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 Clinical Handbook of
Interstitial Lung Disease
 Clinical Handbook of
Interstitial Lung Disease

Edited by

Muhunthan Thillai
Cambridge Interstitial Lung Disease Unit
Royal Papworth Hospital, Cambridge, United Kingdom

David R Moller
Department of Medicine, Division of Pulmonary and
Critical Care Medicine, Johns Hopkins University School
of Medicine, Baltimore, Maryland, USA

Keith C Meyer
Department of Medicine, Division of Allergy, Pulmonary,
Critical Care and Sleep Medicine, University of Wisconsin School
of Medicine and Public Health, Madison, Wisconsin, USA
CRC Press
Taylor & Francis Group
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© 2018 by Taylor & Francis Group, LLC

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978-1-138-29670-1 (Hardback)

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 We dedicate this book to our patients and research volunteers for their courage and support,
to our families and to our mentors.
Muhunthan Thillai dedicates this book to his mentor Donald Mitchell, to his wife Abi and to his family
Raj, Anushya, Kiruthikah, Krishnan and Ambika.
David Moller dedicates this book with love, to his wife Teresa and our family Stephanie, Christopher,
Ryan, Kristen and Avery.
Keith Meyer especially dedicates this book to all the patients who have trusted his guidance and given him
important lessons about coping with interstitial lung disease and to his wife, Emily Auerbach, and his
children and grandchildren.
Contents

Foreword ix
Contributors xi
Introduction xv

1 An overview of the classification and diagnosis of interstitial lung disease 1

Keith C Meyer
2 Histopathology of interstitial lung disease: A pattern-based approach 11
Angela M Takano, Junya Fukuoka and Kevin O Leslie
3 Using thoracic imaging to diagnose ILD 39
Maria Daniela Martin and Jeffrey P Kanne
4 Genetics and genomics of idiopathic pulmonary fibrosis 49
Susan K Mathai and David A Schwartz
5 Clinical evaluation of the patient with suspected ILD 65
Kaïssa de Boer and Joyce S Lee
6 Role of invasive testing in ILD diagnosis 83
J Scott Ferguson and Keith C Meyer
7 General principles of ILD diagnosis and management 95
Melissa Wickremasinghe, Richard J Hewitt and Athol Wells
8 Idiopathic pulmonary fibrosis: Epidemiology, natural history and pathophysiology 113
Zulma Yunt, Jeffrey J Swigris and Amy L Olson
9 Idiopathic pulmonary fibrosis: How should a confident diagnosis be made? 135
Bridget F Collins and Ganesh Raghu
10 Management of idiopathic pulmonary fibrosis 149
Damian AD Bruce-Hickman, Helen Garthwaite, Melissa Heightman and Bibek Gooptu
11 Hypersensitivity pneumonitis 189
Christine Fiddler and Helen Parfrey
12 Idiopathic interstitial pneumonias other than idiopathic pulmonary fibrosis 209
Toby M Maher
13 Eosinophilic interstitial lung disorders 221
Vincent Cottin and Claudia Valenzuela
14 Interstitial lung disease associated with connective tissue disorders 237
Deborah Assayag and Aryeh Fischer
15 Pulmonary sarcoidosis 257
David R Moller and Ling-Pei Ho
16 Sarcoidosis extra-pulmonary manifestations 271
Dominique Valeyre, Hilario Nunes, Florence Jeny, Matthieu Mahévas and Marc A Judson

vii
viii Contents

17 Smoking and interstitial lung disease 289

Joshua J Solomon and Kevin K Brown
18 Drug-induced and iatrogenic interstitial lung disease 311
Philippe Camus and Philippe Bonniaud
19 Occupation-related ILD 329
Traci Adams, Annyce S Mayer, Craig Glazer and Lisa A Maier
20 Pulmonary vasculitis and alveolar haemorrhage syndromes 345
Rebecca C Keith and Stephen K Frankel
21 Lymphangioleiomyomatosis and other cystic interstitial lung diseases 361
Amanda T Goodwin and William YC Chang
22 Pulmonary alveolar proteinosis 379
Cliff Morgan
23 Rare forms of interstitial lung disease 391
Jay H Ryu
24 Childhood ILD 409
Andrew Bush
25 Understanding the role of co-morbidities in interstitial lung diseases 429
Adrian Shifren, Tonya Russell, Adam L Anderson and Steven D Nathan
26 Lung transplantation for ILD 451
Henry Yung and Jasvir S Parmar
27 Diagnosis and management of critical illness in patients with interstitial lung disease 493
Teng Moua
Index 511
Foreword
The Clinical Handbook of Interstitial Lung Disease,
edited by Drs. Thillai, Moller, and Meyer, provides
a comprehensive, thoughtful, and in depth review
of the complexity of interstitial lung disease (ILD),
with a broad perspective provided by 60 authors
with expertise in ILD. The book is extensively ref-
erenced, and provides insights suited not only for
trainees but for clinicians and academicians at all
levels with an interest in ILD.
More than 200 ILDs have been identified, and
a logical approach requires the analysis of clinical,
radiographic, and histological patterns that may
establish a precise and definitive diagnosis. The
first few chapters provide an overview of the evolv-
ing classification schema of ILD, the disparate
histological patterns of ILD, the use of thoracic
imaging [particularly high-resolution thin-sec-
tion computed tomographic scanning (HRCT)] to
diagnose and follow ILDs, and clinical evaluation
of patients with suspected ILD. These initial chap-
ters, as well as those that follow, are replete with
superb color photomicrographs and HRCT scans
to illustrate the salient findings of these various
ILDs. The major patterns (both radiographic and
histologic) are discussed, including: acute and
chronic lung injury; airway-centered (bronchiolo-
centric); alveolar filling (e.g., alveolar hemorrhage,
pulmonary alveolar proteinosis, organising pneu-
monia); nodular patterns (e.g., sarcoidosis, granu-
lomatosis with polyangiitis, silicosis, Langerhans
cell histiocytosis (LCH), infections, malignancy);
cystic patterns [(e.g., lymphangioleiomyomatosis
(LAM), LCH, lymphocytic interstitial pneumonia
(LIP)]; and mixed patterns. Further, the salient
features of the idiopathic interstitial pneumonias
(IIPs) are illustrated and discussed, with in-depth
discussion of usual interstitial pneumonia (UIP)
and nonspecific interstitial pneumonia (NSIP)
patterns. Throughout the book, the pathogenetic
mechanisms are discussed in detail, including
genetic associations and polymorphisms and
external factors (inhaled irritants or allergens,
smoking, environmental factors) that may influ-
ence clinical expression and course of ILD. Over
the past 30 years, several genetic mutations have
been implicated in familial and sporadic ILDs.
Initial epidemiological studies identified muta-
tions in surfactant C and A proteins, and sub-
sequent studies identified a variety of genetic
abnormalities (e.g., telomerase mutations, poly-
morphisms of MUC5B prometer gene, etc.).
Differences in the function of specific genetic loci
affecting host defense, cell adhesion, and DNA
may be central to the pathogenesis and clinical
expression of idiopathic pulmonary fibrosis (IPF)
and other ILDs. Investigations using peripheral
blood mononuclear cell (PBMC) or alveolar epi-
thelial cells in IPF and other ILDs suggest that
specific genetic profiles may be critical to the evo-
lution of the disease process, resulting in a rapid
or slow disease progression, with associated dif-
ferences in survival. A better understanding of
genetic risk factors for IPF and other ILDs may
lead to improved phenotyping of disease and more
targeted therapies.
Clinical approach to ILD includes careful occu-
pational history, exposures (drugs, inhaled anti-
gens), demographics (age, gender), in addition to
physical exam and radiographic tests. Blood tests
may be critical to identify specific causes of ILD
such as connective tissue disease (CTD) or hyper-
sensitivity pneumonia (HP). The role of invasive
techniques including bronchoscopy with bron-
choalveolar lavage (BAL), endobronchial ultra-
sound-guided biopsies (EBUS), and surgical lung
biopsy are discussed. Several authors emphasize the
ix
x Foreword
limitations, as well as risks, associated with these
biopsy procedures, and present specific approaches
and recommendations. The diagnosis of ILD is not
always straightforward, and collaboration among
disciplines (e.g., clinicians, radiologists, patholo-
gists) may be critical to narrow and establish the
diagnosis. Three chapters (chapters 8–10) provide
in-depth discussion of IPF, the most common of
the ILDs, including epidemiology, clinical fea-
tures, diagnostic approach, and management of
this disorder. In the chapters that follow, the major
types of ILD are discussed. Separate chapters
review specific entities including: hypersensitiv-
ity pneumonitis; IIPs other than IPF; eosinophilic
interstitial lung disorders; ILD associated with
CTD; sarcoidosis (both pulmonary and extrapul-
monary); smoking-related ILD; drug-induced and
iatrogenic ILD; occupational ILD; pulmonary vas-
culitis and alveolar hemorrhage syndromes; cys-
tic lung diseases; pulmonary alveolar proteinosis;
Holt and Jo Hickman Endowed Chair of Advanced Lung Disease and Lung Transplantation
Division of Pulmonary, Critical Care Medicine Allergy, and Clinical Immunology
childhood ILD, and other rare ILDs. Within each
chapter, sections on pathogenesis, epidemiology,
clinical, radiographic, and pathological features,
and management are discussed in depth. Specific
aspects of ILD are addressed in separate chapters
regarding: comorbidities; diagnosis and manage-
ment of critical illness in patients with ILD; and
role of lung transplantation for ILD.
This book provides an outstanding perspec-
tive of the evolving field of ILD, and heightens
the imagination for future strategies to develop
more targeted therapies. One of the strengths
of this book is the plethora of images (histologi-
cal and radiographic) and comprehensive figures
and tables throughout. The references cited in this
book are extensive, and allow the reader to easily
retrieve the key sentinel articles in the field. This
book is an outstanding review not only for Fellows
and trainees, but for clinicians and academicians
with an interest in ILD.
Joseph P. Lynch, III, M.D., FCCP, FERS
Professor of Clinical Medicine, Step IX
The David Geffen School of Medicine at UCLA
Los Angeles, CA
Contributors

Traci Adams, MD Andrew Bush, MBBS (HONS), MA, MD, FRCP, FRCPCH, FERS
Department of Medicine Imperial College London
University of Texas Southwestern and
Dallas, Texas National Heart and Lung Institute
Adam L Anderson, MD and
Division of Pulmonary and Critical Care Medicine Royal Brompton Harefield
Washington University School of Medicine NHS Foundation Trust
St. Louis, Missouri London, United Kingdom

Deborah Assayag, MD, MAS, FRCPC Philippe Camus

Department of Medicine Hôpital Le Bocage
McGill University Dijon, France
Montreal, Canada William YC Chang, BA, BMBCh, MA, PhD, MRCP
Kaïssa de Boer, BSc, MD, FRCPC Respiratory Medicine Department
Department of Medicine Nottingham University Hospitals
Division of Respirology NHS Trust
The Ottawa Hospital Nottingham, United Kingdom
University of Ottawa Bridget F Collins, BA, MD
Ottawa, Canada Department of Medicine
Philippe Bonniaud Center for Intestinal Lung Diseases
CHU Dijon Bourgogne University of Washington Medical Center
Hôpital François Mitterrand Seattle, Washington
Dijon, France Vincent Cottin, MD, PhD
Hospices Civils de Lyon
Kevin K Brown, MD
Hôpital Louis Pradel
Department of Medicine
Centre de Référence National des Maladies
Autoimmune Lung Center
Pulmonaires Rares
National Jewish Health
Service de Pneumologie
Denver, Colorado
and
Damian AD Bruce-Hickman Claude Bernard University Lyon 1
Department of Advanced Internal Lyon, France
Medicine
J Scott Ferguson, MD, FACP, FCCP
National University Hospital Singapore
Department of Medicine
Singapore
Division of Allergy, Pulmonary, Critical Care
and and Sleep Medicine
Department of Neuroscience University of Wisconsin School of Medicine and
University College London Medical School Public Health
London, United Kingdom Madison, Wisconsin
xi
xii Contributors

Christine Fiddler, BSc, MBCHB, PhD, MRCP Melissa Heightman

Cambridge ILD Service University College London Hospitals
Royal Papworth and Addenbrooke’s Hospital NHS Trust
Cambridge, United Kingdom London, United Kingdom
Aryeh Fischer, MD Richard J Hewitt, MBBS, BSc, MRCP
Department of Medicine NIHR Academic Clinical Fellow in
Division of Rheumatology Respiratory Medicine
Autoimmune and Interstitial Lung Disease Program Imperial College Healthcare NHS Trust
University of Colorado School of Medicine London, United Kingdom
Aurora, Colorado
Ling-Pei Ho, MD, PhD, FRCP
Stephen K Frankel, MD, FCCM, FCCP Oxford Interstitial Lung
Department of Medicine Disease Service
National Jewish Health Oxford Center for Respiratory Medicine
Denver, Colorado University of Oxford
Junya Fukuoka, MD, PhD Oxford, United Kingdom
Department of Pathology Florence Jeny
Graduate School of Biomedical Sciences University Paris
Nagasaki University Faculty of Medicine Assistance Publique Hôpitaux de Paris
Nagasaki, Japan Hôpital Avicenne
Helen Garthwaite Bobigny, France
University College Marc A Judson
London Hospitals Department of Medicine
NHS Trust Division of Pulmonary and Critical
London, United Kingdom Care Medicine
Craig Glazer, MD, MSPH Albany Medical College
Department of Medicine Albany, New York
University of Texas Southwestern Jeffrey P Kanne, MD
Dallas, Texas Department of Radiology
Amanda T Goodwin Thoracic Imaging
Division of Respiratory Medicine University of Wisconsin School of Medicine
Nottingham University Hospitals NHS Trust and Public Health
University of Nottingham Madison, Wisconsin
Nottingham, United Kingdom Rebecca C Keith, BA, MD
Bibek Gooptu, BSc, MBBChir, PhD, AFHEA, MRCP Pulmonary Critical Care Medicine
Leicester ILD Service and NIHR Department of Medicine
Leicester Biomedical Research National Jewish Health
Centre – Respiratory Denver, Colorado
Institute for Lung Health and
Glenfield Hospital
University of Colorado School of
and
Medicine
Leicester Institute of Structural and Chemical
Aurora, Colorado
Biology
and Joyce S Lee, MD, MAS
Divisions of Infection Department of Medicine
Immunity and Inflammation and Molecular and Division of Pulmonary Sciences and Critical
Cell Biology Care Medicine
University of Leicester University of Colorado Denver
Leicester, United Kingdom Aurora, Colorado
 Contributors xiii

Kevin O Leslie, MD Keith C Meyer, MD, MS

Department of Pathology Department of Medicine
Mayo Clinic Division of Allergy, Pulmonary, Critical Care
Arizona, Minnesota and Sleep Medicine
and University of Wisconsin School of Medicine
and Public Health
Mayo Clinic College of Medicine
Madison, Wisconsin
Rochester, Minnesota
Toby M Maher, MB, MSc, PhD, FRCP David R Moller, MD
NIHR Respiratory Biomedical Research Unit Department of Medicine
Royal Brompton Hospital Division of Pulmonary and Critical Care
and Medicine
Fibrosis Research Group Johns Hopkins University School of Medicine
National Heart and Lung Institute Baltimore, Maryland
Imperial College Cliff Morgan, BM, FRCA, FFICM
London, United Kingdom Royal Brompton and Harefield NHS Foundation
Matthieu Mahévas Trust
University Paris Est Créteil Royal Brompton Hospital
Centre de Référence des Cytopénies Autoimmunes London, United Kingdom
de l’adulte and Assistance Publique Teng Moua, MD
Hôpitaux de Paris Division of Pulmonary and Critical
Hôpital Henri Mondor Care Medicine
Créteil, France Mayo Clinic
Lisa A Maier, MD, MSPH Rochester, Minnesota
Division of Environmental and Occupational Steven D Nathan, MD, FCCP
Sciences Advanced Lung Disease and Lung Transplant
National Jewish Health Program
Denver, Colorado Department of Medicine
and INOVA Fairfax Hospital
Colorado School of Medicine and Public Health Falls Church, Virginia
Aurora, Colorado Hilario Nunes
Maria Daniela Martin, MD University Paris
Department of Radiology Assistance Publique Hôpitaux de Paris
Thoracic Imaging Hôpital Avicenne
University of Wisconsin School of Medicine and Bobigny, France
Public Health Amy L Olson, MD, MSPH
Madison, Wisconsin Department of Medicine
Susan K Mathai, MD Interstitial Lung Disease Program and
Department of Medicine Autoimmune Lung Center
Division of Pulmonary Sciences and Critical Care National Jewish Health
Medicine Denver, Colorado
University of Colorado School of Medicine
Helen Parfrey, BA, MA, BM, BCh, PhD, FRCP
Aurora, Colorado
Cambridge ILD Service
Annyce S Mayer, MD, MSPH Royal Papworth and Addenbrooke’s Hospitals
National Jewish Health Cambridge, United Kingdom
Denver, Colorado
Jasvir S Parmar, BM, PhD, FRCP, FFICM
and Royal Papworth Hospital NHS Foundation Trust
Colorado School of Public Health University of Cambridge
Aurora, Colorado Cambridge, United Kingdom
xiv Contributors

Ganesh Raghu, MD, FACP, FCCP Angela M Takano, MD

Department of Medicine Department of Pathology
Center for Intestinal Lung Diseases Singapore General Hospital (SGH)
University of Washington Medical Center and
Seattle, Washington Duke-NUS Medical School
National University of Singapore
Tonya Russell, BS, MD
Singapore
Division of Pulmonary and Critical Care
Medicine Muhunthan Thillai, MBBS, MRCP, PhD
Washington University School of Medicine Cambridge Interstitial Lung Disease Unit
St. Louis, Missouri Royal Papworth Hospital
Cambridge, United Kingdom
Jay H Ryu, MD
Division of Pulmonary and Critical Care Claudia Valenzuela, MD
Medicine Hospital Universitario de la Princesa
Mayo Clinic College of Medicine and Science Madrid, Spain
Rochester, Minnesota Dominique Valeyre, MD
David A Schwartz, MD University of Paris
Department of Medicine Assistance Publique Hôpitaux de Paris
Division of Pulmonary Sciences and Critical Care Hôpital Avicenne
Medicine Bobigny, France
University of Colorado School of Medicine Athol Wells, MBChB, FRACP, MD, FRCP, FRCR
Aurora, Colorado Interstitial Lung Disease Unit
Adrian Shifren, MD Royal Brompton Hospital
Division of Pulmonary and Critical Care Medicine London, United Kingdom
Washington University School of Medicine Melissa Wickremasinghe, BSc, PhD, FRCP
St. Louis, Missouri Imperial College London
Joshua J Solomon, MD, FCCP Imperial College Healthcare NHS Trust
London, United Kingdom
Department of Medicine
Autoimmune Lung Center Henry Yung, MB, BChir, MRCP
National Jewish Health Royal Papworth Hospital
Denver, Colorado Papworth Everard, United Kingdom
Jeffrey J Swigris, MS, DO Zulma Yunt, MD
Department of Medicine Department of Medicine
Interstitial Lung Disease Program and Interstitial Lung Disease Program and
Autoimmune Lung Center Autoimmune Lung Center
National Jewish Health National Jewish Health
Denver, Colorado Denver, Colorado
Introduction
The intention of writing this book is to provide
readers a comprehensive overview of the lung dis-
ease entities that we recognize as the differing
forms of interstitial lung disease (ILD). Our under-
standing and characterization of these disorders
and recognition of the features which differentiate
the specific forms of ILD has evolved rapidly over
the past few decades. Whilst these advances have
necessitated changes in classification schemes and
terminology, new knowledge of the genetics and
histopathologic manifestations of specific forms of
ILD have improved our ability to provide progno-
ses to patients, develop therapies that specifically
target individual forms of ILD (such as idiopathic
pulmonary fibrosis – IPF) and provide personalized
medicine to our patients. Providing the best care
to patients with ILD depends on the recognition
of clues from their clinical presentation combined
with a careful physical examination, the use of state-
of-the-art thoracic imaging, and the use of tissue
sampling, when needed, to identify diagnostic his-
topathologic patterns and optimize the likelihood of
making an accurate and confident diagnosis.
In the ideal setting, clinicians, thoracic radiolo-
gists, and lung pathologists should review all clini-
cal, radiological, and histopathologic data together
for any patient with a complex presentation of ILD
to reach a consensus diagnosis and provide the
best practice for their patients. In the near future,
specific biomarkers will become validated that
may be useful both in diagnosis and therapeutic
management of ILD. Additionally, our evolving
understanding of the genetic underpinnings and
the role of epigenetic factors in disease risk and
disease behaviour will undoubtedly improve our
ability to provide better and safer therapies for
specific forms of ILD. Our evolving knowledge of
ILDs can also be used to construct better placebo-
controlled, randomized clinical trials to identify
effective therapies for specific forms of ILD, as
has been recently accomplished with novel anti-
fibrotic therapies for IPF.
It is our hope that this book will enhance our
readers’ knowledge of the various aspects of the
disorders we recognize as specific forms of ILD,
and inspire them to engage in meaningful clini-
cal and translational research. Those who provide
care to patients with ILD will find this book useful
in both their ability to diagnose ILD in the clinic
and the provision of appropriate therapies to their
patients. We are greatly indebted to our authors
who were gracious enough to contribute their
chapters, and we believe that this compendium of
knowledge and clinical wisdom will provide a firm
foundation for all clinicians who diagnose and
manage patients with ILD.
Muhunthan Thillai
David R Moller
Keith C Meyer
December 2017
xv

An overview of the classification and
diagnosis of interstitial lung disease
KEITH C MEYER
Historical background and evolution of
terminology 1 diagnosis
Current classification systems for ILD 3 Summary
Idiopathic interstitial pneumonias 4 References
Genetics of ILD: Potential impact on
classification and terminology 5
HISTORICAL BACKGROUND AND
EVOLUTION OF TERMINOLOGY
Recognition of the existence of interstitial lung dis-
ease (ILD) dates back more than 100 years when
Sir William Osler described ‘cirrhosis of the lungs’
and recognized the diversity of its forms and the
difficulty of classifying these disorders (1). Various
terminologies were coined over the span of the
twentieth century as various leaders in the field
described patients whose lungs displayed changes
of interstitial inflammation and fibrosis. Hamman
and Rich (1944) described four cases of rapidly
progressive, diffuse alveolar wall thickening with-
out identifiable cause, which led to use of the term,
‘Hamman–Rich syndrome’ for either acute-onset
or chronic fibrotic ILD. Subsequently, diffuse pul-
monary fibrosis was linked to forms of connec-
tive tissue disease (CTD) and other causes, such as
exposure to organic or inorganic dusts and pneu-
motoxic drug reactions, but many forms remained
unexplained by any associations. Terms such as
‘chronic idiopathic interstitial fibrosis’, ‘diffuse
1
Current approach to making a confident ILD
6
7
8
fibrosing alveolitis’ or ‘idiopathic pulmonary fibro-
sis’ were used to designate fibrotic ILD of unknown
aetiology, and these disorders were thought to
occur as a consequence of alveolar wall inflam-
mation (‘alveolitis’). The term ‘diffuse fibrosing
alveolitis’ was coined by Scadding (2) to describe
widespread fibrotic change beyond the level of the
terminal bronchioles, and Scadding subdivided
entities according to known or unknown associa-
tions and patterns of fibrosis (Figure 1.1). Liebow
and Carrington (3,4) published a classification sys-
tem for chronic idiopathic interstitial pneumonias
that was based on histopathologic changes; one of
the five subgroups that they described was termed
‘usual’ interstitial pneumonia (UIP), and the
Hamman–Rich syndrome was felt to be an acute
form of UIP (Figure 1.1).
The classification systems proposed by Scadding
or Liebow and Carrington were quite similar, but
clinicians tended to overlook histopathologic varia-
tions and termed ‘chronic idiopathic fibrosing ILD’
as ‘cryptogenic fibrosing alveolitis’ (Europeans) or
‘idiopathic pulmonary fibrosis’ (United States).
Katzenstein and Myers (5) re-examined Liebow’s
1
2 An overview of the classification and diagnosis of interstitial lung disease

Diffuse fibrosing alveolitis Idiopathic interstitial pneumonias

(Scadding, 1974) (Liebow and Carrington, 1969, 1975)

Known aetiology (inhaled

substances, infections)
UIP DIP BIP GIP LIP
Defined histopathology
with unknown aetiology

Idiopathic pulmonary fibrosis

Systemic diseases with idiopathic interstitial pneumonias
similar histopathology (Katzenstein and Myers, 1998)

Limited to lung (CFA)

UIP DIP RBILD AIP NSIP

Desquamative
changes only
Interstitial Lung Disease/
Fibrosis with archi- Idiopathic Interstitial Pneumonias
tectural distortion (ATS/ERS Statements, 2002, 2013)

DPLD of known cause (e.g. Granulomatous DPLD (e.g.

Idiopathic interstitial Other DPLD (e.g. LAM,
drugs, CTD, inhaled antigen sarcoidosis, HP, chronic
pneumonias PLCH, PAP, etc.)
or mineral fiber) beryllium disease, etc.)

IPF NSIP RBILD DIP COP ILIP IPPFE UIIP

Figure 1.1 Evolution of classification systems for interstitial lung disease and forms of idiopathic
interstitial pneumonia. (Abbreviations: AIP = acute interstitial pneumonia; BIP = bronchiolitis inter-
stitial pneumonia; CFA = cryptogenic fibrosing alveolitis; COP = cryptogenic organizing pneumonia;
CTD = connective tissue disease; DIP = desquamative interstitial pneumonia; DPLD = diffuse paren-
chymal lung disease; GIP = giant cell interstitial pneumonia; HP = hypersensitivity pneumonia; ILIP =
idiopathic lymphoid interstitial pneumonia; IPF = idiopathic pulmonary fibrosis; IPPFE = idiopathic
pleuropulmonary fibrosis; LAM = lymphangioleiomyomatosis; NSIP = non-specific interstitial pneu-
monia; PLCH = pulmonary Langerhans cell histiocytosis; RBILD = respiratory bronchiolitis interstitial
lung disease; UIIP = undifferentiated interstitial pneumonia; UIP = usual interstitial pneumonia.)

classification system and refined the histopathol-
ogy-based system by adding two new categories
(non-specific interstitial pneumonia [NSIP] and
respiratory-bronchiolitis-associated ILD [RBILD])
while revising/retaining some of Liebow’s catego-
ries (UIP and desquamative interstitial pneumo-
nia [DIP]): acute interstitial pneumonia (AIP) was
coined as a term for the Hamman–Rich syndrome
(Figure 1.1). Their scheme recognized giant cell
interstitial pneumonia (GIP) as caused by hard-
metal exposure and considered lymphoid inter-
stitial pneumonia (LIP) as a lymphoproliferative
disorder, while bronchiolitis interstitial pneu-
monia (BIP) was recognized as an intraluminal
(rather than interstitial) process that could take the
form of organizing pneumonia (aka bronchiolitis
obliterans organizing pneumonia [BOOP]) or dif-
fuse alveolar damage (DAD). They also correlated
their histopathologic pattern-based classification
system with clinical features and natural history.
With the evolution of ongoing clinical and patho-
logic investigations of ILD from the late twentieth
century to the present era combined with the advent
of thoracic high-resolution computed tomography
(HRCT) imaging, schemes for the classification of
ILD that melded clinical syndromes, histopatho-
logic changes and HRCT imaging together to
define specific diagnostic entities were formulated
(6–10). However, it also became apparent that his-
topathologic patterns could have overlap among
 Current classification systems for ILD 3

clinical entities (e.g. a UIP pattern can be idio- Table 1.1 Classification of interstitial lung disease
pathic and consistent with a diagnosis of idiopathic (diffuse parenchymal lung disease)
pulmonary fibrosis [IPF], or a UIP pattern can be
1. Idiopathic interstitial pneumonia
associated with CTD accompanied by lung involve-
• Idiopathic pulmonary fibrosis (i.e. idiopathic
ment). Finally, classification schemes will undoubt-
usual interstitial pneumonia)
edly change as we identify causative genomic and
• Non-specific interstitial pneumonia (NSIP)
epigenetic determinants that appear to be operant
• Desquamative interstitial pneumonia
in risk and causation of the myriad forms of ILD
(DIP)
(11–15), and understanding the genomics of ILD
• Respiratory bronchiolitis-associated
will likely lead to improved, personalized therapies.
interstitial lung disease (RBILD)
• Acute interstitial pneumonia (AIP)
CURRENT CLASSIFICATION • Cryptogenic organizing pneumonia (COP)
SYSTEMS FOR ILD • Lymphocytic interstitial pneumonia
(idiopathic)
• Pleuro-parenchymal fibroelastosis
The pantheon of more than 200 forms of ILD can be
(idiopathic)
classified in a variety of ways. An updated consensus
• Non-classifiable interstitial pneumonia
classification system (Figure 1.1) forged by expert
(NCIP)
opinion (while using a multidisciplinary approach
2. Connective tissue disease associated
that combined clinical characteristics with histo-
• Rheumatoid arthritis
pathologic and HRCT patterns) segregated the vari-
• Systemic sclerosis (scleroderma)
ous forms of ILD into four major categories while
• Anti-synthetase syndromes
focusing on the category of IIPs was published
• Sjögren syndrome
in 2002 (6) and updated in 2013 (7). Alternative
• Systemic lupus erythematosus
approaches that also focus on the combination of
• Ankylosing spondylitis
etiologies, clinical presentation and findings, radio-
3. Primary disease related
logic imaging patterns and histopathologic char-
• Sarcoidosis
acteristics can also be used to represent a clinically
• Pulmonary Langerhans cell histiocytosis
useful classification system (Tables 1.1 and 1.2).
(PLCH)
Forms of ILD can be differentiated by acute (e.g.
• Lymphangioleiomyomatosis (LAM)
acute interstitial pneumonia [AIP]) versus chronic
• Eosinophilic lung disease related (e.g.
onset (e.g. UIP), disorders that tend to be more
eosinophilic pneumonia)
responsive to anti-inflammatory/immunosuppres-
• Chronic aspiration
sive therapies (e.g. sarcoidosis, hypersensitivity
• Pulmonary alveolar proteinosis (PAP)
pneumonitis [HP], CTD-associated ILD, intersti-
• Amyloidosis
tial pneumonia with autoimmune features [IPAF],
• Inflammatory bowel disease associated
cryptogenic organizing pneumonia [COP]) versus
• Hepatic disease associated (e.g. primary
those unlikely to respond to such therapy (e.g. UIP,
biliary cirrhosis, viral hepatitis)
pneumoconioses), disorders that may remit with
• Mimics of ILD (infection or malignancy
appropriate therapy but have a propensity to relapse
associated)
(e.g. COP), disorders linked to exposures (e.g. pneu-
4. Iatrogenic
moconioses, HP), lung-limited disorders (e.g. IIPs)
• Drug induced
versus those linked to extrapulmonary disease pro-
• Radiation pneumonitis/fibrosis
cesses (e.g. sarcoidosis, CTD-associated ILD), those
5. Inhalational exposure related (occupational or
caused by therapeutic interventions for pulmonary
environmental)
or non-pulmonary disorders (e.g. iatrogenic ILD
• Hypersensitivity pneumonitis (organic
due to drug reactions or radiation therapy) and
antigen inhalation)
those that are caused by inherited gene variants (e.g.
• Acute/subacute
Hermansky–Pudlak syndrome).
• Chronic fibrosing
Regardless of the classification system utilized to
characterize and define the various forms of ILD, (Continued)
4 An overview of the classification and diagnosis of interstitial lung disease
Table 1.1 (Continued ) Classification of interstitial
lung disease (diffuse parenchymal lung disease)
• Inorganic dust/fibre/fume related
• Pneumoconiosis (e.g. asbestosis, silicosis,
hard metal lung disease)
• Other (e.g. berylliosis, chronic beryllium
disease, gaseous phase agents)
6. Inherited lung disease
• Familial interstitial pneumonia (FIP)
• Hermansky–Pudlak syndrome (HPS)
• Other (e.g. metabolic storage diseases)
7. Miscellaneous disorders
• Interstitial pneumonia with autoimmune
features (IPAF)
• Diffuse alveolar haemorrhage
(e.g. Goodpasture syndrome)
• Idiopathic diffuse alveolar haemorrhage
• Acute fibrinous and organizing pneumonia
(AFOP)
• Bronchiolocentric pattern of interstitial
pneumonia
considerable overlap will continue to exist among
various observations used to differentiate many
of these disorders from one another. Despite such
overlap, however, findings such as Velcro-like crack-
les on chest auscultation, which are usually detected
in patients with IPF but may be present with other
ILD with advanced fibrosis, can narrow the differen-
tial diagnosis. Other examples include finding a UIP
radiologic and/or histopathologic pattern, which can
be seen not only in IPF but also other ILD such as
CTD-associated ILD, chronic HP, asbestosis or drug
reactions, or by detecting a significant lymphocy-
tosis in bronchoalveolar lavage fluid (BALF), which
essentially rules out IPF but implicates other entities
such as sarcoidosis, acute HP or cellular NSIP, and
can considerably narrow a differential diagnosis and
help attain an ultimate, confident diagnosis. One
must put all the data together to navigate through
various levels of potential overlap among charac-
teristics of specific entities to arrive at a consensus
clinical–radiologic–pathologic diagnosis that is con-
sistent with the specific disease at hand.
IDIOPATHIC INTERSTITIAL
PNEUMONIAS
The usage and definition of the term ‘idiopathic pul-
monary fibrosis’ have changed considerably since it
was initially used by clinicians to signify cases of
pulmonary fibrosis of unknown cause (16). In the
decades leading up to statements and clinical prac-
tice guidelines published over the past two decades,
cases with overlapping clinical features and imaging
characteristics (e.g. non-IPF forms of IIP, chronic
HP, CTD-associated ILD, IPAF) were typically
lumped together and assigned a diagnosis of IPF
(or cryptogenic fibrosing alveolitis [CFA]) by clini-
cians despite the heterogeneity of histopathologic
findings and clinical features. As the most common
form of IIP encountered in the clinic, the term ‘IPF’
has been retained but is now specifically defined
according to the key features of a consistent clinical
presentation, the presence of a confident UIP pat-
tern on HRCT imaging, exclusion of other poten-
tial diagnoses, and, if needed, a UIP pattern on lung
biopsy specimens if the HRCT does not adequately
identify a typical UIP pattern (17). However, a
definitive diagnosis may not be forthcoming despite
obtaining HRCT imaging and an adequately sam-
pled lung biopsy specimen, and a multidisciplinary
discussion may be required to facilitate interob-
server agreement and reach a consensus diagnosis
(18–21). A search for evidence of CTD is also essen-
tial, as UIP, NSIP, AIP or DIP patterns can be seen
when patients have CTD-associated ILD (22) or an
interstitial pneumonia with autoimmune features
(IPAF) for which criteria for a specific CTD diagno-
sis are not met (23). Making an accurate diagnosis of
a specific form of IIP can be even more challenging
when clinical and laboratory data are present that
suggest a diagnosis of CTD but criteria for a specific
CTD are not met. Patients with this situation can be
classified as having IPAF, but if the only finding is a
positive anti-nuclear antibody or rheumatoid factor
without any other criteria for a diagnosis of CTD or
IPAF, a diagnosis of an idiopathic IIP (e.g. IPF) can
still be assigned and maintained (although some
patients may develop criteria for a diagnosis of CTD
as their disease evolves over time).
The updated statement on multidisciplinary
classification of the IIPs (7) recognizes that some
cases that appear to be consistent with an IIP diag-
nosis may not satisfy criteria that allow diagnosis
as a specific form of IIP. Circumstances in which a
final diagnosis may not be reached include a lack of
adequate clinical, radiologic or pathologic data to
allow a specific diagnosis to be rendered or major
discordance among clinical, radiologic and patho-
logic findings that preclude reaching a specific
 Genetics of ILD: Potential impact on classification and terminology   5

Table 1.2 Classification according to disease characteristics

Characteristic ILD diagnosis or complication

Associated with smoking RBILD, DIP, PLCH, IPF, CPFE, NSIP
Associated with occupational, Inorganic dust pneumoconiosis, HP (e.g. bird protein, grain
environmental, medication or radiation dust, humidifiers, hot tubs), drug-induced pneumonitis
exposures (e.g. amiodarone, methotrexate, nitrofurantoin),
radiation pneumonitis, infection
Frequent pleural involvement CTD-ILD (RA, SLE), PPFE
Rapid onset and/or worsening AIP, drug-induced pneumonitis, acute HP, acute EP, COP,
DAD, DAH, acute lupus pneumonitis, AFOP, AEIPF
Associated with GERD, dysphagia CTD-ILD (especially scleroderma), IPF, aspiration
pneumonitis/fibrosis
Predisposition to relapse COP
Responsive to anti-inflammatory or Acute HP, COP, sarcoidosis, cellular NSIP, CTD-associated
immunosuppressive therapy ILD
Poor response to anti-inflammatory or IPF, fibrotic NSIP, AEIPF, AIP
immunosuppressive therapy
Lung-limited disorders IIP (e.g. IPF, idiopathic NSIP, RBILD, DIP, AIP, COP,
idiopathic PPFE, idiopathic LIP), familial interstitial
pneumonia/fibrosis, inhalation-related ILD, PAP, PLCH,
EP, drug/radiation-induced ILD
Disorders frequently associated with Sarcoidosis, CTD-ILD, Hermansky–Pudlak syndrome,
extrapulmonary organ system LAM, malignancy
involvement
Associated with advanced age IPF, RA-associated ILD
Abbreviations: AEIPF = acute exacerbation of idiopathic pulmonary fibrosis; AFOP = acute fibrinous and organizing
pneumonia; AIP = acute interstitial pneumonia; COP = cryptogenic organizing pneumonia; CPFE =
combined pulmonary fibrosis and emphysema; CTD-ILD = connective tissue disease-associated inter-
stitial lung disease; DAD = diffuse alveolar damage; DAH = diffuse alveolar haemorrhage; DIP = des-
quamative interstitial pneumonia; EP = eosinophilic pneumonia; GERD = gastro-oesophageal reflux
disease; HP = hypersensitivity pneumonitis; IIP = idiopathic interstitial pneumonia; IPF = idiopathic
pulmonary fibrosis; LAM = lymphangioleiomyomatosis; LIP = lymphoid interstitial pneumonia; NSIP =
non-specific interstitial pneumonia; PAP = pulmonary alveolar proteinosis; PLCH = pulmonary
Langerhans cell histiocytosis; PPFE = pleuro-parenchymal fibroelastosis; RA = rheumatoid arthritis;
RBILD = respiratory bronchiolitis interstitial lung disease; SLE = systemic lupus erythematosus.

diagnosis. One example of when this situation
may exist is when previous therapies (e.g. cortico-
steroids) may have altered subsequent radiologic
imaging characteristics or histologic findings
obtained at the time a patient undergoes a diag-
nostic evaluation for suspected IIP.
GENETICS OF ILD: POTENTIAL
IMPACT ON CLASSIFICATION
AND TERMINOLOGY
Many forms of ILD/pulmonary fibrosis have
recently been linked to specific inherited gene
mutations and polymorphisms (Table 1.3), and
an evolving understanding of genomics has also
identified numerous epigenetic mechanisms that
are associated with the pathogenesis of many
forms of ILD (11–15). Telomere dysfunction,
polymorphisms for the MUC5B gene, and a vari-
ety of single-nucleotide polymorphisms for genes
such as TOLLIP or TLR3 have been associated
with both disease risk and behaviour for patients
with IPF. Ongoing studies are likely to discover
many other genetic factors that are associated
with various ILD diagnoses and identify specific
genotype–­ phenotype relationships that modu-
late the natural history of disease and/or interact
6 An overview of the classification and diagnosis of interstitial lung disease

Table 1.3 Fibrotic disorders linked to gene mutations or polymorphisms

Abnormal gene(s) and Proposed mechanisms of

Clinical disorder expression patterns pathogenesis
Familial or sporadic PF MUC5B, TOLLIP, TLR3, ATP11A, Host defense impairment
DSP, DPP9, SPPL2C
Familial or sporadic PF TERC (AD), TERT (AD), RTEL1, Telomere shortening/dysfunction
PARN, OBRFC1 DNA repair
Familial PF SFTPA1 (AD), SFTPA2 (AD), SFTPC Surfactant dysfunction
(AD), SFTPB (AD), NKX2-1 (AD),
ABCA3 (AD)
Familial or sporadic PF ELMOD2 Disruption of signalling pathways
Hermansky–Pudlak HPS1 (AR), HPS4 (AR), AP3B1 Intracellular protein trafficking
syndrome (subtypes Cytoplasmic organelle dysfunction
HPS1, HPS2 and HPS4) Surfactant dysfunction
Dyskeratosis congenita DKC1 (XLR), TERC (AD), TERT Telomere shortening/dysfunction
(AD), TINF2 (AD)
Abbreviations: AD = autosomal dominant inheritance pattern; AR = autosomal recessive inheritance pattern;
PF = pulmonary fibrosis; XLR = X-linked recessive inheritance pattern.

with environmental risk factors to increase risk
of developing a specific ILD entity. As useful bio-
markers of disease and genomics of ILD progress,
classification systems are likely to change in accor-
dance with new discoveries in the field.
CURRENT APPROACH TO
MAKING A CONFIDENT ILD
DIAGNOSIS
A systematic approach (24) is required to accurately
diagnose specific forms of ILD (Figure 1.2). Most
patients present with new onset of symptoms such
as dyspnoea on exertion, cough and/or fatigue, but
asymptomatic or relatively asymptomatic patients
with earlier stages of disease may be identified when
interstitial abnormalities are an incidental finding
on thoracic imaging obtained for other indica-
tions. A careful and comprehensive interview that
includes whether there is a history of medication/
drug exposures (e.g. amiodarone, nitrofurantoin,
methotrexate), occupational or environmental
exposures or a history of CTD should be obtained
and can provide important clues to an ultimate
diagnosis. Physical examination may reveal basi-
lar ‘Velcro-like’ crackles on lung auscultation, the
presence of digital ­clubbing, or other findings that
are suggestive of specific forms of ILD such as IPF.
Laboratory testing (pulmonary function testing,
CTD serologies, other testing as appropriate) com-
bined with the history, physical examination and
routine chest radiographic imaging (postero-ante-
rior and lateral view x-rays) may be adequate to
establish a reasonably confident ILD diagnosis.
If additional diagnostic testing is needed, a non-
contrast, HRCT that is performed at full inspiration
with both supine and prone positioning and expira-
tory views can provide essential diagnostic informa-
tion. If HRCT scan results show a definite radiologic
pattern of UIP (subpleural and basilar predominant
changes, reticular pattern, honeycomb change with
or without traction bronchiectasis and absence of
features that are inconsistent with a UIP pattern),
a confident diagnosis of IPF can be made if clinical
features do not suggest the presence of a non-IPF ILD
diagnosis such as ILD associated with CTD-ILD.
If a confident ILD diagnosis cannot be made
via findings from the clinical presentation and
evaluation combined with HRCT imaging results,
invasive testing must be considered to secure a
diagnosis. Bronchoscopy is relatively safe, and
bronchoalveolar lavage (BAL) and/or endoscopic
lung biopsies may provide very useful informa-
tion that can be diagnostic, especially when com-
bined with other clinical data and HRCT imaging.
However, bronchoscopy may be perceived as
unlikely to secure a diagnosis, especially if a form
of IIP is suspected to be present.
Progression to a more invasive type of lung
biopsy without performing bronchoscopy may be
 Current approach to making a confident ILD diagnosis   7

Suspected ILD

History Diagnosis of specific ILD

Physical examination Diagnosis of non-ILD disorder
Routine chest x-ray
Laboratory testing
Non-pulmonary tissue biopsy (if indicated) Indeterminate
diagnosis

HRCT

Confident diagnosis of Indeterminate

specific ILD type diagnosis

Yes Is bronchoscopy likely

Bronchoscopy
to aid diagnosis?

No

Confident diagnosis Indeterminate Can surgical lung biopsy

of specific ILD diagnosis be safely performed?

Yes No

Surgical lung Indeterminate Multi-disciplinary

biopsy diagnosis discussion

Confident diagnosis of ‘Best fit’ provisional

specific ILD type diagnosis

Figure 1.2 A suggested algorithm for ILD diagnosis. (Abbreviations: HRCT = high-resolution com-
puted tomography of the thorax; ILD = interstitial lung disease.)

reasonable, and such may be required if bronchos-
copy is performed but does not provide diagnostic
findings. Obtaining a surgical lung biopsy (SLB),
which is usually performed via a video-assisted
thorascopic surgery (VATS) approach, remains the
procedure of choice at most centres if other diag-
nostic testing cannot allow a confident diagnosis
to be made. However, patients at high risk for seri-
ous complications if a SLB is performed may not
be good candidates to undergo the procedure, and
patients should thoroughly understand the poten-
tial risks and benefits of SLB. Ideally, multidisci-
plinary discussions among clinicians, radiologists,
and pathologists (if tissue biopsies are obtained)
should be held to attain an ultimate, ‘best fit’
diagnosis. Bronchoscopic lung cryobiopsy (BLC),
which can retrieve much larger tissue specimens
than endoscopic transbronchial biopsies, may
become an alternative to SLB, but the utility of
BLC remains to be determined (25).
SUMMARY
Classification schemes that encompass and dis-
tinguish among the various forms of ILD have
evolved tremendously over recent decades and
8 An overview of the classification and diagnosis of interstitial lung disease
will continue to change as our knowledge of these
disorders, especially their genetic and genomic
underpinnings and causative/modulatory epi-
genetic factors, evolves. Nonetheless, such clas-
sification schemes continue to have some degree
of redundancy and overlap. When clinicians
encounter a patient with signs and symptoms
of ILD, a systematic approach that evaluates the
combination of clinical features, potential risk
factors and exposures, appropriate laboratory
testing, measurements of lung function, thoracic
imaging characteristics and, if needed, histopath-
ologic patterns in adequately sampled lung biopsy
specimens is likely to lead to a confident diagnosis
of a specific form of ILD. The currently used ILD
classification systems will continue to evolve and
change as useful biomarkers and genetic factors
that are indicative of specific disorders are discov-
ered and incorporated into diagnostic algorithms
and classification schemes that point to causation
as well as potential responses to specific therapies.
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 2
Histopathology of interstitial lung
disease: A pattern-based approach

ANGELA M TAKANO, JUNYA FUKUOKA AND KEVIN O LESLIE

Introduction 12 Immature fibroblasts: Organizing pneumonia 27

Pattern I: Acute lung injury 12 Macrophages: Desquamative interstitial
Diffuse alveolar damage 12 pneumonia 28
Exudative phase 13 Alveolar filling with eosinophilic material:
Proliferative phase 13 Pulmonary alveolar proteinosis 29
Repair phase 13 Red blood cells and haemosiderin-laden
Acute injury with necrosis 15 macrophages: Alveolar haemorrhage 29
Acute eosinophilic pneumonia 15 Alveolar filling with neutrophils 29
Diffuse alveolar haemorrhage 16 Alveolar filling with microliths: Pulmonary
Pattern II: Fibrosis 18 alveolar microlithiasis 29
Fibrosis with temporal heterogeneity: Usual Pattern V: Nodules 30
interstitial pneumonia 18 Nodules with granulomatous inflammation:
Uniform alveolar wall fibrosis: Non-specific Sarcoidosis 31
interstitial pneumonia 19 Nodules with mineral dusts and
Airway-centred fibrosis 21 macrophages: Silicosis 32
Isolated stellate scars 22 Nodule and stellate scars with Langerhans
Non-specific patterns of fibrosis including cells: Langerhans cell histiocytosis 32
‘microscopic honeycombing only’: Pattern VI: Minimal changes 33
Honeycomb lung 22 Minimal changes with small airway disease:
Pattern III: Cellular infiltrates 22 Constrictive bronchiolitis 34
Pure cellular interstitial pneumonia: Minimal changes with vascular or lymphatic
Cellular NSIP 24 pathology: Plexiform arteriopathy of
Cellular infiltrates with poorly pulmonary hypertension 34
formed granulomas: Hypersensitivity Minimal changes with cysts:
pneumonitis 24 Lymphangioleiomyomatosis 35
Cellular infiltrates with well-formed Transbronchial biopsy material 35
granulomas: Hot tub lung 26 Conclusion 36
Pattern IV: Alveolar filling 26 References 36

11
12 Histopathology of interstitial lung disease
INTRODUCTION
Interstitial lung diseases encompass a diverse
group of more than 200 separate entities affecting
the lung parenchyma. Because these conditions are
multilobar and frequently bilateral in distribution
on imaging, the term ‘diffuse parenchymal lung
disease’ (DPLD) has been suggested as both more
appropriate and less restrictive at the microscopic
pathology level. Today the diagnosis of DPLD
requires correlation of clinical, radiologic and his-
topathologic features for clinical relevance.
The hurdles facing the general surgical patholo-
gist confronted with DPLD are many. Most impor-
tantly, the rarity of the individual diseases combined
with the infrequency of surgical lung biopsy make
the appropriate management of them nearly impos-
sible in general pathology practice. Also notable is the
complex terminology applied over the years, nomen-
clature that has been optimized in recent years by
the efforts of the American Thoracic Society and
European Respiratory Society (ATS/ERS) (1). Finally,
the fact that many of these diseases have multiple
causes, ranging from drug exposure to autoimmune
disease, adds a layer of nuance to the interpretation
that lies beyond the comfort zone of most general
pathologists. Histopathologically, these diverse dis-
eases are most often characterized by varying degrees
of inflammation, repair and fibrosis; the exact histo-
logical picture presented in a lung biopsy specimen
depends on the timing of the biopsy in relationship
to the onset of the disease as well as the possibility
that multiple injuries have accumulated over time
or are occurring simultaneously (2). The final his-
topathologic features resulting from such complex
interactions are generally difficult to decode without
a proper pattern approach, which must be applied
together with adequate clinical information and a
basic understanding of the radiologic findings.
In this chapter we discuss the six histopatho-
logic patterns of interstitial lung disease (ILD) and
their correlation with ILD diagnoses as well as
with thoracic high-resolution computed tomogra-
phy (HRCT) imaging.
PATTERN I: ACUTE LUNG INJURY
This is the first histopathologic pattern to be con-
sidered because these instances are most often
associated with an acute clinical presentation.
Such conditions need immediate intervention
(such as the case of diffuse alveolar haemorrhage
with capillaritis) and can portend a high mortal-
ity rate (such as diffuse alveolar damage in cases of
acute respiratory distress syndrome), or both (3).
The pattern of acute lung injury is characterized by
the presence of one or more of the following ele-
ments: interstitial oedema, intra-alveolar fibrin-
ous exudates, reactive type 2 pneumocytes, hyaline
membranes, tissue necrosis, intra-alveolar blood,
haemosiderin-laden macrophages and intra-alveo-
lar eosinophils.
The duration of symptoms is generally hours to
days, and sometimes up to a few weeks before the
time of biopsy. Clinically, the patients present with
breathlessness, fever, chills and night sweats, the
intensity and combination of which depend on the
type and intensity of injury.
Radiologically, they present with bilateral infil-
trates with different degrees of compromise of
the lung parenchyma, which varies from patchy
opacities to so-called lung ‘white-out’, where
­
there is complete opacification of both lung fields
(Figure 2.1).
Several specific histopathologic entities fall
under this umbrella of ‘acute lung injury’ and cor-
respond to clinical–radiological presentations.
These are presented below.
DIFFUSE ALVEOLAR DAMAGE
The main histopathologic feature is the presence of
intra-alveolar hyaline membranes with a spectrum
of changes depending on the phase of the injury.
Diffuse alveolar damage (DAD) is the histopatho-
logic manifestation of many types of acute alveolar
injury caused by diverse agents and mechanisms
(Table 2.1). In some instances, however, the cause of
the injury remains unknown. The idiopathic type
of DAD corresponds to the clinical presentation
of acute interstitial pneumonia (AIP) (4). Because
infections figure prominently in the list of causes,
special stains for organisms, including immuno-
histochemical stains for viruses, if available, must
be performed as part of the standard workup of
the biopsy. The clinical presentation of this type
of injury is typically the acute respiratory distress
syndrome (ARDS). Patients with ARDS present
with an abrupt onset of refractory respiratory fail-
ure with typical bilateral ground glass opacities
Another random document with
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"Soon enough the men returned from their errand, climbed inside the
eagles, and then with a groan and trumpeting racket, they came alive
and flew up in the air again. That left no doubt in my mind that they
were men's chariots, and when I knew that I felt relieved.
"Though everything looked strange at first it ceased to be so after we
got used to it; yet the problem of sleeping soundly under the continual
booming and barking noises remained unsolved. All those months in
the army I never slept well. No wonder Hira and I were nervous and
fidgety, like newly hatched snakes.
"My first adventure consisted of taking a message from the Rasseldar
at the front where all kinds of dogs barked and spat fire day and
night. I must tell you a word about the Rasseldar. He was in charge of
a lot of Indian warriors from Calcutta. He took me in a cage
completely covered with black canvas, and with his forty men set out
for the front trench. After going for hours and nights—for that is what
it felt like in my darkened cage—we reached our destination. There
the canvas was removed. Now I could see nothing but walls around
me where turbaned men from India crawled like little insects.
Overhead flew the mechanical eagles trumpeting with terror. Here for
the first time I began to grasp sounds. Instead of one confused boom,
boom, boom, there were as many grades of explosion as the ear
could distinguish. The hardest one to make out was the talk of the
men about me. Under the deafening sounds their talk sounded like
the whisper of a lazy breeze in the grass. Now and then they
unmuzzled a metal dog that barked—spitting out fire for a long stretch
of time. Then came the laughter of a hyena. Hundreds of men
goaded those little pups to an awful coughing—puck puff, puck puff,
puck puff! That sound was drowned in the deep-toned cry of the
eagles above who flew in flocks and barked as well as screeched like
mad, slaying each other like so many sparrows. The Rasseldar who
was in charge of me pointed the face of his pup at the sky, then let off
—puck puff—some fire and lo! it brought down one of those eagles
as if it were a rabbit. Now the deepest tone was heard. The boom
bazoom bum bum! The tiger-roar of the large ones' mammoth
majesty rose and spread like a canopy of divine chords, drowning
under its engulfing immensity all other petty sounds. Oh! the
excruciating enchantment of that organ tone. Can I ever forget! Roar
upon roar, titanic tonality on tonality, like cataclysmic boulders of
sounds crashed and clamoured!
"Why does beauty lie so close to death? Hardly had the ineffable
glory of that supernal music overhead seized my soul when balls of
fire fell about us like a torrential rain. Men fell and succumbed like
rats in flooded holes. The Rasseldar, who was bleeding and red,
wrote hastily on a piece of paper, tied it to my feet and uncaged me. I
knew by the look in his eyes that he was in dire distress and wanted
Ghond to bring him succour.
"Of course you know, my master, I flew up; but what I beheld almost
froze my wings. The air above the trenches was one sheet of flying
fire. How to rise above it was my problem. I used my tail rudder, and
steered my flight in every direction. But no matter which way I rose,
above me ran a million shuttles of flame, weaving the garment of red
destruction on the loom of life. But I had to rise, I, Gay-Neck, the son
of my father. And soon I struck a pocket of air which was full of a
current that sucked and whirled me up as if my wing were broken and
I were as light as a leaf. It turned me up and down and up again till I
had torn my way through the fabric of fire that kept on weaving itself
with ever-increasing rapidity. But I had no eye for anything now. 'To
Ghond, to Ghond,' I kept saying to myself. Every time I said that, it
dug like a fresh goad into my spirit and made me put forth my
greatest effort. Now that I had risen very high I made my observations
and flew westward. Just then a shot pierced and broke my rudder.
Half of my tail was burnt and torn away from me. And you know that
made me furious! My tail is my point of honour. I can't bear it to be
touched, let alone shot at. Well, I flew safely home, but just about the
moment I was getting ready to go down, two eagles started a fight
above me. I had not heard their trumpeting nor seen their faces. Had
they killed each other I would not have minded, but they let loose a
hurricane of flames after me. The more they fought the more fire fell
from their beaks. I dived and ducked as well as I could. If only they
had had some trees there. Of course there had been trees, but most
of them had been shot and mutilated so that they stuck out like
stumps, with no shade-giving gracious foliage, nor any prodigious
boughs. So I had to zig-zag my way round and about those
dilapidated spikes like a man fleeing from elephants in the jungle. At
last I reached home and perched on Ghond's wrist. He cut the thread
and took the message with me to the Commander-in-Chief, who
looked like a ripe cherry and exuded a pleasant odour of soap.
Probably, unlike most soldiers, he bathed and soaped himself clean
three or four times a day. After he had read what was scribbled on
that paper by the Rasseldar, he patted me on the head and grunted
like a happy ox."
CHAPTER V
 SECOND ADVENTURE
he next time we were taken to the front was after
the Rasseldar recovered from his slight wounds.
On this occasion he took both Hira and me. I knew
at once that the message we were to carry was so
important that two had to be trusted with it so that
at least one might succeed.
"It was very cold. I felt as if I were living in a
kingdom of ice. It rained all the time. The ground was so foul that
every time you stepped on it your feet got caught in mud like
quicksand, and your feet felt so cold, as if you had stepped on a
corpse. Now we reached a strange place. It was not a trench, but a
small village. Around it beat and burst the tides of burning
destruction. It was, by the look on the men's faces, a very sacred
and important place, for they did not want to give it up though the red
tongues of death licked almost every roof, wall and tree of this place.
I was very glad to be in an open space. One could see the grey sky
low, oh, so very low. And one could see the frost-whited patches of
ground where no shell had yet fallen. Even there, in that very heart
of pounding and shooting, where houses fell as birds' nests in
tempests, rats ran from hole to hole, mice stole cheese, and spiders
spun webs to catch flies. They went on with the business of their life
as if the slaughtering of men by their brothers were as negligible as
the clouds that covered the sky.
"After a while the booming stopped. And it looked as if the village,
that is what was left of it, were safe from attack. It grew darker and
darker. The sky lowered so far that I could put my beak into it. The
dank cold seized every feather of my body and began to pull it out,
as it were. I found it utterly impossible to sit still in our cage. Hira and
I hugged each other tight in order to keep warm.
"Again firing broke out. This time from every direction. Our little
village was an island surrounded by the enemy. Apparently under
cover of the fog that had enwrapped everything, the enemy had cut
off our connection from the rear. Then they started shooting the sky-
rockets. It was dark and clammy like a Himalayan night though it was
hardly past noon. I wondered how men knew it was anything but
night. Men after all know less than birds.
"Hira and I were released to carry our respective messages. We flew
up, but not very far, for in a short time we were devoured by a thick
fog. Our eyes could see nothing. A cold clammy film pressed itself
on them, but I had anticipated something like this. I did what I would
do under such circumstances, whether in a field of battle or in India. I
flew upwards. It seemed as if I could go no further than a foot at a
time. My wings were wet. My breathing was caught in a long process
of sneezing. I thought I should drop dead in an instant. Thank the
Gods of the pigeons I could see for a few yards now! So I flew
higher. Now my eyes began to smart. Suddenly I realized I must
draw down my film—my second eye-lids that I use in flying through a
dust storm—if I were to save myself from blindness, for we were not
in a fog—it was an evil-smelling eye-destroying smoke let out by
men. My eyes pained as if somebody had stuck pins into them. My
films now covered my eyes and holding my breath I struggled
upwards. Hira, who was accompanying me, rose too. He was
choking to death with that gas. But he was not going to give up his
flight. At last we rose clear of the sheet of poison smoke. The air was
pure here, and as I removed the film from my eyes I saw far away
against the grey sky, our line. We flew towards it.
"Hardly had we flown half way homeward when a terrible eagle with
black crosses all over it flew nearer and spat fire at us—puck puff,
puck puff, pop pa.... We ducked and did the best we could. We flew
back to its rear. There the machine could not hit us. Imagine us flying
over the tail of that machine-eagle. It could do nothing. It began to
circle. So did we. It turned somersaults. So did we. It could do
nothing without wriggling its tail, unlike that of a real eagle, its tail
was as stiff as a dead fish. We knew that if we once came in front of
it again we would be killed instantaneously.
"Time was passing. I realized that we could not go on staying over
the tail of that machine eagle for ever. The village covered with
poison gas that we had left behind held the Rasseldar and our
friends. We must get our message through for their safety and
succour.
"Just then the machine-eagle played a trick. It flew back towards its
home. We did not wish to go into the enemy's line flying over its tail
in order to be sniped by sharp-shooters. Now that we were half way
to our own home and in sight of our line, we gave up being careful;
we turned away from the machine-eagle and flew at our highest
speed rising higher every few wing-beats. No sooner had we done
that than the miserable beast turned and followed. Fortunately it took
him a little time. There was no doubt now that we were flying over
our own lines. Just the same that plane rose to our level and kept on
pouring fire on us—puff puff popa! Now we were forced to duck and
dive. I made Hira fly under me. That protected him. So we flew, but
fate is fate. From nowhere came an eagle and fired at the enemy.
We felt so safe now that Hira and I flew abreast of each other. Just
then a bullet buzzed by me and broke his wings. Poor wounded Hira!
He circled and fell through the air like a silver leaf, fortunately in our
line. Seeing that he was dead, I flew at lightning speed, never turning
back to see the duel of the two eagles.
"When I got home I was taken to the Commander-in-Chief. He
patted my back. Then for the first time I realized what an important
message I had brought, for as soon as the old man had read the
piece of paper he touched some queer ticking things, and he lifted a
piece of horn and growled into it. Now Ghond took me to my nest.
There as I perched, thinking of Hira, I felt the very earth shake under
me. Machine-eagles flew in the air thick as locusts. They howled,
whirred and barked. Below from the ground boomed and groaned
innumerable metal dogs. Then came the deep-toned howl of the big
spit-fires like a whole forest of tigers gone mad. Ghond patted my
head and said: 'You have saved the day.' But there was no day in
sight. It was a darkening grey sky under which death coiled and
screamed like a dragon, and crushed all in its grip. How bad it was
you may gauge from this: when I flew near our base for exercise
next morning I found that hardly a mile from my nest the ground was
ploughed up by shells. And even rats and field mice did not manage
to escape: dozens of them had been slaughtered and cut to pieces.
Oh! it was terrible. I felt so melancholy. Now that Hira was dead I
was alone, and so weary!"
CHAPTER VI
 GHOND GOES RECONNOITRING
bout the first week of December, Ghond and
Gay-Neck were to go on a reconnaissance trip all
by themselves. The place they went to was a forest
not far from Ypres, Armentieres, and Hasbrouck. If
you take a map of France and draw a line from
Calais south almost in a straight line, you will come
across a series of places where the British and
Indian armies were situated. Near Armentieres
there are many of Indian Mohommadan soldiers. There are no
graves of Indian Hindu soldiers because the Hindus from time
immemorial have cremated their dead, and those that are cremated
occupy no grave. Their ashes are scattered to the winds, and no
place is marked or burdened with their memory.
To return to Ghond and Gay-Neck. They were sent to a forest near
Hasbrouck which was behind the enemy's line, to find out the exact
location of an enormous underground ammunition dump. If found,
Ghond and the pigeon, singly or together, were to return to the
British Army Headquarters with an exact map of the place. That was
all. So one clear December morning, Gay-Neck was taken on an
aeroplane. It flew about twenty miles over a forest, part of which was
held by the Indian army and the rest by the Germans. When they
had gone beyond the German line Gay-Neck was released. He flew
all over the woods, then, having gained some knowledge of the
nature of the land, he flew back home. This was done to make sure
that Gay-Neck knew his route and had some inkling of what was
expected of him.
That afternoon when the sun had gone down, which happened at
about four o'clock at this latitude ten degrees north of New York,
Ghond, most warmly dressed, with Gay-Neck under his coat, started.
They went on an ambulance as far as the second line of the Indian
army in the great forest. In utter darkness they proceeded to the
front, conducted by some members of the Intelligence Service.
Soon they found themselves in what is called No Man's Land, but
fortunately it was covered with trees most of which had not yet been
destroyed by shell-fire. Ghond, who did not know French or German
and whose knowledge of English was confined to three words, "yes,"
"no," and "very well," was now left to find a German ammunition
dump in a forest, accompanied only by a pigeon fast asleep under
his coat.
First of all he had to remind himself that he was in a country of the
cold Himalayan climate where, during the winter, trees stood bare
and the ground was covered with dry autumn leaves and frost. Since
there was very little foliage on tree or sapling, concealment of
himself proved not an easy task. The night was dark and cold as a
corpse, but since he could see in the dark better than any living man,
and because his sense of smell was as keen as the keenest of all
animals, he knew how to steer his course in No Man's Land.
Fortunately that night the wind was from the east.
Edging his way between tree trunks, he pushed forward as fast as
possible. His nose told him minutes before their arrival that a
company of Germans was passing his way. Like a leopard he
crawled up a tree and waited. They never heard even the flicker of a
sound. Had it been daylight they would have found him, for his bare
feet bled as he walked on the frost-stricken ground, leaving distinct
marks behind.
Once he had a very close shave. As he went up a tree and sat on a
branch to let a couple of German sentries pass below him, he heard
someone whisper from a branch into his ear. He knew at once that it
was a German sharp-shooter. But he bent his head and listened.
The German said: "Guten nacht," then stepped over and slid down
the tree. No doubt he had taken Ghond for one of his fellow soldiers
who had come to relieve him. After a while Ghond descended to the
ground and followed the footprint of that German. Dark though it
was, his bare feet could feel where the ground had been worn down
by the feet of man. No difficult task that for him.
At last he reached a place where a lot of men were bivouacking. He
had to skirt around them softly, still pressing forward. He heard a
strange noise right at his feet. He stopped and listened. No mistake,
this was a familiar sound! He waited. The steps of an animal, "Patter
pat, patter-r-r!" Ghond moved towards the sound and a suppressed
growl ensued. Instead of fear, joy gripped his heart. He who had
spent nights at a time in the tiger-infested jungles of India was not to
be deterred by the growl of a wild dog. Soon enough two red eyes
greeted his vision. Ghond sniffed the air before him carefully as he
stood there and lo! he could not detect there was the slightest odour
of man about that dog; the creature had gone wild. The dog too was
sniffing the air to find out what kind of a being he was facing, for
Ghond did not exude the usual human odour of fear and so he came
forward and rubbed against him and sniffed vigorously. Fortunately
Ghond carried Gay-Neck above the dog's nose and the odour of the
bird's presence was carried up by the wind, so the wild dog
perceived in the man before him nothing but a friendly fearless
fellow. He wagged his tail and whined. Ghond, instead of patting his
head with his hand, slowly put it before the dog's eyes to see and
smell. A moment of suspense followed. Was the dog going to bite
the hand? Another moment passed. Then ... the dog licked it. He
now whined with pleasure. Ghond said to himself: "So this hunter's
dog is without a master. Probably his master is dead. The poor beast
has become wild as a wolf. He lives by preying on the food supply of
the German army, for it is evident he has not yet eaten any human
flesh. So much the better."
Ghond whistled softly, the call of all hunters of all ages no matter in
what country. It meant "Lead." And the dog led. He skirted all the
bivouacs of the German soldiers as deftly as a stag slips by a tiger's
den. After hours of wandering, they reached their destination. There
was no mistake about it; Ghond had found the very depôt not only of
munitions but also of German food supplies. His leader, the wild dog,
went through a secret hole in the ground, then after half an hour
emerged with a large leg of veal between his jaws. That it was
bovine meat Ghond could tell by its odour. The dog sat down to his
dinner on the frosty ground, while the man put on his boots, which he
had carried slung over his shoulder all night long, and then looked up
and took observations. By the position of the stars he could tell
where he was. He waited there some time.
Slowly the day began to break. He took out a compass from his
pocket. Yes, he felt quite sure that he could draw a map of the place.
Just then the dog jumped up and grabbed Ghond's coat with his
teeth. There was no doubt in his mind that the dog wanted to lead
him on again. He ran ahead, and Ghond followed as fast. Soon they
reached a spot so thickly covered with thorns and frozen vines that
passage through it was possible only for an animal. The dog crawled
under a lot of sharp thorns and disappeared.
Now Ghond drew a diagram showing the position of the stars, and
the exact position of his compass, and tied both to Gay-Neck's foot,
and let him go. He watched the pigeon fly from tree to tree, resting
on each for a minute or so, and preening his wings. Then he struck
the message tied to his foot with his beak—probably he was making
sure that it was securely tied, flew up to the top of the tallest tree,
and sat there examining the lay of the land. That moment Ghond,
who was looking up, felt something pull him. He looked down at his
feet; the dog was dragging him to a hole under the thorns. He bent
low, low enough to follow his mentor's direction, but at that moment
he heard the flutter of wings overhead, then the barking of rifles. He
had no desire to get up and investigate whether Gay-Neck had been
killed or not. He crawled down under the thorns till he felt as if his
stomach were glued against his backbone, and both sewed tightly to
the ground. He pushed and crawled till suddenly he slid down, falling
about eight feet into a dark hole. It was pitch dark, but Ghond hardly
noticed that at first, for he was occupied in rubbing his bruised head.
When finally he tried to discover where he was he made out that he
must be sitting on a frozen water-hole covered like a thieves' den by
impenetrable thorn-bushes. Even in winter when no leaf clad the
branches and vines overhead, the darkness in daytime was thick
there. The dog was still with him and had evidently dragged him
there to safety. The poor beast was so happy to have a friend with
him that he wanted to play by the hour with Ghond, but the latter,
being sleepy, dozed off into perfect slumber in spite of the noise of
the guns not very far away.
After about three hours the dog suddenly whined and then yelled as
if he was stricken with madness, after which the earth rocked under
terrific sounds of explosion. Unable to bear it, the animal kept
tugging the sleeve of Ghond's coat. The detonations rose crescendo
upon crescendo till the place where Ghond lay literally swayed like a
cradle but he would not leave his hiding. All he said to himself was:
"O! Gay-Neck, thou incomparable bird, how well thou hast done thy
task. Already thou hast borne the message to the cherry-faced chief,
and this is his thunderous reply. O! thou pearl amongst winged
creatures!" So on he mumbled while the bombs dropped by
aeroplanes ignited the German munition dump.
Then the dog, who had been trying to pull him away by the sleeve of
his coat, whined and shivered like one in high fever and that instant
something sizzled through the air and fell nearby with a thud. With a
desperate yell the poor dog dashed out of his hiding place. Ghond
followed. But too late. For hardly had he crept half way under the
thorns than an ear-splitting explosion seemed to cut the ground from
under him; and a violent pain pierced his shoulder. He felt borne up
by some demoniac power and flung to the ground with great force.
Scarlet diamonds of light danced before his eyes for a few moments,
followed by quenching darkness.
An hour later when he regained consciousness the first thing that he
became aware of was a sound of Hindusthani voices. In order to
hear his native language more distinctly he tried to raise his head.
That instant he felt a shooting pain like the sting of a thousand
cobras. There was no doubt in his mind now that he had been hit
and probably mortally wounded. All the same his soul rejoiced every
time he heard Hindusthani spoken near him, for that meant that
Indian troops, and not the enemy, were in possession of the forest
now. "Ah," he said to himself, "my task is accomplished. I can die in
peace."
CHAPTER VII
 GAY-NECK TELLS HOW HE CARRIED
THE MESSAGE
ll that night preceding the eventful day I slept very
little. Though I lay under his coat, Ghond had no
knowledge that I was awake. You cannot sleep next
to the heart of a man who runs like a stag, climbs
trees like a squirrel or picks up strange dogs for
company every half hour.... Ghond's heart thumped
so hard now and then that you might have heard it
yards away. He did another thing that was not
conducive to sleep at such close quarters; he breathed irregularly all
that night. Sometimes he inhaled long breaths. Sometimes he
breathed fast as a mouse fleeing from a cat. I might as well have tried
to sleep on a storm in the sky as under the coat of such a man.
"Then that dog! Shall I ever forget him? I was frightened when Ghond
first annexed him but he got no scent from my body, and the air that
rose from below told me that somehow, like a clean-smelling ghost,
he had come to befriend us. His footsteps I will remember all my life.
He walked softly as a cat. He must have been a savage dog, for dogs
that live in civilization are noisy. They cannot even walk quietly. Man's
company is corrupting: every animal, excepting cats, becomes
careless and noisy in human society. But that dog was quite wild. He
walked without noise. He breathed without any sound. Then how did I
know that he was there? It was that odour that came up from the
ground and greeted my nostrils.
"After a sleepless and most uncomfortable night Ghond let me go and
I could hardly recognize the place where he had released me. So I
flew from tree to tree to find my bearings, which only drove fright into
my very soul. For now that day had broken, the trees were filling up
with eyes. Strange blue eyes were looking through tubes in different
directions. There were men behind them and one was looking from a
tree-top about a foot from where I perched. He had not heard my
coming, on account of all those metal dogs barking around us—puff
papapa-pack!
"But as I flew up he saw me. I felt that if I did not make haste and hide
under other trees he would shoot me, and he did fire many times but I
was behind a copse thick as the matted hair of a hermit. I decided to
hop from tree to tree, not flying until the prospect was free of danger. I
spent no little time in going about half a mile that way. At last my feet
felt very fatigued and I decided to fly, danger or no danger.
"Fortunately no one had seen me fly up. I rose high after making
large circles in the air. From a place whence the forest of trees
appeared small as saplings, I looked in different directions. Far off in
the east like chariots of gold flew a flock of aeroplanes against the
dawning sky. That meant the enemy's coming upon me if I waited
much longer. So I started westward. That seemed to be the signal for
a thousand sharp-shooters on tree tops to fire at me.
"I think that when I circled up and above their trees, the Germans
were uncertain whether I was their carrier or not, but the moment the
sharp-shooters perceived that I was going west they were sure that I
was not their messenger, and so they shot at me to bring me down
and find out what I carried on my foot.
"I could not go up for ever in the clear winter air without being frozen,
and anyway, I did not want those enemy planes to gain on me. Again
I dashed westward, and again the wall of bullets spread themselves
before me like barbs of death. But I had no choice left; either pierce
my way through, or be killed by the oncoming aeroplanes who were
so near that I could see their passengers. So I dashed towards the
west. Fortunately by now my tail, which was hurt about a month ago,
had grown almost to its normal size. Without that rudder my task
would have been twice as hard. As I kept on going towards our line,
the fusilade increased. There was no doubt now that all the sharp-
shooters and men in the trenches far off were taking a shot at me.
But I zig-zagged, circled, tumbled, and in fact did all the stunts and
tricks I knew to cheat the ever-augmenting swarm of bullets, but all
that zig-zagging business lost me time. One of the aeroplanes had
come within striking distance of even so small a mark as I made, and
began to pour loads of fire from above and behind. There was
nothing to do but go forward, so I dashed on. Oh! how hard I flew—
fast as the fastest storm. Then—ftatattafut—I was hit! My leg was
broken right near the groin, and it, with its message, dangled under
me like a sparrow in a single talon of a hawk. Oh! the pain, but I had
no time to think of that, for that aeroplane was still after me and I flew
harder than before.
"At last, our own line came into view. I fled lower. The machine dived
down too. I tried to tumble, but failed. My leg prevented me from
trying any of my tricks. Then pa-pa-pat-pattut—my tail was hit and a
shower of feathers fell below, obscuring for a moment the view of the
men in the German trenches. So I shot down in a slanting flight
towards our line and—passed it, making a circle. Then I beheld a
strange sight—the aeroplane had been hit by our men. It swayed,
lurched, and fell. But—it had done its worst ere it went down in flames
—it had hit my right wing and broken it. It gave me satisfaction to see
it catch fire in the air and fall, yet my own pain had increased so that I
felt as if twenty buzzards were tearing me to pieces, but, thanks to
the gods of my race, I lost consciousness of either pain or pleasure,
and felt as if a mountainous weight were pulling me down....
 That sound was drowned in the cry of the eagles above who
screeched like mad, slaying each other.

"They kept me at the pigeon hospital for a month. Though my wing

was repaired and my leg sewn up where it belonged, they could not
make me fly again. Every time I hopped up in the air my ears, I know
not how, were filled with terrible noises of guns, and my eyes saw
nothing but flaming bullets. I was so frightened that I would dash
immediately to the ground. You may say that I was hearing imaginary
guns and seeing imaginary walls of bullets: maybe, but their effect on
me was the same as that of real ones. My wings were paralysed, my
entrails frozen with terror.
"Besides, I would not fly without Ghond. Why should I spring from the
hands of a man whose complexion was not brown and whose eyes
were blue? I had not known such people before. We pigeons don't
take to any and every outsider. At last they brought me in a cage to
the hospital where Ghond was, and left me beside him. When I saw
him I hardly recognized him, for his eyes—Ghond's eyes—wore a
look of real fear! Yes, he too had been frightened out of his wits for
once. I know, as all birds and beasts do, what fear looks like, and I
felt sorry for Ghond.
"But on seeing me, that film of terror left his eyes, and they burnt with
a light of joy. He sat up in bed, took me in his hands and kissed my
foot that had held the message that he had sent. Then he patted my
right wing and said: 'Even in great distress, O thou constellation of
divine feathers, thou hast borne thy owner with his message among
friends and won glory for all pigeons and the whole Indian army.'
Again he kissed my foot. His humility touched me and by example
humbled me. I felt no more pride when I remembered how I fell in the
trenches of an Indian brigade after that aeroplane had partly
smashed my wing, for had I fallen in a German trench, then ... they
would have seized the message on my leg, they would have
surrounded the forest where Ghond lay hid with that wild dog—I
shuddered to think of what they would have done! Alas! the dog, our
true friend and saviour, where was he now?"