, Davidson TP, et al. Tuberculosis in
patients with human immuno-deficiency virus infections.
N Engl J Med 1991; 324:1644-8.
26. Guwatudde D, Debanne SM, Diaz M, et al. A reexamination of the potential impact of preventive therapy
on the public health problem of tuberculosis in
contemporary sub-Saharan Africa. Prev Med
2004;39:1036-46.
27. World Health Organization. Report of a lessons learnt
workshop on the six ProTEST pilot projects in Malawi,
South Africa and Zambia 2004;1-42. Geneva, World
Health Organization.
28. Ferebee SH, Palmer CE. Prevention of experi-mental
tuberculosis with isoniazid. Am J Respir Crit Care Med
1956;73:1-18.
28a. Blumberg HM, Leonard MK Jrand, Jasmer RM. Update
on the treatment of tuberculosis and latent tuberculosis.
JAMA 2005; 294: 182
29. Ferebee SH. Controlled chemoprophylaxis trials in
tuberculosis. A general review. Adv Tuberc Res
1969;17:29-106.
30. Comstock GW, Ferebee SH. How much isoniazid is
needed for prophylaxis. Am Rev Respir Dis 1970;101:
780-2.
31. Comstock GW. How much isoniazid is needed for
prevention of tuberculosis among immunocompetent
adults? Int J Tuberc Lung Dis 1999;2:847-50.
32. International Union Against Tuberculosis CoP. Efficacy
of various durations of isoniazid preventive therapy for
tuberculosis: Five years of follow-up in the IUAT trial.
Bull WHO 1982;60: 555-64.
33. Pediatric Tuberculosis Collaborative Group. Targeted
tuberculin skin testing and treatment of latent
tuberculosis infection in children and adolescents.
Pediatrics 2004;114: 1175-1201.
34. Jindal A, Aber VR, Edwards EA, et al. The early
35. Michison DA. The action of antituberculous drugs in
short-course chemotherapy. Tubercule 1956;66:
219-25.
36. Hong Kong Chest Service/Tuberculosis Research Centre.
A double-blind placebo-controlled clinical trial of three
antituberculosis chemoprophylaxis regimens in patients
with silicosis in Hong Kong. Am Rev Respir Dis
1992;145:36-41.
37. Villarino ME, Ridzon T, Weismuller PC, et al. Rifampicin
preventive therapy for tuberculosis infection: Experience
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
with 157 adolescents. Am J Respir Crit Care Med

1997;155:1735-8.
Hong Kong Chest Service/Tuberculosis Research Centre.
A controlled trial of 2 months, 3 months, and 12 months
regimens of chemotherapy for sputum smear-negative
pulmonary tuberculosis. Am Rev Respir Dis 1984;130:
23-8.
Side effects of drug-regimens used in short-course
chemotherapy for pulmonary tuberculosis. A controlled
clinical study. Tubercule 1980;61:41-9.
McNab BD, Marciniuk DD, Alvi RA, et al. Twice weekly
isoniazid and rifampicin treatment of latent tuberculosis
infection in Canadian plains aborigines. Am J Respir Crit
Care Med 2000;162: 989-93.
Ena J, Valls V. Short-course therapy with rifampicin plus
isoniazid, compared with standard therapy with
isoniazid, for latent tuberculosis infection: A metaanalysis. Clin Infect Dis 2005;40:670-6.
Working Group On Tuberculosis, Indian Academy of
Pediatrics (IAP). Consensus Statement on Childhood
Tuberculosis. Indian Pediatr 2010; 47: 41- 55.
Ormerod LP. Rifampicin and isoniazid prophylactic
chemotherapy for tuberculosis. Arch Dis Child
1998;78:169-71.
Joint Tuberculosis Committee of the British Thoracic
Society. Chemotherapy management of tuberculosis in
the United Kingdom. Thorax 1998; 53:536-48.
Gordin F, Chaisson RE, Matts JP, et al. Rifampicin and
pyrazinamide vs. isoniazid for prevention of tuberculosis
in HIV-infected persons: An international randomized
trial. JAMA 2000;283:1445-50.
Update: Fatal and severe liver injuries associated with
rifampicin and pyrazinamide treatment for latent
tuberculosis infection. Morb Mortal Wkly Rep
2002;51:998-9.
Drug therapy in non-HIV infected person Tortajada C,
Martinez-Lacasa J, Sanchex F, et al. Tuberculosis
Prevention Group. Is the combination of pyrazinamide
plus rifampicin safe for treating latent tuberculosis
infection in person not infected by the human immunodeficiency virus? Int J Tuberc Lung Dis 2005;
9: 236.
I dh J, Abate E, Westman A, et al. Kinetics of the
QuantiFERON(R)-TB Gold in-Tube test during treatment
of patients with sputum-smear tuberculosis in relation
to initial TST result and severity of disease. Int J Tuberc
Lung Dis 2010; 14: 819-27.
Update: Fatal and severe liver injuries associated with
rifampicin and pyrazinamide for latent tuberculosis
infection, and revisions in American Thoracic Society/CDC
Recommendations - United States, 2001. Morb Mortal Wkly
Rep 2001; 52:735-9.
Lee SH, Lew WJ, Kim HJ, et al. Serial interferon-gamma
release assays after rifampicin prophylaxis in a
tuberculous outbreak. Resp Med 2009; 20: 1-6.
Mwinga A, Hosp M, Godfrey-Faussett P, et al. Twice
weekly tuberculosis preventive therapy in HIV infection
in Zambia. AIDS 1998;12:2447-57.
Halsey NA, Coberly JS, Desormeaux J, et al. Rifampicin
and pyrazinamide vs. isoniazid for prevention of
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
609
tuberculosis in HIV-1 infected persons: An international

randomized trial. Lancet 1998;351:786-92.
Tortajada C, Martinez-Lascasa J, Sanchez F, et al. Is the
combination of pyrazinamide plus rifampicin safe for
treating latent tuberculosis infection in persons not
infected by the human immuno-deficiency virus? Int J
Stout JE, Engemann JJ, Cheng CC, et al. Safety of 2
months of rifampicin and pyrazinamide for treatment
of latent tuberculosis. Am J Respir Crit Care Med
2003;167:824-7.
Centers for Disease Control. Management of persons
exposed to multidrug resistant tuber-culosis. MMWR
Recomm Rep 1992;41[(RR1)]: 61-71.
Trebucq A. Should ethambutol be recommended for
routine treatment of tuberculosis in children? A review of
the literature. Int J Tuberc Lung Dis 1997;1:12-5.
Seth Vimlesh, Khosla PK, Semwal OP, et al. Visual evoked
responses in tuberculosis children on ethambutol therapy.
Sirgel FA, Fourie PB, Donald PR, et al. The early
bactericidal activities of rifampicin and rifapentine in
pulmonary tuberculosis. Am J Respir Crit Care Med
2005;172:128-35.
Weiner M, Burman W, Vernon A, et al. Low isoniazid
concentrations and outcome of tuber-culosis treatment
with once-weekly isoniazid and rifapentine. Am J Respir
Crit Care Med 2003;167: 1341-7.
Li J, Munsiff SS, Driver CR, et al. Relapse and acquired
rifampicin resistance in HIV-infected patients with
tuberculosis treated with rifampicin- or rifabutin-based
regimens in New York City, 1997- 2000. 2005; Clin Infect
Dis 41: 83-91.
Sulochana S, Rahman F, Paramasivan CN. In vitro activity
of fluoroquinolones against Mycobacterium tuberculosis. J
Chemother 2005;17:169-73.
Schaad U. Use of the quinolones in pediatrics. Drugs
1993;45(suppl 3):37-41.
Mitchell JR, Zimmerman JH, Ishak KG, et al. Isoniazid
liver injury: Clinical spectrum, pathology and probably
pathogenesis. Ann Intern Med 1976; 84:181-92.
Garibaldi RA, Drusin RE, Ferebee SH, et al. Isoniazidassociated hepatitis. Report of an outbreak. Am Rev
Respir Dis 1972;106:357-65.
Kopanoff DE, Snider DE, Caras GJ. Isoniazid-related
hepatitis. Am Rev Respir Dis 1978;117: 991-1001.
Palusci VJ, OHare D, Lawrence RM. Hepato-toxicity and
transaminase measurement during isonizaid
chemoprophylaxis in children. Pediatr Infect Dis J
1995;14:144-8.
Snider DE. Pyridoxine supplementation during isoniazid
therapy. Tubercule 1980;61:191-6.
Tortajada C, Martinez-Lacasa J, Sunchex F, et al. Drug
therapy in non-HIV infected person. Int J Tuberc Lung
Dis 2005;9:236.
Idh J, Abate E, Westman A, et al. Kinetics of quantiFERON(R)-TB Gold in tube test during treatment of
patients with sputum-smear tuberculosis in relation to
initial TST result of severity of disease. Int J Tuberc Dis 2010;
14:819-27.
610

70. Lee SH, Lew WJ, Kim HJ, et al. Serial interferon-gamma
release assays after rifampicin prophylaxis in a
tuberculosis outbreak. Resp Med 2009; 20: 1-6.
71. World Health Organization Tuberculosis Programme.
Treatment of tuberculosis: Guidelines for National
Programmes, 1993.
72. Geiter LJ, OBrien RJ, Kopanoff DE. Short-course
preventive therapy for tuberculosis. Am Rev Respir Dis
1990;141(part 2):A437.
73. World Health Organization. Anti-tuberculosis drug
resistance in the world. Third global report, 2004.
children in contact with adult multidrug resistant
pulmonary tuberculosis: A 30-month follow-up.
Pediatrics 2005;109:765-71.
75. Passannante MR, Gallagher CT, Reichman LB. Preventive
therapy for contacts of multidrug resistant tuberculosis:
a Delphi survey. Chest 1994; 106:431-4.
76. Frieden TR, Sterling T, Pablos-Mendez, et al. The
emergence of drug resistant tuberculosis in New York
City. N Engl J Med 1993;328:521-6.
77. Swanson DS, Starke JR. Drug resistant tuber-culosis in
pediatrics. Pediatr Clin North Am 1997; 42: 553-81.
78. Reichler MR, Reves R, Bur S, et al. Treatment of latent
tuberculosis infection in contacts of new tuberculosis
cases in the United States. South Med J 2002; 95: 414-20.
79. Sumartogo E. When tuberculosis treatment fails: A social
behavioral account of patient adherence. Am Rev Respir
Dis 1993; 147: 1311-20.
80. Morisky DE, Malotte CK, Choi P, Davidson P, et al. A
patient education program to improve adherence rates
with antituberculosis drug regimens. Health Educ Q 1990;
17: 253-67.
81. White MC, Tulsky JP, Reilly P, et al. A clinical trial of a
financial incentive to go to the tuberculosis clinic for
isoniazid after release from jail. Int J Tuberc Lung Dis
1998; 2[506]: 512.
82. Alcabes P, Vossenas P, Cohen R, et al. Compliance with
isoniazid prophylaxis in jail. Am Rev Respir Dis 1989; 140:
1196-7.
83. Scientific Committee on Tuberculosis Treatment of
Disease. Tuberculosis in children: Guidelines for
diagnosis, prevention and treatment. Bull IUATLD 1991;
66: 61-6.
84. Nazar-Stewart V, Nolan CM. Results of a directly
observed intermittent isoniazid preventive therapy
programme in a shelter for homeless men. Am Review
Respir Dis 1992; 146: 57-60.
85. Gourevitch MN, Alcabes P, Wasserman WC, et al. Costeffectiveness of directly observed chemoprophylaxis of
tuberculosis among drug users at high risk for
tuberculosis. Int J Tuberc Lung Dis 1998; 2: 531-40.
Symptom-Based Screening of
Child Tuberculosis Contacts
1. Starke JR. Childhood tuberculosis: Ending the neglect.
2. Walls T, Shingadia D. Global epidemiology of pediatric
tuberculosis. J Infect 2004; 48: 13-22.

4. Marais BJ, Obihara CC, Warren RW, et al. The burden of
childhood tuberculosis: A public health perspective. Int
J Tuberc Lung Dis 2005; 9: 1305-13.
5. Murray CJ, Styblo K, Rouillon A. TB in developing countries:
Burden, intervention, and cost. Bull Int Union Tuberc Lung
Dis 1990; 65: 6-24.
6. Donald PR. Childhood tuberculosis: Out of control? Curr
Opin Pulm Med 2002; 8: 178-82.
7. Chintu C, Mudenda V, Lucas, et al. Lung diseases at
necropsy in African childern dying from respiratory
illnesses: A descriptive necropsy study. Lancet 2002; 360:
985-90.
8. Jeena PM, Pillay P, Pillay T, et al. Impact of HIV-1 coinfection on presentation and hospital-related mortality
in children with culture proven pulmonary TB in Durban,
South Africa. Int J Tuberc Lung Dis 2002; 6: 672-8.
9. Marais BJ, Hesseling AC, Gie RP, Schaaf HS, et al. The
burden of childhood tuberculosis and the accuracy of
community-based surveillance data. Int J Tuberc Lung
Dis 2006; 10: 259-63.
10. World Health Organization. Guidance for national
tuberculosis programs on the management of tuberculosis
in children. World Health Organization, Geneva. WHO/
HTM/TB/2006.371.
11. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of
disease of childhood intra-thoracic tuberculosis: A critical
review of the prechemotherapy literature. Int J Tuberc
Lung Dis 2004; 8: 392-402.
12. Marais BJ, Gie RP, Schaaf HS, Donald PR, et al. Childhood
pulmonary tuberculosisOld wisdom and new
challenges. Am J Resp Crit Care Med 2006; 173: 1078-90.
13. Smieja MJ, Marchetti CA, Cook DJ, et al. Isoniazid for
preventing tuberculosis in non-HIV infected persons.
Cochrane Database Syst Rev 2000; 2: CD001363.
14. International Union against Tuberculosis Committee of
Prophylaxis. Efficacy of various durations of isoniazid
preventive therapy for tuberculosis: Five years of followup in the IUAT trial. Bull World Health Organ 1982; 60:
555-64.
15. Sinfield R, Nyirenda M, Haves S, et al. Risk factors for
TB infection and disease in young childhood contats in
Malawi. Ann Trop Paed 2006; 26: 205-13.
16. Rieder HL. Interventions for tuberculosis control and
elimination. International Union Against Tuberculosis and
Lung Disease 2002, Paris. France.
17. Zachariah R, Spielmann MP, Harries AD, et al. Passive
versus active tuberculosis case finding and isoniazid
prophylaxis among household contacts in a rural
district of Malawi. Int J Tuberc Lung Dis 2003; 7:
1033-9.
18. Marais BJ, Gie RP, Hesseling AC, et al. Radiographic
signs and symptoms in children treated for
tuberculosis: Possible implications for symptom-based
screening in resource-limited setting, Pediatr Infect Dis
J 2006; 25: 237-40.
19. Verver S, Warren RM, Munch Z, et al. Proportion of
tuberculosis transmission that takes place in households
in a high-incidence area. Lancet 2004; 363: 212-4.

20. Department of Health. The South African Tuberculosis
Control Program: Practical Guidelines. 2000: 32-7.
21. Marais BJ, Gie RP, Obihara CC, et al. Well defined
symptoms are of value in the diagnosis of childhood
pulmonary tuberculosis. Arch Dis Child 2005; 90: 1162-5.
22. Marais BJ, Gie RP, Schaaf HS, et al. A refined symptombased approach to diagnose pulmonary tuberculosis in
children. Pediatrics 2006; e1350-9.
23. Marais BJ, Gie RP, Schaaf HS, et al. A proposed
radiological classification of childhood intra-thoracic
tuberculosis. Pediatr Radiol 2004; 34: 886-94.
24. Marais BJ, Pai M. New Approaches and emerging
Respir Rev 2007; 8: 124-33.
25. American Thoracic Society. Targeted tuberculin testing
and treatment of latent tuberculosis infection. Am J Respir
Crit Care Med 2000; 161: S221-47.
26. Theart AC, Marais BJ, Gie RP, et al. Criteria used for the
diagnosis of childhood tuberculosis at primary health care
27.
28.
29.
30.
611
level in a high-burden, urban setting. Int J Tuberc Lung

Dis 2005; 9: 1210-4.
Lienhardt C, Sillah J, Fielding K, et al. Risk factors for
tuberculosis infection in children in contact with
infectious tuberculosis cases in the Gambia, West Africa.
Pediatrics 2003; 11: e608-14.
Marais B, van Zyl S, Schaaf HS, et al. Adherence to
isoniazid preventive chemotherapy in children: A
prospective community based study. Arch Dis Child 2006;
91: 762-5.
Van Zyl S, Marais BJ, Hesseling AC, et al. Adherence to
antituberculosis chemoprophylaxis and treatment in
children. Int J Tuberc Lung Dis 2006; 10: 13-8.
Spyridis NP, Spyridis PG, Gelesme, A, et al. The
effectiveness of a 9-month regimen of isoniazid alone
versus 3- and 4-month regimens of isoniazid plus
rifampin for treatment of latent tuberculosis infection in
children: Result of one year randomized study. Clin Infect
Dis 2007; 45: 715-22.
40
Tuberculosis Control Program in

ChildrenLacunae and Experiences
Rohit Sarin, Sangeeta Sharma
INTRODUCTION
India has the dubious distinction of contributing to over
1/3 of the global burden of tuberculosis and WHO has
ranked the country as No.1 amongst the high disease
burden countries.1,1a Recent estimates suggest that there
are around 8.5 million TB patients prevalent at any point
of time to which 1.8 million are added every year.2 Nearly
half of this group is sputum positive and contributes to
the continued transmission of the disease. It is estimated
that children constitute less than 7% of all cases of TB3
and only around 3% of the sputum-positive patients.4
Even though the proportion of children suffering from
the disease is less but they form the vulnerable group in
the context of their tendency to develop severer forms of
pulmonary and extra pulmonary disease and the high
mortality associated with it. WHO estimates that nearly
1.5 million new cases and 450 000 deaths from TB occur
annually amongst children in the developing countries.5,6
Tuberculosis infection in children is also an indicator
of recent transmission and reflects the epidemiological
status of the disease in the community. Further, it is this
group of infected children which would form the pool
for the breakdown of disease in the future. The emergence
of HIV-TB coinfection and MDR-TB further add to the
gravity of the situation.
In spite of the obvious importance of Tuberculosis
Control in children, the National Tuberculosis Program
(1962) and the Revised National Tuberculosis Control
Program (1997) have not given it the due priority. The
various issues involved have been discussed in this
chapter.
ISSUES AND LACUNAE

The issues in the context of the Tuberculosis Control
Program in children can be discussed under the 6 basic
headings of the Directly Observed Treatment Shortcourse (DOTS) strategy.
Priority
The RNTCP prioritized on detecting and treating smearpositive patients in order to cut the chain of transmission.7
Treating smear-positive adult patients would definitely
reduce transmission in the community and indirectly

would also reduce the spread of disease in children.
However, as majority of the children are not sputumpositive, they would be automatically missed in the
priority.
Diagnosis
Diagnosis under the TB Control Program is from amongst
the self-reporting chest symptomatics.
The definition of chest symtomatics under the TB
Control Program has been productive cough for over 2
weeks (RNTCP).8 Children usually may not appreciate
their symptoms or bring out sputum and hence would
get excluded as per this definition. Moreover, as the
investigation of choice for diagnosing and monitoring
under the RNTCP has been sputum examination, those
children who do not bring out sputum would face
difficulty in diagnosis. The clinicians would then
naturally tend to rely on chest X-rays with its known pit
falls of intra and inter reader variation.9 Further, the
availability of chest X-ray is confined to Community Health
Centres or Taluk Hospitals under the General Health
Services and hence diagnosis can only be done at this level
rather than at Primary Health Centers (PHC). The distance,
time and costs incurred in travel would add to the barriers
in access for diagnosis.
The other diagnostic tool in children is Tuberculin
testing, availability of which is again limited to hospital
settings rather than the PHC. Now, even the hospitals
do not have the standardized 1 TU strength as the
Government source from BCG Laboratory, Guindy has
stopped. The current availability from the private sector
is of 2 TU and 5 TU and this needs Quality Control
Assessment. This is more important with the 1TU PPD
recently made available in the private sector. Moreover,
these higher strengths of tuberculin may need different
guidelines for positive and negative interpretation.
Further, widespread BCG coverage also interferes with
the interpretation of results. Hence, the usefulness of this
diagnostic modality has its limitations.
The other diagnostic tools such as gastric lavage for
sputum and fine needle aspiration cytology (FNAC) for
lymph nodes are not usually available under field
Chapter 40 Tuberculosis Control Program in ChildrenLacunae and Experiences

situations in the National Program. Thus, the General
Health Services which are to implement the National
Program lack the diagnostic tools for tuberculosis. Further,
in the absence of defined diagnostic guidelines in children
the only alternative left, in most situations, is to refer the
child to a pediatrician at the secondary/tertiary level
institutions. To add to the problems, the pediatricians differ
in their diagnostic practices and, without any definite
diagnostic test, rely on the different scoring systems, each
of which has its own limitations. Now, these are considered
unreliable. This is compounded by the fact that at many a
times, the pediatrician may not be available even at the
Secondary Health Care facility.
Drug Availability
In order to ensure an uninterrupted supply of good
quality drugs, the RNTCP has made a provision to
procure the anti TB drugs for the pediatric age group in
blister combi packs and patient-wise boxes, so that all
drugs for the entire treatment duration are available for
the patient prior to initiating the treatment. To assist in
calculating required dosages and administration of antiTB drugs for children linked to the childs weight, the
medication has been made available in 2 types of patient
wise-boxes (PC-13 and PC-14) for 4 weight bands (6-10,
11-17, 18-25, >26 kg body weight). The guidelines define
different combination of these boxes to cover all these
weight bands. In India children are often malnourished
and neglected and during treatment gain weight and
move to higher weight band. However, the anti-TB drugs
available in blister combi packs and patient-wise boxes
linked to the childs weight often fall short as the child is
continued medicines in the lower weight band. Moreover,
for children less than 6 kg body weight, there are no such
treatment boxes available and they are being treated with
loose drugs especially syrups or dispersible tablets.
Hence, this vital logistic strength of the RNTCP is diluted
for this highly vulnerable age group.10
Also, issues relating to drug stock outs and difficulty
in dose titration linked to weight can arise. Further, drug
intake in tablets/capsules for smaller children becomes
a problem.
Directly Observed Treatment Short-course

One of the major strengths of the RNTCP is to ensure the
patient taking each and every dose of medicines in the
Intensive Phase under direct observation and weekly
supervision in the Continuation Phase. This implies that
the patient needs to visit the health facility for drug intake
and this becomes a major barrier for children who are by
and large dependent upon the adults to take them to the
health facility. Nonavailability of the parents due to work
commitment or nonavailability of the child due to
613
schooling may pose a barrier to access. Frequent visits to

health facility also brings out the issues of social stigma,
especially amongst female children. The Program,
therefore, needs to develop a more children friendly
approach in this regard.
Monitoring of Treatment
In the absence of sputum availability, the physician is
largely dependent on the clinical and radiological
improvement. Both of these have their limitations and to
some extent are subjective. More objective criteria need
to be developed in the program for the monitoring of
compliance and response to treatment. Presently, for
monitoring treatment, patient is re-examined at two
months for review of diagnosis and then finally only at
the end of treatment. There is no system to refer the
patient in between, if necessary. Children, unlike adults,
may deteriorate very rapidly and hence the guidelines
need some modification for provision of earlier
monitoring. Moreover under the Program, wherever
sputum examination is not possible or the sputum is
negative and the patient shows no improvement at two
months, patient is re-examined for review of diagnosis.
If the diagnosis is certain, intensive phase is extended for
one more month. After the extended intensive phase (total
3 months of R3H3Z3E3 from start of treatment), child is
put on the continuation phase. If the patient still continues
to deteriorate, the patient is declared as failure and
nonresponder respectively at end of 2nd or 3rd month
respectively and put on category II. This is not being
accepted by many TB Experts to label a patient as failure
and non responder as early as 2 to 3 months during the
course of treatment. Moreover, extension of continuation
phase for disseminated disease and miliary tuberculosis
in the absence of availability of sputum has not been
defined under the program.
Special and Unique Requirements of Children

Problems like visit to the DOTS center due to parental
preoccupation, dependency on parents, clash of school/
center timings, prolonged treatment and ignorance are
important factors for nonadherence. Options which need
to be made available under the program to ensure regular
drug intake and compliance are extending the center
timings outside the school hours, sensitizing the health care
providers to the peculiar needs of very small children, or
making mothers or immediate relatives as DOTS providers
to administer drugs under supervision of community
health DOTS workers. This will not only improve the
compliance but also indirectly create an awareness and
realization in the family regarding the free and prompt
management available under DOTS program.
614
Newer RNTCP Initiatives in Context of Children

MDR-TB and DOTS-plus
Program policy: RNTCP is routinely offering DOTS-plus
treatment to adult MDR-TB cases in which a fixed regime
of standardized drugs as Standardized Treatment
Regimen is given under direct supervision. However, in
pediatric MDR cases, DOTS-plus has not yet been
implemented although, guidelines for management of
pediatric MDR-TB under RNTCP have recently been
formulated and drafted.
Once implemented under the DOTS-plus program,
only children more than 15 kg body weight with
confirmed MDR (PTB, EPTB) diagnosed by culture and
drug sensitivity will be taken into the program. After
confirmation of diagnosis, the patient will be given fully
supervised standardized treatment regimen on the pattern
of DOTS-plus regimen of RNTCP in adults. But there are
still some lacunae in the implementation of DOTS-plus
program in children.
Diagnosis: Diagnosis of pediatric MDR-TB is often
extremely delayed due to reliance on the adult case
definitions of MDR-TB and children being usually
sputum negative or sputum not available. Accordingly,
the criteria for initiating children on DOTS-plus treatment
should be modified. Early diagnosis and treatment is all
the more important in children as they are a vulnerable
group where rapid progression of disease and mortality
could be higher if left untreated. Programmatic changes
could facilitate earlier diagnosis and treatment of pediatric
MDR-TB and it is likely that future measures and
modifications may be necessary in order to prevent the
emergence of incurable tuberculosis in children.1
Treatment: As the duration of treatment will be minimum
of 24 months and there is lack of data relating to longterm ethambutol (E) use in pediatric population, thus,
inclusion of clinical tests/markers in the follow-up
schedule of patients to detect optic neuritis is highly
recommended.
Also, fluoroquinolones are not yet licensed for
pediatric use in India thus their licensing for at least use
in pediatric MDR-TB should be sorted out before the
inclusion of this drug as part of the MDR-TB regimen.
Feasibility of tablet cutters for ethionamide,
levofloxacin, cycloserine, etc. should also be explored to
facilitate weight related dosaging.
The recommended dosages for the different weight
bands are as below:
Pyridoxine 50 mg and 100 mg will be given for 16-25
kg and > 25 kg respectively (Table 40.1)
PAS (para-aminosalicyclic acid) will be added if any
of the above drug is not tolerated.
In case the bioavailability (BA) of PAS is 60% the
dosage is increased to 7 gm; 14 gm and 16 gm respectively.
Table 40.1: Doses of individual drugs based

on body weight (kg) of child
Drugs
16-25 kg
26-45 kg
>45 kg
Kanamycin
Ofloxacin or
Levofloxacin
Ethionamide
Pyrazinamide
Ethambutol
Cycloserine
PAS (80%B.A.)*
500 mg
400 mg
200 mg
375 mg
500 mg
400 mg
250 mg
5 gm
500 mg
400 mg
500 mg
500 mg
1250 mg
800 mg
500 mg
10 gm
750 mg
800 mg
750 mg
750 mg
1500 mg
1000 mg
750 mg
12 gm
TB and HIV Control Strategies

Development of mutual TB and HIV control strategies in
children involving better co-operation between the
RNTCP and National AIDS Control Program will have
an impact on growing HIV epidemic and TB treatment.
Treatment of TB in HIV positive patients should always
be under DOTS because of risk of non-compliance in these
cases.
LRS experience: Inspite of the above mentioned lacunae,
excellent success rates have been achieved for adult TB
patients with WHOs Directly Observed Treatment Shortcourse (DOTS) strategy throughout the world including
India.11 DOTS strategy appears to be highly effective for
pediatric pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) patients.12 Our studies
for PTB and EPTB have demonstrated remarkable
recovery on DOTS. These studies also highlight the need
of access to accurate diagnosis, effective treatment and
promoting adherence particularly in resource poor
endemic areas with greater burden of the disease.
In our study conducted over a 10 year period (January
1995 to July 2004) analyzing the data of 1098 pediatric PTB
patients,13 over half the patients were in the age group of
11 to 14 years and able to bring out sputum for diagnosis.
Further, most of the registered patients were nave (87.7%)
and previously treated comprised only about 12%.
Amongst the previously treated nearly half were treatment
after default. Out of total cases, 414 and 404 were smear
positive and negative respectively while sputum status
was not known in 280 patients. Sputum positivity increased
with age. Hence, sputum examination was an important
diagnosis tool even in children. Majority of the children
were in the adolescent age group.
A total of 427 (38.9%) patients had primary complex
(Ghon focus with hilar lymph node and associated
lymphatics) while 252, 163, 43, 24 and 189 patients had
extensive parenchymal infiltrates, cavities, apical lesions,
consolidation and combination of more than one type of
radiological lesion respectively. Category I, II and III of
treatment was started on 50.6%, 10.5% and 38.9% patients
respectively. The cure rate was 92.4% (302/327) and 92%
Chapter 40 Tuberculosis Control Program in ChildrenLacunae and Experiences

(80/87) for the sputum positive new and retreatment
cases respectively (12 = 0.02, p = 0.901) but the treatment
completion rate amongst the smear negatives was
significantly higher for new cases (97%; 636/656) than
retreatment cases (53.6%; 15/28) (12 = 100.8, p<0.001).
Overall success rate was 95.4% and 82.6% for new and
retreatment cases respectively (12 = 30.35, p<0.001). There
was an overall 3% default rate, 1.9% failure rate and 1%
death rate in the study.
In our study conducted over the same period
analyzing the data of 941 out of 975 children with EPTB,
there was similar age distribution as in pulmonary TB
lymph node TB (71.1%) was the commonest form for all
ages followed by pleurisy 11.3%, bone and joint TB and
abdominal TB in 6.4% cases each and 1.9% cases each of
neuro TB and miliary/disseminated TB.
Out of total 669 cases of lymphnode TB,14 cervical
tuberculous lymphadenitis (88.2%) was the commonest
form for all ages followed by axillary lymphadenitis in
3.3%. TB of other sites was seen in only 8.5% cases. Out of
total 622, 93% cases of lymph node TB where fine needle
aspiration and/or excisional biopsy was done, it was
positive in 84.2% and negative in 15.6% respectively for
AFB/cytology, while it could not be done in 47 patients
due to inaccessible sites. Category I, II and III of treatment
was started on 15.4%, 7.5% and 77.1% patients respectively.
Overall, treatment completion rate was 94.9% and the
default rate was 2.2% with a failure rate of 2.5%. Death
rate was 0.3%.
Similarly our study on 106 cases of tuberculous
pleurisy,15 unilateral effusion (61.3%) was commonest,
followed by empyema (22.6%), massive and bronchopleural
fistula each in 13.2% cases respectively. Bilateral effusion
was seen in 3.8% only. Conventional methods (Mantoux,
radiograph, ultrasound, pleural aspiration) and minimal
invasive surgical techniques, percutaneous pleural biopsy
were done to arrive at the diagnosis. Diagnosis was made
by X-ray Chest in 92.5%, Ultrasound in 19.8%, CT Scan in
10.4%, exudative lymphocytic pleural fluid in 85.8%, AFB
smear and culture in 4.7 and 5.7% cases respectively
Category I, II and III treatment was started on 35.9%, 2.8%
and 61.3% patients respectively. Treatment completion rate
was 94.3%, 4.7% default rate, 0.9% failure rate and no deaths
.The study confirms early detection by simple tests and
ensuring complete treatment using DOTS strategy for
pediatric pleurisy.
Thus, no matter whatever be the type of TB, the
outcome in children is very good under the RNTCP but
this is mostly in the preadolescent and adolescent age group.
CONCLUSION
The RNTCP has achieved 100% country coverage in the
year 2005. However, in order to get the full benefit of the
program for the pediatric age group, the lacunae
615
mentioned above need to be suitably addressed. The

Government has only recently prioritized this issue and
made an effort towards developing a consensus amongst
the experts for the management of children in the
RNTCP.10 However, to resolve the unanswered issues,
the Government of India proposes to have similar
meetings in the near future. The newer initiatives like
management of MDR-TB and HIV-TB are even more
challenging in children than in adults.
REFERENCES
1. World Health Organization. Global Tuberculosis Control:
Surveillance, Planning, Financing. WHO Report 2006.
WHO/HTM/TB 2006;362. Geneva, Switzerland: WHO
2006.
1a. Global Tuberculosis Control Report. 2009. Available from:
URL http://www.who.int/tb/publications/global/
2009/fullreport.pdf. Accessed April 4, 2009.
2. Central TB Division, DGHS, MOHFW, Govt of India.
Expert Committee Report Burden of Tuberculosis, 2005.
4. Suryanarayana L, Suryanarayana HV, Jagannatha PS.
Prevalence of pulmonary tuberculosis among children
in a South Indian community. Ind J Tub 1999; 46: 171-8.
5. Marais BJ, Hesseling AC, Schaaf HS, et al. The burden of
childhood tuberculosis and the accuracy of communitybased surveillance data in an endemic area. Int J Tuberc
Lung Dis 2006; 10: 259-63.
6. World Health Organization (WHO). WHO report on the
Tuberculosis epidemic. Geneva: WHO 1996.
RNTCP Operational Guidelines for Tuberculosis Control
2001, Pg-1.
RNTCP Technical Guidelines for Tuberculosis Control
2000, Pg-3.
9. Tomans K. Tuberculosis, 2nd edn, How Reliable is
Chest X-ray Friden T (Ed), 2nd edn. Geneva WHO 2004;
39-47.
10. Management of Pediatric Tuberculosis under Revised
National TB Control Program: Consensus Statement. Ind
J Pediatrics 2004; 71:341-3.
11. Kharti GR, Frieden TR. Controlling tuberculosis in India.
N Engl J Med 2002; 347: 1420-25.
12. Kabra SK, Lodha R, Seth V. Category based treatment of
tuberculosis in children. Indian Pediatr 2004; 41: 927-37.
South Delhi, India. Int J Tuberc Lung Dis 2008; 12: 74-80.
14. Sharma S, Sarin R, Khalid UK, et al. Clinical profile and
treatment outcome of tuberculous lymphadenitis in
children using DOTS strategy. Indian J Tuberc 2010; 57:
4-11.
15. Sharma S, Sarin R, Khalid UK, et al. Clinical profile and
treatment outcome of tubercular pleurisy in pediatric age
group using DOTS strategy. Indian J Tuberc 2009; 56: 191200.
41
Prospective of Prevention, Diagnosis

and Management of Tuberculosis
in the National Program
LS Chauhan
INTRODUCTION
Tuberculosis is one of the oldest diseases known to affect
mankind as shown by the findings of tuberculous spinal
disease in Egyptian mummies. The Greeks called the
disease phthisis (consumption), emphasizing the
dramatic aspect of general wasting associated with chronic
untreated disease. It has also been referred to in the Vedas
and Ayurvedic Samhitas as the Kshaya Rog. The
infectious etiology was debated until Robert Kochs
discovery of the bacillus in 1882. Effective anti-tuberculosis
drugs were available in the middle of last century, but in
Europe and the United States, mortality rates began to
decrease decades before the introduction of
antimycobacterial drugs due to improvement in
socioeconomic conditions thereby establishing the fact that
TB and poverty are closely related.
BURDEN OF DISEASE
Mycobacterium tuberculosis remains the single most serious
pathogen worldwide and a major global public health
problem in much of the developing world. Globally, it is
estimated that more than 9 million people develop active
tuberculosis (TB) disease every year of which nearly
4 million cases are sputum smear-positive, the majority of
whom are in the developing countries.1 This is due to the
failure to cure a high proportion of sputum smear-positive
cases, population growth, HIV-epidemic and other
socioeconomic and demographic factors (poverty,
migration, etc.). Globally the HIV epidemic worsened the
TB situation, increasing the number of tuberculosis cases
and accelerating the spread of the disease. It is estimated
that one third of the worlds AIDS cases are infected with
TB. HIV increases a persons susceptibility to TB infection.
HIV is now considered the most powerful risk factor for
the progression of TB infection to disease.
TB kills more adults than all other infectious diseases

combined. More children are orphaned because of TB than
due to any other infectious disease. TB was declared a
global emergency by WHO in 1993, and countries round
the world have intensified their measures towards TB
control programs. In fact, the threat of HIV/AIDS alerted
them to potential danger of TB resurgence.
Epidemiological Basis of TB Control Activities

The epidemiological basis of TB control activities in a
community can be simplified using a model to understand
the natural history of tuberculosis (Fig. 41.1).
Exposure to a potentially infectious case is a
prerequisite for becoming infected. Once an individual is
infected, risk factors determine the probability that an
infected individual will develop tuberculosis, and some
risk factors also determine the probability that a diseased
individual will die from TB.
The major factors that determine the risk of becoming
exposed to tubercle bacilli include the number of incident
infectious cases in the community, the duration of their
infectiousness, and the number and nature of interactions
between a case and a susceptible contact per unit of time
of infectiousness. The probability of becoming infected with
M. tuberculosis depends on the number of infectious droplet
nuclei per volume of air (infectious particle density) and
the duration of exposure of a susceptible individual to
that particle density. It is estimated that one infectious
case, if not treated, on an average infects about 10 to 15
new persons every year.3
The most important risk factor for tuber-culosis is
infection with tubercle bacilli. Tubercle bacilli are
necessary, but not a sufficient cause of tuberculosis. While
the risk of becoming infected is largely exogenous in nature,
determined by the characteristics of the source case,
environment, and duration of exposure; the risk of
Fig. 41.1: A model for tuberculosis epidemiology,2,3
Chapter 41 Prospective of Prevention, Diagnosis and Management of Tuberculosis

developing tuberculosis, given that infection has occurred
is, largely endogenous, determined by the integrity of the
cellular immune system. In most instances it cannot be
determined why a particular person does or does not
develop tuberculosis after becoming infected with tubercle
bacilli.
Multitude of factors has been identified which increase
the risk of progression from subclinical infection with
M. tuberculosis to overt tuberculosis. The three most
important of them for all practical purposes are coinfection
with HIV, recent infection with tubercle bacilli, and healed
lesions from previous tuberculosis which was never
treated. Globally, low body weight or malnutrition might
be of considerable epidemiological importance because of
its high prevalence, particularly in low income countries.
The risk of the disease developing in the individual is
highest shortly after getting infected. It is a strong factor,
with recent infection being 10 times more likely to produce
a case than a long-standing infection. A common rule of the
thumb is that the lifetime risk of a newly infected young
child (1-3 yrs) might be 10% and half of the risk falls within
the first five years following infection. The incidence of
tuberculosis disease increases with age. This would be partly
explained by the cumulative increasing prevalence of
tuberculosis infection. There are two peaks in incidence
observed, first in the 1 to 4 age groups, reflecting the
progression from recent infection by TB bacilli and the
second in adolescents and young adults. Another factor
which plays a role in the development of tuberculosis disease
is sex. Men and women are differentially at risk. The risk is
higher for women than men in the 15 to 44 age groups
and lower in women than men beyond 44 years of age.
There are several other risk factors that have been studied
like cigarette smoking, HIV, diabetes mellitus and
malnutrition. They adversely affect the immune system so
could influence the tuberculosis disease incidence. Several
other medical conditions are commonly associated with
tuberculosis such as silicosis, where the risk has been shown
to be 26 times higher to develop tuberculosis disease. It has
also been found to be three times more in diabetics than
general population, 10 to 15 times higher in patients with
end-stage renal failure and those on hemodia-lysis and
5 times higher in male gastrectomy patients.2,3
Tuberculosis case fatality is largely determined by site
and type of disease and by appropriate and timely
intervention. Untreated sputum smear-positive
tuberculosis leads to death in about 30 to 40% of cases
within one year, and cumulatively kills about 50 to 70%
within 5 to 7 years. The extent to which tuberculosis
continues to kill will largely depend on the extent to which
modern intervention strategies become available.
TB in children plays a special role in the understanding
of the epidemiology of tuberculosis. Despite the widespread
recognition that TB in children has a very limited impact on
the dynamics of the TB epidemic in a community, it is more
617
informative about the dynamics than any other

manifestation of the disease. TB in children always points
to recent transmission that was not curtailed in a timely
fashion. Childhood TB prevalence indicates the community
prevalence of sputum smear-positive pulmonary
tuberculosis (PTB), age-related prevalence of sputum smearpositive PTB, prevalence of childhood risk factors for disease
and stage of epidemic.
Children as in adults acquire infection from sputumpositive infectious cases. Proper identification and
treatment of infectious cases will prevent childhood TB.
However often childhood TB is accorded low priority
globally by National TB Control Programs due to
diagnostic difficulties, childhood TB is considered rarely
infectious, limited resources, misplaced faith in BCG and
lack of data on treatment.4,5 But this disregards the impact
of tuberculosis on childhood morbidity and mortality.
Based on the understanding of tubercular epidemiology, the basis of any TB control activity should help to
reduce risk of exposure, transmission, improve upon host
immune response to reduce risk of progression to active
disease and treat the infected to reduce morbidity and
mortality.
Evolution of TB Control Program in India

The evolution and progress of efforts to control tuberculosis
in the country has been need-based relating to the problems
of a technical, operational and managerial nature that
arose over time in the country. As in most of the countries,
the first anti-TB measures taken in India were of an
unplanned and ad hoc nature confined mainly to the
establishment of hospitals and Sanatoria. Attempts to
tackle the problem of TB through organized efforts actually
had their origin in late 1930s. The chronology of important
landmarks in the history of tuberculosis (TB) control can
be divided into three phases: the four decades prior to the
Tuberculosis Control Program; the three decades of
National Tuberculosis Control Program and the current
phase of Revised National Tuberculosis Control Program
(RNTCP).6
Phase 1: The Early Days (1910-1960)

Before the discovery of anti-tuberculosis drugs,
tuberculosis treatment consisted of attempts to strengthen
the patients resistance to the disease. This included
altering local and general host factors through traditional
measures such as avoidance of physical and mental strain,
prolonged bed rest, a rich diet, fresh air and good
ventilation, by establishment of centers of care the TB
Sanatoria. The sanatorium movement which originated
in England, in the absence of chemotherapy, recommended
a balanced diet, fresh air and regulated exercise. The first
open air sanatorium for treatment and isolation of TB
patients in India was founded in 1906 in Tiluania, near
618
Ajmer, followed by one in Almora two years later. The

United Mission Tuberculosis Sanatorium (UMTS) was
built in 1912 at Madanapalle, South India. Dr Frimodt
Moller, its first Medical Superintendent played a large role
in Indias fight against TB through the training of TB
workers, conducting TB surveys (1939) and introduction
of BCG vaccination (1948). In addition, the first TB
dispensary was opened in Bombay in 1917, followed by
another in Madras (now Chennai). Soon anti-TB societies
were formed in Lucknow and Ajmer.
The first concerted effort of TB control in the country as
a whole was through the organization of the King George
V thanks-giving fund in 1929. The funds were utilized for
preventive and educational activities, establishment of
clinics, training of health visitors and preparation of health
education material. The provinces and states which
received money started their TB associations. The TB
Association of India was established on the 23rd of
February 1939, with the objective of providing expert
advice on the development of standard methods to deal
with the disease, setting up model institutions for the
training of TB workers, education of the public regarding
preventive measures, and for organizing meetings and
conferences for scientific discussions. Recognizing the
enormity and complexity of the disease and to meet the
needs of the large numbers of TB patients, the TB
association conceived the idea of domiciliary treatment as
early as 1940. The association established the New Delhi
TB clinic, now called the New Delhi TB Center, and the
Lady Linlithgow Sanatoria in Kasauli. Research was also
taken up in collaboration with the Indian Research Fund
Association, now known as the Indian Council of Medical
Research (ICMR). India became a member of the
International Union Against Tuberculosis (IUAT) in 1929,
forging international cooperation and partnerships.
The Health Survey and Development committee headed
by Sir Joseph Bhore, in its report in 1946 outlined a
conventional phased scheme for the management of TB. It
estimated that there were about 2.5 million patients in need
of treatment and half a million deaths annually and only
6000 beds were available for the treatment of TB patients,
much below the estimated requirement of over 4,000 clinics
and 500,000 beds for TB control according to western
standards prevailing at that time. Realizing the disparity
between enormity of the TB problem and the available
resources for treatment, the committee recommended, in the
form of a regular program, implementation of the long
accepted conventional measures by setting up TB clinics in
the district and mobile TB clinics for rural areas. It placed
organized domiciliary service at the forefront of the
program.
The key role of the government in initiating measures
to control the disease was strongly felt at this juncture. A
TB division in the Directorate General of Health Services
(DGHS) was established in New Delhi in 1946, with an
Adviser in TB as its head. TB was also given a prominent

place in the planning. Planning and execution of the antiTB activities was greatly facilitated by this division.
Around the time India gained independence, effective
drugs against TB began to be available (streptomycin 1944,
para-aminosalicylic acid (PAS) 1946, thiacetazone 1950,
isoniazid 1952 and rifampicin 1966). The very notion that
there could be effective drugs against the tubercle bacilli
was so revolutionary that researchers began to experiment
on the effective dosages and combinations of drugs to be
used. The issue of affordability was also considered.
Indian medical researches and health care providers had
pioneered several landmark clinical and community trials
to test the efficacy of these drugs, as they became available,
using them and overcoming issues confronting them. These
studies revolutionized the management of TB all over the
world.
The cost for large scale establishment for TB control
was not feasible at that point in time, hence attention was
directed to prevention of TB by way of BCG vaccination,
which was felt to be feasible operationally and
economically. The International Union Against TB (IUAT)
gave assistance to the BCG vaccination program in the
country. TB demonstration and training centers were
developed for the training of the required personnel. The
BCG campaign was introduced on a small scale in
Madanapalli in 1948 and was extended on a mass scale
in 1951. This was the first nationwide campaign against
TB. A BCG Vaccine Production Center in Guindy, Madras
was set up in 1948 with the support of WHO and UNICEF.
Mass BCG Campaign

As a part of the mass BCG campaign over 65 million children
were vaccinated and 165 million tuberculin tests were
administered. It was realized that TB is an equally important
problem both in rural and urban areas. BCG campaign
helped in raising awareness of the disease as a public health
problem not only in the minds of the medical community
but also the message of health promotion and prevention of
disease to the remotest part of the country and its population.
The revelation that the prevalence of TB infection was high
in most parts of the country, needed to be checked by
scientifically conducted surveys.
National Sample Survey (1955-1958)

A special committee of the Indian Council of Medical
Research (ICMR) was set up to address the issue of
obtaining detailed information of the prevalence of TB
expeditiously and rationally. From 1955 to 1958, under
the auspices of the ICMR, a large-scale sample survey was
conducted in 6 zones of the country, covering both urban
and rural populations, to obtain as precise information as
possible about the magnitude of TB problem in the country.
The survey confirmed the impression of high prevalence
619
of TB morbidity in the rural areas that had earlier been

suggested by the large-scale tuberculin testing. It was
estimated that of the 8 million suffering from TB disease,
about 80% were in the rural areas.7 With this revelation,
the need for the development of a nationally applicable
control program to tackle the problem of TB, was strongly
felt.
respiratory diseases as well. In 1991, the LRS was

upgraded into an autonomous institute and was taken
over by the Ministry of Health and Family Welfare
(MoHFW), Government of India. Since the up-gradation,
LRS has been serving as a specialized Institute of TB and
Respiratory Diseases.
Establishment of Central TB Institutes
Phase II: Development of the National

TB Control Program (1960-1990)
In 1956, the TB Chemotherapy Center (TCC), now known

as the Tuberculosis Research Center (TRC), was established
in Madras (now Chennai) under the auspices of the ICMR,
with the assistance of the British Medical Research Council,
the World Health Organization (WHO) and the
Government of India (GOI). The center was to provide
information on the application of mass domiciliary
chemotherapy for the treatment of pulmonary TB. The TCC
demonstrated that the time-honored virtues of sanatorium
treatment such as bed rest, well balanced diet and other
sanatoria based measures, were unimportant provided
adequate chemotherapy was prescribed and fully taken.
Further, there was no evidence that close family contacts of
patients treated at home incurred an increased risk of
contracting TB. Therefore, it would be appropriate to treat
infectious patients in their own homes. This finding
revolutionized TB treatment the world over. The discovery
of specific, potent, and readily available anti-TB drugs and
the efficacy of domiciliary treatment as shown by the New
Delhi TB Center and the TCC Chennai, completely changed
the outlook for TB patients.8 The probability of formulating
a comprehensive TB program to combat the disease on a
community wide basis now seemed possible.
National Tuberculosis Institute (NTI) was established
in 1959 at Bangalore (now Bengaluru), by the GoI, with the
active cooperation of the WHO, to evolve through research,
an operationally feasible, practicable TB program that could
be applied to both rural and urban areas, economically
affordable and which would promise a sizeable benefit to
the community in the foreseeable future. The NTI was
expected to initiate research for the development of such a
program, create infrastructure, and train the large numbers
of key personnel from the various states of the country, who
in turn would implement and practice the methodologies
developed in all parts of the country.
The Lala Ram Sarup Institute of Tuberculosis and
Respiratory Diseases (LRS) was established as a
Tuberculosis (TB) Hospital by the TB Association of India
(TAI) in 1952, with an aim to provide sanatorium treatment
to TB patients. It provided both outdoor, as well as, indoor
services to patients. The hospital continued to support the
National TB Control Program (NTP) of the country, whilst
simultaneously began to deliver services for other
The available tools for control of TB consisted of BCG

vaccination for prevention, chest radiography and sputum
microscopy for case finding, and ambulatory domiciliary
chemo-therapy for treatment. A systematic approach for
formulation of sound policies for tackling the problem of
TB was urgently needed.
The development of the National TB Control Program
(NTCP) was based on a number of factors related to the
epidemiological, sociological, operational, technical and
administrative aspects related to TB control in India. NTI
conducted operational research studies keeping in mind
an average Indian district, its population and health facilities
available to enunciate suitable methods for the large-scale
application of TB control measures. The recommendations
that eventually emerged took the program out of the hands
of the specialists by integrating activities into the general
health services and orienting services towards the chest
symptomatics in the community who sought relief of their
suffering from the general health institutions.
The National Tuberculosis Institute at Bengaluru
established that 95% of infectious TB patients are conscious
of their symptoms and most report to the nearest health
institutions to seek medical aid within a few weeks of the
onset of their symptoms indicating that active case finding
is not necessary.9 The emphasis of the program diverted
attention away from the TB Sanatoria and rehabilitation
centers, towards the primary need of providing reliable
and prompt diagnosis, domiciliary treatment and
prevention services for the entire population. The NTP
was pilot tested in Anantapur district of Andhra Pradesh
in 1961, the first model District TB Center (DTC). In the
DTC, the X-ray examination facilities were provided on
three days in a week and sputum examination daily.
Shortly after establishing the Anantapur DTC it became
evident that case finding could be done at any place
without difficulty, but the major problem was that of
keeping the patients on continuous treatment.
Considerable time and effort was devoted to solve the
problem of default. The Anantapur DTC became
operational quickly and functioned well. Based on the
experiences of the pilot, the National TB Control Progam
was launched in 1962, in a phased manner throughout
the country. A DTC, which functioned as the nodal/
620
referral center for TB in the respective District was

established in nearly all the districts.
The program had two objectives:
1. The long-term objective of reducing tuberculosis in the
community to a level that it ceases to be a public health
problem, i.e.
a. One case infects less than one new person annually.
b. The prevalence of infection in children less than 14
years of age is brought down to less than 1%, against
30 percent at the time.
2. The short-term or operational objectives are:
a. To detect maximum number of cases among the
patients attending health care institutions with
symptoms of tuberculosis and treat them effectively.
b. To immunize newborns and infants with BCG
vaccination.
c. To undertake the above objectives in an integrated
manner through the existing primary health care
institutions in the country.
The national program policy as enunciated in the
introduction manual of DTP comprised:
Domiciliary treatment
Use of a standard drug regimen of 12 to 18 months
duration
Treatment free of cost
Priority to newly diagnosed patients, over previously
treated patients
Treatment organization fully decentralized
Efficient defaulter system/mostly self-administered
regimen
Timely follow-up
Chemoprophylaxis not recommended as it is
impractical on mass basis.
The National TB Program was a 100% centrally
sponsored scheme and was fully integrated with the
government health services of the country, thus extending
the scope of TB work to be available through its vast
reaches. Over the years, nearly 600 TB clinics, 390 District
TB Centers (DTC), 47,000 TB beds and 16 TB training and
demonstration centers were established throughout the
country. By 1978, the NTP, which had the district level as
its basic unit, had covered 81% (390) of the total districts
in the country.
Monitoring of the Program

To evaluate the performance of the units of the DTPs in
an ongoing manner and take corrective action simultaneously, and ultimately to improve the program
efficiency in the long run, regular monitoring was deemed
essential. Till 1978, monitoring of the program was done
by northern and southern regional centers on a regional
basis and from then by NTI only. NTI from time to time
gave vital inputs and directions to the program based on
available technical, operational and managerial issues
and problems faced in the implementation of the

program.
Controlled Clinical Trial for Efficacy

of BCG Vaccine
BCG vaccination was the only available protective
measure against TB. Different trials had not revealed
credible proof of its efficacy. Serious concerns were raised
across the scientific community on the efficacy of BCG
and the benefits of large-scale use in the population. It
was thought that it would be in the interest of the country
to undertake a well designed trial to seek clear answers to
the major issues confronting it. In 1968, a meticulously
designed clinical trial to test the efficacy of BCG vaccination
was undertaken in Chingleput district of Tamil Nadu.10
After a period of twelve and a half years, it brought out a
revolutionary report. It showed that BCG vaccination did
not offer significant protection against TB of the lung. The
implication of this study was: Should BCG vaccination be
given up in India? After an in-depth review, it was
concluded that though BCG may not protect against TB of
lung which occurs mostly in adults, it could provide
substantial protection against severe forms of TB among
children such as tubercular meningitis, miliary TB. The
protective effect of BCG against these forms of TB was not
studied in Chingleput Trial. In India BCG vaccination
policy was revised and it was recommended to continue
BCG vaccination in children preferably before the end of
the first year after birth as a part of the Expanded Program
of Immunization (EPI) to give the benefit of protection
against the severe forms of childhood TB. BCG vaccination
policies in many other countries were also revised as a
consequence of the Chingleput study findings.
Era of Short-Course Chemotherapy

The conventional treatment regimens of 12 to 18 months
were developed through chemotherapy trials, and were
used in the program. However, as revealed by program
monitoring reports and observational studies conducted
in the field conditions, the problem of treatment compliance
in the program was a significant one. Only 66% of the TB
patients were taking drugs regularly with a defaulter rate
varying from 20 to 54%, with an overall average at 34%, as
was observed at the Model DTC in Anantapur district of
Andhra Pradesh.
Chemotherapy of TB underwent revolutionary
changes in the seventies owing to the availability of two
well-tolerated and highly effective drugs rifampicin and
pyrazinamide. These drugs allowed short-course chemotherapy (SCC) and made it possible to simplify treatment
and reduce its duration. With the success of the 6 months
short-course chemotherapy (SCC) regimens in clinical
trials, it was possible to reduce the treatment duration from
12 down to 6 months. With the introduction of SCC

regimens, a new era had started in the fight against TB. In
1983, the TRC, Madras, pilot tested the SCC regimens in
18 districts of the country to assess the feasibility of SCC
implementation on a larger scale. Subsequently in 1986,
following successful SCC field trials by TRC and NTI, the
GoI agreed to the introduction of SCC and SCC coverage
was scaled-up to cover 252 districts.
However, this costly intervention alone could not
improve the ground reality. Treatment compliance, even
with the introduction of SCC regimens, showed only a
marginal improvement. Between 1975 and 1992, the
program was evaluated by three independent agencies:
the ICMR in 1975; the Institute of Communication,
Operations Research and Community Involvement
(ICORCI) in 1988; and by GOI, WHO, and SIDA in 1992.
These evaluations documented the already widely known
facts of the wide gap between expectations and actual
achievements of the program.
Phase III: The Revised National TB Control Program

(1992 onwards)
Despite the NTP having been in existence since 1962, no
appreciable change in the epidemiological situation in the
country had been observed. The HIV-AIDS epidemic and
the spread of multidrug resistance TB were threatening to
further worsen the situation. In view of this, in 1992 the
GOI, with WHO and SIDA, reviewed the TB situation and
the performance of the NTP. The observations revealed
that the NTP, though technically sound, suffered from
managerial weaknesses, inadequate funding, an overreliance on X-ray for diagnosis, had frequent interrupted
supplies of drugs, and low rates of treatment completion
and lack of supervision. In 1993, to rectify these lacunae,
the government decided to give a new thrust to TB control
activities by revitalizing the NTP, with assistance from
the international agencies.
In the light of the recommendations and concerns
expressed by the Central Health Council, steps were
taken since 1993 to implement the Revised National TB
Control Program (RNTCP) in selected areas with World
Bank assistance. The Revised National TB Control
Program (RNTCP) thus formulated, adopted the
internationally recommended Directly Observed
Treatment Short-course (DOTS) strategy, as the most
systematic and cost effective approach to revitalize the
TB control program in India.
The RNTCP builds on the very substantial strengths
and accomplishments of the National Tuberculosis
Program (NTP). The NTP created an extensive infrastructure for tuberculosis control, with a network of 446
District TB Centers, 330 TB Clinics and more than 47,600
TB beds. The NTP also raised awareness of TB and TB
treatment facilities, and has succeeded in placing more
than 13 lakh patients on treatment on a yearly basis.
621
A major organizational change in RNTCP is the

creation of the subdistrict level. The RNTCP strengthens
the existing NTP infrastructure by creating a subdistrict
level supervisory team (known as the TB Unit), consisting
of a fulltime treatment supervisor (Senior Treatment
Supervisor, STS) and a laboratory supervisor (Senior TB
Laboratory Supervisor, STLS). These are new posts. In
addition, a medical officer from the general health system
serves as Medical OfficerTB Control at subdistrict level
who is specifically allocated TB control duties in addition
to his other duties. These 3 individuals constitute the
management unit, which is responsible for overseeing
operations in approximately a 5 lakh population
including, on an average, 5 designated microscopy centers.
To further decentralize the diagnostic and treatment
services, RNTCP Designated Microscopy Centers (DMCs)
are established for every 1,00,000 population. The norms
for establishments of TUs and DMCs are relaxed to 250,000
and 50,000 population respectively in hilly/difficult areas
and for tribal areas. In addition, a vast network of DOT
centers (treatment centers), all with a trained DOT provider,
has been established in all RNTCP areas so that patients
can have easy access to their TB treatment. At each
microscopy center, a state-of-the-art binocular microscope,
good quality reagents and new recording and reporting
proforma are available. More importantly, intensive
modular training, supervision, and cross-checking of the
work of the laboratory technician should ensure that
reliable results are obtained. Overall it is the State, District
and Subdistrict staff responsible for organizing,
implementing and supervising RNTCP, and the success
of the program largely depends on them. RNTCP shifts
the responsibility of cure from the patient to the health
system.
The goal of RNTCP is to decrease mortality and
morbidity due to TB and cut transmission of infection until
TB ceases to be a major public health problem. The goal of
RNTCP is achieved through the following objectives.
To achieve and maintain a cure rate of at least 85%
among newly detected infectious (new sputum smearpositive) cases, and
To achieve and maintain detection of at least 70% of
such cases in the population.
Clearly, both good outcomes and high case detection
rates are essential. But it was felt that it is essential that the
system is geared up to reliably cure patients, before any
attempts are made at expanding case detection. In fact,
experience clearly shows that reliably curing patients
results in a recruitment effect wherever effective
services are offered, case detection rates steadily increase.
Cured patients act as one of the best motivators promoting
case detection and patient adherence to treatment. Every
cured patient is a pamphlet.
622
The only effective means by which 85% cure rate or

more has been shown to be achievable on a program basis
is by application of the DOTS strategy. It should be noted
that the principles of diagnosis of TB by sputum
microscopy, ambulatory treatment, and direct observation
of treatment were first established in India at the
Tuberculosis Research Center, Chennai and the National
TB Institute, Bengaluru, in the 1950s and 1960s.
DOTS is a systematic strategy which has 5 components. These
are as follows:
Political and administrative commitment
Good quality diagnosis, primarily by sputum-smear
microscopy
Uninterrupted supply of good quality drugs
Directly observed treatment (DOT)
Systematic monitoring and accountability.
Political and Administrative Commitment

Since tuberculosis can be cured and the epidemic reversed,
it warrants the topmost priority, which has been accorded
by the Government of India. This priority must be
continued and expanded at state, district, and local levels.
Good Quality Diagnosis

Case detection is done primarily by sputum-microscopy
among chest symptomatic patients attending health
facilities. This policy allows effective diagnosis in the
periphery and appropriate prioritization of efforts.
Good Quality Drugs

An uninterrupted supply of good quality anti-TB drugs
must be available. One of the unique innovations under
RNTCP has been the development of Patient-Wise Boxes,
earmarked for every patient registered, which contain the
full course of treatment for one individual patient, ensuring
that treatment of that patient cannot be interrupted due to
a lack of drugs. Hence, in RNTCP the treatment never fails
on account of nonavailability of medicines.
Short-Course Chemotherapy given

in a Program of Direct Observation
RNTCP uses the best anti-TB medications available but
unless patients adhere to treatment, it will fail. This is
why the heart of the DOTS program is directly observed
treatment (DOT) in which a health worker or another
trained person who is not a family member, watches the
patient swallow the anti-TB medicines in his/her presence.
However, directly observed treatment (DOT) is not just
supervised swallowing but a service to the patient. It helps
to develop a human bond between the patients and the
treatment observer, which increases the probability of the
patient completing treatment. With short-course
chemotherapy it is easier to prevent drug-resistance by
using directly observed treatment, and achieve high cure

rates.
Systematic Monitoring and Accountability

RNTCP has effectively decentralized supervision via the
subdistrict TB Units, with in-built systems for monitoring
and evaluation. There are two means of monitoring the
success of treatment. First, sputum is examined during the
course of treatment to monitor the progress and cure of
patients. Second, a revised recording and reporting system
rigorously monitors and evaluates the outcome of every
patient treated at the different levels of the health system,
and if any area is not achieving 90% sputum conversion
rate at the end of 3 months and 85% cure rate, supervision
is intensified. For effective program implementation,
having well-trained and motivated staff is essential.
STOP TB Strategy
Global TB control has made major progress in the past
decade. The widespread implementation of the DOTS
strategy has proved to be an effective tool in controlling TB
on a mass scale and is being practiced in over 200 countries.
Maintaining the current status, the prime task for the next
decade is to achieve the Millennium Development Goals
(MDGs) and related STOP TB Partnership targets for TB
control to combat HIV/AIDS, malaria and other diseases,
including tuberculosis. The target under MDG for
tuberculosis is to halt and begin reversal of incidence of
tuberculosis, malaria and other major diseases by 2015.
The indicators are to reduce the prevalence and death rates
by 50% between 1990 and 2015.
Meeting these targets requires a coherent control strategy.
The strategy should enable achievements to be sustained,
effectively address the remaining constraints and
challenges, and emphasizes the efforts to strengthen health
systems, alleviate poverty and advance human rights.
The new WHO STOP TB Strategy released in 2006 lists
six principal components to realize the global TB-related
MDGs by 2015. They are:
Pursuing high quality DOTS expansion and enhancement;
Addressing TB/HIV, MDR-TB and other challenges;
Contributing to health system strengthening;
Engaging all care providers;
Empowering patients and communities; and
Enabling and promoting research.
The RNTCP is implementing all the components of the
STOP TB Strategy.
Achievements of RNTCP
Starting in October 1993, the RNTCP was implemented
in a population of 2.35 million in 5 sites in different states
(Delhi, Kerala, West Bengal, Maharashtra, and Gujarat).

The program was expanded to a population of 13.85
million in 1995 and 20 million in 1996. Having proved
both its technical and operational feasibility, a soft loan
was negotiated with the World Bank in December 1996
and the credit agreement signed in May 1997. With this
loan, it was envisaged that RNTCP would be
implemented in a select number of districts in a phased
manner while other districts would be strengthened as a
transitional step for introduction of the revised strategy
at a later stage
Full nation-wide coverage was achieved in March
2006 covering over a billion populations (1114 million)
in 632 districts/reporting units. RNTCP is considered
the fastest expanding TB control program in the history
of DOTS. Since its inception, the program has initiated
nearly 11 million patients on treatment by the end of 2009,
thus saving more than 1.9 million additional lives.
Treatment success rates have tripled from 25% in the preRNTCP era to 86% presently. TB death rates have been
cut 7-fold from 29% in the pre-RNTCP era to 4% presently.
The program has consistently maintained the treatment
success rate > 85% and new sputum positive (NSP) case
detection rate close to the global target of 70%. From 2007
onwards, RNTCP has also achieved the NSP case
detection rate of more than 70% in line with the global
targets for TB control. In 2005 alone, 1.29 million TB
patients were initiated on treatment. In 2006, 1.39 million
and in 2007, 1.48 million patients have been enrolled for
treatment. In 2008 over 1.51 million patients have been
initiated on treatment. India has contributed to
approximately 24% of the total global new cases detection
during the year 2007 as per the WHO Global Report 2009.
All states are currently implementing the Supervision
and Monitoring strategy detailing guidelines, tools
and indicators for monitoring the performance from the
PHI level to the national level. Quality assured diagnostic
facilities are available through a network more than
12,500 designated microscopy centers across the country.
To ensure quality, external quality assurance of sputum
microscopy is being routinely conducted throughout the
country. This includes on-site evaluation, panel testing
and blinded cross-checking. To improve access to tribal
and other marginalized groups the program has
developed a Tribal action plan which is being
implemented with the provision of additional TB Units
and DMCs in tribal/difficult areas, additional staff,
compensation for transportation of patient and attendant
in tribal areas and higher rate of salary to contractual
staff, etc.
Policy direction, supervision, drugs and microscopes
are provided by the central government. The funds are
released to hire contractual staff, conduct training, POL,
purchase of vehicles and other items essential for performing
623
functions efficiently. Modular training has been used for all

staff from medical officers to health workers. Multipurpose
workers are responsible for treatment observation; where
they are not available, treatment observation is done by
community volunteers including Anganwadi workers,
traditional dais, and community and religious leaders.
Observation by a family member is not acceptable in the
program. In some larger cities with limited health
infrastructure, the RNTCP has funded specialized, full-time
staff for microscopy and for treatment observation.
Epidemiology of TB in India and

The Impact of RNTCP
Though India is the second-most populous country in the
world,11 India has more new TB cases annually than any
other country. In 2007, out of the estimated global annual
incidence of 9.27 million TB cases, 1.96 million were
estimated to have occurred in India, of whom 0.87 million
were infectious cases (Table 41.1).
Incidence of Tuberculosis Disease

Measuring the incidence of tuberculosis disease is
challenging. Long term cohort studies for direct
measurement of incidence pose enormous operational
difficulties, are prohibitively expensive, and have an
inherent risk of bias, largely due to missed or
misclassification of cases. Measuring the impact of the
tuberculosis control program through routine surveillance
activities requires a consistently effective surveillance system
that captures the great majority of incident cases over a
period of years, as well as stability in underlying population
characteristics. Estimation of disease incidence from
prevalence requires clear understanding of the duration of
disease. Estimates of disease incidence by any means may
be confounded by migration, urbanization, and changes in
the prevalence of comorbidities associated TB (e.g. HIV
infection, diabetes, smoking, malnutrition, etc.)
From 1960-1986, a number of community surveys and
active surveillance activities in mainly South India were
conducted. Results from these surveys have been
summarized in a recent review article.13 These surveys
have suggested that the annual incidence of culture
positive pulmonary tuberculosis ranged from 8002500
per 100,000 population.
Several tuberculin surveys were carried out post
independence, estimating the Annual Risk of Tuberculosis
Infection (ARTI) among children <10 years as 1 to 2% per
year.14,15 However, many of these surveys were nonstandardized and carried out in limited areas mainly in
the southern part of India.
A nation-wide standardized tuberculin survey was
carried out during the period 2000-2003.16-20 For the purpose
of the survey, the country was stratified into 4 zones (north,
624

Table 41.1: Estimated burden of tuberculosis in India
Number (Millions)
(95% CI)
Incidence (2007 WHO estimate)1
All cases
AFB smear-positive
Period Prevalence (2000 GoI estimate)12
AFB positive
Bacillary*
Prevalence, all cases (2000 WHO estimate) 1
Prevalence, all cases (2007 WHO estimate) 1
Rate Per 100 000Persons

(95% CI)
1.962
0.867
168
75
1.7 (1.32.1)
3.8 (2.84.7)
165 (126204)
369 (272457)
4.468
3.304
443
283
* Defined as a person with at least one AFB smear positive by sputum microscopy, or at least one sputum culture positive
for M. tuberculosis
Prevalence rate calculated from estimated number of persons with disease in 2000, divided by 2000 population estimate
Fig. 41.2: Zone-wise selection of districts National ARTI Survey 2000-2003
west, south and east). An identical methodology of

sampling and tuberculin testing was used throughout the
country. Figure 41.2 presents the 4 zones for the ARTI
surveys, and also the sampled districts.
Table 41.2 details the major findings, and shows
interzonal and also rural/urban differences in the rates of
transmission of infection.
State-specific ARTI estimates are available for 2 states
in the country namely, Orissa and Kerala. The estimate
for Orissa overlapped with the confidence limits of the
East zone part of the national survey, in which a site

from Orissa was included. However, the Orissa statewide ARTI point estimate is closer to those of the Northern
zone than to those of the Eastern zone.
Similarly a statewide survey was carried out in Kerala
in the year 20062007. The ARTI in this survey was not
able to be calculated with confidence, due to the fewer
than expected number of infections detected. By any
measure, the ARTI for Kerala would be less than 1% per
annum.21

Table 41.2: Results of National ARTI Survey 2000-2003
Zone
ARTI (95 % CI)

Rural
Urban
Total
1.6 (1.32.0)
2.6 (2.32.9)
1.9 (1.32.5)
East 17
1.2 (1.01.5)
1.7 (1.12.3)
1.3 (1.01.6)
West 18
1.5 (1.11.8)
2.4 (1.63.4)
1.6 (1.02.2)
19
0.8 (0.41.2)
1.6 (0.92.2)
1.0 (0.71.4)
Total 20
1.3 (1.01.5)
2.2 (1.82.6)
1.5 (1.41.6)
North
South
16
Table 41.3: Estimated zonal ARTI and incidence of new

smear-positive TB, 2000-2003
Zone
ARTI (95% CI)
Estimated incidence new

smear-positive
TB per 100 000 (95% CI)
North
1.9 (1.32.5)
95 (65125)
East
1.3 (1.01.6)
65 (5080)
West
1.6 (1.02.2)
80 (50110)
South
1.0 (0.71.4)
50 (3570)
Total
1.5 (1.41.6)
75 (7080)
The use of the ARTI to estimate TB incidence is

controversial. The frequently applied Styblo conversion
estimate of 50 incident cases of new smear-positive
pulmonary tuberculosis per 1% annual risk of
tuberculosis infection22 has been criticized as no longer
valid in the presence of a modern tuberculosis program.23
This conversion, however, was recently validated in the
Indian setting in a community survey in South India.24
Hence using the Styblo conversion, these new smearpositive zonal incidence estimates are used by RNTCP to
calculate state-level case detection of new smear-positive
tuberculosis for the West and North Zones (Table 41.3).
For the South and East Zones, RNTCP has chosen for
operational reasons to use the national ARTI estimate of
1.5% to calculate state-level case detection, despite the
lower incidence estimation from the ARTI surveys.
Two exceptions to be noted are Orissa and Kerala. For
Orissa the state-specific ARTI survey estimate was 1.7%,
the estimated incidence used for new smear-positive
pulmonary TB case detection calculation for Orissa is 85
per 100,000 persons. Similarly, given the results of the
Kerala state-specific ARTI survey, from the year 2007 the
ARTI estimates for the state was revised to 1% (from the
previously applied south-zone average of 1.5%), and the
estimated incidence for NSP case detection calculation is
50 per 100,000 persons.
Prevalence of Tuberculosis Disease

The first estimates of tuberculosis prevalence in India
became available in the 1950s, and the figure of 4/1000
625
for the nation as a whole was accepted then. The findings

of various studies, have been summarized by Chadha.14
Williams et al have suggested that the prevalence rate of
TB fell by 4 to 6% in India between 1990 and 2000.25
Little evidence, however, is available to inform this
assertion. Studies in Bengaluru, 26 Tumkur, 14 and
Chingleput27 districts in South India from the pre-RNTCP
era showed modest to no evidence of change in the
prevalence of tuberculosis. One study carried out in the
BCG trial area in Thiruvallavur district, Tamil Nadu,
showed that in pre-RNTCP era, the prevalence of culture
positive tuberculosis declined by 1.8% per annum, and
smear-positive tuberculosis declined by 2.1% per
annum.28
The prevalence of tuberculosis in India has been
estimated from available ARTI data using the observed
relationship between ARTI and prevalence of bacillary
tuberculosis from Thiruvallavur district.12 Prevalence
estimates from different sources are shown in Table 41.4.
It should be noted that the Government of India
methodology differs from that used by WHO; WHO has
estimated a prevalence of 3304 million persons for all forms
of tuberculosis for the year 2007.1
Mortality and Premature Death

Due to Tuberculosis
Perhaps more than 80% of the burden of tuberculosis
is due to premature death, as measured in terms of
disability-adjusted life years (DALYs) lost. 29 TB
mortality is defined by WHO as the number of TB cases
dying during the treatment, regardless of the cause of
their death. Case fatality rates from India prior to
RNTCP implementation were uniformly high; however,
prior to RNTCP, tuberculosis mortality data were not
collected or analyzed systematically. Therefore, those
figures and comparisons to RNTCP are somewhat
unreliable. Data from specific surveys, however,
suggest that case fatality rates prior to RNTCP were
generally greater than 20%.30
Field surveys in the states of Andhra Pradesh and Orissa
were undertaken to estimate TB specific mortality rates by
Tuberculosis Research Center, Chennai. Unfortunately, the
results of these surveys were inconclusive due to the
operational limitations of the verbal autopsy methodology
to study TB specific mortality.
In the RNTCP era, case fatality has remained below
~5% for new cases. WHO has estimated that in 2007, in
India 331,000 persons died of tuberculosis (rate 28 per
100,000 persons), substantially lower than the 2000
estimate of 381,000 persons (rate 38 per 100,000
persons).1
Lessons from the Model DOTS Project (MDP) Area
on Changes in ARTI and Prevalence of Disease
626

Table 41.4: Results of consecutive ARTI and prevalence surveys in MDP
project area, Tiruvallur District, with RNTCP implementation31,32
19992001
20012003
20042006
% Annual Decrease
Prevalence of Infection (95% CI)
7.8 (7.18.6)
6.9 (6.27.6)
6.0 (5.26.7)
5.8%
Annual Risk of TB infection (95% CI)

Prevalence of TB disease
1.6 (1.51.8)
1.4 (1.31.6)
1.2 (1.11.4)
5.0%
Culture-positive TB (per 100 000 pop)
609
451
311
12.6%
Smear-positive TB (per 100 000 pop)
326
257
169
12.3%
There is some evidence on the effect of RNTCP from the

collaborative TRC/WHO MDP project area in Tiruvallur
district, Tamil Nadu. TB epidemiology in Tiruvallurhas
been closely evaluated by epidemiologists from the
Tuberculosis Research Centre, Chennai, for more than 30
years. RNTCP was implemented in Tiruvallur district in
1999. Three sequential ARTI surveys have suggested that
the incidence of TB in this area has significantly decreased
(Table 41.4).31 Incidence again has been estimated for
consistency using the Styblo conversion, although local
estimates from this area are available.22,24 The annual
rate of decline in the prevalence of infection in children
< 10 years old has been estimated at 5.8%, from the first
survey to the third survey.
The consecutive ARTI surveys provided useful
evidence of the potential effectiveness of RNTCP in
reducing transmission and infection rates. Additional
supportive evidence is available from sequential disease
prevalence surveys in the same area (19992001 and
20042006), demonstrating a change in prevalence of
smear-positive tuberculosis from 326 to 169 per 100,000
persons.33 This corresponds to an annual decline of
12.3%. The rate of decline observed in 5 years of RNTCP
implementation was more than double the 4.3% rate of
decline observed in the same area from 1984 to 1999,
despite the availability of standard short-course chemotherapy throughout.
Although findings from the MDP are not necessarily
applicable to the entire country, this evidence stands as
proof of principle of the effectiveness of the RNTCP DOTS
program on significantly decreasing the burden of TB in
the community.
Progress Towards Millennium Development Goals
(MDGs) with Respect to Reduction in Prevalence and
Mortality Rate
The indicator 23 of the MDGs mentions that between
1990 and 2015 to halve prevalence of TB disease and
deaths due to TB.
TB-related Millennium Development Goal

Goal 6: To combat HIV/AIDS, malaria and other diseases.
Target 8: To have halted by 2015 and begun to reverse the
incidence of malaria and other major diseases, including
tuberculosis.
Indicators for Target 8 to be used to evaluate the implementation and impact of TB control:
Indicator 23: Between 1990 and 2015, to halve the prevalence
and death rates associated with tuberculosis; and
Indicator 24: By 2005, to detect 70% of new smear-positive TB
cases arising annually, and to successfully treat 85% of these
cases
With respect to the progress towards indicator 23, as

per the WHO estimates in the year 1990, the prevalence of
TB in India was 586 per 100,000 populations and the
mortality due to TB was 42 per 100,000 populations. In
comparison, in the year 2007, the prevalence of TB in India
was estimated by WHO to be 283 per 100,000 populations,
and the mortality due to TB is 28 per 100,000 populations.1
The estimates show that India has progressed in reducing
the prevalence rate by 51.8% and mortality rate by 33.3%
(Fig. 41.3).
Researchers have used modeling to demonstrate that
achieving the TB-mortality MDG target will be difficult
without major efforts to reduce mortality among HIVinfected TB patients.25 This interpretation has been
supported by observations from program data, where
higher case fatality rates have been observed from many
areas believed to have relatively high community HIV
seroprevalence. Achievement of the mortality target then
may require rapid scale-up of access to interventions to
reduce mortality in HIV-infected TB patients, particularly
antiretroviral treatment.
As far as the progress towards indicator 24 is
concerned, the country has achieved the targets on case
detection and treatment outcomes, in the year 2007 and
2008 (after whole country coverage). More information
on this indicator is detailed in the section on notification
rates.
627
Fig. 41.3: Progress towards MDG indicator 23
TB in Children and Management

of Childhood TB under RNTCP
Tuberculosis is prevalent worldwide and contagious, and
everyone is at risk of getting infected including children.
Tuberculosis ranks among the ten major causes of mortality
among children. The actual global disease burden of
childhood TB is not known, but it has been assumed that
10% of the actual total TB caseload is found amongst
children.34 In India, the prevalence of primary tubercular
infection in pediatric population is alarming. The annual
risk of tubercular infection is 1.5% in the country and 40%
of children by 16 years have acquired infection. Nearly
10% of infected eventually develop the disease (5% of these
children may be expected to develop TB in the first two
years of life); this large pool of infected people, means that
TB will continue to be a major problem in the foreseeable
future.
Good data on the burden of all forms of TB amongst
children in India are not available. Most surveys conducted
have focused on pulmonary TB and no significant
population based studies on extrapulmonary TB are
available. Pulmonary TB is primarily an adult disease and
it has been estimated that the 0 to 19 years old population
constitute only 7% of the total prevalent cases.35 The
notification of childhood new tuberculosis cases under
the RNTCP has been approximately 6 to 7% of the total
new cases in the country.
Prevention, Diagnosis and Management

of Pediatric Tuberculosis Under RNTCP
In the initial phase of the NTP the major emphasis was
on adults, and very few guidelines are mentioned despite
the fact that the risk of infection and progression to
disease is high in children and the morbidity and
mortality due to severe forms of miliary TB and TB
meningitis is well known. Routine diagnostic tests like
sputum and X-ray are less sensitive and had to be relied
on combination of history, symptoms and signs and
suggestive history of contact with a smear-positive case

and tuberculin test. There were also problems related to
supply of drugs and pediatric formulations. Hence, the
main strategy was preventive, by routine vaccination with
BCG; screening of children with suggestive symptoms
by X-ray and tuberculin, appropriate management of
diagnosed patients; and isoniazid chemoprophylaxis
among contacts of sputum-positive cases.
Hence for RNTCP, there were the issues of underdiagnosis andunder registration of pediatric TB cases in
the program. To seek consensus on improved case detection
and improved treatment outcomes for all diagnosed
pediatric TB cases, a workshop on the Formulation of
guidelines for diagnosis and treatment of pediatric TB cases
under RNTCP was held in New Delhi on 6th and 7th
August 2003. In attendance were National and International Pediatricians, TB experts and TB Control Program
Managers. The consensus on diagnosis, treatment,
follow-up and preventive therapy is summarized below.
Diagnosis
The difficulty in obtaining sputum from children,
nonspecific radiographic findings and the paucibacillary
nature of the disease often makes the diagnosis of
tuberculosis (TB) in children difficult. Clinicians should
suspect pulmonary TB in children presenting with:
Fever and/or cough for more than 3 weeks, with or
without;
Loss of weight/no weight gain; and
History of contact with a suspected or diag-nosed case
of active TB disease within the last 2 years.
Evaluations of some of the many available scoring
systems have shown to have low specificity, which may
lead to over-diagnosis and unnecessary treatment of nonTB patients. Currently, it is not recommended to use such
scoring systems for the diagnosis of patients. Further
screening of TB suspects should be done by:
628
Bacteriological Testing
Pulmonary TB, Smear-negative
Sputum examination should be done wherever possible.

Gastric lavage may be used when sputum is not available.
Multiple samples should be tested by both smear and
culture, if facilities are available.
TB in a patient with symptoms suggestive of TB with

at least three sputum-smear examinations negative
for AFB and radiographic abnormalities consistent
with active pulmonary TB as determined by the
treating Medical Officer followed by a decision to treat
the patient with a full course of anti-tuberculosis
treatment
Or
Diagnosis based on positive culture but negative AFB
sputum-smear examinations.
Tuberculin Test
Mantoux test using 1 TU PPD RT 23 Tween 80 intradermal
should be performed in Pediatric TB suspects. The test
will be read as positive if there is more than 10 mm
induration at 48 to 72 hours. Testing with BCG is not
recommended.
Radiology
Chest X-ray should be taken in upright position PA view.
Radiological lesions are not confirmatory for tuberculosis,
as there are no pathognomonic radiological signs of TB.
However, X-ray findings suggestive of TB include
mediastinal/hilar lymphadenitis with or without
parenchymal lesions, pleural effusion, miliary and
fibrocaseous pictures. Persistent pneumonia beyond 4
weeks in a symptomatic child in spite of antibiotic therapy,
suggests probable TB.
Diagnosis of TB in children should be made by a
Medical Officer. The existing RNTCP case definitions will
be used for all cases diagnosed. Where diagnostic
difficulties are faced, referral of the child should be made
to a pediatrician for further management. A high index of
suspicion must be maintained when the child is aged
< 1 year, there is a recent history of measles/whooping
cough, immunocompromised state and steroid therapy.
Significant superficial lymphadenopathy should be
looked for as it is present in > 40 to 50% of patients.
Children showing neurological symptoms like irritability,
refusal to feed, headache, vomiting or altered sensorium may be
suspected to have TBM.
The existing RNTCP case definitions given are as
follows:
Disease Classification
Pulmonary TB, Smear-positive
TB in a patient with at least two initial sputum-smear
examinations (direct smear microscopy) positive for AFB
Or
TB in a patient with one sputum-smear examination
positive for AFB and radiographic abnormalities
consistent with active pulmonary TB, as determined
by the treating medical officer
Or
TB in a patient with one sputum-smear specimen
positive for AFB and culture-positive for M. tuberculosis.
Extrapulmonary TB
Extrapulmonary tuberculosis TB of any organ other than
the lungs, such as the pleura (TB pleurisy), lymph nodes,
intestines, genitourinary tract, skin, joints and bones,
meninges of the brain, etc. Diagnosis should be based on
culture-positive specimen from the extrapulmonary site,
histological, radiological, or strong clinical evidence
consistent with active extrapulmonary TB followed by
decision of the treating MO to treat with a full course of
anti, TB therapy. Pleurisy is classified as extrapulmonary
TB. A patient diagnosed with both sputum smear-positive
pulmonary and extrapulmonary TB should be labeled as
pulmonary TB.
Types of Cases
New: A TB patient who has never had treatment for TB or
has taken anti-tuberculosis drugs for less than 1 month. A
new case can be either sputum-positive, or sputum-negative
and extrapulmonary.
Previously treated: A TB patient who gives history of
treatment for TB or has taken anti-tuberculosis drugs for at
least 1 month from any source. A previously treated TB patient
can be either a relapse, treatment after default, failure or
others.
Relapse: A TB patient who had been declared cured or
whose treatment had been completed by a physician, but
who reports back to the health service and is now found to
be sputum smear-positive.
Treatment after default: A TB patient who received antituberculosis treatment for at least 1 month from any source
and returns to treatment after having defaulted, i.e. not
taken anti-tuberculosis drugs consecutively for at least 2
months, and is found to be sputum smear-positive.
Failure: Any TB patient who is smear-positive at 5 months
after starting treatment. Failure also includes a patient who
was treated with the Category II regimen but who becomes
smear-positive during treatment.
Others: TB patients who do not fit into the above
mentioned types. Reasons for putting a patient in this type
should be specified.

Transferred in: A TB patient who has been received for
treatment into a TB Unit after starting treatment in another
unit where she/he had been registered.
Treatment of Pediatric TB
DOTS is the recommended strategy for treatment of TB
and all pediatric TB patients should be registered under
RNTCP. Recommended treatment regimens are given in
Table 41.5. Intermittent short-course chemotherapy given
under direct observation, as advocated in the RNTCP,
should be used in children.
Table 41.5 indicates the treatment groups, type of
patients and regimens prescribed.
In patients with TBM on category I treatment, the four
drugs used during the intensive phase should be HRZS
(instead of HRZE). Continuation phase of treatment in
TBM and spinal TB with neurological complications
should be given for 6 to 7 months, extending the total
duration of treatment to 8 to 9 months. Steroids should be
used initially in hospitalized cases of TBM and TB
pericarditis and reduced gradually over 6 to 8 weeks. In
all instances before starting a child on category II treatment,
she/he should be examined by a pediatrician or TB expert
wherever available. As recommended by WHO and in view
of the growing evidence that the use of ethambutol in young
children is safe. Ethambutol is to be used as per RNTCP
regimen for all age groups.
To assist in calculating required dosages and

administration of anti-TB drugs for children, the
medication is made available in the form of combi-packs
in patient-wise boxes, linked to the childs weight (Table
41.6).
Directly Observed Treatment in Children

Administration of DOTS to a child at the center means the
incumbent will have dependability upon either parent,
and could miss the school due to clash with center-timing.
In addition, a female child might be held from seeking
treatment at a public center owing to the social stigma of
disease. However, utilization of service providers has been
shown to result in a successful DOTS execution in TB
patients unable to accept the treatment due to a specific
reason like inconvenient center-timing mingling with job,
study and household work, unavailability of nearby DOTS
center, social stigma or physical disability. With training
and supervision, the mother could serve as a DOTS
provider just like the other community members such as
neighbors, family friends or relatives.
Monitoring
Pediatric-focused monitoring may preferably be an integral
part of the program. Wherever possible, follow-up sputum
examination is to be performed with the same frequency
Table 41.5: Treatment groups, type of patients and regimen prescribed

Regimen1
Intensive Phase (IP) Continuation Phase (CP)
Treatment groups
Type of patient
New
Sputum smear-positive
Sputum smear-negative
Extrapulmonary
Others
Smear-positive relapse
Smear-positive failure
Smear-positive treatment after default
Others2
Treated
2H3R3Z3E3
4H3R3
Previously
2H3R3Z3E3S3/
1H3R3Z3E3
5H3R3E3
Prefix indicates month and subscript indicates thrice weekly.
Table 41.6: Suggested pediatric dosages for intermittent therapy

Dosage
(mg/kg)
6-10
Weight range in kilograms*

11-17
18-25
26-30
Isoniazid
10
75
150
225
300
Rifampicin
10
75
150
225
300
Drug
629
Pyrazinamide
30-35
250
500
750
1250
Ethambutol
30
200
400
600
1000
Streptomycin
15
* Under RNTCP drugs are supplied in patient-wise boxes for children in different weight bands.
630
Fig. 41.4: Algorithm for clinical monitoring of childhood TB patients on treatment
as in adults. Clinical or symptomatic improvement is to be

assessed at the end of the intensive phase of treatment and
at the end of treatment. Improve-ment should be judged by
absence of fever or cough, a decrease in the size of lymph
node(s) and weight gain. Radiological improvement is to
be assessed by chest X-ray examination in all smearnegative pulmonary TB cases at the end of treatment (Fig.
41.4).
Standard treatment outcomes are given for all patients
registered for treatment under RNTCP. The definitions of
these standard treatment outcomes are as follows:
Cured: Initially sputum smear-positive patient who
has completed treatment and had negative sputum
smears, on two occasions, one of which was at the end
of treatment.
Treatment completed: (1) Sputum smear-positive
patient who has completed treatment, with negative
smears at the end of the intensive phase but none at the
end of treatment. (2) Sputum smear-negative TB patient
who has received a full course of treatment and has not
become smear-positive during or at the end of treatment.
(2) Extrapulmonary TB patient who has received a full
course of treatment and has not become smear-positive
during or at the end of treatment.
Death: Patient who died during the course of treatment
regardless of cause.
Failure: Any TB patient who is smear-positive at 5
months or more after starting treatment. Failure also
includes a patient who was treated with Category III
regimen but who becomes smear-positive during

treatment.
Defaulted: A patient who has not taken anti-TB drugs
for 2 months or more consecutively after starting
treatment.
Transferred out: A patient who has been transferred
to another Tuberculosis Unit/District and his/her
treatment outcome is not known.
Switched over to MDR-TB Treatment: A patient who
has been diagnosed as having MDR-TB by an RNTCP
accredited laboratory, prior to being declared as
Failure, and is placed on the RNTCP MDR-TB
treatment regimen is said to have switched over to
MDR-TB treatment.
A patient will have only one outcome. The outcome
which occurs first is considered and recorded in treatment
card and subsequently in the TB register.
Chemoprophylaxis
Chemoprophylaxis is an effective and safe form of
prevention of tuberculosis in childhood because it aims at
the avoidance of development of TB infection into a disease
state. However, the correct dose of isoniazid is still
controversial (5 mg/kg vs. 10 mg/kg). Recent studies36-39
have shown that lower dose given for 6 months is effective
and also has fewer side effects. It has been, therefore,
accepted under the guidelines. Developed countries have
already changed the nomenclature for screening to
targeted tuberculin testing and from preventive therapy to

treatment of latent TB infection in both HIV infected/HIVuninfected patients for elimination of this disease. In India,
because of the epidemiological proportion of disease, efforts
should be made for contact screening of smear-positive
family members especially the mothers. Such contacts (first
targets) should be given isoniazid chemoprophylaxis, so
that spread of the disease can be controlled in pediatric
population. Asymptomatic children under 6 years of age,
exposed to an adult with infectious (smear-positive)
tuberculosis, from the same household, will be given 6
months of isoniazid (5 mg per kg daily) chemoprophylaxis.
Drug-resistant Tuberculosis in Children

The crisis of multidrug resistant TB in adults has been
well documented. However, little attention has been
directed at children also affected by the resurgent TB
epidemic. Drug resistant tuberculosis occurs mainly due
to poor treatment adherence by the patient and poor
management by physicians. Initial drug resistance to
isoniazid is reported to be in the range of 10 to 15% and
for rifampicin, range is 2 to 3%. These rates are much
higher in patients who have taken prior, irregular
treatment. Patterns of drug resistance in children tend to
mirror those found in adult patients in the population.
Proximity to adult patients with multidrug-resistant TB
makes children prone to developing primary multidrugresistant TB, a vulnerability documented in a South
African study.40 As it is difficult to isolate M.tuberculosis
from children with TB, the clue to drug resistance usually
comes from the adult contact. Drug resistant tuberculosis
should be suspected in children if the child is in contact
with a known case of drug resistant tuberculosis; childs
adult contact has been on chronic irregular treatment
and continues to be sputum-positive; adult contact died
after taking irregular treatment; and child shows initial
improvement to anti-tuberculosis treatment but then
deteriorates (clinically and radiologically). Since children
in general have paucibacillary TB, secondary multidrugresistant TB is considered less likely to develop in them,
631
even when the treatment is inadequate. The only

definitive way of diagnosing drug-resistance is by
isolating the strain of M.tuberculosis and assessing its
susceptibility pattern, which takes up to 8 weeks with
culture and drug sensitivity testing (DST).
DOTS-plus services for management of MDR-TB have
been rolled out in 2007 and full country coverage is
expected to be reached by 2012. Under the RNTCPs DOTSplus strategy,41 a MDR-TB suspect is defined as:
Any TB patient who is smear-positive at 5 months or
more after starting treatment with a Cat I or Cat III
regimen (which is also the definition of the treatment
outcome of failure), OR
Any Cat II patient who remains smear-positive at the
end of the fourth month of treatment or later, OR
A contact of a MDR case who is found to be smearpositive, regardless of prior anti-TB treatment.
Patients who meet the definition of MDR-TB suspects in
districts covered under DOTS-plus services are required to
have sputum specimens referred for culture and DST. If the
cases are confirmed by culture and DST, then such patients
are treated with a combination of second line anti-TB drugs.
The MDR-TB case definition is as follows:
An MDR-TB suspect who is sputum-culture positive
and has M. tuberculosis strain resistant to isoniazid and
rifampicin, with or without resistance to other antitubercular drugs based on DST results from an RNTCP
accredited laboratory.
The regimen is as follows:
Intensive phase: 6 months of Kanamycin (inj), ofloxacin,
ethionamide, cycloserine, pyrizinamide and ethambutol (the intensive phase is extended by 3 more
months if the 4th month follow-up sputum culture is
positive)
Continuation phase: 18 months of ofloxacin, ethionamide,
cycloserine and ethambutol
Pyridoxine 100 mg is administered to all patients on
RNTCP MDR-TB treatment regimen.
The dosage and weight band recommendations is given
in Table 41.7.
Table 41.7: The dosage and weight band recommendations

S.No.
Drugs
16-25 kgs
26-45 kgs
>45 kgs
1.
Kanamycin
500 mg
500 mg
750 mg
2.
Ofloxacin
(Levofloxacin)
400 mg
(200 mg)
600 mg
(500 mg)
850 mg
(750 mg)
3.
Ethionamide
375 mg
500 mg
750 mg
4.
Ethambutol
400 mg
800 mg
1000 mg
5.
Pyrazinamide
500 mg
1250 mg
1500 mg
6.
Cycloserine
250 mg
500 mg
750 mg
7.
PAS (80% Bioavailability)*
5 mg
10 mg
12 mg
8.
Pyridoxine
50 mg
100 mg
100 mg
632
Patients on treatment are followed-up during the

intensive phase by monthly sputum culture and during
continuation phase by 3 monthly sputum culture.
TB in HIV Infected Children

HIV infection has a direct and indirect effect on pediatric
tuberculosis. The direct impact is illustrated by rapid
progression of tuberculosis from infection to disease in
children who acquired HIV infection by vertical
transmission. The indirect effect is by the increase in pool
of infected adults thereby increasing the probability of
transmission in the community, including infection of
children. HIV makes diagnosis and management of TB in
children even more difficult than usual, for the following
reasons: several HIV related diseases, including TB may
present in a similar way; the interpretation of tuberculin
skin testing is less reliable; and compliance and completion
of treatment of these children is even more difficult as they
may come from households where either one or both the
parents may be suffering from HIV or may have died. AntiTB treatment is the same for HIV-infected persons as it is
for HIV-negative TB patients. Hence they should be treated
under the DOTS strategy.
Role of BCG in Preventing TB

BCG (bacille Calmette-Gurin) is a live attenuated vaccine
derived from M. bovis. Studies have shown the range of
protection offered by BCG varied from 0 to 80% in different
parts of the world. It has been found to have a definite benefit
in protecting young children against disseminated and
severe TB, e.g. TB meningitis and miliary TB. BCG has little
or no effect in reducing the number of adult cases of pulmonary TB. World Health Organization recommends BCG
for all children except children with symptoms of HIV
disease/AIDS in countries with high prevalence of
tuberculosis.
CONCLUSION
DOTS is effective in treating Pediatric TB, as in adults. There is
a need to quickly implement the Management Guidelines of
Pediatric TB under RNTCP within the country to effect the
control of childhood TB.
REFERENCES
1. Global tuberculosis control epidemiology, strategy,
financing. 2009 WHO Report. Geneva, World Health
Organisation. WHO/HTM/TB/2009. 411.
2. Rieder HL. Oppurtunity for exposure and risk of infection:
The fuel for tuberculosis pandemic (editorial). Infection
1995; 23: 1-4.
3. Rieder HL, (Ed). Epidemiological basis of tuberculosis
control. 1st Edition ed: International Union Against
Tuberculosis and Lung Diseases, Paris. 1999.
4. Eamranond P JE. Tuberculosis in children: Reassessing

the need for improved diagnosis in global control
strategies. Int J Tuberc Lung Dis 2001; 5: 594-603.
5. Arora VK. Issues in pediatric tuberculosis under DOTS
strategy (Editorial). Indian Pediatrics 2004; 41: 891-3.
6. History of Tuberculosis Control in India. Available from
http://www.tbcindia.org/history.asp. Central Tuberculosis
Division, Directorate General of Health Services, Ministry of
Health and Family Welfare, Government of India.
7. Tuberculosis in India: A national sample survey 1955-58.
ICMR technical report series. Indian Council of Medical
Research (ICMR), 1959, New Delhi.
8. Center TC. A concurrence comparison on home and
sanitarium treatment of pulmonary tuberculosis in south
India. Bull Wld Hlth Org: 1959; 21-51.
9. Banerji D. A sociological study of awareness of symptoms
among persons with pulmonary tuberculosis. Bull World
Health Organ 1963; 29: 665-683.
10. Tuberculosis Prevention Trial, Madras; Trial of BCG
vaccines in south India for tuberculosis prevention. Indian
J Med Res 1980; 72: 1-74.
11. Census of India, 2006: Population Projections for India
and States, 2001-2026. New Delhi, India 2006; Office of
the Registrar General and Census Commissioner, India.
12. Gopi PG, Subramani R, Santha T, et al. Estimation of
burden of tuberculosis in India for the year 2000. Indian J
Med Res 2005; 122: 243-8.
13. Chadha VK. Tuberculosis epidemiology in India: a
review. Int J Tuberc Lung Dis 2005; 9: 1072-82.
14. Gothi GD, Chakraborty AK, Nair SS, et al. Prevalence of
tuberculosis in a South Indian district twelve years
after the initial survey. Indian J Tuberc 1979; 26: 121-35.
15. Chakraborty AK, Chaudhuri K, Sreenivas TR, et al.
Tuberculous infection in a rural population of south India:
23-year trend. Tuber Lung Dis 1992; 73: 213-8.
16. Chadha VK, Vaidyanathan PS, Jagannatha PS, et al.
Annual risk of tuberculous infection in the northern zone
of India. Bull World Health Organ 2003; 81:573-80.
17. Chadha VK, Kumar P, Gupta J, et al. The annual risk of
tuberculous infection in the eastern zone of India. Int J
18. Chadha VK, Vaidyanathan PS, Jagannatha PS, et al.
Annual risk of tuberculous infection in the western zone
of India. Int J Tuberc Lung Dis 2003; 7: 536-42.
19. Kolappan C, Gopi PG, Subramani R, et al. Estimation of
annual risk of tuberculosis infection (ARTI) among children
aged 1-9 years in the south zone of India. Int J Tuberc
Lung Dis 2004; 8: 418-23.
20. Chadha VK, Kumar P, Jagannatha PS, et al. Average
annual risk of tuberculous infection in India. Int J Tuberc
Lung Dis 2005; 9: 116-8.
21. Chadha VK. Annual risk of tuberculosis infection, Kerala
2006. Indian J Tuberc 2009; 1: 1-10.
22. Styblo K. The relationship between the risk of tuberculosis
infection and the risk of developing infectious tuberculosis.
Bull Int Union Tuberc Lung Dis 1985; 60: 117-99.
23. van Leth F, van der Werf MJ, Borgdorff MW. Prevalence
of tuberculous infection and incidence of tuberculosis: A
reassessment of the Styblo rule. Bull World Health Organ
2008; 86: 20-6.

24. Gopi PG, Subramani R, Santha T, et al. Relationship of
ARTI to incidence and prevalence of tuberculosis in a district
of south India. Int J Tuberc Lung Dis 2006; 10: 115-7.
25. Williams BG, Granich R, Chauhan LS, et al. The impact of
HIV/AIDS on the control of tuberculosis in India. Proc
Natl Acad Sci USA 2005; 102: 9619-24.
26. National Tuberculosis Institute, Bangalore. Tuberculosis
in a Rural Population in South India: a five year
epidemiological study. Bull World Health Organ 1979;
51: 473-88.
27. Tuberculosis Research Centre, Chennai. Trends in the
prevalence and incidence of tuberculosis in south India.
28. Gopi PG, Subramani R, Radhakrishna S, et al. A baseline
survey of the prevalence of tuberculosis in a community
in south India at the commencement of a DOTS program.
29. Dye C. Global epidemiology of tuberculosis. Lancet 2006;
367: 938-40.
30. Datta M, Radhamani MP, Selvaraj R, et al. Critical
assessment of smear-positive pulmonary tuberculosis
patients after chemotherapy under the district tuberculosis
program. Tuber Lung Dis 1993; 74: 180-6.
31. Gopi PG, Subramani R, Narayanan PR. Trend in the
prevalence of TB infection and ARTI after implementation
of a DOTS program in south India. Int J Tuberc Lung Dis
2006; 10: 346-8.
32. Subramani R, Radhakrishna S, Frieden TR, et al. Rapid
decline in prevalence of pulmonary tuberculosis after
DOTS implementation in a rural area of South India. Int J
Tuberc Lung Dis 2008; 12: 916-20.
633
33. Subramani R, Santha T, Frieden TR, et al. Active

community surveillance of the impact of different
tuberculosis control measures, Tiruvallur, South India,
1968-2001. Int J Epidemiol 2006.
35. Chakraborty AK. Prevalence and incidence of tuberculosis infection and disease in India: A comprehensive
review: World health Organization, Geneva, Switzerland
1997.
36. Seth Vimlesh, Seth SD, Beotra A, et al. Monitoring of
isoniazid and rifampicin in childhood tuberculosis. Am
Rev Respir 1990; 141: 337.
concentrations of rifampicin and isoniazid in tuberculosis.
Indian Pediatr 1993; 30: 1091-8.
38. Beotra A, Seth Vimlesh, Mukhopadhaya S, et al. Serum
rifampicin and isoniazid level in children with tubercular
infections. Eur J Pharmacol 1990; 183: 2389.
39. Seth Vimlesh, Seth SD, Beotra A, et al. Isoniazid and acetyl
isoniazid kinetics in serum and urine in pulmonary
primary complex with intermittent regimen. Indian
Pediatr 1994; 31: 279-85.
children in contact with adult multidrug-resistant
pulmonary tuberculosis: A 30-month follow-up. Pediatrics
2002; 109: 765-71.
41. DOTS plus Guidelines of the Revised National
Tuberculosis Control Program. Central Tuberculosis
Division, Directorate General Of Health Services, Ministry
of Health and Family Welfare, Government of India 2009.
42
Frequently Asked Questions

about Tuberculosis
THE BROAD STATUS OF TUBERCULOSIS AT PRESENT IN

THE WORLD
Points to Ponder about the Problem of Tuberculosis
More young people from the affluent classes are falling
prey to the poor mans disease. In this group immunity
gets compromised due to stress and poor diet (not due
to nonavailablity of food) in a bid to keep their weights
under control. This leads to easy susceptibility to
infection. At the rate of 2.4% new cases, in Delhi itself
there is crop of 3 lakh fresh TB cases every year. Delhi is
one of the two states where the second line TB treatment
DOTS plus has been kicked off to tackle the drug resistant
TB burden. The worrying point is the young victims of
disease. Estimation of this group is never done officially.
This is because of the endemic nature of the disease, all
of us harbour the bug in a latent form. Stress like before
examination or crash dieting to loose weight, late night
shifts at works place can all be the causative factor for
lowered immunity. Another surprising observation
which is a cause of alarm that it is not the pulmonary
tuberculosis which is the commonest, brain and bone TB
are on the rise. Lymphnodal tuberculosis is another
annoying type of disease presentation. In these types the
sputum test is often negative for AFB and xray chest is
often normal. Incidence of spinal tuberculosis in affluent
young is another cause of concern. Again, the definition
of good food, i.e. milk and milk products, fresh fruits
and vegetables have been replaced by junkfood. This
lowers the immunity by causing malnutrition and
making children more vulnerable to opportunistic
infections like TB. Upto 2006 the tackling of problem of
tuberculosis was on an accelerating scale as shown in
the following pamphlet prepared for March 24, 2007
World TB Day in Delhi.
THE SLOGAN WAS TB ANYWHERE IS TB

EVERYWHERE, ONLY PEOPLE CAN STOP TB
Revised National TB Control Program, National
Capital Territory of Delhi
DOTS the best strategy to control TB
Eight folds increase in the number of TB patients treated
from 5582 (1997) to an all time record number of 47,536 (2006)
The case detection rate for new infectious patients has been
increased four folds from 20% (1997) to 91% (2006) against
the international target of 70%
The treatment success rate of all types of TB patients
increased from 3 folds from 30% (1996) to 87% (2006)
Ten fold decline in the TB death rate from 20% (1996) to
2% (2006), therefore, averting 9507 deaths due to TB
Five fold increase in DOT centers from 108(1999) to 540
(2006) with fifty fold increase in NGO participation from
3 centers (1999) to 150 centers (2006).
These above statements of figures of various aspects

of National Control Program are very encouraging.
However, the success of implementation when the
program is carried out with in the existing health
program of the government, the figures do not remain
that rosy.
Untreatable TB Strain Causes Alarm

A survey conducted by WHO and US Center for Disease
Control on data from 2000 to 2004 found that XDR-TB is
most frequent in countries of the former Soviet Union
and Asia. The XDR-TB strain mixing with the AIDS virus,
is causing nearly 100% mortality.
The above fact is a great public health threat that is
taking alarming proportions. A virtually untreatable
form of tuberculosis extreme drug resistant TB (XDRTB) is spreading all over the world, including India.
South Africa is worse affected by the strain and it is being
discussed at the policy level as to how to manage this
deadly strain. Out of 53 patients with XDR-TB, 52 died
in South Africa with in 210 days between January 2005
and March 2006. Deaths occurred on an average with in
25 days even in those HIV patients who were on
antiretroviral drugs. Even in United States of America
which has the best of medicines available, a third of those
who were diagnosed XDR-TB died. Presence of HIV/
AIDS patients in South Africa and India makes it very
worrying.
At present XDR-TB problem is small in India but it is
there. India, like South Africa has prepared its guidelines
keeping in view the severe burden of HIV. India has taken
the initiative of undertaking a survey to guage the extent
Chapter 42 Frequently Asked Questions about Tuberculosis

of XDR-TB presence specially in a high HIV burden area
like Mumbai.
The Government of India should:
i. Increase the number of laboratories to diagnose TB
cases.
ii. Improve management of clinical cases.
iii. Strengthen basic TB care to prevent emergence of
drug-resistance.
iv. Increase collaboration between HIV and TB control
programs to provide necessary prevention and care
to patients infected with both.
As per records of Health Ministry of India, over 3%
of the fresh cases are suffering from XDR-TB while over
12% of old cases undergoing treatment have developed
this strain.
The new strain is not only resistant to isoniazid and
rifampicin, the two important drugs in the first line but
also to the six classes of drugs used for second-tier
therapy.
TB has also become the single largest killer of AIDS.
National AIDS Control Organization (NACO) recently
revealed that over 60% of all AIDS patients contract and
ultimately die of TB. NACO has now decided to scale up
and integrate the National AIDS and TB control programs
from 2006. Every year 1.8 million new TB cases occur in
India of which 0.8 million are infectious.
Unless treated properly every infectious
pulmonary TB patient can infect 10 to 15 persons in a
year. Improperly treated patient can develop resistance
which is potentially untreatable. Since 1968, no new
drugs have been discovered and the germs have started
to develop drug resistances. To keep the infected
patients away from noninfected patients seems to be
an extreme step in South Africa, by forcibly detaining
the patients who refuse treatment. The other measures
taken are trying to ensure better surveillance,
diagnostics and availability of drugs. This has been done
because of the detection of XDR-TB. The clue has been
taken from New York City Health authorities who
authorized the forcible detention of people upto two
years, if required, who refused TB treatment. This led
to a significant dip in cases. It is now simpler because
of short-course strategy of treatment. Most of these
patients had coinfection with HIV. Presence of high
number of HIV/AIDS patients in South Africa and India
makes it very worrying.
Status of Drug-resistant TB Cases Infecting

HIV-Positive Patients in India
Experts who conducted this study almost warned
officials of TB-control program that they must stop
denying that XDR-TB cases exist in India. Extensively
drug-resistant tuberculosis (XDR-TB), the untreatable
form of TB has started to infect HIV-positive cases in
635
India. An AIIMS study (Clinical Microbiology

Department) has revealed that of those enrolled for the
study with both HIV and TB a very high percentage were
suffering from XDR-TB. All the patients died with in three
months of diagnosis.
Resistance Pattern of Strains Isolated

Fifty four patients having HIV-TB coinfection
investigated in 2006, 24 (44.4%) strains of tubercle bacilli
were isolated, 12(50%) of these had resistance to isoniazid
and rifampicin (the first line drugs) where as 4 (33.3%)
were resistant to second line drugs as well. It seems from
this data that XDR-TB exists in India. The extent need to
be evaluated. This infection is a great public health threat.
Researchers from Hinduja National Hospital in Mumbai
first found XDR-TB in 8% of all TB patients. The sample
examined by them was pretty large (3904), in which 1274
were positive for TB. In these 32% were multidrugresistant (MDR-TB) and of this 8% were XDR-TB. They
reported only 42% mortality. This pattern of resistance
is attributed to the failure of the physician to prescribe
proper treatment regimen or due to the fault of the
patient. In the latter, the patient, who is already suffering
from MDR-TB, does not complete lengthy course of
therapy.
In India, it is just in two laboratories in Gujarat and
Maharashtra where MDR-TB is being diagnosed. Fifty
people have been put on DOTS Plus treatment. The
reports from Tuberculosis Research Center (TRC)
Chennai are that out of 1200 TB samples sent by
laboratory in Gujarat, only 200 are MDR-TB. As
emphasized already 60% of all AIDS patients contract
TB and India has to be prepared to face the challenge of
XDR-TB before it is too late.
Fight Against AIDS, TB Gets $100 Million Boost

(December 22, 2007)
The Global Fund to Fight AIDS, Tuberculosis and
Malaria is accredited by the G-8 group of industrialized
nations in 2002. An agreement has been signed with
the Department of Economic Affairs allocating over $100
million to fight AIDS. This has added to the Indias
becoming largest beneficiary of charity in Asia. Out of
the total funds, 80% is being used to fight AIDS. This
big grant of $100 million will help India buy secondline drugs for AIDS from UNITAID or Clinton
Foundation, purchase machines to estimate viral load,
strengthen antiretroviral treatment programs, support
voluntary counseling and testing services. With the
Switzerland-headquarters International Charitys
Support to India has provided antiretroviral treatment
to 80,000 people having AIDS. TB treatment has been
given to 245,000 people.
636
Government Clubs AIDS, TB-Control Drives

(June 2008)
Tuberculosis being the biggest killer of HIV patients in
India. To meet the challenge of double blow, India has
now integrated the National AIDS and TB Control
Programs. Under this program, all patients diagnosed
with TB will be offered free HIV testing in the countrys
4567 integrated counseling and testing centers (ICTC).
Once detected with this coinfection, the patient will be
provided a prophylactic treatment with cotrimoxazole
to prevent opportunistic infections like pneumonia. This
has been the recommendation of WHO. The patient then
will be referred to the closest antiretroviral (ART) center
for treatment.
This intensified TB/HIV services package will first
be rolled out in nine states with high prevalence of both
HIV/TB cases. These states are Manipur, Nagaland,
Tamil Nadu, Andhra Pradesh, Karnataka, Maharashtra,
Meghalaya, Puducherry and Goa.
In these states all TB patients irrespective of their life
style, will be offered HIV testing. At the same time
selective testing for HIV will continue on those cases of
diagnosed TB, if they have high risk behavior and are
suffering from sexually transmitted infections. Rough
estimate is that 50,000 to 80,000 people suffer from HIV/
TB co-infection in India. One needs pretty aggressive
measures to locate them. Opening of more integrated
counseling and testing centers (ICTC) will help to achieve
this goal.
As per report of WHOs consultant at the central TB
division of Ministry of Health and Family Welfare, out
of all known cases of TB, 1.2% are presently HIV positive.
Like ICTCS, which test for HIV, Indias Revised National
TB Control Program (RNTCP) has 12,000 designated
microscopy centers (DMC). Each of these DMCs are
established for every one lakh population.
HIV and TB testing facilities in all these nine states
are decentralized and are near to each other. Once a
person is diagnosed for TB, he/she will be offered
voluntary free testing for HIV. If found positive she/
he will be counseled, put on prophylactic treatment for
HIV and sent to the nearest ART center on priority basis.
Once a person is identified with coinfection it will be
ensured that the patients are following proper treatment
regime. Of the 2.5 million HIV infected Indians, over
10% are expected to have full blown AIDS. Every AIDS
patient has 15% chance of developing TB every year. Due
to stigma attached with both the diseases, patients fail
to seek treatment. World figures for coinfection are
14 million.
General Information about Tuberculosis (TB) in Children

TB is a major killer of children in poor countries
TB kills more young people than any other single
infectious disease. Every minute two children die of TB
worldwide.
Tuberculosis in children is neglected: Pediatric TB does
not have a high priority in many developing countries as
fewer children than adults have the disease and children
are not usually infectious. Limited resources mean that
infectious cases have priority.
Vaccination is not 100% effective: The TB vaccine, bacilli
Calmette Guerin (BCG), does limit some of the severe
forms of tuberculosis which are unique to young children,
but by no means prevents them all. Tens of thousands of
immunized children in the developing world still
suffer from tuberculous meningitis and other forms of
disease.
Children are highly susceptible to tuberculosis: The power
to resist TB infection is normally poor in the first 5 years
of life. The resistance can be further reduced by
malnutrition, human immunodeficiency virus (HIV),
other childhood infections and worm infestations all
too common childhood conditions in poor countries. It
has been estimated that as many as one third of the
worlds population is infected with TB, and an estimated
20 to 50% of children who live in households where an
adult has active tuberculosis become infected. Children
are especially vulnerable to infection from household
contacts as they are often held close and breathed on.
The risk is particularly high in the developing world
where family size is large, living quarters are crowded
and more than half the population are children.
Traditional diagnostic methods of TB in children are
ineffective: A vast number of children infected remain
undiagnosed creating a reservoir of future adult
disease. Diagnosis is difficult in children, and often fatally
delayed early symptoms and signs of tuberculosis in
children are common and easily missed. Lung TB is
particularly difficult to diagnose early as childrens lungs
react differently than adults, and they have little or no
cough (thus not being able to provide sputum for testing).
Microscopic examination only occasionally reveals the
characteristic tubercle bacilli.
TB can have devastating long term effects on children:
They can be left deaf, blind and/or totally paralysed from
TB meningitis, even after it is cured. Spread of infection
to the bone can cause deformities of the spine
(hunchback) or other permanent disabilities.

TB exacerbates poverty: It makes the patient and their
family poorer because they may have to pay for treatment
themselves, and even if TB drugs are free there is often a
cost of traveling to clinics and loss of wages for that day.
If they cannot afford this they may default from
treatmentleading to the added complication of drug
resistance. Children with TB lose out the vital years of
their education, which can affect their future wageearning capacity.
Misconceptions about TB in Children

Childhood tuberculosis is neglected in endemic areas with
resource constraints, as children are considered to develop
mild forms of disease and contribute little to the
maintenance of the tuberculosis epidemic. However,
children contribute a significant proportion of the disease
burden and suffer severe tuberculosis-related morbidity
and mortality, particularly in endemic areas. The
prechemotherapy literature that described the natural
history of disease in children identified three central
concepts: (1) the need for accurate case definitions, (2) the
importance of risk stratification, and (3) the diverse
spectrum of disease pathology, which necessitates accurate
disease classification. The concepts are also linked to the
basic principles of antituberculosis treatment, providing a
simplified approach to the diagnosis and treatment of
childhood tuberculosis that is independent of resource
constraints. The main challenges for future research are
the development of a new BCG vaccine. It is worth
emphasizing that the infrastructure provided by the
directly observed therapy, short course strategy, combined
with well-targeted interventions, slightly improved
resources, and greatly improved political commitment,
may lead to a dramatic reduction in tuberculosis-related
morbidity and mortality among children.
How is Tuberculosis in Children

Different from Adults?
It is important to realize that tuberculosis (TB) in children
is very different from that in adults as far as its mode
of clinical presentation, severity of the disease,
infectiousness, diagnosis, treatment and overall outcome,
i.e. prognosis, are concerned. In nearly 80% of all
tuberculosis cases in children, the disease is localized as
primary pulmonary tuberculosis. The symptoms of
tuberculosis in children are usually vague, viz. low grade
fever, cough, failure to gain weight or weight loss, poor
appetite and laziness, i.e. child is not active. The spectrum
of severity of disease ranges from the uncomplicated
asymptomatic Mantoux positivity (ASMP), symptomatic
Mantoux positivity (SMP), primary pulmonary complex
to miliary and cavitary forms of pulmonary tuberculosis,
and from tuberculous lymphadenitis to disseminated
637
forms viz tuberculous meningitis (TBM). Tuberculous

lymphadenitis, osteoarticular tuberculosis and TBM are
the extrapulmonary manifestations. The bacillary load of
tuberculosis is far less in tuberculosis in children than in
the adult type. The disease is generally noninfectious in
children and response to therapy is good.
Transmission of TB to Children
The source of transmission of TB to a child is usually an
adult (usually a family member) with sputum smearpositive pulmonary (PTB).
Public Health Importance

Cases of TB in children usually represent between 5 to
15% of all TB cases. The frequency of childhood TB in a
given population depends on the: (i) the number of
infectious cases, (ii) the intensity of transmission, and (iii)
the age structure of the population. Children rarely have
sputum smear-positive TB. So they are less commonly
infectious. TB in children is, therefore due to failure of
TB control in adults. Failure of TB control in adults means
failure to cure the infectious cases (patients with sputum
smear-positive PTB).
A Good TB Control Program is the Best Way to Prevent

TB in Children
The highest priority in TB control is to cure the infectious
cases. Children are rarely infectious. However, it is still
important to cure them. Good treatment of TB in
childhood will result in the following: (i) decreased
morbidity and mortality; (ii) improved National
Tuberculosis Control Program credibility and reputation
(iii) decrease in the transmission.
Risk of Infection
Risk of infection depends on two factors: (i) extent
of exposure to infectious droplet nuclei, and
(ii) susceptibility to infection. Consider an infant whose
mother has sputum smear-positive PTB. The infant has a
high risk of acquiring infection: mother and infant are in
very close contact; immune defences are poor. An infant
with HIV infection has an even greater susceptibility to
infection with tubercle bacilli.
Risk of Progression of Infection to Disease

The vast majority of HIV-negative children infected with
M. tuberculosis do not develop TB disease. In these
healthy, asymptomatic, but TB-infected children, the
only evidence of infection may be a positive tuberculin
skin test. However, an infected child can develop TB
disease at any time. The chance of developing disease
638
is greatest shortly after infection and then steadily

decreases as time goes by. Possibility of progression
from infection to disease is very high (up to 50%) in
first year after infection in young children specifically
infants. Various physical or emotional stresses may
trigger progression of infection to disease. The most
important trigger is weakening of immune resistance,
especially by HIV infection. Other important triggers
include other infections (especially measles and
whooping cough) and malnutrition.
Pathogenesis
The usual route of infection and early sequence of events
in primary pulmonary infection are similar in adults and
children. TB disease in children is usually primary TB. A
child may have asymptomatic M. tuberculosis infection:
the tubercle bacilli can lie dormant for many years. If the
tubercle bacilli reactivate some years later, causing
postprimary TB, the child has usually grown into an adult
by then. The age when a child is infected determines the
pattern of primary disease. Up to puberty, blood-borne
spread is common. This results in disseminated (miliary
and extrapulmonary) disease. At puberty, pulmonary
spread is more common and cavitary manifestations may
occur.
How is Tuberculosis in Children Diagnosed?

It is the high index of suspicion in a child pre-senting
with vague clinical symptoms (as already mentioned)
and a history of tuberculosis in family that leads a
pediatrician into investigating the child for tuberculosis.
Tuberculin Skin Test (Mantoux Test)

Tuberculin is a purified protein derived from tubercle
bacilli. Thus, another name for tuber-culin is PPD
(Purified Protein Derivative). Following infection with
M. tuberculosis, a person develops hypersensitivity to
tuberculin. Tuberculin injected into the skin of an infected
person produces a delayed local reaction after 24 to 48
hours. We quantify this reaction by measuring the
diameter of skin induration (thickening) at the site of the
reaction. Various conditions may suppress this reaction.
The reaction indicates hypersensitivity. In other words,
the reaction only shows that the person has at some time
had infection with M. tuberculosis.
A tuberculin test does not measure immunity. By
itself, it does not indicate the presence or extent of
tuberculosis disease; it only indicates infection.
A positive tuberculin skin reaction, i.e. the Mantoux
test, in the form of an induration and not redness, of 10
mm or more after 48 to 72 hours, to 2 tuberculin unit
(1TU) of purified protein derivative (PPD) RT23 with
tween 80, or any dose equivalent to 5 TU PPD-S is highly

indicative of tuberculous infection.
A tuberculin test is negative when the diameter of
skin induration is less than 10 mm. This is regardless of
whether or not the person has had BCG. A negative
tuberculin skin test does not exclude TB. In other words,
a negative test is of no help in deciding that the child
does not have TB.
Conditions Which May Suppress

the Tuberculin Skin Test
HIV Infection
Malnutrition
Severe bacterial infections, including TB itself
Viral infections, e.g. measles, chickenpox, glandular fever
Immunosuppressive drugs, e.g. steroids, cancer
chemotherapy.
BCG and Tuberculin Skin Test Results

Tuberculin test may show some induration after BCG
vaccination for many years. This reaction is usually a
weaker reaction (diameter often less than 10 mm) than
the reaction to natural infection with M. tuberculosis.
Therefore, in a child who has not had BCG, a tuberculin
test is positive when the diameter of skin induration is
10 mm or more. In a child who has had BCG, a test may
be considered positive if the diameter of induration is 15
mm or more. This too only in the first year of BCG
vaccination. A positive tuberculin test is only one piece
of evidence in favor of the diagnosis of TB. The younger
the child and the greater the diameter of induration
(above 10 to 15 mm), the stronger is that one piece of
evidence.
Interferon- Release Assays (IGRAs)

The peripheral blood sample is used for testing for these
assays. The sensitized T-cells from infected child release
interferon- (IFN-). There are two commercial IGRAs
namely Quanti FERON- and T-SPOT. TB are available.
The advantage of these is that they are not interfered in
individuals given BCG and those exposed to
nontuberculous Mycobacterium. However, they can not
be used in isolation as the diagnostic test. Need to be
considered with other tests and clinical symptomatology.
At present these are given lot of importance in the
diagnosis of latent tuberculosis.
X-ray Chest
Showing a parenchymal (P) lesion, or enlarged
mediastinal lymph nodes (N) hilar, paratracheal,
subcarinal or ductal, or a combination of them (P+N) will

indicate the pulmonary primary complex (PPC). A
lesion showing consolidation or collapse or a
combination of collapse consolidation or cavitary lesions
or miliary shadows indicate a progressive primary
disease (PPD) form. Calcified lesions of P, or N or P+N,
or fibrocalcific lesions indicate healed lesions and are
termed as postprimary lesions (PPL).
Gastric Lavage/Induced Sputum

Acid fast bacilli (AFB) can be seen in properly collected
early morning gastric lavage samples in nearly 1/4th of
cases particularly in infants and young children with
PPD, miliary or disseminated tuberculosis. Application
of new rapid laboratory techniques hasten the diagnosis
both with more sensitivity and specificity.
Role of Nonculture Techniques (ELISA) in

the Diagnosis of Tuberculosis in Children
Investigations based on serological assay enzyme linkedimmunoassay (ELISA) is being used very often for
making diagnosis of TB in children thinking that ELISA
is the panacea for diagnosis of tuberculosis. It is a Myth.
The sensitivity and specificity vary with the use of
different antigens and there is lot of overlap. Hence,
ELISA is not recommended as a diagnostic tool. As it is, there
is over-diagnosis of PPC, but with the use of ELISA as a
diagnostic test, it will add to overtreatment.
No discussion on diagnosis for tuberculosis is
complete without the mention of polymerase chain
reactions (PCR). It is still a research tool and is not
recommended for routine use. It is very important to
mention because this is in fashion investigation. In India
there are sophisticated private laboratories, which are
capable of doing this test at exorbitant rates.
Fine needle aspiration cytology (FNAC) or biopsy. AFB
staining, histopathology may establish the diagnosis of enlarged
cervical/axillary or inguinal nodes.
CSF examination, CT scan and now, MRI study of the brain
which show basal exudates and/or ventricular dilatation
help in the diagnosis of TBM.
Besides these, the features assisting in the diagnosis are: A
positive family history, severe proteinenergy malnutrition, and
history of measles or pertussis in previous 3 months. In cases
where Mantoux test is negative, persistence of constitutional
symptoms, excessive irritability, convulsions or paresis or
paralysis, a positive X-ray chest film and the lesion not
responding to antibiotic therapy for two to three weeks with
good compliance also assist in diagnosis.
To Summarize Following is the Approach

to Diagnose TB in Children
If you find the diagnosis of TB in children easy, you are
probably over-diagnosing TB. If you find the diagnosis
of TB in children difficult, you are not alone. It is easy to
639
overdiagnose TB in children. It is also easy to miss TB in

children. Carefully assess all the evidence before making
the diagnosis.
Adults with PTB usually present with cough and
sputum. Although sputum culture is the definitive test,
in practice the readily available usual gold standard
test for adults with PTB is sputum-smear microscopy.
However, there is no such gold standard test in
children. TB in children is a general disease which may
appear in any part of the body. Also, under the age of 10
years, children with PTB rarely cough up sputum. They
usually swallow their sputum. Gastric suction and
laryngeal swabs are generally not useful unless facilities
are available for M. tuberculosis culture. Induced sputum
can help in getting the specimen for smear and culture
for AFB. The diagnosis of TB in children is, therefore,
nearly always presumptive. This means that bacteriological
confirmation is usually not possible. This situation in
children is similar to that in adults with sputum smearnegative PTB or extrapulmonary TB.
The clinical features are constitutional and local
(depending on the part of the body affected). The local
clinical features related to the site of disease are similar
in children and adults. The diagnosis rests on consistent
clinical features and investigation findings. If available,
a tuberculin skin test maybe helpful. In most cases of
suspected PTB, the child has usually received treatment
with a broad-spectrum antibiotic, with no clinical
response. In some hospitals, helpful special diagnostic
investigations maybe available. These may include
specialized X-rays, fine needle aspiration cytology,
biopsy and histology, and TB culture.
Always look for the following two important clues
to TB in children:
i. It is usually possible to identify the adult source of
infection.
ii. Failure to thrive or weight loss (growth faltering).
In the absence of these two clues, TB is less likely.
PRACTICAL POINT
Ask the mother of a child with suspected TB for the childs
road to health card (growth card). Look at the card for
growth faltering or weight loss
Scoring systems have no role in the diagnosis of TB in
children.
How should a pyogenic parenchymal lesion in X-ray

chest be differentiated from a tuberculous one?
I would stress, particularly to general practitioners and
the pediatricians, that in the presence of a positive
Mantoux test, antituberculosis therapy should not be
started right-away if an X-ray chest shows only a
parenchymal lesion. A course of suitable antibiotics in
640
adequate dosage should be given for 7 to 10 days and an

X-ray chest should be repeated after 3 to 4 weeks to see
the resolution of lesion. A pyogenic parenchymal lesion
will either resolve completely or to a significant extent;
whereas a tuberculous lesion will remain as such.
However, in presence of mediastinal adenopathy and
positive Mantoux test, chances of tuberculosis are high
and it is justified to start therapy for tuberculosis
Clinically, a child with pyogenic infection generally
presents with acute onset with comparatively more
vigorous symptoms than a patient with tuberculosis. If
the X-ray chest shows interstitial pattern, then associated
bronchial asthma and eosinophilia should be ruled out
by proper clinical examination and by absolute
eosinophil count. A clear-cut consolidation associated
with collapse is more often due to tuberculosis than
pyogenic infection unless there is associated history of
foreign body inhalation. Thick secretions due to the
bursting of tuberculous lymph nodes into bronchi can
result in collapse due to blockage of bronchial tree.
What do the terms SMP and ASMP denote?

SMP stands for symptomatic Mantoux positive case and
ASMP for asymptomatic Mantoux positive case. These
terms are used to denote substantially large groups of
children who are Mantoux test positive but have a normal
chest X-ray (whether symptomatic or asymptomatic).
Do children falling in these groups need to be treated?

Yes, indeed! I have studied the CT scan of chest of some
of these patients and surprisingly found that they had
enlarged mediastinal lymph nodes which were not
visible in the plain X-ray chest. A few of these (untreated)
did show hilar lymphadenopathy in the Xray film after
2 months and became symptomatic. Therefore, these
groups, particularly those below 5 years of age and
during adolescence need adequate treatment. However,
it is mandatory to rule out other causes for the symptoms.
For symptomatic children with positive Mantoux test,
appropriate category of treatment should be started. For
asymptomatic children with positive mantoux test a
chemoprophylaxis in the form of 6 months of isoniazid
may be started presuming it to be a recent converter.
Questions and Answers About Case Definitions

Why make case definitions? There are two purposes:
a. To determine treatment.
b. For recording and reporting.
Why do case definitions determine treatment? There
are three reasons:
a. To identify priority cases.
b. To make the most cost-effective use of resources (by
targeting resources on priority cases).
c. To minimize side effects for patients (by using the

most intensive regimens only for certain cases).
What determines a case definition? There are four
determinants:
a. Site of TB
b. Result of sputum smear
c. Previous TB treatment
d. Severity of TB.
Always ask a new TB patient if he or she has ever had
TB treatment before. The following gives a description of case
definitions.
Case Definitions by Site and Result of Sputum Smear

PTB
Smear-positive case: At least 2 sputum smears positive for
AFBs OR 1 sputum smear positive for AFBs and chest
X-ray abnormalities consistent with active TB.
Smear-negative case: At least 2 (and preferably 3)
sputum smears negative for AFBs and chest X-ray
abnormalities consistent with active TB. In most cases,
the patient will have had treatment with a broadspectrum antibiotic, with no response.
The following are forms of extrapulmonary TB:
pleural effusion (pleura are outside the lungs); hilar
lymphadenopathy (hilar lymph nodes are outside the
lungs); miliary (TB is widespread throughout the body
and not limited to the lungs).
Case Definitions by Previous Treatment

New
A patient who for sure has never taken anti-TB drugs for
more than one month.
Relapse
A TB patient who:
a. Previously received treatment and was declared
cured and
b. Has once again developed sputum smear-positive TB.
Treatment Failure
A new TB patient who is still sputum smear-positive 5
months or more after starting treatment.
Return After Interruption of Treatment (Default)

A new TB patient who:
a. Completed at least one month of treatment and
b. Returned after at least two months interruption of
treatment.
Transfer-in
A TB patient already registered for treatment in one
district who transfers to another district and continues
treatment.
Other
A TB patient who does not easily fit into one of the above
case definitions. One example is a chronic case (a TB
patient who remains sputum smear-positive after
completing a supervised re-treatment regimen).
Table 42.1 shows the severe and less severe forms of
extrapulmonary TB.
641
been introduced in the market. The dose of streptomycin and ethambutol is 20 to 25 mg/kg/day.
What is the role of quinolones in the

drug-therapy of tuberculosis in children?
I might remind, specially the practitioners, that quinolones
are not the first-line antituberculosis drugs. Their use is
reserved in (i) multidrug resistant (MDR) tuberculosis;
(ii) in conditions of drug induced hepatotoxicity while
treating severe tuberculosis (TBM, miliary tuberculosis)
in which fluoroquinolones (ofloxacin/ moxifloxacin) may
be given in addition to streptomycin and ethambutol.
How safe is it to use quinolones in the pediatric age?

Children
Children and adolescents often fall into category 3 PTB
in children is almost always smear-negative
(actually smear not done, since children rarely cough
up sputum). Young people infected during
adolescence may develop cavitary lesion after primary
TB infection. This usually presents as pleural effusion or
small parenchymal lesions in the lungs. In one series of
adolescents with pleural effusion, without treatment
about 25% went on to develop PTB.
Which simple treatment regimens do you recommend

for different types of tuberculosis in children?
Refer to Chapter on Consensus Statement of Indian
Academy of Pediatrics2010.
What about drug doses in children?

For daily regimen INH should be prescribed in doses
of 5 to 10 mg/kg of body weight per day. However,
this would require close monitoring if used in a daily
regimen. In intermittent regimen, this dose is well
accepted. Presently, INH, rifampicin and pyrazinamide
combination tablets employing this dose schedule have
Table 42.1: The severe and less severe forms of
extrapulmonary TB
Severe extraLess severe extrapulmonary TB
pulmonary TB
meningitis
miliary
pericarditis
peritonitis
bilateral or
extensive pleural
effusion
spinal
intestinal
genitourinary
lymph node
pleural effusion (unilateral)
bone (excluding spine)
peripheral joint
adrenal gland
Clinical studies have shown no serious effects of using

ciprofloxacin in children treated for cystic fibrosis in as
high a dose as 30 mg/kg/day for 6 months. MRI studies
have not shown any detrimental effect on the cartilage of
the growing child.
Should thiacetazone be used in children?

No, thiacitazone should be avoided because of the risk
of skin reaction and Stevens-Johnson syndrome which
is more common when tuberculosis occurs in association
with HIV.
Can ethambutol be used safely in infants and younger

children?
Indeed, Seth et al* have studied that ethambutol in the
dose of 20 mg/kg/day does not produce any ocular
toxicity in children. Visual evoked response (VER) was
measured in those above 3 years of age, both amplitude
and latency of VER were comparable in the children on
ethambutol and control groups. Ethambutol has got good
penetration in the CSF and it helps in preventing
development of resistance. It is not logical to assume that
ethambutol is not safe in children below 3 years. Hence, it
is strongly recommended in any pediatric age where it is
indicated. Now, the VER can be measured in children less
than three years, and infants under general anesthesia, to
have scientific and sound basis for the recommendation of
its use in these groups, particularly cases of TBM.
Ethambutol is also useful in multidrug resistant-tuberculosis
(MDR-TB).
Besides therapy, what other measures are important

in the management?
All siblings of the index child should be subjected to
the Mantoux test and X-ray chest. Those who turn out
* Seth Vimlesh, Khosla PK, Semwal OP, et al. Viusal evoked
responses in tuberculosis in children on ethambutol treatment.
Indian Pediatr 1991; 28:713-7.
642
to be positive or are symptomatic, definitely these

investigations are of immense help. Mother, father and
other adults living in the house need to be X-rayed as it
has been found that many of them to have active
tuberculosis (30%) even though they claim to be healthy.
This point needs to be brought to the attention of
practitioners as their concern remains focussed on the
index child only. Often the physicians treating the adult
tuberculosis cases fail to screen the children of an
infectious adult for tuberculosis. By the time the children
approach the pediatrician for the symptoms, some of
them have already developed progressive primary,
disseminated disease or tuberculous meningitis.
How should the response to therapy in pulmonary

tuberculosis be monitored?
Clinically, it should be monitored by disappearance of
symptoms of fever and cough and documentation of weight
gain. The child should become playful and gain weight.
The latter is a very good criterion of response to therapy.
Objectively, it should be monitored by evaluating the
clearance of radiological lesion. For this, an X-ray chest
at the beginning of therapy and at 3 monthly intervals in
the first year and six monthly in the second year is
recommended. Then the child should be kept under
surveillance for five years. However, radiographic
improvement of intrathoracic tuberculosis in children
occurs very slowly, and frequent monitoring with chest
radiographs is usually not necessary.
How should the resolution of X-ray lesion be graded?

To evaluate the response to therapy, the following
grading is proposed based on experience of Seth (Imaging
chapter)
Grade 1: Complete clearance of the initial tuberculous
lesion.
Grade 2: Moderate to significant clearance1/2 to 2/3
clearance of lesion.
Grade 3: Mild improvementonly 1/3rd clearance.
Grade 4: No improvement, or deterioration.
How helpful are these gradings in judging the response

to therapy?
In usual practice, it has been observed that, practitioners
keep on continuing the antituberculosis treatment for 9
or even upto 12 months just because X-ray chest lesion
has not completely resolved. It is stressed, on this point,
that if regular treatment has been taken and child has
symptomatically improved, it should be stopped at the
scheduled time after completion of the regimen (6 or 9
months) even if there is only moderate radiological
clearance of the lesion. Complete clearance of radiological
lesion sometimes does require more time, particularly

the nodal and calcified lesions, which may take 1-1
years to disappear altogether. Calcification does not
disappear, it remains as a tell-tale mark. If there is only
mild or no improvement, or deterioration of the lesion
after 3 months of therapy, drug compliance should be
thoroughly checked and if found satisfactory, drug
resistance may be suspected which necessitates addition
of other drug(s) to the regimen.
What about drug compliance?

This is the most important aspect of the therapy as the
extent of drug compliance is directly proportional to the
clinicoradiological improvement. (Pulmonary tuberculosis
chapter) Seth has shown that a drug-dose compliance of
at least 80% is to be ensured to have a satisfactory response
to the regime. Compliance may be a major problem with
pediatric patients as they are dependent on parents for
giving them the drugs. Also, the dramatic improvement
seen in adult patients may not be evident in pediatric
patients as they usually have fewer symptoms.
What measures are needed for the infant of a lactating

mother on antituberculosis drugs?
Since the drug concentrations in breast milk are
subtherapeutic there are no adverse effects in the infant.
At the same time, these concentrations do not provide any
protective coverage to the infant from an impending
tuberculosis infection. No separation of baby from mother
is required. The baby should be given preventive therapy
with 3 HR. The general recommendation is to give
isoniazid (5 mg/kg/day) for 6 months. It is important to
have periodic examination of the infant at the beginning
and after three months in the form of Mantoux test and Xray chest. If both are negative, give BCG vaccination. If
Mantoux test is positive and child is asymptomatic
continue therapy for another three months. If both
(Mantoux test, CXR) are positive, categorise the child
and give appropriate treatment. BCG vaccination
is recommended after 3 months, if both the tests are
negative.
What features suggest congenital or neonatal TB?

Three major routes for true congenital tuberculosis
are:
a. Via the umbilical vein from the mother with
lymphohematogenous spread during pregnancy.
b. Hematogenous dissemination leading to infection of
the placenta with transmission to the fetus. In either
event the bacilli first reach the fetuss liver where the
primary complex develops leading to hepatomegaly
or even widespread miliary disease.
c. Aspiration or ingestion of infected amniotic fluid.

The clinical manifestations vary according to the site
and size of caseous lesion. The symptoms usually become
manifest in the second or third week of life. The
presentation is in the form of respiratory distress
syndrome, fever, hepatic or splenic enlargement,
poor feeding, lymphadenopathy, lethargy and/or
irritability.
Diagnosis is often difficult, since the clinical features
can mimic those due to any bacterial infection or
congenital infections like syphilis and cytomegalovirus
infection. The major clue to diagnosis is history of
tuberculosis in the mother. The Mantoux test is mostly
negative. X-ray chest is abnormal in the majority of
neonates and diagnosis is established by finding AFB in
gastric and or, bone marrow aspirate, urine or liver
biopsy.
What should be the therapeutic approach in such cases?

Since the conditions are associated with high mortality,
if not diagnosed in time, early and aggressive therapy is
the deciding factor. 2 HRZE, 4 HR regimen with monthly
review is recommended.
How do you manage a child who is in contact with a

patient infected with tuberculosis?
Children below 5 years of age who are in close contact
with drug susceptible tuberculosis patient and are
asymptomatic, active disease ruled out by appropriate
investigation, should be given INH for six months.
Chemoprophylaxis for those exposed to MDR-TB is not
clear. Two alternatives are suggested in such a situation.
(1) Keep the child in close follow up with 6 months of
INH prophylaxis and treat like MDR-TB on development
of disease. This approach is based on the premise that if
we give two/ three drug prophylaxis and the bacilli
becomes resistant to them, we may not be left with many
drugs for treatment (2) second alternative is to give a
combination of fluoroquinolone and ethambutol for 6 to
12 months. The decision may be taken on case to case basis.
How should the drug-induced hepatotoxicity be

managed?
Drug-induced hepatotoxicity is relatively uncommon in
children, when antituberculosis drugs are given in the
recommended dosage schedule, INH (5 mg/kg),
rifampicin (10 mg/kg) and pyrazinamide (30 mg/kg). In
case a child develops jaundice or deranged liver function
tests (Transaminases > 5 times the normal) , they should
be withdrawn and substituted with streptomycin (S),
ethambutol and fluoroquinolones in serious tuberculosis
with monitoring of liver function tests (LFT). When LFT
return to normal levels, rifampicin is introduced first in
half the dose, i.e. 5 mg/kg/day with continuation of
643
streptomycin and ethambutol. It should be increased to 10

mg/kg/day after 1 week. INH is added in the similar way,
i.e. half dose (2.5 mg/kg) initially for 1 week than in full
dose. Ethambutol is continued and pyrazinamide is left out
except in TBM and miliary tuberculosis cases. In these cases
pyrazinamide is reintroduced initially in half the dose (15
mg/kg) as with other drugs and then in full dose. Usually,
it takes 4 to 6 weeks before all antituberculosis drugs, in
recommended doses, can be reintroduced. Finally extend
the total duration for the period during which child
received improper regimen.
How do you differentiate drug-induced hepatoxicity

from acute viral hepatitis?
The only sure way to differentiate the two is to look for
viral markers. Clinical presentation and results of liver
function tests may not help in differentiation. However,
in clinical practice this differentiation is not essential, as
the management and decisions about antituberculosis
drug therapy are not different (as highlighted above).
How to initiate treatment in a child with liver disease?

Patients with hepatic abnormality who need antituberculosis therapy should be evaluated for hepatic
tuberculosis. There may be greater potential for liver
toxicity from antituberculosis drugs in patients with
underlying liver disease. The doses of most antituberculosis drugs need not be reduced in these patients,
but closer monitoring of liver functions and signs and
symptoms of toxicity is indicated.
WHO recommends that patients with established
chronic liver disease should not receive pyrazinamide.
The recommended regimens are:
1. 2 SHRE/6 HR
2. 2 SHE/10 HE
In tuberculosis regime number one as given above is
preferred treatment during the acute phase of viral or
other hepatitis, a regimen of drugs with low potential for
liver toxicity such as ethambutol and streptomycin. A
recommended regime is 3 SE/6 HR. Other non-hepatotoxic
drugs, which can be used are aminoglycosides,
capreomycin and fluoroquinolones, preferably latter.
What are the indications for screening for HIV infection

in children with tuberculosis?
HIV screening should be done in the following situations:
a. Disseminated tuberculosis.
b. Presence of history of blood transfusion, high risk
behavior in parents.
c. Other features suggestive of immunodeficiency.
At present, there is no consensus about screening of
all children with tuberculosis.
644
How to differentiate tubercular meningitis from partially

treated pyogenic meningitis when investigation facilities
are limited? How to manage such a case?
CSF adenosine deaminase, CSF-CRP, CSF lactate
dehydrogenase, CSF free N-acetyl neuraminic acid,
immunodiagnosis, chemokine profiles in CSF and PCR
can help in distinguishing TBM from partially treated
pyogenic meningitis. These tests are not readily available.
The decision in each patient has to be individualized. In
cases of doubt we end up giving both antituberculosis
therapy (ATT) and antipyogenic treatment and then
reassess the patient after two weeks.
When will you withdraw antituberculosis drugs, if we

started so on strong suspicion of TBM or inability to
differentiate TBM from viral meningoencephalitis?
Do not withdraw ATT but complete the full course.
Can the CSF examination be normal if a child has TBM/

CNS tuberculosis?
CSF can be completely normal in 5.8 to 16.5% cases of
TBM with a proved diagnosis on autopsy. On the
contrary, in about 10% cases the CSF could be almost
simulating pyogenic meningitis.
There are new and/or modified clinical entities
particularly in BCG vaccinated children in which the
child may have normal CSF but positive PCR for
tuberculosis and/or tuberculosis antigen by ELISA.
Tuberculoma, tubercular encephalopathy and intracranial
tubercular abscess can have normal CSF.
How do you manage child contacts of infectious adults?

Children with TB may present to health units when
they are ill. However, most National TB Control
Programs also recommend active contact tracing of
children who are household contacts of infectious
adults. In order to be effective, this screening must be
systematic.The scheme below shows how to manage
child contacts of infectious adults (with sputum smearpositive PTB).
Screen all children living with a household adult
contacts for tubercular disease. If disease is ruled out,
all children below 5 years of age irrespective of
nutritional status, BCG vaccination status, should be
started on INH prophylaxis for 6 to 9 months. Children
should be followed up every month for clinical
screening.
What are the screening procedures before start of

therapy for latent tuberculosis. Before isoniazid
preventive therapy is started, it is important to
undertake the following evaluations?
1. Exclude severe form of pulmonary tuberculosis such
as radiographically progressive primary disease
(PPD), bronchopneumonia. Every person who has
a significant Mantoux test reaction positive, i.e. >10
mm should have a chest radiograph. If there are
findings consistent with pulmonary tuberculosis,
further studies, including medical evaluation, gastric
lavage, and comparison of the current and old
radiographs if any should be made to exclude
progressive disease. Appropriate evaluation should
be performed if extrapulmonary tuberculosis is
suspected. Because of the risk of inducing isoniazid
resistance when isoniazid is used alone in a person
with current tuberculosis, the recommended
regimens for treatment of disease should be used
until the diagnosis is clarified. If the evaluation
confirms previous (not current) tuberculosis,
therapy of multidrug treatment may be stopped after
6 months in children.
2. Question for a history of treatment with antituber
culosis drugs, or therapy for tuberculosis to exclude
those who have been adequately treated.
3. Question for a history of prior isoniazid preventive
therapy to exclude those who have had an adequate
course of the drug.
4. Check for contraindications to the administration of
isoniazid for latent tuberculosis. Theses include:
(i) Previous isoniazid-associated hepatic injury.
(ii) History of severe adverse reactions to isoniazid such
as drug fever, rash, and arthritis. (iii) Acute or unstable
liver disease of any etiology. Hepatitis B surface
antigen positivity per se is not a contraindication.
5. Identify patients for whom special precautions are
indicated. These include: (i) Age less than one year
(ii) Concurrent use of any other medication on a longterm basis in view of possible drug interactions
(iii) History of previous discontinuation of isoniazid
because of possible, but not definite, related side
effects, e.g. headaches, dizziness, nausea (iv) Although
no harmful effects of isoniazid to the fetus have been
observed, preventive therapy generally should be
delayed until after delivery. There does not appear
to be any substantial increase in tuberculosis risk for
women as a result of pregnancy. However, for
pregnant women likely to have been recently infected
or with high-risk medical conditions, especially HIV
infection, treatment for latent tuberculosis therapy

should be again started when the infection is
documented (v) A recent report suggests an increased
risk of fatal hepatitis associated with isoniazid among
women, during the postpartum period.
How should one monitor therapy for latent tuberculosis?

The person receiving therapy for tuberculosis or a
responsible adult in a household with children receiving
latent therapy should be questioned carefully at monthly
intervals for symptoms or signs consistent with liver
damage or other adverse effects. These include any of
the following: unexplained anorexia, nausea, vomiting,
dark urine, icterus, rash, persistent paresthesias of the
hands and feet, persistent fatigue, weakness or greater
than 3 day duration, and/or abdominal tenderness
(especially right upper quadrant discomfort).
If any of these or other signs or symptoms occur
during preventive therapy, patients should be advised
to report immediately to the clinic or healthcare provider
for evaluation, including biochemical tests for hepatitis.
The use of a standardized form for interviewing will help
ensure alertness to all signs and symptoms, expedite the
interview process, and provide for standardized data
collection.
As noted, 10 to 20% of those receiving isoniazid will
develop some mild abnormality of liver function (an
elevated aspartate aminotransferase). These abnormalities
tend to resolve even if isoniazid is continued. A
transaminase measurement should be obtained prior to
the starting and monthly during the course of preventive
therapy in a child who has had infective hepatitis and has
grade III of protein energy malnutrition. More careful
monitoring should be considered in these groups, possibly
including more frequent laboratory monitoring. If any of
these tests exceeds three to five times the upper limit of
normal, discontinuation of isoniazid should be strongly
considered. Liver function tests are not a substitute for a
clinical evaluation at monthly intervals or for the prompt
assessment of signs or symptoms of adverse reactions
occurring between regularly scheduled evaluations.
How will you manage latent tuberculosis if a child is

intolerant to isoniazid?
An approach similar to that taken for contacts of
isoniazid-resistant cases can be used.
How do you manage the close contacts of isoniazidresistant cases?

In the situation where there is confidence that the source
case has isoniazid-resistant organisms, it appears
reasonable to treat child contacts and those adult contacts
who appear particularly susceptible to tuberculosis (e.g.
immunocompromised hosts) with rifampicin. It is
645
adviseable to add a second drug such as ethambutol to

which the organisms is believed to be susceptible. The
drug(s) should be given in standard therapeutic doses
for 6 months. In situations in which there is doubt that
the infection is due to isoniazid-resistant organisms,
isoniazid should not be used.
How do you manage a child with a high probability of

infection with multidrug resistant organisms?
In persons likely to have been infected with bacilli
resistant to both isoniazid and rifampicin, observation
without therapy for latent tuberculosis has usually been
recommended because no other drugs have been
evaluated for latent tuberculosis. However, in persons
with an especially high-risk of tuberculosis (e.g. persons
with HIV infection), therapy for latent tuberculosis
should be considered. If the organisms are thought to be
susceptible, 6 month of daily ethambutol and
pyrazinamide at the usual therapeutic doses may be
considered. If infection is due to organisms resistant to
ethambutol as well, the combination of pyrazinamide
plus a quinolone (gatifloxacin or moxifloxacin) for 6
months is recommended. Careful assessment to exclude
active tuberculosis prior to the initiation of preventive
therapy is mandatory.
What are the complications of BCG vaccination?

BCG rarely causes serious complications; osteomyelitis
and death from disseminated BCG infection have
occurred in only one case per million doses administered.
The frequency of side effects, most commonly prolonged
ulceration and local adenitis, occur in 1 to 10% of
vaccinees, varying with the vaccine used, the intensity
with which adverse reactions are sought, and the
population vaccinated. BCG vaccination may cause
tuberculin skin test conversion, but waning of delayed
hypersensitivity occurs to a significant extent in the 1st
year itself. So it does not interfere with Mantoux test
interpretation.
Inspite of these shortcomings, BCG is recommended
in the following situations.
1. BCG vaccine is strongly recommended for infants and
children with negative tuberculin skin test who: (i)
are at high-risk of intimate and prolonged exposure
to persistently untreated or ineffectively treated
patients with infectious pulmonary tuberculosis, cannot
be removed from the source of exposure, and cannot be
placed on long-term preventive therapy, or (ii) are
continuously exposed to persons with tuberculosis who
have bacilli resistant to both isoniazid and rifampicin.
2. BCG vaccination is also recommended for tuberculinnegative infants and children in groups in which the
rate of new infections exceeds 1% per year and for
whom the usual surveillance and treatment programs
646
have been attempted but are not operationally

feasible. These groups include persons without
regular access to health care, those for whom usual
health care is culturally or socially unacceptable, or
groups who have demonstrated an inability to
effectively use existing accessible care. In view of the
recent outbreaks of multidrug resistant tuberculosis,
these recommendations are currently under review.
Vaccination should be administered only by the
route indicated in the package labeling and only in
the suggested dose. Depressed host immunity (from
illness such as HIV infection or therapy with
immunosuppressive drugs) is a contraindication to
BCG administrations.
Which groups of children are at greater risk for

tuberculosis than others?
Children living in a household with an adult who has
active tuberculosis
Children living in a household with an adult who is
at high-risk for contracting TB
Children infected with HIV or another immunocompromising condition
Children born in a country that has high prevalence
of tuberculosis
Children from communities that are medically under
served.
Should women taking antituberculosis drugs

breastfeed?
Most of the commonly used antituberculosis drugs are
excreted in breast milk of nursing mother. However, only
a small fraction of the adult dose appears in breast milk,
and we estimate that breast fed infants would receive no
more 20% of the usual therapeutic dose for infants for
any of these dose. Based on these considerations, we
believe the risk of toxic reactions to drugs in infants of
nursing mothers receiving antituberculosis drugs is very
low.
TREATMENT OF TB PATIENTS
Introduction
Aims of Anti-TB Drug Treatment
To cure the patient of TB

To prevent death from active TB or its late effects
To prevent TB relapse
To decrease TB transmission to others.
Properly applied anti-TB drug treatment will achieve
these aims and prevent the emergence of drug resistant
M. tuberculosis. Effective anti-TB drug treatment is
properly applied short-course chemotherapy. The course
of a anti-TB drug treatment is long, because it is difficult
to kill the semi-dormant TB bacilli.
Bactericidal Drugs
Isoniazid kills 90% of the total population of bacilli during
the first few days of treatment. It is most effective against
the metabolically active, continuously growing bacilli.
Rifampicin can kill the semi-dormant bacilli which
isoniazid cannot. Pyrazinamide kills bacilli in an acid
environment inside cells, e.g. macrophages.
Sterilizing Action
This means killing all the bacilli. The persisters are
hardest to kill. The aim of killing all the bacilli is to prevent
relapse. Rifampicin is the most effective sterilizing drug.
Its effectiveness makes short-course chemotherapy possible.
Pyrazinamide is also a good sterilizing drug, since it kills
the bacilli protected inside cell.
Preventing Drug Resistance

Consider a population of TB bacilli never previously
exposed to anti-TB drugs. There will be a few naturallyoccurring drug resistant mutant bacil1i. Faced with antiTB drugs, these drug-resistant mutant bacilli will grow
and replace the drug-sensitive bacilli under the following
circumstances:
a. Inadequate anti-TB drug combinations.
b. Anti-TB drug treatment not properly applied.
Isoniazid and rifampicin are most effective in
preventing resistance to other drugs. Streptomycin and
ethambutol are slightly less effective.
TB Treatment Regimens
Treatment regimens have an initial (intensive) phase and
a continuation phase.
New Cases
Initial Phase (2 months)
During the initial phase, there is rapid killing of TB bacilli.
Infectious patients become non-infectious within about 2
weeks. Symptoms improve. The vast majority of patients
with sputum smear-positive TB become sputum smearnegative within 2 months. Directly observed therapy
(DOT) is essential in the initial phase to ensure that the
patient takes every single dose. Rifampicin protects against
the development of drug resistance. The risk of drug
resistance is higher during the early stages of anti-TB drug
treatment when there are more TB bacilli.
Continuation Phase (4 to 6 months)

Fewer drugs are necessary, but for a longer time, in the
continuation phase. The drugs eliminate the remaining
TB bacilli. Killing the persisters prevents relapse after
completion of treatment. Directly observed therapy is the
ideal when the patient receives rifampicin in the

continuation phase. If local conditions do not allow
directly observed therapy, the next best is as close
supervision as possible, for example weekly supervision.
The risk of drug resistance is less during the continuation
phase when there are fewer TB bacilli.
The patient usually receives monthly drug supplies
for self-administered treatment during a continuation
phase.
Retreatment Cases
In DOTS the initial phase lasts 3 months, with directly
observed therapy. The continuation phase lasts 5 months,
with close supervision.
Standard Code for TB Treatment Regimens

There is a standard code for TB treatment regimens. Each
anti-TB drug has an abbreviation. A regimen consists of 2
phases. The number before a phase is the duration
of that phase in months. A number in subscript (e.g. 3)
after a letter is the number of doses of that drug per
week. If there is no number in subscript after a
letter, then treatment with that drug is daily. An alternative
drug (or drugs) appears as a letter (or letters) in brackets.
Examples
2 SHRZ/6 HRthis is a common regimen.
The initial phase is 2 SHRZ. The duration of the phase
is 2 months. Drug treatment is daily (no subscript
number, e.g. 3 after the letters), with streptomycin (S),
isoniazid (H), rifampicin (R) and pyrazinamide (Z). The
continuation phase is 6 HE. The duration of the phase is
6 months. Drug treatment is daily, with isoniazid (H)
and ethambutol (E).
2 SHRZ/4 H3R3in some countries, resources are
available to provide rifampicin in the continuation phase
as well as in the initial phase.
Use of Streptomycin and Thiacetazone

in Areas of High HIV Prevalence
Streptomycin
In high TB/HIV prevalence populations, overcrow
ding is common in TB wards. There is a risk of
transmission of HIV and other blood-born pathogens
between patients
Streptomycin injections are very painful in wasted
HIV-infected TB patients
Many National Tuberculosis Programs (NTPs) now
recommend the use of ethambutol in place of
streptomycin.
647
Thiacetazone
Thiacetazone is associated with a high-risk of severe,
and sometimes fatal, skin reaction in HIV-infected
individuals
Use ethambutol instead of thiacetazone in patients
with known or suspected HIV infection
At present some countries do not have the resources
to substitute ethambutol for thiacetazone. The most
effective treatment available in some countries may
still include thiacetazone. Where it is not possible to
avoid the use of thiacetazone, it is essential to warn
patients about the risk of severe skin reactions. Advise
the patient to stop thiacetazone at once and report to a
health unit if itching or a skin reaction occurs.
However, in general its use is not recommended.
TB Treatment Regimens: Questions and Answers

Why use 4 drugs in the initial phase?
There is a high degree of initial resistance in some
populations. Use of a 3-drug regimen runs the risk of
selecting out drug-resistant mutants. This may happen
especially in patients with high bacillary loads, e.g.
cavitary pulmonary TB.
A 4-drug regimen decreases the risks of drug
resistance, treatment failure, and relapse.
Why use pyrazinamide only in the initial phase?

Pyrazinamide has its maximum sterilizing effect within
the first 2 months. There is less benefit from longer use.
Is a 4 months continuation phase possible?

A 4 months continuation phase is possible with
rifampicin throughout (e.g. 2 SHRZ/ 4 HR). This is
because isoniazid and rifampicin are both potent
bactericidal drugs.
Why is it so important to prevent rifampicin resistance?

Rifampicin is the most effective anti-TB drug. It is
unlikely that a new anti-TB drug will become widely
available in the near future. If rifampicin resistance
becomes widespread, TB will be effectively untreatable.
How do we prevent rifampicin resistance?

Bad TB control programs, lack of supervision of anti-TB
treatment, bad prescribing by clinicians, and the use of
rifampicin alone generate acquired drug resistance. The
best way to prevent rifampicin resistance is to strengthen
NTPs and ensure directly observed therapy as for
648
as possible. It is important to use methods of drug

administration which avoid the danger of the use of
rifampicin alone. These include the use whenever
possible of fixed-dose combination tablets and of antiTB drugs supplied in blister packs.
What is the treatment for multidrug resistant TB?

Multidrug resistant TB arises from failure to deliver antiTB drug treatment properly. Multidrug resistance
represents NTP failure. In many high TB prevalence
countries, second-line drugs are prohibitively expensive
and unavailable, e.g. ethionamide, cycloserine, kanamycin,
capreomycin. Multi-drug resistant TB is, therefore often
untreatable. Inadequate treatment with inappropriate
antituberculosis drugs may lead to development of
extensively drug resistant tuberculosis (XDRTB).
Therefore it is very important to refer to a center with
experience in treatment of MDR tuberculosis.
What should we do when faced with multidrug resistant

TB?
The cause of the problem is NTP failure. The answer is
to devote time, effort and resources in improving the
NTP. In some countries, one or two specialist centers may
have the specialist expertise and second-line drugs
available to treat patients with multidrug resistant
TB.
Use of Anti-TB Drugs in Special Situation

Pregnancy
Streptomycin during pregnancy can cause permanent
deafness in the baby
Do not give streptomycin in pregnancy. Use
ethambutol instead.
Renal Failure
Rifampicin, isoniazid and pyrazinamide are safe
The excretion of streptomycin is renal. The excretion
of ethambutol and thiacetazone is partly renal
Avoid streptomycin and ethambutol if there are
alternatives. Otherwise give in reduced doses at less
frequent intervals
Use of thiacetazone is not recommended. Besides its
Table 42.2: Suggested treatment doses of prednisolone
Indication
Prednisolone treatment
TB meningitis
2 mg/kg/day for weeks 1 to 4, then
decrease over 4 to 6 weeks
TB pericarditis
1-2 mg/kg/day for weeks 1-4, decrease

over 4 to 6 weeks
TB pleural effusion 1-2 mg/kg/day for 1 to 2 weeks
side effects the margin is too narrow between the

therapeutic and toxic dose.
Liver Disease
Most anti-TB drugs can cause liver damage. Jaundiced
patients who develop TB should receive treatment
with the following regimen: 2 SHE/6 HE
Do not give pyrazinamide to patients with liver
disease.
The Role of Steroid Treatment:

Questions and Answers
What are the indications for treatment with steroids?
TB meningitis (decreased consciousness, neurological
defects, or spinal block)
TB pericarditis (with effusion or constriction)
TB pleural effusion (when large with severe
symptoms)
Hypoadrenalism (TB of adrenal glands)
TB laryngitis (with life-threatening airway obstruction)
Severe hypersensitivity reactions to anti-TB drugs
Renal tract TB (to prevent ureteric scarring)
Massive lymph node enlargement with pressure
effects.
What is adjuvant steroid treatment?

Adjuvant steroid treatment is steroid treatment given in
addition to anti-TB drug treatment. Prospective
controlled clinical trials have confirmed the benefit of
steroids in TB meningitis and pleural and pericardial
TB.
What are the recommended treatment doses of

prednisolone?
Rifampicin is a potent inducer of hepatic enzymes which
metabolizes steroids. The effective dose of prednisolone
is, therefore, half the prescribed treatment dose given to
the patient. Table 42.2 shows suggested treatment doses
of prednisolone.
Is steroid treatment safe in TB/HIV patients?

Steroids are immunosuppressants. The worry is that
steroids may further depress immunity and increase risk
of opportunistic infections in HIV positive patients.
However, on balance, TB/HIV patients are still likely to
benefit from the use of steroids for the above indications.
Monitoring of TB Patients during Treatment

Bacteriological monitoring is readily available only for
patients with sputum smear-positive pulmonary TB.
Routine monitoring of treatment response by chest X-ray
649

is unnecessary and wasteful of resource. For other TB
patients, clinical monitoring is the usual guide to treatment
response.
Side Effects of Anti-TB Drugs

Introduction
Most TB patients complete their treatment without any
significant drug side effects. However, a few patients
do develop side effects. So clinical monitoring of all TB
patients for side effects is important during TB
treatment. Routine laboratory monitoring is not
necessary.
How do health personnel monitor patients for drug side

effects?
a. By teaching patients how to recognize symptoms of
common side effects and to report if they develop
such symptoms.
b. By asking specifically about these symptoms when
they see all patients atleast monthly during
treatment.
Prevention of Side Effects

Health personnel should be aware of the special
situations which influence the choice and dose of antiTB drugs.
It is possible to prevent the peripheral neuropathy
caused by isoniazid. This neuropathy usually shows as a
burning sensation of the feet. It occurs more commonly in
HIV-positive individuals, in adults who are drinkers
(alcohol), and in patients with diabetes. These patients
should receive preventive treatment with pyridoxine 10 mg
daily.
Where to Manage Drug Reactions?

Reaction
Minor, e.g.
gastrointestinal
joint pains
Major, e.g.
jaundice severe rash
Where to Manage
Out-patient setting
Refer to district or central
Hospital
When to Stop Anti-TB Drugs?

When a patient has minor drug side effects, explain the
situation, offer symptomatic treatment, and encourage
him/her to continue treatment.
When a patient has a major reaction, stop the
suspected drug(s) responsible at once. A patient who
develops one of the following reactions must never
receive that drug again:
Reaction
Severe rash agranulocytosis
Hearing loss
Visual disturbance (poor
vision and color perception)
Renal failure, shock, or
thrombocytopenia
*It is used rarely now.
Drug responsible
thiacetazone*
streptomycin
ethambutol
rifampicin
Management of Skin Itching/Rash

The approach depends on whether or not the patient is
receiving thiacetazone. In populations with a high TB/
HIV prevalence, thiacetazone is the drug most likely to
cause skin reactions.
Treatment Regimen Includes Thiacetazone

If a patient starts to itch, and there is no other obvious
cause (e.g. scabies), stop the anti-TB drugs at once. The
itching maybe a warning sign of severe skin reaction.
Stopping the thiacetazone at once may avert, or decrease
the severity, of the skin reaction.
Give the patient intravenous fluids if the skin reaction
is severe:
a. Exfoliative dermatitis or toxic epidermal necrolysis
b. Mucous membrane involvement
c. Hypotension.
Many physicians give steroid treatment, although there
is no firm evidence that this helps. A typical dose schedule
consists of 1 to 2 mg/kg/day (maximum 60 mg) daily of
oral prednisolone until there is some improvement. A
gradual reduction in dose over the next few days depends
on the patients response. Initially, if a patient is unable to
swallow, give intravenous hydrocortisone 100 to 200 mg daily
(instead of oral prednisolone). On recovery, restart antiTB drugs, replacing thiacetazone with ethambutol.
Never Give a Patient Thiacetazone Again After any

Thiacetazone Reaction
A severe reaction may mean stopping anti-TB treatment
for 3 to 4 weeks. A severely ill TB patient may die without
anti-TB treatment. In this case, give 2 or more previously
unused drugs until the reaction has resolved. Then
reintroduce the initial regimen (with ethambutol instead
of thiacetazone).
Treatment Regimen Does Not Include Thiacetazone

If a patient starts to itch, exclude other obvious causes.
Try treatment with anti-histamines, continue anti-TB
650
treatment and observe the patient closely. In some cases,

the itching resolves. In other cases, a rash develops. In
this case, stop the anti-TB drugs. Wait for the rash to
resolve. If the reaction is severe, the patient may need
supportive treatment as above.
The problem now is reintroducing TB treatment when
we dont know which anti-TB drug was the one
responsible for the reaction. The table shows the standard
approach to reintroducing anti-TB drugs one by one after
a drug reaction.
Reintroduction of Anti-TB Drugs Following Drugs

Reaction
If possible, while the patient undergoes drug challenging,
give 2 anti-TB drugs (Table 42.3) which the patient has
not had before. The idea of drug challenging is to identify
the drug responsible for the reaction. Drug challenge
starts with the anti-TB drug least likely to be responsible
for the reaction (i.e. isoniazid), start with a small challenge
dose. If a reaction occurs to a small challenge dose, it
will not be such a bad reaction as to a full dose.
Gradually increase the dose over 3 days. Repeat the
procedure, adding in one drug at a time. A reaction after
adding a particular drug identifies that drug as the one
responsible for the reaction.
If the drug responsible for the reaction is pyrazinamide,
ethambutol, or streptomycin, resume anti-TB treatment
without the offending drug. If possible, replace the
offending drug with another drug. It maybe necessary
to extend the treatment regimen. Consider the start of
the resumed regimen as a new start of treatment. This
prolongs the total time of TB treatment, but decreases
the risk of recurrence.
Refer Patients with Severe Drug Reactions to Specialist

Centers
Desensitization
Rarely, patients develop hypersensitivity reactions to the
2 most potent anti-TB drugs, isoniazid and rifampicin.
These drugs form the corner-stone of short-course
Drug
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
Streptomycin
chemotherapy (SCC). If an HIV-negative patient has had

a reaction (but not a severe reaction) to isoniazid or
rifampicin, it may be possible to desensitize the patient to
the drug.
Start desensitization with a tenth of the normal dose.
Then increase the dose by a tenth each day, until the
patient has the full dose on the tenth day. Once drug
sensitization is over, give the drug as part of the usual
treatment regimen. If possible, while carrying out
desensitization, give the patient 2 anti-TB drugs which
the patient has not had before. This is to avoid the risk of
drug resistance developing during desensitization.
Caution: However, never attempt desensitization in TB/
HIV patients because of the high risk of serious toxicity. The
following method for desensitization, therefore, does not apply
to TB/HIV patients.
Never Attempt Desensitization in TB/HIV Patients

Management of Hepatitis
Most anti-TB drugs can damage the liver. Isoniazid and
pyrazinamide are most commonly responsible.
Ethambutol is rarely the causative drug. When a patient
develops hepatotoxicity during anti-TB treatment, it may
not be the anti-TB treatment but another cause. It is often
difficult to find out. Try to rule out other possible causes
before deciding that the hepatotoxicity is drug-induced.
Hepatitis presents with anorexia, jaundice and often
tender liver enlargement.
If you diagnose drug-induced hepatotoxicity, stop the
anti-TB drugs. Wait until the jaundice resolves. It is
strange, but fortunate, that in most cases the patient can
restart the same anti-TB drugs without hepatotoxicity
returning. A severely ill TB patient can die without
anti-TB drugs. To avoid this, treat the patient with 2 of the
least hepatotoxic drugs, streptomycin and ethambutol.
When the hepatotoxicity resolves, re-start usual anti-TB
treatment as detailed earlier.
Few Important Questions about Abdominal Tuberculosis

TB of the gastrointestinal tract (digestive system) and
abdominal cavity is known as abdominal tuberculosis.
Table 42.3: Reintroduction of drugs after a reaction

Likelihood of causing a reaction
Challenging doses
Day 1
Day 2
least likely
50 mg
300 mg
75 mg
300 mg
250 mg
1 gm
100 mg
500 mg
most likely
125 mg
500 mg
Day 3
300 mg
Full dose
Full dose
Full dose
Full dose
How does abdominal TB occur?

Ingestion of the tuberculous germ by drinking
unpasteurized milk of a cow infected with TB is one of
the mechanisms of abdominal TB.
Abdominal TB can also occur by spread of the TB
bacillus from the lungs to the intestines by the blood stream.
In 2/3rd of children, there is predominant involvement of
the digestive system. Involvement of the abdominal cavity
(peritoneum) occurs in remaining patients. Involvement of
the lymph glands only in the abdomen is rare.
651
However, other supportive tests that may be done are

the Mantoux test, Chest X-ray, Abdominal X-rays (with
or without barium) and scans such as ultrasound and CT
scan.
What are the complications of abdominal TB?

Untreated TB of the intestine may lead to intestinal
obstruction, fistula or even abscess and perforation with
resultant peritonitis.
What is the treatment of abdominal TB?

What are the signs and symptoms of abdominal TB?
Clinical feature of abdominal tuberculosis are varied. The
most common symptoms are pain in the abdomen, loss
of weight, anorexia, recurrent diarrhea, low grade fever,
cough and distention of abdomen.
The doctor on examination may feel a lump, fluid or a
doughy feel in the abdomen. Also there may be enlarged
lymph glands elsewhere in the body.
Abdominal TB needs to be treated with at least

3 to 4 anti-TB drugs for the initial 2 months and
subsequently 2 anti-TB drugs for at least 7 to 10 months.
The commonly used drugs during the initial 2 months
therapy (Intensive phase) are isoniazid (INH), rifampicin,
ethambutol and pyrazinamide. During the next 7 to 10
months (continuation phase) the two drugs commonly
used are INH and rifampicin.
How is diagnosis of abdominal TB made?
When is surgery required for abdominal TB?
Diagnosis can be confirmed by isolating the TB germ from

the digestive system by either a biopsy or endoscopy.
Surgery is required whenever there is perforation,

abscess or fistula formation.
43
Ethical Issues and Concerns about

Tuberculosis Research in Children
Roli Mathur, Prashant Mathur, Vimlesh Seth
INTRODUCTION
Tuberculosis (TB) is the most important infectious cause
of adult deaths, and persons carrying acid-fast bacilli
(AFB) in their sputum are the most infectious group in
the community.1,2 Children exposed to adults with
smear-positive pulmonary TB have a high risk for
acquiring infection, and this risk increases with the
closeness in the degree of contact.3,4 In countries with
high incidence of TB, risk of infection among children in
contact with adults with TB is 30 to 50%, which is much
higher than that reported by industrialized countries.5
Although rates have fallen in industrialized countries,
TB still remains a scourage in marginalized communities.
Despite evidence of its cost-effectiveness, program
delivery in developing countries faces several
impediments in serving adults as well as children. The
necessary health infrastructure is to be prevented from
decay, and efficient drugs and diagnostics are to be
adequately funded.6
Selgelid et al6 observed that though TB is second to
HIV/AIDS as a cause of death, it still may be more
important for two reasons: (i) TB has been treatable and
curable for over 50 years at low cost (ii) its public health
impact is even greater than HIV due to its airborne
transmission.
The impact of national TB programs delivered
through the public health system was recognized by the
World Bank in 1990 as the most cost-effective life-saving
intervention, equal to immunization, but the international
community was slow to scale up. As a result, poorly
managed programs led to the emergence of drugresistant TB. The cause of extensively drug-resistant TB
(XDR), often attributed to poor patient compliance, is
more likely the result of poor services, lack of infection
control, human resource shortages, delayed diagnosis,
poor quality drugs and treatment interruption. There is
inadequate emphasis on children among TB studies
conducted in adults. The responsibility for all of this must
be widely shared, and an ethical discourse encouraged
addressing it. Sir William Osler (18491919) described
tuberculosis (TB) as a social disease with a medical
aspect.7 The clear link between TB and poverty deserves

an ethical discourse.
ETHICS, HUMAN HEALTH AND RESEARCH

General Issues
Access to adequate level of health care is recognized as a
universal and fundamental human right and equity is a
fundamental principle of all health policies. Availability
of effective, accessible, affordable and locally acceptable
health services is an ethical requirement. A meaningful
participation of communities in the development of
health research, services and policies is the need of the
hour.
Research in developing countries is going to become
increasingly important in order to solve the existing and
upcoming health problems. As a consequence it becomes
necessary to mobilize funds from national and
international sources to carry on relevant research and
to harness the technical guidance from developed
countries. In this process it is essential that countries
develop adequate capacity in research capabilities, ethical
conduct of research and ethical review procedures. Major
Ethical, Legal and Social Issues (ELSI) need to be
continuously debated and require attention to
understand reasons and ways to protect autonomy,
privacy, confidentiality, preventing stigmatization and
discrimination of research subjects. All these above
mentioned procedures are also required for conduct of
any research in drugs, devices and vaccines, like BCG in
the case of tuberculosis.
Recent advances in science and technology have
brought along numerous ethical dilemmas. Advances
in biotechnology, genomics, genetic engineering, organ
and tissue transplantation, new reproductive
technologies, cloning, medical devices, recombinant
products, surgical innovations, life support systems all
pose challenges to the conscientious researchers and the
society has to evolve acceptable solutions to benefit the
majority. Each of these requires careful scrutiny by
appropriate scientific and ethics committees before any
Chapter 43 Ethical Issues and Concerns about Tuberculosis Research in Children

research is undertaken. There is no single solution to
any issue and decisions are taken on case-to-case basis.
The goal of science is to explain and predict natural
phenomena. A discussion regarding the need to:
i. Conduct research that is scientifically rigorous, and
ii. Accords the participants benefits and protections
that are due to them as human subjects is crucial.
These two goals can conflict with one another, leaving
researchers institutional ethics committees, grant
application review groups, and funding agencies with
the responsibility of striking an appropriate balance.
Thus, both patients and healthy people become targets
of such studies. The practice culminates in surveillance,
health programs and monitoring and program
evaluation. Their outputs apply to communities and
improve epidemiological practice, whereas clinical
research targets individuals or a small group of subjects
to improve clinical care. In carrying out their research,
one should abstain from conduct that may injure or
jeopardize the welfare of study participants either
through their intentional or unintentional behavior
actions (e.g. negligence or unjustified departure from
study protocols or standards of practice) or omissions.
Consideration of risks includes attention not only to
physical risks as a result of direct contact with the
participants but also to psychological, economic, legal,
or social risks.8
Principles of Biomedical Ethics

The ethical guidelines of the Indian Council of Medical
Research (ICMR) were first prepared in 1980 as a Policy
Statement9 and were subsequently revised in 200010 and
2006.11 These documents were prepared after wide
stakeholder consultations and public debates. The
guidelines are recognized internationally.
The basic principles enshrined in the Ethical
guidelines are the following:
Nonmaleficence Do no harm
Beneficence Fruitful result, do good
Autonomy Respect for persons
Justice Distributive justice, equitable distribution of
risks and benefits.
The purpose of research, its potential benefits to
participants, the anticipated risks and compensations for
the same, the unexpected consequences and steps
proposed to tackle the same, the evaluation of risk benefit
ratio are all covered under the principles of Nonmaleficence and Beneficence. The fundamental moral
principle of Respect for Persons demands voluntary,
informed consent from individuals participating in
research and is termed as the Autonomy principle. This
includes right to privacy and confidentiality and
obligations to protect the vulnerable groups including
653
children by obtaining informed consent from the legal

guardians wherever necessary and obtaining assent from
minors. Recruitment of those with diminished autonomy
also requires special consideration and adequate
justification. Hence obtaining Informed Consent has
become the most crucial requirement in any clinical
research. The principle of Justice demands that the fruit
of research is equitably distributed amongst the
beneficiaries and participants of research. This has
gained global importance in view of growing international collaboration between developed and developing countries. Selection of subjects, equitable study
design and access to post-trial benefits are the hallmarks
of this principle.
All clinical research involving human subjects should
take the above principles into consideration while
planning, conducting and evaluating the research and
during utilization of the research results. Several
international documents are available which have been
prepared by different agencies and these have also
highlighted the above.12-15
Vulnerability and Children

Biomedical research, including clinical trials and related
scientific research, rely on the successful recruitment of
human participants in order to yield meaningful results.
In this sense, human participants are instrumental in
securing data useful to the researcher, which is often
extrapolated to develop clinical techniques/drugs/
methodologies applicable across a broader range of
human populations. This interplay between results
driven research and the necessary involvement of human
participants naturally creates tension between procuring
scientific data and the proper ethical treatment of research
participants.16
All vulnerable populations stand in unequal power
relationships with others that typically do not
characterize normal (or most) members of society. Such
relationships may instantiate themselves in numerous
ways to create differing vulnerabilities across groups.
The clinical researcher must be aware of the concerns
specific to each vulnerable population and adjust his
research protocols to compensate. Each vulnerable
population deserves individual treatment according to
their specific circumstances. Of concern are individuals
who are already disadvantaged or vulnerable to harm
independent of their involvement in clinical trials. Such
participants, for whatever reasons, have been
marginalized by society and are susceptible to
exploitation. They typically stand in unequal power
relationships with others and/or possess substandard
mental faculties, rendering them incompetent: key
examples include the mentally disabled, abjectly
impoverished persons, prisoners/refugees, women/
pregnant women, children, and ethnic minorities, etc.
654
Vulnerable populations are attractive for research

purposes precisely because of their vulnerability.
Transgressions of ethical boundaries become easier as
does the consequent procurement of scientific data.
Thus, the entire field of research ethics has been built
upon and refined according to examples of extreme
clinical research that have dotted modern history.
The historical origin of current ethical principles for
conducting research with children arises from the
Nuremberg Trials, which took place after the Second
World War, and the Nuremberg Code,17 which emerged
from these. The Code sets out statements of certain moral,
ethical and legal principles relating to research involving
human subjects. Later, the emergence of the Declaration
of Helsinki14 in 1964, amended in 1989, 1996, 200818
includes an examination of the issue of children as
research subjects in relation to informed consent.
Children are a vulnerable population in even the
richest parts of the world, yet the role of health
researchers involving children in the poorest regions is
a particularly pressing issue that should be addressed
by the pediatric research community in a timely and
meaningful manner. Ethical considerations are integral
to all child health research throughout the world.19
Research involving children has historically been
discouraged on ethical grounds, and was essentially
barred by the Nuremberg Code (1949).17 However, there
is growing recognition of the ethical imperative to include
children in research studies,20 particularly in light of
evidence that child health research is not only beneficial,
but that the absence of pediatric research can be
harmful.21 There is likewise the obligation to adhere to
ethical guidelines to protect the safety, human rights and
cultural integrity of the children, their families and their
communities. A proactive ethical approach to global child
health research serves children in two broad ways:
1. Adherence to ethical principles leads to the
development of a set of rational and relevant priorities
and objectives.
2. Promoting ethics ensures that observational or
interventional methodologies are consistent with the
customs and needs of the specific population with
whom the investigators are working, and are mindful
of the reality within which the community exists.
Efforts to improve the health of children depend on
clinical investigations that use children as research
subjects. Children are a vulnerable population, however,
and so are accorded special protection from research
risks. Researchers in pediatrics may encounter conflicts
between protecting the children who are vulnerable
research subjects and, developing generalizable
knowledge to benefit children. Furthermore, there are
many pitfalls for the researcher in carrying out the
communication with both parents and children that is
required for responsible decision-making about

participation by children or adolescents in experiments.
Child health providers must always remain cognizant
of the link between health and human rights. 22 An
investigators presence in a developing country entails his
or her responsibility to take an interest in the general health
and welfare of the population, emphasizing an awareness
of nonmedical factors, such as war and drought, which
clearly have an impact on the health of children. An
understanding of the determinants of health in each
unique community, combined with close collaboration
with local health professionals, should guide the
development of ethical health research agendas in the
future.
Ethical research aims to reduce health inequities, by
serving to benefit primarily the population from which
the study participants are recruited, and benefit
secondarily all children on a global scale through the
transposition of the acquired knowledge. The second
factor underlying unethical priority-setting in child
health research is that children have been notoriously
ignored in the process by which new drugs are approved
and brought to the market, a problem that has led
investigators to characterize children as Therapeutic
Orphans. A recent report23 reveals that the drug gap is
widening due to a virtual complete lack of interest of the
major pharmaceutical corporations in diseases that afflict
those who are poor. Investigators involved in the design
of a pediatric research project should consider three levels
at which a study may impact a society.24
1. The direct effect of the specific research project on
study participants and their families.
2. The impact of the study in terms of expected health
outcomes among children in the community or
country in which the study is conducted.
3. The broad effect of intervention by foreign health
professionals on the community or region.
In relation to drug related research for TB in children,
two important aspects are:
1. Use of drug regimens according to the severity of
disease.
2. Pharmacokinetic studies of various antitubercular
drugs in relation to age, nutritional and acetylator
phenotype (pharmacogenomics).
As regards ethnic groups, people in the South of India
are rapid acetylators and up North are slow. It is
especially important in relation to drug isoniazid.
The degree to which a child stands to benefit from a
particular experimental intervention depends on the risk
of morbidity or mortality resulting from the illness to
which the intervention is targeted. Guidelines sponsored
by the Canadian Pediatric Society state that exporting
research to other countries to avoid placing our own

children at risk neglects the social responsibility to protect
and benefit all children.21 However, given the higher
incidence of adverse outcomes of infectious diseases and
nutritional deficiencies in impoverished regions, some
interventions may have relatively greater benefits for
participants in these settings (e.g. zinc supplementation
to reduce the incidence of pneumonia).25 Therefore, a
higher level of risk may be deemed to be acceptable if
the overall risk-benefit ratio remains unchanged or
improved. It is unethical, however, to locate children with
greater background risks with whom to conduct a study
to justify higher-risk research.26 In general, research
should not be conducted in children where:
1. The information can be gained equally well in adult
volunteers;
2. It will expose children to significant risk that exceeds
the magnitude and likelihood of potential benefit; and
3. Suitable preliminary studies have not been conducted
in adults first. For example, children should not usually
be the subject of first in man and other early phase
studies of new drugs.
There are clear exceptions to this principle such as
testing drugs or devices in diseases found most
commonly, or exclusively in children.
There are some situations wherein research in
children maybe warranted, e.g.
1. To ensure optimal diagnosis, assessment, treatment
and prevention of disease during childhood;
2. Advance the health and welfare of children;
3. Identify the determinants of child health;
4. Contribute to understanding the pathophysiology of
childhood disease;
5. Contribute to understanding of the childhood origins
of adult health or disease; and/or
6. Improve the methodology of research in children.
Establishing a Valid Informed

Consent/Assent Process
There is a long-standing moral and legal tradition that
supports parents as the primary decision-makers for their
minor children, including the right to make proxy
decisions for children about participation in research.
Parental decision-making is a critical factor in the study
of pediatric research ethics, even though it is recognized
that parents, as well as health researchers, may have
interests that conflict with the best interests of the child.
Today, the legitimate role of the child in decisions
about research participation is recognized. The ethical
concept of assent provides a framework to assist
investigators and parents with efforts to incorporate the
views of children who are recruited as research subjects.
Assent is analogous to consent where the subject has a
655
reduced capacity to understand the matter to which they

are assenting.
The process of obtaining voluntary, informed consent
needs consideration. The case does not indicate the
socioeconomic level of the participants. If they are from
a low socioeconomic and educational background, there
is a possibility that they will be unduly swayed by the
offer of free tests and modest environmental interventions. Human subjects research guidelines for
children require that the permission of parents or
guardians must be obtained, since children are
considered unable to give legally valid informed consent.
The information given to subjects and parents should
certainly include the purpose of the experiment and the
risks and benefits involved. In the case of the control
group, it should be made clear to both parents and
children that their involvement is not for their own
benefit but for the benefit of others. The information must
be made available in a manner easily understood by both
parents and children, particularly if they are from a
disadvantaged population.
A process of valid informed consent is necessary in
almost all research settings, and assent from minors must
accompany consent of a legal guardian where possible.18
The intricacies of proxy consent required in pediatric
research is further complicated by the challenge of
obtaining valid informed consent in a developing world
perspective.27,28 There are at least two ways in which we
can increase the contextual suitability of informed
consent/assent processes, without compromising
universal ethical standards. First, we should conduct
prospective, empirical studies of the informed consent
process in developing countries such that our practices
will reflect evidence-based ethics. Second, we should
promote the routine creation of community advisory
boards, which have been used successfully to facilitate
the implementation of informed consent processes that
reflect the needs and wishes of study participants.29
One of the most important ways in which ethical
research methodology promotes health equity is by
exemplifying the principle of distributive justice, which
states that studies should be designed to obtain
knowledge that benefits the class of persons of which
the subjects are representative. 30 Even if ethical
priorities exist, it is not enough to simply conduct
pediatric research within a developing country; rather,
the design of every study must be such that the
outcomes can be feasibly used to improve child health
within that same region. The effect of research is not
only in the application of the knowledge acquired by
analyzing the collected data, but also results from the
act of doing the study itself, and by the process of
intervening as health professionals in a foreign country.
A basic tenet of biomedical ethics, primum non-nocere
656
(do no harm), reminds us that sometimes doing nothing

at all is better than doing something potentially
damaging. Despite the ethical obligation to promote
pediatric research abroad, investigators must consider
the overall impact of intervening and/or interfering,
given the endless list of examples of failed and even
damaging development projects in the past.31
It is essential that the child has full information about
the research in order to give their informed consent to
take part, and that consent is freely volunteered. The child
should also know that he/she can withdraw at any time.
Information presented to the child and parent, should
explain: What will happen; what is being asked of the child;
that the child can agree or disagree to take part without
adverse consequences; and may withdraw at any time;
and be given in clear language at a level that the child can
understand, using visual aids if necessary. The consent
from a child who is a minor is called as assent. This may
be verbal or written. Generally it is expected that the
investigator/researcher makes an assessment of the
capacity of the child to give assent or not. Generally for
children between the ages of 7 to 12 years, only verbal
assent may be required. For children between 12 to 18
years, an assent form in simple language may be designed.
In dealing with children, dissent plays an important role
too. Children who give dissent or do not agree there choice
should be respected and they should not be enrolled.
However, in cases where the research is of immediate
direct health benefit to the child, if the parents are willing
the child may be enrolled in the study.
Under the US regulations, children should be enrolled
in clinical research only when it offers a compensating
potential for benefit or poses sufficiently low risks.32-34
The research risks should be higher than what the
children would experience in their daily living or routine
examinations.35 However, the risk varies significantly
with age.36 Thus, Institutional Ethics Committees (IEC)
could follow the options of either adopt the minimum
risk threshold that applies to research with children of
all ages, or adopt a different risk threshold for each stage
of development, or follow a minimal risk threshold for
each age. The IEC could follow either options, but this
would pose a problem in multisite studies wherein IEC
differences may be there.
Parental Consent
Parental consent is required where it is viewed that a
child is incapable of understanding the implications of
taking part in a study or where the child is regarded as
incompetent to give consent. Although the childs assent
is advisable, the power to consent, in law, is that of his/
her parents or legal guardian. Those acting for a child
are only acting legally if participation in the project is of
benefit to the child. If it is not, the parent or guardian
could be said to be acting illegally. One parent can give

consent but it is preferable to have both. Where there is
parental disagreement as to whether an incompetent
child should be volunteered for research, it is possible
that one parent could apply to court to block the childs
participation. The Ethics Committee may in such
circumstances advice that where there is disagreement,
the child should not be included in the research.
Confidentiality Issues
Confidentiality must be explained in a way that children
can understand that his/her identity will be protected
by the investigator. The researcher present at the
interview is rarely the only person to see the results. It
must therefore be made very clear who will have access
to the data and what will happen to the data when the
research is complete. The methods of removing names
and other identifying information should be explained
in case the research involves anonymization. The extent
of the anonymity and any potential areas where the
confidentiality of the interview may be broken should
be explained to the child at the outset of the interview.
For example, the researcher has a duty to take steps to
protect the child or other children, if they are considered
to be at risk of significant harm. The child needs to know
what action may be taken in the event that she discloses
that they or others are at risk of significant harm, or
where the researcher observes or receives information
of incidents likely to cause harm. Arrangements need to
be made in advance, following professional advice, on
agreed procedures in these cases, and for support for the
child. Information can be given about the storage of data
and who will have access to it, and how it will be used,
in the same clear language as used about the research. It
can be argued that use by secondary researchers is not
greatly different from that of primary researchers on the
research team, who have not been directly involved in
the collection of the data. Assurances can be given about
the anonymity of the data, with the removal of names
and any identifying information, to meet the concerns of
the child and responsible adult. It is recommended that
written information should always be provided for the
child and responsible adult, and a contact telephone
number, should they wish to contact the researchers.
Ethical Issues in Conduct of

Vaccine Trials Among Children
There is a recognized special need to develop TB vaccines
appropriate to children because of the high disease
burden. But any clinical trial for the development of new
vaccine must be closely reviewed by an appropriately

constituted ethics committee. The different aspects
considered include the balance of benefits and risks, the
choice of control groups, the selection of participants,
vaccine development strategies, the informed consent
process, the appropriate standard of care, post-trial access
to efficacious vaccines, trial management and oversight,
and follow-up of participants after a trial has ended.36
Due to the special vulnerability of child participantion
in vaccine trials, additional safeguards should be in place
in any vaccine study. These safeguards include
identification and addressing their vulnerability and
protecting them from any exploitation, and from mental,
emotional and physical harm. Considering the principles
of beneficence and justice, it is important that the choice
of the particular group of children to be included in a
trial requires clear justification of the scientific need to
use that population, and an equitable sharing of benefits
and risks among possible groups.37 If the targeted group
belongs to a community it is advisable to include a
member of the community in the discussions of the ethics
committee. This would help to assess the needs and look
at ways to fulfill the requirements of the community and
in addition also provide appropriate representation and
acceptability by the targeted community for the vaccine
trial. If the vaccine being developed is for neonates or
infants, it may be unethical to carry out the trials in older
children as this may expose them to risks though they
cannot benefit from the vaccine. However, it may be
acceptable to carry out such trials in adult participants
who can give voluntary informed consent after
understanding the risks without any direct benefits.
Particular care and consideration should be given to
populations that are especially vulnerable and to overresearched populations. Another critical issue comes up
in the placebo controlled clinical trials. In children
administration of an inactive placebo by injection
involves pain and discomfort without any corresponding
benefit. Therefore, it should be considered taking into
consideration the scientific validity of research if an active
comparator that comprises an available marketed vaccine
related or unrelated to the condition and would provide
some benefit to child participants may be given as an
active control. While reviewing protocols for vaccine
trials the institutional ethics committees should see and
ensure that the trial sponsors and researchers would also
contribute to the improvement of healthcare infrastructure especially in the situation of low socioeconomic
communities that experience a high burden of disease
and low standards of healthcare. A standard of care
should be offered that improves the health conditions of
the trial participants and community. The IEC should
also review the plans for post-trial benefits and long-term
follow-up of the participating children. Preferably a
657
medical insurance should be in place to provide for

medical care for injury or death related to the trial.
Compensation for participation need a special mention.
The amount of compensation should be commensurate
with the expenses or loss or wages, cover for the fare.
However, this amount should not be so large that this
becomes an undue inducement to the parents to put their
child/ infant to risk for obtaining the money. It is
preferable to either have actual reimbursements or
compensate in kind rather than cash by providing
healthcare facilities. Adequate monitoring by a Data and
Safety Monitoring Board should be recommended by the
Ethics committee to the sponsor.
There is growing global concern for maintaining
uniform ethical standards in biomedical research and
practice all over the world in view of the exceptional
potentials of science and technology for betterment of
mankind. There is need for review, build consensus on
the technical and ethical safeguards and to consider how
to move forward from moral reasoning to global action
in the interest of advancing human well being. The
challenge before all is to clarify the meaning of the rising
ethical issues, help to assess current needs and practices
and find solutions for the same. Since 2007, there is a
Clinical Trials Registry of India (CTRI) funded by the
Department of Science and Technology (DST) and Indian
Council of Medical Research and managed at the
National Institute Medical Statistics under the Indian
Council of Medical Research (ICMR), Department of
Health Research, Ministry of Health and Family Welfare,
Govt. of India. Since 15th June, 2009, it is mandatory to
register any clinical trial approved by Drug Controller
General of India with CTRI.38 Further, a large number of
medical journals have made it mandatory that they will
not publish any clinical research article unless clinical
trials registry number is there. The clinical trials can be
registered at www.ctri.in.
TUBERCULOSIS DIAGNOSIS, TREATMENT, CONTROL,

PREVENTION, ERADICATION
AND ETHICS
Infectious diseases raise difficult questions about how
the aim to promote public health should be balanced
against the aim to protect human rights and liberties; and,
because infectious diseases primarily affect the poor and
disempowered, the topic of infectious disease is closely
connected to the topic of justice. There are, furthermore,
reasons for thinking that the problem of TB is, ethically
speaking, even more important than AIDS. In the vast
majority of cases, TB drugs provide cure and they are
much less expensive than AIDS medications. TB
mortality is, economically speaking, much easier to
prevent. Finally, being airborne, TB can be contracted
658
via casual contact and is much more contagious. In many

ways, then, the threat to innocent individuals
particularly children under five years of age those who
become immunocompromised due to infectious disease
of infancy such as measles and malnutrition and also a
threat to the public health in generalis greater in the
case of TB. TB is arguably the most important neglected
topic in bioethics.7
It is well recognized that it is unethical to conduct
research on children if it could be done equally well
among adults. However, there is a huge disease burden
among children and a paucity of research being done
that directly relates to the health needs of children. It used
to be considered that TB in children is not a public health
problem because it is paucibacillary, is usually not
responsible for transmission of disease in the community
except the adolescent who develops open TB from an
adult in the family (bacillary). This is a myth because
this group with primary disease can transmit the disease
in the community when as adults they develop bacillary
form of pulmonary TB.1
Tuberculosis is considered a neglected disease by
Drugs for Neglected Diseases initiative (DNDi). The
neglect is more pronounced in children because drugs
available are not child-friendly and the second-line drugs
are toxic, either hepatotoxic or more dangerous
nephrotoxic. Streptomycin can be neurotoxic (deafness) if
it is used in early infancy without monitoring of ear
function for hearing.
Several ethical concepts and conflicts have been
identified around TB treatment and control.6
a. Restriction of movement: Which involves isolation,
quarantine and migrant screening. The debate is
liberty versus utility, freedom of movement versus
public health, protection of individual versus society
and responsibility for public health.
b. National surveillance: Privacy and stigma.
c. Obligation to avoid infecting others: Duty to do not
harm, legislating mortality.
d. Third party notification: Right to confidentiality versus
protection of the innocent, trust in healthcare system
and its implications for public health.
e. Duty to treat: Professional obligations, autonomy and
societies responsibility to promote safe working
conditions.
f. Treatment exclusion: Right to healthcare, discrimination, primacy of patient Vs public health.
g. Clinical research: Standards of care, managing third
party risks.
h. Justice and the distribution of health resources: Right
to healthcare access and availability, distribution of
research resources, rich country obligations to
increase aid for self interests.
The Public health actions around TB prevention and

control should consider the following:
1. Address principally the fundamental causes of
disease and requirements for health, aiming to
prevent adverse health outcomes.
2. Achieve community health in a way that respects the
rights of individuals in the community.
3. Policies, programs, and priorities should be
developed and evaluated through processes that
ensure an opportunity for input from community
members.
4. Advocate and work for the empowerment of
disenfranchised community members, aiming to
ensure that the basic resources and conditions
necessary for health are accessible to all.
5. Seek the information needed to implement effective
policies and programs that protect and promote
health.
6. Programs and policies should incorporate a variety
of approaches that anticipate and respect diverse
values, beliefs, and cultures in the community.
7. Programs and policies should be implemented in a
manner that most enhances the physical and social
environment.
The Institutions involved in providing care should:
1. Provide communities with the information they have
that is needed for decisions on policies or programs
and should obtain the communitys consent for their
implementation.
2. Act in a timely manner on the information they have
within the resources and the mandate given to them
by the public.
3. Protect the confidentiality of information that can
bring harm to an individual or community if made
public. Exceptions must be justified on the basis of
the high likelihood of significant harm to the
individual or others.
4. Institutions should ensure the professional competence of their employees.
5. Institutions and their employees should engage in
collaborations and affiliations in ways that build the
publics trust and the institutions effectiveness.
CONCLUSION
The spectrum of childhood TB involves primordial
prevention, identification of susceptible contacts of cases,
prevention of disease transmission, management of cases,
and public health programs. Research is undertaken at
these levels by local and international investigators.
Children constitute a vulnerable population and hence
demand careful ethical introspection. Issues and concerns
which are relevant to the overall child health research form
the framework for TB research and practice. Bioethics is a
constantly evolving field which nourishes from changing
scientific issues and subject vulnerability.
HIGHLIGHTS
Tuberculosis in children continues to be a major
public health problem in India.
Ethical considerations need to be kept in mind while
planning clinical care, research, diagnostic and
therapeutic interventions in children.
Ethics is a constantly evolving issue and requires
ongoing debate and resolution so as to protect the
vulnerability of children.
REFERENCES
1. Rose CE Jr, Zerbe GO, Lantz SO, et al. Establishing
priority during investigation of tuberculosis contacts. Am
Rev Respir Dis. 1979; 119: 6039.
2. Shaw JB, Wynn-Williams N. Infectivity of pulmonary
tuberculosis in relation to sputum status. Am Rev Tuberc
1954;69:72432.
3. Grzybowski S, Barnett GD, Styblo K. Contacts of cases
of active pulmonary tuberculosis. Bull Int Union Tuberc
1975; 50: 90106.
4. Loudon RG, Williamson J, Johnson JM. An analysis of
3,485 tuberculosis contacts in the city of Edinburgh
during 1954-1955. Am Rev Tuberc 1958; 77: 62343.
5. Almeida LM, Barbieri MA, Da Paixao AC, et al. Use of
purified protein derivative to assess the risk of infection
in children in close contact with adults with tuberculosis
in a population with high Calmette-Guerin bacillus
coverage. Pediatr Infect Dis J 2001; 20: 10615.
6. Selgelid MJ, Kelly PM, Sleigh A. Ethical challenges in TB
control in the era of XDR-TB. Int J Tuberc Lung Dis 2008;
12: 2315.
7. Fanning A. An ethical consideration of TB: Still a social
disease with a medical aspect?. Int J Tuberc Lung Dis
2008; 12: 229.
8. American College of Epidemiology Ethical Guidelines
2000. www.acepidemiology2.org/default.asp (accessed
on 15th September 2009).
9. Policy Statement for Research on Human Subjects, ICMR,
1980.
10. Ethical Guidelines for Biomedical Research on Human
Participants, ICMR, 2000.
11. Ethical Guidelines for Biomedical Research on Human
Participants, ICMR, 2006.
12. The Belmont Report (USA): Ethical Principles and
Guidelines for the protection of human subjects of
research, 1979. Accessed on 20 December 2009 at http:/
/ohsr.od.nih.gov/guidelines belmont.html.
13. World Medical Association. Declaration of Helsinki. Rev.
2000. Accessed on 16 December 2009 at (www.wma.net).
14. Council for International Organizations of Medical
Sciences. International ethical guidelines for biomedical
research involving human subjects, 2002. Accessed on
18 December 2009 at www.cioms.ch.
15. Nuffield Council on Bioethics. The ethics of research
related to healthcare in developing countries. London,
April 2002. Accessed on 18 December 2009 at
www.nuffieldbioethics.org.
659
16. Lott JP. Vulnerable/special participant populations.

Module Three, Developing World Bioethics, 2005. Vol 1
(5 Blackwell Publishing Ltd): 1471-8847 (online): pgs
30-54.
17. The Nuremberg Code. Trials of War Criminals Before
the Nuremberg Military Tribunals under Control Council
Law No. 10. Washington: US Government Printing
Office, 1949; 2: 181-2.
18. World Medical Association. Declaration of Helsinki:
Ethical Principles for Medical Research Involving Human
Subjects. Rev. 2008 <http://www.wma. net/e/approvedhelsinki.html> (Version current at September, 2009.
19. International ethical guidelines for biomedical research
involving human subjects. Geneva: World Health
Organization and the Council for International
Organizations of Medical Sciences, 1993.
20. Guidelines for the ethical conduct of medical research
involving children. Royal College of Pediatrics, Child
Health: Ethics Advisory Committee. Arch Dis Child 2000;
82: 177-82.
21. Consent Panel Task Force of the National Council on
Bioethics in Human Research (NCBHR). Report on
Research Involving Children. Ottawa: National Council
on Bioethics in Human Research, 1992.
22. Mann JM, Gostin L, Gruskin S, et al. Health and human
rights. Health Hum Rights 1994; 1: 19-23.
23. Fatal Imbalance: The Crisis in Research and Development
for Drugs for Neglected Diseases. MSF Access to Essential
Medicines Campaign and the Drugs for Neglected
Diseases Working Group. Mdecins Sans Frontires
October 9, 2001. <http://www.msf.org/> (Version
current at January 21, 2003).
24. Roth D. An ethics-based approach to global child health
research. Paediatr Child Health 2003; 8: 6771.
25. Bhandari N, Bahl R, Taneja S, et al. Effect of routine zinc
supplementation on pneumonia in children aged 6
months to 3 years: Randomised controlled trial in an
urban slum. BMJ 2002; 324: 1358-62.
26. Roggin KK, Chwals WJ, Tracy T. Institutional review
board approval for prospective experimental studies on
infants and children. J Ped Surg 2001; 36: 205-8.
27. Lynoe N, Hyder Z. Obtaining informed consent in
Bangladesh. N Engl J Med 2001; 344: 460-1.
28. Adityanjee. Informed consent: Issues involved for
developing countries. Med Sci Law 1986; 26: 305-7.
29. Strauss RP, Sengupta S, Quinn S, et al. The role of
community advisory boards: Involving communities in
the informed consent process. Am J Public Health 2001;
91: 1938-43.
30. International Guidelines for Ethical Review of
Epidemiological Studies. CIOMS, 1991. <http://
www.cdc.gov/od/ads/intlgui3.htm> (Version current
at September 21, 2003).
31. Hancock G. Lords of Poverty: The Power, Prestige, and
Corruption of the International Aid Business. New York:
Atlantic Monthly Press, 1989.
32. Institute of Medicine. Ethical Conduct of Clinical
Research Involving Children. Washington, DC: National
Academies Press; 2004.
660

33. Nicholson RH. Medical Research With Children: Ethics,
Law, and Practice. Oxford, England: Oxford University
Press; 1986.
34. Kopelman LM. Children and Health Care: Moral and
Social Issues. When is the risk minimal enough for
children to be research subjects? In: Kopelman LM,
Moskop JC, eds. Boston, MA: Kluwer; 1989; 89-99.
35. Guidelines for Institutional Review Committees for
Health Research in Nepal. Kathmandu: Nepal Health
Research Council; 2005.
36. Thompson K. Kids Risk Project, Harvard University.

http://www.kidsrisk.harvard edu. Accessed April 2009.
37. Ethical considerations arising from vaccine trials
conducted in paediatric populations with high disease
burden in developing countries WHO/IVR ethics
meeting, 2628 November 2002, Accra, Ghana.
38. Clinical Trials Registry of India (CTRI). Accessed online
on 18 December 2009 at http://www.ctri.in/Clinicaltrials/
index.jsp.
44
Tuberculosis in Children:
Research Priorities
Vimlesh Seth
RESEARCH IN PEDIATRIC PRACTICE

The current status of medical research as such in children
in India is in an abysmal state as stated by President of
Indian Academy of Pediatrics in 2007. He opined that
there is dearth of good quality publications particularly
in reputed indexed international journal.
In India with crash commercialization of health sector
and entry of big corporate houses in health-care facilities,
the quality medical research has suffered and lost its
prominence. Need of investing in research seems to be a
non-profitable expenditure by these big business houses.
Reasons for Poor State of Medical Research in India

Lack of research culture even in medical colleges barring
a few centers of excellence which can be counted on finger
tips is evident. There is lack of aptitude for original
research, acknowledgment of quality research work, and
opportunities for those entering this field. Due to lack of
proper infrastructure to carryout quality research work
there is a lack of research opportunities and scholar jobs.
Independent research avenues are glaringly few and far
between. There are few independent bodies of
Government of India sponsoring, facilitating and
supervising research activities in the country. To name a
few these are the following:
1. Department of Health Research, the Indian Council
of Medical Research is only one national body
significantly contributing in health research in all its
aspects, including tuberculosis in children.
2. Department of Science and Technology. This also
finances big industrial houses engaged in research
not necessarily medicine leave aside pediatrics.
3. Council of Scientific and Industrial research. This also
finances research in tuberculosis and also
pharmaceutical companies in drug development.
4. Department of Biotechnology. Its head now is a
medical person and is a very positive researcher and
helps in financing big projects in medical research.
However, this started about 3 to 4 years ago and
hopefully this will show some results. To procure
funds from this body one has to be a keen researcher
and be able to crystalize the problems to be researched
particularly in children and that too specifically in
TB in children.
5. International Agencies like WHO, STOP, TB, etc. also

concentrate on TB in adults; children are again a
neglected lot.
President of the Indian Academy of Pediatrics in 2007
emphasized that there is an urgent need to invest in
medical research, the IAP has prepared three consensus
reports on diagnosis and management of TB in children
the last being published in 2010 (discussed in a chapter
of the book). These are merely guidelines for having
uniformity in diagnosis and management of TB in
children. These do not emphasize the areas of TB to be
researched. The president emphasized the need to
encourage the practicing pediatricians in research. The
pediatricians of medical colleges need to become role
model in the research. Practicing pediatrician are too busy
providing preventive and curative services to children.
Only a few can be motivated for research.
Before pediatric research in office setting is to be
started, its first the medical colleges (Pediatric
Department) that should follow a uniform pattern of
diagnosis and treatment of TB in children. In this book
in the chapter on how to start a TB and HIV Pediatric
clinic, various case record forms for both has been
designed. Even to start with if this practice is followed
and as DOT center being present in all medical colleges,
some beginning can be made. It is suggested by Seth1
that even if one DOT worker is provided to the Pediatric
TB clinic in each medical college, some semblance of
uniformity of at least collection of data on TB in children
can be achieved.
In Government of India, there is a separate TB division
with senior Deputy Director General (DG) in the Ministry
of Health and Family Welfare. He is responsible for
facilitating smooth running of Revised National
Tuberculosis Control Program (RNTCP). Some effort is
being made in the form of guidelines for diagnosis and
treatment of TB in children in this program. These need
to be religiously followed. Till late even 1 TU strength
PPD was not available at libitum for doing tuberculin
test. There are lots of lacunae in the national program as
discussed by program managers in another chapter in
the book.
Problems of general importance such as annual risk
of TB infection, surveillance of MDR-TB in few selected
662
areas have been the point of investigations but there is

need to give specific attention relevant to children only.
In the international forum, a research agenda for childhood
tuberculosis for improving the management of childhood
tuberculosis with in National Tuberculosis Programs, research
priorities based on a literature review have been drawn. This
was done in 2007 by STOP.TB, Department of Child and
Adolescent Health and World Health Organization.2
The points emphasized in this are discussed below:
which could be applicable to India.
The main elements of the proposed research agenda
are:
1. The burden and diagnosis of childhood tuberculosis.
2. Treatment of childhood tuberculosis.
3. Roles and responsibilities.
4. Recording and reporting.
5. BCG vaccination in children.
EPIDEMIOLOGY
Childhood TB is seldom confirmed under program
conditions by culture of M. tuberculosis, let alone sputum
smear-positivity by microscopy. It is a neglected aspect
of national TB control program. Childhood TB arises
most often as a result of the inhalation of M. tuberculosis
bacilli expectorated by sputum smear-positive adult
with pulmonary TB patient with an aerosol droplet of
5-10 m in diameter containing 1-3 bacilli. If infection
is successfully established, a primary focus forms in
lung parenchyma, most often subpleural in location, and
bacilli spread to the regional lymph nodes and later via
the lymph and blood to organs throughout the body.
In younger children particularly those aged less than 2
years, progression of the various elements of the
primary complex and overwhelming dissemination of
TB are particularly likely to occur. At the other extreme
of childhood, progression to adult-type pulmonary TB
becomes much more frequent in adolescents, although
there is reduced propensity to disseminated TB.
The document published in 2007 which lays emphasis
on research agenda in TB in children, has the background
document of WHO on incidence and prevalence data on
tuberculosis in children though only of bacillary form.
The latest report of WHO (2009) does not mention the
problem of TB in children at all not even bacillary form.
So in the absence of this, action at the operational level
for TB in children becomes difficult. DOTS strategy which
encompasses the following five aspects, should focus on
children of all ages in mind. To begin with special risk
categories (less than 5 years and adolescent) should be
given priority.
1. Sustained political commitment to increase human
and financial resources and make TB control
(including children) a nation wide priority integral
to the national health system.
2. Access to quality-assured sputum microscopy for all

cases of TB. Special attention is necessary for case
detection among the HIV-infected and other high risk
groups, such as household contacts of infectious cases.
In children to have sputum for smear-microscopy is
an extremely difficult task. Recent introduction of
induced sputum technique, for collection of sputum
specimen seemingly has some hope but its feasibility
at the operational level needs a concerted effort.
Gastric lavage though mentioned frequently is very
infrequently practiced.
3. Standardized short-course chemotherapy for all cases
of TB under proper case-management conditions.
Logistics of it to be able to have access for every child
need to be worked out. Diagnosis of TB in children is
very difficult at the grass root level.
4. Uninterrupted supply of quality-assured drugs with
reliable drug procurement and distribution systems.
Currently made weight wise boxes of anti TB drugs
for different age categories of children are a positive
step in this direction. However, these are not available
for children less than 16 kg. The latter conveniently
excludes most vulnerable group of children under
two years.
5. Recording and reporting systems enabling outcome
assessment of all children and over all performance
of program is also difficult. The case record form
which is to be filled by a DOT worker has to be
extremely simple and short to be grassroot level
worker friendly.
DIAGNOSIS
It is stated by WHO in the document on research
priorities in TB in children that the diagnosis of childhood
TB is a critical aspect of the integration of childhood TB
into national TB control program. Without the assurance
of an accurate and consistent diagnosis, the precise
burden of childhood TB and its importance will remain
uncertain and controversial. Many children who are
treated for TB may not have TB. It is further stated that
as a short term goal, there is little prospect of achieving a
widely available, gold standard for diagnosis of TB in
children either by means of culture, microscopy, polymerase chain reaction (PCR) or serology. Three criteria:
clinical, chest radiography and tuberculin testing
suggested by WHO (2006 b) should be followed. It is
estimated by using these criteria that 15 to 20 percent
children may be found to have TB in high-incidence
communities.
Research priorities defined under the heading of
diagnosis are:
1. Evaluation of the use of criteria suggested by WHO
policy document (2006b) to suspect the diagnosis of
childhood TB and evaluate new methodologies for
Chapter 44 Tuberculosis in Children: Research Priorities

assisting or confirming the diagnosis of TB in children.
2. Evaluate Mantoux skin test responses in HIVinfected and non-infected children to determine
sensitivity, specificity and predictive value of the
suggested cutoff points to support the diagnosis of
M. tuberculosis infection.
3. Determine the proportion of children dying of
suspected TB who do actively have TB, e.g. through
postmortem studies.
TREATMENT
The lack of importance assigned to childhood TB has lead
to very few studies that have been conducted in children.
Without considering the pharmacotherapeutic basis,
children are given the same mg/kg body weight dosages
of antitubercular drugs as adults. This is called one size
fits all. The body composition is very important with
regard to the drug dosage in children. The children have
greater extravascular fluid compartment and the
relatively greater liver mass in proportion to body mass.
In several instances it been demonstrated that children
receiving equivalent dose mg/kg body weight, doses of
antituberculosis drugs result in considerably lower serum
concentrations than adults. (see chapter on antituberculosis drugs-pharmacokinetics).
Because of the diversity of disease in childhood in
relation to age to evaluate the success of treatment, the
studies should cover all the pediatric age groups
(children aged < 2 years, 2-6 years and 7-14 years). Also
include children with HIV/AIDS and without HIV.
There is now considerable literature documenting
poor absorption of antituberculosis drugs in adults with
TB and HIV infection. Few data are currently available
describing the poor absorption of antituberculosis drugs
in children with TB and with and without HIV infection.
This is obviously an area of research. There is one study
in which malabsorption in general has been reported in
South Indian children with TB and HIV infection.
Drug Resistance in Childhood

The research priorities as suggested by WHO are:
1. Regular quantification of the number of children who
present following contact with an adult with drugresistant TB.
2. The consequences of that contact and the best options
for managing the children so exposed.
3. Surveillance of the incidence of drug resistance
among children as being one of the best means of
determining the number of drug resistant strains
currently circulating in the community.
663
Research Priorities
Review existing literature and identify already
existing information regarding the pharmacokinetics
of antituberculosis drugs in children
Undertake pharmacokinetic studies of each of the
first-line antituberculosis drugs under different
conditions of nutrition and HIV-infection status and
across a range of ages
Undertake pharmacokinetic studies of second line
drugs. A literature review might reveal sufficient
information with regard to agents such as fluoroquinolones and aminoglycosides
Study drug-drug interactions, particularly in HIVinfected children who receive multiple drugs other
than antituberculosis agents. Study drug toxicity in
this complex situation
Evaluate rates of treatment failure and recurrence,
particularly in association with HIV/AIDS
Evaluate 3 and 4 month treatment regimens in
paucibacillary form of childhood TB and the
necessary longer periods of treatment in HIV-infected
children
Evaluate the treatment of drug-resistant TB in
children and determine the most effective regimens.
CONTACT-SCREENING AND MANAGEMENT

The value of chemoprophylaxis among children in close
contact with sputum smear-positive, fully drug sensitive
adults with pulmonary tuberculosis or children known
to be infected having positive tuberculin test is
unquestionable. Chemoprophylaxis definitely prevents
miliary tuberculosis and meningitis. This aspect is quite
a bit neglected in the national TB programs in developing
countries inspite of the recommendation of WHO (1966b)
guidelines.
In relation to HIV/AIDS in developing countries,
children are increasingly exposed to sputum smearnegative cases of pulmonary tuberculosis and an accurate
assessment of impact of these contacts is needed to offer
rational advice concerning chemoprophylaxis. The latter
has been able to reduce the incidence of disease among
the childhood contacts of adults with multidrug-resistant
TB but a precise delineation of the drugs, dosages and
duration of chemoprophylaxis is needed. Adolescents are
a vulnerable group both for the development of TB after
infection and for HIV infection if they are sexually active.
Pregnant teenagers might well constitute an appropriate
group for a targeted evaluation of the voluntary HIVtesting and counseling and tuberculin testing and
chemoprophylaxis.
664
Research Priorities
Carryout epidemiological studies to determine the
number of HIV infected and non-infected children in
contact with both sputum smear-positive and smearnegative adults. This group will qualify for
chemoprophylaxis
Assess the value of standard isoniazid chemoprophylaxis (isoniazid = 5 mg/kg/day for 9 months)
and compare it to shorter multidrug chemoprophylaxis in both HIV-infected and noninfected
children
Explore different methodologies to ensure adherence
with recommendations for chemoprophylaxis
Study chemoprophylaxis for the childhood contacts
of adults with sputum smear-negative and smearpositive drug-resistant TB
Study the concurrence of TB and HIV coinfection in
pregnant teenagers and evaluate TB chemoprophylaxis in those infected.
Roles and Responsibilities of Health Staff and Families

In developing countries, children frequently present to
the health system with symptoms which lead them to
the diagnosis of TB. When children are diagnosed as a
result of contact tracing activities, another family or
household member often also has TB.
Research is necessary to evaluate the effectiveness of
family-oriented approach to contact tracing and mobilize
family members as treatment supporters. The establishment of family centered clinics and services could
make a valuable contribution in this respect.
Private Sector
It has been estimated that the private sector in India,
which comprises 6.4 million of the 8 million registered
Indian medical practioners, handles approximately 1/

6th of the worlds TB cases. Management by them is
inconsistent with National Tuberculosis Program (NTP)
policy and there are deficiencies both in diagnosis and
treatment. It is important that childhood TB be seen as
an integral part of evaluation of epidemiology of
childhood tuberculosis and role of the private sector.
Research Priorities
Evaluate the availability of qualified staff and
necessary investigations at various levels of care
under different circumstance and the accuracy of the
diagnosis of TB in children. Make sure that chest
radiography and tuberculin testing is available to a
satisfactory level
Study the effectiveness of family-oriented approach
to contact tracing of the mobilization of family
members as treatment supporters
Evaluation of the role of family centered clinics and
services in managing children with TB, including those
with HIV coinfection
Document the role of private sector in all aspects of
management of childhood TB and the extent to which
they can be involved.
However, seeing the past experience in India there
is need felt for private sector to participate in
Government run schemes.
REFERENCES
1. Seth Vimlesh. Suggestions to get pediatric faculty
incharge of TB and HIV clinic in children involved for
taking benefit from DOTS center for drugs particularly
antiretroviral and those for MDR-TB in children.
2. WHO/HTM/TBM/2007.381 WHO/FCH/CAH/07.02.
Index
A
Abdominal
adenopathy 362
symptoms 159
tuberculosis 128, 132, 361, 488, 650
ultrasound 137
Abnormal sexual development 158
Absorption 428, 431, 451
Acetylator
phenotypes 472
status and side effects of INH 473
Achievements of RNTCP 622
Acquired or secondary
drug-resistance 508
Action and pharmacokinetics 417
Actions of antiretroviral
treatment 231
Acute
abdomen 158
complications 164
gastrointestinal bleeding 158
leukemia 242
miliary tuberculosis 257
toxicity 409
of isoniazid 409
viral hepatitis 643
Administration of
skin test 495
tuberculin test 300
Adolescent
female genital tuberculosis 263
tuberculosis 263
and future infertility 265
Adrenal tuberculosis 274
Adult-type disease 106
Advantages of FDCS 460
AFB positivity diagnosis 477
Aims of anti-TB drug treatment 646
Airway obstruction 105
Allergic consolidation 105
Alternating hemiplegia 159
Amikacin 439
Aminoglycosides 439
Amnestic syndrome 159
Animal pathogenicity 54
Ansamycin 434
Antibacterial activity 406, 413, 415
Anticancer therapy 245
Antidote 409
Antiepileptic drugs 172

Antigen/antibody-based tests 77
Antigens in skin test reagents 310
Antimycobacterial
activity 431
agents 597
drugs 449
Antimycobacterical activity 435
Antiretroviral drugs 232
Antiretroviral therapy rollout 231
Antitubercular
therapy 489
treatment 172
Antituberculosis
drugs 205, 403, 427, 449, 458
drugs breastfeed 646
therapy for congenital
tuberculosis 281
vaccines 568
Antituberculous drugs 260
Appearance of tuberculoma during
treatment of TBM 160
Ascitic fluid
adenosine deaminase 143
analysis 141
Assessment of
drug activity against latent TB 600
immunotherapy for
leprosy 319
tuberculosis 319
Associated molecules of cell wall 47
Association of nontuberculous
mycobacteria 61
Asthma 252
Autoimmune reactions 411
Autonomic nervous system
dysfunction 158
Azithromycin 437
B
Bacillary populations and drugresistance 498
Bacillus calmette-guerin 289, 555
Bacterial
pneumonia 228
resistance 473
Bactericidal drugs 646
Barium
enema 136
study 361
Basis of
pharmacotherapy 488
tuberculin test 296
BCG 477
adenitis 374
and tuberculin skin test results 638
related complications 253
strain family 556
test 486, 571
vaccinated children 153
vaccination 221, 235, 301, 555, 582
against tuberculosis 318
and HIV infection 570
vaccine
and tuberculin surveys 565
production in India 558
Beta-lactams with beta-lactamase
inhibitors 436
Biopsy 202
Blood 201
B-lymphocytes 72
Bobble-head doll syndrome 161
Bone
and joint infections 60
marrow transplant recipients 244
scan with TC-99m 178
Booster phenomenon 302
Border zone encephalitis 153
Brain edema and hemorrhage 154
Breastfeeding 410, 461
Bronchial
disease 102, 105
obstruction 106
Bronchiectasis 228
Bronchopneumonic consolidation 105
Bronchoscopy and bronchoalveolar
lavage 109
Burden of disease 616
C
Capreomycin 439
Case record form pediatric
HIV clinic 546
TB clinic 529
Caseating consolidation. 105
Categories and drugs-regimen
under DOTS 478
Cell
death 74
666
envelope proteins 48
mediated immune response 113, 568
wall core 47
Cement kidney 251
Central
nervous system 409
nervous system tuberculosis 375
Cervical lymph node tuberculosis 316
Characteristics of BCG disease 570
Chemoprophylaxis 491, 630
Chemotherapy 202, 211, 219
Chicken pox 581
Childhood tuberculosis 541
Children with tuberculosis disease 514
Chlorpromazine 441
Choroid
plexitis 153
tubercles 248
Chronic
pulmonary disease 373
systemic disease 273
toxicity 409
Ciprofloxacin 432
Circulating immune complex 113
Clarithromycin 436
Classification of
drugs 404
neurological outcomes 174
NTM on basis of pigment
production 57
quinolones 431
CNS tuberculosis 273
Cold abscess 209
Combating TB-HIV infection 230
Complications of
abdominal TB 651
BCG vaccination 259, 645
LV 257
spinal tuberculosis 179
tuberculous meningitis 164
Computed tomography 169
Computerized tomography 345
Concept of DOTS plus 516
Confirm active disease 382
Congenital
and perinatal tuberculosis 377
infections 580
tuberculosis 277, 279, 281
with multisystem involvement 281
Contacts of
leprosy patients 317
other mycobacterial diseases 317
Contraindications to BCG
vaccination 559
Corticosteroids 117, 171
in tuberculosis 478
CSF analysis 167
CT
abdomen 139

of vertebral tuberculosis 365
scanning 360
Cushing disease 158
Cutaneous
and soft tissue infections 60
syndrome 412
tuberculosis 255
Cycloserine 438
Cystic tuberculosis 363
Cytokine therapy 516
Cytotoxic T-lymphocytes 71
D
Daily and intermittent use of FDCS 461
Damage to motor roots 154
Definition of drug-resistance 505
Deformity 209
Demographic parameters 255
Demonstration of
acid fast bacilli 371
host response on exposure to
M. tuberculosis 111
M. tuberculosis or its components 109
Description of genus 42
Desensitization 650
Detection of drug-resistance 510
Determinants of
developing tuberculosis disease 31
infection and disease 30
outcome of treatment of
childhood tuberculosis 118
tuberculosis 32
tuberculosis in children 21
Development of drug-resistance and
discovery of basic principles of
drug-resistant tuberculosis 497
Development of
new vaccines 315
tuberculous meningitis 102
Diagnosis of
cutaneous tuberculosis 259
drug-resistant tuberculosis in
children 500
TB in HIV infected children 331
tubercular meningitis 165
Dihydromycoplanecin 441
Directly observed treatment
in children 629
short-course 613
Disadvantages of FDCS 461
Disease
burden in children 28
classification 628
Disseminated disease 60, 104
Distribution of
TB infection and disease 32
DNA vaccines 83
Dose modification in renal failure 216
Drug
collection center 527
regimens for pulmonary
tuberculosis 116
resistant tuberculosis 32, 497, 517
toxicity 235
resistance in children 511
resistant
tuberculosis 511, 631
virus in AIDS patients 229
E
Early bactericidal activity 397, 405, 450
Effect of migration 16
Effective anti-TB drug treatment 398
Endometrial TB 264
Environmental mycobacteria 312, 566
and disease susceptibility 314
Epidemiology of
HIV-tuberculosis 222
pediatric tuberculosis 11
TB in India and impact of
RNTCP 623
tuberculosis 19
Episodes of sensory disturbances 159
Era of short-course chemotherapy 620
Eradication of tuberculosis 22
Erythema nodosum 102
Esophageal tuberculosis 250
Establishment of central TB
institutes 619
Ethambutol 415, 465, 474, 641
Ethionamide 428
Evidence of extraneural TB 167
Evolution of
skin test responses after BCG
vaccination 314
TB control program in India 617
Extrapulmonary tuberculosis 13, 374,
478, 487
Extrathoracic tuberculosis 108
F
Female genital tuberculosis 275
Fine needle aspiration cytology 202, 324
Fixed
dose
drug combination for treatment
of tuberculosis 418
formulation 459
drug combination 293, 489
joint 206
Fluoroquinolones 430, 598
Focal
cerebral lesions 159
cerebritis 358
Folate antagonists 441
667
Index
Follow-up schedule for pediatric TB
clinic 538
Frontal lobe syndrome 159
Fusidic acid 441
Future of TB research 271
G
Gas liquid chromatography 111
Gastric lavage 109
Gastrointestinal
disorders 430
tract 453
tuberculosis 361
General information about tuberculosis
in children 636
Genetics of mycobacteria 48
Genital tuberculosis 275
Genitourinary tuberculosis 214, 375
Genomics of tuberculosis 471
Gestational age 576
Ghons focus 104, 105
Good TB control program 637
Gouty arthralgia 414
Granulomas in tuberculosis 369
H
Helper T-lymphocytes 70
Hematogenous spread 106
Hepatic and renal impairment 429
Hepatitis 414
B infection 581
Hepatobilliary disorders 430
Hepatotoxicity 408, 411, 473, 480
High performance liquid
chromatography 111
History of tuberculosis 3
HIV
and tuberculosis 34
infection 389, 596
and tuberculin test 303
TB coinfection 399
Horizontal gaze palsy 160
Host
immunity 21, 103
infection 242
resistance 32
Human immunodeficiency virus and
drug-resistant TB 500
Hydrocephalus 164, 172
Hyperglycemia 158
I
Imaging of tuberculosis 344
Immune
cells of body 69
reconstitution
disease associated with

mycobacterial infections 96
inflammatory syndrome 221
status in HIV infection 226
test for AIDS 228
Immunochemistry of tuberculin skin
test 299
Immunology of
NTM infections 61
tubercular infection 241
tuberculosis 66
tuberculous
lymphadenitis 93
meningitis 95
Immunomodulation 441
Immunopathology
in HIV infection 225
of TB 242
Impact of HIV on TB 225
Incidence of tuberculosis disease 623
Indications for tuberculin testing 303
Induced sputum 639
Infection with
human immunodeficiency virus 317
nontuberculous
mycobacteria 301, 567
Infectiousness of drug-resistant
M. Tuberculosis strains 499
Inflammatory bowel disease 143
INH
resistance 473
resistant vaccine 568
Injection technique 300
Interaction with antiretroviral drugs 442
Intercurrent infection 31
Interferon
gamma release assays 381, 487, 638
release assays 228
Internuclear ophthalmoplegia 160
Interventions in thoracic TB 354
Intestinal tuberculosis 376
Intracranial
tuberculomas 356
tuberculosis 354
Intradermal injection 576
Intramedullary tuberculoma 178
Intrathoracic tuberculosis 107
Intravenous urography 359
Introduction to rifampicin
pharmacokinetics 455
Isolated
hepatic inferior vena cava
thrombosis in case of
tuberculosis 251
spinal tuberculous meningitis 155
Isoniazid 461, 472, 597
preventive therapy 231
resistant 645
Isotope scintigraphy 202
Issues regarding category therapy 292
K
Kanamycin 439
KDA antigen 78
Kidney 359
Korsakoffs syndrome 157
L
Lactation 430
Lacunae 612
in treatment 229
Large vessels 151
Late neonatal respiratory distress 281
Latent tuberculosis 234, 589, 645
in children and adolescents 589, 607
infection 115, 595
children 590
Length of time after acquiring
infection 32
Leprosy 316
Leukocyte migration inhibition test 91
Leukotomy 159
Lichen scrofulosorum 258
Lipoarabinomannan 47, 78
Live attenuated vaccines 81
Liver
and spleen 374
disease 643, 648
Localized meningitis on superiolateral
surface of brain 155
Lomefloxacin 432
Long bones of extremities 362
Lupus vulgaris 256
Lymph node
disease 105
focus 106
involvement 346
tuberculosis 374
Lymphadenitis 59
Lymphadenopathy 346
Lymphocytic interstitial
pneumonitis 227
Lymphohematogenous
dissemination 373
M
M. bohemicum 59
M. celatum type I 59
M. elephantis 59
M. genavense 59
M. heidelbergense 59
M. interjectum 59
M. lentiflavum 60
Macrolides 436
Macrophage 69
Magnetic resonance imaging 170, 345
Male genital tuberculosis 276
668
Management of
hepatitis 650
multidrug-resistant tuberculosis 512
neonate born to mother with
tuberculosis 493
skin itching/rash 649
tuberculosis 476
Mantoux
test 126, 136, 201, 300, 301,
323, 578, 580
tuberculin skin test 495
Mass BCG campaign 618
MDR tuberculosis 514
Measles vaccine 579
Medical management of cerebral
edema 172
Meningeal
exudate 151
tuberculoma 155
Methods for identification of
M. tuberculosis 109
Miliary
tuberculosis in young children 102
Mobile joint 205
Molecular diagnosis of MDR
tuberculosis 474
Moxifloxacin 433
MRI scan 202
Multidrug-resistant
Multifocal
skeletal tuberculosis 252
tuberculosis 363
Mycobacterial
capsule 45
culture of biopsy on FNA
material 372
disease 315
envelope 45
genome 49
infection in children 322
population 395
species 44
strains 337
Mycobacteriophages 54
Mycobacterium
ulcerans disease 316
Mycobaterial infection in
community 565
Myelography 211
N
Natural history of
HIV-infection 225
tubercular infections 102
Needle biopsy 211
Neonatal TB 642
Nerves 152
Nervous system disorders 430
Neuromuscular blockade 413
Neurotuberculosis 150
Nitroimidazopyrans 441
NK cells 73
Nonhealing ulcer 579
Nonisoniazid/rifamycin
combinations 598
Nonspecific test for monitoring 117, 480
Nontuberculous
mycobacteria 57
mycobacterial lung disease 59
NTM infection 61
Nutritional status of vaccines 565
O
Ocular
lesions 165
toxicity 416, 481
Ofloxacin 432, 466
Orificial tuberculosis 258
Osteoarticular tuberculosis 102, 200, 362
Ototoxicity 413
Ovarian TB 264
Oxazolidinones 442
P
Pancreatic tuberculosis 275
Panophthalmitis 249
Papulonecrotic tuberculides 259
Para-aminosalicylic acid 438
Paramomycin 439
Parasitic disease 318
Pathologic spectrum of tuberculosis
in children 368
Pathophysiology of infections in
cancer 242
PCR test 487
Pediatric tuberculosis
score chart 228
under RNTCP 627
Percutaneous fistulogram 136
Performance of tuberculin skin test 305
Pericardial tuberculosis 374
Peripheral
lymph node 142
nerve damage 154
neuritis 409, 481
Peritoneal tuberculosis 131, 362, 376
Persistent
abnormal shadows on CXR 480
pyrexia 158
Persistently negative tuberculin
reactions 303
Pharmacogenetics of tuberculosis 471
Pharmacokinetics of
ethambutol in children 458
and adults with tuberculosis 466
isoniazid in isoniazid resistant
pyrazinamide in literature 456
Phenazines 437
Phenothiazines 441
Phlyctenular conjunctivitis 248
Pituitary
stalk tuberculosis 252
tuberculoma 274
Plasma membrane 47
Pleural
disease 106
effusion 487
involvement 350
tuberculosis 374
Pneumocystis jiroveci pneumonia 227
Poisoning 412
Polymerase chain reaction 110, 215, 260
in diagnosis of tuberculosis 372
Positive tuberculin skin test 102
Postprimary lesion 353
Potential causes of drug-resistance 509
Potts
disease 364
spine 177, 207
PPD skin test 296
Precocious puberty 157
Pregnancy 648
Presentation of pediatric TB 11
Prevaccination skin tests 318
Prevention of drug-resistance 398
Primary
drug-resistance 508
infection of conjunctiva 248
pulmonary tuberculosis 373
tuberculous chancre 257
Principles of
disease 102
therapy 395
treatment of MDR-TB 513
Progressive
primary disease 348
pulmonary tuberculosis 373
Prophylaxis 221
Psychomotor seizures 159
Public health importance 637
Pulmonary
disease 105
infection 105
in childhood 102
metastasis 244
primary complex 345
reactivation disease 102
tuberculosis 13, 101, 115, 344,
373, 642,
669
Index
Pyramid of childhood tuberculosis 26
Pyrazinamide 414, 464, 473
Q
Quadruple skin testing 311
Quinolones in pediatric age 641
R
Rapid identification of
mycobacterium 215
Rare hypersensitivity reactions 412
Regulatory T-cells 72
Renal
failure 648
toxicity 413
tuberculosis 251
Reporting smear results 326
Research in pediatric practice 661
Resistant tuberculosis 510
Respiratory disease 59
Rifabutin 434
Rifampicin 463, 473
resistance 647
Rifampin 410, 597
Rifamycin 434
Rifapentine 435
Role of
BCG in preventing TB 632
bronchoscopy and bronchoalveolar
lavage fluid examination 244
CT and MRI in tuberculous
spondylitis 365
ethnicity and genetic susceptibility
to NTM infections 60
nonculture techniques 639
steroid treatment 648
surgery in
abdominal tuberculosis 146
management of MDR and XDRTB 503
S
Scrofula 374
Scrofuloderma 255
Second-line antituberculosis drugs 503
Selection of FDCS 461
Sequelae of TBM 274
Serodiagnosis of tuberculosis 143
Serological testing in CSF 168
Short-course chemotherapy
and reactivation of TB 245
given in program of direct
observation 622
with antituberculosis drugs 233
Simultaneous tuberculous
meningoencephalitis 251
Single dose ampoules 581
Skeletal tuberculosis 375

Skin test and assessment of vaccine
efficacy 314
Small arteries 152
Smear and culture 201
Sonoenteroclysis 143
Sparfloxacin 433
Spinal
tuberculosis 178
tuberculous arachnoiditis 165, 179
Sputum smear 640
Standard code for TB treatment
regimens 647
Starting tuberculosis clinic for
children 523
Status of fluoroquinolones in treatment
of tuberculosis 433
Steroids in tuberculosis 293, 489
Streptolydigin 441
Streptomycin 412, 465, 647
Symptomatic mantoux positive
group 353
Symptoms of abdominal TB 651
Syndrome of inappropriate secretion of
antidiuretic hormone 157
Synovial fluid 201
Syringomyelia 160
T
Taxonomy 41, 57
TB
in children 637
in HIV infected children 236, 632
lymphadenitis 487
treatment regimens 646
TBM in children 166
Tests for diagnosis of HIV 229
Thalidomide 440
Therapeutic drug monitoring of
rifampicin and isoniazid 466
Thiacetazone 417, 641, 647, 649
Thioamides 427
Thyroid tuberculosis 275
T-lymphocytes 70
Transmission of
drug-resistance 508
TB to children 637
Transrenal mycobacterial DNA 78
Treatment directed to
achieve fixed joint 206
achieve mobile joint 206
Treatment for spinal tuberculosis 179
Treatment of
abdominal TB 651
BCG
osteomyelitis 557
vaccination induced disease in
HIV infected children 571
childhood tuberculosis 287

cutaneous tuberculosis 260
drug-resistant
infection 514
tuberculosis disease 514
hepatotoxicity 408
HIV-TB coinfection 233
INH-monoresistant TB 501
late sequelae 206
latent tuberculosis infection 597
MDR and XDR-TB 502
pediatric TB 629
polydrug-resistant TB 502
RMP-monoresistant TB 502
TB patients 646
TBM 170
Trifluoperazine 441
Trimethoprim-sulfamethoxazole 221
Tuberactinomycin 436
Tubercular
brain abscess 376
cerebrovascular disease 165
disease 33
lymphadenitis 124
meningitis 273, 375, 488, 644
in HIV infected children 174
Tuberculides 258
Tuberculin
reaction in relation to isoniazid
therapy 303
skin test 296, 323, 638
test 228, 296, 485, 495, 628
Tuberculoma 488
Tuberculoma of brain 175
Tuberculosis 248, 273, 315, 643
Tuberculosis and HIV
clinic 522
infection 218, 237
Tuberculosis in
adolescents 377
children 661
diagnosed 638
different from adults 637
HIV-infected children 223
Tuberculosis of
ankle and elbow 207
breast in adolescent girl 252
cervix, vagina and vulva 264
eye and
conjunctiva 248
middle ear 376
fallopian tubes 263
hip joint 204, 364
knee joint 206
ribs 363
sacroiliac joint 364
short
bones of hands and feet 363
long bones 207
670
spine 207, 364

vertebral column 177
Tuberculous
abscess 357
arthritis 363
bronchopneumonia 351
dactylitis 363
disease 581
lesion 353
lymphadenitis 122
meningitis 160, 354
metastatic abscesses 257
osteitis/osteomyelitis 362
otitis media and mastoiditis 250
spondylitis 364
Types of drug-resistance 505
U
Ultrasound 344, 361
Unilateral contralateral
hemiballismus 157
Ureters 360
Urinary
bladder 360
tract tuberculosis 358
Urine examination 215
Use of
anti-TB drugs in special situation 648
combination of rifampicin and PZA
in treating latent TB 600
V
Vaccine strains 564
Vaccines against leprosy 318
Ventriculitis 153
Vertebral tuberculosis 366
Vertical gaze palsy 160
Viral vectored vaccines 82
Virtual CT
colonoscopy 142
enteroclysis 142
Virulence of M. tuberculosis
strains 565
Visceral tuberculosis 362
Vitamin D 441
Volatile mycobacterial markers
in breath 79
Vole vaccine 568
Vulnerability and children 653
W
Wild type resistance 508
X
X-ray chest 638

Tuberculosis in Children

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Tuberculosis in Children

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Essentials of

Vimlesh Seth MD FAMS FCAI FISCD

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

Ahmedabad, e-mail: ahmedabad@jaypeebrothers.com

JPBMP typesetting unit

Essentials of Tuberculosis in Children

Professor TB/Community Project

Emeritus Professor of Pediatrics

Essentials of Tuberculosis in Children

Essentials of Tuberculosis in Children

Emeritus Professor of Pediatrics

Preface to the Fourth Edition

Preface to the First Edition

About the Review of the Previous

History of Tuberculosis ......................................................................................................................................... 3

3. Interaction of Epidemiological Factors................................................................................... 19

4. Epidemiology: Special Reference to Children ...................................................................... 26

Pyramid of Childhood Tuberculosis .................................................................................................................. 26

Essentials of Tuberculosis in Children

Section 3: Microbiology and Immunopathogenesis

6. Nontuberculous Mycobacteria ................................................................................................. 57

7. Immunology of Tuberculosis: Basic Aspects and Relevance for

8. Clinicoimmunological Profile .................................................................................................. 90

Section 4: Clinical Spectrum

10. Tuberculous Lymphadenitis .................................................................................................. 122

Epidemiology ...................................................................................................................................................... 122

11. Abdominal Tuberculosis ......................................................................................................... 128

Presentation According to Site of Involvement .............................................................................................131

Neurotuberculosis ................................................................................................................... 150

12.1. Pathology and Pathogenesis .................................................................................................. 150

12.2. Clinical Manifestations, Diagnosis and Management ..................................................... 161

12.3. Case Studies ............................................................................................................................... 180

13. Osteoarticular Tuberculosis ................................................................................................... 200

Joint Involvement ...............................................................................................................................................200

14. Genitourinary Tuberculosis ................................................................................................... 214

15. Tuberculosis and the HIV Infection ..................................................................................... 218

Epidemiology ...................................................................................................................................................... 218

Essentials of Tuberculosis in Children

15.2. Tuberculosis and HIV Infection ............................................................................................ 222

Epidemiology of HIV-tuberculosis .................................................................................................................. 222

16. Tuberculosis and Childhood Malignancy ........................................................................... 241

Immunology of Tubercular Infection ..............................................................................................................241

17. Unusual Manifestations of Tuberculosis............................................................................. 248

Tuberculosis of Eye and Conjunctiva ..............................................................................................................248

18. Cutaneous Tuberculosis .......................................................................................................... 255

Epidemiology ...................................................................................................................................................... 255

19. Adolescent Tuberculosis: Prelude to Future Infertility .................................................... 263

20. Endocrine Manifestations of Tuberculosis ......................................................................... 273

Endocrine Effects of Tuberculosis Due to Chronic Systemic Disease .........................................................273

21. Congenital Tuberculosis ......................................................................................................... 277

Pathophysiology ................................................................................................................................................. 277

23. Tuberculin Test ......................................................................................................................... 296

History .................................................................................................................................................................. 297

24. Newer Tuberculins: Profile in Developing Countries ...................................................... 310

The Reagents .......................................................................................................................................................310

Essentials of Tuberculosis in Children

25. Laboratory Diagnosis of Mycobacterial (Tuberculosis) Infection in Children ............ 322

The Diagnostic Challenges ................................................................................................................................322

25.2. Molecular Diagnostic Methods .............................................................................................. 332

26. Imaging of Tuberculosis in Children ................................................................................... 344

Pulmonary Tuberculosis ....................................................................................................................................344

27. Pathologic Spectrum ................................................................................................................ 368

28. New Approaches to TB Diagnosis in Children .................................................................. 380

30. Antituberculosis Drugs: First-line Agents ........................................................................... 403