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 Vincent Cottin ·
Luca Richeldi · Kevin Brown ·
Francis X. McCormack Editors

Orphan Lung
Diseases
A Clinical Guide to Rare Lung Disease
Second Edition

123
Orphan Lung Diseases
Vincent Cottin • Luca Richeldi
Kevin Brown • Francis X. McCormack
Editors

Orphan Lung Diseases

A Clinical Guide to Rare Lung Disease

Second Edition
Editors
Vincent Cottin Luca Richeldi
Department of Respiratory Medicine, National Fondazione Policlinico A. Gemelli IRCCS
Coordinating Reference Centre for Rare Università Cattolica del Sacro Cuore
Pulmonary Diseases (OrphaLung) Roma, Italy
Louis Pradel Hospital, University of Lyon
Lyon, France Francis X. McCormack
Division of Pulmonary, Critical Care, and
Kevin Brown Sleep Medicine
National Jewish Health Department of Internal Medicine
Denver, CO, USA University of Cincinnati
Cincinnati, OH, USA

ISBN 978-3-031-12949-0    ISBN 978-3-031-12950-6 (eBook)

https://doi.org/10.1007/978-3-031-12950-6

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2015, 2023
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction
on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation,
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed
to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty,
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This Springer imprint is published by the registered company Springer Nature Switzerland AG
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This book is dedicated to Claudia, and to patients who suffer from rare
pulmonary diseases and serve as a constant reminder of the importance of
our commitment.
Vincent Cottin
Preface to the First Edition

So-called orphan diseases are those conditions that attract little interest by physicians and sci-
entists, which are not widely researched, and where specific treatments are lacking. Orphan
diseases are nevertheless characterized by particularly high needs and expectations from
patients, who feel abandoned in the world of health care and expect their treating physician to
make every possible effort to help them by managing at best their disease. However, as one
cannot expect physicians to be knowledgeable with each of the 6000–8000 orphan diseases,
they generally lack experience of most orphan diseases and are left with insufficient knowl-
edge to manage these patients. Indeed, most orphan diseases are rare, at least in Europe and
North America. Not all orphan diseases are rare, however, and especially neglected tropical
infectious diseases are endemic in Africa, Asia, and the Americas, affecting one billion people
worldwide and causing tremendous morbidity and mortality.
Rare diseases are defined numerically. In Europe, a disease is rare if it affects fewer than 1
person in 2000. In the USA, a rare disease is a disease that affects fewer than 200,000 people
or that affects more than 200,000 but for which there is no reasonable expectation to be eco-
nomically profitable, with the cost of drug development and availability for such a disease to
be recovered from sales. Overall, given the plethora of different conditions, rare diseases are a
major health-care burden worldwide. Regarding lung medicine alone, it is estimated that
1.5–3 million Europeans and 1.2–2.5 million Americans are affected by a rare lung disease.
Despite the many difficulties and obstacles, the new millennium witnessed an astonishing
gain in the momentum to improve our understanding and the management of many rare dis-
eases, some of which are, therefore, no longer orphan. Interest in rare diseases has increased
greatly worldwide. Patients with orphan diseases have joined associations providing them with
a previously unknown sense of community, unprecedented awareness, and strong advocacy for
more research and better treatments. A steadily increasing number of international organiza-
tions and websites contribute to education, support, and research. Governments and agencies
have introduced incentives to encourage the pharmaceutical industry to invest in research
despite the small target populations. Specialized centers and clinical networks are now devel-
oping and have been identified in many countries: This crucial step provides up-to-date man-
agement to patients, allows basic and clinical research, establishes registries, interacts with
regulatory agencies, and supports patient associations. Novel conditions and syndromes are
discovered. The genetic determinants of many diseases and their underlying pathophysiology
are progressively better understood. An increasing number of drug candidates are identified
and may be granted an orphan drug designation with more clinical trials completed, thereby
leading to the approval and licensing of drugs in diseases heretofore considered not treatable.
Diseases such as pulmonary arterial hypertension and idiopathic pulmonary fibrosis, formerly
devoid of any treatment, are now treatable although they are still deadly severe and not
curable.
In this context, diagnosing and managing patients with orphan pulmonary diseases is an
increasing challenge to pulmonologists and internal medicine specialists as it is increasingly
difficult to keep up to the current pace of growth of knowledge, especially in basic science. To
witness the evolution of this field is tremendously stimulating since progress made in patho-
physiology, organization of care, and management rapidly translates into clinical practice for

vii
viii Preface to the First Edition

the benefit and better-being of patients. As progress continues, it is sure that additional diag-
nostic instruments and treatment options will soon be available. We, as doctors, should not let
our patients miss any opportunity to get the correct diagnosis (avoiding unnecessary proce-
dures) and the best management. Our goal in this book is to provide synthesized and easily
accessible information about the main orphan lung diseases. Although some literature is avail-
able through original articles and review articles, it is often difficult to find in a timely manner
the answers to questions that clinicians caring for patients are facing. They will find here
information oriented toward clinical practice, especially the diagnostic approach (including
manifestations suggesting the disease, methods for diagnostic confirmation, diagnostic crite-
ria, and differential diagnosis). The reader will understand that although comprehensive and
covering most rare and orphan pulmonary diseases, this textbook is not fully exhaustive in an
attempt to keep its size reasonable. Topics are divided into five parts, respectively, on diseases
affecting the airways, systemic disorders with lung involvement, orphan conditions limited to
the lung, interstitial lung diseases, and miscellaneous conditions with lung involvement (for
which information is not readily available elsewhere). We are very grateful to the authors, all
leading experts experienced in the field, who contributed time and effort to this endeavor and
committed to provide clinically oriented manuscripts with a comprehensive overview, rich
illustrations, real case examples, and guidance for the diagnostic process. They shared their
expert opinion when evidence base was lacking, as it is often the case in this setting. We hope
people will like this book and find it useful and look forward to hearing comments, sugges-
tions, and feedback so that the next edition can be even better.
Successful examples have demonstrated that despite constraint resources, the concerted
effort of dedicated patient organizations, clinicians, academic researchers, pharmaceutical
companies, and health authorities can translate into major progress. We strongly hope that this
book will contribute to the better sharing of knowledge on orphan lung diseases for the imme-
diate benefit of our patients.

Lyon, France Vincent Cottin

Roma, Italy Luca Richeldi
Lyon, France Jean-François Cordier
Preface to the Second Edition

The first edition of Orphan Lung Diseases: A Clinical Guide to Rare Lung Disease was pub-
lished in 2015. The book was very well received, as rare lung diseases are increasingly attract-
ing attention, especially in the context of very active research on new treatments, with the
milestone represented by the approval in 2014 of antifibrotic drugs to treat idiopathic pulmo-
nary fibrosis. The book covers the field of rare pulmonary diseases as a whole, and not just
interstitial lung diseases, which of course represent the largest share. Due to the progress in the
field, the variably limited number of patients with each condition, and the number of condi-
tions involved, it is very difficult for clinicians to remain current in this field. However, patients
with rare pulmonary diseases collectively represent a significant fraction of the patients fol-
lowed by practicing pulmonologists, as well as rheumatologists, internists, and other special-
ists. With the possible exception of idiopathic pulmonary fibrosis and progressive pulmonary
fibrosis, rare pulmonary diseases typically receive less attention by clinicians, researchers, and
industry than those more frequently seen in daily clinics. This textbook is oriented toward
clinical practice and is accessible online, to provide busy practitioners with ready access to
information needed in a timely manner.
The main change for the second edition is that the number of chapters has been increased
from 36 in the previous edition to the current 43, now divided into seven parts. This enabled us
to create new chapters on topics that have become increasingly relevant, such as pleuropulmo-
nary fibroelastosis, unclassifiable interstitial lung disease, complex thoracic lymphatic disor-
ders of adults, and interstitial pneumonia with autoimmune features and overlap interstitial
pneumonia. The parts on interstitial lung diseases and on systemic disorders with lung involve-
ment have been expanded to better cover these important fields, and new chapters were created
on diagnostic modalities, including separate chapters on imaging, bronchoscopic and inte-
grated diagnostic approaches to interstitial lung diseases. A new part on rare lung diseases of
genetic origin has been included: genetic and familial pulmonary fibrosis related to monogenic
diseases, diffuse bronchiectasis of genetic or idiopathic origin, pulmonary vascular manifesta-
tions of hereditary hemorrhagic telangiectasia, pulmonary alveolar microlithiasis, and rare dif-
fuse lung diseases of genetic origin. Although no book could hope to cover the immense and
ever-growing area of rare pulmonary diseases, we welcome suggestions for the next edition.
The editorial board was joined by two new editors, Dr Kevin K. Brown and Dr Francis
McCormack, who brought new ideas and expertise. As Prof. J.F. Cordier has now retired, this
new edition was supervised by four editors. We also welcome new authors coming from a
variety of countries and regions. As in the previous edition, our goal in this book was to syn-
thesize and organize emerging clinical and research advances in an easily accessible format
that is oriented toward the practicing clinician. We thank all authors who have dedicated time
to this textbook, and have provided clinically oriented manuscripts, comprising numerous
illustrations, representative case examples, and guidance for both the diagnostic process and
the practical management, often without the luxury of official diagnostic criteria or guidelines.

ix
x Preface to the Second Edition

In rare diseases, expert opinion is key when evidence is lacking, and we are very grateful to the
authors to have shared their experience to guide the clinicians in their practice. Our sincere
wish is that this book may benefit the care of our patients.

Lyon, France Vincent Cottin

Roma, Italy Luca Richeldi
Denver, CO, USA Kevin Brown
Cincinnati, OH, USA Francis X. McCormack
Contents

Part I Introduction

1 
Orphan Lung Diseases: From Definition to Organization of Care �����������������������   3
Vincent Cottin
2 
Challenges of Clinical Research in Orphan Diseases ��������������������������������������������� 11
Paolo Spagnolo and Nicol Bernardinello

Part II Orphan Diseases of the Airways

3 Chronic Bronchiolitis in Adults��������������������������������������������������������������������������������� 25

Talmadge E. King Jr.
4 Allergic Bronchopulmonary Aspergillosis ��������������������������������������������������������������� 37
Danielle Stahlbaum, Karen Patterson, and Mary E. Strek
5 Orphan Tracheopathies ��������������������������������������������������������������������������������������������� 55
Fabien Maldonado, Sara Tomassetti, and Jay H. Ryu

Part III Systemic Disorders with Lung Involvement

6 
Amyloidosis and the Lungs and Airways����������������������������������������������������������������� 77
Helen J. Lachmann and Jennifer H. Pinney
7 
Eosinophilic Granulomatosis with Polyangiitis������������������������������������������������������� 95
Yann Nguyen and Loïc Guillevin
8 Granulomatosis with Polyangiitis����������������������������������������������������������������������������� 109
Christian Pagnoux and Alexandra Villa-Forte
9 Alveolar Hemorrhage������������������������������������������������������������������������������������������������� 139
Yosafe Wakwaya and Stephen K. Frankel
10 
Pulmonary Involvement in Takayasu Arteritis and Behçet Disease����������������������� 163
Laurent Arnaud, Miguel Hie, and Zahir Amoura
11 
Portopulmonary Hypertension and Hepatopulmonary Syndrome����������������������� 177
Arun Jose, Shimul A. Shah, Chandrashekar J. Gandhi,
Francis X. McCormack, and Jean M. Elwing
12 
Systemic Sclerosis and the Lung������������������������������������������������������������������������������� 193
Athol U. Wells, George A. Margaritopoulos, Katerina M. Antoniou,
and Andrew G. Nicholson
13 
Rheumatoid Arthritis and the Lungs ����������������������������������������������������������������������� 207
Joshua J. Solomon, Kevin Brown, and Mary Kristen Demoruelle

xi
xii Contents

14 Lung
 Disease in Systemic Lupus Erythematosus,
Myositis, Sjögren’s Disease, and Mixed Connective Tissue Disease����������������������� 223
Mada Ghanem, Eirini Vasarmidi, Lise Morer, Pierre Le Guen,
and Bruno Crestani
15 Interstitial
 Pneumonia with Autoimmune Features������������������������������������������������� 241
Amen Sergew, Aryeh Fischer, and Kevin Brown
16 Primary
 Histiocytic Disorders of the Lung ������������������������������������������������������������� 251
Melanie Dalton, Cristopher Meyer, Jennifer Picarsic,
Michael Borchers, and Francis X. McCormack

Part IV Lung-Dominant or -Limited Orphan Diseases

17 Eosinophilic Pneumonia��������������������������������������������������������������������������������������������� 277

Vincent Cottin
18 Langerhans
 Cell Granulomatosis and Smoking-Related
Interstitial Lung Diseases������������������������������������������������������������������������������������������� 311
Carlo Vancheri and Silvia Puglisi
19 Lymphangioleiomyomatosis��������������������������������������������������������������������������������������� 335
Simon R. Johnson
20 Diffuse
 Cystic Lung Disease��������������������������������������������������������������������������������������� 353
Francis X. McCormack and Brian M. Shaw
21 Complex
 Thoracic Lymphatic Disorders of Adults������������������������������������������������� 369
Hassan Mujahid, Anita Gupta, Adrienne Hammill,
Christopher T. Towe, and Francis X. McCormack
22 Pulmonary Alveolar Proteinosis Syndrome������������������������������������������������������������� 389
Marissa O’Callaghan, Cormac McCarthy, and Bruce C. Trapnell
23 Gastroesophageal
 Reflux: Idiopathic Pulmonary Fibrosis and Lung
Transplantation����������������������������������������������������������������������������������������������������������� 405
Ciaran Scallan and Ganesh Raghu

Part V Genetic Rare Lung Diseases

24 Genetic
 and Familial Pulmonary Fibrosis Related to Monogenic Diseases ��������� 423
Raphael Borie, Caroline Kannengiesser, and Bruno Crestani
25 Diffuse
 Bronchiectasis of Genetic or Idiopathic Origin ����������������������������������������� 441
Jane S. Lucas, Katharine C. Pike, Woolf T. Walker, and Amelia Shoemark
26 Pulmonary
 Vascular Manifestations of Hereditary
Hemorrhagic Telangiectasia��������������������������������������������������������������������������������������� 463
Els M. de Gussem and Marie E. Faughnan
27 Pulmonary Alveolar Microlithiasis��������������������������������������������������������������������������� 475
Chadwick D. Lampl, Kathryn A. Wikenheiser-Brokamp,
Jason C. Woods, J. Matthew Kofron, and Francis X. McCormack
28 Rare
 Diffuse Lung Diseases of Genetic Origin��������������������������������������������������������� 487
Paolo Spagnolo and Nicol Bernardinello
Contents xiii

Part VI Interstitial Lung Diseases, Non Systemic

29 
Imaging Approach to Interstitial Lung Disease������������������������������������������������������� 505
Teresa M. Jacob, Tahreema N. Matin, and Joseph Jacob
30 
Bronchoscopic Approach to Interstitial Lung Disease ������������������������������������������� 525
Claudia Ravaglia, Silvia Puglisi, Christian Gurioli, Fabio Sultani,
Antonella Arcadu, and Venerino Poletti
31  Integrated Approach to Diagnosing Interstitial Lung Disease������������������������� 535
An
Christopher J. Ryerson
32 
Idiopathic Pulmonary Fibrosis and the Many Faces of UIP����������������������������������� 549
Fabrizio Luppi and Luca Richeldi
33 
The Syndrome of Combined Pulmonary Fibrosis and Emphysema ��������������������� 561
Vincent Cottin
34 
Nonspecific, Unclassifiable, and Rare Idiopathic Interstitial Pneumonia:
Acute Interstitial Pneumonia, Respiratory Bronchiolitis
Interstitial Pneumonia, Desquamative Interstitial Pneumonia,
Nonspecific Interstitial Pneumonia��������������������������������������������������������������������������� 589
Prince Ntiamoah, Russell Purpura, Susan Vehar, Curtis J. Coley II,
Jennifer Hasvold, Lindsay A. Schmidt, Kevin R. Flaherty,
and Leslie B. Tolle
35 
Organizing Pneumonias and Acute Interstitial Pneumonia����������������������������������� 605
Romain Lazor and Marie-Eve Müller
36 Pleuroparenchymal Fibroelastosis ��������������������������������������������������������������������������� 627
Takafumi Suda
37 
Interstitial Lung Diseases of Occupational Origin ������������������������������������������������� 641
Antje Prasse, Caroline Quartucci, Gernot Zissel, Gian Kayser,
Joachim Müller-Quernheim, and Björn Christian Frye
38 
Unclassifiable Interstitial Lung Disease������������������������������������������������������������������� 671
Sabina A. Guler and Christopher J. Ryerson

Part VII Miscellaneous Orphan Lung Diseases

39 Lymphoproliferative Lung Disorders����������������������������������������������������������������������� 685

Venerino Poletti, Sara Piciucchi, Sara Tomassetti, Silvia Asioli,
Alessandra Dubini, Marco Chilosi, and Claudia Ravaglia
40 
Pulmonary Manifestations of Hematological Malignancies����������������������������������� 705
Laïla Samy, Louise Bondeelle, and Anne Bergeron
41 
Pulmonary Hypertension in Orphan Lung Diseases����������������������������������������������� 715
David Montani, Pierre Thoré, Étienne-Marie Jutant, and Marc Humbert
42 
Drug-Induced/Iatrogenic Respiratory Disease: With Emphasis
on Unusual, Rare, and Emergent Drug-Induced Reactions����������������������������������� 735
Philippe Bonniaud and Philippe Camus
43 
Malignant Mimics of Orphan Lung Diseases����������������������������������������������������������� 777
Nicolas Girard

Index������������������������������������������������������������������������������������������������������������������������������������� 791
 Part I
Introduction
 Orphan Lung Diseases: From Definition
to Organization of Care 1
Vincent Cottin

Definitions between “somewhat rare” and “ultra-rare” lung diseases is

useful to consider. Somewhat rare diseases include condi-
The term “orphan” has been coined to describe rare diseases tions that may or may not fit the definition of a rare disease,
because of the affected sense by patients that many physi- depending on the epidemiological method used or geo-
cians are uncomfortable with the management of their dis- graphic or ethnic disparities (e.g., sarcoidosis) [3, 4]. This
ease, and, as such, hope for the future is dim because so little category of ultra-rare lung diseases was introduced by the
research has been devoted to understanding such rare disor- National Institute for Health and Care Excellence for drugs
ders in patients and improving their quality of life [1]. Their with indications for diseases that have a prevalence of <1 per
feeling of abandonment is intensified by comparisons with 50,000 persons [2]. Studies in ultra-rare lung diseases must
patients who suffer from common diseases and who benefit be conducted at a national or regional level to assemble even
from extensive research and continuous drug development. a handful of patients, which poses major challenges to con-
The struggle for equal access to care and research by patients ducting clinical trials of robust methodology [5, 6]. Examples
and the organizations that represent them is common to all of rare lung diseases in this category would include pulmo-
orphan lung diseases. The associated ethical and social issues nary alveolar microlithiasis [7], pulmonary alveolar pro-
are complex and drive many of the particularities of how the teinosis of genetic origin [8], light chain deposition disease
care for these conditions is organized. In fact, in some coun- [9], ataxia telangiectasia [10], Birt–Hogg–Dubé syndrome
tries, patients have a legal right to equal access to health care, [11], and others.
regardless of the epidemiology of their condition [2]. It is worthwhile mentioning that not all orphan diseases
The definition of a rare disease in Europe is a condition are rare. Some conditions may be common but neglected
with a prevalence of less than 1 in 2000 people (equivalent to because they affect people in poor countries (e.g., chronic
a prevalence of less than 50 in 100,000 people) and affecting infectious tropical diseases) [12]. Conversely, not all rare
fewer than 200,000 people in the USA (which equates to diseases are orphan, as progress in organization of care and
about 1 in 1700 people). Although arbitrary, these definitions research can eventually lead to progress in the management
are not trivial, as they have practical implications for all of rare diseases, sometimes with highly active research in
stakeholders including patients, regulatory bodies, drug networks of specialized centers and efficient drug develop-
developers, and payers (Fig. 1.1). In contrast, currently, there ment. Examples of rare lung diseases, which to some may
is no established definition for the so-called “ultra-rare” dis- not be considered orphan anymore, include idiopathic pul-
eases, which affect even smaller populations, with a preva- monary fibrosis, pulmonary arterial hypertension, and
lence as low as 1 in 2,000,000 or even less [1]. The distinction lymphangioleiomyomatosis (LAM).

V. Cottin (*)
Department of Respiratory Medicine, National Coordinating
Reference Centre for Rare Pulmonary Diseases (OrphaLung),
Louis Pradel Hospital, University of Lyon, Lyon, France
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 3

V. Cottin et al. (eds.), Orphan Lung Diseases, https://doi.org/10.1007/978-3-031-12950-6_1
4 V. Cottin

Fig. 1.1 The main

stakeholders in the care of
patients with orphan lung
diseases • Accurate and timely diagnosis
Diagnosis • Multidisciplinary discussion
• Access to specialty resources

• Pharmacologic and nonpharmacologic management

• Treatment decisions based on guidelines and expert opinion
• Multidisciplinary discussion of management
Management
• Infrastructure to provide comprehensive care

• Longitudinal monitoring to inform management

decisions
• “Shared-care” model of care between local
Monitoring
pulmonologists and expert centres to facilitate
timely access to care, minimise patient travel, and
“off-load” specialty clinics

• Medical education for clinicians and trainees

Medical
• Research on knowledge gaps and effective education strategies
education

Patients’
• Patient education, support, and advocacy as a
support,
key component of specialized centers.
education,
• Facilitate direct patient interaction and community engagement.
and
advocacy

• Access to clinical trials

Research • Infrastructure, momentum, and commitment to research

 he Wide Spectrum of Rare Pulmonary

T between 6000 and 8000, with a large proportion being of
Diseases genetic origin. Despite being rare, “collectively” rare dis-
eases may affect up to 5% of the population, translating into
The number of “all” rare diseases and syndromes has not ~30 million in Europe and the USA [1]. Although most rare
been hitherto established, although rough estimates range “lung” diseases are idiopathic and chronic rather than of
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