Rare Diseases of The Respiratory System

ERS monograph
Rare Diseases of the Respiratory System

ERS monograph
Rare Diseases of the
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European Respiratory Society (ERS) has published Rare
Diseases of the Respiratory System. Structured into thematic Edited by Thomas O.F. Wagner,
sections, the book covers: the identification of rare diseases
of the respiratory system and their differential diagnosis; Marc Humbert, Marlies Wijsenbeek,
rare diseases of the lung interstitium; rare diseases of the
airways or alveoli; and rare pulmonary vascular diseases. The
Michael Kreuter and Helge Hebestreit
Guest Editors and authors belong to and/or support the vision
and mission of the European Reference Network for Rare
Diseases of the Respiratory System (ERN-LUNG), which offers
expert support to both patients and professionals. As such,
this comprehensive book will prove an excellent resource for
healthcare professionals, researchers and students interested
in rare diseases of the respiratory system.
ERS monograph 100
ISBN 978-1-84984-166-5
Print ISSN: 2312-508X
Online ISSN: 2312-5098
Print ISBN: 978-1-84984-166-5
Online ISBN: 978-1-84984-167-2
June 2023
€60.00
9 781849 841665
Respiratory System
Edited by
Thomas O.F. Wagner, Marc Humbert, Marlies Wijsenbeek,
Editor in Chief
Peter M.A. Calverley
This book is one in a series of ERS Monographs. Each individual issue

provides a comprehensive overview of one specific clinical area of
respiratory health, communicating information about the most advanced
techniques and systems required for its investigation. It provides factual and
useful scientific detail, drawing on specific case studies and looking into
the diagnosis and management of individual patients. Previously published
titles in this series are listed at the back of this Monograph.
ERS Monographs are available online at books.ersjournals.com and print

copies are available from www.ersbookshop.com
Editorial Board: Christian B. Laursen (Deputy Chief Editor; Odense, Denmark), Francesco Bonella (Essen,
Germany), Daniela Gompelmann (Vienna, Austria), David S. Hui (Hong Kong), Holly R. Keir (Dundee, UK) and
Maria Molina Molina (Catalunya, Spain).
Managing Editor: Rachel Gozzard

European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK
Tel: 44 114 2672860 | E-mail: monograph@ersnet.org
Production and editing: Caroline Ashford-Bentley, Alice Bartlett, Clarissa Charles, Jonathan Hansen,
Claire Marchant, Catherine Pumphrey and Kay Sharpe
Published by European Respiratory Society ©2023

June 2023
Print ISBN: 978-1-84984-166-5
Online ISBN: 978-1-84984-167-2
Typesetting by Nova Techset Private Limited
Printed by Charlesworth Press, Wakefield, UK
All material is copyright to European Respiratory Society. It may not be reproduced in any way including
electronic means without the express permission of the company.
Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory
Society, editors or publishers.
ERS monograph
Contents
Rare Diseases of the Respiratory System Number 100
June 2023
Preface vii
Guest Editors viii
Introduction xi
List of abbreviations xiv
1. How to identify rare diseases of the respiratory system 1

Helge Hebestreit, Florian Gahleitner, Simon Veldhoen and Matthias Griese
2. Differential diagnosis of reciprocal mimics of neoplastic and 10

non-neoplastic pulmonary disorders: multidisciplinary approaches
Nicolas Girard
Rare diseases of the lung interstitium

3. Interstitial lung diseases: an overview 23
Theodoros Karampitsakos, Marlies Wijsenbeek, Jose D. Herazo-Maya,
Argyris Tzouvelekis and Michael Kreuter
4. Rare interstitial lung diseases of environmental origin 40

Carlos Robalo Cordeiro, Tiago Alfaro and Sara Freitas
5. Amyloidosis and the lungs and airways 53

Joshua A. Bomsztyk, Jennifer H. Pinney and Helen J. Lachmann
6. Diffuse cystic lung diseases including lymphangioleiomyomatosis 69

Davide Elia, Antonella Caminati, Lisa Tescaro, Roberto Cassandro and Sergio Harari
Rare disease of the airways or alveoli

7. Bronchiolitis 85
Venerino Poletti, Claudia Ravaglia, Alessandra Dubini, Sissel Kronborg-White,
Salvatore Cazzato and Sara Piciucchi
8. Pulmonary alveolar proteinosis 103

Evelyn Lynn, Omaima Omar, Ali Ataya, Elisabeth Bendstrup, Alessandro N. Franciosi
and Cormac McCarthy
9. Primary ciliary dyskinesia 118

Petra Pennekamp, Johanna Raidt, Kai Wohlgemuth, Heike Olbrich and Heymut Omran
10. Cystic fibrosis and other ion channel-related diseases 135

Simon Y. Graeber and Marcus A. Mall
11. Bronchiectasis: from orphan disease to precision medicine 150
Hayoung Choi and James D. Chalmers
12. α1-Antitrypsin deficiency and other rare forms of emphysema 165

Joanna Chorostowska-Wynimko, Sabina Janciauskiene, Magdalena Pelc,
Pavel Strnad and David Parr
Pulmonary vascular diseases

13. Pulmonary arterial hypertension 180
Sarah Cullivan and Sean Gaine
14. Chronic thromboembolic pulmonary hypertension 192

Marion Delcroix, Laurent Godinas, Rozenn Quarck, Catharina Belge, Bart Meyns,
Geert Maleux and Tom Verbelen
15. Pulmonary hypertension in orphan lung diseases 204

David Montani, Mithum Kularatne, Etienne-Marie Jutant and Marc Humbert
16. Hepatopulmonary syndrome: a liver-induced oxygenation defect 224

Laurent Savale, Fabien Robert, Ly Tu, Marie-Caroline Certain, Audrey Baron,
Audrey Coilly, Léa Duhaut, Marc Humbert, Christophe Guignabert and Olivier Sitbon
Rare lung diseases in systemic inflammatory disorders

17. Systemic inflammatory diseases with lung involvement 237
Eirini Vasarmidi, Eleni Bibaki and Katerina Antoniou
18. ANCA-associated vasculitis and other pulmonary haemorrhage 254

syndromes
Samuel Falde and Ulrich Specks
19. Eosinophilic granulomatosis with polyangiitis 267

Yann Nguyen and Loïc Guillevin
20. Idiopathic eosinophilic pneumonias 281

Vincent Cottin
21. Sarcoidosis 293

Francesco Bonella, W. Ennis James and Paolo Spagnolo
22. Granulomatous and lymphocytic interstitial lung disease in common 310

variable immunodeficiency
Heba M. Bintalib, Siobhan O. Burns and John R. Hurst
Other rare lung diseases

23. Thoracic endometriosis and catamenial pneumothorax 320
Antonio Bobbio, Vincent de Pauw, Imane Lefqih, Antoine Sion and Marco Alifano
24. Chronic lung allograft dysfunction after lung transplantation 331

Berta Saez Gimenez, Merel Hellemons, Stijn E. Verleden, Jens Gottlieb and
Geert M. Verleden
25. Malformations and idiopathic disorders of the trachea 343
Valentina Luzzi, Francesca Conway, Diletta Cozzi, Luca Ciani, Leonardo Giuntoli,
Marco Trigiani and Sara Tomassetti
26. Rare diseases of respiratory drive 357

Katie Rose, Tamarin Foy, Christopher Grime and Ian P. Sinha
27. Pleural mesothelioma 367

Joachim G.J.V. Aerts and Jan P. van Meerbeeck
Preface
Peter M.A. Calverley
Welcome to this, the 100th issue of the ERS Monograph. The

Monograph is one of the European Respiratory Society’s longest
running publications and from its inception it has been a reliable
and accessible source of authoritative, up-to-date information about
all aspects of respiratory disease. Over the years, we have covered
an enormous number of topics, some on several occasions. This
revisiting of topics reflects the changes in understanding and
progress in therapy that have occurred in our field. In this
anniversary issue, we look again at the diagnostic and therapeutic
problems raised by pulmonary conditions that are relatively rare but
nonetheless very impactful for those who suffer from them.
Although they are individually infrequent, taken together, one or more

of the wide range of disorders described in this issue is likely to crop
up in clinical practice on a regular basis. Thanks to the hard work
of our expert Guest Editors, led by Professor Thomas O.F. Wagner,
we now have access to an excellent source of information and
guidance when caring for these illnesses.
This volume is timely, not just because it marks an important milestone

in the history of the ERS Monograph but because it allows us to
celebrate the success of the European Reference Network for Rare
Diseases of the Respiratory System (ERN-LUNG; https://ern-lung.eu/),
which is itself a lesson in the value of collaboration between experts in
many different countries. This is an approach very much in line with
the mission of the European Respiratory Society. The contributors
writing here are largely drawn from that network and the chapters they
have written will engage and inform all who read them.
So, we have completed our first 100 issues – now on to the next
100, but not before you have sampled the many interesting topics
covered herein.
Disclosures: P.M.A. Calverley reports receiving grants, personal fees and

non-financial support from pharmaceutical companies that make medicines to
treat respiratory disease. This includes reimbursement for educational activities
and advisory work, and support to attend meetings.
Copyright ©ERS 2023. Print ISBN: 978-1-84984-166-5. Online ISBN: 978-1-84984-167-2. Print ISSN: 2312-508X. Online
ISSN: 2312-5098.
https://doi.org/10.1183/2312508X.10010323 vii
Guest Editors
Thomas O.F. Wagner
Thomas O.F. Wagner is a professor of internal medicine, and from

1997 to 2016, was Head of the Department of Pneumology and
Allergology, as well as Head of the Christiane Herzog CF Center
for Children and Adults, at University Hospital Frankfurt
(Frankfurt, Germany). Since 2010, he has been Head of the
Frankfurt University Hospital Reference Centre for Rare Diseases
(Frankfurt).
Thomas received his medical and research training at Bonn

University (Bonn, Germany) and Freiburg University (Freiburg,
Germany), and his post-doc training at Colorado State University
(Fort Collins, CO, USA) and at Medizinische Hochschule
Hannover (Hannover, Germany). He is an MD, holds a PhD
equivalent (Prof. Dr med. habil.) and has board qualifications in
pneumology, allergology, endocrinology and intensive care
medicine.
Thomas’ main research activities include lung transplantation,

cystic fibrosis, ventilator therapy, rare diseases, and public health
issues, including the economics of healthcare. He has numerous
publications and has supervised more than 25 medical dissertations.
Thomas is the Coordinator of the European Reference Network for

Rare Diseases of the Respiratory System (ERN-LUNG; https://
ern-lung.eu/). He has been a member of the European Commission
(EC) Rare Diseases Task Force (EUCERD), is an active partner in
the RD Joint Action and coordinates a number of European and
national projects (ERN-LUNG, the RD Registry Data Warehouse,
eSupport, etc.).
Since his active role in a European pilot project in RD networking

(ECORN-CF), a European online expert advisory board for patients
and care team members, Thomas has been heavily involved in
European networking projects, bringing together patients, patient
organisations and all care team members. ECORN-CF is a good
example of his networking skills: after initial funding from the EC,
the project is now sustainably supported by patient organisations,
more than 12 years after its starting date.
ISSN: 2312-5098.
viii https://doi.org/10.1183/2312508X.10010023
Marc Humbert
Marc Humbert is Dean and Professor of Respiratory Medicine at

the Université Paris-Saclay Faculty of Medicine in Le Kremlin-
Bicêtre, France. He is the Director of the Respiratory and Intensive
Care Medicine Department, French PH Reference Centre,
Assistance Publique Hôpitaux de Paris (Le Kremlin-Bicêtre).
Marc is Past President of the European Respiratory Society (ERS).

He was also Chief Editor of the European Respiratory Journal
from 2013 to 2017 and is now the Section Editor in charge of
Pulmonary Vascular Medicine.
Marc has received several distinctions, including the 2006 ERS

Cournand Lecture Award, the 2009 Descartes-Huygens Award from
the Royal Netherlands Academy of Arts and Sciences, the 2016
Rare Disease Award of the Fondation de France, the 2018 ERS
Award for Lifetime Achievement in Pulmonary Arterial
Hypertension, the Excellence 2019 Award from the Fondation du
Souffle, and the 2020 American Heart Association’s 3CPR
(Council on Cardiopulmonary, Critical Care, Perioperative and
Resuscitation) Distinguished Achievement Award.
Since 2017, Marc has been the Vice-Coordinator of the European

Reference Network for Rare Diseases of the Respiratory System
(ERN-LUNG; https://ern-lung.eu/).
In 2018, Clarivate Analytics listed Marc as one of the world’s most

highly cited researchers in the field of clinical medicine.
Marlies Wijsenbeek
Marlies Wijsenbeek is a pulmonary physician and Professor of

Interstitial Lung Diseases at the Erasmus University Medical Centre
in Rotterdam, a national expert centre for interstitial lung diseases
in the Netherlands and member of ERN-LUNG (the European
Reference Network for Rare Lung Diseases European Reference
Network for Rare Diseases of the Respiratory System; https://
ern-lung.eu/). She is Chair of the multidisciplinary ILD centre.
Marlies’ research interests include e-health, patient-centred outcome

measures in ILD, cough in ILD, and new therapies in ILD and
sarcoidosis.
Marlies is Chair of the Idiopathic Interstitial Pneumonia Group of

the European Respiratory Society (ERS), Lead of the Functional
Committee for Training and Continued Medical Education of
ERN-LUNG, a member of the scientific advisory board of the
European Idiopathic Pulmonary Fibrosis and Related Disorders
https://doi.org/10.1183/2312508X.10010023 ix
Federation (EU-IPFF), an Associate Editor of the European
Respiratory Journal and a member of the International Advisory
Board of Lancet Respiratory Medicine. In 2021 she was awarded
the ERS mid-career gold medal in ILD.
Michael Kreuter
Michael Kreuter is Director of the Lung Center Mainz (Mainz,

Germany) and Professor of Pneumology at the University of Mainz.
In this role, he is Head of the Department of Pneumology at the
University Clinic Mainz, and of Pneumology and Critical Care
Medicine at the Marienhaus Klinikum Mainz. He is also principal
investigator of the German Centre for Lung research (Germany).
Michael is board certified in internal medicine, pulmonology and

haematology-oncology. Following a clinical fellowship in Münster
(Germany) and a research fellowship at Harvard Medical School
(Boston, MA, USA), Michael moved to the Thoraxklinik
(Heidelberg, Germany), where has been since 2005. In 2023 he
took over the academic and clinical position in Mainz.
Michael’s clinical and scientific interest focuses on interstitial and

rare lung diseases. He is conducting various research projects on
comorbidities, epidemiology, biomarkers, and diagnosis and
therapy of interstitial lung diseases. He is also committed to
educational programmes and is one of the organisers of the annual
European Respiratory Society (ERS) virtual school on ILD.
Helge Hebestreit
Helge Hebestreit is Professor and Vice Director of Paediatrics,

Director of the Centre for Rare Diseases, and Head of Paediatric
Pulmonology and of the Cystic Fibrosis Centre at the University
Hospital in Würzburg (Germany). He also coordinates the
Commission on Rare Diseases of the German Society of Paediatrics
and is Chair of the German Working Group of the Centres for
Rare Diseases.
Helge’s main research interests include: health service research in

rare diseases in general; and exercise as a diagnostic and therapeutic
tool in people with chronic lung conditions, especially cystic fibrosis.
Helge is Lead of the Core Network for Other Rare Lung Diseases
at the European Reference Network for Rare Diseases of the
Respiratory System (ERN-LUNG; https://ern-lung.eu/).
x https://doi.org/10.1183/2312508X.10010023
Introduction
Thomas O.F. Wagner1,2, Marc Humbert 2,3,4,5, Marlies Wijsenbeek2,6,
Michael Kreuter 2,7 and Helge Hebestreit 2,8
1
Department of Pneumology, University Hospital Frankfurt, Frankfurt, Germany. 2European Reference Network for
Rare Diseases of the Respiratory System (ERN-LUNG), Frankfurt, Germany. 3Assistance Publique – Hôpitaux de Paris
(AP-HP), Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center,
Hôpital Bicêtre, Le Kremlin-Bicêtre, France. 4Université Paris-Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France.
5
INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Le Kremlin-Bicêtre, France.
6
Center of Excellence for Interstitial Lung Diseases and Sarcoidosis, Department of Respiratory Medicine, Erasmus
Medical Center-University Medical Center Rotterdam, Rotterdam, The Netherlands. 7Mainz Center for Pulmonary
Medicine, Department of Pneumology, Mainz University Medical Center and Department of Pulmonary, Critical Care
& Sleep Medicine, Marienhaus Clinic Mainz, Mainz, Germany. 8Pediatric Pulmonology & Cystic Fibrosis, Children’s
Hospital, University Hospital Würzburg, Würzburg, Germany.
Corresponding author: T.O.F. Wagner (t.wagner@em.uni-frankfurt.de)
@ERSpublications
Rare respiratory diseases pose a significant burden and can be challenging to diagnose and treat. This
Monograph provides an up-to-date, comprehensive resource to the clinician, both for educational purposes
and for clinical care. https://bit.ly/ERSM100intro
ISSN: 2312-5098.
Respiratory system disorders play a crucial role in the burden of disease and account for a huge
portion of morbidity and mortality. People with rare diseases – according to the European definition,
affecting not more than five in 10 000 – share symptoms and functional impairments with many
more common diseases. Diagnosing these diseases can be challenging due to their rarity, and
treating these conditions is complex because of often quite specific needs and treatment options.
To address this, the European Respiratory Society (ERS) has published Rare Diseases of the
Respiratory System – the 100th issue of the ERS Monograph. The previous Monograph in this
thematic area, entitled Orphan Lung Diseases and edited by Jean-Francois Cordier [1], was
published in 2011 and needed an update.
To reflect the close collaboration of ERS with the European Reference Network for Rare
Diseases of the respiratory system (ERN-LUNG; https://ern-lung.eu/), Thomas O.F. Wagner,
was honoured to guest edit this new Monograph within a team of esteemed co-guest editors,
since dealing with rare diseases nowadays requires networking and teamworking. This
collaboration of networks has allowed for most of the recent progress made. A good example of
the impact of networking on the improvement of care and research for people with rare lung
diseases are the clinical trials networks. These collaborative infrastructures have fostered the
development and market authorisation of many new drugs for rare diseases.
Another evolutional change of this book compared with its predecessor is that the reviews it
contains now offer a more comprehensive overview of the whole spectrum of rare diseases of
https://doi.org/10.1183/2312508X.10009923 xi
the respiratory system, providing readers with essential information about these diseases, their
diagnosis and their treatment.
The book is structured into thematic sections, with significant overlap between some of the sections.
The first two chapters provide an overview of how to identify rare diseases of the respiratory system
and their differential diagnosis [2, 3]. The sections that follow cover rare diseases of the lung
interstitium [4–7], rare diseases of the airways or alveoli [8–13], and rare pulmonary vascular
diseases [14–17]. The authors of each chapter are experts in their respective fields, and they provide
valuable insight into the diagnosis and treatment of rare respiratory diseases. For instance, chapter 3
discusses ILDs and covers differential diagnosis, definitions, clinical phenotype, radiological
classifications and histological characterisation [4]. Section 4 covers rare diseases of the airways
or alveoli, such as bronchiolitis [8] and alveolar proteinosis [9], as well as primary ciliary
dyskinesia [10], cystic fibrosis [11], bronchiectasis [12] and α1-antitrypsin deficiency [13]. Section 5
provides a comprehensive overview of pulmonary vascular diseases, including pulmonary arterial
hypertension [14], chronic thromboembolic PH [15], and PH complicating the course of other rare
lung diseases [16]. The authors in this section provide clinical guidance, diagnostic and therapeutic
approaches, and refer the reader to the right sources for detailed up-to-date information.
Overall, this book should constitute an excellent resource for healthcare professionals,
researchers and students interested in rare diseases of the respiratory system. The authors
provide comprehensive coverage of the whole spectrum of rare respiratory diseases, highlighting
both the progress made in recent years and the areas where more work is needed. They also
promote the idea of exchange, encouraging healthcare professionals to work together and share
knowledge to improve diagnostic and therapeutic options for patients with rare respiratory
diseases. Authors and editors belong to and/or support the vision and mission of ERN-LUNG.
This network, funded by the European Commission in 2017, is the European information and
collaboration hub offering expert support to patients and professionals and will be able to
connect readers who want more detailed or specific information on any topic within the field of
rare diseases of the respiratory system with the respective experts.
We are confident that Rare Diseases of the Respiratory System will prove a valuable resource
for anyone interested in respiratory medicine. It provides a comprehensive overview of rare
respiratory diseases, their diagnosis, and treatment, and promotes the exchange of knowledge
among healthcare professionals.
References
1 Cordier J-F, ed. Orphan Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2011.
2 Hebestreit H, Gahleitner F, Veldhoen S, et al. How to identify rare diseases of the respiratory system. In: Wagner
TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph).
Sheffield, European Respiratory Society, 2023; pp. 1–9.
3 Girard N. Differential diagnosis of reciprocal mimics of neoplastic and non-neoplastic pulmonary disorders:
multidisciplinary approaches. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the
Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 10–22.
4 Karampitsakos T, Wijsenbeek M, Herazo-Maya JD, et al. Interstitial lung diseases: an overview. In: Wagner TOF,
Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield,
European Respiratory Society, 2023; pp. 23–39.
5 Robalo Cordeiro C, Alfaro T, Freitas S. Rare interstitial lung diseases of environmental origin. In: Wagner TOF,
6 Bomsztyk JA, Pinney JH, Lachmann HJ. Amyloidosis and the lungs and airways. In: Wagner TOF, Humbert M,
Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European
Respiratory Society, 2023; pp. 53–68.
xii https://doi.org/10.1183/2312508X.10009923
7 Elia D, Caminati A, Tescaro L, et al. Diffuse cystic lung diseases including lymphangioleiomyomatosis. In:
Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph).
8 Poletti V, Ravaglia C, Dubini A, et al. Bronchiolitis. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds.
Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023;
pp. 85–102.
9 Lynn E, Omar O, Ataya A, et al. Pulmonary alveolar proteinosis. In: Wagner TOF, Humbert M, Wijsenbeek M,
et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society,
2023; pp. 103–117.
10 Pennekamp P, Raidt J, Wohlgemuth K, et al. Primary ciliary dyskinesia. In: Wagner TOF, Humbert M, Wijsenbeek
M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory
Society, 2023; pp. 118–134.
11 Graeber SY, Mall MA. Cystic fibrosis and other ion channel-related diseases. In: Wagner TOF, Humbert M,
12 Choi H, Chalmers JD. Bronchiectasis: from orphan disease to precision medicine. In: Wagner TOF, Humbert M,
13 Chorostowska-Wynimko J, Janciauskiene S, Pelc M, et al. α1-Antitrypsin deficiency and other rare forms of
emphysema. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System
(ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 165–179.
14 Cullivan S, Gaine S. Pulmonary arterial hypertension. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare
Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 180–191.
15 Delcroix M, Godinas L, Quarck R, et al. Chronic thromboembolic pulmonary hypertension. In: Wagner TOF,
16 Montani D, Kularatne M, Jutant E-M, et al. Pulmonary hypertension in orphan lung diseases. In: Wagner TOF,
17 Savale L, Robert F, Tu L, et al. Hepatopulmonary syndrome: a liver-induced oxygenation defect. In: Wagner TOF,
Disclosures: T.O.F. Wagner reports receiving the following, outside the submitted work: grants or contracts to the
University Hospital Frankfurt from the European Commission, the Innovation Fund of the Federal Joint Committee
(Germany), Bosch Stiftung, Christiane Herzog Stiftung, Amgen Oncology, AstraZeneca Oncology, Boehringer
Ingelheim, Bristol Meyers Squibb, Chiesi, CSL Behring, Ewimed, Fujifilm, Lilly, MSD, Mediolanum, Olympus, Pfizer
Oncology, Roche, Vitalaire, Leo, Medtronic, Covidien, Grifols, Medac Onkologie, Otsuka, Pierre Fabre, Aposan Dr.
Kü nzer GmbH, Chiesi, Mylan Healthcare, Nutrcia, PARI, TEVA, VERTEX, Vital/Aire and Zambon; payment or honoraria
from Boehringer Ingelheim GmbH, Germany, Dierks and Comp. GmbH, and Institut für Qualität und Wirtschaftlichkeit
im Gesundheitswesen (IQWiG); and support for attending meetings and/or travel from the University of Milan and the
University Hospital Frankfurt. T.O.F. Wagner reports unpaid board, society, committee or advocacy group activities for
rare respiratory diseases. M. Humbert reports receiving the following, outside the submitted work: grants or contracts
from Acceleron, AOP Orphan, Janssen, Merc and Shou Ti; consulting fees from Acceleron, Aerovate, Altavant, AOP
Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti and United Therapeutics; and payment or
honoraria for lectures, presentations, speakers ’ bureaus, manuscript writing or educational events from Janssen and
Merck. M. Humbert reports participation on a data safety monitoring boards or advisory boards for Acceleron,
Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. M. Wijsenbeek reports no personal
fees; the Erasmus MC received consultancy or speaker fees from AstraZeneca, Bristol Myers Squibb, CSL Behring,
Galapagos, Galecto, Horizon Therapeutics, Kinevant Sciences, Molecure, NeRRe Therapeutics, Novartis, PureTech
Health, Respivant and Thyron; and grants, from Boehringer Ingelheim, AstraZeneca/Daiichi-Sankyo and Hoffmann-La
Roche, outside the submitted work. M. Kreuter reports grants to Thoraxklinik from Boehringer Ingelheim and Roche
as well as consultancy and speaker fees from CSL Behring, Galapagos, Kinevant, Boehringer Ingelheim and Roche,
outside the submitted work. H. Hebestreit reports the following, outside the submitted work: grants or contracts
from Vertex Pharmaceuticals, Bavarian Ministry of Science, and Innovation Fund of the Federal Joint Committee
(Germany); payment or honoraria from RG Gesellschaft für Information und Organisation mbH, Ärztefortbildung
AGPAS, Springer Verlag, Chiesi and Alexion; support for attending meetings and/or travel from University of
Edinburgh; unpaid board, society, committee or advocacy group for Deutsche Gesellschat für Kinder- und
Jugendmedizin (German Society for Pediatrics and Adolescent Medicine), Chair of the Committee for Rare Diseases,
and Working Group of Centers for Rare Diseases in Germany, Speaker.
https://doi.org/10.1183/2312508X.10009923 xiii
List of abbreviations
ANCA antineutrophil cytoplasmic autoantibodies

BAL bronchoalveolar lavage
CT computed tomography
DLCO diffusing capacity of the lung for carbon monoxide
FVC forced vital capacity
GM-CSF granulocyte–macrophage colony stimulating factor
HRCT high-resolution CT
ILD interstitial lung disease
MRI magnetic resonance imaging
PAS periodic acid–Schiff
PFT pulmonary function test/ing
PH pulmonary hypertension
Chapter 1
How to identify rare diseases of the

respiratory system
Helge Hebestreit1,2, Florian Gahleitner3, Simon Veldhoen4 and Matthias Griese5
1
Pediatric Pulmonology & Cystic Fibrosis, Children’s Hospital, University Hospital Würzburg, Würzburg, Germany.
2
European Reference Network for Rare Diseases of the Respiratory System (ERN-LUNG), Frankfurt, Germany.
3
Paediatric Respiratory and Sleep Medicine, Royal Hospital for Children & Young People, Edinburgh, UK. 4Division
of Pediatric Radiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and
Humboldt-Universität zu Berlin, Berlin, Germany. 5Dept of Paediatric Pneumology, Dr von Hauner Children’s
Hospital, German Center for Lung Research, University of Munich, Munich, Germany.
Corresponding author: Helge Hebestreit (hebestreit@uni-wuerzburg.de)
Cite as: Hebestreit H, Gahleitner F, Veldhoen S, et al. How to identify rare diseases of the respiratory system. In:
Sheffield, European Respiratory Society, 2023; pp. 1–9 [https://doi.org/10.1183/2312508X.10017122].
@ERSpublications
Rare lung diseases can present with variable phenotypes and may mimic common conditions. Being
suspicious and integrating diagnostic information employing “crowd intelligence” may provide the highest
diagnostic yield, enabling early and targeted therapy. https://bit.ly/ERSM100
ISSN: 2312-5098.
Diagnosing a rare disease of the respiratory system may be straightforward, for example with positive
neonatal screening or typical radiographic findings. However, in many cases, only unspecific signs and
symptoms are present. Among other clues, a suspicious family history, an atypical clinical course or a
poor response to treatment may trigger first thoughts about an underlying rare condition. Integrating
information from medical history, clinical signs, laboratory values, BAL findings, whole-exome or whole-
genome sequencing, PFTs, imaging and/or histology is usually required to establish a diagnosis. Case
conferences may prove essential in the process. This chapter highlights important elements, from medical
history to diagnostic tools and data integration, for diagnosing a rare disease of the respiratory system.
Introduction
In most European countries, rare diseases in general are defined as health conditions affecting
fewer than 1 in 2000 residents. The large group of rare lung diseases includes three main
categories: congenital malformations, airway diseases and diffuse parenchymal lung diseases
(or ILDs) (table 1) [1]. The latter are subcategorised into lung native conditions, caused mainly
by monogenetic disorders, and systemic disease-related disorders, which are often the
pulmonary manifestation of multisystem diseases such as idiopathic rheumatoid arthritis,
ulcerative colitis or Marfan syndrome. Further exposure-related and vascular disorders are also
differentiated. In all these groups of conditions, the disorders can be genetically caused,
predisposed diseases or acquired conditions (table 1) [1].
Thus, the spectrum of clinical presentations and optimal diagnostic approach vary widely from case to
case. However, it is important to classify each patient’s diagnosis with as much granularity as possible.
https://doi.org/10.1183/2312508X.10017122 1
ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM
TABLE 1 Overview and categorisation of rare pulmonary diseases
Category Examples
Congenital malformations Congenital pulmonary airway malformation, sequestration,

(gross structural abnormalities) bronchogenic cyst
Airway disorders Cystic fibrosis, primary ciliary dyskinesia
ILDs (diffuse parenchymal)
Lung native parenchymal disorders Alveolar capillary dysplasia, surfactant deficiency disorders
(SFTPC, ABCA3)
Systemic disease-related disorders Connective tissue-related ILDs, telomerase deficiencies, pulmonary
alveolar proteinosis due to immunodeficiency
Exposure-related disorders Hypersensitivity disorder, drug-induced ILD
Vascular disorders Diffuse alveolar haemorrhage, primary PH
SFTPC: surfactant protein C; ABCA3: ATP-binding cassette subfamily A member.
This chapter outlines some general approaches for individuals with signs and symptoms
suggestive of a pulmonary disease or involvement, and summarises the advantages and possible
pitfalls of diagnostic tools. Specific tests to confirm a particular diagnosis of a rare condition,
such as the sweat test, will not be covered.
Clinical clues
The diagnosis of a rare respiratory disease can potentially be straightforward, as in many cases
with easily recognisable congenital malformations (identified on antenatal ultrasound screening)
or in infants identified by newborn screening programmes (i.e. cystic fibrosis). However, other
conditions such as bronchogenic cysts or primary ciliary dyskinesia (PCD) may present
clinically as common conditions such as recurrent bronchitis, and thus diagnosis may be
delayed for many years. A lack of awareness and education among health professionals has
been highlighted as a possible cause for diagnostic delays of rare respiratory diseases [2].
Indeed, the European Lung White Book states that “Improved knowledge of the main features of
rare diseases is a real ethical duty for all respiratory physicians [3].”
The following points from medical history, clinical examination and/or PFTs should raise
suspicion of a rare disease of the respiratory tract: 1) a family history or parental consanguinity;
2) exposure to rare infections, toxic agents or other environmental factors (e.g. tuberculosis,
asbestos, pigeons); 3) signs and symptoms indicating a multiorgan disease; 4) tachypnoea/
cyanosis in the absence of an acute infection; 5) no or less than expected improvement with
standard treatment; and 6) a restrictive pattern in PFTs.
Measures of respiratory function at rest and during exercise

Spirometry and body plethysmography allow classification of ventilatory impairments
(i.e. obstruction and/or restriction) [4]. Typical patterns may be suggestive of a certain health
condition but cannot in isolation confirm or exclude a particular diagnosis without integrating
medical history and additional clinical findings. Importantly, all measures of respiratory function
may be normal, despite the presence of a rare lung disease. However, measures of respiratory
function can provide prognostic information [5], and repeated measurements are important to
monitor the progression of a rare respiratory disease.
2 https://doi.org/10.1183/2312508X.10017122
IDENTIFYING RARE DISEASES | H. HEBESTREIT ET AL.
Gas-exchange measures and full cardiopulmonary exercise testing can add further pieces of the
puzzle to a definitive diagnosis but again are not specific enough to establish a diagnosis in
isolation. A standardised exercise test may, however, suggest certain health conditions. For
example, if oxygen saturation drops with progressive exercise and does not respond significantly
to supplemental oxygen, a condition with right-to-left shunts of pulmonary blood flow may be
suspected, for example hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu disease)
(figure 1) or hepatopulmonary syndrome.
Laboratory values
Blood values may help to differentiate between groups of rare lung conditions or suggest a
certain disease but are rarely sufficient to establish a firm diagnosis. Even in α1-antitrypsin
deficiency, it is recommended that a low blood level is confirmed with a second independent
test (i.e. by genotyping) [6]. However, markers of inflammation such as C-reactive protein, and
erythrocyte sedimentation rate, differential blood count, abnormal immunoglobulin levels and
more specific laboratory values such as elevated autoantibody levels (i.e. ANCA,
anti-glomerular basement membrane (anti-GBM)) [7–9], detection of antigen-specific IgG
antibodies [10], increased levels of IgG4 [11, 12] or high angiotensin-converting enzyme levels
⩾150% of the upper limit of normal may support focusing the evaluation further [10, 13, 14].
a) Flow L·s–1 b)
c)
4 2 0 2 4 160 Suppl. O2 100
F/V in F/V ex 6 L·min–1
120 Room air 90
Power, W
TLC SpO2, %
2 80
1 80
ITGV
70
1 40
RV
Vol, L Time, s
60
Pred Meas
0 50
0 2 4 6 8 –2 0 2 4 6 8 10 12
Time, min
d) e) f)
FIGURE 1 Evaluation of a 13-year-old girl who presented with dyspnoea, cough and thoracic pain on exertion.
“Blue lips” were also reported with strenuous exercise. The family history was negative for bronchial, pulmonary
and vascular diseases. a) Pulmonary volumes and flow–volume (F/V) loops with spirometry. There was no sign of
bronchial obstruction or restrictive lung disease. b) Oxygen (O2) saturation (SpO2) during two standardised
progressive cycling tasks, one with room air (black line) and the other with supplemental O2 (6 L·min−1). There
was a significant drop in SpO2 with exercise, even with supplemental O2. c) Chest radiograph showing some
opacity in the right upper thorax (indicated by arrowheads). d) Coronal CT scan with vascular malformation in
the right upper lobe. e, f ) Tilted CT images reconstructed from low-dose CT indicating pulmonary arteriovenous
malformations. The diagnosis of hereditary haemorrhagic telangiectasia was confirmed, and the father was
subsequently also diagnosed. TLC: total lung capacity; ITGV: intrathoracic gas volume; RV: residual volume; Pred:
predicted; Meas: measured.
https://doi.org/10.1183/2312508X.10017122 3
a) b) c)
FIGURE 2 Radiographic findings of congenital pulmonary airway malformation (CPAM) in a 1-week-old boy. The
diagnosis was suspected from a prenatal ultrasound. a) The chest radiograph demonstrates cystic
hyperlucencies in the left upper and lower field with consecutive shift of the mediastinal structures to the right
hemithorax. b, c) CT shows cysts of varying sizes in the enlarged left lower lobe consistent with CPAM. Further
evaluation is required to distinguish between CPAM type 1 and CPAM type 4, although the radiographic finding
of mediastinal shift and a cyst >8 cm in diameter (not fully visible in b) might hint towards CPAM type 4 [16].
Imaging
Diagnostic imaging is usually required as part of the algorithm to diagnose a rare lung disease. The
method of imaging chosen depends on the medical history and clinical findings, and thus on the
clinical suspicion for a particular disease or disease group. Some rare lung diseases may be
suspected or even diagnosed at fetal imaging [15]. Postnatally, it is certainly widely accepted that a
chest radiograph should be obtained as a baseline investigation when a lung disease is suspected. In
some rare disease entities, such as congenital malformations including congenital pulmonary airway
malformation (CPAM) and lobar emphysema, the diagnosis can often be made based on a
conventional chest radiograph (figures 2 and 3). Here, the need for cross-sectional imaging may
arise in the course of decision making and planning for surgical resection, for which a multidetector
CT (MDCT) is regularly used. Contrast-enhanced MDCT helps to diagnose malformations of the
pulmonary vessels such as pulmonary sequestration, and to classify the subtype [17].
Besides congenital malformations, another relevant group of rare lung diseases is categorised
under the term ILD or diffuse parenchymal lung disease, which are used synonymously. The
a) b) c)
FIGURE 3 Radiographic findings in a 17-month-old boy with lobar emphysema presenting with a history of
recurrent bronchopulmonary infections. a) A chest radiograph demonstrates only a subtle hyperlucency in the
upper left field. b, c) CT shows high-grade congenital stenosis of the left upper lobe bronchus (arrows) with
consecutive lobar overinflation leading to hyperlucency of the left upper lobe.
4 https://doi.org/10.1183/2312508X.10017122
term encompasses a heterogeneous group of lung diseases originating in the pulmonary

interstitium, which are characterised by overlapping clinical, radiological, physiological and
pathological features [18].
For ILD subtypes, which preferentially occur in childhood and adolescence, the term “chILD”
(childhood ILD) was coined to memorise the conditions more easily. A recent classification
integrates ILD and chILD [19], as many of the chILD conditions now reach adulthood or are
diagnosed at that age. ILD and chILD require MDCT for diagnosis and classification. For
imaging, low-dose CT with a radiation exposure of <2 mSv is regularly used where possible [20].
Numerous ultra-low-dose protocols with sub-mSv exposure levels have been presented, and their
diagnostic performance in the context of ILD has been discussed [21]. In general, MDCT scans
used to assess ILD are evaluated for the presence of certain changes that may indicate ILD.
Attenuation changes include ground-glass opacities, consolidation, mosaic attenuation and crazy
paving, emphysema and cysts. Reticular changes include septal thickening and honeycombing,
whereas nodular changes imply the presence of small parenchymal nodules. The distribution of
the above-mentioned CT findings may indicate specific abnormalities and is an essential part of
image analysis [22]. However, in most rare lung diseases, radiological findings overlap
considerably, so that a specific diagnosis can rarely be made on the basis of the CT scan alone. In
most diseases and cases, imaging is only one diagnostic component that must be combined with
information from other diagnostic procedures and clinical findings to reach a definitive diagnosis.
In recent years, the importance of MRI of the lung has increased significantly and it is regularly
used by expert centres to assess progression in specific diseases [23, 24]. In particular, newer
ultra-short echo time sequences are currently being clinically evaluated, which allow better
visualisation of the lung parenchyma through a higher signal yield. The role of MRI in the
evaluation of rare lung diseases is expected to continue to increase. Considering the
concomitant reduction in medical radiation exposure, this development is most welcome.
BAL
Flexible bronchoscopy with BAL is a commonly used tool for the paediatric and adult
respiratory physician to gain diagnostic information. It can either be the main diagnostic tool or
provide additional information to clinical, laboratory and imaging findings in the diagnostic
process. Targeting one of the most affected lung lobes is recommended [25].
In many instances, BAL is used to determine the airspace pattern of inflammation and for
microbiological analysis (microscopy, culture and PCR). Tests are carried out for specific
pathogens such as viruses, fungi, (non)tuberculous mycobacteria and, in the immunocompromised
host, Pneumocystis jirovecii and cytomegalovirus. Pathological analysis with Oil Red O staining
for fat-laden macrophages can add information about the likelihood of aspiration causing or
contributing to lung disease [25]. Fat-laden macrophages may also be found in the context
of lipoid pneumonia, which can be caused by electronic cigarette use and inhalation of
tetrahydrocannabinol-containing oils [26]. Alveolar macrophages from cigarette smokers are
significantly enlarged and contain inclusion bodies [27].
BAL has a specific diagnostic value in certain rare ILDs including pulmonary haemorrhage
syndromes (Prussian blue staining to show haemosiderin in alveolar macrophages) [28] and
alveolar proteinosis (PAS staining, milky BAL fluid, foamy macrophages) [29], where both
clinical presentation and HRCT findings may be nonspecific. The differential diagnosis of
diffuse haemorrhage syndromes is, however, significant and other investigations must be
considered to establish the cause of bleeding.
https://doi.org/10.1183/2312508X.10017122 5
The differential cell counts can add weight to the likely diagnosis or rule out rare lung
diseases such as eosinophilic lung disease/pneumonia (eosinophils >25%), hypersensitivity
pneumonitis and sarcoidosis (both with lymphocytosis >25% but different CD4+/CD8+ ratios,
which are usually, but not always, decreased in hypersensitivity pneumonitis and significantly
elevated in sarcoidosis) [27]. If Langerhans cell histiocytosis is part of the differential
diagnosis, CD1a-positive or Langerin-positive cells should be specifically determined (by
immunocytochemistry, immunofluorescence or flow cytometry using monoclonal antibodies),
but Langerhans cells in low proportions can also be seen in other conditions [27]. As BAL
differential cell counts appear to differ between healthy children and adults, BAL findings
should also be interpreted with respect to available reference data [30–32].
To advance the diagnosis of children’s ILDs and diffuse lung diseases, research groups have
looked at aptamer-based proteomics to identify proteins and related pathways in BAL fluid, as
well as BAL cytokine profiles [33, 34]. Most recently, the role of exosomes obtained via BAL
has been explored in various types of lung disease including sarcoidosis and idiopathic
pulmonary fibrosis [35].
Histology
Lung biopsies can confirm a suspected diagnosis in several rare pulmonary conditions, such as
hypersensitivity pneumonitis and idiopathic pulmonary fibrosis [10, 32], or multiorgan
conditions with ( pure) lung involvement, such as IgG4-associated diseases, granulomatosis with
polyangiitis and anti-GBM disease [9, 11, 36]. In suspected sarcoidosis, if the diagnosis cannot
be made in specific clinical scenarios, endobronchial ultrasound transbronchial needle aspiration
biopsy of hilar lymph nodes is diagnostic in most cases [14, 37]. However, nonpulmonary tissue
may be collected in multiorgan diseases if the procedure appears more feasible/less invasive
and/or more diagnostically promising [14]. In evaluation for PCD, nasal brushing or sampling
of tracheobronchial mucosa is part of the diagnostic work-up, which may include electron
microscopy, ciliary beat pattern analysis and immunostaining [38].
Biopsies of lung tissue are typically taken either transbronchially or during video-assisted
thoracoscopy. While the former technique is less invasive, the latter has a higher diagnostic
yield. In small children, thoracotomy is sometimes performed to obtain sufficient samples of the
affected lung tissue.
Next-generation sequencing
In several rare respiratory diseases such as α1-antitrypsin deficiency and cystic fibrosis, genetic
testing has long been part of the diagnostic work-up and is even currently used in newborn
screening programmes. In PCD, the diagnostic algorithms suggested by the European Respiratory
Society and American Thoracic Society both include genetic testing, at least as an option to
confirm diagnosis [38, 39]. Genetic testing is recommended for neonates and infants with unclear
ILD after relatively common conditions have been excluded [1, 25, 40].
If a rare respiratory disease is suspected, especially in children, and there is no direct clinical clue,
next-generation sequencing including whole-exome and whole-genome sequencing should be
considered. In ultra-rare conditions or for an atypical clinical phenotype, genetic testing may be the
best means to obtain a conclusive early diagnosis, thereby avoiding unnecessary invasive procedures.
Traditionally considered only at the end of a diagnostic workflow, next-generation sequencing

technologies with the potential for rapid discovery of novel disease-associated genes and yield
6 https://doi.org/10.1183/2312508X.10017122
of a genetic diagnosis have gained increasing importance in the diagnostic work-up and
therefore are often used earlier now than in the past.
Artificial intelligence and clinical decision support systems

To date, artificial intelligence (AI) techniques such as machine learning are not widely used to
support diagnosis of a rare condition of the respiratory system, but many projects are currently
addressing this topic. Regarding diagnostic imaging, many proof-of-concept studies showing
the potential of AI techniques have been published [1, 25, 41, 42]. Large, anonymised,
open-source databases of pulmonary imaging are being created that will serve as the data
basis for sophisticated machine-learning algorithms addressing diagnosis and monitoring of
specific conditions such as ILD in the future [41–43]. For histopathological evaluation of
lung tissue, machine-learning algorithms have also been employed focusing mainly on lung
tumours and the detection of tuberculosis [44]. Some algorithms have also been trained to
estimate prognosis.
Several clinical decision support systems have been developed to facilitate diagnosing a rare
condition [45]. For example, FindZebra was developed especially for rare diseases and offers a
search algorithm based on signs and symptoms entered as free text [46]. Advanced searches
including, for example, age or laboratory values are available. Based on the information entered,
a list of potential differential diagnoses and links to additional information are provided [47].
Diagnosis with the best fit to the search terms are listed first in the output. Another tool, the
Phenomizer, is based on the human phenotype ontology to classify clinical and laboratory
findings and focuses on hereditary conditions. The algorithm provides p-values for the
likelihood of diagnoses and thus gives a ranking [48, 49]. There is no thorough evaluation of
the performance of clinical decision support systems on rare pulmonary diseases. In a
comparison among Google, PubMed, OMIM and FindZebra, searching for a diagnosis in 56
rare disease cases in 2014, FindZebra performed best in including the correct diagnosis among
the top 10 and top 20 list (59% and 64%, respectively) [49]. For pulmonary diseases, the
respective numbers were 56.8% and 70.5%. However, the accuracy of these systems is lower if
two inherited disorders coexist in a single person [50].
Case conferences
In complex cases, especially those with unusual presentation, case conferences are valuable in
assessing all available information, identifying additional differential diagnoses and
determining the next most promising diagnostic steps. For chILD, a peer review of cases has
been established to pool and increase expertise, and to determine the natural history of such
rare conditions [50]. Evaluation of this paediatric web-based system (www.childeu.net)
showed that the diagnosis reached by the referring team was not confirmed by peer review in
13% of submitted cases. Among these, the diagnosis initially given was wrong (27%) or
imprecise (50%), or significant information was added (23%). Beyond initial multidisciplinary
case discussion, a continuing updating of the long-term disease course is supported by the
system [51].
Case conferences on a national or international level are supported by specifically developed

software solutions following European data protection legislation. In the European Community,
the Clinical Patient Management System (CPMS) is available for such conferences through the
European Reference Networks (ERN-LUNG). Patient information can be entered by any of the
healthcare providers in the network, and the network coordinator can also provide a guest status
for nonmembers to ask for advice.
https://doi.org/10.1183/2312508X.10017122 7
Conclusion
Rare lung diseases can present with variable phenotypes and may mimic common conditions.
Being suspicious and integrating information from past medical and family history, physical
examination, PFTs, imaging and additional, sometimes invasive, diagnostic procedures is
usually required to confirm a diagnosis. In complex cases, “crowd intelligence” employing case
conferences may provide the highest diagnostic yield, enabling early and targeted therapy.
References
1 Griese M. Etiologic classification of diffuse parenchymal (interstitial) lung diseases. J Clin Med 2022; 11: 1747.
2 Requena-Fernandez MA, Dasi F, Castillo S, et al. Knowledge of rare respiratory diseases among paediatricians
and medical school students. J Clin Med 2020; 9: 869.
3 Rare and orphan lung diseases. In: Gibson J, Loddenkemper R, Sibille Y, et al., eds. European Lung White Book.
4 Stanojevic S, Kaminsky DA, Miller MR, et al. ERS/ATS technical standard on interpretive strategies for routine
lung function tests. Eur Respir J 2022; 60: 2101499.
5 Hebestreit H, Hulzebos EHJ, Schneiderman JE, et al. Cardiopulmonary exercise testing provides additional
prognostic information in cystic fibrosis. Am J Respir Crit Care Med 2019; 199: 987–995.
6 Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in
the adult. Chronic Obstr Pulm Dis 2016; 3: 668–682.
7 Groh M, Pagnoux C, Baldini C, et al. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA)
Consensus Task Force recommendations for evaluation and management. Eur J Intern Med 2015; 26: 545–553.
8 Shiroshita A, Oda Y, Takenouchi S, et al. Accuracy of anti-GBM antibodies in diagnosing anti-glomerular
basement membrane disease: a systematic review and meta-analysis. Am J Nephrol 2021; 52: 531–538.
9 Robson JC, Grayson PC, Ponte C, et al. 2022 American College of Rheumatology/European Alliance of
Associations for Rheumatology classification criteria for granulomatosis with polyangiitis. Arthritis Rheumatol
2022; 74: 393–399.
10 Raghu G, Remy-Jardin M, Ryerson CJ, et al. Diagnosis of hypersensitivity pneumonitis in adults. an official ATS/
JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2020; 202: e36–e69.
11 Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European League Against
Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020; 79: 77–87.
13 Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An official American Thoracic
Society clinical practice guideline. Am J Respir Crit Care Med 2020; 201: e26–e51.
14 Trisolini R, Spagnolo P, Baughman RP. Principles of diagnosis. In: Bonella F, Culver DA, Israël-Biet D, eds.
Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 57–74.
15 Sintim-Damoa A, Cohen HL. Fetal imaging of congenital lung lesions with postnatal correlation. Pediatr Radiol
2022; 52: 1921–1934.
16 Wu H, Tian J, Li H, et al. Computed tomography features can distinguish type 4 congenital pulmonary airway
malformation from other cystic congenital pulmonary airway malformations. Eur J Radiol 2020; 126: 108964.
17 Lee EY, Dorkin H, Vargas SO. Congenital pulmonary malformations in pediatric patients: review and update on
etiology, classification, and imaging findings. Radiol Clin North Am 2011; 49: 921–948.
18 Schwarz MI, King TE Jr. Interstitial Lung Disease. 5th Edn. Shelton, People’s Medical Publishing House, 2011.
19 Griese M. Chronic interstitial lung disease in children. Eur Respir Rev 2018; 27: 170100.
20 Larke FJ, Kruger RL, Cagnon CH, et al. Estimated radiation dose associated with low-dose chest CT of
average-size participants in the National Lung Screening Trial. AJR Am J Roentgenol 2011; 197: 1165–1169.
21 Taekker M, Kristjansdottir B, Graumann O, et al. Diagnostic accuracy of low-dose and ultra-low-dose CT in
detection of chest pathology: a systematic review. Clin Imaging 2021; 74: 139–148.
22 Elicker BM, Webb WR. Fundamentals of High-Resolution Lung CT: Common Findings, Common Patterns,
Common Diseases and Differential Diagnosis. Philadelphia, Lippincott Williams & Wilkins, 2018.
23 Hatabu H, Ohno Y, Gefter WB, et al. Expanding applications of pulmonary MRI in the clinical evaluation of lung
disorders: Fleischner Society position paper. Radiology 2020; 297: 286–301.
24 Dournes G, Walkup LL, Benlala I, et al. The clinical use of lung MRI in cystic fibrosis: what, now, how? Chest
2021; 159: 2205–2217.
25 Bush A, Cunningham S, de Blic J, et al. European protocols for the diagnosis and initial treatment of interstitial
lung disease in children. Thorax 2015; 70: 1078–1084.
26 Beck LR, Landsberg D. Lipoid Pneumonia. Treasure Island, StatPearls Publishing. www.ncbi.nlm.nih.gov/books/
NBK554577/
27 Stanzel F. Bronchoalveolar Lavage. In: Ernst A, Herth FJF, eds. Principles and Practice of Interventional
Pulmonology. New York, Springer Science+Business Media, 2013; pp. 165–176.
8 https://doi.org/10.1183/2312508X.10017122
28 de Lassence A, Fleury-Feith J, Escudier E, et al. Alveolar hemorrhage. Diagnostic criteria and results in 194
immunocompromised hosts. Am J Respir Crit Care Med 1995; 151: 157–163.
29 Maygarden SJ, Iacocca MV, Funkhouser WK, et al. Pulmonary alveolar proteinosis: a spectrum of cytologic,
histochemical, and ultrastructural findings in bronchoalveolar lavage fluid. Diagn Cytopathol 2001; 24: 389–395.
30 Picinin IF, Camargos PA, Marguet C. Cell profile of BAL fluid in children and adolescents with and without lung
disease. J Bras Pneumol 2010; 36: 372–385.
31 Ratjen F, Bredendiek M, Brendel M, et al. Differential cytology of bronchoalveolar lavage fluid in normal
children. Eur Respir J 1994; 7: 1865–1870.
32 Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/
ALAT clinical practice guideline. Am J Respir Crit Care Med 2018; 198: e44–e68.
33 Deterding RR, Wagner BD, Harris JK, et al. Pulmonary aptamer signatures in children’s interstitial and diffuse
lung disease. Am J Respir Crit Care Med 2019; 200: 1496–1504.
34 Popler J, Wagner BD, Tarro HL, et al. Bronchoalveolar lavage fluid cytokine profiles in neuroendocrine cell
hyperplasia of infancy and follicular bronchiolitis. Orphanet J Rare Dis 2013; 8: 175.
35 Liu Z, Yan J, Tong L, et al. The role of exosomes from BALF in lung disease. J Cell Physiol 2022; 237: 161–168.
36 McAdoo SP, Pusey CD. Anti-glomerular basement membrane disease. Clin J Am Soc Nephrol 2017; 12:
1162–1172.
37 Crombag LMM, Mooij-Kalverda K, Szlubowski A, et al. EBUS versus EUS-B for diagnosing sarcoidosis: the
International Sarcoidosis Assessment (ISA) randomized clinical trial. Respirology 2022; 27: 152–160.
38 Lucas JS, Barbato A, Collins SA, et al. European Respiratory Society guidelines for the diagnosis of primary
ciliary dyskinesia. Eur Respir J 2017; 49: 1601090.
39 Shapiro AJ, Davis SD, Polineni D, et al. Diagnosis of primary ciliary dyskinesia. An official American Thoracic
Society clinical practice guideline. Am J Respir Crit Care Med 2018; 197: e24–e39.
40 Kurland G, Deterding RR, Hagood JS, et al. An official American Thoracic Society clinical practice guideline:
classification, evaluation, and management of childhood interstitial lung disease in infancy. Am J Respir Crit
Care Med 2013; 188: 376–394.
41 Mekov E, Miravitlles M, Petkov R. Artificial intelligence and machine learning in respiratory medicine. Expert Rev
Respir Med 2020; 14: 559–564.
42 Soffer S, Morgenthau AS, Shimon, et al. Artificial intelligence for interstitial lung disease analysis on chest
computed tomography: a systematic review. Acad Radiol 2022; 29: Suppl. 2, S226–SS35.
43 Open Source Imaging Consortium (OSIC). www.osicild.org/ Date last accessed: 22 March 2023.
44 Viswanathan VS, Toro P, Corredor G, et al. The state of the art for artificial intelligence in lung digital
pathology. J Pathol 2022; 257: 413–429.
45 Schaaf J, Sedlmayr M, Schaefer J, et al. Diagnosis of rare diseases: a scoping review of clinical decision support
systems. Orphanet J Rare Dis 2020; 15: 263.
46 Dragusin R, Petcu P, Lioma C, et al. FindZebra: a search engine for rare diseases. Int J Med Inform 2013; 82:
528–538.
47 Kohler S, Oien NC, Buske OJ, et al. Encoding clinical data with the human phenotype ontology for
computational differential diagnostics. Curr Protoc Hum Genet 2019; 103: e92.
48 Kohler S, Gargano M, Matentzoglu N, et al. The human phenotype ontology in 2021. Nucleic Acids Res 2021; 49:
D1207–D1217.
49 Svenstrup D, Jorgensen HL, Winther O. Rare disease diagnosis: a review of web search, social media and
large-scale data-mining approaches. Rare Dis 2015; 3: e1083145.
50 Wadhwa RR, Park DY, Natowicz MR. The accuracy of computer-based diagnostic tools for the identification of
concurrent genetic disorders. Am J Med Genet A 2018; 176: 2704–2709.
51 Griese M, Seidl E, Hengst M, et al. International management platform for children’s interstitial lung disease
(chILD-EU). Thorax 2018; 73: 231–239.
Disclosures: H. Hebestreit reports the following, outside the submitted work: grants or contracts from Vertex
Pharmaceuticals, Bavarian Ministry of Science, and Innovation Fund of the Federal Joint Committee (Germany);
payment or honoraria from RG Gesellschaft für Information und Organisation mbH, Ärztefortbildung AGPAS,
Springer Verlag, Chiesi and Alexion; support for attending meetings and/or travel from University of Edinburgh;
unpaid board, society, committee or advocacy group for Deutsche Gesellschat für Kinder- und Jugendmedizin
(German Society for Pediatrics and Adolescent Medicine), Chair of the Committee for Rare Diseases, and Working
Group of Centers for Rare Diseases in Germany, Speaker. M. Griese reports the following, outside the submitted
work: grants or contracts from Böhringer Ingelheim; consulting fees from Böhringer Ingelheim; payment or
honoraria from Böhringer Ingelheim; support for attending meetings and/or travel from Böhringer Ingelheim; and
participation on a Data Safety Monitoring Board or Advisory Board for Böhringer Ingelheim. The remaining authors
have nothing to disclose.
https://doi.org/10.1183/2312508X.10017122 9
Chapter 2
Differential diagnosis of reciprocal mimics of

neoplastic and non-neoplastic pulmonary
disorders: multidisciplinary approaches
Nicolas Girard1,2,3
1
Institut du Thorax Curie Montsouris, Institut Curie, Paris France. 2Paris Saclay University, UVSQ, Versailles, France.
3
European Reference Network EURACAN, Centre Léon Bérard, Lyon, France.
Corresponding author: Nicolas Girard (nicolas.girard2@curie.fr)
Cite as: Girard N. Differential diagnosis of reciprocal mimics of neoplastic and non-neoplastic pulmonary
disorders: multidisciplinary approaches. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of
the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 10–22 [https://doi.org/
10.1183/2312508X.10017222].
@ERSpublications
A multidisciplinary approach is key for differential diagnosis in mimics of lung cancers https://bit.ly/ERSM100
ISSN: 2312-5098.
A variety of rare malignant and benign tumours that develop in the lung may have a propensity to mimic
rare lung disorders at some level of examination, as they can share clinical, imaging, pathological, and
even molecular and genomic features. Illustrative examples include bronchioloalveolar carcinoma, primary
pulmonary lymphomas and vascular sarcomas. Pseudotumours as well as neoplastic/non-neoplastic
borderline entities and true malignancies all share proliferation of fibroblastic and inflammatory cells.
Thus, multiple differential diagnoses need to be considered; among these, truly malignant as well as
neoplastic/non-neoplastic borderline entities have been identified. Molecular oncogenic alterations that are
observed in pulmonary carcinomas may be shared by borderline orphan lung diseases; these may be used
as diagnostic tools, as well as drivers of treatment decisions. Ultimately, as in cancer management,
multidisciplinary expertise and discussion are warranted for the management of reciprocal mimics of
neoplastic and non-neoplastic pulmonary disorders and pseudotumours, from diagnosis to definition of
pretreatment work-up and therapeutic approach. Implementing multidisciplinary expert and reference
networks is ongoing to ensure a high quality and equality of care for patients.
Introduction
A variety of rare malignant and benign tumours that develop in the lung may have a propensity to
mimic orphan lung diseases at some level of examination, as they can share clinical, imaging,
pathological, and even molecular and genomic features. Lung cancer is by far the most frequent
intrathoracic malignancy, so it is the first diagnosis to consider when facing a rapidly growing lesion
involving the lung, pleura and/or mediastinum, especially in smokers [1–4]. However, some
physicians may be aware of uncommon and rare neoplastic and non-neoplastic disorders that have a
propensity to mimic other pulmonary diseases at some level of examination, especially rare, orphan
entities that are less frequent for physicians, who may not be aware of differential diagnoses. Several
frequent and rare malignancies may share some of the clinical, radiological, pathological, and even
molecular and genomic features of non-neoplastic frequent or orphan lung disorders.
10 https://doi.org/10.1183/2312508X.10017222
MIMICS OF NEOPLASTIC AND NON-NEOPLASTIC PULMONARY DISORDERS | N. GIRARD
In addition, pseudotumours have been described in the thorax, corresponding to a

heterogeneous group of diseases characterised by a circumscribed fibrous tissue associated with
inflammatory and myofibroblastic cells [5, 6].
Molecular oncogenic alterations that are observed in pulmonary carcinomas may be shared by
borderline orphan lung diseases. Other rare pulmonary disorders may be considered as
borderline neoplastic/non-neoplastic entities, with a need for dedicated expertise in the fields of
both orphan pulmonary diseases and thoracic oncology.
Cancers mimicking orphan lung diseases at imaging

Malignant disorders may mimic some of the landmark orphan lung diseases, as these may
present radiologically as organising pneumonia, ILD or even multiple cysts. Awareness by
clinicians is key, as well as a strict pretreatment work-up, which may include molecular and
genomic analyses.
Cancer mimics of organising pneumonia

Organising pneumonia presents a classical diagnostic pitfall for lung cancer evaluation, as it can
occasionally present as a solitary mass-like lesion, leading to unnecessary diagnostic procedures
and even surgical resection, especially in heavy smokers who harbour a chronic lesion [7, 8]. In
patients treated for malignancies, anticancer drugs may also induce organising pneumonia.
Although usually not presenting as a focal lesion, organising pneumonia may also mimic
multiple pulmonary metastases. Currently, this occurs relatively frequently due to the use of
immunotherapy with immune checkpoint inhibitors [9, 10]. Even in patients with a history of
cancer, differential diagnosis is a clinical challenge, and may require multidisciplinary expert
discussion to distinguish organising pneumonia from recurrent cancer. 18F-fluorodeoxyglucose
positron emission tomography (18F-FDG-PET), as well as biopsy, may be required.
Conversely, some primary lung malignancies, including bronchioloalveolar carcinoma and

primary pulmonary lymphoma, share the organising pneumonia imaging pattern related to
tumour cell spread in the alveolar spaces, leading to a common radiological pattern of alveolar
opacities with air bronchograms.
Lung adenocarcinoma/bronchioloalveolar carcinoma

Bronchioloalveolar carcinoma has been described extensively elsewhere [11, 12]. It has usually
been a term referring to several clinical–radiological–pathological entities of lung
adenocarcinoma, with some diverse degree of noninvasive lepidic cell growth pattern, with no
pleural, stromal or vascular invasion. These include: 1) mixed-type invasive adenocarcinoma
with predominant lepidic growth, which has a very similar clinical and radiological presentation
to other nonsmall cell lung carcinomas; 2) adenocarcinoma in situ, a pure lepidic growth
proliferation; and 3) pneumonic-type lung adenocarcinoma (PTLA), which is a distinct clinical–
radiological–pathological entity. As stated, the filling of alveolar spaces is a landmark feature of
typical organising pneumonia. The 2015 World Health Organization classification of lung
adenocarcinoma deleted the term “bronchioloalveolar carcinoma” from the nomenclature [12].
Adenocarcinoma in situ, formerly known as pure bronchioloalveolar carcinoma, usually presents

as a localised coin-like lesion, ⩽3 cm in size, showing a predominant ground-glass pattern
usually surrounding a solid lesion, possibly with air bronchograms, and located at the periphery
of the lung parenchyma [12]. Molecularly, these tumours frequently harbour epidermal growth
factor receptor (EGFR) mutations; KRAS mutations are frequently found in cases of
mucin-producing tumours [12]. These tumours are more frequent in nonsmokers. Patients are
https://doi.org/10.1183/2312508X.10017222 11
usually asymptomatic. The lesion may show normal metabolic activity with 18F-FDG-PET [13].
Given the localised nature of adenocarcinoma in situ, treatment usually consists of upfront
surgery, sparing the lung parenchyma as much as possible.
PTLA is a clinical–radiological–pathological entity that is not strictly defined in the

histopathological adenocarcinoma classification [14]. The clinical criteria to make a diagnosis of
PTLA are as follows: 1) evidence of a pneumonia-like consolidation, defined as a homogeneous
opacity in the lung characterised by little or no loss of volume, disappearance of blood vessel
shadows and, sometimes, the presence of an air bronchogram; and 2) no concomitant bacterial
pneumonia or obstructive pneumonia due to an exophytic lesion occluding the lumen of the
main or lobar bronchi. The tumour is usually multifocal (65% of cases) and slow growing with
rare metastatic disease (5% of cases). It is associated with highly productive cough and
progressive restrictive respiratory failure (figure 1) [14]. The recommendations of treatment as
for other lung nonsmall cell carcinomas apply. Chemosensitivity is limited, given the
slow-growing pattern [15]. Molecular alterations are observed in about half of patients [16], and
may include EGFR and KRAS mutations, as well as ROS1 (tyrosine-protein kinase), RET
(rearranged during transfection) and NTRK (neurotrophic tyrosine receptor kinase) gene fusions:
these alterations predict the efficacy of targeted agents that are marketed or under investigation [16].
Comprehensive genomic profiling is mandatory in these cases.
Primary pulmonary lymphoma

Primary pulmonary lymphomas are historically strictly defined as lymphomas affecting one or
both lungs, without evidence of extrapulmonary involvement at the time of diagnosis [17–20].
However, extrapulmonary lesions are actually found in up to 30% of cases when extensive
work-up is conducted. Pulmonary lymphomas associated with small-sized satellite mediastinal
and/or systemic nodes are regarded by clinicians as originating from the lung; similarly, large
pulmonary lesions of lymphoma associated with a single extrapulmonary lesion are regarded as
a primary pulmonary lymphoma. The most frequent subtype is mucosa-associated lymphoid
tissue (MALT)-type lymphoma.
a) b)
FIGURE 1 Pneumonic-type lung adenocarcinoma. a) CT scan of a 66-year-old former female smoker, who
presented with progressive cough. Multiple bilateral alveolar condensation-like masses with irregular margins are
observed, some of which contain air bronchograms (arrow). b) 18F-fluorodeoxyglucose positron emission
tomography scan showing hypermetabolism of all of the lesions. A transparietal biopsy showed adenocarcinoma
cells with bronchioloalveolar and papillary architecture. KRAS mutation was observed. The patient received
platinum-based chemotherapy, followed by immunotherapy with a response sustained over 5 years, and
subsequently KRAS inhibitor.
12 https://doi.org/10.1183/2312508X.10017222
Pulmonary MALT lymphoma is referred to as nodal marginal-zone B-cell lymphoma, with

similar cytopathological features to other MALT lymphomas, especially gastric lymphoma [3].
At pathological examination, MALT lymphoma appears as a diffuse infiltrate of small
monomorphic lymphoid cells, with a typical lymphangitic growth pattern spreading along the
bronchovascular bundles and interlobular septa, and forming solid nodules that fill the alveolar
spaces and obliterate the normal lung architecture. Immunohistochemistry forms the basis of the
subtype classification, with expression of the pan-B-cell markers CD20 and CD79 and absence
of staining for CD5 and CD10. MALT lymphomas are associated with unique chromosomal
translocations, such as t(11;18)(q21;q21) resulting in a fusion of the apoptosis inhibitor API2
and MALT lymphoma translocation protein 1 (MALT1) genes, t(1;14) ( p22;q32) involving the
B-cell lymphoma/leukaemia 10 (BCL10) and IgH genes (which is overall much less frequent,
more specific to lung locations and never found in high-grade lymphoma) and t(14;18)(q32;q21)
involving the IgH and MALT1 genes [21, 22]. Clinically, MALT lymphoma has been observed
mainly in patients >45 years, with a slight male predominance, but it may also arise in younger
patients with underlying immunosuppression, or with inflammatory conditions such as Sjögren
disease or rheumatoid arthritis [17–20]. Less than 50% of patients are symptomatic, with
nonspecific symptoms including cough, dyspnoea and chest pain. Unlike the situation with
other lymphomas, systemic signs such as fever, swelling and weight loss are uncommon.
Association with IgM or IgG blood monoclonal gammopathy is observed in 30% of cases.
Radiologically, MALT lymphoma exhibits three imaging patterns, which are challenging for
differential diagnosis: 1) “pneumonia-like” alveolar consolidation with air bronchograms
typically localised in the middle lobe, which is the most frequent and suggestive (figure 2); 2) a
“tumour-like” appearance with a solitary circumscribed nodular opacity (30% of cases) and
possible central air bronchogram; and 3) an “infiltrative” pattern with diffuse poorly defined
ground-glass opacities, assumed to represent early-stage disease before tumour cells invade
alveolar spaces. Pleural effusion is unusual. Multiple cystic lesions may be observed, which
may be associated with light-chain deposition disease. About one-third of MALT lymphomas
are multifocal at the time of diagnosis, a presentation that may hamper the determination of the
primary pulmonary origin of the disease [23]. Pathological diagnosis requires a large, possibly
a) b)
FIGURE 2 Pulmonary primary mucosa-associated lymphoid tissue lymphoma in a 56-year-old man. a) Chest
radiography and b) a CT scan showed persistent alveolar opacities in the right lower lobe (arrows), despite
prolonged antibiotic therapy. Pathological examination of a surgical biopsy showed lymphoplasmacytic-like cells
of the marginal-zone lymphoma associated with amyloid deposits. The patient received treatment with
chlorambucil, which led to complete regression of the lesion. The patient is alive with no evidence of disease
after a follow-up of 9 years.
https://doi.org/10.1183/2312508X.10017222 13
surgical lung biopsy, because cytological examination of BAL fluid or fine-needle biopsy may
show the CD20+ B-cell infiltration but fail to exclude differential diagnoses. MALT1 gene
rearrangements may be identified on BAL [22]. In the majority of patients, the standard of care
is a combination of rituximab, an anti-CD20 antibody, with chlorambucil [24]. Several
alternative options have been described, from single-agent therapy with chlorambucil,
fludarabine or rituximab to combined cytotoxic agents used for diffuse large B-cell lymphomas.
Cancer mimics of ILDs

Cancer mimics of ILDs include frequent disorders, such as lymphangitis carcinomatosis, and
more orphan diseases, such as epithelioid haemangioendothelioma (EHE) and lymphomatoid
granulomatosis.
Lymphangitic carcinomatosis
Pulmonary lymphangitic carcinomatosis is a metastatic lung disease characterised by the diffuse
infiltration and obstruction of the pulmonary parenchymal system by tumour cells [25, 26].
Dyspnoea is usually the chief symptom [26]. Weight loss and cough are frequent, as well as
hypoxaemia. HRCT may show: 1) uneven thickening of bronchovascular bundles, from the
hilum to the periphery, that resembles Kerley B lines; 2) a more limited or diffuse peripheral
interlobular septal thickening producing polygonal arcades; and/or 3) a radiographic pattern
referred to as “beaded chain” or “string of pearls” thickening of interlobular septa [25]. These
patterns may be diffuse or localised, uni- or bilateral, and symmetric or not. Micronodules are
observed within the thickened septa. Asymmetric lymph node enlargement is seen in 30% of
patients. 18F-FDG-PET shows diffuse, or more linear or hazy areas of uptake.
Tumour cells of adenocarcinoma type are the most likely to produce lymphangitic
carcinomatosis, originating from the following primary anatomic locations: breast (33%),
stomach (29%), lung (15%), pancreas (4%) and prostate (3%) [25]. Survival is usually poor,
ranging from 3 to 6 months [25, 26].
In patients with cancer, lymphangitic carcinomatosis may also be confused with drug-induced
ILD from chemotherapy, targeted agents, immune checkpoint inhibitors or antibodies (drug
conjugated or not). Imaging patterns are nonspecific and may include ground-glass opacities
and interlobular septal thickening.
Lymphomatoid granulomatosis
Lymphomatoid granulomatosis is a malignant B-cell angiocentric and angiodestructive
lymphoproliferative disorder [27–29]. It is recognised as a true Epstein–Barr virus
(EBV)-related lymphoid malignancy. The lung is the most frequent location, but the disease
may also involve the brain, skin and liver [28]. Pathologically, large B-cells are infected with
EBV in 65% of cases, a fact that correlates with the grade of the lesion. Lymphomatoid
granulomatosis arises in middle-aged patients aged 40–50 years, with a male predominance.
Nearly all patients present with respiratory and systemic symptoms, consisting of cough,
dyspnoea, haemoptysis, chest pain, fever and weight loss. Peripheral and mediastinal
lymphadenopathy is absent. Prolonged immunosuppression is a frequent underlying condition.
The typical radiological presentation consists of multiple smooth bilateral nodules ranging from
2 to 10 cm, localised mainly in the lower lobes, exhibiting a peribronchovascular pattern and
mimicking multiple metastases (figure 3). As in other granulomatoses, convergent nodules may
migrate and form cavitated pseudotumoural masses [28, 29].
14 https://doi.org/10.1183/2312508X.10017222
Lymphomatoid granulomatosis is considered a low-grade or early-stage lymphoma, and a

histopathological grading system has been developed, based on the degree of cellular atypia and
necrosis, to predict the risk of evolution to high-grade lymphoma and to select patients for early
aggressive treatment [28].
EHE and angiosarcoma

EHE is a low- to intermediate-grade mixed epithelioid, endothelial and vascular tumour
[30, 31]. The lung is the most frequent extrahepatic location (10% of cases); EHE can also arise
from the liver (63% of cases), bone (8% of cases) and skin (6% of cases). Around 90% of
EHEs are caused by fusion of the transcriptional coactivator with a PDZ motif (TAZ) gene with
the calmodulin binding transcription activator 1 (CAMTA1) gene, a central nervous
system-specific transcription activator; the 10% of EHEs that lack the TAZ–CAMTA1 fusion
instead have fusion of the Yes-associated protein (YAP) and transcription factor E3 (TFE3)
genes [32]. EBV RNA sequences are detected in 90% of cases. Overlapping entities with
IgG4-related disease have been described. Clinically, 80% of cases of EHE are diagnosed in
white females. The tumour is asymptomatic in 50% of cases; when present, symptoms are
nonspecific and include pleuritic chest pain, nonproductive cough, dyspnoea and, rarely,
haemoptysis. On CT imaging, EHE appears either with bilateral slow-growing perivascular
multiple nodules, usually located adjacent to small vessels or bronchi, or with predominant
infiltrative ground-glass opacities with a micronodular pattern, mimicking carcinomatous
lymphangitis. EHE nodules usually range from 3 to 50 mm, and their number varies from 10 to
20 lesions. Nodules in patients with EHE may show increased uptake on 18F-FDG-PET.
Although there are a few reports of spontaneous remission, complete resection of all pulmonary
nodules is the only curative treatment of EHE, which is a slow-growing tumour. In contrast,
EHE is generally insensitive to chemotherapy (cisplatin based) or radiotherapy. Treatment with
rituximab or antiangiogenic kinase inhibitors, such as sorafenib or bevacizumab, has been
reported to be effective in isolated case reports [33, 34].
FIGURE 3 Lymphomatoid granulomatosis. Contrast-enhanced CT scan of a 67-year-old man, who developed

rapidly progressing dyspnoea, displayed in the lung windows, showing multiple small nodules distributed along
the bronchovascular bundles, and growing rapidly over a 3-month period. The patient received steroids for
6 months with improvement and sustained stabilisation.
https://doi.org/10.1183/2312508X.10017222 15
Angiosarcoma is a high-grade primary pulmonary vascular sarcoma considered to be a counterpart

of EHE. The clinical features of angiosarcoma are similar to EHE, but massive haemoptysis is
more frequent. The radiological features of angiosarcoma include multiple nodules with a typical
surrounding halo of ground-glass attenuation, with a specific “cauliflower-like” appearance on
T2-weighted MRI [35]. Management of angiosarcoma is not established. In immunocompromised
patients, reduction of immunosuppressive agents may reduce the burden of the disease.
Cancer mimics of multiple cystic/cavitary lung disorders

Multiple cystic lung disease is discussed in another chapter in this Monograph [36]. Metastastic
cancers of extrapulmonary origin may mimic multiple cystic lung disease when metastasising to
the lung, especially soft-tissue sarcomas including angiosarcomas [37, 38], leiomyosarcomas,
osteosarcomas and synovial sarcoma. Metastatic cysts may be associated with small-sized
nodules. Pathologically, tumour cells are usually observed in the wall of the cysts.
Cancer mimics of PH
Pulmonary artery sarcoma corresponds to an endoluminal polypoid or nodular tumour, which
spreads along the intima of the pulmonary artery. Leiomyosarcoma is the most frequent subtype
(60% of cases) [39–42]. Pulmonary artery sarcomas develop mainly in patients in their fifth to
sixth decade. Symptoms may mimic pulmonary embolism, with dyspnoea, chest pain, cough
and haemoptysis. The failure of anticoagulants in this setting, as well as the presence of
symptoms of weight loss and fever (arising in 40% of cases), may also suggest the diagnosis.
Imaging findings help differentiate between pulmonary artery sarcoma and pulmonary embolism
[40, 42]: a CT scan may show a polypoid filling defect in the pulmonary artery, but, in contrast
to thromboembolic disease, sarcoma forms a contiguously soft, smooth, tapering tissue, with
possible extravascular nodular spread in the parenchyma (40% of cases) and localised
ground-glass opacities (figure 4). Sarcoma also presents with a heterogeneous appearance
including areas of necrosis and haemorrhage, and with intense hyperactivity on 18F-FDG-PET.
MRI shows an intermediate to mildly increased signal on T1-weighted images, often with
heterogeneous enhancement, and T2-weighted images show an intermediate to diminished
signal relative to skeletal muscle; furthermore, the intravascular mass may be enhanced, a
feature not typically encountered with uncomplicated thromboembolic disease. Surgery is the
only potentially curative treatment and, even if performed emergently in the setting of acute
right-sided heart failure, allows resectability in 60–75% of cases [39, 41, 43]. Alternatively,
heart and lung transplantation may be an alternative option for unresectable tumours but has
rarely been reported. In contrast to soft-tissue sarcoma, prognosis is mainly related to tumour
location, because half of patients die as a result of progressive obstruction of the pulmonary trunk.
Lung “pseudo”-myofibroblastic tumours

Inflammatory myofibroblastic tumour (IMT) is the most representative entity of the pulmonary
pseudotumours [44] and encompasses a wide spectrum of lesions previously called
“inflammatory pseudotumour”, “fibroma”, “fibroxanthoma”, “fibrous histiocytoma”, “plasma-
cell/mast-cell/solitary granuloma”, “plasma-cell histiocytoma complex” or “pseudosarcomatous
tumour”. IMT appears as an intraparenchymatous, well-circumscribed mass of variable size.
Histologically, the tumour is made of an irregular proliferation of fibroblasts and myofibroblasts
intermixed with an infiltrate of inflammatory cells, mainly lymphocytes and plasma cells.
Myofibroblastic cells show no cellular atypia, no necrosis and only rare mitotic figures. The
concept of IMT as a true neoplasm has been debated. More recently, clonal gene rearrangements
have been observed, especially involving the anaplastic lymphoma kinase (ALK) and ROS1 genes
[45, 46]. ALK rearrangement is identified in <30% of pulmonary IMT cases, and most frequently
16 https://doi.org/10.1183/2312508X.10017222
FIGURE 4 Primary pulmonary artery sarcoma. Contrast-enhanced CT scan of a 79-year-old woman, showing
complete obstruction and enlargement of the pulmonary artery trunk. Hypermetabolism was detected by an
18
F-fluorodeoxyglucose positron emission tomography. The patient underwent pulmonary endarterectomy,
complete resection of the tumour and extensive left pneumonectomy. The patient died 25 months after surgery.
consists of the t(1;2)(q21;p23) translocation, implicating the tropomyosin 3 (TMP3) gene.

Vascular invasion, occurrence of recurrences in up to 25% of patients and the existence of
multifocal lesions favour the malignant process. IMT is also a consequence of immunological
disorders, which consist of EBV and human herpesvirus 8 infection of myofibroblastic cells [47],
and, of more relevance, IgG4 expression in polyclonal plasma cells extracted from intrathoracic
IMTs; such proliferation of IgG4-positive cells has also been associated with autoimmune
disorders, including sclerosing pancreatitis and retroperitoneal and mediastinal fibrosis [48]. IMTs
may also correspond to the more global entity of IgG4-related disease.
In contrast to its presentation at extrathoracic locations, pulmonary IMT is usually solitary. Surgery
is the primary treatment [49]. In nonoperable patients, corticosteroids may lead to a reduction in
the burden of the tumour, especially in predominantly plasma cell tumours and IgG4-positive
lesions. In recurrent or multifocal lesions, chemotherapy based on soft-tissue sarcoma regimens
may be effective. ALK inhibitors are effective in cases of ALK-rearranged IMT [46].
Similar to IMT, sclerosing mediastinitis and hyalinising granuloma both consist of tissue
infiltration by dense, collagen fibrosis-forming lamellar bands, interspersed with lymphocytes and
plasma cells [50, 51]. These two entities differ by their primary anatomic location: sclerosing
mediastinitis predominantly involves the mediastinum (figure 5), with possible extension to the
lung parenchyma; hyalinising granuloma occurs within the lung parenchyma without contiguous
involvement of the mediastinum. Again, overlap exists between these entities and other fibrosing
disorders such as IMT, retroperitoneal fibrosis and other IgG4-related disorders.
Borderline neoplastic/non-neoplastic disorders

Excluded from this chapter are benign tumours and preneoplastic conditions of the lung, which
have been reviewed extensively elsewhere [6]. Borderline malignant and nonmalignant disorders
may be considered benign, despite corresponding to true neoplasms or presenting with some
pathological or molecular characteristics of cancer, including clonal proliferation [52].
https://doi.org/10.1183/2312508X.10017222 17
a) b)
FIGURE 5 Sclerosing mediastinitis. a) CT scan of a 32-year-old woman who presented with progressive dyspnoea
and superior vena cava syndrome. Connective tissue proliferation has infiltrated the entire mediastinum. Surgical
biopsy was performed to make the diagnosis. b) Magnetic resonance angiography showed that the calibre of the
superior vena cava was reduced (arrow). An endoprosthetic tube was placed for palliation. The patient received
several lines of systemic therapies, including steroids, methotrexate and ultimately anaplastic lymphoma kinase
inhibitor.
Respiratory tract papillomatosis

Papillomas usually present in the upper respiratory tract but may rarely spread to the lung
parenchyma (<5% of cases) [53, 54]. Papillomas may exhibit imaging features similar to those
of lung cancer, including heterogeneous, cavitating or poorly defined masses. Pulmonary
papillomas may be solitary or multiple; if multiple, these are usually part of papillomatosis of
the upper respiratory and aerodigestive tract. As in other locations, the pathogenesis of
squamous papillomas is linked with human papillomavirus (HPV) infection, often acquired at
birth. Specifically, HPV-11 infection has been reported to bear a high risk of transformation of
papilloma to squamous-cell carcinoma [54]. Molecularly, loss of the tumour-suppressor genes
TP53 (tumour protein p53), RB (retinoblastoma) and P21 (cyclin-dependent kinase inhibitor 1)
has been reported in squamous-cell carcinomas originating from papillomas. Mutation of
HPV-11 with duplication of promoter and oncogene regions has been described in a case
responding to vorinostat [54]. 18F-FDG-PET may not be useful given the mild hypermetabolism
of high-grade papillomas. Given this uncertain malignant potential and the difficult differential
diagnosis with lung cancer, complete resection of papillomas is recommended if possible;
complete resection may not be possible in the setting of multiple and bilateral lesions. The role
of vaccines, antiangiogenic agents and antiviral treatment in preventing the evolution of
pulmonary papillomas is unclear.
Amyloid and nonamyloid immunoglobulin deposition disorders

Amyloidosis presents with variable clinical–radiological features. Lung lesions are observed in
30–80% of cases. Pulmonary amyloidosis may be localised or associated with systemic
amyloidosis. Pulmonary amyloid nodules usually consist of amyloid light chain, which is the
most common subtype of amyloidosis deposit, consisting of lambda light chains, and may mimic
malignancy [55, 56]. Further details are provided in another chapter of this Monograph [57].
Pulmonary Langerhans cell histiocytosis

Pulmonary Langerhans cell histiocytosis (LCH) is a heterogeneous disease defined by the
proliferation of Langerhans cells, corresponding to CD1a+ histiocytes exhibiting Birbeck
granules on electron microscopy [58]. LCH is believed to be related to an uncontrolled immune
response to an as-yet-undetermined stimulus, leading to the recruitment of Langerhans cells in
18 https://doi.org/10.1183/2312508X.10017222
the lung parenchyma. The true nature of LCH remains elusive. Strongly favouring the
hypothesis of a neoplastic disorder is the observation that Langerhans cells isolated from
patients with either pulmonary or disseminated LCH are clonal, and may harbour activating
serine/threonine-protein kinase B-Raf (BRAF) mutations, as well as mutation of the
mitogen-activated protein kinase kinase 1 (MAP2K1) pathway [59, 60]. Nevertheless,
proliferation of Langerhans cells remains low, cellular atypia are not found, Langerhans cells are
not proliferating in high-stage lesions and spontaneous regression may be observed. LCH is
discussed in more detail elsewhere in this Monograph [61].
Lessons learned: rare tumours versus orphan lung diseases

When facing any lung abnormality consistent with orphan disease or cancer, the primary
hypothesis for clinicians depends on the setting of their clinical practice; for example, thoracic
oncologists will primarily apply a lung cancer diagnostic pathway, while pulmonologists will
prioritise hypotheses of non-neoplastic disorders. Rare lung tumours and pseudotumours are
usually diagnosed in patients with a different clinical profile and a younger age, and who are
probably never-smokers. Given the frequent initial suspicion of lung cancer, most patients
undergo complete oncological work-up. 18F-FDG-PET is not usually helpful for differential
diagnosis. Small biopsies including frozen sections may not be sufficiently representative of the
tumour to ensure accurate histopathological diagnosis, especially in biphasic or composite
tumours, which could be misidentified as more frequent histotypes. The primary pulmonary
nature of some rare tumours may actually be difficult to establish, for example because of early
systemic spread, as for EHE, which presents with synchronous pulmonary and hepatic lesions in
20% of cases.
Sophisticated molecular studies, including flow cytometry and comprehensive genomic and
cytogenetic analyses, may have a critical role in making an accurate diagnosis of rare pulmonary
tumours, as the morphology may not be sufficient for classification and evaluation of tumour
grade. This is especially mandatory for lymphoma, IMT and sarcomas. Systematic
high-throughput genomic analyses, including DNA/RNA sequencing and possibly whole-exome
sequencing, is increasingly also used to identify deregulated molecular pathways, which is not
possible based on targeted, panel-based analyses designed for frequent tumours; this may lead
to discussion and assessment of potential treatment strategies based on targeted agents [62]. The
family history is of interest to understand possible predispositions, as well as occupational/
professional questionnaires to identify potential carcinogens; so far, limited data are available in
these areas for rare pulmonary tumours.
In Europe, the recent establishment of the European Reference Networks, such as ERN-LUNG
and EURACAN, has been helpful in providing an infrastructure to achieve the highest quality of
care for patients with such complex diagnoses, including pseudotumours, rare cancers and
borderline entities; a multidisciplinary tumour board across these networks is hosted by a
pan-European online platform called the Clinical Patient Management System, which allows
such discussions across all experts, with the aim of building a prospective database that will be
available for future research projects to achieve a better understanding of these entities.
Conclusion
A variety of rare malignant and benign tumours that develop in the lung may have a propensity
to mimic orphan lung diseases at some level of examination, as they can share clinical, imaging,
pathological, molecular and genomic features. Pseudotumours may be observed, corresponding
to a heterogeneous group of proliferating disorders characterised by circumscribed fibrous tissue
https://doi.org/10.1183/2312508X.10017222 19
and inflammatory cells, which may lead to multiple differential diagnoses. Molecular oncogenic
alterations that are observed in pulmonary carcinomas may also be shared by borderline orphan
lung diseases; these may be used as diagnostic tools, as well as drivers of treatment decision.
As in cancer management, multidisciplinary expertise and discussion is warranted for the

management of reciprocal mimics of neoplastic and non-neoplastic pulmonary disorders and
pseudotumours from diagnosis to definition of pretreatment work-up and therapeutic approach.
Implementing multidisciplinary expert and reference networks is ongoing to ensure a high level
of quality and equality of care of patients.
References
1 Girard N, Barbareschi M, Cordier J-F, et al. What is a rare tumour, and how should it be dealt with clinically? In:
Timens W, Popper HH, eds. Pathology of the Lung (ERS Monograph). Sheffield, European Respiratory Society, 2007;
pp. 85–133.
2 Miller DL. Rare pulmonary neoplasms. Semin Respir Crit Care Med 1997; 18: 405–415.
3 Travis WD, Brambilla E, Muller-Hermelink HK, et al. Pathology and genetics of tumors of the lung, pleura,
thymus, and heart. World Health Organization Classification of Tumors. Lyon, IARC Press, 2004.
4 Girard N, Cordier J-F. Pseudo-tumours and reciprocal mimics of neoplastic and non-neoplastic pulmonary
disorders. In: Cordier J-F, ed. Orphan Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society,
2011; pp. 341–365.
5 Eyden B, Banerjee SS, Shenjere P, et al. The myofibroblast and its tumors. J Clin Pathol 2009; 62: 236–249.
6 Borczuk AC. Benign tumors and tumorlike conditions of the lung. Arch Pathol Lab Med 2008; 132: 1133–1148.
7 Cordier JF. Cryptogenic organising pneumonia. Eur Respir J 2006; 28: 422–446.
8 Kloth C, Thaiss WM, Beer M, et al. The many faces of cryptogenic organizing pneumonia (COP). J Clin Imaging
Sci 2022; 12: 29.
9 Khunger M, Rakshit S, Pasupuleti V, et al. Incidence of pneumonitis with use of programmed death 1 and
programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of
trials. Chest 2017; 152: 271–228.
10 Nobashi TW, Nishimoto Y, Kawata Y, et al. Clinical and radiological features of immune checkpoint
inhibitor-related pneumonitis in lung cancer and non-lung cancers. Br J Radiol 2020; 93: 20200409.
11 Garfield DH, Cadranel JL, Wislez M, et al. The bronchioloalveolar carcinoma and peripheral adenocarcinoma
spectrum of diseases. J Thorac Oncol 2007; 1: 344–359.
12 Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American
Thoracic Society/European Respiratory Society international multidisciplinary classification of lung
adenocarcinoma. J Thorac Oncol 2011; 6: 244–285.
13 Kim TJ, Park CM, Goo JM, et al. Is there a role for FDG PET in the management of lung cancer manifesting
predominantly as ground-glass opacity? AJR Am J Roentgenol 2012; 198: 83–88.
14 Wislez M, Massiani MA, Milleron B, et al. Clinical characteristics of pneumonic-type adenocarcinoma of the lung.
Chest 2003; 123: 1868–1877.
15 Duruisseaux M, Baudrin L, Quoix E, et al. Chemotherapy effectiveness after first-line gefitinib treatment for
advanced lepidic predominant adenocarcinoma (formerly advanced bronchioloalveolar carcinoma): exploratory
analysis of the IFCT-0401 trial. J Thorac Oncol 2012; 7: 1423–1431.
16 Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
Nat Rev Cancer 2019; 19: 495–509.
17 Borie R, Wislez M, Antoine M, et al. Pulmonary mucosa-associated lymphoid tissue lymphoma revisited. Eur
Respir J 2016; 48: 1252.
18 Sanguedolce F, Zanelli M, Zizzo M, et al. Primary pulmonary B-cell lymphoma: a review and update. Cancers
(Basel) 2021; 13: 415.
19 Zhang MC, Zhou M, Song Q, et al. Clinical features and outcomes of pulmonary lymphoma: a single center
experience of 180 cases. Lung Cancer 2019; 132: 39–44.
20 Sirajuddin A, Raparia K, Lewis VA, et al. Primary pulmonary lymphoid lesions: radiologic and pathologic
findings. Radiographics 2016; 36: 53–70.
21 Zompi S, Couderc LJ, Cadranel J, et al. Clonality analysis of alveolar B lymphocytes contributes to the
diagnostic strategy in clinical suspicion of pulmonary lymphoma. Blood 2004; 103: 3208–3215.
22 Vela V, Juskevicius D, Dirnhofer S, et al. Mutational landscape of marginal zone B-cell lymphomas of various origin:
organotypic alterations and diagnostic potential for assignment of organ origin. Virchows Arch 2022; 480: 403–413.
20 https://doi.org/10.1183/2312508X.10017222
23 Thieblemont C, Berger F, Dumontet C, et al. Mucosa-associated lymphoid tissue lymphoma is a disseminated

disease in one third of 158 patients analyzed. Blood 2000; 95: 802–806.
24 Zucca E, Arcaini L, Buske C, et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up. Ann Oncol 2020; 31: 17–29.
25 Klimek M. Pulmonary lymphangitis carcinomatosis: systematic review and meta-analysis of case reports, 1970–
2018. Postgrad Med 2019; 131: 309–318.
26 Bruce DM, Heys SD, Eremin O. Lymphangitis carcinomatosa: a literature review. J R Coll Surg Edinb 1996; 41: 7–13.
27 Tanière P, Thivolet-Béjui F, Vitrey D, et al. Lymphomatoid granulomatosis – a report on four cases: evidence for
B phenotype of the tumoral cells. Eur Respir J 1998; 12: 102–106.
28 Melani C, Jaffe ES, Wilson WH. Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven
disorder. Blood 2020; 135: 1344–1352.
29 Balakrishnan P, Ing M, Househ Z, et al. Pulmonary lymphomatoid granulomatosis: an uncommon disease but
not to be forgotten – a single centre experience. Respirol Case Rep 2021; 9: e00789.
30 Woo JH, Kim TJ, Lee KS, et al. Epithelioid hemangioendothelioma in the thorax: clinicopathologic, CT, PET, and
prognostic features. Medicine 2016; 95: e4348.
31 Lau K, Massad M, Pollak C, et al. Clinical patterns and outcome in epithelioid hemangioendothelioma with or
without pulmonary involvement: insights from an internet registry in the study of a rare cancer. J Thorac Oncol
2011; 6: 651–652.
32 Lamar JM, Motilal Nehru V, Weinberg G. Epithelioid hemangioendothelioma as a model of YAP/TAZ-driven
cancer: insights from a rare fusion sarcoma. Cancers (Basel) 2018; 10: 229.
33 Ye B, Li W, Feng J, et al. Treatment of pulmonary epithelioid hemangioendothelioma with combination
chemotherapy: report of three cases and review of the literature. Oncol Lett 2013; 5: 1491–1496.
34 Mizota A, Shitara K, Fukui T. Bevacizumab chemotherapy for pulmonary epithelioid hemangioendothelioma
with severe dyspnea. Chest 2011; 140: 1312–1318.
35 Atasoy C, Fitoz S, Yiğit H, et al. Radiographic, CT, and MRI findings in primary pulmonary angiosarcoma. Clin
Imaging 2001; 25: 337–340.
36 Elia D, Caminati A, Tescaro L, et al. Diffuse cystic lung diseases including lymphangioleimyomatosis. In: Wagner TOF,
37 Traweek T, Rotter AJ, Swartz W, et al. Cystic pulmonary metastatic sarcoma. Cancer 1990; 65: 1805–1811.
38 Mahadeva R, Stewart S. Metastatic endometrial stromal sarcoma masquerading as pulmonary
lymphangioleiomyomatosis. J Clin Pathol 1999; 52: 147–148.
39 Parish JM, Rosenow EC 3rd, Swensen SJ, et al. Pulmonary artery sarcoma. Clinical features. Chest 1996; 110:
1480–1488.
40 Yi CA, Lee KS, Choe YH, et al. Computed tomography in pulmonary artery sarcoma: distinguishing features from
pulmonary embolic disease. J Comput Assist Tomogr 2004; 28: 34–39.
41 Mussot S, Ghigna MR, Mercier O, et al. Retrospective institutional study of 31 patients treated for pulmonary
artery sarcoma. Eur J Cardiothorac Surg 2013; 43: 787–793.
42 Assi T, Kattan J, Rassy E, et al. A comprehensive review on the diagnosis and management of intimal sarcoma
of the pulmonary artery. Crit Rev Hematol 2020; 147: 102889.
43 Alozie A, Werner D, Schafmayer C, et al. Management of pulmonary artery synovial sarcoma: the 3-step surgical
approach. Ann Thorac Surg 2022; 114: e443–e445.
44 Taylor MS, Chougule A, MacLeay AR, et al. Morphologic overlap between inflammatory myofibroblastic tumor
and IgG4-related disease: lessons from next-generation sequencing. Am J Surg Pathol 2019; 43: 314–324.
45 Snyder CS, Dell’Aquila M, Haghighi P, et al. Clonal changes in inflammatory pseudotumor of the lung: a case
report. Cancer 1995; 76: 1545–1549.
46 Butrynski JE, d’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor.
N Engl J Med 2010; 363: 1727–1733.
47 Gómez-Román JJ, Sánchez-Velasco P, Ocejo-Vinyals G, et al. Human herpesvirus-8 genes are expressed in
pulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). Am J Surg Pathol 2001; 25: 624–629.
48 Yamamoto H, Yamaguchi H, Aishima S, et al. Inflammatory myofibroblastic tumor versus IgG4-related sclerosing
disease and inflammatory pseudotumor: a comparative clinicopathologic study. Am J Surg Pathol 2009; 33:
1330–1340.
49 Fabre D, Fadel E, Singhal S, et al. Complete resection of pulmonary inflammatory pseudotumors has excellent
long-term prognosis. J Thorac Cardiovasc Surg 2009; 137: 435–440.
50 Flieder DB, Suster S, Moran CA. Idiopathic fibroinflammatory (fibrosing/sclerosing) lesions of the mediastinum:
a study of 30 cases with emphasis on morphologic heterogeneity. Mod Pathol 1999; 12: 257–264.
51 Rossi SE, McAdams HP, Rosado-de-Christenson ML. Fibrosing mediastinitis. Radiographics 2001; 21: 737–757.
52 Syred K, Morrison I. Benign tumours of the bronchopulmonary system. Histopathology 2021; 78: 918–931.
https://doi.org/10.1183/2312508X.10017222 21
53 Fortes HR, von Ranke FM, Escuissato DL, et al. Recurrent respiratory papillomatosis: a state-of-the-art review.
Respir Med 2017; 126: 116–121.
54 Yuan H, Myers S, Wang J, et al. Use of reprogrammed cells to identify therapy for respiratory papillomatosis.
N Engl J Med 2012; 367: 1220–1227.
55 Zhang LN, Xue XY, Wang N, et al. Mimicking pulmonary multiple metastatic tumors: a case of primary nodular
parenchymal pulmonary amyloidosis with review of the literature. Oncol Lett 2004: 1366–1370.
56 Eggleston RH, Hartman TE, Walkoff LA, et al. Clinical, radiologic, and pathologic features and outcomes of
pulmonary transthyretin amyloidosis. Respir Med 2022; 194: 106761.
57 Bomsztyk JA, Pinney JH, Lachmann HJ. Amyloidosis and the lung and airways. In: Wagner TOF, Humbert M,
58 Shaw B, Borchers M, Zander D. Pulmonary Langerhans cell histiocytosis. Semin Respir Crit Care Med 2020; 41:
269–279.
59 Jouenne F, Chevret S, Bugnet E, et al. Genetic landscape of adult Langerhans cell histiocytosis with lung
involvement. Eur Respir J 2020; 55: 1901190.
60 Héritier S, Emile JF, Barkaoui MA, et al. BRAF mutation correlates with high-risk Langerhans cell histiocytosis
and increased resistance to first-line therapy. J Clin Oncol 2016; 34: 3023–3030.
61 Montani D, Kularatne M, Jutant EM, et al. Pulmonary hypertension in orphan lung diseases. In: Wagner TOF,
62 de Rojas T, Kasper B, van der Graaf W, et al. EORTC SPECTA-AYA: a unique molecular profiling platform for
adolescents and young adults with cancer in Europe. Int J Cancer 2020; 147: 1180–1184.
Disclosures: None declared.
22 https://doi.org/10.1183/2312508X.10017222
Chapter 3
Interstitial lung diseases: an overview

Theodoros Karampitsakos 1, Marlies Wijsenbeek2,3, Jose D. Herazo-Maya1,
Argyris Tzouvelekis4 and Michael Kreuter 3,5
1
Ubben Center for Pulmonary Fibrosis Research, Division of Pulmonary, Critical Care and Sleep Medicine,
Department of Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. 2Center of
Excellence for Interstitial Lung Diseases and Sarcoidosis, Department of Respiratory Medicine, Erasmus Medical
Center-University Medical Center Rotterdam, Rotterdam, The Netherlands. 3European Reference Network for Rare
Diseases of the Respiratory System (ERN-LUNG), Frankfurt, Germany. 4Department of Respiratory Medicine,
University Hospital of Patras, Rio, Greece. 5Mainz Center for Pulmonary Medicine, Department of Pneumology,
Mainz University Medical Center and Department of Pulmonary, Critical Care & Sleep Medicine, Marienhaus Clinic
Mainz, Mainz, Germany.
Corresponding author: Michael Kreuter (michael.kreuter@unimedizin-mainz.de; michael.kreuter@marienhaus.de)
Cite as: Karampitsakos T, Wijsenbeek M, Herazo-Maya JD, et al. Interstitial lung diseases: an overview. In: Wagner TOF,
Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European
Respiratory Society, 2023; pp. 23–39 [https://doi.org/10.1183/2312508X.10017322].
@ERSpublications
The heterogeneity of ILDs renders diagnosis challenging and highlights the importance of multidisciplinary
discussion. Future trials focusing on pharmacogenetic approaches and symptom-based treatment are
strongly encouraged. https://bit.ly/ERSM100
ISSN: 2312-5098.
ILDs represent a heterogeneous group of parenchymal lung diseases. Outcomes vary considerably and
range from spontaneous reversibility to progressive pulmonary fibrosis. Timely identification and
management are crucial for patients’ quality of life and survival. However, diagnosis is often
challenging and thus referral to specialised centres is of paramount importance. This chapter aims to
provide an introduction to epidemiology, classification, pathogenesis, clinical features, diagnosis and
management of ILDs, as well as to novel developments in the field.
Introduction
ILDs represent a group of heterogeneous parenchymal lung diseases [1, 2]. More than 200 lung
disorders characterised by variable amounts of inflammatory, fibrotic lesions and pulmonary
parenchyma architectural distortion belong to ILDs [1]. In fact, the term ILD might be a
misnomer in some cases, given that, for example, the hallmark of pulmonary alveolar
proteinosis is alveolar filling and not the interstitial involvement. However, ILDs are classified
together mainly due to their overlapping clinical and radiological features [3].
Some ILDs, such as drug-induced ILDs, sarcoidosis and non-fibrotic hypersensitivity

pneumonitis (HP), are mainly characterised by inflammation, respond well to
immunosuppressive therapy, and thus, have a better prognosis if treated appropriately and in a
timely manner [2, 4]. By contrast, fibrotic lung diseases such as idiopathic pulmonary fibrosis
(IPF) or diseases presenting with progressive pulmonary fibrosis (PPF) still have a poor
prognosis [5]. In such cases, an approach of lumping together rather than splitting is
https://doi.org/10.1183/2312508X.10017322 23
increasingly implemented given that antifibrotic treatment strategies confer benefit in different
forms of pulmonary fibrosis irrespective of underlying aetiology [6, 7]. This chapter aims to
provide an introduction to epidemiology, classification, pathogenesis, clinical features, diagnosis
and management of ILDs, as well as to novel developments in the field.
Classification and epidemiology of ILDs

ILDs can be categorised into 1) exposure-related ILDs, 2) autoimmune-ILDs, 3) idiopathic
interstitial pneumonias, 4) sarcoidosis, and 5) ILDs with cysts and/or airspace filling, as recently
listed in American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/
Asociación Latinoamericana de Tórax guidelines (figure 1) [1, 5]. Another widely used
classification categorises ILDs into 1) diseases of known aetiology such as drug-induced ILDs
and connective tissue disease (CTD)-associated ILDs (CTD-ILDs), 2) idiopathic interstitial
pneumonias, 3) granulomatous ILDs, and 4) other rare ILDs [2, 8].
Current epidemiological evidence demonstrates considerable variability in the prevalence and

incidence of ILDs depending on gender, age, region and ethnicity [9–11]. Pneumoconioses and
IPF are more frequent in men than women. A female preponderance for CTD-ILDs,
lymphangioleiomyomatosis (LAM), sarcoidosis and lymphoid interstitial pneumonitis has also been
shown [9]. IPF affects the elderly (typically >60 years of age) with incidence ranging from 0.9–9.3
diagnosed patients per 100 000 per year in North America and Europe to 3.5–13.0 new cases per
100 000 per year in South America and Asia [9–12]. Limited high-quality epidemiological
evidence suggests that incidence of idiopathic nonspecific interstitial pneumonia (NSIP) is 0.8
cases per 100 000 people per year, while incidence of CTD-ILDs ranges between 2.7 and 4.3 cases
per 100 000 per year [8, 13, 14]. The estimated incidence of sarcoidosis and fibrotic HP is 4.9
cases per 100 000 per year and 0.6–1.1 cases per 100 000 per year, respectively [2, 15, 16]. The
overall prevalence of ILDs seems to range from 6.3 to 76.0 cases per 100 000 individuals [2, 16].
Pathogenesis of ILDs
Genetics
A strong genetic association has been established in several ILDs. The most common
polymorphisms and variants identified in patients with ILDs are mainly associated with host
defence, telomere length, surfactant biogenesis and cellular mitogenesis. The variant showing the
strongest association with pulmonary fibrosis development is a polymorphism associated with
deregulated mucosal host immune defence in the promoter region of MUC5B (rs35705950)
[17–21]. This polymorphism is a risk factor both for IPF and rheumatoid arthritis (RA)-usual
interstitial pneumonia (UIP) development and has been associated with the extent of fibrosis in
HP [17–22]. Surfactant protein (SP) variants including SP-A1, SP-A2 and SP-C [23–25] and
telomerase complex mutations have been also linked to development of familial pulmonary
fibrosis (FPF) [26–30]. Interstitial lung abnormalities (ILAs) have been recently associated with
decreased mean telomere length [31]. Short telomere length is a frequent finding in patients with
pulmonary fibrosis compared with aged-matched healthy individuals [30], and has been associated
with disease severity in IPF and HP [22, 32]. Despite the aforementioned genetic commonalities
between IPF and HP, there also key differences. Lung tissue profiling showed that the HP gene
expression signature was mainly enriched for genes related to inflammation, immune response and
T-cell activation, while the IPF gene signature was mainly associated with tissue remodelling,
myofibroblast and epithelial genes [33]. With regards to other variants with a role in fibrotic lung
diseases, different variants in Toll-interacting protein seem to exert a controversial role in the risk
of lung fibrosis development [34, 35]. Genome-wide association studies have shown at least 20
frequent variant signals related to pulmonary fibrosis, highlighting the association of impaired host
24 https://doi.org/10.1183/2312508X.10017322
https://doi.org/10.1183/2312508X.10017322
ILDs
1) Exposure-related ILDs 2) Autoimmune ILDs 3) IIPs 4) Sarcoidosis 5) ILDs with cysts and/or
airspace filling
• HP • RA, SSc • PAP
• Occupational • MCTD, myositis • Lymphoproliferative
• Drug-induced • Sjögren, SLE • LAM
• Radiotherapy/immunotherapy • Vasculitides • PLCH
INTERSTITIAL LUNG DISEASE OVERVIEW | T. KARAMPITSAKOS ET AL.

• Pneumonoconioses • Other rare ILDs
• Post-infectious
• RB-ILD
Chronic fibrosing Smoking-related Acute/subacute Rare

Unclassifiable
IPF iNSIP Desquamative Acute Cryptogenic Lymphoid Pleuroparenchymal

interstitial pneumonia interstitial organising interstitial fibroelastosis
pneumonia pneumonia pneumonia
FIGURE 1 Classification of ILDs. HP: hypersensitivity pneumonitis; RB-ILD: respiratory bronchiolitis-ILD; RA: rheumatoid arthritis; SSc: systemic sclerosis; IIP: idiopathic
interstitial pneumonia; MCTD: mixed connective tissue disease; SLE: systemic lupus erythematosus; PAP: pulmonary alveolar proteinosis; LAM: lymphangioleiomyomatosis;
PLCH: pulmonary Langerhans cell histiocytosis; IPF: idiopathic pulmonary fibrosis; iNSIP: idiopathic nonspecific interstitial pneumonia.
25
defence, cell-to-cell adhesion, signalling and telomere maintenance with disease susceptibility
[20, 34, 36, 37]. Genome-wide analysis of six families from Finland with FPF suggested ELMOD2,
a gene expressed in alveolar epithelial type II cells and alveolar macrophages, as a candidate gene
for pulmonary fibrosis susceptibility [38]. Several other gene mutations have been linked to other
rare ILDs (e.g. BRAF and MAPK genes for pulmonary Langerhans cell histiocytosis, mutations
in HPS1 and HPS3 with Hermansky–Pudlak syndrome, mutations in the RNF168 gene leading to
RIDDLE syndrome and the Acadian variant in Fanconi syndrome-associated ILD) [39–45].
Inflammation
In genetically predisposed individuals, but not limited to those, inflammatory pathways leading
to ILD can occur. A typical paradigm represents the deregulated citrullination and the
development of autoantibodies in RA-ILD [46]. Subsequently, a wide range of cytokines such
as tumour necrosis factor-α, prostaglandins, interleukin (IL)-1 and IL-6 are released. Another
frequent phenomenon in inflammatory ILDs is the formation of granulomas. Granulomas can be
identified in a plethora of ILDs including sarcoidosis and HP. They are the result of tight
aggregation of macrophages that might fuse to form large multinucleated cells. Non-caseating
granulomas comprised of CD4+ T-cells, B-cells, regulatory T-cells (Tregs) and fibroblasts are
the cardinal feature of sarcoidosis [47]. By contrast, peribronchiolar lymphoid hyperplasia
coupled with small poorly formed granulomas and evidence of chronic bronchiolitis in patients
exposed to common triggers such as avian and fungal proteins is the typical pathological
finding of non-fibrotic HP [48]. Multiple other inflammatory pathways are deregulated in
specific ILDs, such as the mTOR signalling that is constitutively activated in smooth muscle
cells in LAM and lipid-laden macrophages that are accumulated in pulmonary alveolar
proteinosis, due to disruption in GM-CSF signalling [3, 49].
Fibrosis
The aforementioned inflammatory cascade could lead to pulmonary fibrosis development.
However, activation of inflammatory pathways is not necessarily a prerequisite for pulmonary
fibrosis development. Profibrotic pathways could be upregulated either alone or in combination
with inflammatory pathways. Transforming growth factor-β-mediated differentiation of fibroblasts
to myofibroblasts has a cardinal role in the fibrotic process. Aberrant wound healing processes in
response to repetitive epithelial cell damage following lifetime exposure to several inhaled injurious
stimuli leading to pulmonary fibrosis involve several epigenetic (downregulation of let-7d, miR-29
and upregulation of miR-21, miR-154) [50–54], metabolic (ageing, abnormal autophagy and
mitochondriogenesis, lower thyroid hormone in the alveolar epithelium, Warburg effect) [55–57]
and immune-mediated (abnormal expression in CCL17, CCL18, CCL22, TOLLIP, TLR3, CD4+
Τ-cells, CD4+ CD25+ FOXP3+ Τregs) pathways [35, 58–60]. This abnormal wound-healing
response also involves the transition of basal cells and stem cells of the bronchial epithelium from
the conducting zones to the alveoli, as type 2 to type 1 alveolar epithelial cell differentiation is
ineffectual [61]. A considerable proportion of alveolar epithelial cells of the distal lung are replaced
with cells typically found in the proximal lung and in the airways [62, 63]. The final result of this
process is the replacement of alveolar-gas exchange units with bronchiolar units that do not
contribute to gas exchange, thus leading to respiratory failure [63]. This process is denominated
proximalisation of distal airways and explains the formation of bronchiolectatic and honeycomb
cystic-like changes characterising the UIP pattern [64–66]. Moreover, an unopposed production of
extracellular matrix and collagen leads to further architectural disruption of alveoli and remodelling
of the pulmonary vasculature, resulting to the development of secondary PH. Finally, alterations in
the composition of the extracellular matrix and the profibrotic microenvironment lead to further
progression of fibrosis [67, 68].
26 https://doi.org/10.1183/2312508X.10017322
Diagnosis of ILDs
A multidimensional approach combining clinical, laboratory, functional, radiological and
sometimes histological data is needed for the diagnosis of ILDs (figure 2). Careful evaluation of
the patient’s history and thorough clinical examination are critical steps for the correct
diagnosis. Identification of occupational or domestic exposure to particular injurious stimuli
(e.g. birds, feathers in pillows or mould) that can cause HP, dusts associated with pneumoconioses
(e.g. silica or asbestos), or compounds that cause drug-induced ILD (e.g. nitrofurantoin, or
amiodarone; www.pneumotox.com) are key elements for the correct diagnosis [1, 70, 71].
Pulmonary function indices typically demonstrate a restrictive pattern with/or without reduced
DLCO. Of note, patients with ILDs without reduced DLCO (i.e. patients with ILAs) represent a
very special population in need of further investigation. Other patterns of functional impairment
can also be seen in ILDs [72]. HRCT has a cardinal role for the diagnosis in ILDs [5]. A
specific radiological pattern should fuel the appropriate diagnostic work-up, given that, for
example, a NSIP pattern can be identified in several diseases (table 1) [8]. BAL fluid can both
exclude infections and contribute to diagnosis [1, 3, 39].
The above findings should be discussed in a multidisciplinary setting. In some cases, the
diagnosis cannot be established following multidisciplinary discussion and histology is needed.
The percentage of patients undergoing surgical lung biopsy has decreased considerably following
the advent of transbronchial cryobiopsy [5, 73, 74], and the latest guidelines for patients with a
probable or definitive UIP pattern on HRCT and clinical suspicion of IPF [75]. Finally, disease
phenotype may change over time and regular re-evaluation is strongly recommended.
Disease course of ILDs, definition of PPF and prognosis

The disease course of ILDs is heterogeneous and varies from reversible or self- limiting to
rapidly progressive disease despite optimal management [48, 70, 72, 76–81]. ILDs with
inflammatory radiological patterns such as NSIP and organising pneumonia can be stabilised or
even resolve with appropriate treatment [8, 82]. By contrast, patients with IPF experience
progressive disease and current antifibrotics can only slow down disease progression. Of note,
15–40% of patients with other fibrotic ILDs also experience disease progression and the impact
of the underlying ILD is similar to IPF with regards to mortality [83–86].
Based on the above, recent guidelines introduced the term “progressive pulmonary fibrosis
(PPF)” [5]. The term PPF refers to fibrotic ILDs other than IPF associated with deterioration in
at least two of the following: 1) respiratory symptoms, 2) functional indices, and 3) radiological
findings [5, 87]. Deterioration should be identified during the past 12 months and meticulous
evaluation to exclude other causes of deterioration (i.e. infections, anaemia, pulmonary
embolism, heart failure, musculoskeletal deconditioning) is a prerequisite. Functional
deterioration refers to an absolute decline by 5% predicted in FVC or 10% predicted in DLCO
within 1 year of follow-up. Radiological evidence of disease progression should include one or
more of the following: increased extent or severity of bronchiolectasis, new ground-glass
opacities with traction bronchiectasis, new fine reticulation, increased extent or increased
coarseness of reticular abnormalities, new or increased honeycombing and increased lobar
volume loss [5, 87].
Risk stratification in patients with ILDs is often based on functional indices and HRCT [88–93].
Composite physiologic index (CPI) and GAP (Gender, Age and Physiology) index are among
the most widely used risk-stratification indices [94, 95]. Presence of particular autoantibodies
https://doi.org/10.1183/2312508X.10017322 27
28

Clinical suspicion of ILD
History: symptoms, exposures (occupational/domestic), systemic diseases, familial history, drugs/smoking, previous history
Clinical examination: lung auscultation (velcro crackles), finger clubbing, features of systemic disease, signs of right heart failure
Functional indices: spirometry/body plethysmography, DLCO, ABGs, 6MWT, ergospirometry
Baseline HRCT: without contrast, if contrast is needed images without contrast should be generated first
Multidisciplinary discussion of radiological and clinical information: decision for a working diagnosis
Possible sarcoidosis Organising Possible Fibrotic ILD/other Cystic lung disease Possible pulmonary
pneumonia pneumoconiosis non-fibrotic ILD/ alveolar proteinosis
unclassifiable ILD
Diﬀerential diagnosis:
Bronchoscopy with BAL, TBB, Autoimmune panel: Consider BAL, in LAM, PLCH, LIP, DIP,
EBUS-TBNA/B (meticulous ANA, ENA, myositis general no need of BAL (PAS), GM-CSF
amyloidosis, antibodies
evaluation for other diseases panel, ANCA, RF, biopsy Birt–Hogg–Dubé
e.g. culture for TB)
https://doi.org/10.1183/2312508X.10017322
anti-CCP, syndrome, others

immunoglobulins.
Also CK
meticulous evaluation VEGF-D for LAM
for systemic diseases Auto-antibodies for LIP, etc.
Bronchoscopy Bronchoscopy
BAL, TBB and/or other techniques BAL (CD1a for PLCH, etc.)
depending on the case and/or other techniques
FIGURE 2 Continued overleaf.

https://doi.org/10.1183/2312508X.10017322
Serology:
Autoantibodies: ANA, ENA, ANCA, IgM, RF, ACPA (anti-CCP), myositis panel, CK, immunoglobulins
Specific IgE to identify a trigger mechanisms (e.g. HP)
No other cause of UIP: IPF, Cause of ILD not Working diagnosis CTD-ILD Drug-induced ILD
BAL is recommended in some identified of HP
cases (see guidelines), biopsy is (i.e. iNSIP) (see guidelines)
recommended in a minority of
cases (see guidelines)

Bronchoscopy with BAL and/or TBB, cryobiopsy on a case-by-case basis
Consider surgical lung biopsy following multidisciplinary discussion in case of non-diagnostic other biopsy
Multidisciplinary discussion taking into consideration clinical, radiological and histological data → diagnosis
Regular re-evaluation of new clinical, laboratory, radiological, functional and/or histological data: in case of new findings, repeat multidisciplinary discussion
Working diagnosis can change over time – diagnosis should be revised
FIGURE 2 Simplified diagnostic algorithm for ILDs. ABG: arterial blood gas analysis; 6MWT: 6-min walk test; TBB: transbronchial biopsy; EBUS-TBNA/B: endobronchial
ultrasound-guided transbronchial needle aspiration/biopsy; TB: tuberculosis; ANA: antinuclear antibody; ENA: extractable nuclear antigen; RF: rheumatoid factor; CCP: cyclic
citrullinated peptide; CK: creatine phosphokinase; LAM: lymphangioleiomyomatosis; PLCH: pulmonary Langerhans cell histiocytosis; LIP: lymphocytic interstitial pneumonia;
DIP: desquamative interstitial pneumonia; VEGF-D: vascular endothelial growth factor D; Ig: immunoglobulin; HP: hypersensitivity pneumonitis; UIP: usual interstitial
pneumonia; IPF: idiopathic pulmonary fibrosis; iNSIP: idiopathic nonspecific interstitial pneumonia; CTD-ILD: connective tissue disease-associated ILD. Reproduced from [69]
with permission.
29
TABLE 1 Main differential diagnosis of nonspecific interstitial pneumonia (NSIP)
Immunocompetence History/onset Differential diagnosis
Immunodeficient HIV Opportunistic infections, Pneumocystis jirovecii, COVID-19,

patients other viruses, drug toxicity#
Chemotherapy Opportunistic infections, Pneumocystis jirovecii, viruses,
drug toxicity#, pulmonary oedema (fluid overload),
alveolar haemorrhage
Immunocompetent Insidious iNSIP, CTD-ILD, HP, DIP, RB-ILD, PAP, NSIP overlap with
patients dyspnoea/cough causes of OP, adenocarcinoma (especially lepidic type),
lymphoma, eosinophilic pneumonia, familial ILD, bone
marrow transplant-associated NSIP, drug toxicity#, slow
resolving lung injury
Acute dyspnoea/ COVID-19, other viruses and bacteria, CADM, heart failure/
cough pulmonary oedema, vasculitides, diffuse alveolar
haemorrhage, HP, AIP, AEP, lipoid pneumonia
COVID-19: coronavirus disease 2019; iNSIP: idiopathic NSIP; CTD-ILD: connective tissue disease-associated ILD;
HP: hypersensitivity pneumonitis; DIP: desquamative interstitial pneumonia; RB-ILD: respiratory
bronchiolitis-ILD; PAP: pulmonary alveolar proteinosis; OP: organising pneumonia; CADM: clinically amyopathic
dermatomyositis; AIP: acute interstitial pneumonia; AEP: acute eosinophilic pneumonia. #: drug toxicity
includes a plethora of compounds including amiodarone, nitrofurantoin, anti-tumour necrosis factor-α,
chemotherapy and immunotherapy.
has a prognostic role in CTD-ILDs, e.g. presence of anti-MDA5 has a negative prognostic role
in patients with myositis-associated ILD [82]. A clinically applicable peripheral blood
prognostic biomarker, monocyte count, has been recently identified for patients with various
fibrotic ILDs [96–99]. Despite the recent scientific explosion and the promising data for several
other prognostic biomarkers including a 52-gene signature in the peripheral blood, short
telomere length, telomerase mutations, increased mitochondrial DNA, CA19-9, CA-125, matrix
metalloproteinase-7, SP-D, MUC5B polymorphism (rs35705950), a functional variant of
TOLLIP (rs5743890), a TLR3 functional variant (Leu412Phe, TLR3L412F), (C-X-C motif )
ligand 13, chemokine ligand 18 (CCL18) and extracellular matrix neoepitopes, the
aforementioned have not been incorporated into clinical practice [17, 32, 34, 100–108]. Finally,
except the disease per se, underlying, prevalent comorbidities such as lung cancer and PH have
a major prognostic role, as well [19, 110]. Therefore, early identification and appropriate
management of them is of paramount importance.
Management
Pharmacological management
Pharmacological management of ILDs is summarised in figure 3. Compounds can be
categorised into the following groups: 1) antifibrotic drugs for patients with IPF and PPF,
2) immunosuppressive compounds for patients with an “inflammatory pattern”, i.e. granulomatous
ILDs, NSIP and organising pneumonia, and 3) disease-specific drugs such as mTOR inhibitors
for LAM and inhaled GM-CSF for pulmonary Langerhans cell histiocytosis [5, 111–113].
Both pirfenidone and nintedanib have been approved for IPF. Nintedanib is recommended in
recent guidelines for patients with fibrotic lung disease presenting with a PPF phenotype.
Further research is recommended into the efficacy of pirfenidone for patients with PPF [5, 114].
Antifibrotics and immunosuppressive compounds can be combined in patients with PPF, but the
additive effects and timing still needs further research [115]. Contrary to the evidence for
30 https://doi.org/10.1183/2312508X.10017322
No
Is antigen or potential causative agent removed? Remove
Yes
Is there a treatment indication?
• Life-threatening (e.g. as in DAD, alveolar haemorrhage, severe
hypoxaemia, and some cases of autoimmune inflammatory No
myopathies, ANCA-associated vasculitis, and SLE) Follow-up
• Organ-threatening (e.g. as in physiological impairment with
low FVC or DLCOc or hypoxaemia)
• Severe symptom burden
Yes
Is a first-line therapy available that is based on evidence and
specific to diease?
No Yes
Pulmonary
Sarcoidosis SSc-associated ANCA-associated
LAM alveolar IPF
ILD ILD
proteinosis
Rituximab or
MMF WLL and and Antifibrotic
cyclophosphamide mTOR inhibitor
Tocilizumab GM-CSF treatment
followed by
Cyclophosphamide
maintenance
therapy
Is there a chance of reversibility or stability with immunosuppression?
Yes# Maybe# No#

Sarcoidosis#, RA-associated ILD, Overt usual UIP pattern
SSc-associated ILD, fibrotic HP, iNSIP, in context of any ILD
SLE, OP, or unclassifiable ILD
inflammatory
myopathy-associated
ILD
Is there disease progression despite immunosuppression?

No Yes, non-fibrotic Yes, fibrotic
Titrate guided by
tolerability Offer second-line or Offer antifibrotic
Consider trial of tapering third-line therapies treatment
Were the needs of the patient addressed?

Yes No
Symptom relief Tolerance and effectiveness Disease education Advanced care

Pulmonary rehabilitation of medication Peer support planning
Psychological support Lung transplant referral? Trial options Treatment limitations
FIGURE 3 Simplified treatment algorithm for different ILDs. DAD: diffuse alveolar damage; SLE: systemic lupus
erythematosus; DLCOc: corrected DLCO; LAM: lymphangioleiomyomatosis; IPF: idiopathic pulmonary fibrosis; MMF:
mycophenolate mofetil; SSc: systemic sclerosis; WLL: whole lung lavage; OP: organising pneumonia; RA:
rheumatoid arthritis; HP: hypersensitivity pneumonitis; iNSIP: idiopathic nonspecific interstitial pneumonia; UIP:
usual interstitial pneumonia; #: discuss risks and benefits in cases of off-label use with the patient. Reproduced
from [2] with permission.
https://doi.org/10.1183/2312508X.10017322 31
antifibrotics in IPF and PPF, there is a lack of evidence-based treatment recommendations for
several diseases treated with immunosuppression, and thus, off-label treatment or treatment
based on evidence from diseases with a similar phenotype is common [2].
Doses of corticosteroids higher than 10 mg·day−1 should be avoided in systemic sclerosis

(SSc)-ILD due to an increased risk of acute renal crisis [116]. Mycophenolate has shown a
favourable effect in SSc-ILD as monotherapy and some data support a combination with
nintedanib [7, 117]. Tocilizumab has been shown to be an efficacious regimen for SSc-ILD
using FVC decline and HRCT parameters as endpoints, and thus has been approved for
SSc-ILD by the US Food and Drug Administration [118]. Cyclophosphamide and stem cells
might be an option in selected cases [117, 119]. Recently, a study enrolling patients with
scleroderma-ILD, myositis-associated ILD or mixed CTD showed that rituximab was not
superior to cyclophosphamide; however, it was associated with fewer adverse events [120].
Most data for RA-ILD are derived from retrospective studies. Previous reports have shown that
methotrexate can cause pneumonitis in patients with RA; nonetheless, recent reports supported
the notion that methotrexate is rarely a cause for fibrotic ILDs in RA and even seems to have a
preventive or protective effect. Patients with CTD-ILD presenting with PPF should be discussed
to receive antifibrotic therapy [5]. Finally, myositis-associated ILD responds to various
immunosuppressive compounds, if diagnosed in a timely manner. Specific cases such as cases
of clinically amyopathic dermatomyositis and positive anti-MDA5 antibodies can be rapidly
progressive and need timely implementation of treatment, e.g. intravenous methylprednisolone,
cyclophosphamide or rituximab followed by steroid-sparing agents [82], as well as referral to a
centres of expertise to consider other treatment approaches including calcineurin inhibitors and
JAK-inhibitors or in some cases even lung transplantation [121, 122].
Immunosuppressive regimens have been proven beneficial in several other ILDs including
non-fibrotic HP, drug-induced ILDs and sarcoidosis. Treatment with azathioprine or
mycophenolate mofetil has been associated with DLCO improvement in patients with HP [123].
Corticosteroids are the cornerstone of treatment for drug-induced ILDs [70]. Recent treatment
guidelines for sarcoidosis highlight corticosteroids, methotrexate and infliximab as first-,
second- and third-line therapy, respectively [111]. Similarly, patients with HP, and other ILDs
presenting with a PPF disease behaviour, should receive antifibrotic therapy with or without an
immunosuppressive agent on a case-by-case basis [5]. There is a great need for studies into the
role, choice and timing of immunosuppression in many ILDs, both as monotherapy as well as
in combination with antifibrotic treatments.
Supportive and non-pharmacological management

A requirement for HP is complete antigen eviction as this is associated not only with resolution
of inflammatory phenotypes but also with improved survival even in fibrotic HP [124]. As
many ILDs have a high symptom burden and decreased quality of life, healthcare providers
should support patients and families to not only live as long as possible but also as well as
possible, according to patients’ personal values [125, 126]. Patient support associations can play
an important role in access to information. Viral and pneumococcal vaccinations are
recommended to prevent potential triggers of disease progression or exacerbations. Discussions
to make the patient aware of potential non-infectious triggers of acute exacerbations, including
radiation, mechanical ventilation, chemotherapy and surgery, are encouraged [2]. Counselling
for a specific diet to improve nutritional status and a specific way of life could have beneficial
effects in patients receiving antifibrotics [127]. Pulmonary rehabilitation can also improve
exercise capacity and health-related quality of life, especially if started early [128, 129]. Timely
identification and management of comorbidities can positively impact patients’ quality of life
32 https://doi.org/10.1183/2312508X.10017322
[109, 110, 130, 131]. As anxiety and depression are common in many ILDs [130],
psychological support should be offered to those that wish to receive it. Online mindfulness
based cognitive therapy has been shown to decrease fatigue in patients with sarcoidosis
[132, 133]. Ambulatory oxygen is another option able to improve dyspnoea and quality of life
in patients with exertional hypoxaemia [134, 135]. Advanced care planning and treatment
limitations should be discussed in a timely and sensitive manner especially in patients with IPF
and those manifesting with PPF.
Lung transplantation
A substantial proportion of patients with ILDs experience disease progression despite optimal
management. Lung transplantation seems to be the only life-extending option for these patients.
Recent years have seen an increasing proportion of transplants for ILDs [136]. However, there
are complexities for patients with ILDs that impact candidacy, and pre- and post-transplant
management. Some patients have coexisting comorbidities that might exclude them from being
transplant candidates, while a considerable percentage might have major complications
following transplantation [136]. Timely referral and discussion with a transplant centre remain
crucial [137].
The future of ILDs and concluding remarks

Despite the scientific explosion of the past decade, there are still multiple unmet needs for a
large number of patients including early diagnosis, appropriate disease monitoring and
management, better treatments, and genetic counselling. Important caveats for early diagnosis
are the nonspecific symptoms and delays/difficulties of referral to a specialised centre [138].
The latter is also a caveat for appropriate monitoring and management. The best way to
overcome these barriers is the implementation of biomarkers (not necessarily molecular) with
actionable information. Such biomarkers must be clinically applicable and lead to early
diagnosis, highlight disease activity and/or suggest treatment modification.
Early diagnosis could be achieved in several ways including: 1) biomarkers of disease

susceptibility in the peripheral blood that can be used for screening [18, 20, 34, 36, 37],
2) novel techniques such as eNose [139, 140], and 3) deep learning in the interpretation of
HRCT [141, 142]. Disease monitoring could be improved through advances in digital health,
i.e. home spirometry, pulse oximetry and accelerometry [143–145]. Disease monitoring could
also be improved with disease activity biomarkers able to highlight the time point to intervene
or change treatment regimen.
Molecular biomarkers might hopefully lead to more tailored disease management. Data are still
scarce with regards to the role of antifibrotics on ILAs. Recently, antifibrotic treatment was
proven beneficial for patients with PPF irrespective of the underlying ILD [6, 7, 86]. These
findings should not be considered a move away from personalised medicine. On the contrary,
they should pave the way and highlight the need to focus on the treatment of mechanisms
instead of discrete clinical entities. Clinical implementation of biomarkers related to disease
pathogenesis could be the first step towards treating mechanisms instead of clinical entities.
There is a pressing need for theragnostic biomarkers that can lead to well-designed
biomarker-based randomised controlled trials with a pharmacogenetic approach. Such
biomarkers could help the design of well-designed trials for antifibrotics, immunosuppressants
or combined regimens. To this end, contrary to antifibrotics, there is a lack of high-quality,
randomised controlled trials comparing different immunosuppressive regimens for different
ILDs. Furthermore, studies comparing inhaled and oral administration seem to have potential in
https://doi.org/10.1183/2312508X.10017322 33
an effort to maximize effectiveness and concomitantly spare the adverse events of systemic
administration. Inhaled pirfenidone and thyroid hormone are among the promising inhaled
compounds, currently [56, 146]. Finally, clinical trials aiming to improve quality of life are
strongly encouraged. A typical recent paradigm is nalbuphine. Nalbuphine is the
extended-release form of the dual-acting κ opioid receptor agonist/μ opioid receptor antagonist
and has shown great potential in chronic cough reduction in patients with pulmonary fibrosis
(https://clinicaltrials.gov/ct2/show/NCT04030026). Taken together, shifting to a patient-centred
approach might be the key for the optimisation of ILDs management in the future.
References
1 Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society
statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Am J Respir Crit Care Med 2013; 188: 733–748.
2 Wijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet 2022; 400: 769–786.
3 Trapnell BC, Nakata K, Bonella F, et al. Pulmonary alveolar proteinosis. Nat Rev Dis Primers 2019; 5: 16.
4 Costabel U, Miyazaki Y, Pardo A, et al. Hypersensitivity pneumonitis. Nat Rev Dis Primers 2020; 6: 65.
5 Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic Pulmonary Fibrosis (an Update) and progressive
pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care
Med 2022; 205: e18–e47.
6 Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J
Med 2019; 381: 1718–1727.
7 Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung
disease. N Engl J Med 2019; 380: 2518–2528.
8 Belloli EA, Beckford R, Hadley R, et al. Idiopathic non-specific interstitial pneumonia. Respirology 2016; 21:
259–268.
9 Karampitsakos T, Papaioannou O, Katsaras M, et al. Interstitial lung diseases and the impact of gender. Clin
Chest Med 2021; 42: 531–541.
10 Duchemann B, Annesi-Maesano I, Jacobe de Naurois C, et al. Prevalence and incidence of interstitial lung
diseases in a multi-ethnic county of Greater Paris. Eur Respir J 2017; 50: 1602419.
11 Maher TM, Bendstrup E, Dron L, et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir
Res 2021; 22: 197.
12 Natsuizaka M, Chiba H, Kuronuma K, et al. Epidemiologic survey of Japanese patients with idiopathic
pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med 2014; 190: 773–779.
13 Raimundo K, Solomon JJ, Olson AL, et al. Rheumatoid arthritis-interstitial lung disease in the United States:
prevalence, incidence, and healthcare costs and mortality. J Rheumatol 2019; 46: 360–369.
14 Li Q, Wallace L, Patnaik P, et al. Disease frequency, patient characteristics, comorbidity outcomes and
immunosuppressive therapy in systemic sclerosis and systemic sclerosis-associated interstitial lung disease: a
US cohort study. Rheumatology (Oxford) 2021; 60: 1915–1925.
15 Fernández Pérez ER, Kong AM, Raimundo K, et al. Epidemiology of hypersensitivity pneumonitis among an
insured population in the United States: a claims-based cohort analysis. Ann Am Thorac Soc 2018; 15: 460–469.
16 Olson AL, Patnaik P, Hartmann N, et al. Prevalence and incidence of chronic fibrosing interstitial lung diseases
with a progressive phenotype in the United States estimated in a large claims database analysis. Adv Ther
2021; 38: 4100–4114.
17 Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter polymorphism and survival
in patients with idiopathic pulmonary fibrosis. JAMA 2013; 309: 2232–2239.
18 Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis.
N Engl J Med 2011; 364: 1503–1512.
19 Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism and interstitial lung
abnormalities. N Engl J Med 2013; 368: 2192–2200.
20 Allen RJ, Guillen-Guio B, Oldham JM, et al. Genome-wide association study of susceptibility to idiopathic
pulmonary fibrosis. Am J Respir Crit Care Med 2020; 201: 564–574.
21 Juge P-A, Lee JS, Ebstein E, et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung
22 Ley B, Newton CA, Arnould I, et al. The MUC5B promoter polymorphism and telomere length in patients with
chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir Med 2017; 5: 639–
647.
34 https://doi.org/10.1183/2312508X.10017322
23 Nogee LM, Dunbar AE 3rd, Wert SE, et al. A mutation in the surfactant protein C gene associated with familial
interstitial lung disease. N Engl J Med 2001; 344: 573–579.
24 Liu L, Qin J, Guo T, et al. Identification and functional characterization of a novel surfactant protein A2
mutation ( p.N207Y) in a Chinese family with idiopathic pulmonary fibrosis. Mol Genet Genomic Med 2020; 8:
e1393.
25 Nathan N, Giraud V, Picard C, et al. Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia
and lung cancer. Hum Mol Genet 2016; 25: 1457–1467.
26 Lawson WE, Grant SW, Ambrosini V, et al. Genetic mutations in surfactant protein C are a rare cause of
sporadic cases of IPF. Thorax 2004; 59: 977–980.
27 van Moorsel CH, Ten Klooster L, van Oosterhout MF, et al. SFTPA2 mutations in familial and sporadic
idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2015; 192: 1249–1252.
28 Stainer A, Faverio P, Busnelli S, et al. Molecular biomarkers in idiopathic pulmonary fibrosis: state of the art
and future directions. Int J Mol Sci 2021; 22: 6255.
29 Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis.
N Engl J Med 2007; 356: 1317–1326.
30 Cronkhite JT, Xing C, Raghu G, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J
Respir Crit Care Med 2008; 178: 729–737.
31 Putman RK, Axelsson GT, Ash SY, et al. Interstitial lung abnormalities are associated with decreased mean
telomere length. Eur Respir J 2022; 60: 2101814.
32 Stuart BD, Lee JS, Kozlitina J, et al. Effect of telomere length on survival in patients with idiopathic
pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med 2014; 2:
557–565.
33 Selman M, Pardo A, Barrera L, et al. Gene expression profiles distinguish idiopathic pulmonary fibrosis from
hypersensitivity pneumonitis. Am J Respir Crit Care Med 2006; 173: 188–198.
34 Noth I, Zhang Y, Ma SF, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and
mortality: a genome-wide association study. Lancet Respir Med 2013; 1: 309–317.
35 Karampitsakos T, Woolard T, Bouros D, et al. Toll-like receptors in the pathogenesis of pulmonary fibrosis. Eur
J Pharmacol 2017; 808: 35–43.
36 Mushiroda T, Wattanapokayakit S, Takahashi A, et al. A genome-wide association study identifies an
association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis. J Med Genet
2008; 45: 654–656.
37 Fingerlin TE, Murphy E, Zhang W, et al. Genome-wide association study identifies multiple susceptibility loci
for pulmonary fibrosis. Nat Genet 2013; 45: 613–620.
38 Hodgson U, Pulkkinen V, Dixon M, et al. ELMOD2 is a candidate gene for familial idiopathic pulmonary
fibrosis. Am J Hum Genet 2006; 79: 149–154.
39 Liu H, Osterburg AR, Flury J, et al. MAPK mutations and cigarette smoke promote the pathogenesis of
pulmonary Langerhans cell histiocytosis. JCI Insight 2020; 5: e132048.
40 Alayed K, Medeiros LJ, Patel KP, et al. BRAF and MAP2K1 mutations in Langerhans cell histiocytosis: a study of
50 cases. Hum Pathol 2016; 52: 61–67.
41 Salvator H, Cheng A, Rosen LB, et al. Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis,
cryptococcal meningitis and severe nocardiosis. Respir Res 2022; 23: 280.
42 Huizing M, Malicdan MCV, Wang JA, et al. Hermansky-Pudlak syndrome: mutation update. Hum Mutat 2020; 41:
543–580.
43 Pietrucha B, Heropolitańska-Pliszka E, Geffers R, et al. Clinical and biological manifestation of RNF168
deficiency in two polish siblings. Front Immunol 2017; 8: 1683.
44 Papaioannou O, Karampitsakos T, Sampsonas F, et al. Fanconi syndrome-associated interstitial lung disease.
BMJ Case Rep 2022; 15: e249242.
45 Borie R, Le Guen P, Ghanem M, et al. The genetics of interstitial lung diseases. Eur Respir Rev 2019; 28:
190053.
46 Buch MH, Eyre S, McGonagle D. Persistent inflammatory and non-inflammatory mechanisms in refractory
rheumatoid arthritis. Nat Rev Rheumatol 2021; 17: 17–33.
47 Lee S, Birnie D, Dwivedi G. Current perspectives on the immunopathogenesis of sarcoidosis. Respir Med 2020;
173: 106161.
48 Vasakova M, Selman M, Morell F, et al. Hypersensitivity pneumonitis: current concepts of pathogenesis and
potential targets for treatment. Am J Respir Crit Care Med 2019; 200: 301–308.
49 Taveira-DaSilva AM, Moss J. Epidemiology, pathogenesis and diagnosis of lymphangioleiomyomatosis. Expert
Opin Orphan Drugs 2016; 4: 369–378.
50 Tzouvelekis A, Kaminski N. Epigenetics in idiopathic pulmonary fibrosis. Biochem Cell Biol 2015; 93: 159–170.
51 Pandit KV, Corcoran D, Yousef H, et al. Inhibition and role of let-7d in idiopathic pulmonary fibrosis. Am J
https://doi.org/10.1183/2312508X.10017322 35
52 Cushing L, Kuang PP, Qian J, et al. miR-29 is a major regulator of genes associated with pulmonary fibrosis.
Am J Respir Cell Mol Biol 2011; 45: 287–294.
53 Liu G, Friggeri A, Yang Y, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung
fibrosis. J Exp Med 2010; 207: 1589–1597.
54 Milosevic J, Pandit K, Magister M, et al. Profibrotic role of miR-154 in pulmonary fibrosis. Am J Respir Cell Mol
Biol 2012; 47: 879–887.
55 Papaioannou O, Karampitsakos T, Barbayianni I, et al. Metabolic disorders in chronic lung diseases. Front Med
(Lausanne) 2017; 4: 246.
56 Yu G, Tzouvelekis A, Wang R, et al. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial
mitochondrial function. Nat Med 2018; 24: 39–49.
57 Karampitsakos T, Tzilas V, Tringidou R, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Pulm
Pharmacol Ther 2017; 45: 1–10.
58 Gilani SR, Vuga LJ, Lindell KO, et al. CD28 down-regulation on circulating CD4 T-cells is associated with poor
prognoses of patients with idiopathic pulmonary fibrosis. PLoS ONE 2010; 5: e8959.
59 Kotsianidis I, Nakou E, Bouchliou I, et al. Global impairment of CD4+CD25+FOXP3+ regulatory T cells in
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009; 179: 1121–1130.
60 DePianto DJ, Heiden JAV, Morshead KB, et al. Molecular mapping of interstitial lung disease reveals a
phenotypically distinct senescent basal epithelial cell population. JCI Insight 2021; 6: e143626.
61 Jiang P, Gil de Rubio R, Hrycaj SM, et al. Ineffectual Type 2-to-Type 1 alveolar epithelial cell differentiation in
idiopathic pulmonary fibrosis: persistence of the KRT8(hi) transitional state. Am J Respir Crit Care Med 2020;
201: 1443–1447.
62 Strunz M, Simon LM, Ansari M, et al. Alveolar regeneration through a Krt8+ transitional stem cell state that
persists in human lung fibrosis. Nat Commun 2020; 11: 3559.
63 Adams TS, Schupp JC, Poli S, et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell
populations in idiopathic pulmonary fibrosis. Sci Adv 2020; 6: eaba1983.
64 Neumark N, Cosme C, Jr, Rose KA, et al. The idiopathic pulmonary fibrosis cell atlas. Am J Physiol Lung Cell
Mol Physiol 2020; 319: L887–L893.
65 Schupp JC, Yan X, Kaminski N. Toward a cell atlas of the human airway. Am J Respir Crit Care Med 2020; 202:
1611–1612.
66 Tsukui T, Sun KH, Wetter JB, et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct
localization and relevance to fibrosis. Nat Commun 2020; 11: 1920.
67 Philp CJ, Siebeke I, Clements D, et al. Extracellular matrix cross-linking enhances fibroblast growth and
protects against matrix proteolysis in lung fibrosis. Am J Respir Cell Mol Biol 2018; 58: 594–603.
68 Parker MW, Rossi D, Peterson M, et al. Fibrotic extracellular matrix activates a profibrotic positive feedback
loop. J Clin Invest 2014; 124: 1622–1635.
69 Kreuter M, Behr J, Bonella F, et al. S1-Leitlinie Interdisziplinäre Diagnostik interstitieller Lungenerkrankungen
im Erwachsenenalter [Consensus guideline on the interdisciplinary diagnosis of interstitial lung diseases].
Pneumologie 2023; 77: 269–302.
70 Skeoch S, Weatherley N, Swift AJ, et al. Drug-induced interstitial lung disease: a systematic review. J Clin Med
2018; 7: 356.
ALAT Clinical Practice Guideline. Am J Respir Crit Care Med 2018; 198: e44–e68.
72 Raghu G, Remy-Jardin M, Ryerson CJ, et al. Diagnosis of hypersensitivity pneumonitis in adults: an official
ATS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2020; 202: e36–e69.
73 Troy LK, Grainge C, Corte TJ, et al. Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung
disease diagnosis (COLDICE): a prospective, comparative study. Lancet Respir Med 2020; 8: 171–181.
74 Tomassetti S, Ravaglia C, Wells AU, et al. Prognostic value of transbronchial lung cryobiopsy for the
multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study. Lancet Respir
Med 2020; 8: 786–794.
75 Tzouvelekis A, Bouros D. Endotyping of progressive fibrotic interstitial lung diseases: it is the final destination
that matters and not the journey. EBioMedicine 2020; 51: 102591.
76 Wijsenbeek M, Cottin V. Spectrum of fibrotic lung diseases. N Engl J Med 2020; 383: 958–968.
77 Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases: knowns and unknowns. Eur Respir Rev
2019; 28: 180100.
78 Tzouvelekis A, Herazo-Maya J, Sakamoto K, et al. Biomarkers in the evaluation and management of idiopathic
pulmonary fibrosis. Curr Top Med Chem 2016; 16: 1587–1598.
79 Spagnolo P, Sverzellati N, Rossi G, et al. Idiopathic pulmonary fibrosis: an update. Ann Med 2015; 47: 15–27.
80 Rosas IO, Kaminski N. Update in diffuse parenchymal lung disease 2013. Am J Respir Crit Care Med 2015; 191:
270–274.
36 https://doi.org/10.1183/2312508X.10017322
81 Gimenez A, Storrer K, Kuranishi L, et al. Change in FVC and survival in chronic fibrotic hypersensitivity
pneumonitis. Thorax 2018; 73: 391–392.
82 Karampitsakos T, Tzilas V, Papaioannou O, et al. Clinical features and outcomes of patients with myositis
associated-interstitial lung disease. Front Med 2023; 9: 1096203.
83 George PM, Spagnolo P, Kreuter M, et al. Progressive fibrosing interstitial lung disease: clinical uncertainties,
consensus recommendations, and research priorities. Lancet Respir Med 2020; 8: 925–934.
84 Wijsenbeek M, Kreuter M, Olson A, et al. Progressive fibrosing interstitial lung diseases: current practice in
diagnosis and management. Curr Med Res Opin 2019; 35: 2015–2024.
85 Hoffmann-Vold AM, Allanore Y, Alves M, et al. Progressive interstitial lung disease in patients with systemic
sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis 2021; 80: 219–227.
86 Maher TM, Corte TJ, Fischer A, et al. Pirfenidone in patients with unclassifiable progressive fibrosing
interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med
2020; 8: 147–157.
87 Tzilas V, Tzouvelekis A, Ryu JH, et al. 2022 update on clinical practice guidelines for idiopathic pulmonary
fibrosis and progressive pulmonary fibrosis. Lancet Respir Med 2022; 10: 729–731.
88 Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis:
evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788–824.
89 Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet 2017; 389: 1941–1952.
90 du Bois RM, Albera C, Bradford WZ, et al. 6-minute walk test distance is an independent predictor of mortality
in patients with idiopathic pulmonary fibrosis. Eur Respir J 2013; 43: 1421–1429.
91 du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validation
and minimal clinically important difference. Am J Respir Crit Care Med 2011; 183: 1231–1237.
92 Nathan SD, Yang M, Morgenthien EA, et al. FVC variability in patients with idiopathic pulmonary fibrosis and
role of 6-min walk test to predict further change. Eur Respir J 2020; 55: 1902151.
93 Walsh SLF, Mackintosh JA, Calandriello L, et al. Deep learning–based outcome prediction in progressive
fibrotic lung disease using high-resolution computed tomography. Am J Respir Crit Care Med 2022; 206: 883–
891.
94 Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary
fibrosis. Ann Intern Med 2012; 156: 684–691.
95 Wells AU, Desai SR, Rubens MB, et al. Idiopathic pulmonary fibrosis: a composite physiologic index derived
from disease extent observed by computed tomography. Am J Respir Crit Care Med 2003; 167: 962–969.
96 Shao G, Hawle P, Akbari K, et al. Clinical, imaging, and blood biomarkers to assess 1-year progression risk in
fibrotic interstitial lung diseases—Development and validation of the honeycombing, traction bronchiectasis,
and monocyte (HTM)-score. Front Med (Lausanne) 2022; 9: 1043720.
97 Scott MKD, Quinn K, Li Q, et al. Increased monocyte count as a cellular biomarker for poor outcomes in
fibrotic diseases: a retrospective, multicentre cohort study. Lancet Respir Med 2019; 7: 497–508.
98 Karampitsakos T, Torrisi S, Antoniou K, et al. Increased monocyte count and red cell distribution width as
prognostic biomarkers in patients with Idiopathic Pulmonary Fibrosis. Respir Res 2021; 22: 140.
99 Kreuter M, Lee JS, Tzouvelekis A, et al. Monocyte count as a prognostic biomarker in patients with idiopathic
pulmonary fibrosis. Am J Respir Crit Care Med 2021; 204: 74–81.
100 Herazo-Maya JD, Sun J, Molyneaux PL, et al. Validation of a 52-gene risk profile for outcome prediction in
patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study. Lancet Respir Med
2017; 5: 857–868.
101 Maher TM, Oballa E, Simpson JK, et al. An epithelial biomarker signature for idiopathic pulmonary fibrosis: an
analysis from the multicentre PROFILE cohort study. Lancet Respir Med 2017; 5: 946–955.
102 Spagnolo P, Oldham JM, Jones MG, et al. Personalized medicine in interstitial lung diseases. Curr Opin Pulm
Med 2017; 23: 231–236.
103 O’Dwyer DN, Armstrong ME, Trujillo G, et al. The Toll-like receptor 3L412F polymorphism and disease
progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2013; 188: 1442–1450.
104 Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009; 179: 717–723.
105 Herazo-Maya JD, Noth I, Duncan SR, et al. Peripheral blood mononuclear cell gene expression profiles predict
poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med 2013; 5: 205ra136.
106 DePianto DJ, Chandriani S, Abbas AR, et al. Heterogeneous gene expression signatures correspond to distinct
lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis. Thorax 2015; 70: 48–56.
107 Ryu C, Sun H, Gulati M, et al. Extracellular mitochondrial DNA is generated by fibroblasts and predicts death
in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2017; 196: 1571–1581.
108 Bowman WS, Echt GA, Oldham JM. Biomarkers in progressive fibrosing interstitial lung disease: optimizing
diagnosis, prognosis, and treatment response. Front Med (Lausanne) 2021; 8: 680997.
https://doi.org/10.1183/2312508X.10017322 37
109 Karampitsakos T, Spagnolo P, Mogulkoc N, et al. Lung cancer in patients with idiopathic pulmonary fibrosis: a
retrospective multicentre study in Europe. Respirology 2023; 28: 56–65.
110 Karampitsakos T, Tzouvelekis A, Chrysikos S, et al. Pulmonary hypertension in patients with interstitial lung
disease. Pulm Pharmacol Ther 2018; 50: 38–46.
111 Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur
Respir J 2021; 58: 2004079.
112 Trapnell BC, Inoue Y, Bonella F, et al. Inhaled molgramostim therapy in autoimmune pulmonary alveolar
proteinosis. N Engl J Med 2020; 383: 1635–1644.
113 McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl
J Med 2011; 364: 1595–1606.
114 Behr J, Prasse A, Kreuter M, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases
other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b
trial. Lancet Respir Med 2021; 9: 476–486.
115 Kreuter M, Maher TM, Corte TJ, et al. Pirfenidone in unclassifiable interstitial lung disease: a subgroup analysis
by concomitant mycophenolate mofetil and/or previous corticosteroid use. Adv Ther 2022; 39: 1081–1095.
116 Trang G, Steele R, Baron M, et al. Corticosteroids and the risk of scleroderma renal crisis: a systematic review.
Rheumatol Int 2012; 32: 645–653.
117 Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in
scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group
118 Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomised, double-blind,
placebo-controlled, phase 3 trial. Lancet Respir Med 2020; 8: 963–974.
119 Spierings J, Chiu YH, Voortman M, et al. Autologous stem-cell transplantation in systemic sclerosis-associated
interstitial lung disease: early action in selected patients rather than escalation therapy for all. Ther Adv
Musculoskelet Dis 2021; 13: 1759720X211035196.
120 Maher TM, Tudor VA, Saunders P, et al. Rituximab versus intravenous cyclophosphamide in patients with
connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind,
double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med 2023; 11: 45–54.
121 Hozumi H, Fujisawa T, Nakashima R, et al. Efficacy of glucocorticoids and calcineurin inhibitors for
anti-aminoacyl-tRNA synthetase antibody–positive polymyositis/dermatomyositis–associated interstitial lung
disease: a propensity score–matched analysis. J Rheumatol 2019; 46: 509–517.
122 Paudyal A, Zheng M, Lyu L, et al. JAK-inhibitors for dermatomyositis: a concise literature review. Dermatol Ther
2021; 34: e14939.
123 Morisset J, Johannson KA, Vittinghoff E, et al. Use of mycophenolate mofetil or azathioprine for the
management of chronic hypersensitivity pneumonitis. Chest 2017; 151: 619–625.
124 Petnak T, Thongprayoon C, Baqir M, et al. Antigen identification and avoidance on outcomes in fibrotic
hypersensitivity pneumonitis. Eur Respir J 2022; 60: 2101336.
125 Kreuter M, Bendstrup E, Russell AM, et al. Palliative care in interstitial lung disease: living well. Lancet Respir
Med 2017; 5: 968–980.
126 Wijsenbeek MS, Holland AE, Swigris JJ, et al. Comprehensive supportive care for patients with fibrosing
interstitial lung disease. Am J Respir Crit Care Med 2019; 200: 152–159.
127 Faverio P, Bocchino M, Caminati A, et al. Nutrition in patients with idiopathic pulmonary fibrosis: critical
issues analysis and future research directions. Nutrients 2020; 12: 1131.
128 Dowman LM, McDonald CF, Hill CJ, et al. The evidence of benefits of exercise training in interstitial lung
disease: a randomised controlled trial. Thorax 2017; 72: 610–619.
129 Dowman L, Hill CJ, May A, et al. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst
Rev 2021; 2: CD006322.
130 Tzouvelekis A, Karampitsakos T, Kourtidou S, et al. Impact of depression on patients with idiopathic
pulmonary fibrosis. Front Med (Lausanne) 2020; 7: 29.
131 Kreuter M, Ehlers-Tenenbaum S, Palmowski K, et al. Impact of comorbidities on mortality in patients with
idiopathic pulmonary fibrosis. PLoS ONE 2016; 11: e0151425.
132 Hinz A, Brähler E, Möde R, et al. Anxiety and depression in sarcoidosis: the influence of age, gender, affected
organs, concomitant diseases and dyspnea. Sarcoidosis Vasc Diffuse Lung Dis 2012; 29: 139–146.
133 Kahlmann V, Moor CC, van Helmondt SJ, et al. Online mindfulness-based cognitive therapy for fatigue in
patients with sarcoidosis (TIRED): a randomised controlled trial. Lancet Respir Med 2022; 11: 265–272.
134 Jacobs SS, Krishnan JA, Lederer DJ, et al. Home oxygen therapy for adults with chronic lung disease. An
Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2020; 202: e121–e141.
135 Visca D, Mori L, Tsipouri V, et al. Effect of ambulatory oxygen on quality of life for patients with fibrotic lung
disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial. Lancet
Respir Med 2018; 6: 759–770.
38 https://doi.org/10.1183/2312508X.10017322
136 Kapnadak SG, Raghu G. Lung transplantation for interstitial lung disease. Eur Respir Rev 2021; 30: 210017.
137 Leard LE, Holm AM, Valapour M, et al. Consensus document for the selection of lung transplant candidates:
an update from the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2021;
40: 1349–1379.
138 Spagnolo P, Ryerson CJ, Putman R, et al. Early diagnosis of fibrotic interstitial lung disease: challenges and
opportunities. Lancet Respir Med 2021; 9: 1065–1076.
139 Moor CC, Oppenheimer JC, Nakshbandi G, et al. Exhaled breath analysis by use of eNose technology: a novel
diagnostic tool for interstitial lung disease. Eur Respir J 2021; 57: 2002042.
140 van der Sar IG, Moor CC, Oppenheimer JC, et al. Diagnostic performance of electronic nose technology in
Sarcoidosis. Chest 2022; 161: 738–747.
141 Walsh SLF, Calandriello L, Silva M, et al. Deep learning for classifying fibrotic lung disease on high-resolution
computed tomography: a case-cohort study. Lancet Respir Med 2018; 6: 837–845.
142 Karampitsakos T, Kalogeropoulou C, Tzilas V, et al. Safety and effectiveness of mycophenolate mofetil in
interstitial lung diseases: insights from a machine learning radiographic model. Respiration 2022; 101: 262–271.
143 Marcoux V, Wang M, Burgoyne SJ, et al. Mobile health monitoring in patients with idiopathic pulmonary
fibrosis. Ann Am Thorac Soc 2019; 16: 1327–1329.
144 Moor CC, Mostard RLM, Grutters JC, et al. Home monitoring in patients with idiopathic pulmonary fibrosis. a
randomized controlled trial. Am J Respir Crit Care Med 2020; 202: 393–401.
145 Nakshbandi G, Moor CC, Wijsenbeek MS. Home monitoring for patients with ILD and the COVID-19 pandemic.
Lancet Respir Med 2020; 8: 1172–1174.
146 Khoo JK, Montgomery AB, Otto KL, et al. A Randomized, double-blinded, placebo-controlled, dose-escalation
phase 1 study of aerosolized pirfenidone delivered via the PARI investigational eFlow nebulizer in volunteers
and patients with idiopathic pulmonary fibrosis. J Aerosol Med Pulm Drug Deliv 2020; 33: 15–20.
Disclosures: T. Karampitsakos has nothing to declare. M. Wijsenbeek reports no personal fees; the Erasmus MC
received consultancy or speaker fees from AstraZeneca, Bristol Myers Squibb, CSL Behring, Galapagos, Galecto,
Horizon Therapeutics, Kinevant Sciences, Molecure, NeRRe Therapeutics, Novartis, PureTech Health, Respivant and
Thyron; and grants, from Boehringer Ingelheim, AstraZeneca/Daiichi-Sankyo and Hoffmann-La Roche, outside the
submitted work. J.D. Herzo-Maya has nothing to declare. A. Tzouvelekis has received consultancy fees and
honoraria from Boehringer Ingelheim, Hoffmann La-Roche, GlaxoSmithKline, Chiesi, Elpen, AstraZeneca, Gilead,
Pfizer and Menarini, outside the submitted work. M. Kreuter reports grants to Thoraxklinik from Boehringer
Ingelheim and Roche as well as consultancy and speaker fees from CSL Behring, Galapagos, Kinevant, Boehringer
Ingelheim and Roche, outside the submitted work.
https://doi.org/10.1183/2312508X.10017322 39
Chapter 4
Rare interstitial lung diseases of

environmental origin
Carlos Robalo Cordeiro1,2,3, Tiago Alfaro 1,2,3
and Sara Freitas1,2,3
1
Pulmonology Dept, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. 2Faculty of Medicine,
University of Coimbra, Coimbra, Portugal. 3Clinical Academic Center of Coimbra, Coimbra, Portugal.
Corresponding author: Carlos Robalo Cordeiro (carlos.crobalo@gmail.com)
Cite as: Robalo Cordeiro C, Alfaro T, Freitas S. Rare interstitial lung diseases of environmental origin. In: Wagner TOF,
@ERSpublications
Clinical suspicion, early identification of the offending agent and immediate suspension of exposure are key
to minimising rare ILDs of environmental origin, which have a wide severity spectrum and deep association
with duration and intensity of exposure https://bit.ly/ERSM100
ISSN: 2312-5098.
The lung represents an immense interface with the external environment, inhaling close to 20 000 L of
air every day containing a diversity of aggressive and polluting agents, not only in the general
environment but also at the occupational and housing level. Therefore, a detailed respiratory clinical
history is essential to identify current or previous inhalation risks. Rare ILDs of environmental origin
require a personalised approach, involving a high degree of clinical suspicion, which must
fundamentally include removal of the offending agent, monitoring of the clinical, radiological and
functional evolution, and differentiated therapeutic options when necessary. This chapter discusses
hypersentivity pneumonitis, pneumoconiosis and other ILDs caused by environmental exposures, and
the effects of environmental exposures on other ILDs.
Introduction
This chapter discusses the importance of being able to recognise the impact of exposure to
various inhaled agents at the interstitial level and of understanding the management of the main
related clinical ILDs. Hypersensitivity pneumonitis (HP) is described in detail, differentiating
the exposure to organic and nonorganic agents, and including the most recent diagnostic
algorithm for this interstitial entity. Pneumoconioses are reviewed in terms of inorganic
exposure, outlining the main exposure scenarios and the respective resulting nosological entities.
Finally, other ILDs caused by environmental agents and the effects of environmental exposures
on other ILDs are described.
Hypersensitivity pneumonitis
Definition
HP is a rare ILD characterised by a disproportionate immune response following repeated exposure
to an inhaled agent by a susceptible host [1]. The disease was first reported in farmers in 1932, but
reports of respiratory diseases caused by inhalation of grain dusts date back to the 16th century [2].
40 https://doi.org/10.1183/2312508X.10017422
LUNG DISEASES OF ENVIRONMENTAL ORIGIN | C. ROBALO CORDEIRO ET AL.
Epidemiology
There is limited information on the incidence and prevalence of HP. As it is an
exposure-associated disease, there is wide variation in its incidence related to geographical area,
customs and climate, but probably also diversity in genetic predisposition [3]. HP occurs in all
age groups and both sexes, with a median age at diagnosis of 50–60 years. The most common
types of HP are bird-fancier’s disease and farmer’s lung [1].
A recent hospital-based European study performed on six countries reported an incidence of

0.3–3.2 cases per 100 000 person-years and a prevalence of 1.9–14.3 cases per
100 000 person-years, with Portugal displaying the highest prevalence compared with other
participating countries [4].
Pathogenesis
The development of HP is dependent on the interplay between the inciting agent, the specific
environment where the exposure is occurring and the host’s genetic background. The list of
known causal antigens is extensive, and includes animal and plant proteins, microorganisms,
enzymes and chemicals. Most are organic and are thus recognised by antigen-presenting cells, but
some are chemicals and act as haptens after linking to host albumin, creating a new antigen [5, 6].
Following exposure and antigen presentation, individuals may become sensitised to these
antigens, producing specific antibodies that can be detected in the serum. The progression to overt
disease only occurs in some subjects, possibly due to the need for a second hit, which may be a
viral infection or exposure to air pollution [7, 8]. The disease pathways are highly heterogeneous,
with some patients showing acute disease and others a more persistent course, with some of these
progressing to fibrosis, which is associated with a worse prognosis. This course is partly related to
the exposure pattern and magnitude of exposure, with intermittently high exposure levels leading
to acute disease and continuous low-level exposure leading to the chronic form [6].
The immunopathogenesis of HP involves both cellular and humoral mechanisms. The main
mediators are antigen-specific immunoglobulins (Igs) (type III hypersensitivity) in patients with
acute disease and T-helper (Th) cells (type IV hypersensitivity) in chronic forms. As well as
cells and immunoglobulins, a wide network of immune signalling molecules is involved,
following a Th1 pattern during the development of the disease, which transitions to a Th2-like
pattern when the disease becomes chronic and fibrotic [9]. The determinants of progression to
fibrosis are incompletely known, but some types of antigen (avian proteins) and a chronic
low-level pattern of exposure are associated with increased risk for this outcome. Smoking and
a higher age are also associated with a higher risk of fibrosis [1]. Genetic mechanisms are also
involved. Patients with shorter leukocyte telomere lengths are less responsive to
immunosuppression and have a worse prognosis [10]. The mechanisms for this development are
partially shared with those for idiopathic pulmonary fibrosis (IPF) and include expansion of the
fibroblast population, which differentiates into myofibroblasts, leading to excess deposition of
extracellular matrix [11].
Diagnosis and treatment

The diagnosis of HP has been the focus of recent guidelines, one sponsored by the American
College of Clinical Pharmacy and another by the American Thoracic Society (ATS), Japanese
Respiratory Society ( JRS) and Asociación Latinoamericana del Tórax (ALAT) [12, 13]. The
recommendations are similar, but the latter is more reliant on pathology [14]. Most
recommendations mirror current clinical practice, which includes the recognition of adequate
exposure, typical HRCT findings, BAL and biopsy in selected cases. Testing for
https://doi.org/10.1183/2312508X.10017422 41
antigen-specific IgG antibodies could indicate potential inciting antigens, but clinicians should
not rely solely on this for confirming or ruling out the diagnosis. The disease is now classified
as fibrotic or nonfibrotic (figure 1). Fibrotic disease shows signs of fibrosis on HRCT or on
biopsy and has a distinctively worse prognosis. As for any ILD, the value of multidisciplinary
discussion cannot be overemphasised [15].
Data on HP treatment are scarce, and most recommendations are based on retrospective cohorts
and expert opinion. A strong recommendation for elimination of the causal antigen is generally
agreed. The use of steroids and immunosuppressants is common, with mycophenolate being as
effective as azathioprine [16]. One clinical trial supported the use of nintedanib for progressive
pulmonary fibrosis (PPF), including progressive fibrotic HP [17], leading to approval of
nintedanib by the European Medicines Agency (EMA) and US Food and Drug Administration
(FDA), and inclusion of this recommendation in the ATS/ERS/JRS/ALAT guidelines for the
treatment of IPF and PPF [18]. Another antifibrotic, pirfenidone, was tested on patients with PPF
in the RELIEF trial (Exploring efficacy and safety of oral pirfenidone for progressive, non-IPF
lung fibrosis), which included a subgroup of 57 patients with HP. Despite premature termination,
the group given pirfenidone showed a slower decline in FVC percentage at 48 weeks [19].
In line with other chronic ILDs, HP patients may benefit from oxygen therapy, rehabilitation,
management of comorbidities, lung transplantation (LTx) and palliative care [20–24].
Prognosis
The prognosis of HP is quite variable, in line with the disease heterogeneity. A significant
proportion of patients with fibrotic HP show progression and fulfil the PPF phenotype, which
has a prognosis similar to IPF [18]. Additional predictors of worsening prognosis include lack
of identification of the inciting antigen, worse lung function and PH [1, 25].
Pneumoconiosis
Definition
Environmental or occupational exposure to inorganic dusts can induce lung injury in different
pathological forms, depending on the morphological structure, aetiological agent involved, and
intensity or durability of the exposure. Pneumoconiosis is a heterogeneous group of ILDs,
mainly occupational, caused by inhalation of mineral dusts, primarily silica dust, coal dust,
a) b)
FIGURE 1 HRCT scans showing a) typical nonfibrotic hypersensitivity pneumonitis and b) fibrotic hypersensitivity
pneumonitis.
42 https://doi.org/10.1183/2312508X.10017422
asbestos fibres or mixed silicate dust [26]. The list of known occupational agents with
interstitial potential hazard, however, has increased significantly, and new sources of exposure
to “old” agents have emerged [27]. Despite much effort, pneumoconiosis is still prevalent
worldwide and its incidence has not declined in recent years. Worryingly, pneumoconiosis has
re-emerged, even in countries with highly developed standards of workplace safety procedures,
adequate health systems and good control practices that reduce workers’ exposure to
particles [28, 29].
Epidemiology
Epidemiological data remain scarce, mainly because of the long latency period of the disease
and the lack of standardised diagnostic criteria [30]. Official international registries often lack
homogeneity in diagnostic criteria, data sources or data analysis.
According to the Global Burden of Disease studies [31–34], there has been a decrease in the
worldwide prevalence of pneumoconiosis since 2015, although this still involves a large number
of patients, with a prevalence of approximately 527 500 cases, and more than 60 000 new
patients reported in 2017 globally [31]. The mortality rate for pneumoconiosis patients has been
more than 21 000 deaths per year since 2015 [33, 34]. The patterns of incidence for different
aetiologies are heterogeneous across regions and among countries. The most prevalent
pneumoconioses worldwide are silicosis, coal worker’s pneumoconiosis and asbestosis, but
other forms of pneumoconiosis may account for up to 25% [34].
It is likely that these numbers are underestimated due to a lack of reporting, inadequate reporting
systems, and even social and economic constraints, as the diagnosis of pneumoconiosis may lead
to job loss. This is particularly concerning in developing countries and may account for the
higher-than-anticipated rates of morbidity and mortality due to pneumoconiosis.
New sources of exposure and aetiological agents are also emerging. Reports of silicosis among
denim sandblasting workers [35], China’s tatami mat manufacturers [36], artificial stone workers [37]
and dental supply factory workers [38] are some examples of new or previously unsuspected
sources. Some additional underestimated exposures (bystander exposures) relate to co-workers,
spouses or nearby exposures. Good examples are the occurrence of chronic beryllium disease
(CBD) and asbestos-related disease in household members of exposed individuals and in
communities with significant environmental contamination [39, 40].
Pathogenesis
Although the pathogenic mechanisms of pneumoconiosis are not fully understood, it is known
that host and exposure factors are complementary and that both are necessary for development
of the disease [41, 42]. It is also understood that different aetiological agents may cause distinct
pathogenic responses.
Substantial research has been performed over the past decade regarding the molecular
mechanisms of dust-induced lung damage. When dust is inhaled, the larger particulates are
deposited on the mucosa of the upper airways and cleared by mucociliary transport, while the
smaller particles reach the alveoli and are phagocytosed by alveolar macrophages. A high
particulate burden rapidly overwhelms these mechanisms, and cellular and humoral responses
are then triggered [43]. The key mechanisms leading to fibrogenesis are oxidative stress and
activation of inflammatory target cells with subsequent release of various mediators, especially
following exposure to fibrous and nonfibrous dusts. For these agents, cumulative exposure is the
determinant for fibrosis [41, 44]. The best-known mechanism has been described for silicosis
https://doi.org/10.1183/2312508X.10017422 43
where silica particles are phagocytised by alveolar macrophages, which in turn upregulate
several pro-inflammatory and pro-fibrotic pathways. The interleukin (IL)-1 signalling pathway is
stimulated directly by macrophages and indirectly via Toll-like receptors, which in turn produce
IL-1, tumour necrosis factor (TNF) and capase-1, stimulating fibroblast growth factor.
Inflammation and fibrosis can occur independently of lymphocyte interaction by modulation of
the NALP3 (NACHT, LLR and PYD domains containing protein 3) inflammasome (similar to
asthma), which increases expression of cytotoxic T-lymphocyte antigen 4, IL-10 and
transforming growth factor-β by regulatory T-cells [45].
Another mechanism involving the immune system is immune sensitisation, which can result in
immune-mediated inflammation and fibrosis, as has been described for CBD but also for other
metal and organic exposures [46, 47].
Identification of markers of prediction and early detection of pneumoconiosis are essential for
the implementation of timely intervention and would be helped by a thorough understanding of
the mechanisms involved. Current research is focused on biomarkers of exposure, effect and
susceptibility for this disease [48, 49].
To identify high-risk individuals, we need to understand the role of genetic variability and the
interaction between genetic and environmental factors. In CBD, a positive correlation with a
polymorphism of the human leukocyte antigen-DP β1-chain gene (Glu69) was found,
suggesting that this is a risk factor for beryllium sensitisation. TNF-α polymorphisms have also
been associated with silicosis and coal workers’ susceptibility to pneumoconiosis [50, 51].
Diagnosis and treatment

The diagnosis of pneumoconiosis still relies on three major criteria: 1) sufficient exposure in
time and intensity to a known inorganic agent, 2) compatible radiographic changes, and
3) exclusion of a mimicking disease [26]. Although respiratory signs and symptoms, together
with functional impairment, are frequently found, neither is a requisite for diagnosis. In contrast,
a solid exposure history with an identifiable agent is a determining factor and all efforts should
be made to identify the possible source of harmful dust.
Chest radiography is of particular value, and international guidelines on the interpretation of

radiological changes have been published and updated by the International Labour Organization [52].
However, the various forms of pneumoconiosis may have nonspecific radiographic features,
which often do not correlate with the severity of the disease. HRCT is a more sensitive tool for
diagnosis for pneumoconiotic lesions and can be used for more accurate categorisation of the
parenchymal changes in this disease (figure 2). The International Classification of
High-resolution Computed Tomography for Occupational and Environmental Respiratory
Diseases (ICOERD) has therefore developed and recommended a list of diagnoses for
occupation- and environment-related lung diseases. However, there is currently no global
standard. Ideally, a combination of conventional thick-section CT and thin-section HRCT scans
would be used for the early detection of pneumoconiotic micronodules. The use of spiral CT
scans can also aid in early detection and is helpful in asbestos-related pleural disease [53].
PFTs are used to monitor the disease. Most frequently, patients show a predominant restrictive
defect but occasionally may show an obstructive or mixed pattern. The severity of radiological
abnormalities relates to the impairment in lung function [54]. Abnormal transfer factor of the
lung for carbon monoxide may be the presenting functional feature, even in the presence of
normal spirometry [55].
44 https://doi.org/10.1183/2312508X.10017422
a) b)
c) d)
FIGURE 2 HRCT scans showing a and b) chronic simple silicosis, and c and d) complicated silicosis ( progressive
massive fibrosis).
BAL or induced sputum analysis can sometimes be used to confirm the diagnosis by
demonstrating dust-laden macrophages by electron microscopy [56, 57]. Light microscopy can
detect asbestos bodies, and their number is a useful indication of the asbestos burden. The
beryllium lymphocyte proliferation test is also a useful diagnostic tool [58].
Rarely, a biopsy is needed to confirm the diagnosis and elucidate some specific pneumoconiotic
features, such as birefringent particles within lung tissue, silicotic nodules, coal macules or
asbestos fibres. Video-assisted thoracic surgical lung biopsy is the gold standard, but other
forms of biopsy may be appropriate.
There is no effective treatment for pneumoconiosis capable of inducing regression or stopping

progression of the disorder, except for CBD. After diagnosis, cessation of exposure is
mandatory for the patient and co-workers [26]. However, some published data confirm
progression of the disease even in the absence of further exposure [26].
An integrated approach is recommended, addressing the symptoms and complications of the

disease and reinforcing the utility of pulmonary rehabilitation [21, 59, 60]. Smoking cessation
and latent tuberculosis treatment are complementary measures. Bronchodilators may help
obstructive patients and corticosteroids may alleviate symptoms and improve lung function in
CBD, despite the absence of controlled randomised trials [58].
https://doi.org/10.1183/2312508X.10017422 45
Recently, two antifibrotic drugs were trialled in PPF other than IPF, leading to the approval of
nintedanib by the EMA and FDA and the inclusion of this recommendation in the ATS/ERS/
JRS/ALAT guidelines for the treatment of IPF and PPF [18]. In the INBUILD study (Efficacy
and safety of nintedanib in patients with progressive fibrosing interstitial lung disease), 39
patients with exposure-induced ILD participated, but the trial was not powered to determine the
benefit in specific disease groups. The other antifibrotic, pirfenidone, was tested in the RELIEF
trial, which included a subgroup of six patients with asbestosis. Despite premature termination,
the group given pirfenidone showed a slower decline in FVC percentage at 48 weeks [19].
These results raise the possibility of a clinical benefit for patients with pneumoconiosis and a
progressive fibrotic phenotype.
Pneumoconiosis patients may also benefit from oxygen therapy, LTx and palliative care [20, 24, 61].
Prognosis and prevention

Prognosis in pneumoconiosis is highly dependent on the inciting agent and stage of disease. As
most patients are diagnosed at advanced stages, prognosis is poor. Moreover, sustained exposure
leads to progressive lung impairment and lack of stabilisation. In the absence of a specific
treatment or cure, disease progression is inevitable.
It is therefore essential that prevention measures are implemented and controlled. Elimination or
substitution of the hazardous agent is the preferred method, beyond the setting of standards of
occupational exposure to respirable dust contents, engineering control and individual protective
equipment [62].
Specific environments and exposures associated with rare ILDs

Farming
Organic dust toxic syndrome is an acute disease caused by inhalation of organic dust
contaminated with microorganisms. The clinical manifestations of the disease are similar to
acute HP and include dyspnoea, fever, myalgia and cough, starting 4–8 h after exposure [63].
It has been reported in agricultural workers, swine breeders and shrimp-processing workers
[64–66]. One fundamental difference from HP is that organic dust toxic syndrome results from
an inflammatory response to endotoxin and is not antibody mediated, so there is no sensitisation
or progression to chronic disease. The treatment is supportive, and prevention includes the
use of personal protective equipment whenever there is exposure to high levels of organic
dusts [63, 67].
Silo filler’s disease results from a direct toxic effect of nitrogen dioxide (NO2). This gas is
produced by fermentation of green materials to which workers may be exposed when entering
the silo. The severity of the acute disease is variable but can progress to acute respiratory
distress syndrome, which may be fatal. Treatment includes immediate removal from exposure,
supportive treatment and steroids for acute respiratory distress syndrome. A subacute form of the
disease caused by prolonged low levels of exposure to NO2 has also been reported. The disease
pattern is suggestive of bronchiolitis obliterans, but symptoms tend to resolve on cessation of
exposure and steroid treatment [68–70].
Food manufacturing
The use of diacetyl for creating an artificial butter flavour on popcorn, coffee beans and cookie
dough has been associated with the development of obstructive bronchiolitis in exposed workers
known as “popcorn lung” [71–73]. Affected individuals usually present ∼1.5 years after starting
exposure with dyspnoea and cough and have a fixed obstructive pattern on PFTs. HRCT
46 https://doi.org/10.1183/2312508X.10017422
typically shows signs of air trapping and mosaic attenuation. Unfortunately, the disease can
progress, despite removal from exposure. The only effective known treatment is LTx [74].
Substitutes for diacetyl have been created, but these can also be associated with the same
disease [75]. The use of engineering controls can reduce exposure, and screening of those
exposed with immediate removal on loss of function is recommended [74].
Textile manufacturing
Flock worker’s lung is caused by the inhalation of fine nylon particles, generated by the
industrial process of flocking in which short synthetic fibres are applied to fabric, creating plush
material. The typical disease pattern is of lymphocytic bronchiolitis, with persistent dyspnoea
and cough, a restrictive pattern on PFTs and peripheral ground-glass infiltrates on HRCT with
variable degrees of fibrosis [76]. Cessation of exposure leads to recovery in most patients. The
disease can be prevented by improved industrial processes [77].
The use of textile print spray with Acramin FWN (a polyamide amine) was associated with
occupational organising pneumonia in 1992 [78]. The disease was named Ardystil syndrome
after the name of the company where the first deaths occurred. The outbreak affected 72
workers, mostly young females, and caused six deaths, serving as a dire example of how
important is to be alert to new occupational exposure diseases [79, 80].
Nanoparticles
Nanoparticles are engineered structures produced by chemical and/or physical processes, with
a diameter of <100 nm; they have specific properties that are not usually displayed at
a macro-scale [81]. The occupational health risks of nanomaterials remain uncertain [82].
Nanoparticles can be produced from carbon (e.g. nanotubes, nanowires, fullerenes), metals
(e.g. gold, silver, quantum dots, titanium or zinc metal oxides) and even biological materials
(e.g. liposomes, viruses for gene or drug delivery) [83].
Silica and titanium nanoparticles are the most frequently used nanomaterials [84] and have been
reported to trigger inflammation [85]. Carbon nanotubes are a highly representative product of
nanotechnology and have been used in a number of commercial products such as rechargeable
batteries and automotive parts [86]. Electron microscopy has shown that some carbon nanotubes
have a needle-like structure similar to asbestos, and animal studies have indicated that they can
demonstrate asbestos-like pathogenic behaviour [87].
Indium lung
Indium–tin oxide is a sintered mixture of indium oxide (In2O3) and tin oxide (SnO2) that is
used to manufacture liquid crystal display (LCD) screens and related high-technology
applications [88]. A number of studies have shown a relationship between indium–tin exposure
and ILDs, with a direct correlation between exposure and the levels of indium in serum [89].
Reported latencies range from 1 to 5 years, and chronic symptoms are reported as progressive
dyspnoea, cough and/or sputum. Analysis by HRCT shows a fine reticulonodular pattern,
ground-glass areas and emphysema. Peribronchiolar fibrosis is seen, as well as foreign body
giant cells and intra-alveolar accumulations of macrophages containing indium visible as brown
particles [89]. Alveolar proteinosis has also been described [90], and animal studies suggest
that a variety of lung processes may be relatable to indium exposure, including alveolar
proteinosis [91].
https://doi.org/10.1183/2312508X.10017422 47
TABLE 1 Proposal for a strategy for searching and managing exposure and exposure risk according to
the condition
Condition Search for exposure Aims
ILD of unknown cause Causal exposures (organic, Reach a specific diagnosis through a
nonorganic, smoking, MDT meeting
e-cigarettes)
Consider the use of IgGs
Nonexposure-related ILD (e.g. IPF, Potential noxious exposures Prevent exposure-related worsening
autoimmune ILD, sarcoidosis)
Exposure-related ILD Specific cause or causes for Prevent progression, by elimination of
(e.g. HP, pneumoconiosis, the disease further exposure
smoking-related ILD, EVALI)
No ILD Any noxious exposure Promote individual and community
respiratory health; primary prevention
IPF: idiopathic pulmonary fibrosis; HP: hypersensitivity pneumonitis; EVALI: e-cigarette or vaping use-associated
lung injury; Ig: immunoglobulin; MDT: multidisciplinary team.
Effects of environmental exposure on other ILDs

As well as being the cause of some ILDs, environmental exposure can also have an effect on
the development of most ILDs. Some occupational exposures have been investigated showing
an association between occupational exposures and the risk of idiopathic and autoimmune ILDs
(table 1). There is a higher risk for IPF in those with exposure to metal, wood, stone or sand
dust, and in those raising birds or livestock or working in agriculture. Likewise, occupational
exposure to silica, asbestos, textile dust, pesticides, mineral oil and organic solvents has been
linked with rheumatoid arthritis risk, and scleroderma is associated with exposure to crystalline
silica, trichlorethylene, chlorinated solvents, welding fumes and many types of solvent [92, 93].
A recent systematic review reported a high occupational population attributable fraction in IPF,
sarcoidosis, HP and pulmonary alveolar proteinosis, among other diseases [94]. Other studies
have found an association between exposure to particulate matter and the rate of lung function
decline in IPF patients [95]. There is a well-known association between occupational exposure
to silica and scleroderma [96], as well as between coal exposure and rheumatoid arthritis [42].
A model where environmental exposure is considered as a risk factor for ILD, acting together
with genetic or acquired susceptibility and other cofactors, has been proposed [97]. The
identification of any environmental exposure must be part of the assessment of any patient with
new or progressing lung disease, including a discussion with occupational disease experts where
needed [98, 99].
References
1 Costabel U, Miyazaki Y, Pardo A, et al. Hypersensitivity pneumonitis. Nat Rev Dis Primers 2020; 6: 65.
2 Barnes H, Jones K, Blanc P. The hidden history of hypersensitivity pneumonitis. Eur Respir J 2022; 59: 2100252.
3 Freitas C, Lima B, Martins N, et al. Cytokine gene polymorphisms in pigeon breeder’s disease expression.
Sarcoidosis Vasc Diffuse Lung Dis 2020; 37: e2020004.
4 Hilberg O, Hoffmann-Vold AM, Smith V, et al. Epidemiology of ILDs and their progressive-fibrosing behaviour in
six European countries. ERJ Open Res 2021: 00597-02021.
5 Girard M, Lacasse Y, Cormier Y. Hypersensitivity pneumonitis Allergy 2009; 64: 322–334.
6 Nogueira R, Melo N, Novais EBH, et al. Hypersensitivity pneumonitis: antigen diversity and disease implications.
Pulmonology 2019; 25: 97–108.
7 Cormier Y, Israël-Assayag E. The role of viruses in the pathogenesis of hypersensitivity pneumonitis. Curr Opin
Pulm Med 2000; 6: 420–423.
8 Singh S, Collins BF, Bairwa M, et al. Hypersensitivity pneumonitis and its correlation with ambient air pollution
in urban India. Eur Respir J 2019; 53: 1801563.
48 https://doi.org/10.1183/2312508X.10017422
9 Barrera L, Mendoza F, Zuñiga J, et al. Functional diversity of T-cell subpopulations in subacute and chronic
hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008; 177: 44–55.
10 Adegunsoye A, Morisset J, Newton CA, et al. Leukocyte telomere length and mycophenolate therapy in chronic
hypersensitivity pneumonitis. Eur Respir J 2021; 57: 2002872.
11 Wuyts WA, Agostini C, Antoniou KM, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J
2013; 41: 1207–1218.
12 Fernández Pérez ER, Travis WD, Lynch DA, et al. Diagnosis and evaluation of hypersensitivity pneumonitis:
CHEST guideline and expert panel report. Chest 2021; 160: e97–e156.
13 Raghu G, Remy-Jardin M, Ryerson CJ, et al. Diagnosis of hypersensitivity pneumonitis in adults. An official ATS/
JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2020; 202: e36–e69.
14 Buendia-Roldan I, Aguilar-Duran H, Johannson KA, et al. Comparing the performance of two recommended
criteria for establishing a diagnosis for hypersensitivity pneumonitis. Am J Respir Crit Care Med 2021; 204:
865–868.
15 Glenn LM, Troy LK, Corte TJ. Diagnosing interstitial lung disease by multidisciplinary discussion: a review. Front
Med (Lausanne) 2022; 9: 1017501.
16 Morisset J, Johannson KA, Vittinghoff E, et al. Use of mycophenolate mofetil or azathioprine for the
management of chronic hypersensitivity pneumonitis. Chest 2017; 151: 619–625.
17 Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med
2019; 381: 1718–1727.
18 Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive
pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med
2022; 205: e18–e47.
20 Jacobs SS, Krishnan JA, Lederer DJ, et al. Home oxygen therapy for adults with chronic lung disease. An official
American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2020; 202: e121–e141.
21 Dowman L, Hill CJ, May A, et al. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst
Rev 2021; 2: CD006322.
22 Wälscher J, Gross B, Morisset J, et al. Comorbidities and survival in patients with chronic hypersensitivity
pneumonitis. Resp Res 2020; 21: 12.
23 Kern RM, Singer JP, Koth L, et al. Lung transplantation for hypersensitivity pneumonitis. Chest 2015; 147:
1558–1565.
24 Kreuter M, Bendstrup E, Russell AM, et al. Palliative care in interstitial lung disease: living well. Lancet Respir
Med 2017; 5: 968–980.
25 Fernández Pérez ER, Swigris JJ, Forssén AV, et al. Identifying an inciting antigen is associated with improved
survival in patients with chronic hypersensitivity pneumonitis. Chest 2013; 144: 1644–1651.
26 Qi XM, Luo Y, Song MY, et al. Pneumoconiosis: current status and future prospects. Chin Med J 2021; 134:
898–907.
27 Robalo Cordeiro C, Alfaro TN, Freitas S, et al. Rare interstitial lung diseases of environmental origin. In: Cordier
J-F, ed. Orphan Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2011; pp. 301–316.
28 Hoy RF, Brims F. Occupational lung diseases in Australia. Med J Aust 2017; 207: 443–448.
29 Blackley DJ, Halldin CN, Laney AS. Continued increase in prevalence of coal workers’ pneumoconiosis in the
United States, 1970–2017. Am J Public Health 2018; 108: 1220–1222.
30 Glazer CS, Newman LS. Occupational interstitial lung disease. Clin Chest Med 2004; 25: 467–478.
31 GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence,
prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–
2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392: 1789–1858.
32 GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence,
prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for
the Global Burden of Disease Study 2015. Lancet 2016; 388: 1545–1602.
33 GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282
causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of
Disease Study 2017. Lancet 2018; 392: 1736–1788.
34 Shi P, Xing X, Xi S, et al. Trends in global, regional and national incidence of pneumoconiosis caused by
different aetiologies: an analysis from the Global Burden of Disease Study 2017. Occup Environ Med 2020; 77:
407–414.
35 Akgun M, Araz O, Akkurt I, et al. An epidemic of silicosis among former denim sandblasters. Eur Respir J 2008;
32: 1295–1303.
https://doi.org/10.1183/2312508X.10017422 49
36 Xiao GB, Morinaga K, Wang RY, et al. World at work: manufacturing “tatami” mats in China. Occup Environ Med
2004; 61: 372–373.
37 Leso V, Fontana L, Romano R, et al. Artificial stone associated silicosis: a systematic review. Int J Environ Res
Public Health 2019; 16: 568.
38 de la Hoz RE, Rosenman K, Borczuk A. Silicosis in dental supply factory workers. Respir Med 2004; 98: 791–794.
39 Maier LA, Martyny JW, Liang J, et al. Recent chronic beryllium disease in residents surrounding a beryllium
facility. Am J Respir Crit Care Med 2008; 177: 1012–1017.
40 Peipins LA, Lewin M, Campolucci S, et al. Radiographic abnormalities and exposure to asbestos-contaminated
vermiculite in the community of Libby, Montana, USA. Environ Health Perspect 2003; 111: 1753–1759.
41 Demets M, Nemery B, Elmes P. Pneumoconioses. In: Gibson J, Geddes D, Costabel U, et al., eds. Respiratory
Medicine. London, Saunders, 2003; pp. 675–690.
42 Nemery B, Bast A, Behr J, et al. Interstitial lung disease induced by exogenous agents: factors governing
susceptibility. Eur Respir J Suppl 2001; 32: 30s–42s.
43 Seaman DM, Meyer CA, Kanne JP. Occupational and environmental lung disease. Clin Chest Med 2015; 36:
249–268.
44 Rimal B, Greenberg AK, Rom WN. Basic pathogenetic mechanisms in silicosis: current understanding. Curr Opin
Pulm Med 2005; 11: 169–173.
45 Barnes H, Goh NSL, Leong TL, et al. Silica-associated lung disease: an old-world exposure in modern industries.
Respirology 2019; 24: 1165–1175.
46 Kreiss K, Day GA, Schuler CR. Beryllium: a modern industrial hazard. Annu Rev Public Health 2007; 28: 259–277.
47 McCleskey TM, Buchner V, Field RW, et al. Recent advances in understanding the biomolecular basis of chronic
beryllium disease: a review. Rev Environ Health 2009; 24: 75–115.
48 Gulumian M, Borm PJ, Vallyathan V, et al. Mechanistically identified suitable biomarkers of exposure, effect,
and susceptibility for silicosis and coal-worker’s pneumoconiosis: a comprehensive review. J Toxicol Environ
Health B Crit Rev 2006; 9: 357–395.
49 Matsuzaki H, Kumagai-Takei N, Lee S, et al. Search for biomarkers of asbestos exposure and asbestos-induced
cancers in investigations of the immunological effects of asbestos. Environ Health Prev Med 2017; 22: 53.
50 Borm PJ, Schins RP. Genotype and phenotype in susceptibility to coal workers’ pneumoconiosis. The use of
cytokines in perspective. Eur Respir J Suppl 2001; 32: 127s–133s.
51 Yucesoy B, Luster MI. Genetic susceptibility in pneumoconiosis. Toxicol Lett 2007; 168: 249–254.
52 International Labour Office. Guidelines for the use of the ILO international classification of radiographs of
pneumoconioses. Geneva, International Labour Office, 2011.
53 Walkoff L, Hobbs S. Chest imaging in the diagnosis of occupational lung diseases. Clin Chest Med 2020; 41:
581–603.
54 Blackley DJ, Laney AS, Halldin CN, et al. Profusion of opacities in simple coal worker’s pneumoconiosis is
associated with reduced lung function. Chest 2015; 148: 1293–1299.
55 Gandhi SA, Cohen RA, Blanc PD, et al. Early radiographic pneumoconiosis is associated with impaired exercise
gas exchange among coal miners with normal resting spirometry. Am J Ind Med 2021; 64: 453–461.
56 Cordeiro CR, Jones JC, Alfaro T, et al. Bronchoalveolar lavage in occupational lung diseases. Semin Respir Crit
Care Med 2007; 28: 504–513.
57 Fireman E. Induced sputum and occupational diseases other than asthma. Curr Opin Allergy Clin Immunol 2009;
9: 93–96.
58 Balmes JR, Abraham JL, Dweik RA, et al. An official American Thoracic Society statement: diagnosis
and management of beryllium sensitivity and chronic beryllium disease. Am J Respir Crit Care Med 2014; 190:
e34–e59.
59 Cockcroft AE, Saunders MJ, Berry G. Randomised controlled trial of rehabilitation in chronic respiratory
disability. Thorax 1981; 36: 200–203.
60 Dowman LM, McDonald CF, Hill CJ, et al. The evidence of benefits of exercise training in interstitial lung
disease: a randomised controlled trial. Thorax 2017; 72: 610–619.
61 Joubert KD, Awori Hayanga J, Strollo DC, et al. Outcomes after lung transplantation for patients with
occupational lung diseases. Clin Transplant 2019; 33: e13460.
62 Cullinan P, Muñoz X, Suojalehto H, et al. Occupational lung diseases: from old and novel exposures to effective
preventive strategies. Lancet Respir Med 2017; 5: 445–455.
63 Seifert SA, von Essen S, Jacobitz K, et al. Organic dust toxic syndrome: a review. J Toxicol Clin Toxicol 2003; 41:
185–193.
64 Rask-Andersen A. Organic dust toxic syndrome among farmers. Br J Ind Med 1989; 46: 233–238.
65 Vogelzang PF, van der Gulden JW, Folgering H, et al. Organic dust toxic syndrome in swine confinement
farming. Am J Ind Med 1999; 35: 332–334.
66 Bertelsen RJ, Svanes Ø, Madsen AM, et al. Pulmonary illness as a consequence of occupational exposure to
shrimp shell powder. Environ Res 2016; 148: 491–499.
50 https://doi.org/10.1183/2312508X.10017422
67 Centers for Disease Control and Prevention. NIOSH alert: request for assistance in preventing organic dust toxic
syndrome. MMWR Morb Mortal Wkly Rep 1994; 43: 486.
68 Douglas WW, Hepper NG, Colby TV. Silo-filler’s disease. Mayo Clin Proc 1989; 64: 291–304.
69 Amaza IP, Kreidy MP. Silo-filler’s disease: one health system’s experience and an update of the literature.
J Agromedicine 2020; 25: 8–13.
70 Epler GR. Silo-filler’s disease: a new perspective. Mayo Clin Proc 1989; 64: 368–370.
71 Kreiss K, Gomaa A, Kullman G, et al. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant.
N Engl J Med 2002; 347: 330–338.
72 Centers for Disease Control and Prevention. Obliterative bronchiolitis in workers in a coffee-processing facility –
Texas, 2008–2012. MMWR Morb Mortal Wkly Rep 2013; 62: 305–307.
73 Cavalcanti Zdo R, Albuquerque Filho AP, Pereira CA, et al. Bronchiolitis associated with exposure to artificial
butter flavoring in workers at a cookie factory in Brazil. J Bras Pneumol 2012; 38: 395–399.
74 Rose CS. Early detection, clinical diagnosis, and management of lung disease from exposure to diacetyl.
Toxicology 2017; 388: 9–14.
75 Holden VK, Hines SE. Update on flavoring-induced lung disease. Curr Opin Pulm Med 2016; 22: 158–164.
76 Kern DG, Crausman RS, Durand KT, et al. Flock worker’s lung: chronic interstitial lung disease in the nylon
flocking industry. Ann Intern Med 1998; 129: 261–272.
77 Turcotte SE, Chee A, Walsh R, et al. Flock worker’s lung disease: natural history of cases and exposed workers
in Kingston, Ontario. Chest 2013; 143: 1642–1648.
78 Turuguet D, Pou R. Outbreak of organising pneumonia in textile sprayers. Lancet 1994; 344: 1168.
79 Montoro A, Sebastià N, Hervás D, et al. Analysis of the possible persistent genotoxic damage in workers linked
to the ardystil syndrome. Genet Test Mol Biomarkers 2016; 20: 94–97.
80 Moya C, Martí Boscà JV. [30 years since Ardystil Syndrome]. Arch Prev Riesgos Labor 2022; 25: 353–357.
81 Gwinn MR, Vallyathan V. Nanoparticles: health effects – pros and cons. Environ Health Perspect 2006; 114: 1818–
1825.
82 Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (NIOSH).
Approaches to Safe Nanotechnology. Managing the Health and Safety Concerns Associated with Engineered
Nanomaterials. Washington, NIOSH, 2009. www.cdc.gov/niosh/docs/2009-125/pdfs/2009-125.pdf
83 Bonner JC. Nanoparticles as a potential cause of pleural and interstitial lung disease. Proc Am Thorac Soc 2010;
7: 138–141.
84 Mitrano DM, Motellier S, Clavaguera S, et al. Review of nanomaterial aging and transformations through the life
cycle of nano-enhanced products. Environ Int 2015; 77: 132–147.
85 Yazdi AS, Guarda G, Riteau N, et al. Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3)
inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β. Proc Natl Acad Sci U S A
2010; 107: 19449–19454.
86 de Volder MF, Tawfick SH, Baughman RH, et al. Carbon nanotubes: present and future commercial applications.
Science 2013; 339: 535–539.
87 Vietti G, Lison D, van den Brule S. Mechanisms of lung fibrosis induced by carbon nanotubes: towards an
adverse outcome pathway (AOP). Part Fibre Toxicol 2016; 13: 11.
88 Suganuma N, Natori Y, Kurosawa H, et al. Update of occupational lung disease. J Occup Health 2019; 61: 10–18.
89 Chonan T, Taguchi O, Omae K. Interstitial pulmonary disorders in indium-processing workers. Eur Respir J 2007;
29: 317–324.
90 Cummings KJ, Donat WE, Ettensohn DB, et al. Pulmonary alveolar proteinosis in workers at an indium
processing facility. Am J Respir Crit Care Med 2010; 181: 458–464.
91 Tanaka A, Hirata M, Omura M, et al. Pulmonary toxicity of indium-tin oxide and indium phosphide after
intratracheal instillations into the lung of hamsters. J Occup Health 2002; 44: 99–102.
92 Park Y, Ahn C, Kim TH. Occupational and environmental risk factors of idiopathic pulmonary fibrosis: a
systematic review and meta-analyses. Sci Rep 2021; 11: 4318.
93 Diot E, Lesire V, Guilmot JL, et al. Systemic sclerosis and occupational risk factors: a case–control study. Occup
Environ Med 2002; 59: 545–549.
94 Blanc PD, Annesi-Maesano I, Balmes JR, et al. The occupational burden of nonmalignant respiratory diseases.
An official American Thoracic Society and European Respiratory Society statement. Am J Respir Crit Care Med
2019; 199: 1312–1334.
95 Winterbottom CJ, Shah RJ, Patterson KC, et al. Exposure to ambient particulate matter is associated with
accelerated functional decline in idiopathic pulmonary fibrosis. Chest 2018; 153: 1221–1228.
96 Boudigaard SH, Schlünssen V, Vestergaard JM, et al. Occupational exposure to respirable crystalline silica and
risk of autoimmune rheumatic diseases: a nationwide cohort study. Int J Epidemiol 2021; 50: 1213–1226.
97 Lee CT, Feary J, Johannson KA. Environmental and occupational exposures in interstitial lung disease. Curr
Opin Pulm Med 2022; 28: 414–420.
https://doi.org/10.1183/2312508X.10017422 51
98 Copeland CR, Collins BF, Salisbury ML. Identification and remediation of environmental exposures in patients
with interstitial lung disease: evidence review and practical considerations. Chest 2021; 160: 219–230.
99 Carlier S, Nasser M, Fort E, et al. Role of the occupational disease consultant in the multidisciplinary discussion
of interstitial lung diseases. Respir Res 2022; 23: 332.
Disclosures: C. Robalo Cordeiro reports the following, outside the submitted work: receipt of consulting fees from
Boehringer Ingelheim and Roche; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript
writing or educational events from Boehringer Ingelheim and Roche; payment for expert testimony
from Boehringer Ingelheim and Roche; and participation on a data safety monitoring board or advisory board for
Boehringer Ingelheim. T. Alfaro reports the following, outside the submitted work: receipt of consulting fees
from Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript
writing or educational events from Boehringer Ingelheim; support for attending meetings and/or travel from
Boehringer Ingelheim; participation on a data safety monitoring board or advisory board for Boehringer Ingelheim;
and a leadership or fiduciary role on a board, society, committee or advocacy group for Sociedade Portuguesa de
Pneumologia. S. Freitas reports the following, outside the submitted work: consultancy fees from Boehringer
Ingelheim; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational
events from Boehringer Ingelheim; support for attending meetings and/or travel from Boehringer Ingelheim; and
participation on a data safety monitoring board or advisory board for Boehringer Ingelheim.
52 https://doi.org/10.1183/2312508X.10017422
Chapter 5
Amyloidosis and the lungs and airways

1
Joshua A. Bomsztyk , Jennifer H. Pinney2 and Helen J. Lachmann1
1
UK National Amyloidosis Centre, Division of Medicine, University College London and Royal Free London NHS
Foundation Trust, London, UK. 2Dept of Renal Medicine, University Hospital Birmingham NHS Foundation Trust,
Birmingham, UK.
Corresponding author: Helen J. Lachmann (h.lachmann@ucl.ac.uk)
Cite as: Bomsztyk JA, Pinney JH, Lachmann HJ. Amyloidosis and the lungs and airways. In: Wagner TOF, Humbert M,
Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory
Society, 2023; pp. 53–68 [https://doi.org/10.1183/2312508X.10017522].
@ERSpublications
Amyloidosis can result in deposits in the respiratory system itself and also affects other respiratory
conditions. Management involves resection of symptomatic deposits for localised disease or treatment of
the underlying condition in acquired disease. https://bit.ly/ERSM100
ISSN: 2312-5098.
Amyloidosis can both complicate long-standing respiratory conditions and be deposited within the
respiratory system itself. In acquired systemic amyloidosis, control of the underlying condition that is
producing the circulating amyloid precursor protein is paramount. Systemic AA amyloidosis can result
from unremitting chronic inflammation or infection such as in bronchiectasis. Control of the
inflammation is paramount to amyloid regression. For systemic AL amyloidosis, treatment requires the
use of chemotherapy or novel immunotherapies targeting the underlying plasma cell dyscrasia or
lymphoproliferative disease that produce the abnormal amyloidogenic light chain. Localised amyloidosis
can occur anywhere along the respiratory tract and can present with marked heterogeneity. In localised
amyloidosis, management generally involves resection or ablation of symptomatic deposits. On occasion,
localised pulmonary amyloidosis can be a manifestation of underlying Sjögren syndrome. Novel
treatments are beginning to become available, including specific drug therapies to prevent translation of
amyloidogenic proteins, stabilise amyloid precursor proteins and interfere with amyloid fibrillogenesis.
Introduction
Amyloidosis is due to the deposition of abnormal insoluble fibrillar plasma proteins within the
extracellular space resulting in disruption of tissue structure and organ function. It may be
acquired or inherited, and at least 30 proteins can form amyloid fibrils (table 1) [2]. There are
essentially three circumstances in which amyloid deposition occurs: 1) with sustained
abnormally high abundance of normal proteins, such as serum amyloid A (SAA) protein in
chronic inflammation or β2-microglobulin in chronic renal failure; 2) when there is normal
abundance of an inherently amyloidogenic protein over a prolonged period, such as
transthyretin; and 3) in the presence of an abnormal protein that is amyloidogenic, such as
monoclonal immunoglobulin light chains in AL amyloidosis or genetic variants of transthyretin,
apolipoprotein AI and fibrinogen Aα-chain (table 1).
All amyloid fibrils possess the ability to bind molecules of the dye Congo red, resulting in the
pathognomonic apple-green birefringence when viewed under cross-polarised light. Amyloid
https://doi.org/10.1183/2312508X.10017522 53
TABLE 1 Classification of the common types of systemic amyloidosis in humans
Type Fibril protein precursor Clinical syndrome
AA Serum amyloid A protein Reactive systemic amyloidosis associated with chronic

inflammatory diseases
AL Monoclonal immunoglobulin light chains Systemic amyloidosis associated with monoclonal
plasma-cell dyscrasias
AH Monoclonal immunoglobulin heavy chains Systemic amyloidosis associated with monoclonal
plasma-cell dyscrasias
Aβ2M Normal plasma β2-microglobulin Periarticular and, occasionally, systemic amyloidosis
associated with long-term dialysis
Aβ2M Variant β2-microglobulin Autosomal-dominant hereditary systemic amyloidosis
ATTR Normal plasma transthyretin Wild-type systemic transthyretin amyloidosis with
prominent cardiac involvement
ATTR Genetically variant transthyretin Autosomal-dominant systemic amyloidosis; familial
amyloid polyneuropathy or cardiomyopathy
ACys Genetically variant cystatin C Hereditary cerebral haemorrhage with cerebral and
systemic amyloidosis
AGel Genetically variant gelsolin Autosomal-dominant systemic amyloidosis;
predominant cranial nerve involvement with lattice
corneal dystrophy
ALys Genetically variant lysozyme Autosomal-dominant systemic amyloidosis;
non-neuropathic with prominent visceral
involvement
AApoAI Genetically variant apolipoprotein AI Autosomal-dominant systemic amyloidosis;
predominantly non-neuropathic with prominent
visceral involvement
AApoAII Genetically variant apolipoprotein AII Autosomal-dominant systemic amyloidosis;
non-neuropathic with prominent renal involvement
AApoAIV Apolipoprotein AIV Sporadic systemic amyloidosis with predominant
cardiac and renal involvement
AApoCII Genetically variant apolipoprotein CII Autosomal-dominant systemic amyloidosis;
AApoCIII Genetically variant apolipoprotein CIII Autosomal-dominant systemic amyloidosis;
AFib Genetically variant fibrinogen Aα-chain Autosomal-dominant systemic amyloidosis;
ALect 2 Leukocyte chemotactic factor 2 Sporadic slowly progressive renal amyloidosis with
nephrotic syndrome and liver involvement
ALys Genetically variant lysozyme Autosomal-dominant systemic amyloidosis;
non-neuropathic with prominent renal and hepatic
involvement
Reproduced and modified from [1] with permission.
deposits always contain the normal plasma glycoprotein serum amyloid P (SAP) as a
nonfibrillar constituent. The universal presence of SAP in amyloid forms the basis for
diagnostic scintigraphic imaging of amyloid with radiolabelled SAP [3].
The phenotypes associated with amyloid deposition are diverse, ranging from an asymptomatic,
small, localised deposit to a systemic, rapidly lethal, multisystemic disease [4]. Amyloid deposits
are constantly turned over, and clinical progression reflects the situation when fibrillar deposition
is greater than clearance [5]. Amyloid deposits can therefore regress if this balance is tipped, and
current available therapies focus on halting the production of the amyloidogenic protein.
54 https://doi.org/10.1183/2312508X.10017522
AMYLOIDOSIS | J.A. BOMSZTYK ET AL.
Diagnosis of amyloidosis
Amyloidosis is a heterogeneous disease presenting to a variety of different medical specialties
including the respiratory physician. Chronic pulmonary conditions can give rise to systemic
amyloidosis, most commonly of AA type (table 1), due to prolonged inflammation.
Alternatively, patients may present with pulmonary amyloidosis, either localised to the
respiratory tract or as part of a systemic process [6]. Lastly, pulmonary complications may also
arise from treatment, especially in the context of AL amyloidosis (table 1).
The diagnostic gold standard is by histological confirmation through Congo red staining (figure 1)
[7, 8]. Alternative stains such as thioflavin T or S can be used but are generally reserved for the
research setting. Biopsy of any organ can be hazardous in amyloidosis, and there are reports of fatal
lung haemorrhage following transbronchial biopsy due to amyloid infiltration into the pulmonary
vasculature [9]. Haemorrhage is due to the increased fragility of the involved blood vessels, reduced
elasticity of amyloidotic tissues and, occasionally in AL type, due to an acquired factor IX or X
deficiency [10–12]. Alternatively, fine-needle aspiration has been used successfully in the respiratory
tract [13–15]. The fibril protein type is then determined using immunohistochemical (IHC) stains
[6, 16] or laser capture tandem mass spectrometry [17]. There are advantages and disadvantages to
each method. Generally, IHC is relatively inexpensive and useful in dual amyloid pathology but is
reliant on expertise in interpreting the results and is subject to false-positive rates, especially with
some commercial antibodies. In practice, type determination of amyloid by IHC should be
performed in specialist laboratories [18]. In contrast, MS techniques are generally more sensitive
but require a high level of technical expertise to perform and interpret. If a genetic variant is
suspected, more detailed analyses to look for specific mutations should be performed.
Following histological confirmation, the extent of deposition in the respiratory tract needs to be
ascertained, although this can be challenging. Plain radiography can be helpful but is generally
normal. CT scanning can further define ILD. More commonly, pulmonary nodular amyloidosis is
characterised on CT scan by a variable number of nodules, in a peripheral or bilateral subpleural
location, with well-defined contours, variable size, slow growth and occasionally cavitation that can
a) b)
FIGURE 1 a) Bronchial biopsy showing the characteristic histological appearance of amorphous amyloid deposits
stained with Congo red. b) The same section viewed under cross-polarised light demonstrating apple-green
birefringence.
https://doi.org/10.1183/2312508X.10017522 55
result in the formation of thin-walled, cystic-like lesions [19]. A more uncommon presentation is
diffuse amyloid infiltration between the alveolar septum and vessel wall, which can manifest on CT as
well-defined micronodules (2–4 mm diameter), reticulation, thickening of the interlobular septa and
peribronchovascular interstitium, ground-glass opacity, reticulonodular opacities or fine linear
subpleural opacity that may converge and consolidate [20]. CT-positron emission tomography
(CT-PET) can better define the metabolic activity of a solid lesion, differentiating amyloid from more
typical intrathoracic malignancies [21, 22]. MRI and bronchoscopy may be useful alongside
comprehensive PFTs. PFTs are an important objective tool to formally establish the severity of
clinically relevant disease and are useful in guiding therapeutic decisions [23, 24]. Evidence of
systemic disease should be sought clinically and by performing haematological and biochemical
profiles including serum-free light-chain assays, immunofixation of serum and urine, and bone marrow
examination to detect a potential subtle monoclonal disorder causing AL amyloidosis [25–28].
SAP scintigraphy is useful in visualising amyloid in solid organs; localisation to the lungs is
poor and of limited use in pulmonary amyloidosis [3]. Cardiac amyloidosis is best evaluated by
a combination of echocardiography, ECG and cardiac MRI. Amyloid causes diastolic
dysfunction with preserved contractility until a very late stage [29]. The ECG may show small
voltages, pathological “Q” waves ( pseudo-infarct pattern) in the anterior chest leads and
conduction abnormalities in advanced disease. Cardiac MRI is extremely useful in identifying
cardiac amyloid. Typical appearances are of homogeneous late gadolinium enhancement [30].
Technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy is a specific test for
ATTR amyloid (table 1), but only if there is no evidence of an underlying clonal disorder [31, 32].
Systemic AA amyloidosis
Systemic AA amyloidosis is a potential complication of any disorder associated with a sustained
acute-phase response (table 2). The prevalence of AA amyloid deposition in patients with
chronic inflammatory diseases is 3.6–5.8%, although a smaller proportion of patients have
clinically significant amyloidosis [33–35]. The amyloid fibrils are derived from the circulating
acute-phase reactant, SAA [36]. SAA is a high-density apolipoprotein and is synthesised by
hepatocytes under the regulation of cytokines including interleukin (IL)-1, IL-6 and tumour
necrosis factor-α [37]. Normally, the circulating concentration of SAA is around 1 mg·L−1, but
this can rise by more than 1000-fold in the presence of inflammation.
The median age at presentation is 48 years, and the median latency between presentation with a
chronic inflammatory disorder and clinically significant amyloidosis is almost two decades [38].
Bronchiectasis is the most common respiratory disease underlying AA amyloidosis in the UK,
accounting for 5% of cases. Patients with primary immunodeficiency are at higher risk and
should be closely monitored [39].
Lung neoplasia including Castleman tumours, lymphoma and adenocarcinoma account for 3%.
Castleman disease is a rare B-cell lymphoproliferative disorder often associated with marked
constitutional symptoms [40]. Acquired systemic amyloidosis is a recognised rare complication
and is usually of systemic AA type, occurring as a result of the persistent acute-phase response
[41–44]. In Castleman disease, there is production of IL-6 by the tumour, and anti-IL-6
therapies can be highly effective [43–48].
Other purely respiratory causes of AA amyloidosis are now fairly rare in the UK, although
tuberculosis remains in the developing world [49–51]. Other rare associations include cystic
fibrosis [52, 53], sarcoidosis [54] and Kartagener syndrome [55].
56 https://doi.org/10.1183/2312508X.10017522
TABLE 2 Conditions with respiratory manifestations associated with systemic AA amyloidosis
Category Disease
Chronic infections Bronchiectasis

Q fever
Subacute bacterial endocarditis
Tuberculosis
Other conditions predisposing to chronic infections Cystic fibrosis
Kartagener syndrome
Quadraplegia
Sickle-cell anaemia
Immunodeficiency states Common variable immunodeficiency
Cyclic neutropenia
Hyperimmunoglobulin M syndrome
Hypogammaglobulinaemia
Sex-linked agammaglobulinaemia
HIV/AIDS
Neoplasia Adenocarcinoma of the lung
Carcinoid tumour
Castleman disease
Hodgkin disease
Mesothelioma
Inflammatory arthritis Adult Still disease
Ankylosing spondylitis
Rheumatoid arthritis
Systemic vasculitis Behçet disease
Systemic lupus erythematosis
Other SAPHO syndrome
Sarcoidosis
Sinus histiocytosis with massive lymphadenopathy
SAPHO: synovitis, acne, pustulosis, hyperostosis, osteitis. Reproduced and modified from [1] with permission.
AA amyloidosis usually presents with proteinuria, nephrotic syndrome and progressive renal
failure [56]. Splenic involvement is almost universal but often asymptomatic. Hepatic
involvement and autonomic neuropathy are seen in advanced disease. Cardiac amyloidosis is
extremely rare. Respiratory tract involvement has not been a clinical feature.
The most effective form of basic screening is regular urinalysis in high-risk patients, as >95%
of patients with AA amyloidosis will have significant proteinuria. When the supply of fibril
precursor protein is substantially reduced for sustained periods, AA amyloid deposits frequently
regress and renal function can improve [38, 56, 57]. If the acute-phase response continues
unabated, progressive amyloid deposition often results in end-stage renal failure.
Treatment depends on the underlying diagnosis and may include surgery for cytokine-secreting
tumours or localised bronchiectasis, long-term antimicrobials and postural drainage for chronic
infections, immunosuppression in inflammatory diseases such as sarcoidosis and even lung
transplantation for bronchiectasis [58].
Almost 40% of patients with AA amyloidosis eventually require dialysis and have a median
survival of 53 months. Mortality is higher in the first year, and this has been attributed to
ongoing nephrotic syndrome and increased risk of sepsis [59, 60]. A minority of patients go on
to receive renal transplants [60–62].
https://doi.org/10.1183/2312508X.10017522 57
Systemic AL amyloidosis
AL amyloidosis is the commonest type of systemic amyloidosis, accounting for >60% of cases [63],
and can occur with any form of monoclonal B-cell dyscrasia. The precursor proteins are monoclonal
free light chains (FLCs) consisting of the whole or part of the variable (VL) domain [64].
A degree of amyloid deposition is seen in up to 15% of patients with myeloma, but >80% who
present with clinically significant AL amyloidosis have low levels of plasma-cell marrow infiltration
[65]. AL amyloidosis usually presents over the age of 50 years, although it can occur in young
adults [65]. Clinical manifestations are extremely variable, as almost any organ other than the brain
can be directly involved [66]. Although specific clinical features can be strongly suggestive of AL
amyloidosis (table 3), multiple vital organ dysfunction is common, and many patients present with
nonspecific symptoms such as malaise and weight loss. Current staging criteria are based on the
cardiac biomarkers troponin T and N-terminal prohormone of brain natriuretic peptide
(NTPro-BNP) [67]. Those with an NTProBNP level >8500 ng·L−1 or a systolic blood pressure of
<100 mmHg have the worst prognosis [68]. The outlook for untreated systemic AL amyloid is poor,
with a 5-year survival of ∼27% and a 10-year survival of 10% [65, 69]. Most affected individuals
eventually die of heart failure, uraemia or autonomic failure, and 24–37% die within 6 months of
diagnosis [70]. This concerns systemic AL amyloidosis, in contrast to localised AL amyloidosis
(discussed later), which is usually organ limited and overall has a better outcome.
Restrictive cardiomyopathy is the presenting feature in 30% of patients and ultimately the cause
of death in half [71]. Renal involvement is frequent in AL amyloidosis and presents in the same
manner as renal AA amyloid [72]. Gut involvement can cause motility disturbances,
malabsorption, perforation, haemorrhage or obstruction [73]. Peripheral neuropathy occurs in
20% of cases and typically presents with a painful sensory polyneuropathy [65]. Autonomic
neuropathy may occur with or without a peripheral neuropathy [66].
A number of pulmonary conditions can underlie systemic AL amyloidosis. An isolated thoracic

plasmacytoma can secrete enough monoclonal FLCs into the circulation to produce systemic AL
amyloid deposits (figure 2) [74]. A Castleman tumour is a rare cause of AL amyloidosis [75],
as is Sjögren syndrome (discussed later).
Although microscopic deposits of amyloid are universally present in the lungs, in most cases
dyspnoea is secondary to cardiac involvement [76, 77]. Amyloid deposition in the small airways
TABLE 3 Clinical features associated with systemic AL amyloidosis
Organ involvement Clinical manifestation
Soft-tissue infiltration Bruising, especially periorbital; macroglossia; muscle/joint pseudohypertrophy

Renal Proteinuria; nephrotic syndrome; hypertension very rarely
Cardiac Restrictive cardiomyopathy; arrhythmias; congestive cardiac failure
Hepatic Hepatomegaly; liver failure very rarely
Peripheral nervous Carpal tunnel syndrome; symmetrical sensorimotor neuropathy
system
Autonomic nervous Orthostatic hypotension; impotence; disturbed bowel motility; impaired
system bladder emptying
Gastrointestinal Weight loss; blood loss; disturbed bowel motility
Lymphoreticular Splenomegaly; lymphadenopathy
Adrenal axis Hypoadrenalism (rare)
58 https://doi.org/10.1183/2312508X.10017522
a) b)
FIGURE 2 a) A chest radiograph demonstrating a mass in the left upper lobe, which was diagnosed as a
plasmacytoma with associated AL amyloid deposition following a biopsy. b) A posterior whole-body scintigraphic
image from the same patient obtained following intravenous injection of 123I-labelled human serum amyloid P,
showing abnormal uptake into the amyloid deposits within the plasmacytoma and deposition in the spleen.
can result in a picture similar to pulmonary fibrosis. PFTs may show a restrictive pattern and
reduced gas transfer [78]. Radiographically, the features can mimic interstitial infiltrative diseases
[79]. Plain films are normal or show a reticular pattern, and CT shows interstitial infiltrates
mimicking ILDs. Fine interlobular thickening is often seen peripherally and/or subpleurally.
HRCT can show thin-walled cystic spaces resembling emphysema and bullae that are secondary
to amyloid deposition [80]. The lesions are largely inert, showing low or no metabolic activity
on PET imaging [81]. Chronic effusions secondary to pleural amyloid are often refractory to
diuretics and require recurrent drainage or pleurodesis [82]. Sleep-disordered breathing and
apnoea can reflect cardiomyopathy, macroglossia, neuropathy and myopathy [83, 84].
The aim of treatment in AL amyloidosis is to suppress the underlying B-cell clone and
production of the amyloidogenic FLCs [85]. Despite effective therapy, regression of amyloid is
gradual and may not lead to measurable clinical improvement [86, 87]. Cardiac amyloidosis is
particularly slow to regress, so patients with cardiac dysfunction may not live long enough to
benefit from chemotherapy [88]. However, many patients with AL amyloidosis do benefit, and
chemotherapy has led to improved survival [89]. Treatment approaches are tailored to the
individual, based on guidelines established by the European Haematology Association and
International Society for Amyloidosis [90, 91]. Rigorous patient selection for high-dose
chemotherapy is essential, as treatment-related mortality is extremely high in individuals with
multiple organ involvement [92–94]. The treatment response is monitored using the serum FLC
assay. A reduction in FLCs is associated with improved survival and organ response [95–97].
https://doi.org/10.1183/2312508X.10017522 59
Immunomodulatory therapies such as lenalidomide and thalidomide, proteasome inhibitors such

as bortezomib, and monoclonal antibody therapies such as daratumumab form the backbone of
therapy. Serious pulmonary side-effects are rare but are recognised with bortezomib [98].
Patients present with fever and asthma-like symptoms, which progress to respiratory failure and
pulmonary infiltrates [99]. There have also been reports of lung toxicity following treatment
with thalidomide [100] and lenalidomide [101], with toxic granulomatous ILD, which is steroid
responsive. Thromboembolic risk is increased in some patients, especially with thalidomide and
lenalidomide treatment, and prophylactic anticoagulation should be considered [102].
Localised amyloidosis
First described by Lesser in 1877, this ranges from asymptomatic pulmonary nodules to diffuse
parenchymal deposits [79, 103]. Localised amyloid deposition results either from local production
of fibril precursors [104, 105], or from properties inherent to the particular micro-environment that
favour fibril formation of a widely distributed precursor protein [106]. The vast majority of
localised amyloid deposits are AL in type [103, 107–109], and symptomatic deposits occur most
frequently in the eye [110], skin [111], or respiratory [112, 113] and urogenital [114, 115] tracts.
They are often associated with extremely subtle focal monoclonal B-cell proliferation confined to
the affected site, and surgical resection of these localised “amyloidomas” can sometimes be
curative [115]. Symptomatic localised amyloid deposits can rarely be manifestations of systemic
disease, but patients should always be fully investigated to exclude systemic amyloidosis [16].
The paucity of controlled clinical trials means that management decisions have to be made on
an individual basis. Generally, systemic chemotherapy is for systemic AL amyloidosis, and local
intervention, according to symptoms, is for its localised forms.
Laryngeal amyloidosis
The larynx is the most frequent site of localised amyloidosis affecting the head and neck
[116, 117]. It represents 0.5–1% of benign laryngeal disease. Its incidence increases with age
but it can affect young adults or children [118]. The amyloid deposits commonly occur in the
ventricles, followed by the subglottis, the aryepiglottic folds and the true vocal cords [109].
Presentation is usually with hoarseness, a sensation of “fullness”, choking, dyspnoea and, rarely,
stridor [119]. The aetiology remains unclear, and there is no reported association with alcohol,
smoking, vocal abuse or infection [116]. One proposed explanation for the predilection is
production of light chains arising from mucosa-associated lymphoid tissue (MALT) [113, 120].
Light-chain restriction is predominantly λ [114, 121].
The diagnosis is usually made following laryngoscopy and biopsy. MRI is preferred when
evaluating the extent of infiltration [122]. Systemic amyloidosis should be excluded, including
investigation for an underlying plasma-cell dyscrasia [117, 123]. There are case reports of
extramedullary plasmacytoma with amyloid deposition affecting the larynx [124].
Localised laryngeal amyloid is usually benign but can be progressive or recur. Fatal
haemorrhage has been reported [125]. Endoscopic surgical [126, 127] or carbon-dioxide laser
excision [128, 129] is the treatment of choice, aiming to preserve voice quality and maintain
airway patency [130]. Corticosteroids have no effect [131]. There are reports of successful
external beam radiation therapy [132]. Disease can recur in up to 25% of cases with a median
time to recurrence of 34.5 months but reassuringly a mortality of <1% [133].
Very rarely, localised laryngeal amyloid deposits can be due a feature of hereditary systemic
apolipoprotein AI amyloidosis (AApoAI). Four separate apolipoprotein variants have been
60 https://doi.org/10.1183/2312508X.10017522
reported to cause this [105, 134–136], but due to variable penetrance, a family history is often
lacking. Apolipoprotein AI is a constituent of high-density lipoprotein [137]. Wild-type
apolipoprotein AI is amyloidogenic and is present as traces of amyloid in aortic atherosclerotic
plaques in 10–20% of autopsies [138]. AApoAI deposits as small, irregular, floppy
proliferations affecting the borders of the vocal folds.
Tracheobronchial amyloidosis
Tracheobronchial amyloidosis is uncommon, although it is probably underreported. Amyloid
usual deposits in the trachea and large bronchi, with occasional extension into segmental bronchi.
It can present with single or multiple nodules, luminal stenosis or obstruction [112, 139, 140]. A
literature review identified 67 cases, of which 57 were diffusely infiltrative (multifocal submucosal
plaques) and the remainder were nodular or “tumour like” [141]. The mean age of occurrence is
52 years [139], and women tend to present more commonly and at a younger age (25–45 years)
than men (50–70 years), with more extensive disease and faster progression [142].
The presenting symptoms include dyspnoea, persistent cough, wheeze, haemoptysis, chest
tightness and hoarseness [142]. Deposits may cause distal atelectasis, recurrent pneumonia or
lobar collapse [143], and solitary nodules may be mistaken for neoplasia [144], although 70%
of one series had normal radiography [145]. Typically, deposits have intermediate T1-weighted
signal intensity on MRI and low T2-weighted signal intensity similar to skeletal muscle [122].
Early-phase fluorodeoxyglucose metabolic activity can be seen on CT-PET, but delayed images
show reduced activity, differentiating it from malignancy [146]. Diagnosis is often delayed and
is made following bronchoscopy and biopsy [147]. Differential diagnoses include
tracheobronchopathia osteoplastica [148–150] and relapsing polychondritis [151, 152].
An overall survival of 31–43% is reported at 6 years [112].
Management is largely dependent on symptoms. There is no proven drug therapy, but systemic
chemotherapy has been tried in patients with progressive disease [142], as has dimethylsulfoxide.
The most common strategies reported in the series by LU et al. [139] with 53 patients included
use of an Nd-YAG (neodymium-doped yttrium aluminium garnet) laser, argon plasma
coagulation, cryotherapy, a topical drug, clamping, resection, high-frequency electrotome cautery,
stent implantation and microwaves. Extensive airway involvement may require open resection
[153]. Endobronchial brachytherapy has been reported in a handful of cases with encouraging
early results [154]. Management will always need to be tailored, and multimodal therapeutic
strategies combining airway recanalisation and radiotherapy can be considered [155].
Parenchymal pulmonary amyloidosis

Amyloid within the lung parenchymal tissue is the most frequently detected respiratory
manifestation of amyloidosis [156]. It can be divided radiographically into solitary/multiple
nodules or a diffuse alveolar–septal pattern [157, 158]; the latter is usually a manifestation of
systemic amyloidosis, most commonly AL, but has also been reported with the ATTR type [6].
Nodular pulmonary amyloidosis is almost always localised AL type and is usually an incidental
finding on chest radiography with an excellent prognosis. In theory, CT-PET should be useful
in distinguishing between amyloid nodules and malignancy, but case reports suggest that
CT-PET can give false-positive results so must be confirmed by histological diagnosis. Amyloid
nodules are usually peripheral and subpleural, occurring preferentially in the lower lobes. They
may be bilateral and range in diameter from 0.4 to 15 cm. They grow slowly and may cavitate
or calcify [156, 157, 159]. Larger nodules can occasionally produce space-occupying effects or
pneumothorax, but generally no treatment is required. Rarely, pulmonary amyloid nodules have
https://doi.org/10.1183/2312508X.10017522 61
been reported to be ATTR in type [140, 160]. Pulmonary nodules associated with AA
amyloidosis have been found in patients with rheumatoid arthritis [161] and Crohn disease [162]
and in intravenous drug abuse [163], and run a benign course.
Amyloidosis in Sjögren syndrome

This chronic organ-specific autoimmune disease is characterised by lymphocytic infiltration into
the salivary and lacrimal glands with an estimated prevalence of 0.5%, predominantly affecting
women in middle life [164]. It is associated with a 44-fold increase in lymphoproliferative
disorders, and 5% of patients develop malignant lymphoma. This evolution from polyclonal
lymphoproliferation to clonal disease, MALT lymphoma or high-grade lymphoma is associated
with an increasing risk of AL amyloidosis. Sjögren syndrome is associated with a wide
spectrum of respiratory manifestations ranging from sicca and obstructive small airway disease
to ILD, PH and pleural involvement [165, 166].
Pulmonary amyloidosis associated with Sjögren syndrome is a rare but well recognised complication
and is most often associated with localised nodular pulmonary amyloidosis [167]. It can also affect
the breast tissues [168] or result in systemic disease [169]. In one series, 96.5% of patients were
women with a median age of 59 years (range 29–79 years) at presentation [170]. The most common
symptoms were cough and dyspnoea. Over 90% occurred in primary Sjögren syndrome, and
lymphoma was associated with 9% of cases. The diagnosis of pulmonary amyloidosis took a
median of 7 years (range 0–30 years) after initial symptoms. Amyloidosis associated with Sjögren
syndrome is predominantly AL type; however, there have been a few isolated case reports of diffuse
septal AA amyloidosis without evidence of amyloid deposition elsewhere [171, 172].
Amyloid lymphadenopathy
Infiltration of lymphoid tissue by amyloidosis can result in massive lymphadenopathy [141].
Sjögren syndrome complicated by lymphoma is a recognised cause [141, 173]. The majority of
patients have a detectable circulating monoclonal immunoglobulin typically associated with very
low-grade lymphoplasmacytic lymphoma or Waldenstrom macroglobulinaemia [174]. Initial
investigations can be suspicious of lung cancer or granulomatous diseases, and false-positive
PET findings have been described [175]. CT imaging of amyloid lymphadenopathy has
demonstrated considerable variety; calcification is not uncommon and low-density areas within
lymph nodes are described [158, 176]. The diagnosis is often incidental following biopsy, and
should prompt the search for an underlying B-cell dyscrasia.
Disease progression is slow and calcification is well recognised [158, 177]. Amyloid
adenopathy can occasionally cause tracheal compression and superior vena cava obstruction.
Treatment centres on managing the underlying lymphoproliferative disease, but surgical
resection may become necessary.
Pleural amyloidosis
Pleural involvement is commonly reported in systemic amyloidosis [178, 179] and can present
with pleural effusion and pleural thickening [180]. Diagnosis can be made via video-assisted
thorascopic pleural biopsy. Unlike nodular pulmonary amyloidosis or tracheobronchial amyloidosis,
pleural disease generally represents systemic disease such as AL amyloidosis or myeloma [79, 181].
Conclusion
Systemic amyloid can complicate long-standing respiratory conditions or cause respiratory
complications either directly or iatrogenically. Localised amyloid deposits can affect any part of
the respiratory tract and may be incidental or symptomatic. In the absence of clinical trials,
62 https://doi.org/10.1183/2312508X.10017522
management of localised amyloid deposits is guided by case series and is tailored on an

individual basis.
References
1 Pinney JH, Lachmann HJ. Amyloidosis and the lung. In: Cordier J-F, ed. Orphan Lung Diseases (ERS
Monograph). Sheffield, European Resiratory Society, 2011; pp. 152–170.
2 Chiti F, Dobson CM. Protein misfolding, amyloid formation, and human disease: a summary of progress over
the last decade. Annu Rev Biochem 2017; 86: 27–68.
3 Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled
serum amyloid P component. N Engl J Med 1990; 323: 508–513.
4 Pepys MB, Hawkins PN. Amyloidosis. In: Warrell DA, Cox TM, Firth JD, eds. Oxford Text Book of Medicine.
5th Edn. Oxford, Oxford University Press, 2010; pp. 1766–1779.
5 Hawkins PN. Amyloidosis. Med Int (n.d.), 221994: 76–82.
6 Baumgart JV, Stuhlmann-Laeisz C, Hegenbart U, et al. Local vs. systemic pulmonary amyloidosis – impact on
diagnostics and clinical management. Virchows Arch 2018; 473: 627–637.
7 Puchtler H, Sweat F, Levine M. On the binding of Congo red by amyloid. J Histochem Cytochem 1962; 10: 355–364.
8 Ma D, Lu H, Zhang C, et al. Use of polarized light microscopy is essential in the efficient diagnosis of
respiratory amyloidosis and could decrease disease prevalence. Clin Respir J 2017; 11: 691–695.
9 Strange C, Heffner JE, Collins BS, et al. Pulmonary hemorrhage and air embolism complicating transbronchial
biopsy in pulmonary amyloidosis. Chest 1987; 92: 367–369.
10 Thompson CA, Kyle R, Gertz M, et al. Systemic AL amyloidosis with acquired factor X deficiency: a study of
perioperative bleeding risk and treatment outcomes in 60 patients. Am J Hematol 2010; 85: 171–173.
11 Mumford AD, O’Donnell J, Gillmore JD, et al. Bleeding symptoms and coagulation abnormalities in 337
patients with AL amyloidosis. Br J Haematol 2000; 110: 454–460.
12 Morgenthal S, Bayer R, Schneider E, et al. Nodular pulmonary amyloidosis with spontaneous fatal blood
aspiration. Forensic Sci Int 2016; 262: e1–e4.
13 Dahlgren SE, Lewenhaupt A, Ovenfors CO. Fine needle biopsy diagnosis in nodular pulmonary amyloidosis.
Acta Pathol Microbiol Scand A 1970; 78: 1–5.
14 Kaw YT, Esparza AR. Solitary pleural amyloid nodules occurring as coin lesions diagnosed by fine-needle
aspiration biopsy. Diagn Cytopathol 1991; 7: 304–307.
15 Ishiguro T, Takayanagi N, Katoh N, et al. Waldenström’s macroglobulinemia accompanying systemic
amyloidosis: the usefulness of endobronchial ultrasound-guided transbronchial needle aspiration for
detecting amyloid deposits. Intern Med 2014; 53: 2798–2793.
16 Shah PL, Gillmore JD, Copley SJ, et al. The importance of complete screening for amyloid fibril type and systemic
disease in patients with amyloidosis in the respiratory tract. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 134–142.
17 Gilbertson JA, Theis JD, Vrana JA, et al. A comparison of immunohistochemistry and mass spectrometry for
determining the amyloid fibril protein from formalin-fixed biopsy tissue. J Clin Pathol 2015; 68: 314–317.
18 Benson MD, Berk JL, Dispenzieri A, et al. Tissue biopsy for the diagnosis of amyloidosis: experience from
some centres. Amyloid 2022; 29: 8–13.
19 Core JM, Alsaad AA, Jiang L, et al. Nodular pulmonary amyloidosis: a complex disease with malignancy
association. BMJ Case Rep 2017; 2017: bcr2017220428.
20 Liu Y, Jin Z, Zhang H, et al. Diffuse parenchymal pulmonary amyloidosis associated with multiple myeloma: a
case report and systematic review of the literature. BMC Cancer 2018; 18: 802.
21 Soussan M, Ouvrier MJ, Pop G, et al. Tracheobronchial FDG uptake in primary amyloidosis detected by PET/CT.
Clin Nucl Med 2011; 36: 723–724.
22 Quan XQ, Yin TJ, Zhang CT, et al. 18F-FDG PET/CT in patients with nodular pulmonary amyloidosis: case report
and literature review. Case Rep Oncol 2014; 7: 789–798.
23 Takahashi N, Glockner J, Howe BM, et al. Taxonomy and imaging manifestations of systemic amyloidosis.
Radiol Clin North Am 2016; 54: 597–612.
24 Baumgart JV, Stuhlmann-Laeisz C, Hegenbart U, et al. Local vs. systemic pulmonary amyloidosis-impact on
diagnostics and clinical management. Virchows Arch 2018; 473: 627–637.
25 Shaheen SP, Levinson SS. Serum free light chain analysis may miss monoclonal light chains that urine
immunofixation electrophoreses would detect. Clin Chim Acta 2009; 406: 162–166.
26 Palladini G, Russo P, Bosoni T, et al. Identification of amyloidogenic light chains requires the combination of
serum-free light chain assay with immunofixation of serum and urine. Clin Chem 2009; 55: 499–504.
27 Katzmann JA, Clarke RJ, Abraham RS, et al. Serum reference intervals and diagnostic ranges for free kappa
and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains.
Clin Chem 2002; 48: 1437–1344.
https://doi.org/10.1183/2312508X.10017522 63
28 Beetham R, Wassell J, Wallage MJ, et al. Can serum free light chains replace urine electrophoresis in the
detection of monoclonal gammopathies? Ann Clin Biochem 2007; 44: 516–522.
29 Klein AL, Hatle LK, Burstow DJ, et al. Doppler characterization of left ventricular diastolic function in cardiac
amyloidosis. J Am Coll Cardiol 1989; 13: 1017–1026.
30 Fontana M, Chung R, Hawkins PN, et al. Cardiovascular magnetic resonance for amyloidosis. Heart Fail Rev
2015; 20: 133–144.
31 de Haro-Del Moral FJ, Sanchez-Lajusticia A, Gomez-Bueno M, et al. Role of cardiac scintigraphy with
99m
Tc-DPD in the differentiation of cardiac amyloidosis subtype. Rev Esp Cardiol 2012; 65: 440–446.
32 Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation
2016; 133: 2404–2412.
33 Schnitzer TJ, Ansell BM. Amyloidosis in juvenile chronic polyarthritis. Arthritis Rheum 1977; 20: 245–252.
34 de Beer FC, Mallya RK, Fagan EA, et al. Serum amyloid A protein (SAA) concentration in inflammatory diseases
and its relationship to the incidence of reactive systemic amyloidosis. Lancet 1982; 320: 231–234.
35 Myllykangas-Luosujärvi R, Aho K, Kautiainen H, et al. Amyloidosis in a nationwide series of 1666 subjects with
rheumatoid arthritis who died during 1989 in Finland. Rheumatology 1999; 38: 499–503.
36 Pras M, Schubert M, Zucker-Franklin D, et al. The characterisation of soluble amyloid prepared in water. J Clin
Invest 1968; 47: 924–933.
37 Yamada T. Serum amyloid A (SAA): a concise review of biology, assay methods and clinical usefulness. Clin
Chem Lab Med 1999; 37: 381–388.
38 Lachmann HJ, Goodman HJB, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis.
N Engl J Med 2007; 356: 2361–2371.
39 Delplanque M, Galicier L, Oziol E, et al. AA Amyloidosis secondary to primary immune deficiency: about 40 cases
including 2 new French cases and a systematic literature review. J Allergy Clin Immunol Pract 2021; 9: 745–752.e1.
40 Castleman B, Iverson L, Menendez P. Localized mediastinal lymph-node hyperplasia resembling thymoma.
Cancer 1956; 9: 822–830.
41 Lachmann HJ, Gilbertson JA, Gillmore JD, et al. Unicentric Castleman’s disease complicated by systemic AA
amyloidosis: a curable disease. QJM 2002; 95: 211–218.
42 Talat N, Belgaumkar AP, Schulte KM. Surgery in Castleman’s disease: a systematic review of 404 published
Cases. Annals of Surgery 2012; 255: 677–684.
43 Kawabata H, Kotani S, Matsumura Y, et al. Successful treatment of a patient with multicentric Castleman’s
disease who presented with thrombocytopenia, ascites, renal failure and myelofibrosis using tocilizumab, an
anti-interleukin-6 receptor antibody. Intern Med 2013; 52: 1503–1507.
44 Nagai K, Ueda A, Yamagata K. Successful Use of tocilizumab in a case of multicentric Castleman’s disease and
end-stage renal disease. Ther Apher Dial 2014; 18: 210–211.
45 Nishimoto N, Sasai M, Shima Y, et al. Improvement in Castleman’s disease by humanized anti-interleukin-6
receptor antibody therapy. Blood 2000; 95: 56–61.
46 Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of
multicentric Castleman disease. Blood 2005; 106: 2627–2632.
47 Matsuyama M, Suzuki T, Tsuboi H, et al. Anti-interleukin-6 receptor antibody (tocilizumab) treatment of
multicentric Castleman’s disease. Intern Med 2007; 46: 771–774.
48 Song SNJ, Tomosugi N, Kawabata H, et al. Down-regulation of hepcidin resulting from long-term treatment
with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman
disease. Blood 2010; 116: 3627–3634.
49 Celik AF, Altiparmak MR, Pamuk GE, et al. Association of secondary amyloidosis with common variable
immune deficiency and tuberculosis. Yonsei Med J 2005; 46: 847–850.
50 Kennedy AL, Burton JA, Allison MEM. Tuberculosis as a continuing cause of renal amyloidosis. Br Med J 1974;
3: 795–797.
51 Hassen M, Bates W, Moosa MR. Pattern of renal amyloidosis in South Africa. BMC Nephrol 2019; 20: 406.
52 Yahiaoui Y, Jablonski M, Hubert D, et al. Renal involvement in cystic fibrosis: diseases spectrum and clinical
relevance. Clin J Am Soc Nephrol 2009; 4: 921–928.
53 Simpson T, Elston C, Macedo P, et al. Amyloidosis in cystic fibrosis. Paediatr Respir Rev 2019; 31: 32–34.
54 Rezgui A, Hassine IB, Karmani M, et al. Amyloïdosis, sarcoidosis and systemic lupus erythematosus. Pan Afr
Med J 2016; 24: 23.
55 Osman EM, Abboud OI, Sulaiman SM, et al. End-stage renal failure in Kartagener’s syndrome. Nephrol Dial
Transplant 1991; 6: 747.
56 Yilmaz M, Unsal A, Sokmen M, et al. Renal involvement in AA amyloidosis: clinical outcomes and survival.
Kidney Blood Press Res 2013; 37: 33–42.
57 Ueno T, Takeda K, Nagata M. Remission of proteinuria and preservation of renal function in patients with
renal AA amyloidosis secondary to rheumatoid arthritis. Nephrol Dial Transplant 2012; 27: 633–639.
64 https://doi.org/10.1183/2312508X.10017522
58 Yutaka Y, Sugimoto A, Yuasa I, et al. Successful control of AA amyloidosis by bilateral lung transplantation for
bronchiectasis. Transplantation 2021; 105: e33–ee4.
59 Bollee G, Guery B, Joly D, et al. Presentation and outcome of patients with systemic amyloidosis undergoing
dialysis. Clin J Am Soc Nephrol 2008; 3: 375–381.
60 Lachmann HJ, Gillmore JD, Wechalekar AD, et al. Survival on dialysis and outcome after renal transplantation
in AA amyloidosis. Amyloid 2010; 17: Suppl. 1, 73.
61 Kofman T, Grimbert P, Canoui-Poitrine F, et al. Renal transplantation in patients with AA amyloidosis
nephropathy: results from a French multicenter study. Am J Transplant 2011; 11: 2423–2431.
62 Pinney JH, Lachmann HJ, Sattianayagam PT, et al. Renal transplantation in systemic amyloidosis –
importance of amyloid fibril type and precursor protein abundance. Am J Transplant 2013; 13: 433–441.
63 Wechalekar AD, Hawkins PN. AL amyloidosis: new drugs and tests, but old challenges. Oncology (Williston
Park) 2012; 26: 161–162.
64 Glenner GG, Ein D, Eaves ED, et al. Creation of “amyloid” fibrils from Bence Jones protein in vitro. Science
1971; 174: 712–714.
65 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol
1995; 32: 45–59.
66 Gertz MA, Kyle RA. Primary systemic amyloidosis – a diagnostic primer. Mayo Clin Proc 1989; 64: 1505–1519.
67 Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide:
a staging system for primary systemic amyloidosis. J Clin Oncol 2004; 22: 3751–3757.
68 Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346
patients with cardiac stage III AL amyloidosis. Blood 2013; 121: 3420–3427.
69 Kumar N, Zhang NJ, Cherepanov D, et al. Global epidemiology of amyloid light-chain amyloidosis. Orphanet J
Rare Dis 2022; 17: 278.
70 Muchtar E, Gertz MA, Kumar SK, et al. Improved outcomes for newly diagnosed AL amyloidosis between 2000
and 2014: cracking the glass ceiling of early death. Blood 2017; 129: 2111–2119.
71 Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with
heart involvement. QJM 1998; 91: 141–157.
72 Gertz MA, Kyle RA. Prognostic value of urinary protein in primary systemic amyloidosis (AL). Am J Clin Pathol
1990; 94: 313–317.
73 Lovat LB, Pepys MB, Hawkins PN. Amyloid and the gut. Dig Dis 1997; 15: 155–171.
74 Koss MN, Hochholzer L, Moran CA, et al. Pulmonary plasmacytomas: a clinicopathologic and
immunohistochemical study of five cases. Ann Diagn Pathol 1998; 2: 1–11.
75 West KP, Morgan DR, Lauder I. Angiofollicular lymph node hyperplasia with amyloidosis. Postgrad Med J 1989;
65: 108–111.
76 Shenin M, Xiong W, Naik M, et al. Primary amyloidosis causing diffuse alveolar hemorrhage. J Clin Rheumatol
2010; 16: 175–177.
77 Sato H, Ono A, Okada F, et al. A case of diffuse alveolar septal amyloidosis associated with multiple myeloma.
J Thorac Imaging 2015; 30: W73–W75.
78 Berk JL, O’Regan A, Skinner M. Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med 2002;
23: 155–165.
79 Milani P, Basset M, Russo F, et al. The lung in amyloidosis. Eur Respir Rev 2017; 6: 170046.
80 Gruden JF, Naidich DP, Machnicki SC, et al. An algorithmic approach to the interpretation of diffuse lung
disease on chest CT imaging: a theory of almost everything. Chest 2020; 157: 612–635.
81 Wagner T, Page J, Burniston M, et al. Extracardiac 18F-florbetapir imaging in patients with systemic
amyloidosis: more than hearts and minds. Eur J Nucl Med 2018; 45: 1129–1138.
82 Berk JL, Keane J, Seldin DC, et al. Persistent pleural effusions in primary systemic amyloidosis: etiology and
prognosis. Chest 2003; 124: 969–977.
83 Bodez D, Guellich A, Kharoubi M, et al. Prevalence, severity, and prognostic value of sleep apnea syndromes in
cardiac amyloidosis. Sleep 2016; 39: 1333–1341.
84 Mahmood S, Sovani M, Smith P, et al. High prevalence of recurrent nocturnal desaturations in systemic AL
amyloidosis: a cross-sectional pilot study. Sleep Med 2017; 32: 191–197.
85 Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood 2002;
99: 4276–4282.
86 Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine 1991; 70:
246–256.
87 Hawkins PN. Diagnosis and treatment of amyloidosis. Ann Rheum Dis 1997; 56: 631–633.
88 Kyle RA, Gertz MA, Greipp PR, et al. Long-term survival (10 years or more) in 30 patients with primary
amyloidosis. Blood 1999; 93: 1062–1066.
89 Kumar SK, Gertz MA, Lacy MQ, et al. Recent improvements in survival in primary systemic amyloidosis and the
importance of an early mortality risk score. Mayo Clin Proc 2011; 86: 12–18.
https://doi.org/10.1183/2312508X.10017522 65
90 Sanchorawala V. Summary of the EHA-ISA working group guidelines for high-dose chemotherapy and stem
cell transplantation for systemic AL amyloidosis. Hemasphere 2022; 6: e681.
91 Wechalekar AD, Cibeira MT, Gibbs SD, et al. Guidelines for non-transplant chemotherapy for treatment of
systemic AL amyloidosis: EHA-ISA working group. Amyloid 2023; 30: 3–17.
92 Moreau P, Leblond V, Bourquelot P, et al. Prognostic factors for survival and response after high-dose therapy
and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol
1998; 101: 766–769.
93 Gillmore JD, Apperley JF, Pepys MB, et al. High dose chemotherapy for systemic AL amyloidosis. Kidney Int
1999; 55: 2103.
94 Bomsztyk J, Khwaja J, Wechalekar AD. Recent guidelines for high-dose chemotherapy and autologous stem
cell transplant for systemic AL amyloidosis: a practitioner’s perspective. Expert Rev Hematol 2022; 15: 781–788.
95 Lane T, Rannigan L, Foard D, et al. ALchemy – a large prospective ‘real world’ study of chemotherapy in AL
amyloidosis. ASH Annu Meet Abstr 2011; 118: 992.
96 Matsuzaki K, Ohsawa I, Nishitani T, et al. Marked improvement by high-dose chemotherapy and autologous
stem cell transplantation in a case of light chain deposition disease. J Nephrol 2011; 24: 246–249.
97 Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal
response to chemotherapy in AL amyloidosis. Blood 2014; 124: 2325–2332.
98 Balsman E. Bortezomib therapy-related lung disease in a patient with light chain amyloidosis: a case report.
J Oncol Pharm Pract 2017; 23: 545–548.
99 Miyakoshi S, Kami M, Yuji K, et al. Severe pulmonary complications in Japanese patients after bortezomib
treatment for refractory multiple myeloma. Blood 2006; 107: 3492–3494.
100 Valero FC, Gonzalez VB. Toxicidad pulmonar por talidomida. [Lung toxicity due to thalidomide.] Arch
Bronconeumol 2002; 38: 492–494.
101 Chen CD, Huff ME, Matteson J, et al. Furin initiates gelsolin familial amyloidosis in the Golgi through a defect
in Ca2+ stabilization. EMBO J 2001; 20: 6277–6287.
102 Cini M, Zamagni E, Valdre L, et al. Thalidomide–dexamethasone as up-front therapy for patients with newly
diagnosed multiple myeloma: thrombophilic alterations, thrombotic complications, and thromboprophylaxis
with low-dose warfarin. Eur J Haematol 2010; 84: 484–492.
103 Mahmood S, Bridoux F, Venner CP, et al. Natural history and outcomes in localised immunoglobulin
light-chain amyloidosis: a long-term observational study. Lancet Haematol 2015; 2: e241–e250.
104 Pasternak S, White VA, Gascoyne RD, et al. Monoclonal origin of localised orbital amyloidosis detected by
molecular analysis. Br J Ophthalmol 1996; 80: 1013–1017.
105 Hamidi Asl L, Liepnieks JJ, Hamidi Asl K, et al. Hereditary amyloid cardiomyopathy caused by a variant
apolipoprotein A1. Am J Pathol 1999; 154: 221–227.
106 Livneh A, Shtrasburg S, Martin BM, et al. Light chain amyloidosis of the urinary bladder. A site restricted
deposition of an externally produced immunoglobulin. J Clin Pathol 2001; 54: 920–923.
107 Kourelis TV, Kyle RA, Dingli D, et al. Presentation and outcomes of localized immunoglobulin light chain
amyloidosis: the Mayo Clinic experience. Mayo Clin Proc 2017; 92: 908–917.
108 Westermark P, Sletten K, Pitkanen P, et al. Localized laryngeal amyloidosis: partial characterization of an
amyloid fibril protein AL. Mol Immunol 1982; 19: 447–450.
109 Lewis JE, Olsen KD, Kurtin PJ, et al. Laryngeal amyloidosis: a clinicopathologic and immunohistochemical
review. Otolaryngol Head Neck Surg 1992; 106: 372–377.
110 Murdoch IE, Sullivan TJ, Moseley I, et al. Primary localised amyloidosis of the orbit. Br J Ophthalmol 1996; 80:
1083–1086.
111 Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis: a long-term follow-up study. Br J
Dermatol 2001; 145: 105–109.
112 Utz JP, Swensen SJ, Gertz MA. Pulmonary amyloidosis. The Mayo Clinic experience from 1980 to 1993. Ann
Intern Med 1996; 124: 407–413.
113 Thompson LD, Derringer GA, Wenig BM. Amyloidosis of the larynx: a clinicopathologic study of 11 cases. Mod
Pathol 2000; 13: 528–535.
114 Berg AM, Troxler RF, Grillone G, et al. Localized amyloidosis of the larynx: evidence for light chain
composition. Ann Otol Rhinol Laryngol 1993; 102: 884–889.
115 Tirzaman O, Wahner-Roedler DL, Malek RS, et al. Primary localized amyloidosis of the urinary bladder: a case
series of 31 patients. Mayo Clin Proc 2000; 75: 1264–1268.
116 Ma L, Bandarchi B, Sasaki C, et al. Primary localized laryngeal amyloidosis: report of 3 cases with long-term
follow-up and review of the literature. Arch Pathol Lab Med 2005; 129: 215–218.
117 Rudy SF, Jeffery CC, Damrose EJ. Clinical characteristics of laryngeal versus nonlaryngeal amyloidosis.
Laryngoscope 2018; 128: 670–674.
118 Phillips NM, Matthews E, Altmann C, et al. Laryngeal amyloidosis: diagnosis, pathophysiology and
management. J Laryngol Otol 2017; 131: S41–S47.
66 https://doi.org/10.1183/2312508X.10017522
119 Siddachari RC, Chaukar DA, Pramesh CS, et al. Laryngeal amyloidosis. J Otolaryngol 2005; 34: 60–63.
120 Talbot AR. Laryngeal amyloidosis. J Laryngol Otol 1990; 104: 147–149.
121 Preud’homme JL, Ganeval D, Grunfeld JP, et al. Immunoglobulin synthesis in primary and myeloma
amyloidosis. Clin Exp Immunol 1988; 73: 389–394.
122 Gilad R, Milillo P, Som PM. Severe diffuse systemic amyloidosis with involvement of the pharynx, larynx, and
trachea: CT and MR findings. AJNR Am J Neuroradiol 2007; 28: 1557–1558.
123 Ginat DT, Schulte J, Portugal L, et al. Laryngotracheal involvement in systemic light chain amyloidosis. Head
Neck Pathol 2018; 12: 127–130.
124 Rutherford K, Parsons S, Cordes S. Extramedullary plasmacytoma of the larynx in an adolescent: a case report
and review of the literature. Ear Nose Throat J 2009; 88: E1–E7.
125 Chow LT, Chow WH, Shum BS. Fatal massive upper respiratory tract haemorrhage: an unusual complication of
localized amyloidosis of the larynx. J Laryngol Otol 1993; 107: 51–53.
126 d’Arcy F. Localized amyloidosis of the larynx. J Laryngol Otol 1972; 86: 929–931.
127 Walker PA, Courey MS, Ossoff RH. Staged endoscopic treatment of laryngeal amyloidosis. Otolaryngol Head
Neck Surg 1996; 114: 801–805.
128 Finn DG, Farmer JC Jr. Management of amyloidosis of the larynx and trachea. Arch Otolaryngol Head Neck
Surg 1982; 108: 54–56.
129 McIlwain JC, Shepperd HW. Laser treatment of primary amyloidosis of the larynx. J Laryngol Otol 1986; 100:
1079–1080.
130 Piazza C, Cavaliere S, Foccoli P, et al. Endoscopic management of laryngo-tracheobronchial amyloidosis: a
series of 32 patients. Eur Arch Otorhinolaryngol 2003; 260: 349–354.
131 Mitrani M, Biller HF. Laryngeal amyloidosis. Laryngoscope 1985; 95: 1346–1347.
132 Neuner GA, Badros AA, Meyer TK, et al. Complete resolution of laryngeal amyloidosis with radiation treatment.
Head Neck 2010; 34: 748–752.
133 Pai KK, Omiunu AO, Llerena PA, et al. Localized laryngeal amyloidosis: a systematic review. Am J Otolaryngol
2022; 43: 103550.
134 Hamidi Asl K, Liepnieks JJ, Nakamura M, et al. A novel apolipoprotein A-1 variant, Arg173Pro, associated with
cardiac and cutaneous amyloidosis. Biochem Biophys Res Commun 1999; 257: 584–588.
135 de Sousa MM, Vital C, Ostler D, et al. Apolipoprotein AI and transthyretin as components of amyloid fibrils in a
kindred with apoAI Leu178His amyloidosis. Am J Pathol 2000; 156: 1911–1917.
136 Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL ( primary) amyloidosis.
N Engl J Med 2002; 346: 1786–1791.
137 Assmann G, Schmitz G, Funke H, et al. Apolipoprotein A-I and HDL deficiency. Curr Opin Lipidol 1990; 1: 110–115.
138 Westermark P, Mucchiano G, Marthin T, et al. Apolipoprotein A1-derived amyloid in human aortic
atherosclerotic plaques. Am J Pathol 1995; 147: 1186–1192.
139 Lu X, He B, Wang G, et al. Bronchoscopic diagnosis and treatment of primary tracheobronchial amyloidosis: a
retrospective analysis from China. Biomed Res Int 2017; 2017: 342812.
140 Cordier JF, Loire R, Brune J. Amyloidosis of the lower respiratory tract. Clinical and pathologic features in a
series of 21 patients. Chest 1986; 90: 827–831.
141 Thompson PJ, Citron KM. Amyloid and the lower respiratory tract. Thorax 1983; 38: 84–87.
142 O’Regan A, Fenlon HM, Beamis JF Jr, et al. Tracheobronchial amyloidosis. The Boston University experience
from 1984 to 1999. Medicine (Baltimore) 2000; 79: 69–79.
143 Kunal S, Dhawan S, Kumar A, et al. Middle lobe syndrome: an intriguing presentation of tracheobronchial
amyloidosis. BMJ Case Rep 2017; 2017: bcr2017219480.
144 Cotton RE, Jackson JW. Localized amyloid ‘tumours’ of the lung simulating malignant neoplasms. Thorax
1964; 19: 97–103.
145 Ding L, Li W, Wang K, et al. Primary tracheobronchial amyloidosis in China: analysis of 64 cases and a review
of literature. J Huazhong Univ Sci Technolog Med Sci 2010; 30: 599–603.
146 Tan H, Guan Y, Zhao J, et al. Findings of pulmonary amyloidosis on dual phase FDG PET/CT imaging. Clin Nucl
Med 2010; 35: 206–207.
147 Fukumura M, Mieno T, Suzuki T, et al. Primary diffuse tracheobronchial amyloidosis treated by bronchoscopic
Nd-YAG laser irradiation. Jpn J Med 1990; 29: 620–622.
148 Sakula A. Tracheobronchopathia osteoplastica: its relationship to primary tracheobronchial amyloidosis.
Thorax 1968; 23: 105–110.
149 Jones AW, Chatterji AN. Primary tracheobronchial amyloidosis with tracheobronchopathia osteoplastica. Br J
Dis Chest 1977; 71: 268–272.
150 Nienhuis DM, Prakash UB, Edell ES. Tracheobronchopathia osteochondroplastica. Ann Otol Rhinol Laryngol
1990; 99: 689–694.
151 Prakash UB. Tracheobronchopathia osteochondroplastica. Semin Respir Crit Care Med 2002; 23: 167–175.
152 Ozbay B, Dilek FH, Yalcinkaya I, et al. Relapsing polychondritis. Respiration 1998; 65: 206–207.
https://doi.org/10.1183/2312508X.10017522 67
153 Dahl KA, Kernstine KH, Vannatta TL, et al. Tracheobronchial amyloidosis: a surgical disease with long-term
consequences. J Thorac Cardiovasc Surg 2004; 128: 789–792.
154 Moore A, Kramer MR, Silvern D, et al. Endobronchial brachytherapy – a novel approach for the management
of airway amyloidosis. Brachytherapy 2018; 6: 966–972.
155 Sommer P, Kumar G, Lipchik RJ, et al. Tracheobronchial amyloidosis managed with multimodality therapies.
Ther Adv Respir Dis 2014; 8: 48–52.
156 Himmelfarb E, Wells S, Rabinowitz JG. The radiologic spectrum of cardiopulmonary amyloidosis. Chest 1977;
72: 327–332.
157 Ayuso MC, Gilabert R, Bombi JA, et al. CT appearance of localized pulmonary amyloidosis. J Comput Assist
Tomogr 1987; 11: 197–199.
158 Urban BA, Fishman EK, Goldman SM, et al. CT evaluation of amyloidosis: spectrum of disease. Radiographics
1993; 13: 1295–1308.
159 Rubinow A, Celli BR, Cohen AS, et al. Localized amyloidosis of the lower respiratory tract. Am Rev Respir Dis
1978; 118: 603–611.
160 Roden AC, Aubry MC, Zhang K, et al. Nodular senile pulmonary amyloidosis: a unique case confirmed by
immunohistochemistry, mass spectrometry, and genetic study. Hum Pathol 2010; 41: 1040–1045.
161 Calatayud J, Candelas G, Gomez A, et al. Nodular pulmonary amyloidosis in a patient with rheumatoid
arthritis. Clin Rheumatol 2007; 26: 1797–1798.
162 Beer TW, Edwards CW. Pulmonary nodules due to reactive systemic amyloidosis (AA) in Crohn’s disease.
Thorax 1993; 48: 1287–1288.
163 Shah SP, Khine M, Anigbogu J, et al. Nodular amyloidosis of the lung from intravenous drug abuse: an
uncommon cause of multiple pulmonary nodules. South Med J 1998; 91: 402–404.
164 Masaki Y, Sugai S. Lymphoproliferative disorders in Sjögren’s syndrome. Autoimmun Rev 2004; 3: 175–182.
165 Flament T, Bigot A, Chaigne B, et al. Pulmonary manifestations of Sjögren’s syndrome. Eur Respir Rev 2016;
25: 110–123.
166 Depascale R, Del Frate G, Gasparotto M, et al. Diagnosis and management of lung involvement in systemic lupus
erythematosus and Sjögren’s syndrome: a literature review. Ther Adv Musculoskelet Dis 2021; 13: 1759720X211040696.
167 Jeong YJ, Lee KS, Chung MP, et al. Amyloidosis and lymphoproliferative disease in Sjögren syndrome: thin-section
computed tomography findings and histopathologic comparisons. J Comput Assist Tomogr 2004; 28: 776–781.
168 Kambouchner M, Godmer P, Guillevin L, et al. Low grade marginal zone B cell lymphoma of the breast
associated with localised amyloidosis and corpora amylacea in a woman with long standing primary Sjögren’s
syndrome. J Clin Pathol 2003; 56: 74–77.
169 Delevaux I, Andre M, Amoura Z, et al. Concomitant diagnosis of primary Sjögren’s syndrome and systemic AL
amyloidosis. Ann Rheum Dis 2001; 60: 694–695.
170 Rajagopala S, Singh N, Gupta K, et al. Pulmonary amyloidosis in Sjogren’s syndrome: a case report and
systematic review of the literature. Respirology 2010; 15: 860–866.
171 Parambil JG, Myers JL, Lindell RM, et al. Interstitial lung disease in primary Sjögren syndrome. Chest 2006;
130: 1489–1495.
172 Wong BC, Wong KL, Ip MS, et al. Sjögren’s syndrome with amyloid A presenting as multiple pulmonary
nodules. J Rheumatol 1994; 21: 165–167.
173 Gallego FG, Canelas JLC. Hilar enlargement in amyloidosis. New Eng J Med 1974; 291: 531.
174 Zatloukal P, Bezdicek P, Schimonova M, et al. Waldenstrom’s macroglobulinemia with pulmonary amyloidosis.
Respiration 1998; 65: 414–416.
175 Hourseau M, Virally J, Habib E, et al. Amyloïdome associé à un lymphome du Malt pulmonaire primitif. [Nodular
amyloidoma associated with primary pulmonary MALT lymphoma.] Rev Mal Respir 2008; 25: 1123–1126.
176 Turner CA, Tung K. CT appearances of amyloid lymphadenopathy in a patient with non-Hodgkin’s lymphoma.
British J Radiol 2007; 80: e250–e252.
177 Gross BH. Radiographic manifestations of lymph node involvement in amyloidosis. Radiology 1981; 138: 11–14.
178 Graham DR, Ahmad D. Amyloidosis with pleural involvement. Eur Respir J 1988; 1: 571–572.
179 Knapp MJ, Roggli VL, Kim J, et al. Pleural amyloidosis. Arch Pathol Lab Med 1988; 112: 57–60.
180 Yamada M, Takayanagi N, Yamakawa H, et al. Amyloidosis of the respiratory system: 16 patients with
amyloidosis initially diagnosed ante mortem by pulmonologists. ERJ Open Res 2020; 6: 00313-2019.
181 Ramos AL, Trindade M, Santos Pinto A, et al. Pleural effusion and multiple myeloma – more than meets the
eye: a case report. Mol Clin Oncol 2021; 15: 238.
Disclosures: J.H. Pinney reports receiving payment for lectures on AL amyloidosis and the kidneys from Janssen,
outside the submitted work. The remaining authors have nothing to disclose.
68 https://doi.org/10.1183/2312508X.10017522
Chapter 6
Diffuse cystic lung diseases including

lymphangioleiomyomatosis
Davide Elia1, Antonella Caminati1, Lisa Tescaro2, Roberto Cassandro1 and
Sergio Harari 1,2
1
UO di Pneumologia e Terapia Semi-Intensiva Respiratoria – Servizio di Fisiopatologia Respiratoria ed Emodinamica
Polmonare, MultiMedica IRCCS, Milan, Italy. 2Dept of Clinical Sciences and Community Health, Università degli Studi
di Milano, Milan, Italy.
Corresponding author: Sergio Harari (sergio@sergioharari.it)
Cite as: Elia D, Caminati A, Tescaro L, et al. Diffuse cystic lung diseases including lymphangioleiomyomatosis. In:
@ERSpublications
Diffuse cystic lung diseases may show a typical CT pattern, allowing diagnosis of the underlying disease.
Spontaneous pneumothorax is often the first manifestation, but correct evaluation is important for
diagnosis and appropriate management and treatment. https://bit.ly/ERSM100
ISSN: 2312-5098.
Diffuse cystic lung diseases (DCLDs) are a heterogeneous group of pulmonary disorders characterised
by cysts within the lung parenchyma. In some cases, a characteristic HRCT image indicates a
diagnosis. There are a large number of cystic lung diseases, which have been divided into six groups
according to their pathogenesis: neoplastic, congenital/genetic, lymphoproliferative, infectious,
associated with ILD and other causes. In this chapter, the main characteristics of DCLDs are described,
along with more detailed descriptions of ultra-rare cystic disorders such as lymphangioleiomyomatosis,
pulmonary Langerhans cell histiocytosis and Birt–Hogg–Dubé syndrome.
Introduction
Diffuse cystic lung diseases (DCLDs) are a heterogeneous group of pulmonary disorders
characterised by cysts within the lung parenchyma [1]. The aetiology and pathophysiological
mechanisms of this group of diseases allow classification into six groups: neoplastic, congenital/
genetic, lymphoproliferative, infectious, inflammatory or associated with another ILD, or related
to other causes (table 1). The majority are rare or ultra-rare diseases, and their diagnosis is often
underestimated [2].
The pathogenic mechanisms leading to cyst formation are still not well elucidated, although
several hypotheses have been suggested, particularly for lymphangioleiomyomatosis (LAM) and
pulmonary Langerhans cell histiocytosis (PLCH) [3]. The ball–valve effect is a mechanism that
allows air to enter small airways without being exhaled, leading to their expansion. This
mechanism has been observed in the pathogenesis of cysts in follicular bronchiolitis, cystic
neoplasms and pneumatoceles associated with pulmonary infections [4, 5]. Necrosis and
https://doi.org/10.1183/2312508X.10017622 69
TABLE 1 Classification of diffuse cystic lung diseases
Classification Diseases
Neoplastic Sporadic lymphangioleiomyomatosis

Tuberous sclerosis complex–lymphangioleiomyomatosis
Pulmonary Langerhans cell histiocytosis
Erdheim–Chester disease
Primary or metastatic tumours
Genetic/congenital Birt–Hogg–Dubé syndrome
Tuberous sclerosis complex–lymphangioleiomyomatosis
Neurofibromatosis
Congenital pulmonary airway malformation
Lymphoproliferative Lymphocytic interstitial pneumonia#
Follicular bronchiolitis#
Sjögren syndrome
Amyloidosis
Light-chain deposition disease
Infectious Pneumocystis jiroveci
Streptococcus pneumoniae
Recurrent respiratory papillomatosis
Coccidioidomycosis
Associated with another ILD Hypersensitive pneumonitis
Desquamative interstitial pneumonia#
Respiratory bronchiolitis#
Associated with other causes Post-traumatic pseudocysts
Fire-eater’s lung
Hyper-IgE syndrome
#
: these are a pathological diagnosis showing a cystic pattern and may be related to other disorders.
ischaemic dilation of small airways and alveoli because of the infiltration and obstruction of
small vessels and capillaries serving the terminal bronchioles by LAM or inflammatory cells
may cause cyst formation [6]. In LAM and PLCH in particular, the matrix and metalloproteases
seem to play an important role in parenchymal remodelling and degradation, leading to cyst
pathogenesis [3].
In this chapter, the main characteristics of DCLDs are described, along with more detailed descriptions
of the ultra-rare cystic disorders LAM, PLCH and Birt–Hogg–Dubé (BHD) syndrome.
Radiological features
Cysts are defined as thin-walled (<2 mm wall thickness), regular or irregular, spherical lucencies
with a well-defined interface within normal lung tissue. Although they are filled mainly with
air, occasionally fluid or solid material may be found inside [7, 8].
The widespread use of HRCT has allowed a better understanding of DCLD development,
progression and prognosis. A better definition of the characteristics of the cyst can help identify
the underlying disease, especially focusing on the shape, wall thickness, pulmonary distribution,
and rate of development or progression [1]. It is very important to distinguish cysts from other
air-filled structures that may be observed within a CT scan, such as cavities, blebs, bullae and
pneumatoceles. Compared with cysts, cavities have a thicker (>2 mm) wall and the shape is
generally more irregular, while a bulla is a spherical, thin-walled lucency >1 cm in diameter and
70 https://doi.org/10.1183/2312508X.10017622
DIFFUSE CYSTIC LUNG DISEASES | D. ELIA ET AL.
typically associated with emphysematous changes in the surrounding parenchyma. Blebs, which
are tiny cystic air holes with a diameter of ∼1 cm, are found near to the visceral pleura. Other
conditions, such as bronchiectasis and pulmonary emphysema, can be confused with cystic
diseases, but careful examination of the images allows them to be differentiated [9].
Unusual characteristics may be observed in the cystic pattern of specific diseases. LAM is
characterised by the presence of small, round, bilateral cysts with a random distribution (figure 1),
while in PLCH, chest imaging shows a combination of nodules, cavitations of nodular lesions,
and thick- or thin-walled cysts that may coalesce forming irregular shapes (figure 2). An HRCT
scan in BHD syndrome shows elliptical and lentiform cysts with a prevalent basilar, peripheral
subpleural and mediastinal distribution, generally near vessels (figure 3).
Septa and vessels can be observed in cysts related to follicular bronchiolitis or lymphocytic
interstitial pneumonia but not in LAM or PLCH. In follicular bronchiolitis and BHD syndrome,
the presence of eccentric vessels is often observed on the margins of the cysts [2].
Clinical management
The first step in determining the correct diagnosis after a radiological finding of DCLD relies on
the clinical presentation: an acute onset accompanied by constitutional symptoms suggests an
infectious or inflammatory origin, although nontuberculous mycobacterial infection and
tuberculosis may show a cystic pattern at HRCT but not always present an acute onset.
However, when a complete history is taken, a traumatic aetiology can be ruled out.
The formation of cysts with a paucity of constitutional symptoms suggests a chronic process
due to vascular, congenital or neoplastic disorders. A history of smoking (relevant in PLCH) or
renal tumours in relatives (relevant in BHD) can also be helpful.
Spontaneous pneumothorax is the most frequent clinical presentation in the presence of a DCLD
and has been described in >50% of LAM patients, 25–75% of BHD patients and 15–30% of
PLCH patients [10–13]. Due to the high rate of relapse, surgical pleurodesis should be offered
to all DCLD patients from the first manifestation. Recently, in LAM patients, the use of total
pleural covering and modified total pleural covering, or surgical pleural covering of the entire
lung, mainly in specialised centres in Japan and China, was introduced as a surgical treatment
option for pneumothorax for patients with LAM. This technique consists of covering the entire
visceral pleura with reinforcing materials, such as an ORC mesh (Surgicel®; Johnson &
Johnson, Brunswick, New Jersey, USA) [14].
FIGURE 1 Chest CT in a patient affected by lymphangioleiomyomatosis showing diffuse, smooth, round,

thin-walled parenchymal cysts.
https://doi.org/10.1183/2312508X.10017622 71
a) b) c)
FIGURE 2 Chest CT showing PLCH at an early stage with the characteristic association of nodules, cavitated
nodules, and thick- and thin-wall cysts. The apex is more involved than the base (viewing the images from a to
c), while sparing of the costophrenic angles can be observed (c).
During physical examination, attention should be paid to symptoms and/or signs of possible
underlying connective tissue disease and skin lesions suggestive of tuberous sclerosis complex
(TSC) in patients with LAM [4].
LAM and PLCH patients, especially in advanced stages of the disease, should undergo serial
echocardiographic evaluations to check for PH, as its presence may significantly impact
patients’ quality of life and prognosis. Furthermore, although no treatment has been approved
for PH associated with LAM and PLCH, off-label use of pulmonary vasodilators could be
considered in specialised centres [15, 16].
As mentioned earlier, HRCT features and the distribution of cysts are of particular
importance for a correct diagnosis, although alone they are not sufficient to identify the
underlying disorder [17]. For this reason, serum biomarkers, genetic studies and sometimes
pathological evaluation should be considered for correct management of DCLDs, as
summarised in figure 4.
LAM
LAM is an ultra-rare neoplastic cystic disease, belonging to the group of PEComas, a
mesenchymal tumour composed of histologically and immunohistochemically distinctive
perivascular epithelioid cells (PECs) [18]. It is characterised by the presence of smooth muscle
cells of unknown origin infiltrating the lungs, causing cystic lesions, or forming tumours, called
angiomyolipomas, in the abdomen, generally on the kidneys, or involving the lymphatic vessel,
giving rise to lymphangioleiomyomas [3].
FIGURE 3 Chest CT showing lentiform cysts in a patient affected by Birt–Hogg–Dubé syndrome.
72 https://doi.org/10.1183/2312508X.10017622
https://doi.org/10.1183/2312508X.10017622
Acute or chronic clinical presentation

Pulmonary diffuse cysts with systematic symptoms (e.g. fever, Investigate for infections
chills, asthenia)
Clinical history: PNX, chylothorax, Clinical history: PNX, smoking, tumours (blood Clinical history: PNX, familiar tumours (renal Clinical history: blood disorders and
chyloascites, family clinical history (TSC) malignancies, lung cancer) tumours), tumours (in particular, malignancies
Physical examination: skin examination Physical examination: skin examination chromophobe renal cell carcinomas or Systemic involvement: Sjögren syndrome,
(ANF, shagreen patches, ash-leaf patches), (erythematous, maculopapular or nodular lesions; oncocytoma) amyloidosis
abdominal masses seborrhoeic and crusted lesions on the scalp) Physical examination: skin examination,
Systemic involvement: TSC Systemic involvement: diabetes insipidus FF, TD
LAM PLCH BHD syndrome LIP/FB, amyloidosis, LCDD
Focus on cyst features: shape, size, quantity and distribution
Small, diffuse, Irregular, bizarre cysts may be associated Elliptical/lentiform cysts Round, diffuse cysts of different sizes Cystic pattern not specific for
round, regular with nodules and cavities Basilar subpleural May be associated with GGO, septal thicking, other diseases described
U/M lobes distribution with C/P angle sparing distribution near vessels nodules

LAM PLCH BHD syndrome LIP/FB, amyloidosis, LCDD Trauma
Metastatic neoplasm
Infectious aetiologies
Presence of TSC/AML/chylothorax/ BAL: CD1a+ Lung Major criteria: Supportive tests and features:
lymphangioleiomyoma/ cells >5% biopsy# ≥5 FF or TD (histology) Sicca symptoms
chylous ascites FLCN mutation SSA, SSB
Minor criteria: SPEP, UPEP
Yes Characteristic CT scan Presence of autoimmune/immune deficiency
Yes Family history of BHD syndrome Myeloma
LAM Serum VEGF-D Renal cancer
>800 pg·mL–1 PLCH
No VATS biopsy¶
≥1 major or ≥2 minor criteria
Consider lung
biopsy BHD syndrome LIP/FB, amyloidosis, LCDD
FIGURE 4. Legend overleaf.

73
FIGURE 4 Diagnostic algorithm for diffuse cystic lung diseases (DCLDs). PNX: pneumothorax; TSC: tuberous
sclerosis complex; ANF: angiofibroma; FF: fibrofolliculoma; TD: trichodiscoma; LAM: lymphangioleiomyomatosis;
PLCH: pulmonary Langerhans cell histiocytosis; BHD: Birt–Hogg–Dubé; LIP: lymphocytic interstitial pneumonia;
FB: follicular bronchiolitis; LCCD: light-chain deposit disease; U/M: upper and middle lung; C/P: costophrenic;
GGO: ground-glass opacities; AML: angiomyolipoma; FLCN: folliculin gene; SSA/B: Sjögren syndrome antigen A/B;
SPEP: serum protein electrophoresis; UPEP: urine protein electrophoresis; VEGF-D: vascular endothelial growth
factor D; VATS: video-assisted thoracic surgery. #: lung biopsy is not always required, as a diagnosis may be
reached on a clinical basis in the right context. The presence of Langerhans cells (dendritic cells involved in the
mucosal airway immunity), which present as pale, eosinophilic cells with indistinct borders, a grooved nucleus
with small nucleoli and positivity for Langerin (CD207) and CD1a antigen at >5%, is characteristic of PLCH. S100
protein is not specific for diagnosis of Langerhans cell histiocytosis but may be present. ¶: many patients with
DCLDs due to suspected follicular bronchiolitis in the setting of sicca/Sjögren syndrome or positivity for
SSA/SSB can be diagnosed clinically and do not require a biopsy. Pale shading indicates a suspected diagnosis,
while darker shading indicates a definite diagnosis.
LAM generally affects females of reproductive age and its prevalence has been estimated as
three to seven cases per million women [19]. It is frequently sporadic (S-LAM) or may arise in
the presence of TSC, an autosomal-dominant disorder, characterised by the presence of
hamartomatous lesions in different organs [20].
Pathogenesis
The mutations causing LAM involve the TSC1 and TSC2 genes, which encode the proteins
hamartin and tuberin, respectively. Dysfunction of these proteins upregulates the mammalian
target of rapamycin (mTOR) pathway, leading to inappropriate cellular proliferation and
migration and to overexpression of lymphangiogenic vascular endothelial growth factors C and
D (VEGF-C and VEGF-D).
In TSC-LAM, TSC1 and TSC2 mutations are germinal, and neoplasms occur where a second
somatic mutation appears, while in S-LAM, mutations appear to involve only TSC2 and recur in
somatic tissues of the lungs, kidneys and lymph nodes [21, 22].
Although the role of oestrogen in the onset and progression of the disease is not fully known,
research indicates that it may activate protein kinase B, facilitate metastasis and promote
dysregulated protein translation by upregulating Fos-related antigen 1 (FRA1) [23].
Clinical manifestation and diagnosis

Dyspnoea is the most frequent symptom described at diagnosis (>70% of cases), while in some
cases, pneumothorax, generally recurrent and bilateral, or chylous pleural or abdominal effusion
may be the first manifestation of the disease.
In the presence of a characteristic HRCT image (>10 small, round, diffuse, bilateral cysts), a
diagnosis of definite LAM can be obtained if TSC, renal angiomyolipoma, cystic
lymphangioleiomyoma, or abdominal or chest chylous pleural effusions is observed [24].
In the latest American Thoracic Society/Japanese Respiratory Society guidelines, serum levels
of VEGF-D >800 pg·mL−1 have been included as one of the criteria used to reach a diagnosis
in the presence of a compatible clinical history and a characteristic HRCT of the chest, with
high sensitivity and specificity reported [25]. In fact, serum levels of VEGF-D have been
observed to be higher in LAM patients compared with healthy volunteers, as well as in other
cystic lung diseases, and they were also higher in TSC-LAM patients than in TSC patients with
no pulmonary involvement on HRCT [25, 26].
74 https://doi.org/10.1183/2312508X.10017622
When confirmatory characteristics are lacking, lung biopsy should be considered. Pulmonary
samples may be obtained by a transbronchial lung biopsy, before considering a surgical
approach [27]. Recently, cryobiopsy seems to be a promising tool to obtain a pulmonary tissue
sample in this disease, but further investigations are required [28–30].
Histologically, lung-infiltrating cells can be distinguished as two main morphologies: small

spindle-shaped cells and epithelioid–cuboid cells. They stain positively for smooth muscle actin,
vimentin and desmin, and for elanocytic markers such as gp100 and MelanA/MART1. In
addition, they have oestrogen and progesterone receptors, and expression of VEGF-C and -D
has been observed on the LAM cell surface [31].
Once the diagnosis has been obtained, PFTs should be performed to stratify the severity of the
disease. An obstructive pattern is frequently observed, along with a reduction in DLCO [32–35].
The rate of decline in lung function in untreated patients is unpredictable and has been reported
as 60–120 mL·year–1 in retrospective studies [36, 37] and 90.3–134 mL·year–1 in two clinical
trials [38, 39]. In patients with advanced disease, respiratory failure may be observed, so a
6-min walk test with oximetry and/or arterial blood gas analysis should be performed to assess
whether supplemental oxygen is required.
Treatment: present and future

The natural history of LAM includes progressive dyspnoea and lung function decline with
obstruction and hyperinflation. The decline is faster in patients with S-LAM and elevated
VEGF-D, and is accelerated by oestrogen-containing medications and pregnancy [40].
Sirolimus was approved for LAM patients by the US Food and Drug Administration (FDA) in
2015 and by the European Medicines Agency (EMA) in 2016. In the case of TSC, everolimus
obtained approval by the EMA in 2011 and by the FDA in 2018 for the treatment of
subependymal giant-cell astrocytoma and angiomyolipomas. Its use is recommended in the case
of a compromised lung function at baseline (forced expiratory volume in 1 s (FEV1) <70%) or
rapid deteriorating lung function (>90 mL·year–1) [41], and also in the case of symptomatic
chylous effusion and angiomyolipomas before invasive management.
Sirolimus is an mTOR inhibitor that has been investigated in a randomised

placebo-controlled trial in patients affected by LAM with moderate functional impairment
(MILES trial) [38]. In this trial, stabilisation of FEV1 during the 12-month study period was
observed in the treated arm, while the decline in lung function resumed after treatment
discontinuation and paralleled that in the placebo group. Moreover, the sirolimus group
experienced a better quality of life and functional performance in contrast to the group
receiving placebo. Minor adverse events have been reported, such as mucositis,
gastrointestinal events, hypercholesterolaemia, acneiform rash and swelling in the lower
limbs. Serious adverse events were similar in both groups. Elevated VEGF-D appears to be a
predictor of a better treatment response. In 2013, a Japanese study showed that, in
comparison with the 5–15 ng·mL−1 of the MILES trial, a serum level of <5 ng·mL−1 was
still effective [42]. Similar efficacy was observed for everolimus, although a higher rate of
minor side-effects was observed [43].
Although the use of sirolimus has changed the prognosis of LAM, it has been observed that
some patients develop a decline in FEV1 after 12 months of treatment [44, 45], suggesting
different disease phenotypes or an acquired resistance to this drug.
https://doi.org/10.1183/2312508X.10017622 75
These observations have led to the necessity for different treatment targets. In both in vitro and
animal models, it has been observed that autophagy and mTOR inhibitors in combination are more
effective than single treatment alone [46]. A phase I clinical trial has been conducted to investigate
the safety and tolerability of sirolimus plus hydroxychloroquine in LAM patients. No serious adverse
events have been reported, and an improvement in FEV1 and FVC was observed after 24 weeks of
treatment with the higher dose of hydroxychloroquine (400 mg), as the secondary end-point [47].
More studies are needed to validate hydroxychloroquine as an effective treatment for LAM.
A better understanding of other kinases involved in LAM pathogenesis has allowed the
development of other studies involving inhibitors targeting these molecules, such as saracatinib,
nintedanib and imatinib. The clinical trials are listed in table 2; the majority are still underway
with the results not yet available.
In end-stage LAM, lung transplantation is an important therapeutic option. In a cohort of US

LAM patients who underwent lung transplantation, a 10-year survival was observed in 56%,
which is significantly higher compared with other lung disorders (32%) [51]. Two retrospective
analyses confirmed this positive trend [52–54], although in one of the studies, a higher rate of
long-term complications was described [53].
PLCH
Langerhans cell histiocytosis (LCH) is the most common disease among histiocytic disorders,
characterised by abnormal accumulation of cells derived from dendritic cells. LCH has been
classified as a systemic or single-organ manifestation according to the number of organs
involved. The systemic form is characterised by a worse prognosis, in particular when the liver,
spleen and haematopoietic organs are affected (“risk organs”) [55]. The lungs may be involved
in systemic manifestations in both children and adults, but single-organ involvement of the lung
is observed in young adult smokers or ex-smokers (PLCH).
Pathogenesis
The pathogenesis PLCH is not completely understood, but identification of recurrent
BRAFV600E mutation in ∼50% of LCH lesions in different tissues, including the lung, has
supported the idea of a clonal/neoplastic disease [56]. This proto-oncogene is localised in the
canonical mitogen-activated protein kinase (MAPK) pathways, whose activation leads to the
phosphorylation of MAPK kinase (MEK1 and -2) and extracellular signal-regulated kinase
(ERK), which drives the activation of several substrates responsible for different cellular
processes [57, 58]. The BRAFV600E mutation is responsible for constitutive activation of MAPK
pathways, leading to reduced control of cell differentiation and survival.
The independent activation of MAPK pathways, even without BRAFV600E, has highlighted their
role in the pathogenesis of LCH, and recently several mutations at different levels of the
pathway have been reported [59, 60]. Mutation of TSC2 has been identified in blood and urine
cells in PLCH patients but not in healthy volunteers; however, the pathogenic relevance of this
finding has not been well elucidated so far [61].
Tobacco smoking is widely recognised as a key role in the pathogenesis of PLCH, and is
known to induce modifications in the epithelium of distal bronchioles associated with
accumulation of CD1a+ cells in healthy smokers and in other pulmonary diseases. Furthermore,
tobacco smoking promotes the production of local cytokines, leading to differentiation and
activation of dendritic cells in PLCH lesions [55].
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TABLE 2 Clinical trials for lymphangioleiomyomatosis
ClinicalTrials.gov Drug Design Primary Status Results First author

identifier (trial name) end-point [ref.]
NCT00414648 (MILES) Sirolimus Randomised, double FEV1 Completed Reached the primary end-point YOUNG [40]
blinded, placebo Improved some measures of qualify of life
controlled
NCT01059318 Everolimus Open label, dose Safety, PK, Completed Treatment was safe and, in addition, improved GOLDBERG [43]
escalating PD some measures of lung function and exercise
capacity, and reduced serum VEGF-D and
collagen IV
The dose used was quite high and prone to
side-effects
NCT01687179 (SAIL) Sirolimus plus Open label Safety Completed Treatment was safe EL-CHEMALY [47]
hydroxychloroquine
NCT01353209 (TRAIL) Letrozole Randomised, double FEV1 Completed Treatment was safe LU [48]
blinded, placebo Failed to enrol the target number of patients,

controlled so efficacy of letrozole could not be assessed
as planned
NCT00989742 Doxycycline Randomised, double FEV1 Completed Underpowered study CHANG [39]
blinded, placebo Treatment was safe
controlled
NCT02737202 (SLAM-2) Saracatinib Open label, single FEV1 Completed Results not available
arm
NCT02484664 (COLA) Celecoxib Open label, single Safety Completed Treatment was safe KRYMSKAYA [49]
arm It did not change PFTs and VEGF-D values
NCT03062943 (LAM) Nintedanib Open label, single FEV1 Completed Results not available
arm
Continued
77
78

TABLE 2 Continued
ClinicalTrials.gov Drug Design Primary Status Results First author

identifier (trial name) end-point [ref.]
NCT03131999 (LAMP1) Imatinib Randomised, blinded, VEGF-D Completed Results not available
placebo controlled
NCT03253913 (RESULT) Sirolimus plus Open label, single VEGF-D Completed Primary end-point was not reached, but a GUPTA [50]
resveratrol arm reduction significant reduction in VEGF-D values was
⩾42% observed, as well as a significant improvement
in quality of life
Treatment was safe
NCT02061397 (SOS) mTOR inhibitors plus Open label, single Safety Completed Well tolerated
simvastatin arm Associated with decline in FEV1
MILES: Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus; SAIL: Safety Study of Sirolimus and Hydroxychloroquine in Women with
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Lymphangioleiomyomatosis; TRAIL: Trial of Aromatase Inhibition in Lymphangioleiomyomatosis; SLAM-2: Safety and Efficacy of Saracatinib in Subjects with
Lymphangioleiomyomatosis; COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC; LAM: A Study of Nintedanib for LymphAngioleioMyomatosis; LAMP1: LAM Pilot
Study with Imatinib Mesylate; RESULT: Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial; SOS: Safety of Simvastatin in LAM and TSC; FEV1: forced expiratory
volume in 1 s; PK: pharmacokinetics; PD: pharmacodynamics; VEGF-D: vascular endothelial growth factor D; mTOR: mammalian target of rapamycin.

In most cases, PLCH is silent or associated with nonspecific respiratory symptoms, such as
cough (50–70%), dyspnoea (40–60%) and thoracic pain, and occasionally with constitutional
symptoms such as fatigue, weight loss and fever. Spontaneous pneumothorax has been observed
as the first disease manifestation in 10–20% of cases [55, 62, 63].
In some cases, the first manifestation may be related to extrathoracic involvement. Pain and/or
pathological bone fractures, generally solitary and affecting flat bones, are related to the
presence of osteolytic lesions due to bone infiltration [55, 64]. Pituitary stalk involvement may
lead to diabetes insipidus characterised by polyuria–polydipsia syndrome, and skin involvement
may be observed as erythematous, maculopapular or nodular lesions. Seborrheic and crusted
lesions have occasionally been found on the scalp [65].
PH may be a complication of PLCH, particularly in advanced stages of the disease, although in

some cases it may be detected at the time of diagnosis. The New York Heart Association stage
of dyspnoea was the only predictor of mortality in patients with a mean pulmonary artery
pressure of 45 mmHg [15].
PLCH may be associated with malignancies, in particular haematological disorders.

Furthermore, an increased incidence of primary lung cancer, related to the patient’s smoking
history, and various other types of solid tumours has been described [66, 67].
The HRCT characteristics of PLCH have been described earlier. In the presence of this specific
pattern, bronchoscopy is not necessary, but it may be useful to exclude alternative diagnoses in
the case of atypical manifestation. When performed, BAL is usually characterised by increased
eosinophils (generally ⩽10%) and CD1a+ cells. Values >5% are suggestive of PLCH but have a
low sensitivity and specificity. The available data come from several case reports analysing this
technique in small samples of patients. Taken together, these studies report the presence of >5%
cells with CD1a expression in BAL in 0–25% of patients affected by PLCH [68–70].
Tissues samples should be obtained in atypical cases in order to reach a definitive diagnosis,
but, as lesions are focal and bronchiolocentric, surgical biopsy should be preferred to a
transbronchial lung biopsy.
Histologically, PLCH is characterised by the presence of Langerhans cells, dendritic cells

involved in the mucosal airway immunity, appearing as pale, eosinophilic cells with indistinct
borders, grooved nuclei with small nucleoli and positivity for Langerin (CD207) and CD1a
antigen. S-100 protein is not specific for LCH diagnosis but may be present.
In the early manifestation of PLCH, dendritic cells accumulate in the peribronchiolar space in
granulomas. The initial micro- and macronodules around terminal and respiratory bronchioles
evolve to paucicellular stellate fibrotic scars; pericicatricial airspace enlargement due to airway
remodelling and nodule cavitation can be found in the later stages, probably due the action of
metalloproteinases [71]. Altered venous and arterial structures are common [72, 73].
Intraluminal fibrosis is often present.
The role of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is still debated

in the case of isolated lung involvement. As lesions are generally FDG enhancing, the disease
activity could be estimated, as well as the response to treatment. Unfortunately, 18F-FDG-PET is
not useful to distinguish PLCH nodules from malignancies [74]. 18F-FDG-PET is useful in the
https://doi.org/10.1183/2312508X.10017622 79
presence of extrapulmonary involvement [75]. In a retrospective analysis of 15 children affected

by LCH (five with single- and 10 with multisystem organ involvement), this tool allowed the
detection of disease activity in bone, pituitary gland, spleen, lymph nodes and lung [76].
PFTs are generally performed at the time of diagnosis and show a wide range, from normal in
the early stages to an obstructive, restrictive or mixed pattern. DLCO reduction has been reported
in 80–90% of cases [55, 62].
Treatment
Smoking cessation is the first recommendation for patients diagnosed with PLCH. Generally,
this intervention can lead to disease stabilisation and lesion regression and resolution [77]. A
small percentage of patients may experience lung function decline [78], despite successful
smoking cessation, and in this case, treatment should be taken in consideration.
Systemic steroids have been used empirically without any evidence of efficacy [55]. The
efficacy of vinblastine on pulmonary manifestations of LCH is limited, although it is used in the
multisystemic disease. Cladribine (2-chlorodeoxyadenosine) as monotherapy has been shown to
provide improvements in lung function and sometimes resolution of the lung parenchymal
lesions [79], but the side-effects of this highly immunosuppressive drug must always be
carefully considered. Its efficacy and tolerance in the symptomatic form of PLCH is under
investigation (Clinicaltrials.gov identifier NCT01473797).
The discovery of gene mutations in MAPK pathways has opened the way to treatment ad hoc in
patients with refractory disease. Vemurafenib, a BRAFV600E inhibitor, led to the stabilisation of
disease in a subset of patients affected by systemic LCH [80]. Trametinib, a molecule that
inhibits MEK1 and -2, both downstream of BRAF, has been shown to be beneficial in patients
with LCH who exhibited activating MEK1 deletion mutations [81].
Patients with severe pulmonary function impairment may be referred for lung transplantation,
although a relapse of the disease has been reported in patients who resumed smoking after the
transplantation [82].
BHD
BHD is a rare autosomal-dominant disorder characterised by hair follicle tumours, early-onset
renal neoplasm and pulmonary cysts. It is usually diagnosed during the fourth or fifth decade of
life with no sex predilection [83].
Pathogenesis
The dysregulation of mTOR signalling caused by mutated folliculin (encoded by the FLCN
gene on chromosome 17) is most likely behind the pathogenesis of BHD. FLCN mutations also
affect the regulation of Wnt, tumour necrosis factor-β and DENN (differentially expressed in
normal and neoplastic cells) proteins, although the exact mechanism that leads to cyst formation
remains unclear [84].

BHD should be suspected in young patients presenting with pneumothorax and a family history
of pneumothorax, renal tumours and suggestive skin lesions (fibrofolliculoma or trichodiscomas).
Renal neoplasms occur in 25% of BHD patients and are often bilateral and multifocal; the most
common histologies are oncocytomas and chromophobe adenomas [85]. Genetic testing is
indicated to confirm the diagnosis in suspected cases and in close family members. The
80 https://doi.org/10.1183/2312508X.10017622
detection of FLCN or a histological diagnosis of fibrofolliculoma or trichodiscomas is sufficient

to reach the diagnosis (major criteria); otherwise, two minor criteria are required, such as the
presence of a typical chest CT scan (described earlier) and/or a family history of BHD and/or
renal cancer. Lung biopsy is often uninformative and should be avoided.
Lung function in BHD tends to be preserved, with a mild reduction of DLCO, and it is
uncommon for the disease to result in lung failure [86].
Those with a positive genetic test result, even when asymptomatic, should undergo renal mass
evaluation for renal tumours every 3 years from the age of 20 years. Renal neoplasms generally
do not exhibit an invasive behaviour, but it is recommended that nephron-sparing resection is
performed for tumours >3 cm, as these are more likely to become invasive [87].
Conclusion
DCLDs are a group of diseases with a similar radiological appearance but with different
pathogenesis and clinical behaviour, leading to different prognosis and treatment options.
Recognising the differences between these entities through a thorough evaluation of clinical,
epidemiological and radiological peculiarities of each disease can substantially affect the clinical
management, including the choice of the correct treatment. The increasing interest in DLCDs
has led to the identification of biomarkers that can be helpful in the diagnostic process and
should be further implemented through active research in the field. In addition, to allow
adequate management of these ultra-rare diseases, patients should be referred to centres with
specific expertise in DCLDs.
References
1 Gupta N, Vassallo R, Wikenheiser-Brokamp KA, et al. Diffuse cystic lung disease. Part I. Am J Respir Crit Care
Med 2015; 191: 1354–1366.
2 Elia D, Torre O, Cassandro R, et al. Ultra-rare cystic disease. Eur Respir Rev 2020; 29: 190163.
3 Torre O, Elia D, Caminati A, et al. New insights in lymphangioleiomyomatosis and pulmonary Langerhans cell
histiocytosis. Eur Respir Rev 2017; 26: 170042.
4 Dines DE. Diagnostic significance of pneumatocele of the lung. JAMA 1968; 204: 1169–1172.
5 Kikuchi E, Kinoshita I, Yamazaki K, et al. Epithelioid sarcoma presenting as pulmonary cysts with cancer
antigen 125 expression. Respirology 2006; 11: 826–829.
6 Ohdama S, Akagawa S, Matsubara O, et al. Primary diffuse alveolar septal amyloidosis with multiple cysts and
calcification. Eurn Respir J 1996; 9: 1569–1571.
7 Hansell DM, Bankier AA, MacMahon H, et al. Fleischner Society: glossary of terms for thoracic imaging.
Radiology 2008; 246: 697–722.
8 Cordier J-F, Johnson SR. Multiple cystic lung diseases. In: Cordier J-F, ed. Orphan Lung Diseases (ERS
Monograph). Sheffield, European Respiratory Society, 2011; pp. 46–83.
9 Ryu JH, Tian X, Baqir M, et al. Diffuse cystic lung diseases. Front Med 2013; 7: 316–327.
10 Bobbio A, Dechartres A, Bouam S, et al. Epidemiology of spontaneous pneumothorax: gender-related
differences. Thorax 2015; 70: 653–658.
11 Johannesma PC, Reinhard R, Kon Y, et al. Prevalence of Birt–Hogg–Dubé syndrome in patients with apparently
primary spontaneous pneumothorax. Eur Respir J 2015; 45: 1191–1194.
12 Hagaman JT, Schauer DP, McCormack FX, et al. Screening for lymphangioleiomyomatosis by high-resolution
computed tomography in young, nonsmoking women presenting with spontaneous pneumothorax is
cost-effective. Am J Respir Crit Care Med 2010; 181: 1376–1382.
13 Gonano C, Pasquier J, Daccord C, et al. Air travel and incidence of pneumothorax in lymphangioleiomyomatosis.
Orphanet J Rare Dis 2018; 13: 222.
14 Sakurai T, Arai T, Hirose M, et al. Reduced risk of recurrent pneumothorax for sirolimus therapy after surgical
pleural covering of entire lung in lymphangioleiomyomatosis. Orphanet J Rare Dis 2021; 16: 466.
15 Le Pavec J, Lorillon G, Jaïs X, et al. Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension:
clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest 2012; 142: 1150–1157.
https://doi.org/10.1183/2312508X.10017622 81
16 Cottin V, Harari S, Humbert M, et al. Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in

20 patients. Eur Respir J 2012; 40: 630–640.
17 Paciocco G, Uslenghi E, Bianchi A, et al. Diffuse cystic lung diseases: correlation between radiologic and
functional status. Chest 2004; 125: 135–1342.
18 Fletcher CD, Unni KK, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon,
International Agency for Research on Cancer, 2002.
19 Harknett EC, Chang WY, Byrnes S, et al. Use of variability in national and regional data to estimate the
prevalence of lymphangioleiomyomatosis. QJM 2011; 104: 971–979.
20 Franz DN, Brody A, Meyer C, et al. Mutational and radiographic analysis of pulmonary disease consistent with
lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J
21 Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with
tuberous sclerosis complex. Mayo Clin Proc 2000; 75: 591–594.
22 Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of
sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000; 97: 6085–6090.
23 Li C, Lee PS, Sun Y, et al. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and
tumorigenesis in TSC2-deficient LAM cells. J Exp Med 2014; 211: 15–28.
24 Gupta N, Finlay GA, Kotloff RM, et al. Lymphangioleiomyomatosis diagnosis and management: high-resolution
chest computed tomography, transbronchial lung biopsy, and pleural disease management. An Official
American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med
2017; 196: 1337–1348.
25 Young LR, Vandyke R, Gulleman PM, et al. Serum vascular endothelial growth factor-D prospectively
distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010; 138: 674–681.
26 Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl
J Med 2008; 358: 199–200.
27 Harari S, Torre O, Cassandro R, et al. Bronchoscopic diagnosis of Langerhans cell histiocytosis and
lymphangioleiomyomatosis. Respir Med 2012; 106: 1286–1292.
28 Gupta N, Wikenheiser-Brokamp K, Zander D, et al. Successful diagnosis of lymphangioleiomyomatosis with
transbronchial lung cryobiopsy. Lymphology 2017; 50: 154–157.
29 Yoshida M, Awano N, Inomata M, et al. Diagnostic usefulness of transbronchial lung cryobiopsy in two patients
mildly affected with pulmonary lymphangioleiomyomatosis. Respir Investig 2020; 58: 295–299.
30 Han Q, Chen X, Xu X, et al. The application of transbronchial lung cryobiopsy and uniportal and tubeless
video-assisted thoracic surgery in the multidisciplinary diagnosis of interstitial lung disease – a real-world
prospective study. Front Mol Biosci 2021; 8: 681669.
31 Matsumoto Y, Horiba K, Usuki J, et al. Markers of cell proliferation and expression of melanosomal antigen in
lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 1999; 21: 327–336.
32 Ryu JH, Doerr CH, Fisher SD, et al. Chylothorax in lymphangioleiomyomatosis. Chest 2003; 123: 623–627.
33 Taveira-DaSilva AM, Stylianou MP, Hedin CJ, et al. Maximal oxygen uptake and severity of disease in
lymphangioleiomyomatosis. Am J Respir Crit Care Med 2003; 168: 1427–1431.
34 Hayashida M, Seyama K, Inoue Y, et al. The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide
cross-sectional study of presenting features and prognostic factors. Respirology 2007; 12: 523–530.
35 Taveira-DaSilva AM, Steagall WK, Rabel A, et al. Reversible airflow obstruction in lymphangioleiomyomatosis.
Chest 2009; 136: 1596–1603.
36 Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and
progesterone treatment. Am J Respir Crit Care Med 1999; 160: 628–633.
37 Baldi BG, Freitas CS, Araujo MS, et al. Clinical course and characterisation of lymphangioleiomyomatosis in a
Brazilian reference centre. Sarcoidosis Vasc Diffuse Lung Dis 2014; 31: 129–135.
38 McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J
Med 2011; 364: 1595–1606.
39 Chang WY, Cane JL, Kumaran M, et al. A 2-year randomised placebo-controlled trial of doxycycline for
lymphangioleiomyomatosis. Eur Respir J 2014; 43: 1114–1123.
40 Young L, Lee HS, Inoue Y, et al. Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis
severity and treatment response: a prospective analysis of the Multicenter International
Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med 2013; 1: 445–452.
41 Johnson SR, Cordier JF, Lazor R, et al. European Respiratory Society guidelines for the diagnosis and
management of lymphangioleiomyomatosis. Eur Respir J 2010; 35: 14–26.
42 Ando K, Kurihara M, Kataoka H, et al. Efficacy and safety of low-dose sirolimus for treatment of
lymphangioleiomyomatosis. Respir Investig 2013; 51: 175–183.
43 Goldberg HJ, Harari S, Cottin V, et al. Everolimus for the treatment of lymphangioleiomyomatosis: a phase II
study. Eur Respir J 2015; 46: 783–794.
82 https://doi.org/10.1183/2312508X.10017622
44 Bee J, Fuller S, Miller S, et al. Lung function response and side effects to rapamycin for
lymphangioleiomyomatosis: a prospective national cohort study. Thorax 2018; 73: 369–375.
45 Harari S, Torre O, Elia D, et al. Improving survival in lymphangioleio-myomatosis: a 16-year observational study
in a large cohort of patients. Respiration 2021; 100: 989–999.
46 Parkhitko A, Myachina F, Morrison TA, et al. Tumorigenesis in tuberous sclerosis complex is autophagy and
p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci USA 2011; 108: 12455–12460.
47 El-Chemaly S, Taveira-Dasilva A, Goldberg HJ, et al. Sirolimus and autophagy inhibition in
lymphangioleiomyomatosis: results of a phase I clinical trial. Chest 2017; 151: 1302–1310.
48 Lu C, Lee H, Pappas GP, et al. A phase II clinical trial of an aromatase inhibitor for postmenopausal women
with lymphangioleiomyomatosis. Ann Am Thorac Soc 2017; 14: 919–928.
49 Krymskaya VP, Courtwright AM, Fleck V, et al. A phase II clinical trial of the Safety Of Simvastatin (SOS) in
patients with pulmonary lymphangioleiomyomatosis and with tuberous sclerosis complex. Respir Med 2020;
163: 105898.
50 Gupta N, Zhang B, Zhou Y, et al. Safety and efficacy of combined resveratrol and sirolimus in
lymphangioleiomyomatosis. Chest 2023; 163: 1144–1155.
51 Khawar MU, Yazdani D, Zhu Z, et al. Clinical outcomes and survival following lung transplantation in patients
with lymphangioleiomyomatosis. J Heart Lung Transplant 2019; 38: 949–955.
52 Salman J, Ius F, Sommer W, et al. Long-term results of bilateral lung transplantation in patients with end-stage
pulmonary lymphangioleiomyomatosis. Prog Transplant 2019; 29: 115–121.
53 Kurosaki T, Otani S, Miyoshi K, et al. Favorable survival even with high disease-specific complication rates in
lymphangioleiomyomatosis after lung transplantation – long-term follow-up of a Japanese center. Clin Respir J
2020; 14: 116–123.
54 Boehler A, Speich R, Russi EW, et al. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 1996;
335: 1275–1280.
55 Vassallo R, Harari S, Tazi A. Current understanding and management of pulmonary Langerhans cell
histiocytosis. Thorax 2017; 72: 937–945.
56 Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood
2010; 116: 1919–1923.
57 Jouenne F, Benattia A, Tazi A. Mitogen-activating protein kinase pathway alterations in Langerhans cell
histiocytosis. Curr Opin Oncol 2021; 33: 101–109.
58 Fiskus W, Mitsiades N. B-Raf inhibition in the clinic: present and future. Annu Rev Med 2016; 67: 29–43.
59 Jouenne F, Le Goff J, Bugnet E, et al. Lack of evidence for the involvement of Merkel cell polyomavirus in
pulmonary Langerhans cell histiocytosis. ERJ Open Res 2020; 6: 00230-2019.
60 Liu H, Osterburg AR, Flury J, et al. MAPK mutations and cigarette smoke promote the pathogenesis of
pulmonary Langerhans cell histiocytosis. JCI Insight 2020; 5: e132048.
61 Elia D, Torre O, Vasco C, et al. Pulmonary Langerhans cell histiocytosis and lymphangioleiomyomatosis have
circulating cells with loss of heterozygosity of the TSC2 gene. Chest 2022; 162: 385–393.
62 Elia D, Torre O, Cassandro R, et al. Pulmonary Langerhans cell histiocytosis: a comprehensive analysis of 40
patients and literature review. Eur J Intern Med 2015; 26: 351–356.
63 Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in
adults. N Engl J Med 2002; 346: 484–490.
64 Kobayashi M, Ando S, Kawamata T, et al. Clinical features and outcomes of adult Langerhans cell histiocytosis:
a single-center experience. Int J Hematol 2020; 112: 185–192.
65 Crickx E, Bouaziz JD, Lorillon G, et al. Clinical spectrum, quality of life, BRAF mutation status and treatment of
skin involvement in adult Langerhans cell histiocytosis. Acta Derm Venereol 2017; 97: 838–842.
66 Egeler RM, Neglia JP, Aricò M, et al. The relation of Langerhans cell histiocytosis to acute leukaemia,
lymphomas, and other solid tumors: The LCH-Malignancy Study Group of the Histiocyte Society. Hematol Oncol
Clin North Am 1998; 12: 369–378.
67 Bagnasco F, Zimmermann SY, Egeler RM, et al. Langerhans cell histiocytosis and associated malignancies: a
retrospective analysis of 270 patients. Eur J Cancer 2022; 172: 138–145.
68 Lommatzsch M, Bratke K, Stoll P, et al. Bronchoalveolar lavage for the diagnosis of pulmonary Langerhans cell
histiocytosis. Respir Med 2016; 119: 168–174.
69 Baqir M, Vassallo R, Maldonado F, et al. Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis.
J Bronch Intervent Pulm 2013; 20: 309–312.
70 Radzikowska E, Wiatr E, Błasińska-Przerwa K, et al. Clinical features and outcome of adult patients with
pulmonary Langerhans cell histiocytosis. Eur Respir J 2019; 54: PA3683.
71 Colombat M, Caudroy S, Lagonotte E, et al. Pathomechanisms of cyst formation in pulmonary light chain
deposition disease. Eur Respir J 2008; 32: 1399–1403.
72 Colby TV, Lombard C. Histiocytosis X in the lung. Hum Pathol 1983; 14: 847–856.
https://doi.org/10.1183/2312508X.10017622 83
73 Roden AC, Yi ES. Pulmonary Langerhans cell histiocytosis: an update from the pathologists’ perspective. Arch
Pathol Lab Med 2016; 140: 230–240.
74 Obert J, Vercellino L, van der Gucht A, et al. 18F-fluorodeoxyglucose positron emission tomography-computed
tomography in the management of adult multisystem Langerhans cell histiocytosis. Eur J Nucl Med Mol Imaging
2017; 44: 598–610.
75 Agarwal KK, Seth R, Behra A, et al. 18F-Fluorodeoxyglucose PET/CT in Langerhans cell histiocytosis: spectrum of
manifestations. Jpn J Radiol 2016; 34: 267–276.
76 Niu J, Liang J, Feng Q, et al. 18F-FDG PET/MR assessment of pediatric Langerhans cell histiocytosis. Int J Gen
Med 2021; 14: 6251–6259.
77 Schönfeld N, Dirks K, Costabel U, et al. A prospective clinical multicentre study on adult pulmonary
Langerhans’ cell histiocytosis. Sarcoidosis Vasc Diffuse Lung Dis 2012; 29: 132–138.
78 Tazi A, Marc K, Dominique S, et al. Serial computed tomography and lung function testing in pulmonary
Langerhans’ cell histiocytosis. Eur Respir J 2012; 40: 905–912.
79 Grobost V, Khouatra C, Lazor R, et al. Effectiveness of cladribine therapy in patients with pulmonary
Langerhans cell histiocytosis. Orphanet J Rare Dis 2014; 9: 191.
80 Diamond EL, Subbiah V, Lockhart AC, et al. Vemurafenib for BRAF V600-mutant Erdheim–Chester disease and
Langerhans cell histiocytosis: analysis of data from the histology-independent, phase 2, open-label VE-BASKET
study. JAMA Oncol 2018; 4: 384–388.
81 Lorillon G, Jouenne F, Baroudjian B, et al. Response to trametinib of a pulmonary Langerhans cell histiocytosis
harboring a MAP2K1 deletion. Am J Respir Crit Care Med 2018; 198: 675–678.
82 Dauriat G, Mal H, Thabut G, et al. Lung transplantation for pulmonary Langerhans’ cell histiocytosis: a
multicenter analysis. Transplantation 2006; 81: 746–750.
83 Kunogi M, Kurihara M, Ikegami TS, et al. Clinical and genetic spectrum of Birt–Hogg–Dube syndrome patients in
whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet 2010; 47: 281–287.
84 Baba M, Hong SB, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1,
and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci USA 2006; 103: 15552–15557.
85 Pavlovich CP, Grubb RL, Hurley K, et al. Evaluation and management of renal tumors in the Birt–Hogg–Dubé
syndrome. J Urol 2005; 173: 1482–1486.
86 Tobino K, Hirai T, Johkoh T, et al. Differentiation between Birt–Hogg–Dubé syndrome and
lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in
66 females. Eur J Radiol 2012; 81: 1340–1346.
87 Stamatakis L, Metwalli AR, Middelton LA, et al. Diagnosis and management of BHD-associated kidney cancer.
Fam Cancer 2013; 12: 397–402.
Disclosures: S. Harari reports receiving grants from Boehringer Ingelheim, outside the submitted work. The
remaining authors have nothing to disclose.
84 https://doi.org/10.1183/2312508X.10017622
Chapter 7
Bronchiolitis
Venerino Poletti 1,2,3, Claudia Ravaglia2, Alessandra Dubini4,

Sissel Kronborg-White3, Salvatore Cazzato5 and Sara Piciucchi 6
1
Pulmonology Unit, Department of Medical Specialities, GB Morgagni Hospital/Bologna University-Forlì Campus,
Forlì, Italy. 2DIMEC, University of Bologna, Bologna, Italy. 3Department of Respiratory Diseases & Allergy, Aarhus
University, Aarhus, Denmark. 4Department of Pathology, GB Morgagni Hospital/Bologna University-Forlì Campus,
Forlì, Italy. 5Pediatric Unit, Department of Mother and Child Health, Salesi Children’s Hospital, Ancona, Italy.
6
Department of Radiology, GB Morgagni Hospital/Bologna University-Forlì Campus, Forlì, Italy
Corresponding author: Venerino Poletti (venerino.poletti@gmail.com)
Cite as: Poletti V, Ravaglia C, Dubini A, et al. Bronchiolitis. In: Wagner TOF, Humbert M, Wijsenbeek M, et al. Rare
Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 85–102
[https://doi.org/10.1183/2312508X.10003823].
@ERSpublications
Bronchiolitis is an inflammatory/fibrotic process involving the small airways. CTs show characteristic
elements and should be interpreted with variegated pathology in mind. Bronchiolitis has a variety of causes
and is idiopathic in a minority of cases. https://bit.ly/ERSM100
ISSN: 2312-5098.
The wide spectrum of inflammatory and fibrosing processes that are linked to the bronchioles are
grouped under the umbrella term of “bronchiolitis”. In these disorders, the distribution and amount of
the cellular or mesenchymal components can vary from case to case, and form the basis of a wide range
of histopathological, radiological and clinical aspects of bronchiolitis. The diagnosis of small airways
disease is reliant upon the integration of multiple data, including clinical context and medical history,
laboratory data, microbiological investigations, radiological patterns and PFTs. Lung biopsy is not
always necessary. The classification of bronchiolar disorders differs in the available literature, as they
can occur in a clinical context (i.e. due to inhalation of fumes/gases, infections, drugs, immunologically
driven disorders or idiopathic entities that may manifest as a form of bronchiolitis) or as a result of
underlying histology. Histology helps stratify this broad spectrum of inflammatory and/or fibrotic
process into three main patterns: cellular bronchiolitis; bronchiolitis obliterans with intraluminal/
inflammatory polyps ( proliferative bronchiolitis); and constrictive bronchiolitis. Imaging reflects the
pathological background and is fundamental in the detection and differentiation of these disorders.
Introduction
Bronchiolar abnormalities are relatively common, as the small airways can be primarily or
secondarily involved in diseases that mainly affect the lung parenchyma or bronchial tree [1–3].
Parenchymal disorders with prominent bronchiolar involvement include hypersensitivity pneumonitis
(HP), organising pneumonia and pulmonary Langerhans cell histiocytosis [4]. Large airways diseases
include bronchiectasis, asthma, COPD and cystic fibrosis [4]. Diffuse idiopathic pulmonary
neuroendocrine cell hyperplasia can be accompanied by bronchiolar fibrosis with constrictive
features, but has recently been classified as a preneoplastic disorder [5]. The aim of this chapter is
to analyse the inflammatory and fibrosing processes that are linked to the bronchioles.
https://doi.org/10.1183/2312508X.10003823 85
The small airways are located between the cartilage-walled bronchi and the site where the
ciliated epithelium disappears. In primary bronchiolitis, the distribution and amount of cellular
and mesenchymal components varies from case to case, forming the basis of a wide range of
histopathological, radiological and clinical aspects of bronchiolitis.
Aetiology and histopathology

The broad spectrum of inflammatory and fibrotic lesions found in bronchiolitis can be stratified
into three histological patterns: cellular bronchiolitis; bronchiolitis obliterans with intraluminal/
inflammatory polyps ( proliferative bronchiolitis); constrictive (or cicatricial) bronchiolitis (CB)
(table 1) [6, 7]. Importantly, various elementary lesions may coexist in a single patient.
Moreover, peribronchiolar epithelial metaplasia (Lambertosis) and mucostasis may be ancillary
findings [7].
Cellular bronchiolitis
Cellular bronchiolitis is defined as the presence of an inflammatory infiltrate involving the wall
and the lumen of the bronchioles [6, 7].
Acute bronchiolitis
The acute presentation is more typically diagnosed in infants and adolescents, and is
characterised by neutrophilic infiltrates with necrosis. In adults, different potential causes can
lead to the acute form, such as viral or bacterial infection, acute exposure to fumes, and toxins.
Chronic bronchiolitis
The chronic form has a more variegated morphological expression. When characteristic aspects
cannot be identified, the pathological pattern is labelled “not otherwise specified”. Nevertheless,
peculiar subtypes are recognizable, as follows.
Follicular bronchiolitis
Follicular bronchiolitis (FB) is defined by the presence of peribronchiolar hyperplastic lymphoid
follicles with reactive germinal centres, resulting in compression of the lumen (figure 1a) [6, 7].
It has been associated with a variety of immune-driven diseases, including connective tissue
diseases (CTDs) ( particularly rheumatoid arthritis (RA) and Sjögren syndrome), AIDS,
immunoglobulin (Ig)A deficiency and common variable immunodeficiency. Recently, it has
been reported in patients suffering from COPA syndrome [7].
TABLE 1 Histopathological forms of bronchiolitis

Cellular bronchiolitis
Acute
Chronic, not otherwise specified
Chronic, specific subtypes
Follicular bronchiolitis
Lymphocytic bronchiolitis
Eosinophilic bronchiolitis
Granulomatous bronchiolitis
Chronic aspiration bronchiolitis
Diffuse panbronchiolitis
Bronchiolitis obliterans with intraluminal/inflammatory polyps (proliferative bronchiolitis)
Constrictive (or cicatricial) bronchiolitis
86 https://doi.org/10.1183/2312508X.10003823
BRONCHIOLITIS | V. POLETTI ET AL.
a) b)
c) d)
FIGURE 1 a) A patient with Sjögren syndrome, follicular bronchiolitis. The membranous bronchioles are
surrounded and infiltrated by lymphoid aggregates with poorly formed reactive follicles. The lumen of the small
airways is totally or partially occluded. There is an evident goblet cell metaplasia in the epitheluim.
Haemotoxylin and eosin (H&E) stain, ×20 magnification. b) Transbronchial cryobiopsy in an allogeneic HSCT
patient with chronic graft-versus-host disease. A membranous bronchiole presents in the wall infiltrated by small
lymphocytes (lymphocytic bronchiolitis). The surrounding parenchyma is normal. H&E stain, ×20 magnification.
c) Transbronchial cryobiopsy in a patient with blood and BAL eosinophilia, irreversible airflow obstruction, a
clinical history of asthma and CT findings showing small airways involvement. A bronchiole presents a lumen
smaller than the adjacent pulmonary artery lumen. Subepithelial fibrosis, mild smooth muscle hypertrophy and
infiltration of eosinophils and lymphocytes/plasma cells are present. The lumen contains eosinophils, cellular
debris and mucus. Eosinophilic bronchiolitis (clinical diagnosis: hypereosinophilic obliterative bronchiolitis). H&E
stain, ×10 magnification. d) Constrictive (cicatricial) bronchiolitis. An acellular scar is the remnant of a small
airway. H&E stain, ×20 magnification.
Lymphocytic bronchiolitis
Lymphocytic bronchiolitis (LB) presents as infiltration of the airway wall by lymphocytes that
are not organised into germinal centres [6, 7]. This kind of airway inflammation can occur in
various conditions and has been seen in lung transplant patients, and in patients with infections
and CTDs (figure 1b). A peculiar LB pattern connected to peribronchiolitis with lymphoid
hyperplasia has been described in workers in the nylon flocking industry [8]. A unique
histopathological pattern characterised by the combination of LB, alveolar ductitis and
emphysema has also recently been described in never-smokers employed in a manufacturing
facility for industrial machines [9].
Eosinophilic bronchiolitis
Eosinophilic bronchiolitis (EB) can be observed in eosinophilic granulomatosis with
polyangiitis, or in a syndrome known as hypereosinophilic obliterative bronchiolitis (OB)
(figure 1c) [10].
https://doi.org/10.1183/2312508X.10003823 87
Granulomatous bronchiolitis
Granulomatous bronchiolitis (GB) is usually documented in mycobacterial infections, Crohn
disease, and where there is exposure to dirty environments, as described in the military [11].
Chronic aspiration bronchiolitis

Chronic aspiration bronchiolitis is characterised by an airway-centred inflammatory infiltrate,
which consists of giant cells around foreign body material [6, 7].
Diffuse panbronchiolitis (DPB) is characterised by chronic inflammation involving the entire
wall of terminal bronchioles, follicular hyperplasia of the peribronchiolar lymphoid tissue,
accumulation of purulent material in the lumen, and lymphoplasmocytic and foam cell
infiltration of the walls of the respiratory bronchioles and their adjacent ducts and alveoli
septa [12].
Proliferative bronchiolitis
Proliferative bronchiolitis is characterised by the presence of polyps of granulation tissue
projecting or completely filling the lumen of membranous and/or respiratory bronchioles [6].
These polyps can have a myxoid or pale-staining matrix (rich in acid mucopolysaccharides), in
which elongated myofibroblasts and inflammatory cells are embedded. They can also be richer in
collagen fibres. Proliferative bronchiolitis can be idiopathic or can occur secondary to a wide
variety of lung injuries (such as aspiration, post-obstruction, exposure to fumes and toxins, CTDs,
a reaction to drugs, haematopoietic stem cell transplantation or lung transplantation (LTx)).
CB
CB is characterised by the presence of subepithelial acellular fibrosis in the walls of the
membranous and of the respiratory bronchioles (surrounding rather than filling the lumen), with
consequent concentric narrowing or complete obliteration of the airway lumen [6, 7]. Areas of
fibrosis are patchy and subtle, even in severely affected patients, and diagnosis can be missed if
lesions are inadequately sampled or specific stains for elastic fibres are not used. Ancillary
histological findings include distortion of the lumen and mucostasis. In the most severe cases,
complete luminal obliteration with replacement of the bronchiole by an acellular scar may occur
(figure 1d).
An ongoing T-helper cell type-1 adaptive immune response seems to trigger airway wall
remodelling in different clinical forms of CB [13]. This peculiar form of bronchiolitis may be
detected in a variety of settings: as a sequela of viral infections or toxic inhalational, in
inflammatory bowel disease (IBD), in paraneoplastic autoimmune multiorgan syndrome
(PAMS) or paraneoplastic pemphigus, in transplanted patients (e.g. haematopoietic stem cells or
lung) or in drug-induced lung disease. Finally, CB may be idiopathic.
Surgical lung biopsy is still the referral tool used to obtain valid samples for identification of
bronchiolar lesions. However, in recent years, transbronchial cryobiopsy has been acquiring
credit as a valid alternative [14, 15]; in a minority of cases (mainly in transplanted patients),
regular transbronchial biopsy may still be diagnostic.
Clinical aspects
Clinical profile (identification of a cause, identification of an underlying systemic disorder or a
specific clinical setting) is an important part of the classification of bronchiolitis (table 2) [16].
88 https://doi.org/10.1183/2312508X.10003823
TABLE 2 Causes/clinical settings of bronchiolitis: a classification scheme

Inhalation bronchiolitis
Toxic fume inhalation
Irritant gases and mineral dusts
Organic dusts
Infectious and postinfectious bronchiolitis
Drug-induced bronchiolitis
CTD-associated bronchiolitis
IBD-associated bronchiolitis
Post-transplant bronchiolitis
PAMS-associated bronchiolitis
Genetic disorders
Lysinuric protein intolerance
Ataxia–teleangectasia
COPA syndrome
Sickle cell disease
Idiopathic obliterative bronchiolitis
CTD: connective tissue disease; IBD: inflammatory bowel disease; PAMS: paraneoplastic autoimmune
multiorgan syndrome.
Clinical findings in patients suffering from bronchiolitis may vary but usually in a spectrum
with two well-recognised extremes (table 3) [16]. Beyond plasma cell-free DNA in chronic lung
allograft dysfunction [17] and microbiological tests, diagnostic laboratory investigations with
appropriate accuracy/reliability do not exist. Because of their minor contribution to airway
resistence, the small airways can undergo considerable damage before the usual tests of either
static or dynamic lung function become abnormal [16]. More sophisticated tests should be used
for early detection of obstructive impairment: forced oscillation technique, impulse oscillometry,
simple-breath nitrogen washout, multiple-breath nitrogen washout and closing volume [18].
Imaging
Comprehension of the features of a CT scan is based on correlation with the histopathological
background of bronchiolar disorders. CT findings of these entities can be categorised into direct
and indirect signs (tables 4 and 5) [19].
Direct signs are represented by bronchiolar wall thickening (due to inflammation or fibrosis),
bronchiolar dilatation (bronchiolectasis) and luminal impaction filling the airways. The latter can
TABLE 3 Clinical profiles of bronchiolitis (two extremes of a spectrum)
Symptoms Signs Specific forms (prototypes)

of bronchiolitis
Subacute course Fever Purulent sputum Infectious bronchiolitis

Purulent sputum Inspiratory–expiratory ronchi Diffuse panbronchiolitis
Dyspnoea on effort Headache (sinusitis)
(Pan)sinusitis
Chronic course with Dry cough End-inspiratory squeaks Mineral dust bronchiolitis
insidious onset Dyspnoea on effort Wheezing Idiopathic constrictive
bronchiolitis
https://doi.org/10.1183/2312508X.10003823 89
TABLE 4 CT features of bronchiolitis

Direct signs
Bronchiolar wall thickening
Bronchiolectasis
Tree-in-bud pattern
Centrilobular ground-glass nodules
Indirect signs
Subsegmental atelectasis
Expiratory air trapping
Ancillary findings
Bronchial wall thickening
Tubular bronchiectasis
Pneumothorax, pneumomediastinum, interstitial emphysema
result in poorly defined centrilobular nodules, as seen in FB and LB, or well-defined branching
resembling the tree-in-bud pattern, as visible in infectious entities.
Among the indirect signs, the most relevant is mosaic attenuation, characterised by sharply
demarcated areas of low and high attenuation in the inspiratory scan. Once an expiratory scan
has been obtained, the mosaicism results in areas of air trapping characterised by patchy
expanses of decreased attenuation adjacent to regions of normal or increased perfusion. This
phenomenon relates to the fibrotic obliteration of bronchiolar lumen, with abnormal air retention
in the distal airspaces and secondary vasoconstriction. The “three density pattern” is typically
observed in HP and Mycoplasma pneumoniae pneumonia, and is caused by the involvement of
alveoli around the bronchioles; it is therefore not a characteristic radiological sign of primary
bronchiolitis [20].
Abnormalities of the bronchi are a variable feature of CT scans in patients with documented
bronchiolitis and are not unexpected given the anatomical continuity of bronchi with the small
airways. Episodes of spontaneous pneumothorax, pneumomediastinum and interstitial
emphysema may be a clinic-radiological manifestation of CB or proliferative bronchiolitis,
mainly in subjects following haematopoietic stem cell transplantation (HSCT). CT lung
densitometry could serve as a quantitative marker to detect bronchiolitis [21].
TABLE 5 Correllations between CT scan features and the histopathological background
CT scan features Histopathological background
Directs signs
Centrilobular nodules Cellular chronic bronchiolitis (mainly follicular and respiratory)
(ground-glass opacities) Proliferative bronchiolitis (mainly when the process spills over
into the centrilobular airspaces)
Tree-in-bud pattern Acute bronchiolitis (mainly infectious)
Indirect signs
Mosaic oligaemia with expiratory Cicatricial bronchiolitis
air trapping Proliferative bronchiolitis (when the process is mainly limited to
Mosaic oligaemia/centrilobular nodules membranous bronchioles)
Ancillary findings
Bronchioloectasis/bronchiectasis Acute and chronic inflammation spilling over into the wall and
lumen of bronchi; destruction of the elastic framework and
injury of the cartilage plate and muscle layer in the wall of
bronchi; epithelial ulceration
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Finally, MRI, particularly hyperpolarised 3He, 99mTc-Technegas and 133Xe dynamic single-photon
emission CT, has achieved a noninvasive, reproducible measurement of the structure–function
relationship in the small airways [22] .
Diagnostic approach
The diagnosis of small airways disease relies on the integration of multiple data, including
clinical context and medical history, laboratory data, PFTs, and microbiological investigations.
Of utmost importance are the data provided by CT for identification of the “anatomical”
diagnosis and, not infrequently, for suggesting the most probable aetiological diagnosis. BAL is
useful for detecting micro-organisms and may contribute to diagnosis in a number of ways:
when eosinophils are increased (as in EB); when there is significant lymphocytosis, mainly
consisting of T-cells and a slight increase in polyclonal B-cells (such as in FB and LB); and
when characteristic inorganic dusts are found (asbestos bodies, birifrangent silica dust) [2, 3].
Histopathology is not always required.
CT is therefore key to identification of specific forms of bronchiolitis. The histopathological

background may be inferred afterwards. Detection of a cause thanks to data provided by clinical
history, laboratory tests and BAL, or when that is not possible, recognition of specific clinical
contexts, or precise histopathological confirmation are the next steps in the diagnostic work-up.
Finally, quantification of the lung impairment via functional tests and the choice of the
therapeutic options are part of the clinical work.
In the following section, the specific forms of bronchiolitis will be concisely presented.
Specific forms of bronchiolitis

An overview of the specific forms of bronchiolitis is presented in table 2.
Exposure-related bronchiolitis
Exposure-related bronchiolitis [6, 7, 16, 23–25] has been reported after exposure to ammonia,
oxides of nitrogen, smoke from fires, hydrogen selenide, phosgene, hydrogen bromide,
manganese sulfate, sulfur dioxide, chlorine gas, thionyl chloride, grain and cotton dust, free
base cocaine, incinerator fly ash, heated polyester powders, and nanoparticles and styrene in
fiberglass boat builders (figure 2) [26]. Cases of bronchiolitis associated with inhalation of hard
metals, such as tungsten, cobalt and tantalium compounds, have also been reported [27].
Inhaled gases and fumes can produce acute ulceration and inflammation, followed by occlusion
of the airways by loose connective tissue and finally, complete occlusion.
In nylon flocking industry workers, LB manifests with repeated flu-like illness, cough and
worsening dyspnoea (“nylon flock worker’s lung”) [8]. It is likely that many more agents can
produce this condition.
A form of small airway disease has been observed in soldiers reporting inhalational exposures
to sandstorms, combustion products from burn pits, in which waste was burned with diesel fuel,
combat dusts, and/or exposure to a sulfur mine fire from which sulfur oxides were released [11].
Lung biopsies showed GB, bronchiolitis obliterans with inflammatory polyps or CB and
peribronchial pigment.
https://doi.org/10.1183/2312508X.10003823 91
a) b) c)
d) e) f)
FIGURE 2 Fibreglass-induced constrictive bronchiolitis. A 48-year-old male, never-smoker, factory worker with
professional exposure to fibreglass, presents with moderate dyspnoea. CT scan shows bilateral mosaic
attenuation with air trapping in the expiratory scans (d, e and f). Some cylindrical and varicoid bronchiectases
are also present in the right middle lobe (arrow).
Diacetyl was identified as the chemical responsible for CB in workers in the microwave
popcorn manufacturing industry [28–30]. Similar respiratory illnesses associated with exposure
to diacetyl and 2,3-pentanediol have been identified in workers in other food production
settings, including cookie production and coffee-processing facilities [29].
Recently, there was an outbreak of subacute/chronic bronchiolocentric injury associated with

vaping or the use of electronic cigarettes (e-cigarettes) [31, 32].
There is no known treatment to reverse occupational bronchiolitis. A few studies, primarily in

cohorts of sulfur mustard-exposed individuals, have examined the therapeutic role of inhaled
and systemic steroids, N-acetylcysteine and macrolides, but there is variable evidence of
improvement [16]. The role of immunomodulatory medications in stabilising lung function
decline in patients with bronchiolitis remains uncertain [16]. In severe or progressive cases of
bronchiolitis, patients may require treatment with supplemental oxygen and/or referral for LTx.
Mineral dust-associated diseases

There are a number of recognised mineral dust-associated diseases, including asbestosis,
silicosis and coal miner’s pneumoconiosis. Their clinical profile overlaps with that of COPD.
Histological changes typically consist of deposition of inhaled dust around the small airways,
sometimes extending down the alveolar ducts with fibrosis/inflammation [7].
Diffuse bronchiolar disease as a result of chronic occult aspiration

Diffuse bronchiolar disease as a result of chronic occult aspiration is an under-recognised form of
aspiration-related lung disease [33]. Symptoms are insidious, mainly chronic cough and/or
episodes of low-grade fever; changes in voice timbre and dyspnoea are rarely the leading
symptoms. Risk factors for aspiration include: altered consciousness (due to organic pathology or
medication), dysphagia, vomiting, gastro-oesophageal reflux disease and structural abnormalities
92 https://doi.org/10.1183/2312508X.10003823
involving the upper gastrointestinal tract. The condition may also occur in relatively young
individuals without symptoms. CT scans reveal centrilobular nodules and tree-in-bud opacities.
The distribution of parenchymal abnormalities is not always basal-predominant [33].
Infectious bronchiolitis
The development of infectious bronchiolitis has been associated with several microorganisms
[34, 35]. Agents commonly associated with bronchiolitis include viruses and M. pneumoniae,
acid-fast Mycobacteria, Nocardia spp. and Bordetella pertussis. Patients may present with
symptoms such as fever, cough, sore throat, sinusitis, rhinitis, dyspnoea, wheezing or, more
rarely, rapidly progressive respiratory failure. Elderly and immunocompromised hosts are more
frequently involved. Histologically, nonspecific, acute, chronic or granulomatous cellular
bronchiolitis are observed. Human T-cell leukaemia virus type 1-associated bronchioloalveolar
disorder may manifest with an LB or a DPB-like pattern in lung samples [36].
Postinfectious bronchiolitis
Postinfectious bronchiolitis appears with asymmetric mosaic oligaemia on CT (Swyer–James
syndrome) with or without associated bronchiectasis and, in more advanced cases, severe
airflow obstruction [34, 35]. In the majority of cases, detection of the disease is made on chest
radiography performed in paucisymptomatic subjects. At onset, the symptoms may be
misinterpreted as asthma.
Bronchiolar complications of CTDs

Bronchiolar complications of CTDs occur most commonly in females with RA or Sjögren
syndrome [37]. Patients may suffer from chronic cough, dyspnoea and recurrent sinusitis.
Bronchiolitis may be the first manifestation of CTD. CT scans are characterised by signs of
small airways abnormalities and/or cysts, according to the underlying histopathology (figure 3).
Bronchiectasis is found in ∼30% of patients with RA and less frequently in patients with other
CTDs. Histological findings in these patients are heterogeneous: cellular bronchiolitis (FB and
LB) mainly in Sjögren syndrome [38], CB and, very rarely, DPB [39].
Bronchiolitis is associated with poor prognosis, largely in patients with severe airflow limitation
and marked hyperinflation, and these features mostly occur in patients with CB. In cases where
the dominant histology pattern is characterised by lymphoid hyperplasia, a response to systemic
steroids and/or low-dose macrolides may be observed.
Treatment with rituximab could represent a therapeutic option in aggressive inflammatory/

cellular disease CTDs [40]. Novel therapies under investigation include aerosolised liposomal
cyclosporine, Janus kinase inhibitors and antifibrotic drugs [41]. In the most severe cases, LTx
or HSCT may be suggested.
PAMS
PAMS is an autoimmune disease typically associated with lymphoproliferative or
haematological malignancies, and less frequently with solid malignancies [42].Chronic severe
mucositis and polymorphic skin lesions are clue clinical features. PAMS is characterised by the
presence of IgG autoantibodies against a variety of antigens: mainly the plakin family of
proteins, most often envoplakin, periplkin and desmoplakin I and II, and different cadherins,
such as desmoglein 1 and 3.
https://doi.org/10.1183/2312508X.10003823 93
FIGURE 3 Follicular bronchiolitis. A 40-year-old female affected by undifferentiated connective tissue disease,
Raynaud syndrome and sicca syndrome. Characteristic symptoms are mild relapsing fever, non-productive cough
and chest pain. CT scan shows centrilobular nodules, with and without tree-in-bud pattern, prevalent in the
right upper lobe, middle lobe and lingula.
CB occurs in ∼30% of patients and tends to cause progressive airflow obstruction manifesting
with cough, episodes of acute bronchitis (superinfection of blisters in the tracheal mucosa) and
respiratory failure [43]. CB may manifest prior to the discovery of the underlying neoplasm and
the diagnosis of PAMS.
CT imaging shows bronchiectasis, bronchial wall thickening, mosaic oligaemia. The large
airways appear to be involved early in the course of the disease, with subglottic stenosis and
diffuse mucosal thickening and blisters. Acantholysis of differentiated ciliary epithelium from
the underlying basal lamina is evident in endobronchial biopsy specimens.
Prognosis is poor. Complete resection of the underlying neoplasm when feasible appears to
offer a survival advantage. High-dose steroids, rituximab, ibrutinib and pheresis have been
reported to be beneficial [41]. Successful treatment with obinutuzumab and bendamustine has
been reported when associated with follicular lymphoma [44].
CB has also been reported as a complication of Stevens–Johnson syndrome [45].
Post-transplant bronchiolitis obliterans syndrome

Post-transplant bronchiolitis obliterans syndrome (BOS) can occur after allogenic HSCT and
LTx. BOS after allogeneic bone marrow/HSCT is usually a lung manifestation of chronic
graft-versus-host disease (GVHD) [46, 47].
94 https://doi.org/10.1183/2312508X.10003823
Diagnosis is mainly based on clinical signs/symptoms (chronic productive cough, episodes of

acute bronchitis, sinusitis, wheezing, dyspnoea on effort, spontaneous pneumothorax),
documentation of airflow obstruction and detection of air trapping on CT, usually in the
presence of extrapulmonary chronic GVHD (table 6) [46]. CT scan features of bronchiectasis
and pleuroparenchymal fibroelastosis may coexist. Asymptomatic patients may be identified
during routine monitoring of pulmonary function.
The overall prevalence of BOS after allogeneic bone marrow/HSCT is reported to be 1.2–11%
(5% on average). GVHD-BOS usually develops between 100 days and 2 years after allogeneic
bone marrow/HSCT, but onset beyond 5–6 years has been noted, usually in patients experiencing
an extrapulmonary GVHD flare.
Histopathological studies show heterogeneous lesions [48]. One study showed two distinct
patterns: LB and CB [49]. In LB, fibrosis is absent, lymphocytes infiltrate the airways wall and
up to the epithelium, presenting a typical “up and down” aspect. Patients with LB tend to have
better survival.
The clinical course of BOS is highly variable [47]. In the majority of patients, after initial
worsening in the first 6 months, lung function stabilises. A minority present a rapidly
progressive deterioration. 2-year survival is ∼70–80%.
Risk factors for GVHD-BOS are impaired lung function before and early after HSCT, a
myeloablative/busulfan-containing conditioning regimen, cytomegalovirus seropositivity, a
pre-transplant history of pulmonary disease, a female donor, an unrelated donor and prior acute
GVHD. Receipt of antithymocyte globulin, which decreases the possibility of chronic GVHD,
also reduces the risk of BOS. Limited data on the pathogenesis of bronchiolitis obliterans after
allogeneic HSCT exist [50]. It is a manifestation of chronic GVHD and results obtained in
humans and in animal models confirm that chronic GVHD is caused by central tolerance failure
and B-cell and auto-antibody production. The subset of T-cells that are primarily responsible for
the development of pulmonary GVHD are not characterised, although it is likely that CD4+
T-helper 17 cells are involved. Pulmonary microbiomes may also have a role.
Timely and precise treatment of infections and a well-planned supportive care programme
(prophylaxis for infection, pulmonary rehabilitation, nutritional support) are important therapeutic
steps. The European Society for Blood and Marrow Transplantation (EBMT) recommends a
TABLE 6 Diagnostic criteria of bronchiolitis obliterans syndrome (BOS) after haematopoietic stem cell
transplantation
FEV1 <75% pred with a ⩾10% decline over <2 years; FEV1 should not correct to >75% pred with albuterol and
absolute decline for corrected values should remain ⩾10% over 2 years
FEV1/vital capacity ratio of <0.7 or the fifth percentile of predicted#
Absence of respiratory tract infection documented with investigations and directed by clinical symptoms¶
One of two supporting features of BOS:
Evidence of air trapping on expiratory CT, or small airway thickening or bronchiectasis by high-resolution
chest CT; or
Evidence of air trapping by pulmonary function testing+
FEV1: forced expiratory volume in 1 s; % pred: % predicted. #: vital capacity includes forced vital capacity or slow
vital capacity, whichever is greater; ¶: for example, chest radiographs, CT scans, microbiological cultures (sinus
aspiration, upper respiratory tract viral screen, sputum culture, BAL); +: residual volume >120% pred or residual
volume/total lung capacity elevated outside the 90% CI. Reproduced and modified from [47] with permission.
https://doi.org/10.1183/2312508X.10003823 95
combination of fluticasone, azithromycin and montelukast, with a steroid pulse and rapid taper
over 1 month [46]. The therapeutic role of low-dose azithromycin [51] and montelukast alone [52]
is more controversial. An emerging therapy for BOS after HSCT is the Janus kinase inhibitor
ruxolitinib [46]. Other therapies that are still under investigation include tumour necrosis factor
blockade, anti-CD20 and anti-CD52 monoclonal antibodies (rituximb and alemtuzumab,
respectively) and antifibrotic agents (e.g. nintedanib and pirfenidone) [47]. The feasibility,
tolerability and safety of intravenous infusions of allogeneic mesenchymal stem cell therapy are
not well established. Finally, extracorporeal photopheresis seems to improve survival, without
significantly impacting pulmonary function [47]. LTx may be considered but data are anecdotal.
BOS is discussed further in chapter 24 of this Monograph [53].
Drugs associated with bronchiolitis

Drugs associated with bronchiolitis include treatments for RA (gold compounds, penicillamine,
lomustine and tiopronin) and busulfan-based conditioning for allogeneic haematopoietic cell
transplantation [54]. Other drugs that have been associated with bronchiolitis obliterans are gold,
5-fluorouracil, imatinib, psyllium, flecainide, thalidomide, crack cocaine, afatinib, mesalamine,
rituximab and immune checkpoint inhibitors [55], as well as repeated aspiration of particulate
matter for medical purposes (e.g. talc, cellulose, crospovidone and sodium polystyrene sulfonate).
Clinical aspects are quite nonspecific and are mainly dominated by dry cough and dyspnoea.
Haemopthysis is quite infrequent.
An outbreak of bronchiolitis obliterans associated with the consumption of Sauropus

androgynous (used as an anorexigen) was reported in Taiwan [56]. Respiratory symptoms
( persistent cough and progressive dyspnoea) occurred 10 weeks after ingesting the vegetable.
Most of the patients were young or middle-aged females and had absorbed uncooked
S. androgynous juice or dry powder for a mean period of 6 months. Other symptoms included
dizziness, insomnia, and palpitations. CT scans revealed bilateral bronchiolar wall thickening
and dilatation, as well as low attenuation areas with air trapping. Response to prednisolone was
very limited. LTx may be the only valid therapeutic option.
IBD
IBD is associated with pulmonary manifestations in an estimated 0.21% of patients.
Bronchiolitis is extremely rare, with large airways diseases (such as tracheobronchitis, chronic
bronchitis or bronchiectasis) being the most common manifestation [57, 58].
Chronologically, small airways involvement can develop at any time during the course of IBD;
however, in ∼80% of cases, the onset of pulmonary symptoms follows diagnosis of IBD by
months to years.
Patients may have a productive cough, dyspnoea, extraintestinal manifestations such as iritis,
pyoderma gangrenosus [34, 59] or systemic symptoms, such as fever or asthenia.
The spectrum of CT changes is broad: bronchiectasis, thickening of the bronchiolar walls, air
trapping findings, centrilobular nodules and tree-in-bud pattern (figure 4). A DPB-like pattern
has been described in patients with ulcerative colitis [60]. In Crohn disease, GB associated with
necrobiotic pulmonary nodules has been reported [7, 60].
Inhaled or oral steroids are the first-line treatment.
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FIGURE 4 Cellular/granulomatous bronchiolitis associated with inflammatory bowel disease. A 49-year-old male,
affected by Crohn disease, presented with productive cough and mild dyspnoea. CT scan shows hyperinflated
lungs with diffuse thickening of the bronchial walls and centrilobular ground-glass opacities, mainly in the right
upper and middle lobe.
DPB
DPB is rare; it was originally described in Japan but is now known to occur worldwide [61]. It
is characterised by bronchiolar inflammation and chronic pansinusitis, usually in the second to
sixth decade. The male:female ratio is ∼1.5:1. Two-thirds are nonsmokers. Environmental
factors may be important, as DPB is very uncommon in people of Asian ancestry living abroad;
an association with specific HLA genotypes (HLA-B54 and HLA-A11) or polymorphisms in
MUC5B mucin has, however, been documented. Neutrophils and T-lymphocytes, particularly
CD8 cells, together with cytokines, interleukin-8 and macrophage inflammatory protein-1 might
play key roles in the development of this disease.
DPB is clinically characterised by recurrent pansinusitis, airway infection, often with

Pseudomonas aeruginosa or Haemophilus influenzae. Presenting symtoms are fever, wheezing,
purulent sputum production that exceeds 50 mL·day−1 and dyspnoea on effort. The most
characteristic laboratory abnormalities are persistent marked elevation of CA19–9 and serum
cold agglutinins.
CT findings are peculiar, as nodular shadows are distributed in a centrilobular fashion, often
extending to small, branching linear areas of attenuation. Peripheral air trapping is usually
confirmed in expiratory films. Dilatation of the airways and bronchial wall thickening are also
https://doi.org/10.1183/2312508X.10003823 97
present. The distinctive imaging and histological features (also documented by regular or
transbronchial lung cryobiopsy) [62], the coexisting pansinusitis and the isolation of
P. aeruginosa or H. influenzae in the sputum enhance disease recognition.
Long-term therapy with low-dose macrolides has been associated with significant improvement [63].
LTx has been used in some patients, although DPB may recur in the allograft. Cases of cellular
bronchiolitis with clinical and CT findings indistinguishable from those of DPB but with only
scattered interstitial foam cells have been reported (figure 5) [64].
EB
EB was first reported by TAKAYANAGI et al. [65] as one of the manifestations of lung
eosinophilia. CORDIER et al. [66] described this condition as hypereosinophilic OB defined by:
1) blood eosinophilia or eosinophilia in BAL or both; 2) irreversible airflow obstruction; and
3) characteristic signs of bronchiolitis on CT or of EB in lung biopsy (figure 1c and figure 6).
Besides steroids, mepolizumab or benralizumab may be useful.
Respiratory bronchiolitis
Respiratory bronchiolitis is a clinical–pathological entity characterised mainly by centrilobular
accumulation of smoker’s macrophages [67]. It has been recognised as extremely common in
cigarette smokers but has rarely been reported in nonsmokers with other inhalational exposures,
especially asbestos. CT shows centrilobular ground-glass nodules with upper lobe
predominance. Patients mainly suffer from chronic non-productive cough.
Rare genetic disorders

Rare genetic disorders may manifest with bronchiolitis. An association between lysinuric protein
intolerance and ataxia–telangiectasia has been reported [68, 69]. Recently, a novel familial form of
autoimmune disorder (COPA syndrome) associated with FB has been described [67, 70, 71].
Onset of pulmonary symptoms and progressive lung damage may appear years or decades after
the first extrapulmonary manifestations. CT scanning demonstrates diffuse small lung nodules
FIGURE 5 Diffuse panbronchiolitis-like process. A 59-year-old male with a prior history of resection of a
capsulated AB thymoma and recent onset of a productive cough. CT scan shows bilateral centrilobular noduled
with tree-in-bud, mainly in the middle to lower lung zones. The bronchial walls are thickened.
98 https://doi.org/10.1183/2312508X.10003823
FIGURE 6 Hypereosinophilic obliterative bronchiolitis. A 41-year-old male with bilateral areas of mosaic
attenuation, thickening of the bronchial wall and mucus plugging.
often associated with small cysts. Patients tend to experience gradual progression of their lung
disease despite treatment with glucocorticoids and other immunomodulatory therapy; some
undergo LTx. CB manifesting with cysts in the lungs has been reported in sickle cell disease [72].
Idiopathic OB
Idiopathic OB (with CB or, more rarely, proliferative bronchiolitis as histopathology) is very
rare, presenting with nonspecific symptoms (coryza, persistent cough, worsening dyspnoea), and
mostly among never-smoking young or middle-aged women [25, 73–75]. BAL shows a high
percentage of neutrophils. At least part of the cases could represent pre-existing undetected viral
infections, HP or a still-hidden CTD. Idiopathic OB has variable prognoses, ranging from
slowly progressive to rapidly deteriorating disease. Steroids may be associated with some
benefits, and trials with low-dose macrolides should be encouraged; however, some patients
have a poor prognosis despite the use of immunosuppressive treatments.
References
1 Colby TV. Bronchiolar pathology. In: Epler GR, ed. Diseases of the Bronchioles. New York, Raven Press, 1994: pp.
77–100.
2 Poletti V, Zompatori M, Cancellieri A. Clinical spectrum of adult chronic bronchiolitis. Sarcoidosis Vasc Diffuse
Lung Dis 1999; 16: 183–196.
3 Poletti V, Costabel U. Bronchiolar disorders: classification and diagnostic approach. Semin Respir Crit Care Med
2003; 24: 457–464.
https://doi.org/10.1183/2312508X.10003823 99
4 Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med 2003; 168: 1277–1292.
5 Rossi G, MacMahon H, Marchevsky AM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. In:
WHO Classification of Tumors. Thoracic Tumours. 5th Edn. Lyon, International Agency for Research on Cancer,
2021: pp. 130–132.
6 Miller RR, Muller NL, Thurlbeck WM. Diffuse diseases of the lungs. In: Silverberg SG, ed. Principles and Practice
of Surgical Pathology and Cytopathology. 3rd Edn. New York, Churchill Livingstone, 1999; pp. 1152–1187.
7 Barbareschi M, Mengoli MC, Cavazza A. Nonneoplastic pathology of the large and small airways. In: Smith ML,
Leslie KO, Wick MR, eds. Practical Pulmonary Pathology. 4th Edn. Philadelphia, Elsevier, 2023; pp. 303–344.
8 Kern DG, Kuhn C, Ely EW, et al. Flock worker’s lung: broadening the spectrum of clinicopathology, narrowing
the spectrum of suspected etiologies. Chest 2000; 117: 251–259.
9 Cummings KJ, Stanton ML, Nett RJ, et al. Severe lung disease characterized by lymphocytic bronchiolitis,
alveolar ductitis, and emphysema (BADE) in industrial machine-manufacturing workers. Am J Ind Med 2019; 62:
927–937.
10 Poletti V. Eosinophilic bronchiolitis: is it a new syndrome? Eur Respir J 2013; 41: 1012–1013.
11 Rose CS, Moore CM, Zell-Baran LM, et al. Small airways and airspace inflammation and injury distinguish lung
histopathology in deployed military personnel from healthy and diseases lungs. Hum Pathol 2022; 124: 56–66.
12 Iwata M, Coly TV, Kitaichi M. Diffuse panbronchiolitis: diagnosis and distinction from various pulmonary
diseases with centrilobular interstitial foam cell accumulations. Hum Pathol 1994; 25: 357–363.
13 Gutor SS, Richmond BW, Du RH, et al. Characterization of immunopathology and small airway remodeling in
constrictive bronchiolitis. Am J Respir Crit Care Med 2022; 206: 260–270.
14 Sirol Aflah Syazatul S, Piciucchi S, Tomassetti S, et al. Cryoiopsy in the diagnosis of bronchiolitis: a
retrospective analysis of twenty-three consecutive patients. Sci Rep 2020; 10: 10906.
15 Lentz RJ, Fessel JP, Jonson JE, et al. Transbronchial cryobiopsy can diagnose constrictive bronchiolitis in
veterans of recent conflicts in the Middle East. Am J Respir Crit Care Med 2016; 193: 806–808.
16 Greenland JR, Jones KD, Singer JP. Bronchiolitis. In: Broaddus VC, ed. Murray & Nadel’s Textbook of Respiratory
Medicine. 7th Edn. Philadelphia, Elsevier, 2022; pp. 994–1004.
17 Rosenheck JP, Ross DJ, Botros M, et al. Cllinical validation of a plasma donor-derived cell-free DNA assay to
detect allograft rejection and injury in lung transplant. Transplant Direct 2022; 8: e1317.
18 Grippi AM, Tino G. Pulmonary function testing. In: Grippi MA, ed. Fishman’s Pulmonary Diseases and Disorders.
6th Edn. New York, McGraw Hill, 2023; pp. 544–578.
19 Lee GM, Carroll MB, Galvin JR, et al. Mosaic attenuation pattern: a guide to analysis with HRCT. Radiol Clin
North Am 2022; 60: 963–978.
20 Dabiri M, Jehangir M, Khoshopouri P, et al. Hypersensitivity pneumonitis: a pictorial review based on the new
ATS/JRS/ALAT clinical practice guideline for radiologists and pulmonologists. Diagnostics 2022; 12: 28–74.
21 Lee HI, Kim SK, Lee W, et al. Quantitative CT lung densitometry as an obstructive marker for the diagnosis of
bronchiolitis obliterans in children. PLoS One 2022; 17: e0271135.
22 Schiebler ML, Parraga G, Gefter WB, et al. Synopsis from expanding applications of pulmonary MRI in the
clinical evaluation of lung disorders: Fleischner society position paper. Chest 2021; 159: 492–495.
23 Banks DE, Morris MJ. Inhalational constrictive bronchiolitis: the evolution of our understanding of this disease.
Lung 2021; 199: 327–334.
24 Douglas WW, Hepper NG. Colby TV: Silo-filler’s disease. Mayo Clin Pro 1989; 64: 291–304.
25 Barker AF, Bergeron A, Rom WN, et al. Obliterative bronchiolitis. N Engl J Med 2014; 370: 1820–1828.
26 Cullinan P, McGavin CR, Kreiss K, et al. Obliterative bronchiolitis in fibreglass workers: a new occupational
disease? Occup Environ Med 2013; 70: 357–359.
27 Nureki S, Miyazaki E, Nishio S, et al. Hard metal lung disease successfully treated with inhaled corticosteroids.
Inter Med 2013; 52: 1957–1961.
28 Fetcher-Leggett ED, White SK, Fedan K, et al. Burden of respiratory abnormalities in microwave popcorn and
flavouring manufacturing workers. Occup Environ Med 2018; 75: 709–715.
29 Hubbs AF, Kreiss K, Cummings KJ, et al. Flavorings-related lung disease: a brief review and new mechanistic
data. Toxicol Pathol 2019; 47: 1012–1026.
30 van Holden K, Hines SE. Update on flavoring-induced lung disease. Curr Opin Pulm Med 2016; 22: 158–164.
31 Butt YM, Smith ML, Tazelaar HD, et al. Pathology of vaping-associated lung injury. N Engl J Med 2019; 38:
1780–1781.
32 Eddy RL, Serajeddini H, Knipping D, et al. Pulmonary functional MRI and CT in a survivor of bronchiolitis and
respiratory failure caused by e-cigarette use. Chest 2020; 158: e147–e151.
33 Ryu AJ, Navin PJ, Hu X, et al. Clinico-radiologic features of lung disease associated with aspiration identified on
lung biopsy. Chest 2019; 156: 1160–1166.
34 Poletti V, Chilosi M, Zompatori M. Bronchiolitis. In: Gibson GJ, Geddes DM, Costabel U, et al., eds. Respiratory
Medicine. 3rd Edn. London, Saunders, 2003; pp. 1526–1541.
100 https://doi.org/10.1183/2312508X.10003823
35 Becroft DMO. Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in
young children. J Clin Pathol 1971; 24: 72–82.
36 Einsiedel L, Chiong F, Jersmann H, et al. Human T-cell leukaemia virus type 1 associated pulmonary disease:
clinical and pathological features on an under-recognized complication of HTLV-1 infection. Retrovirology 2021;
18: 1.
37 Arcadu A, Ryu JH. Constrictive (obliterative) bronchiolitis as presenting manifestation of connective tissue
diseases. J Clin Rheumatol 2020; 26: 176–180.
38 Chung A, Wilgus ML, Fishbein G, et al. Pulmonary and bronchiolar involvement in Sjogren’s syndrome. Semin
39 Cagle PT, Roggli VL. Pathology of small airways. In: Tomashefski JF Jr, ed. Dail and Hammar’s Pulmonary
Pathology. 3rd Edn. New York, Springer, 2008; pp. 886–910.
40 Lipatov K, Kubbara AF, Weerheim LE, et al. Improvement of constrictive bronchiolitis (bronchiolitis obliterans)
after rituximab therapy in two patients with primary Sjogren syndrome. Respir Med Case Rep 2021; 33: 101432.
41 Matthaiou EI, Sharifi H, O’Donnell C, et al. The safety and tolerability of pirfenidone for bronchiolitis obliterans
syndrome after hematopoietic stem cell transplant (STOP-BOS) trial. Bone Marrow Transplant 2022; 57:
1319–1326.
42 Antiga E, Bech R, Maglie R, et al. S2k guidelines on the management of paraneoplastic pemphigus/
paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and
Venereology (EADV). J Eur Dermatol Venereol 2023; 37: 1118–1134.
43 Maldonado F, Pittelkow MR, Ryu JH. Constrictive bronchiolitis associated with paraneoplastic autoimmune
multi-organ syndrome. Respirology 2009; 14: 129–133.
44 Kuriyama K, Kittamura Y, Tsuji T, et al. Successful treatment of paraneoplastic pemphigus and bronchiolitis
obliterans associated with follicular lymphoma with obinutuzumab and bendamustine. Curr Probl Cancer 2022;
46: 100813.
45 Mitani K, Hida S, Fujino H, et al. Rare case of Stevens-Jonshon syndrome with bronchiolitis obliterans as a
chronic complication. BMJ Case Rep 2022; 15: e249224.
46 Verleden GM, Glanville AR, Lease ED, et al. Chronic lung allograft dysfunction: definition, diagnostic criteria, and
approaches to treatment – a consensus report from the Pulmonary Council of the ISHLT. J Heart Lung
Transplant 2019; 38: 493–503.
47 Glanville AR, Benden C, Bergeron A, et al. Bronchiolitis obliterans syndrome after lung or haematopoietic stem
cell transplantation: current management and future directions. ERJ Open Res 2022; 8: 00185-2022.
48 Verleden SE, McDonough JE, Schoemans H, et al. Phenotypical diversity of airway morphology in chronic lung
graft vs host disease after stem cell transplantation. Mod Pathol 2019; 32: 817–829.
49 Holbro A, Lehmann T, Girsberger S, et al. Lung histology predicts outcome of bronchiolitis obliterans syndrome
after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 973–980.
50 Bos S, Beeckmans H, Vanstapel A, et al. Pulmonary graft-versus host disease and chronic lung allograft
dysfunction: two sides of the same coin? Lancet Respir Med 2022; 10: 796–810.
51 Kutzke JL, Merten JA, Taraba JL, et al. Risk of relapse in patients receiving azithromycin after allogeneic HSCT.
Bone Marrow Transplant 2021; 56: 960–962.
52 Williams KM, Pavletic SZ, Lee SJ, et al. Prospective phase II trial of montelukast to treat bronchiolitis obliterans
syndrome after hematopoietic cell transplantation and investigation into bronchiolitis obliterans syndrome
pathogenesis. Transplant Cel Ther 2022; 28: 264.e1–264.e9.
53 Gimenez BS, Hellemons M, Verleden SE, et al. Chronic lung allograft dysfunction after lung transplantation. In:
54 King TE Jr. Miscellaneous causes of bronchiolitis: inhalation, infectious, drug-induced and idiopathic. Sem
55 Mitropoulou G, Daccord C, Sauty A, et al. Immunotherapy-induced airway disease: a new pattern of lung
toxicity of immune checkpoint inhibitors. Respiration 2020; 99: 181–186.
56 Lai RS, Chiang AA, Wu MT, et al. Outbreak of bronchiolitis obiterans associated with consumption of Sauropus
androgynus in Taiwan. Lancet 1996; 348: 83–85.
57 Camus P, Piard F, Ashcroft T, et al. The lung in inflammatory bowel disease. Medicine (Baltimore) 1993; 72:
151–183.
58 Camus P, Colby TV. The lung in inflammatory bowel disease. Eur Respir J 2000; 15: 510.
59 Kar PM, Aronoff G, Schuette P. Bronchopulmonary disease: an association with ulcerative colitis and pyoderma
gangrenosum. J Ky Med Assoc 1993; 91: 320–323.
60 Chiu K, Wright JL. Large and small airway disease related to inflammatory bowel disease. Arch Pathol Lab Med
2017; 141: 470–473.
61 Poletti V, Casoni G, Chilosi M, et al. Diffuse panbronchiolitis. Eur Respir J 2006; 28: 862–871.
https://doi.org/10.1183/2312508X.10003823 101
62 Yamakawa H, Takemura T, Sato S, et al. The usefulness of a transbronchial lung cryobiopsy for diffuse
bronchiolitis. Intern Med 2021; 60: 1457–1462.
63 Weng D, Wu Q, Chen XQ, et al. Azithromycin treats diffuse panbronchiolitis by targeting T cells via inhibition of
mTOR pathway. Biomed Pharmacother 2019; 110: 440–448.
64 Poletti V, Chilosi M, Trisolini R, et al. Idiopathic bronchiolitis mimicking diffuse panbronchiolitis. Sarcoidosis
Vasc Diffuse Lung Dis 2003; 20: 62–68.
65 Takayanagi N, Kanazawa M, Kawabata Y, et al. Chronic eosinophilic bronchiolitis with associated eosinophilic
lung disease (eosinophilic bronchiolitis). Respiration 2001; 68: 319–322.
66 Cordier JF, Cottin V, Khouatra C, et al. Hypereosinophilic obliterative bronchiolitis: a distinct unrecognized
syndrome. Eur Respir J 2013; 41: 1126–1134.
67 Ryu JH, Azadeh N, Samhouri B, et al. Recent advances in the understanding of bronchiolitis in adults. F1000Res
2020; 9: F1000 Faculty Rev-568.
68 Parto K, Svedstrom E, Majurin ML, et al. Pulmonary manifestations in lysinuric protein intolerance. Chest 1993;
104: 1176–1182.
69 Ito M, Nakagawa A, Hirabayashi N, et al. Bronchiolitis obliterans in ataxia-telangectasia. Vorchows Arch 1997;
430: 131–137.
70 Cazzato S, Omenetti A, Ravaglia C, et al. Lung involvement in monogenic interferonopathies. Eur Respir Rev
2020; 29: 200001.
71 Taveira-DaSilva AM, Markello TC, Kleiner DE, et al. Expanding the phenotype of COPA syndrome: a kindred with
typical and atypical features. J Med Genet 2019; 56: 778–782.
72 Koort F, Habibi A, Lionnet F, et al. Diffuse cystic lung disease in sickle cell anemia: a series of 22 cases and a
case-control study. Thorax 2022; 77: 91–93.
73 Kraft M, Mortenson RL, Colby TV, et al. Cryptogenic constrictive bronchiolitis. A clinicopathologic study. Am Rev
Respir Dis 1993; 148: 1093–1101.
74 Yoshii N, Kamoi H, Matsui E, et al. Idiopathic obliterative bronchiolitis in a young woman: a rare case of a
transbronchial lung biopsy contributing to the diagnosis. Intern Med 2022; 61: 2759–2764.
75 Callahan SJ, Vranic A, Flors L, et al. Sporadic obliterative bronchiolitis: case series and systematic review of the
literature. Mayo Clin Proc Innov Quat Out 2019; 3: 86–93.
Disclosures: V. Poletti reports receiving personal fees from Boehringer Ingelheim, Roche, AMBU and ERBE, outside
the submitted work. C. Ravaglia reports receiving payment or honoraria for lectures, presentations, speakers’
bureaus, manuscript writing or educational events from Boehringer Ingelheim, outside the submitted work. The
remaining authors have nothing to disclose.
102 https://doi.org/10.1183/2312508X.10003823
Chapter 8
Pulmonary alveolar proteinosis

Evelyn Lynn1,2, Omaima Omar1, Ali Ataya3, Elisabeth Bendstrup 4,5
,
Alessandro N. Franciosi 1,2 and Cormac McCarthy 1,2
1
Dept of Respiratory Medicine, St Vincent’s University Hospital, Dublin, Ireland. 2School of Medicine, University
College Dublin, Dublin, Ireland. 3Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida
Health, Gainesville, FL, USA. 4Dept of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus,
Denmark. 5Dept of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Corresponding author: Cormac McCarthy (cormac.mccarthy@ucd.ie)
Cite as: Lynn E, Omar O, Ataya A, et al. Pulmonary alveolar proteinosis. In: Wagner TOF, Humbert M, Wijsenbeek M,
et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society,
2023; pp. 103–117 [https://doi.org/10.1183/2312508X.10017822].
@ERSpublications
Pulmonary alveolar proteinosis is a rare syndrome characterised by abnormal accumulation of pulmonary
surfactant resulting in dyspnoea and respiratory failure. The majority of cases are autoimmune, with
antibody testing a robust diagnostic tool. https://bit.ly/ERSM100
ISSN: 2312-5098.
Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterised by progressive accumulation of

pulmonary surfactant. This results in dyspnoea, secondary pulmonary and systemic infection, and in
occasional cases respiratory failure. PAP syndrome occurs in distinct diseases, classified according to
pathogenetic mechanism; these include primary PAP (due to disruption of GM-CSF signalling),
secondary PAP (due to reduction in alveolar macrophage numbers/functions) and congenital PAP (due
to disruption of surfactant production). The most common cause is autoimmune PAP, in which
antibodies against GM-CSF disrupt alveolar macrophage function resulting in reduced surfactant
clearance. The current standard therapy is whole-lung lavage, which must be performed in carefully
selected patients. However, there is increasing evidence to support the use of inhaled GM-CSF and
other novel therapies.
Introduction
Pulmonary alveolar proteinosis (PAP) is a rare respiratory syndrome characterised by excess
surfactant lipoprotein accumulation within the alveoli. It refers to a group of diseases that result
from defective clearance or excess production of surfactant [1–4]. PAP syndrome is classified
according to its underlying pathogenic mechanism: primary, secondary or congenital (table 1).
Primary PAP occurs where there is disruption in GM-CSF signalling, which causes dysfunction
of alveolar macrophages. This disrupted signalling occurs due to either the development of
autoantibodies to GM-CSF or genetic mutations in CSF2RA or CSF2RB (which encode the
α- and β-chain of the GM-CSF receptor, respectively) [5–7]. Secondary PAP is caused by
reduced number and/or function of alveolar macrophages and can occur due to haematological
disorders, environmental toxin exposure or drugs [1, 2, 8]. Congenital PAP, also referred to as
pulmonary surfactant metabolic dysfunction, represents multiple diseases caused by mutations
in the genes required for normal surfactant production. Very rarely, the cause of PAP is
https://doi.org/10.1183/2312508X.10017822 103
TABLE 1 Classification of pulmonary alveolar proteinosis (PAP)-causing diseases
Disorder Mechanism/examples
Disorders of surfactant clearance

Primary PAP GM-CSF signalling disruption
Autoimmune PAP Mediated by autoantibodies to GM-CSF
Hereditary PAP GM-CSF signalling disruption due to GM-CSF receptor mutations
(CSF2RA or CSF2RB)
Secondary PAP Reduced alveolar macrophage function or number not related
to abnormal GM-CSF signalling
Haematological conditions Acute lymphocytic leukaemia, acute myeloid leukaemia, aplastic
anaemia, chronic lymphocytic leukaemia, chronic myeloid
leukaemia, myelodysplastic syndromes, multiple myeloma,
lymphoma, Waldenstrom macroglobulinaemia, GATA2
deficiency
Nonhaematological malignancies Adenocarcinoma, glioblastoma, melanoma
Immunodeficiency and chronic Acquired immunodeficiency syndrome, amyloidosis, Fanconi
inflammatory conditions syndrome, agammaglobulinaemia, juvenile dermatomyositis,
renal tubular acidosis, severe combined immunodeficiency
disease
Occupational and environmental Aluminium, cement, silica, titanium, indium, flour, fertiliser,
exposures sawdust, chlorine fumes, cleaning products, gasoline/
petroleum fumes, nitrogen dioxide, paint fumes, synthetic
plastic fumes, varnish
Chronic infections Cytomegalovirus, Mycobacterium tuberculosis, Nocardia spp.,
Pneumocystis jirovecii
Others, including mutations affecting Lysinuric protein intolerance, mutations in methionyl-tRNA
mononuclear phagocytes synthetase
Disorders of surfactant production
Pulmonary surfactant metabolic
dysfunction disorders
Mutations in SFTPB, SFTPC, ABCA3 Surfactant homeostasis affected due to mutations causing
or NKX2.1 surfactant protein deficiency, lipid transporter deficiency or
mutations that affect lung development
CSF2RA and CSF2RB: GM-CSF receptor α- and β-chain genes, respectively; GATA2: GATA-binding factor 2; tRNA:
transfer RNA; SFTPB and SFTPC: surfactant protein B and C genes, respectively; ABCA3: ATP-binding cassette
subfamily A member 3 gene; NKX2.1: NK2 homeobox 1 gene.
undetermined (i.e. unclassified PAP). The clinical course of PAP varies among patients from
very mild with spontaneous regression to a disease course complicated by recurrent infections,
fibrotic lung disease, and hypoxaemic respiratory failure and death. Serum anti-GM-CSF
autoantibodies are diagnostic of autoimmune PAP (aPAP) and negate the need for lung biopsy.
Whole-lung lavage (WLL) is the current standard therapeutic approach, with novel treatments,
including inhaled GM-CSF, under investigation as part of clinical trials.
Pathophysiology
PAP results from either excess secretion or inadequate clearance of surfactant, which is
synthesised by alveolar type II epithelial cells (AEC-II). Surfactant, which is made up of >90%
lipids, is responsible for preventing alveolar collapse during the end of expiration by reducing
surface tension at the interface between the alveolar wall, air and liquid [9]. The role of
GM-CSF in the surfactant homeostasis pathway has been well studied in animal and mouse
models. This 23 kDa cytokine is a monomeric glycoprotein secreted by a variety of cells and
104 https://doi.org/10.1183/2312508X.10017822
PULMONARY ALVEOLAR PROTEINOSIS | E. LYNN ET AL.
has roles in autoimmune disease, inflammation and host defence clearance [4, 10–16].
Clearance of surfactant occurs via a combination of recycling and catabolism by AEC-II and
alveolar macrophages [9]. Purine box binding protein 1 (PU.1), peroxisome proliferator-
activated receptor-γ (PPARγ) and ATP-binding cassette transporter G1 (ABCG1) have been
shown in animal and human studies to be implicated in the formation of foamy macrophages in
PAP under the effect of GM-CSF, which also controls cholesterol efflux from cells, resulting
in cholesterol-ester-filled intracytoplasmic accumulation in alveolar macrophages (figure 1)
[10, 12, 13, 17–19].
Impaired function of neutrophils in PAP is thought to account for the increased incidence of
pulmonary infection in these patients. Studies have shown decreased phagocytosis, bactericidal
activity, reduced cell adhesion and production of reactive oxygen species [20]. This was
previously termed idiopathic PAP, and patients demonstrated elevated levels of autoantibodies
to GM-CSF in serum, which were not present in secondary PAP or other lung diseases [21, 22].
SAKAGAMI and co-workers [23, 24] demonstrated that GM-CSF autoantibodies were
pathognomonic: when antibodies purified from PAP patients were isolated and inoculated into
healthy nonhuman primates, the animals subsequently developed PAP lung disease.
Epidemiology
The estimated incidence and prevalence of PAP are 0.49±0.13 and 6.2–6.87 per million of the
population, respectively [8, 25]. Approximately one-third of patients in the study by INOUE et al. [8]
were asymptomatic and only identified through mandatory health screening; thus, it is likely
that the true prevalence is higher. Indeed, recent data suggest that the incidence and prevalence
of aPAP could be as high as 1.65 and 26.6 per million of the population, respectively. aPAP
accounts for >90% of cases [8, 25], and the mean age of diagnosis is between 39 and 43 years,
with males more likely to be affected [2, 26]. The prevalence and incidence of other causes of
PAP are not known and are difficult to estimate, but do account for <10% of all cases. Indeed,
many are very rare, affecting as few as 1 in 1.7 million for some surfactant production disorders [27].
Clinical features
Clinical presentation
Most patients with PAP present with dyspnoea of insidious onset, with other nonspecific
respiratory symptoms present including prolonged cough, white frothy sputum and
constitutional symptoms such as fatigue and weight loss. Presentation can vary in children, with
symptoms or signs of pneumonia, failure to thrive or hypoxaemia. The majority of cases are
aPAP, and this often presents in the third to fifth decade with progressive dyspnoea, cough,
fatigue and weight loss. Some patients describe frothy sputum production. The onset can be
insidious, and patients can experience delayed diagnosis of up to 18 months, with the clinical
presentation mimicking asthma or pulmonary infection [1, 8, 28–32]. Symptoms of pulmonary
infection are also a recognised presenting symptom of PAP, and ∼30% of patients are
asymptomatic [8]. Physical examination is generally unremarkable, but crackles and cyanosis
have been reported in a small proportion of patients. Digital clubbing is not a manifestation of
aPAP but can represent associated underlying diseases. Presenting symptoms are often not
proportionate to the changes on imaging [33].
Pulmonary infections
Pulmonary infections are a common complication of PAP as a manifestation of disruption in the
innate immune system caused by GM-CSF autoantibodies [20, 34, 35]. These infections
account for up to 18–20% of the attributable mortality [2]. Reduced alveolar macrophages in
https://doi.org/10.1183/2312508X.10017822 105
a) Surfactant Air
Surface liquid
Type II
1 pneumocyte
Immature alveolar macrophage
Alveolar macrophage
4
Clearance
3
GM-CSF
Regulation
2
Type I
pneumocyte
Alveolar membrane
b) c)
6
GM-CSF GM-CSF
5
d)
Clearance 8
GM-CSF
106 https://doi.org/10.1183/2312508X.10017822
FIGURE 1 a) During normal alveolar surfactant homeostasis, pulmonary surfactant is synthesised and secreted
by alveolar type II epithelial cells (AEC-II) (1). GM-CSF (2) binds to GM-CSF receptors on immature alveolar
macrophages promoting maturation and regulating phagocytosis and immune and other nonimmune functions in
mature macrophages (3). Clearance of surfactant occurs via uptake and recycling of AEC-II and via phagocytosis
and catabolism in macrophages (4). b) In autoimmune pulmonary alveolar proteinosis (PAP), anti-GM-CSF
autoantibodies (5) disrupt the maturation and activation of macrophages. c) In hereditary PAP, mutations in the
α- and β-chains of the GM-CSF receptor result in conformational changes and reduced receptor function or
cell-surface expression (6). d) In autoimmune and hereditary PAP, the resultant impaired clearance and build-up
of lipid (7) leads to impaired macrophage function (8) and accumulation of surfactant in the alveolus.
those with secondary PAP can increase the rates of severe respiratory infections, which can be
fatal [29, 30, 36]. Nocardia, Mycobacterium and Aspergillus spp. are among the common
pathogens responsible for infection in PAP [2, 20], and patients can either present with PAP in
the context of infection or can experience this complication later in their disease.
Pulmonary fibrosis
Pulmonary fibrosis is also recognised in those with PAP, the incidence of which is unknown
and the pathogenesis of which is poorly understood. It occurs more commonly in surfactant
production disorders caused by mutations in the ATP-binding cassette subfamily A member 3
(ABCA3) and surfactant protein B (SFTPB) and C (SFTPC) genes [31, 32], often following
resolution of the classic feature of PAP, alveolar lipid accumulation. The roles of WLL,
GM-CSF augmentation and oxygen administration have been proposed in the subsequent
development of fibrotic lung disease [37–40]. Animal studies have recognised fibrotic changes
in the liver of GM-CSF-deficient mice, suggesting that it may be related to disruption of
GM-CSF signalling rather than a treatment-related toxicity [39–43].
Diagnostic approach
The differential diagnosis for PAP is varied, including pulmonary infection, pulmonary oedema
and ILD. Restrictive physiology, suggestive HRCT and typical lavage fluid with a milky
appearance should raise the consideration of PAP. Antibody testing is sensitive and specific for
those with aPAP [4, 14, 44].
PFTs
PFTs are of limited use for the diagnosis of PAP, as they lack sensitivity and specificity for the
disease. Spirometry can be within normal limits or show a restrictive pattern with a reduced
FVC [2, 45]. In advanced disease, there can be a disproportionate, severe reduction of DLCO.
Hypoxaemia is caused by ventilation–perfusion mismatch and intrapulmonary shunting,
resulting in a widened alveolar–arteriolar diffusion gradient (A-aDO2).
Radiology
HRCT is required for the assessment of PAP, as chest radiography is not specific or sensitive
for the disease, with changes that can mimic pulmonary oedema [46]. HRCT changes include
ground-glass opacities with underlying septal thickening very clearly defined between areas of
normal lung parenchyma. This is referred to as a “geographic” appearance, which can result in
the classical “crazy-paving” pattern (figure 2) [47, 48]. These changes described in PAP are
also seen in other respiratory disorders such as infection, inhalation injuries and malignant
disease, and as such, the CT findings are not pathognomonic [48].
Bronchoscopy and biopsy

Bronchoscopy and BAL are useful in both the diagnosis of PAP and assessment of associated
infections. BAL fluid has a typical milky appearance explained by the presence of surfactant
https://doi.org/10.1183/2312508X.10017822 107
a) b)
c) d)
FIGURE 2 CT image findings in pulmonary alveolar proteinosis (PAP) syndrome. a) Axial CT thorax image
demonstrating scattered areas of ground-glass opacification with smooth interlobar septal thickening, in the
described “geographic” pattern seen in PAP. b) Interlobular septal thickening is superimposed on ground-glass
changes in the lung. c) Axial and d) coronal CT images of the chest of a patient with progressive autoimmune
PAP showing diffuse ground-glass opacities with evidence of smooth interlobular septal thickening consistent
with a “crazy-paving” pattern.
sediment, which settles in specimen pots (figure 3). BAL fluid has increased phospholipids,
cholesterol, surfactant proteins and cytokines associated with PAP [49].
Transbronchial biopsy and surgical biopsy should be reserved where there is diagnostic
uncertainty. In circumstances where biopsy is performed, clinicians should consider the
false-negative rates due to the distribution of disease in the lung parenchyma [14], and biopsy
location should be carefully guided by HRCT imaging. Histologically, the architecture of the
lung parenchyma is preserved, with alveoli and terminal airways filled with eosinophilic
PAS-positive material and alveolar macrophages, and immunohistochemistry staining positive
for surfactant proteins [1].
Laboratory investigations
Routine laboratory investigations are not useful in the diagnosis of PAP. Serum lactate
dehydrogenase can be elevated, especially in those with severe disease, but this is not specific
to PAP. In PAP associated with underlying disease, patients may have abnormal results relating
to that disease. Some serum biomarkers have been found to be associated with the severity of
108 https://doi.org/10.1183/2312508X.10017822
FIGURE 3 The appearance of BAL fluid from a whole-lung lavage of a patient with pulmonary alveolar
proteinosis demonstrating the classic milky opaque fluid.
PAP including Krebs von den Lungen 6 (KL-6) [50–52], chitinase-3-like protein 1 (YKL-40) [53],
carcinoembryonic antigen (CEA) [54] and cytokeratin fragment 19 (CYFRA 21) [50, 55], but
these are not diagnostic.
Serum GM-CSF autoantibodies are key to the diagnosis of aPAP [9, 14, 20, 45, 56], with
high levels carrying a sensitivity and specificity of close to 100% [57, 58]. Antibody testing
does not facilitate diagnosis in hereditary or secondary disease. Serum GM-CSF signalling
tests are abnormal in those with aPAP and hereditary PAP, and are not useful in secondary or
congenital PAP [59–62]. aPAP can be differentiated from hereditary PAP by measuring serum
levels of GM-CSF, which is undetectable in aPAP and increased in hereditary PAP. Moreover,
the GM-CSF neutralising capacity of blood (tested by performing a signal transducer and
activator of transcription 5 (STAT5)-phosphorylation index test) can be a useful follow-up
confirmatory test, and sequencing to detect mutations in CSF2RA or CSF2RB is diagnostic
[61, 63–65]. Secondary PAP is diagnosed by the identification of an underlying condition or
an exposure known to cause secondary PAP [30, 66–73], a normal GM-CSF autoantibody test
and normal GM-CSF signalling tests [74]. Solute carrier family 7 member 7 (SLC7A7) and
methionyl-tRNA synthetase (MARS) testing may be useful in some cases where secondary
PAP is considered (figure 4) [75–77].
Management
The treatment of patients with PAP depends on the acuity, progression and severity of
symptoms. This can range from supportive care and monitoring for asymptomatic patients to
WLL, medical treatment with GM-CSF therapy and, rarely, lung transplantation (LTx) in
patients with end-stage respiratory failure. In general, patients should be encouraged to abstain
from smoking, be updated on their vaccinations and use supplemental oxygen when indicated.
Given the predisposition to opportunistic infections, such as Nocardia and Cryptococcus spp.,
early recognition and treatment of infections is required [2, 20].
https://doi.org/10.1183/2312508X.10017822 109
History and clinical findings compatible with PAP

Determine severity
• PFT
• 6MWT
• Comorbidities?
• HRCT findings compatible with PAP
• HRCT MDT discussion
+
Autoimmune PAP GM-CSF autoantibody test
Presence of exposure or disease known +

to cause PAP Secondary PAP
–
+ –
Abnormal GM-CSF levels test and GM-CSF
signalling test
+
Abnormal CSF2RA and Abnormal mutation tests in Histology compatible

CSF2RB mutation tests surfactant-related genes with PAP
+ + +
Hereditary PAP Congenital PAP Unclassified PAP
FIGURE 4 A diagnostic algorithm for pulmonary alveolar proteinosis (PAP). PAP syndrome should be suspected
where there is a compatible history, HRCT and BAL findings, and after multidisciplinary team (MDT) discussion.
GM-CSF autoantibody testing will confirm diagnosis in the majority of patients. If negative, patients should be
assessed for associated diseases that are linked to secondary PAP. If neither of these criteria is met, a GM-CSF
signalling test and serum GM-CSF test should guide further genetic testing (for the gene for the GM-CSF receptor
α- or β-chain (CSF2RA or CSF2RB)). These will identify hereditary PAP. If GM-CSF signalling testing is normal, gene
mutation testing (e.g. in surfactant protein B and C (SFTPB and SFTPC), ATP-binding cassette subfamily A
member 3 (ABCA3) or NK2 homeobox 1 (NKX2.1)) may identify surfactant production disorders. In a small
number of cases, a lung biopsy (transbronchial or surgical) may be required to confirm diagnosis of unclassified
PAP. 6MWT: 6-min walk test.
WLL
WLL is considered the first-line treatment for symptomatic PAP with progressive dyspnoea,
functional impairment and hypoxaemia. Many patients require WLL during the first year of
diagnosis [2], with those with increasing oxygen requirements, reduced DLCO and progressive
radiographic findings on imaging benefiting the most from WLL [78, 79]. Comorbidities need
to be considered when determining which patients should undergo this procedure. There is no
standardised approach to performing WLL, which varies among centres. To clear
lipoproteinaceous material from the alveoli, the patient undergoes endotracheal intubation using
a double-lumen tube with single-lung ventilation. Each lung is isolated and lavaged separately,
starting with the most involved lung first. Warmed saline is infused and drained in serial
aliquots until the returned fluid is clear of any alveolar sediment. The volume of saline required
is dictated by the severity of lung disease but can involve as much as 5–40 L of saline per
lung [80]. With adequate sedation, patients are placed in the Trendelenburg position, and a chest
percussion vest is applied or manual percussion is performed to assist in drainage. In patients
who are unable to tolerate single-lung ventilation due to advanced disease or significant
hypoxia, bronchoscopic lobar lavage and the use of extracorporeal membrane oxygenation
support during WLL may be considered. While the procedure is considered safe in experienced
110 https://doi.org/10.1183/2312508X.10017822
hands, the most reported complications of WLL include the development of fevers, worsening
hypoxaemia, pneumonia, fluid leakage to the contralateral lung, pleural effusions and
pneumothorax [78]. Patients who require a repeat WLL may need one on average every
15 months; however, some patients require multiple lavages over a short period, as frequent as
monthly, to achieve clinical stability [2].
GM-CSF augmentation therapy

The use of s.c. GM-CSF therapy was initially shown to result in improvements in oxygenation
and radiographic imaging [81, 82]. Many small studies have indicated utility following inhaled
GM-CSF as a therapeutic option (table 2) [92]. Recent randomised controlled trials using
inhaled recombinant GM-CSF have demonstrated improvements in A-aDO2, CT chest findings
and serum biomarkers compared with placebo [89, 91]. A more recent randomised study on the
use of inhaled recombinant GM-CSF molgramostim demonstrated a significant improvement in
DLCO, radiographic findings and functional health status compared with placebo, with no
increased rate of adverse events [91]. Pooled analysis of multiple studies has demonstrated
potentially greater benefit from inhaled administration compared with s.c. administration in aPAP,
with a greater improvement in A-aDO2 and arterial oxygen tension in the inhaled group [93].
In addition, inhaled GM-CSF seems to be better tolerated due to the high rates of injection site
pain described with s.c. injections of GM-CSF [82]. Currently, a further multicentre randomised
controlled trial is ongoing to evaluate the role of inhaled GM-CSF (molgramostim) against
placebo in adults with aPAP (Clinical Trials.gov identifier NCT04544293).
Therapies targeting autoantibodies to GM-CSF

Following the discovery of GM-CSF autoantibodies and their causative effect, therapeutic
strategies have been employed in an attempt to deplete the levels of autoantibodies [94].
TABLE 2 Clinical trials of inhaled GM-CSF therapy
Year Trial design Subjects, n A−aDO2 DLCO Imaging First

author
[ref.]
2004 First-in-human single site, 1 Improved Improved Improved ARAI [55]

open label
2005 Phase I/II, single site, open label 3 Improved Not Not TAZAWA [83]
reported reported
2006 Retrospective, observational 12 Improved Improved Improved WYLAM [84]
2010 Phase I/II, multisite, open label 35 Improved Improved Improved TAZAWA [85]
2012 Phase II, single site, open label 6 Improved Not Not OHASHI [86]
reported reported
2014 Retrospective, observational 6 Improved Improved Improved PAPIRIS [87]
2016 Phase II, single site, open label 18 Improved Improved Not CAMPO [88]
significant
2019 Phase III, multisite randomised, 64 Improved Improved Improved TAZAWA [89]
double blind, placebo controlled
2020 Phase II, multisite, randomised, 36 No Improved No change TIAN [90]
open label change
2020 Phase III, multinational, 138 Improved Improved Improved TRAPNELL
randomised, double blind, placebo [91]
controlled
A−aDO2: alveolar–arterial difference in oxygen concentration. Data from [4].
https://doi.org/10.1183/2312508X.10017822 111
Corticosteroids appear to be more harmful than beneficial [95], while other approaches have
mixed evidence; these include plasma exchange and B-cell depletion using rituximab [96–99].
In one small retrospective study of 13 patients, rituximab failed to show any improvement at
6 months [100]. In another open-label study of 10 patients with aPAP, two doses of rituximab
given 2 weeks apart resulted in a small improvement in A-aDO2 and radiographic imaging with
treatment [96]. The use of plasmapheresis to reduce circulating antibodies has been described in
various reports with little evidence to suggest any clinically significant changes or
improvements for patients, despite reported lower levels of autoantibodies [101, 102]. The lack
of definitive efficacy with these approaches may reflect the lack of correlation between severity
of disease and GM-CSF autoantibody levels [103]. Plasma exchange and rituximab are
frequently used as rescue therapies in severe cases where all other therapy has failed, but it
remains uncertain whether they are effective, and no consensus exists regarding their use.
Emerging therapies
Oral statins and PPARγ have been demonstrated in mice models to help ameliorate PAP by
increasing cholesterol efflux in alveolar macrophages, improving macrophage function and
reducing disease severity [13, 19]. In early human studies, statins have been shown to reduce
surfactant accumulation in the lung via quantitative CT densitometry, as well as improve patient
symptoms and oxygenation [19]. In addition, the use of the oral PPARγ agonist pioglitazone to
reduce cholesterol clearance from macrophages has been reported to improve PAP symptoms [104].
These studies suggest a promising new treatment option for aPAP.
The therapeutic approach for hereditary and secondary PAP is different to aPAP, with the
current approach in secondary PAP being to treat the underlying cause [105–108]. In some
cases of secondary PAP, haematopoietic stem cell transplantation (HSCT) has been successful;
however, it is worth noting that HSCT is limited by significant morbidity and mortality
associated with myeloablation, and indeed secondary PAP is itself also a rare complication of
bone marrow transplantation [109, 110]. In hereditary PAP in humans, there have been reported
cases of successful HSCT [111], and murine studies have assessed the efficacy of novel
cell-therapy approaches. Pulmonary macrophage transplantation, a process where healthy-donor
or gene-corrected bone marrow-derived macrophages are delivered directly to the lungs of PAP
mice, resulted in improved lung disease and mortality [6, 112–114]. With recent scientific
developments allowing the genetic correction of macrophages from patient-derived pluripotent
stem cells [115, 116], this has led to a first-in-human trial of pulmonary macrophage
transplantation using gene-corrected bone marrow-derived macrophages being planned and
murine studies supporting the likely efficacy and feasibility [6, 117].
LTx
For some patients with progressive PAP who no longer respond to WLL and medical therapies,
or who develop end-stage respiratory failure and fibrotic lung disease, bilateral LTx may be the
only remaining option for treatment. Recurrence of aPAP after LTx has been reported [118].
Future directions and advances in PAP

PAP is a rare but important disease leading to end-stage respiratory failure in a cohort of
patients. It can raise some diagnostic challenges as its presentation can mimic other pulmonary
diseases, but antibody testing is diagnostic in the majority of cases. Multidisciplinary
discussions are important in confirmation of the diagnosis. While the mainstay of treatment is
WLL, recent studies support the possible utility of statins and, more importantly, inhaled
GM-CSF therapy as a potential treatment. Despite major advances in the knowledge of
112 https://doi.org/10.1183/2312508X.10017822
pathogenesis and therapeutic options, many questions remain unanswered and future research
will be needed to address these issues [119]. Currently, consensus expert-led guidelines are not
available for PAP, and the first such guideline will be published in the next 18 months.
References
1 Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med 2003; 349: 2527–2539.
2 Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care
Med 2002; 166: 215–235.
3 Carey B, Trapnell BC. The molecular basis of pulmonary alveolar proteinosis. Clin Immunol 2010; 135: 223–235.
4 McCarthy C, Carey BC, Trapnell BC. Autoimmune pulmonary alveolar proteinosis. Am J Respir Crit Care Med
2022; 205: 1016–1035.
5 Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show
no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci
U S A 1994; 91: 5592–5596.
6 Arumugam P, Suzuki T, Shima K, et al. Long-term safety and efficacy of gene-pulmonary macrophage
transplantation therapy of PAP in Csf2ra−/− mice. Mol Ther 2019; 27: 1597–1611.
7 Dranoff G, Crawford AD, Sadelain M, et al. Involvement of granulocyte–macrophage colony-stimulating factor
in pulmonary homeostasis. Science 1994; 264: 713–716.
8 Inoue Y, Trapnell BC, Tazawa R, et al. Characteristics of a large cohort of patients with autoimmune
pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med 2008; 177: 752–762.
9 Trapnell BC, Nakata K, Bonella F, et al. Pulmonary alveolar proteinosis. Nat Rev Dis Primers 2019; 5: 16.
10 Shibata Y, Berclaz PY, Chroneos ZC, et al. GM-CSF regulates alveolar macrophage differentiation and innate
immunity in the lung through PU.1. Immunity 2001; 15: 557–567.
11 Schneider C, Nobs SP, Kurrer M, et al. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is
critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol 2014; 15: 1026–1037.
12 Bonfield TL, Raychaudhuri B, Malur A, et al. PU.1 regulation of human alveolar macrophage differentiation
requires granulocyte–macrophage colony-stimulating factor. Am J Physiol Lung Cell Mol Physiol 2003; 285:
L1132–L1136.
13 Sallese A, Suzuki T, McCarthy C, et al. Targeting cholesterol homeostasis in lung diseases. Sci Rep 2017; 7: 10211.
14 McCarthy C, Carey B, Trapnell BC. Blood testing for differential diagnosis of pulmonary alveolar proteinosis
syndrome. Chest 2019; 155: 450–452.
15 Gschwend J, Sherman SPM, Ridder F, et al. Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2
cells before and after birth. J Exp Med 2021; 218: e20210745.
16 Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte–macrophage
colony-stimulating factor. N Engl J Med 1992; 327: 28–35.
17 Moore KJ, Rosen ED, Fitzgerald ML, et al. The role of PPAR-γ in macrophage differentiation and cholesterol
uptake. Nat Med 2001; 7: 41–47.
18 Yancey PG, Jerome WG. Lysosomal sequestration of free and esterified cholesterol from oxidized low density
lipoprotein in macrophages of different species. J Lipid Res 1998; 39: 1349–1361.
19 McCarthy C, Lee E, Bridges JP, et al. Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis.
Nat Commun 2018; 9: 3127.
20 Uchida K, Beck DC, Yamamoto T, et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary
alveolar proteinosis. N Engl J Med 2007; 356: 567–579.
21 Kitamura T, Tanaka N, Watanabe J, et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune
disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med 1999;
190: 875–880.
22 Tanaka N, Watanabe J, Kitamura T, et al. Lungs of patients with idiopathic pulmonary alveolar proteinosis
express a factor which neutralizes granulocyte–macrophage colony stimulating factor. FEBS Lett 1999; 442:
246–250.
23 Sakagami T, Uchida K, Suzuki T, et al. Human GM-CSF autoantibodies and reproduction of pulmonary alveolar
24 Sakagami T, Beck D, Uchida K, et al. Patient-derived granulocyte/macrophage colony-stimulating factor
autoantibodies reproduce pulmonary alveolar proteinosis in nonhuman primates. Am J Respir Crit Care Med
2010; 182: 49–61.
25 McCarthy C, Avetisyan R, Carey BC, et al. Prevalence and healthcare burden of pulmonary alveolar proteinosis.
Orphanet J Rare Dis 2018; 13: 129.
26 Campo I, Mariani F, Rodi G, et al. Assessment and management of pulmonary alveolar proteinosis in a
reference center. Orphanet J Rare Dis 2013; 8: 40.
https://doi.org/10.1183/2312508X.10017822 113
27 Gower WA, Nogee LM. Surfactant dysfunction. Paediatr Respir Rev 2011; 12: 223–229.
28 Hildebrandt J, Yalcin E, Bresser HG, et al. Characterization of CSF2RA mutation related juvenile pulmonary
alveolar proteinosis. Orphanet J Rare Dis 2014; 9: 171.
29 Ishii H, Seymour JF, Tazawa R, et al. Secondary pulmonary alveolar proteinosis complicating myelodysplastic
syndrome results in worsening of prognosis: a retrospective cohort study in Japan. BMC Pulm Med 2014; 14: 37.
30 Ladeb S, Fleury-Feith J, Escudier E, et al. Secondary alveolar proteinosis in cancer patients. Support Care
Cancer 1996; 4: 420–426.
31 Ballard PL, Nogee LM, Beers MF, et al. Partial deficiency of surfactant protein B in an infant with chronic lung
disease. Pediatrics 1995; 96: 1046–1052.
32 Nogee LM. Genetic mechanisms of surfactant deficiency. Biol Neonate 2004; 85: 314–318.
33 Hawkins P, Chawke L, Cormican L, et al. Autoimmune pulmonary alveolar proteinosis: a discrepancy between
symptoms and CT findings. Lancet 2021; 398: e7.
34 Berclaz PY, Carey B, Fillipi MD, et al. GM-CSF regulates a PU.1-dependent transcriptional program determining
the pulmonary response to LPS. Am J Respir Cell Mol Biol 2007; 36: 114–121.
35 Trapnell BC, Carey BC, Uchida K, et al. Pulmonary alveolar proteinosis, a primary immunodeficiency of
impaired GM-CSF stimulation of macrophages. Curr Opin Immunol 2009; 21: 514–521.
36 Patiroglu T, Akyildiz B, Patiroglu TE, et al. Recurrent pulmonary alveolar proteinosis secondary to
agammaglobulinemia. Pediatr Pulmonol 2008; 43: 710–713.
37 Jennings VM, Dillehay DL, Webb SK, et al. Pulmonary alveolar proteinosis in SCID mice. Am J Respir Cell Mol
Biol 1995; 13: 297–306.
38 Ikegami M, Whitsett JA, Chroneos ZC, et al. IL-4 increases surfactant and regulates metabolism in vivo. Am J
Physiol Lung Cell Mol Physiol 2000; 278: L75–L80.
39 Agarwal PP, Seely JM, Perkins DG, et al. Pulmonary alveolar proteinosis and end-stage pulmonary fibrosis: a
rare association. J Thorac Imaging 2005; 20: 242–244.
40 Akira M, Inoue Y, Arai T, et al. Pulmonary fibrosis on high-resolution CT of patients with pulmonary alveolar
proteinosis. Am J Roentgenol 2016; 207: 544–551.
41 Hunt AN, Malur A, Monfort T, et al. Hepatic steatosis accompanies pulmonary alveolar proteinosis. Am J Respir
Cell Mol Biol 2017; 57: 448–458.
42 Chroneou A, Zias N, Tronic BS, et al. A case of uncomplicated pulmonary alveolar proteinosis evolving to
pulmonary fibrosis. Monaldi Arch Chest Dis 2007; 67: 234–237.
43 Luisetti M, Bruno P, Kadija Z, et al. Relationship among diffuse pulmonary fibrosis, alveolar proteinosis and
anti-GM-CSF autoantibodies. Respir Care 2011; 56: 1608–1610.
44 McCarthy C, Carey B, Trapnell BC. Blood testing in the diagnosis of pulmonary alveolar proteinosis. Lancet
Respir Med 2018; 6: e54.
45 Presneill JJ, Nakata K, Inoue Y, et al. Pulmonary alveolar proteinosis. Clin Chest Med 2004; 25: 593–613.
46 Goldstein LS, Kavuru MS, Curtis-McCarthy P, et al. Pulmonary alveolar proteinosis: clinical features and
outcomes. Chest 1998; 114: 1357–1362.
47 Lee KN, Levin DL, Webb WR, et al. Pulmonary alveolar proteinosis: high-resolution CT, chest radiographic, and
functional correlations. Chest 1997; 111: 989–995.
48 Johkoh T, Itoh H, Muller NL, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and
pathologic findings. Radiology 1999; 211: 155–160.
49 Doyle IR, Davidson KG, Barr HA, et al. Quantity and structure of surfactant proteins vary among patients with
alveolar proteinosis. Am J Respir Crit Care Med 1998; 157: 658–664.
50 Bonella F, Bauer PC, Griese M, et al. Pulmonary alveolar proteinosis: new insights from a single-center cohort
of 70 patients. Respir Med 2011; 105: 1908–1916.
51 Nara M, Sano K, Ogawa H, et al. Serum antibody against granulocyte/macrophage colony-stimulating factor
and KL-6 in idiopathic pulmonary alveolar proteinosis. Tohoku J Exp Med 2006; 208: 349–354.
52 Takahashi T, Munakata M, Suzuki I, et al. Serum and bronchoalveolar fluid KL-6 levels in patients with
pulmonary alveolar proteinosis. Am J Respir Crit Care Med 1998; 158: 1294–1298.
53 Bonella F, Long X, He X, et al. Serum YKL-40 is a reliable biomarker for pulmonary alveolar proteinosis.
Respirology 2017; 22: 1371–1378.
54 Fujishima T, Honda Y, Shijubo N, et al. Increased carcinoembryonic antigen concentrations in sera and
bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Respiration 1995; 62: 317–321.
55 Arai T, Hamano E, Inoue Y, et al. Serum neutralizing capacity of GM-CSF reflects disease severity in a
patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF. Respir Med 2004; 98:
1227–1230.
56 Kitamura T, Uchida K, Tanaka N, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am
J Respir Crit Care Med 2000; 162: 658–662.
57 Carey B, Chalk C, Stock J, et al. A dried blood spot test for diagnosis of autoimmune pulmonary alveolar
proteinosis. J Immunol Methods 2022; 511: 113366.
114 https://doi.org/10.1183/2312508X.10017822
58 Uchida K, Nakata K, Carey B, et al. Standardized serum GM-CSF autoantibody testing for the routine clinical
diagnosis of autoimmune pulmonary alveolar proteinosis. J Immunol Methods 2014; 402: 57–70.
59 Ito M, Nakagome K, Ohta H, et al. Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine
profile. BMC Pulm Med 2017; 17: 40.
60 Suzuki T, Maranda B, Sakagami T, et al. Hereditary pulmonary alveolar proteinosis caused by recessive
CSF2RB mutations. Eur Respir J 2011; 37: 201–204.
61 Suzuki T, Sakagami T, Young LR, et al. Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation,
diagnosis, and therapy. Am J Respir Crit Care Med 2010; 182: 1292–1304.
62 Martinez-Moczygemba M, Doan ML, Elidemir O, et al. Pulmonary alveolar proteinosis caused by deletion of the
GM-CSFRα gene in the X chromosome pseudoautosomal region 1. J Exp Med 2008; 205: 2711–2716.
63 Suzuki T, Sakagami T, Rubin BK, et al. Familial pulmonary alveolar proteinosis caused by mutations in
CSF2RA. J Exp Med 2008; 205: 2703–2710.
64 Suzuki T, Sakagami T, Carey BC, et al. Preclinical evaluation of pulmonary macrophages transplantation
therapy of hereditary pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2011; 183: A2505.
65 Carey BC, Suzuki T, Uchida K, et al. An algorithm for diagnosis of familial pulmonary alveolar proteinosis
(PAP). Am J Respir Crit Care Med 2009; 179: A3679.
66 Cordonnier C, Fleury-Feith J, Escudier E, et al. Secondary alveolar proteinosis is a reversible cause of
respiratory failure in leukemic patients. Am J Respir Crit Care Med 1994; 149: 788–794.
67 Hildebrand FL Jr, Rosenow EC 3rd, Habermann TM, et al. Pulmonary complications of leukemia. Chest 1990;
98: 1233–1239.
68 Schiller V, Aberle DR, Aberle AM. Pulmonary alveolar proteinosis: occurrence with metastatic melanoma to
lung. Chest 1989; 95: 466–467.
69 Ruben FL, Talamo TS. Secondary pulmonary alveolar proteinosis occurring in two patients with acquired
immune deficiency syndrome. Am J Med 1986; 80: 1187–1190.
70 Miller RR, Churg AM, Hutcheon M, et al. Pulmonary alveolar proteinosis and aluminum dust exposure. Am Rev
Respir Dis 1984; 130: 312–315.
71 Webster JR Jr, Battifora H, Furey C, et al. Pulmonary alveolar proteinosis in two siblings with decreased
immunoglobulin A. Am J Med 1980; 69: 786–789.
72 Carnovale R, Zornoza J, Goldman AM, et al. Pulmonary alveolar proteinosis: its association with hematologic
malignancy and lymphoma. Radiology 1977; 122: 303–306.
73 Xipell JM, Ham KN, Price CG, et al. Acute silicoproteinosis. Thorax 1977; 32: 104–111.
74 Kusakabe Y, Uchida K, Hiruma T, et al. A standardized blood test for the routine clinical diagnosis of impaired
GM-CSF signaling using flow cytometry. J Immunol Methods 2014; 413: 1–11.
75 Ceruti M, Rodi G, Stella GM, et al. Successful whole lung lavage in pulmonary alveolar proteinosis secondary
to lysinuric protein intolerance: a case report. Orphanet J Rare Dis 2007; 2: 14.
76 Enaud L, Hadchouel A, Coulomb A, et al. Pulmonary alveolar proteinosis in children on La Reunion Island: a
new inherited disorder? Orphanet J Rare Dis 2014; 9: 85.
77 Hadchouel A, Wieland T, Griese M, et al. Biallelic mutations of methionyl-tRNA synthetase cause a specific
type of pulmonary alveolar proteinosis prevalent on Reunion Island. Am J Hum Genet 2015; 96: 826–831.
78 Campo I, Luisetti M, Griese M, et al. Whole lung lavage therapy for pulmonary alveolar proteinosis: a global
survey of current practices and procedures. Orphanet J Rare Dis 2016; 11: 115.
79 Campo I, Luisetti M, Griese M, et al. A global survey on whole lung lavage in pulmonary alveolar proteinosis.
Chest 2016; 150: 251–253.
80 Awab A, Khan MS, Youness HA. Whole lung lavage-technical details, challenges and management of
complications. J Thorac Dis 2017; 9: 1697–1706.
81 Seymour JF, Dunn AR, Vincent JM, et al. Efficacy of granulocyte–macrophage colony-stimulating factor in
acquired alveolar proteinosis. N Engl J Med 1996; 335: 1924–1925.
82 Venkateshiah SB, Yan TD, Bonfield TL, et al. An open-label trial of granulocyte macrophage colony stimulating
factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest 2006; 130: 227–237.
83 Tazawa R, Hamano E, Arai T, et al. Granulocyte–macrophage colony-stimulating factor and lung immunity in
pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2005; 171: 1142–1149.
84 Wylam ME, Ten R, Prakash UB, et al. Aerosol granulocyte–macrophage colony-stimulating factor for
pulmonary alveolar proteinosis. Eur Respir J 2006; 27: 585–593.
85 Tazawa R, Trapnell BC, Inoue Y, et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy
for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2010; 181: 1345–1354.
86 Ohashi K, Sato A, Takada T, et al. Direct evidence that GM-CSF inhalation improves lung clearance in
pulmonary alveolar proteinosis. Respir Med 2012; 106: 284–293.
87 Papiris SA, Tsirigotis P, Kolilekas L, et al. Long-term inhaled granulocyte macrophage-colony-stimulating factor
in autoimmune pulmonary alveolar proteinosis: effectiveness, safety, and lowest effective dose. Clin Drug
Investig 2014; 34: 553–564.
https://doi.org/10.1183/2312508X.10017822 115
88 Campo I, Mariani F, Paracchini E, et al. Inhaled sarmogramostim and whole lung lavage (WLL) as therapy of
autoimmune pulmonary alveolar proteinosis (aPAP). Eur Respir J 2016; 48: PA3870.
89 Tazawa R, Ueda T, Abe M, et al. Inhaled GM-CSF for pulmonary alveolar proteinosis. N Engl J Med 2019; 381:
923–932.
90 Tian X, Yang Y, Chen L, et al. Inhaled granulocyte–macrophage colony stimulating factor for mild-to-moderate
autoimmune pulmonary alveolar proteinosis – a six month phase II randomized study with 24 months of
follow-up. Orphanet J Rare Dis 2020; 15: 174.
91 Trapnell BC, Inoue Y, Bonella F, et al. Inhaled molgramostim therapy in autoimmune pulmonary alveolar
92 McCarthy C, Bartholmai BJ, Woods JC, et al. Automated parenchymal pattern analysis of treatment responses
in pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2019; 199: 1151–1152.
93 Sheng G, Chen P, Wei Y, et al. Better approach for autoimmune pulmonary alveolar proteinosis treatment: inhaled
or subcutaneous granulocyte–macrophage colony-stimulating factor: a meta-analyses. Respir Res 2018; 19: 163.
94 Kavuru MS, Bonfield TL, Thomassen MJ. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am J Respir Crit
Care Med 2003; 167: 1036.
95 Akasaka K, Tanaka T, Kitamura N, et al. Outcome of corticosteroid administration in autoimmune pulmonary
alveolar proteinosis: a retrospective cohort study. BMC Pulm Med 2015; 15: 88.
96 Kavuru MS, Malur A, Marshall I, et al. An open-label trial of rituximab therapy in pulmonary alveolar
proteinosis. Eur Respir J 2011; 38: 1361–1367.
97 Amital A, Dux S, Shitrit D, et al. Therapeutic effectiveness of rituximab in a patient with unresponsive
autoimmune pulmonary alveolar proteinosis. Thorax 2010; 65: 1025–1026.
98 Borie R, Debray MP, Laine C, et al. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur
Respir J 2009; 33: 1503–1506.
99 Malur A, Kavuru MS, Marshall I, et al. Rituximab therapy in pulmonary alveolar proteinosis improves alveolar
macrophage lipid homeostasis. Respir Res 2012; 13: 46.
100 Soyez B, Borie R, Menard C, et al. Rituximab for auto-immune alveolar proteinosis, a real life cohort study.
Respir Res 2018; 19: 74.
101 Luisetti M, Rodi G, Perotti C, et al. Plasmapheresis for treatment of pulmonary alveolar proteinosis. Eur Respir J
2009; 33: 1220–1222.
102 Garber B, Albores J, Wang T, et al. A plasmapheresis protocol for refractory pulmonary alveolar proteinosis.
Lung 2015; 193: 209–211.
103 Seymour JF, Doyle IR, Nakata K, et al. Relationship of anti-GM-CSF antibody concentration, surfactant protein
A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with
idiopathic alveolar proteinosis. Thorax 2003; 58: 252–257.
104 Dupin C, Hurtado M, Cazes A, et al. Pioglitazone in pulmonary alveolar proteinosis: promising first clinical
experience. Respir Med Res 2020; 78: 100756.
105 Cuellar-Rodriguez J, Gea-Banacloche J, Freeman AF, et al. Successful allogeneic hematopoietic stem cell
transplantation for GATA2 deficiency. Blood 2011; 118: 3715–3720.
106 Numata A, Matsuishi E, Koyanagi K, et al. Successful therapy with whole-lung lavage and autologous
peripheral blood stem cell transplantation for pulmonary alveolar proteinosis complicating acute
myelogenous leukemia. Am J Hematol 2006; 81: 107–109.
107 Fukuno K, Tomonari A, Tsukada N, et al. Successful cord blood transplantation for myelodysplastic syndrome
resulting in resolution of pulmonary alveolar proteinosis. Bone Marrow Transplant 2006; 38: 581–582.
108 Tholouli E, Sturgess K, Dickinson RE, et al. In vivo T-depleted reduced-intensity transplantation for
GATA2-related immune dysfunction. Blood 2018; 131: 1383–1387.
109 Tabata S, Shimoji S, Murase K, et al. Successful allogeneic bone marrow transplantation for myelodysplastic
syndrome complicated by severe pulmonary alveolar proteinosis. Int J Hematol 2009; 90: 407–412.
110 Pidala J, Khalil F, Fernandez H. Pulmonary alveolar proteinosis following allogeneic hematopoietic cell
transplantation. Bone Marrow Transplant 2011; 46: 1480–1483.
111 Fremond ML, Hadchouel A, Schweitzer C, et al. Successful haematopoietic stem cell transplantation in a case
of pulmonary alveolar proteinosis due to GM-CSF receptor deficiency. Thorax 2018; 73: 590–592.
112 Shima K, Suzuki T, Arumugam P, et al. Pulmonary macrophage transplantation therapy in Csf2ra gene-ablated
mice: a novel model of hereditary pulmonary alveolar proteinosis in children. Am J Respir Crit Care Med 2017;
195: A4857.
113 Shima K, Arumugam P, Ma Y, et al. Development and validation of Csf2ra gene-deficient mice as a clinically
relevant model of children with hereditary pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2017;
195: A4837.
114 Suzuki T, Arumugam P, Sakagami T, et al. Pulmonary macrophage transplantation therapy. Nature 2014; 514:
450–454.
116 https://doi.org/10.1183/2312508X.10017822
115 Suzuki T, Mayhew C, Sallese A, et al. Use of induced pluripotent stem cells to recapitulate pulmonary alveolar
proteinosis pathogenesis. Am J Respir Crit Care Med 2014; 189: 183–193.
116 Lachmann N, Happle C, Ackermann M, et al. Gene correction of human induced pluripotent stem cells repairs
the cellular phenotype in pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2014; 189: 167–182.
117 Shima K, Arumugam P, Sallese A, et al. A murine model of hereditary pulmonary alveolar proteinosis caused
by homozygous Csf2ra gene disruption. Am J Physiol Lung Cell Mol Physiol 2022; 322: L438–L448.
118 Parker LA, Novotny DB. Recurrent alveolar proteinosis following double lung transplantation. Chest 1997; 111:
1457–1458.
119 McCarthy C, Kokosi M, Bonella F. Shaping the future of an ultra-rare disease: unmet needs in the diagnosis
and treatment of pulmonary alveolar proteinosis. Curr Opin Pulm Med 2019; 25: 450–458.
Disclosures: E. Bendstrup reports receiving the following, outside the submitted work: speakers’ bureau fees from
Hoffman la Roche and Boehringer Ingelheim; and support for attending meetings and/or travel from Boehringer
Ingelheim. C. McCarthy reports consultancy for Savara Inc., outside the submitted work. The remaining authors
have nothing to disclose.
https://doi.org/10.1183/2312508X.10017822 117
Chapter 9
Primary ciliary dyskinesia

Petra Pennekamp1,2, Johanna Raidt1,2, Kai Wohlgemuth1, Heike Olbrich1 and
Heymut Omran1
1
Dept of General Pediatrics, University Children’s Hospital Muenster, Muenster, Germany. 2These authors
contributed equally.
Corresponding author: Heymut Omran (Heymut.Omran@ukmuenster.de)
Cite as: Pennekamp P, Raidt J, Wohlgemuth K, et al. Primary ciliary dyskinesia. In: Wagner TOF, Humbert M,
@ERSpublications
Primary ciliary dyskinesia is a rare group of diseases affecting the airways. Global prevalence is
underestimated as it is often diagnosed too late or not at all. It requires lifelong treatment to prevent
respiratory complications. https://bit.ly/ERSM100
ISSN: 2312-5098.
Primary ciliary dyskinesia (PCD) is a rare genetically and clinically heterogeneous group of diseases
with more than 50 associated genes. PCD is characterised by dysfunction of multiple motile cilia,
resulting in aberrant mucociliary clearance. Hallmark symptoms are chronic airway infections due to
mucostasis that may lead to irreversible lung damage. Approximately 50% of affected individuals
display situs inversus totalis or, less commonly, situs ambiguous. Additional symptoms can occur such
as hydrocephalus and infertility or subfertility. PCD diagnosis should be established as early as possible
to prevent permanent lung damage. PCD diagnosis is complex and consists of a combination of
multiple tests, as many PCD variants cannot be detected with a single method. There is currently no
curative therapy for PCD. Thus, the focus is on symptomatic measures such as regular airway cleaning
and treatment of recurrent respiratory infections. Most recommendations for patient management are
modelled on therapeutic approaches for other respiratory diseases such as cystic fibrosis, COPD and
idiopathic bronchiectasis.
Introduction
Primary ciliary dyskinesia (PCD, ORPHA:244) is a rare, genetically and clinically
heterogeneous group of diseases affecting the airways. The estimated prevalence of PCD is 1 in
7500–20 000 [1–4]. Global prevalence is likely to be underestimated due to the high incidence
of unreported cases, as diagnosis is often made too late or not at all due to the heterogeneous
phenotype and complexity of diagnosis [5, 6]. PCD is characterised by dysfunction of motile
cilia, the microscopic hair-like structures lining the airways. This dysfunction leads to aberrant
ciliary clearance of the airways [7, 8]. Additional symptoms can occur because multiciliated
surfaces are also found in brain ventricles, fallopian tubes and ductuli efferentes. Sperm flagella
and motile monocilia of the left–right organiser, relevant for left–right body axis development,
are special forms of motile cilia [7, 9, 10]. PCD is usually diagnosed in childhood and requires
lifelong management to prevent respiratory complications and infections [6, 11, 12], resulting in
chronic destructive lung disease.
118 https://doi.org/10.1183/2312508X.10017922
PRIMARY CILIARY DYSKINESIA | P. PENNEKAMP ET AL.
Classical clinical presentation of PCD

PCD is a congenital disease. Symptoms usually appear immediately after birth or in the first
12–24 h of life [1, 10, 13–15]. More than 80% of full-term newborns with PCD present with
respiratory distress [14, 16]. On the basis of clinical symptoms (e.g. tachy(dys)pnoea,
supplementary oxygen, need for ventilation, atelectasis on chest radiograph), neonatal
pneumonia is often suspected and antibiotic treatment is given. In <50% of newborns with
PCD, situs inversus totalis or, less commonly, heterotaxy associated with congenital cardiac
malformations is evident [17–21]. From the first days of life, PCD individuals often suffer from
constant rhinitis or difficulty breathing through the nose, potentially affecting breastfeeding.
Later, chronic (rhino-)sinusitis/rhinorrhoea without seasonal improvement, partially restricted
smelling ability and nasal polyps are observed [22, 23].
Daily chronic wet cough is present in almost 100% of PCD individuals [16], and 75% of all
preschool children with PCD present with recurrent respiratory tract infections such as otitis
media, sinusitis, bronchitis and pneumonia. Secretion and consecutive pulmonary ventilation
disorders such as atelectasis and dystelectasis are frequent. PCD individuals often experience
tympanic effusions with conductive hearing loss and consecutive speech developmental delay
[1, 10, 13, 14]. As the disease progresses, bronchiectasis develops, typically affecting the
lingula and middle lobe, as well as both lower lobes of the lungs [24]. Involvement of the upper
lobes is rarely observed [25]. Male infertility/subfertility is a common finding in PCD [26, 27],
but depends on the underlying structural and/or functional defect of sperm flagella [28] or
motile cilia of the efferent ducts, connecting the rete testis with the epididymis [8]. Fertility
problems may also occur in females as the fallopian tubes are lined with multiciliated
epithelium [26, 29].
Noncharacteristic phenotypes associated with PCD

“Syndromal” PCD variants associated with mental retardation, neurological symptomatology or
different malformations/dysfunctions of other organ systems are extremely rare [7]. These
variants are probably caused by dysfunction of associated gene products such as oral–facial–
digital syndrome type I (OFD1) [30] and retinitis pigmentosa GTPase regulator (RPGR) [31] in
both motile and nonmotile cilia [7, 9].
Motile cilia
Motile cilia are composed of numerous proteins and protein complexes [7]. In cross-sections of
motile cilia, two central-pair (CP) single tubules are surrounded by nine peripheral tubule
doublets (table 1, figure 1). Outer and inner dynein arms (ODAs and IDAs, respectively) are
attached to the A-tubule of each doublet. ODAs generate the force for ciliary beating and act as
large motors, while IDAs modify the beating pattern. The CP tubules and radial spokes (RSs)
TABLE 1 Pathobiology of primary ciliary dyskinesia (PCD): cilia structure and function
Cilia are evolutionarily highly conserved, hair-like projections of the cell surface with a characteristic
ultrastructure (figure 1)
Motile cilia actively perform movements that set fluids in motion (e.g. in the respiratory tract) or help cells to
move (e.g. sperm)
Dysfunction of motile cilia in the respiratory tract leads to lack of mucociliary clearance and chronic infections
Dysfunction of embryonic nodal cilia results in randomised formation of left–right body asymmetry in most
PCD variants, leading to situs inversus totalis in nearly 50% of cases; however, other laterality defects such
as situs ambiguous, including left or right isomerism syndromes (Ivemark syndrome), can also occur
https://doi.org/10.1183/2312508X.10017922 119
Axoneme Outer dynein arm

Inner dynein arm
Radial spoke
A-tubule
Central tubule
Central sheet
B-tubule
B-tubule
Nexin-link
Cytoplasmic
assembly
FIGURE 1 Basic structure of motile cilia. Schematic of a respiratory epithelial cell with nucleus and outgrowing
cilia (left), structure of a motile respiratory cilium in cross-section (middle) and TEM cross-section of a healthy
control individual (right). The most important components are labelled. The dynein arms are composed of
several proteins that are pre-assembled in the cytoplasm before being transported into the growing cilia.
also play an essential role in ciliary beat regulation. ODAs and IDAs are not identical in their
structure and vary along the ciliary axonemal scaffold [33]. Hence, transmission electron
microscopy (TEM) may generate normal findings when partial ODA/IDA defects are present [34].
In addition to these major complexes, numerous other proteins and complexes are required for
the proper structure and function of motile cilia [7].
Genetics of PCD
To date, more than 50 genes have been associated with PCD (table 2) [7, 91]. However, it is
currently estimated that in 20–30% of individuals with phenotypically well-characterised PCD,
no disease-causing genetic variants in any of the currently associated genes can be detected [92].
Usually, PCD follows autosomal-recessive inheritance, with both sexes being equally affected.
The most commonly affected genes are the axonemal dynein genes DNAH5, DNAI1, DNAI2
and DNAH11 [4]. The likelihood of inheriting PCD is increased in consanguineous families.
Some rare variants show X-linked recessive inheritance (e.g. PIH1D3, OFD1 and RPGR) [30, 31,
57, 93]. Here, female offspring can be carriers and male offspring have a 50% probability of
inheriting the disease. Autosomal-dominant de novo variants have also been described
(e.g. FOXJ1) [84].
The estimated prevalence of PCD in Europe is 1 in 7500–20 000 or higher but varies depending
on the population [4, 94]. A recent study based on analysis of publicly available genetic data
from the Genome Aggregation Database [95] showed that PCD is likely to be about twice as
common as previously believed [5].
Diagnostic workflow
The diagnosis of PCD should be established as early as possible [96]. Diagnostic guidelines
recommend a combination of multiple tests, as many PCD variants cannot be detected reliably
with a single diagnostic method [97–99]. PCD diagnostics should be performed at specialised
centres. Recommendations may differ between continents, depending on the healthcare system
and availability of resources [100–102].
120 https://doi.org/10.1183/2312508X.10017922
TABLE 2 Pathobiology of primary ciliary dyskinesia (PCD): cilia structure and function
Gene OMIM Locus Structural defect First author [ref.]
DNAH5 CILD3 5p15 ODA OLBRICH [35]

DNAH11 CILD7 7p15-21 Proximal ODA SCHWABE [36]
DNAH9 CILD40 17p12 Distal ODA LOGES [37], FASSAD [38]
DNAI1 CILD1 9p21-p13 ODA PENNARUN [39]
DNAI2 CILD9 17q25.1 ODA LOGES [40]
TXNDC3/NME8 CILD6 7p14.1 ODA DURIEZ [41]
DNAL1 CILD16 14q24.3 ODA HORVÁTH [42]
CCDC103 CILD17 17q12 ODA PANIZZI [43]
ODAD1/CCDC114 CILD20 19q13.33 ODA DC ONOUFRIADIS [44]
ODAD2/ARMC4 CILD23 10p21 ODA DC HJEIJ [45]
ODAD3/CCDC151 CILD30 19p13.2 ODA DC HJEIJ [46]
ODAD4/TTC25 CILD35 17q21.2 ODA DC WALLMEIER [47]
CLXN/EFCAB1 8q11.21 ODA DC HJEIJ [48]
DAW1 2q36.3 Distal ODA LESLIE [49]
TTC12 CILD45 11q23.2 ODA+IDA THOMAS [50]
DNAAF1/LRRC50 CILD13 16q24 ODA+IDA LOGES [51],
DUQUESNOY [52]
DNAAF2/KTU CILD10 14q21.3 ODA+IDA OMRAN [53]
DNAAF3/C19ORF51 CILD2 19q13 ODA+IDA MITCHISON [54]
DNAAF4/DYX1C1 CILD25 15q21 ODA+IDA TARKAR [55]
DNAAF5/HEATR2 CILD18 7p22.3 ODA+IDA HORANI [56]
DNAAF6/PIH1D3 CILD36 Xq22.3 ODA+IDA PAFF [57]
DNAAF7/ZMYND10 CILD22 3p21.3 ODA+IDA ZARIWALA [58]
DNAAF11/LRRC6 CILD19 8q24 ODA+IDA ZARIWALA [58]
DNAAF13/SPAG1 CILD28 8q22 ODA+IDA KNOWLES [59]
DNAAF16/CFAP298 CILD26 21q22.1 ODA+IDA AUSTIN-TSE [60]
DNAAF17/C11ORF70/ CILD38 11q22.1 ODA+IDA HÖBEN [61]
CFAP300
HYDIN CILD5 16q22 Central pair OLBRICH [62]
SPEF2 Spermatogenic 5p13.2 Central pair CINDRIĆ [63]
failure 43
CFAP221 2q14.2 Central pair BUSTAMANTE-MARIN [64]
DNAJB13 CILD34 11q13.4 Central pair EL KHOURI [65]
RSPH1 CILD24 21q22.3 Radial spoke KOTT [66]
RSPH3 CILD32 6q25.3 Radial spoke JEANSON [67]
RSPH9 CILD12 6p21 Radial spoke CASTLEMAN [68]
RSPH4A CILD11 6q22 Radial spoke CASTLEMAN [68]
STK36 CILD46 2q35 Central pair EDELBUSCH [69]
CFAP74 CILD49 1p36.33 Central pair SHA [70], BIEBACH [71]
RSPH23/NME5 CILD48 5q31.2 Radial spoke CHO [72]
DRC1/CCDC164 CILD21 2p23 N-DRC WIRSCHELL [73]
DRC4/GAS8 CILD33 16q24.3 N-DRC OLBRICH [74]
DRC2/CCDC65 CILD27 12q13.12 N-DRC AUSTIN-TSE [59]
CCDC39 CILD14 3q26 N-DRC+IDA MERVEILLE [75]
CCDC40 CILD15 17q25 N-DRC+IDA BECKER-HECK [76]
CFAP57/WDR65 1p34.2 IDA BUSTAMANTE-MARIN [77]
DNAH1 CILD37 3p21.1 IDA IMTIAZ [78]
RPGR Xp21.1 Cilia transition zone MOORE [31]
OFD1 Xp22 Reduced generation of BUDNY [30]
multiple motile cilia
LRRC56 CILD39 11p15.5 Distal ODA BONNEFOY [79]
GAS2L2 CILD41 17q12 Cilia orientation BUSTAMANTE-MARIN [80]
Continued
https://doi.org/10.1183/2312508X.10017922 121
TABLE 2 Continued
Gene OMIM Locus Structural defect First author [ref.]
NEK10 CILD44 3p24.1 Cilia length AL MUTAIRI [81]

CCNO CILD29 5q11.2 Reduced generation of WALLMEIER [82]
MCIDAS CILD42 5q11.2 Reduced generation of BOON [83]
FOXJ1 CILD43 17q25.1 Reduced generation of WALLMEIER [84]
TP73 CILD47 1p36.32 Reduced generation of WALLMEIER [85]
MNS1 HTX9 15q21.3 Microtubule inner proteins TA-SHMA [86]
CFAP53/CCDC11 HTX6 18q21.1 Microtubule inner proteins NARASIMHAN [87]
CFAP106/ENKUR 10p12.1 Microtubule inner proteins SIGG [88]
CFAP45/CCDC19 1q23.2 Microtubule inner proteins DOUGHERTY [89]
CFAP52/WDR16 17p13.1 Microtubule inner proteins DOUGHERTY [89],
TA-SHMA [90]
OMIM: Online Mendelian Inheritance in Man designation; CILD: ciliary dyskinesia; ODA: outer dynein arm;
ODA DC: outer dynein arm docking complex; IDA: inner dynein arm; N-DRC: nexin–dynein regulatory complex;
HTX: heterotaxy.
Medical history
Family history
PCD is a hereditary disease group. The relationship of parents/grandparents (consanguinity),
situs abnormalities (situs inversus, heterotaxy), history of pulmonary or cardiac disease,
miscarriages, abortions or infertility in the family, or familial occurrence of “syndromal”
diseases may indicate a PCD diagnosis.
Individual medical history

PCD is a congenital condition. The main PCD features of the full-term newborn are neonatal
respiratory distress in >80% of cases and situs abnormalities [13, 14, 17–21]. Information on
daily cough, nasal congestion, recurrent bronchitis and/or pneumonia, ear, nose and throat
symptoms, medical interventions such as placement of a tympanostomy tube and/or sinus
surgery [103–106] or the need for hospitalisation for intravenous antibiotic administration are
relevant [6, 107–109]. However, it is important to note that mild clinical phenotypes of PCD
are also observed. In particular, PCD individuals with pathogenic variants in DNAH11, DNAH9
and RSPH1 can present with milder respiratory symptoms, such as productive wet cough and
obstructed nose only [57, 110, 111]. In addition, specific genetic variants can result in residual
protein function and, in consequence, a milder clinical phenotype [112]. Advanced age,
recurrent infections, a frequent need for antibiotics, frontal headache, hearing impairment and
fertility problems should be a focus of attention. Detection of Pseudomonas aeruginosa and
previous eradication attempts may indicate PCD. Previous diagnostic findings, especially
imaging data (radiography, CT, MRI, echocardiography) should be evaluated, focusing on
evidence of atelectasis, dystelectasis or bronchiectasis, sinusitis, nasal polyps, congenital cardiac
defects, other organ abnormalities and even hydrocephalus [6, 11].
Imaging diagnostics in PCD care

Lung imaging should be performed every 2–4 years. Native radiographs are sensitive enough to
detect atelectasis and infiltrates but not bronchiectasis. It is recommended that at least one
122 https://doi.org/10.1183/2312508X.10017922
cross-sectional imaging study, such as CT, is performed in individuals diagnosed with PCD.
Common CT findings include bronchiectasis of the lower lobes and/or destruction of the middle
lobe and/or lingula. Other features include pronounced mucus plugging (“tree in bud” sign),
dys- and atelectasis, especially postpartum and in the first years of life, and pneumonic
infiltrations during pulmonary exacerbations. MRI is a useful alternative [113, 114]. Follow-up
examinations, especially in children and adolescents, should be performed with MRI. However,
MRI still has disadvantages compared with CT, such as a longer examination time, confined
space and lower image resolution. MRI is recommended for the evaluation of upper respiratory
tract disorders such as recurrent infections/exacerbations of sinusitis with or without nasal
polyposis and, if necessary, for planning surgical intervention. At least one abdominal
ultrasound should be performed to assess possible situs abnormalities such as poly- or asplenia.
A ( paediatric) cardiology examination including echocardiography is recommended due to the
high prevalence of laterality defects and congenital cardiac defects [17–21].
Further diagnostics of the airways

In PCD, spirometry typically initially shows no abnormalities early in the course of the disease
obstruction, but later shows a mixed picture of obstruction and restriction due to chronic
mucopurulent destructive lung disease [115]. Regular measurements are recommended to
monitor disease progression. In PCD, there is usually no improvement in obstruction after
administration of bronchodilators [116–118]. However, if positive bronchospasmolysis can be
demonstrated, bronchodilators may be used. The gas washout method (multiple breath washout)
with determination of the lung clearance index is able to detect earlier changes in the small
airways by measuring the homogeneity of lung ventilation. Although multiple breath washout is
very time consuming and not now widely used [119–121], it has been shown to be more
sensitive than forced expiratory volume in 1 s (FEV1) in detecting lung disease in young
patients with PCD. Thus, the lung clearance index is suggested as a noninvasive diagnostic tool
for early diagnostic monitoring and also as a potential end-point in clinical trials [122, 123].
Bronchoscopy is not mandatory for confirming diagnosis, as sufficient ciliated epithelium can
easily be obtained by nasal brush biopsy. It is used in cases of atelectasis to assess and aid
bronchus obstruction. In rare cases, bronchoscopy including BAL can be helpful, for example to
detect a distinct pathogen in complicated pneumonia.
Diagnostic methods
Nasal nitrite oxide measurements
Measurement of nasal nitrite oxide (nNO) production rate is used because most PCD variants
result in significantly reduced levels compared with controls [124]. The commonly used cut-off
for nNO production rate is 77 nl·min−1 [124]. A recent study suggested raising the cut-off to
108 nl·min−1 because nNO production rates seem to be higher in PCD individuals with
normal ciliary ultrastructure [125]. The use of a chemiluminescence device is recommended
[97, 98, 101, 126, 127]. Valid reference data are available for nNO measurements in children
>5 years using a standardised protocol [126]. In younger children/infants who are unable to
perform the required exhalation manoeuvre, a valid method is still lacking [128, 129]. nNO
measurements are not diagnostic as a single test, as both normal nNO values in some PCD
patients and decreased nNO values in other diseases such as sinusitis, cystic fibrosis or nasal
polyps are observed [125, 130, 131].
High-speed videomicroscopy
High-speed videomicroscopy analysis (HVMA) of ciliary beat frequency (CBF) and ciliary beat
pattern (CBP) is currently part of the first-line diagnostic tools for PCD in most European
https://doi.org/10.1183/2312508X.10017922 123
expert centres [97]. However, some variants present with only subtle/no changes in CBF and/or
CBP [132]. In addition, there is a lack of standardisation on how to perform HVMA [133, 134].
Standard operation procedures are mandatory because secondary factors can influence CBF
[135, 136]. Respiratory epithelium can easily be obtained by nasal brush biopsy from the lower
turbinate using a moistened cytology brush. Bronchoscopy is only indicated in exceptional
cases. The material can subsequently be used for immunofluorescence (IF) microscopy, TEM or
air–liquid interface (ALI) cell culture to distinguish between primary (genetic origin) and
secondary (e.g. inflammation, drug treatment) causes of ciliary dyskinesia [137].
Electron microscopy
Classical TEM can reliably detect ODAs, combined ODAs/IDAs and tubular disorganisation
defects [33]. However, it cannot detect subtle abnormalities of ciliary ultrastructure, which are
present in ∼15–30% of PCD variants [138]. Three-dimensional electron tomography can
support diagnosis in rare cases [139]. However, it is time consuming, expensive and only
available in a very few centres, and is thus not suitable for a standardised diagnostic approach.
TEM also relies on the experience of the investigator, as secondary changes caused by
infection, medication or preparation artefacts may lead to misdiagnoses [97, 98, 140].
IF analysis
IF was initially developed to understand the molecular pathology of genetic PCD [141].
Compared with TEM, it is far less labour intensive and facilitates diagnosis of all hallmark PCD
variants (e.g. ODAs, ruler defects). IF also detects PCD variants with no or subtle abnormalities
in TEM (e.g. RS and CP tubule defects) (figure 2) [63, 142]. A specific combination of
antibodies allows the assessment of major ciliary complexes such as ODAs (e.g. DNAH5),
nexin–dynein regulatory complexes (e.g. GAS8), CP projection C1d (e.g. SPEF2) and RSs
(e.g. RSPH9) (figure 2) [63, 141, 142]. IF is also less susceptible to misinterpretation in case of
secondary changes in ciliary structure and function [143]. IF is also used to support genetic
findings, especially the interpretation of variants of unknown significance in order to assess the
functional impact, such as for HYDIN (figure 2) and DNAH11 [63, 144].
ALI culture
In ALI culture, respiratory cells are grown on a porous membrane that separates cells from the
underlying nutrient medium. This ALI culture creates an epithelial layer mimicking conditions
in human airways [132]. As these ALI cultures contain functional cilia, standard diagnostic
techniques such as HVMA, TEM and IF can be applied [145, 146]. Ciliary clearance capacity
can also be assessed [84].
Genetic analysis
So far, mutations in more than 50 genes are known to cause PCD. Knowledge on genetics,
clinical presentation, and functional and structural parameters (e.g. CBF, CBP, TEM, IF) is
needed to interpret the genetic data. Genetic analysis is performed by targeted-panel,
whole-exome or whole-genome sequencing. Depending on the population, in more than
two-thirds of all PCD cases, biallelic or in rare cases X-linked or dominant disease-causing
variants can be identified. This high diagnostic yield has led to genetic analysis moving from a
complementary method to the method of first choice in most settings [147]. Variants of
unknown significance are often identified, and clarification of pathogenicity requires
combination with other diagnostic methods, preferably functional studies showing deleterious
effects, such as the absence of distinct proteins or interaction partners in multicellular respiratory
epithelial cells by IF, absence of ciliary complexes by TEM or mRNA analysis to detect
splicing defects [148].
124 https://doi.org/10.1183/2312508X.10017922
a) DNAH5 GAS8 Merge DIC
Control
DNAH5 GAS8 Merge DIC
DNAH5 mutant
b) Ac. tub. RSPH9 Merge DIC
Control
Ac. tub. RSPH9 Merge DIC
RSPH9 mutant
c) Ac. tub. SPEF2 Merge DIC
Control
Ac. tub. SPEF2 Merge DIC
HYDIN mutant
https://doi.org/10.1183/2312508X.10017922 125
FIGURE 2 Immunofluorescence (IF) analysis in primary ciliary dyskinesia (PCD) diagnostics. Respiratory epithelial
cells from healthy control and PCD individuals harbouring biallelic disease-causing variants in DNAH5, RSPH9
and HYDIN, respectively, were co-stained with antibodies directed against a) DNAH5 (green) and GAS8 (red), b)
acetylated α-tubulin (Ac. tub., green) and RSPH9 (red), and c) acetylated α-tubulin (green) and SPEF2 (red).
Nuclei were stained with Hoechst 33342 (blue in the merged image). Whereas IF staining demonstrates
pan-axonemal localisation of proteins, no signal or a severely reduced signal is observed in the mutant PCD
individuals harbouring DNAH5, RSPH9 and HYDIN mutations. DIC: differential interference contrast image. Scale
bars: 10 μm.
Predictive tools for PCD

Due to the low availability of diagnostic methods in most centres almost a decade ago, simple
and widely available screening tools were developed to select patients requiring referral to
diagnostic centres: the clinical index [149, 150] and the more widely used PrImary CiliARy
DyskinesiA Rule (PICADAR) [151], and the North America criteria defined clinical features
(NA-CDCF) [152]. All predictive tools have an overlap in terms of the signs and symptoms
included in each individual predictive tool and have shown reasonable predictive power for
patients diagnosed with PCD [150]. However, the sensitivity and specificity of these tools should
be analysed in large cohorts to prevent exclusion of PCD patients from further diagnostics.
Treatment of PCD
There is currently no curative therapy for PCD. Evidence-based recommendations for
therapeutic care in PCD are scarce, as there are hardly any randomised controlled trials. Most
recommendations are based on the consensus of expert opinions, guided by treatment concepts
for other respiratory diseases such as cystic fibrosis, COPD and idiopathic bronchiectasis. The
focus is on symptomatic measures such as regular airway cleaning and treatment of recurrent
respiratory infections [3, 6]. To improve this situation, the ERN LUNG Clinical Trial Network
for Primary Ciliary Dyskinesia (PCD-CTN) was established in 2022 [153].
Lower airways
Inhalation
Cough clearance in PCD should be facilitated and not suppressed. Regular inhalation of
hypertonic saline (3–6%) for secretolysis is widely used. The efficacy of other mucus-reducing
drugs is unclear. Inhaled corticosteroids should be reconsidered, as they may increase
susceptibility to infection in PCD. Inhaled corticosteroids should only be recommended in cases
of additional evidence of bronchial asthma including T-helper 2 cell-mediated inflammation [154].
Antibiotic therapies
Recently, the first multicentre randomised controlled trial of the use of azithromycin for
immunomodulatory maintenance therapy showed a significant reduction in the exacerbation rate
in PCD patients [155]. Other long-term antibiotic therapies for PCD have not been adequately
evaluated and approved. Off-label use may be considered, especially if there have been frequent
exacerbations requiring antibiotics. Inhaled aminoglycosides or colistin can be used in patients
with bronchiectasis and (chronic) respiratory infection caused by P. aeruginosa [156].
Combination therapy with high-dose oral ciprofloxacin may be considered. Suppressive
antibiotic therapy against P. aeruginosa is also expected to be beneficial in PCD. The choice of
antibiotic therapy should be based on the microbiological results of prior sputum surveillance.
Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis and Streptococcus
pneumoniae are commonly found in the airways of PCD patients [3, 157]. In advanced lung
disease, P. aeruginosa or other Gram-negative organisms such as Klebsiella spp. are frequently
found [158]. For exacerbations that do not require hospitalisation, oral broad-spectrum
126 https://doi.org/10.1183/2312508X.10017922
antibiotics are often used [11]. I.v. antibiotic therapy may also be necessary. There is no
evidence that antibiotic eradication therapy or prophylactic treatment is indicated in the absence
of clinical symptoms of bronchopulmonary infection when bacteria are detected in the airways.
In the case of P. aeruginosa colonisation, many PCD centres recommend eradication therapy
according to established protocols analogous to cystic fibrosis, as chronic P. aeruginosa
infection can be expected to have similar negative effects on the clinical course of PCD patients
[159, 160].
Surgical interventions
Bronchiectasis can be associated with atelectasis, allergic bronchopulmonary aspergillosis,
chronic infection (especially with P. aeruginosa, nontuberculous mycobacteria or moulds),
recurrent pneumonia, cavitation, haemoptysis or pneumothorax. In most cases, these
complications can be managed with conservative therapeutic measures, and stabilisation of the
clinical condition and lung function can be achieved. Surgical lung interventions should
therefore only be performed in exceptional cases [161]. In cases of significant pulmonary
impairment, lung transplantation may be the last resort [162].
Upper airways
Secretolysis
The management of chronic rhinosinusitis in PCD patients is mainly conservative. Secretolysis
is often attempted by regular nasal rinsing or vibrating/pulsating (hypertonic) saline into the
sinuses to mobilise viscous secretions. Upper airway clearance techniques should be taught by
trained physiotherapists with experience of chronic purulent upper airway disease.
Anti-inflammatory treatment
Topical steroids are commonly used in patients with chronic rhinosinusitis, especially when nasal
polyps are present or to prevent recurrence after polyp removal. Whether steroid treatment
increases the risk of bacterial infection in PCD patients is not clear, but it should be considered,
especially in the case of systemic administration and chronic bacterial colonisation of the airways.
Antibiotic therapies
Treatment of acute rhinosinusitis is based on the general guidelines for acute and chronic
rhinosinusitis [163]. Selection of antibiotic therapy should be based on current microbiological
culture results. If unavailable, oral broad-spectrum antibiotics are often used. Local antibiotic
therapy as sinonasal inhalation may be useful in individual cases such as (chronic)
P. aeruginosa infection, especially if frequent sinonasal exacerbations are present or if
eradication is desired [6].
Tympanic drainage tubes and hearing aids

Insertion of a tympanic drain may improve hearing, but chronic purulent otorrhoea is often a
consequence, reducing the hearing improvement [6]. European guidelines tend to recommend
against the use of tympanostomy tubes, and follow a wait-and-see approach with hearing aids
prescribed as needed [97, 164]. The American recommendations instead advise the placement of
tympanic drainage tubes [11, 165]. In most cases, involvement of the middle ear decreases
spontaneously with increasing patient age. Therefore, the provision of hearing aids is a
straightforward solution that can be adapted to individual needs [103, 166].
Surgical intervention
Surgical interventions on the paranasal sinuses should be used very cautiously and on an
individual basis, for example in the case of pronounced obstructive polyposis and failure of
https://doi.org/10.1183/2312508X.10017922 127
conservative therapy [105]. Experience has shown that many PCD patients undergo multiple
surgeries if their symptoms do not improve. It seems sensible to perform regular secretion
drainage of the paranasal sinuses after surgery in order to prevent recurrence [167].
Fertility
In cases of infertility/subfertility, PCD individuals and their partners should be offered
counselling in a qualified fertility centre and human genetic counselling [26]. For male PCD
patients, assisted reproduction (in vitro fertilisation or intracytoplasmic sperm injection) can be
an option [8, 168, 169]. For female PCD patients, risk factors during pregnancy are a severely
impaired FEV1, low body mass index, and the presence of complications such as active allergic
bronchopulmonary aspergillosis or PH. The main problems are increased risk of preterm
delivery and bronchopulmonary exacerbations [170].
References
1 Storm van’s Gravesande K, Omran H. Primary ciliary dyskinesia: clinical presentation, diagnosis and genetics.
Ann Med 2005; 37: 439–449.
2 Legendre M, Zaragosi LE, Mitchison HM. Motile cilia and airway disease. Semin Cell Dev Biol 2021; 110: 19–33.
3 Mirra V, Werner C, Santamaria F. Primary ciliary dyskinesia: an update on clinical aspects, genetics, diagnosis,
and future treatment strategies. Front Pediatr 2017; 5: 135.
4 Hannah WB, Seifert BA, Truty R, et al. The global prevalence and ethnic heterogeneity of primary ciliary
dyskinesia gene variants: a genetic database analysis. Lancet Respir Med 2022; 10: 459–468.
5 Shah A, Laguna TA. Primary ciliary dyskinesia: a rare and often underdiagnosed disease. Pediatr Ann 2022; 51:
e82–e85.
6 Raidt J, Brillault J, Brinkmann F, et al. Management of primary ciliary dyskinesia. Pneumologie 2020; 74: 750–765.
7 Wallmeier J, Nielsen KG, Kuehni CE, et al. Motile ciliopathies. Nat Rev Dis Primers 2020; 6: 77.
8 Aprea I, Nöthe-Menchen T, Dougherty GW, et al. Motility of efferent duct cilia aids passage of sperm cells
through the male reproductive system. Mol Hum Reprod 2021; 27: gaab009.
9 Fliegauf M, Benzing T, Omran H. When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 2007; 8:
880–893.
10 Hyland RM, Brody SL. Impact of motile ciliopathies on human development and clinical consequences in the
newborn. Cells 2021; 11: 125.
11 Shapiro AJ, Zariwala MA, Ferkol T, et al. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD
foundation consensus recommendations based on state of the art review. Pediatr Pulmonol 2016; 51: 115–132.
12 Strippoli MPF, Frischer T, Barbato A, et al. Management of primary ciliary dyskinesia in European children:
recommendations and clinical practice. Eur Respir J 2012; 39: 1482–1491.
13 Mullowney T, Manson D, Kim R, et al. Primary ciliary dyskinesia and neonatal respiratory distress. Pediatrics
2014; 134: 1160–1166.
14 Fitzgerald DA, Shapiro AJ. When to suspect primary ciliary dyskinesia in children. Paediatr Respir Rev 2016; 18:
3–7.
15 Goutaki M, Meier AB, Halbeisen FS, et al. Clinical manifestations in primary ciliary dyskinesia: systematic
review and meta-analysis. Eur Respir J 2016; 48: 1081–1095.
16 Knowles MR, Daniels LA, Davis SD, et al. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics,
and characterization of clinical disease. Am J Respir Crit Care Med 2013; 188: 913–922.
17 Shapiro AJ, Davis SD, Ferkol T, et al. Laterality defects other than situs inversus totalis in primary ciliary
dyskinesia: insights into situs ambiguus and heterotaxy. Chest 2014; 146: 1176–1186.
18 Nakhleh N, Francis R, Giese RA, et al. High prevalence of respiratory ciliary dysfunction in congenital heart
disease patients with heterotaxy. Circulation 2012; 125: 2232–2242.
19 Kennedy MP, Omran H, Leigh MW, et al. Congenital heart disease and other heterotaxic defects in a large
cohort of patients with primary ciliary dyskinesia. Circulation 2007; 115: 2814–2821.
20 Nöthe-Menchen T, Wallmeier J, Pennekamp P, et al. Randomization of left-right asymmetry and congenital
heart defects: the role of DNAH5 in humans and mice. Circ Genom Precis Med 2019; 12: e002686..
21 Barber AT, Shapiro AJ, Davis SD, et al. Laterality defects in primary ciliary dyskinesia: relationship to
ultrastructural defect or genotype. Ann Am Thorac Soc 2022; 20: 397–405.
22 Bequignon E, Dupuy L, Zerah-Lancner F, et al. Critical evaluation of sinonasal disease in 64 adults with
primary ciliary dyskinesia. J Clin Med 2019; 8: 619.
128 https://doi.org/10.1183/2312508X.10017922
23 Plantier DB, Pilan RRM, Athanazio R, et al. Computed tomography evaluation of the paranasal sinuses in
adults with primary ciliary dyskinesia. Int Arch Otorhinolaryngol 2023; 27: e130–e137.
24 Dettmer S, Ringshausen F, Vogel-Claussen J, et al. Computed tomography in adult patients with primary
ciliary dyskinesia: typical imaging findings. PLoS One 2018; 13: e0191457.
25 Kennedy MP, Noone PG, Leigh MW, et al. High-resolution CT of patients with primary ciliary dyskinesia. AJR
Am J Roentgenol 2007; 188: 1232–1238.
26 Newman L, Chopra J, Dossett C, et al. The impact of primary ciliary dyskinesia on female and male fertility: a
narrative review. Hum Reprod Update 2023; 29: 347–367.
27 Jayasena CN, Sironen A. Diagnostics and management of male infertility in primary ciliary dyskinesia.
Diagnostics (Basel) 2021; 11: 1550.
28 Aprea I, Raidt J, Höben IM, et al. Defects in the cytoplasmic assembly of axonemal dynein arms cause
morphological abnormalities and dysmotility in sperm cells leading to male infertility. PLoS Genet 2021; 17:
e1009306.
29 Raidt J, Werner C, Menchen T, et al. Ciliary function and motor protein composition of human fallopian tubes.
Hum Reprod 2015; 30: 2871–2880.
30 Budny B, Chen W, Omran H, et al. A novel X-linked recessive mental retardation syndrome comprising
macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet 2006; 120:
171–178.
31 Moore A, Escudier E, Roger G, et al. RPGR is mutated in patients with a complex X linked phenotype
combining primary ciliary dyskinesia and retinitis pigmentosa. J Med Genet 2006; 43: 326–333.
32 Omran H, Olbrich H. Zilienkrankheiten unter besonderer Berücksichtigung der primären ziliären Dyskinesie.
[Ciliary diseases with particular attention to primary ciliary dyskinesia.] Medizinische Genetik 2010; 22: 315–321.
33 Shoemark A, Boon M, Brochhausen C, et al. International consensus guideline for reporting transmission
electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria). Eur Respir J
2020; 55: 1900725.
34 Shoemark A. Inner dynein arm defects in primary ciliary dyskinesia. J Genet Syndr Gene Ther 2013; 4: 7.
35 Olbrich H, Häffner K, Kispert A, et al. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization
of left–right asymmetry. Nat Genet 2002; 30: 143–144.
36 Schwabe GC, Hoffmann K, Loges NT, et al. Primary ciliary dyskinesia associated with normal axoneme
ultrastructure is caused by DNAH11 mutations. Hum Mutat 2008; 29: 289–298.
37 Loges NT, Antony D, Maver A, et al. Recessive DNAH9 loss-of-function mutations cause laterality defects and
subtle respiratory ciliary-beating defects. Am J Hum Genet 2018; 103: 995–1008.
38 Fassad MR, Shoemark A, Legendre M, et al. Mutations in outer dynein arm heavy chain DNAH9 cause motile
cilia defects and situs inversus. Am J Hum Genet 2018; 103: 984–994.
39 Pennarun G, Escudier E, Chapelin C, et al. Loss-of-function mutations in a human gene related to
Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet 1999; 65: 1508–1519.
40 Loges NT, Olbrich H, Fenske L, et al. DNAI2 mutations cause primary ciliary dyskinesia with defects in the
outer dynein arm. Am J Hum Genet 2008; 83: 547–558.
41 Duriez B, Duquesnoy P, Escudier E, et al. A common variant in combination with a nonsense mutation in a
member of the thioredoxin family causes primary ciliary dyskinesia. Proc Natl Acad Sci USA 2007; 104: 3336–3341.
42 Horváth J, Fliegauf M, Olbrich H, et al. Identification and analysis of axonemal dynein light chain 1 in primary
ciliary dyskinesia patients. Am J Respir Cell Mol Biol 2005; 33: 41–47.
43 Panizzi JR, Becker-Heck A, Castleman VH, et al. CCDC103 mutations cause primary ciliary dyskinesia by
disrupting assembly of ciliary dynein arms. Nat Genet 2012; 44: 714–719.
44 Onoufriadis A, Paff T, Antony D, et al. Splice-site mutations in the axonemal outer dynein arm docking
complex gene CCDC114 cause primary ciliary dyskinesia. Am J Hum Genet 2013; 92: 88–98.
45 Hjeij R, Lindstrand A, Francis R, et al. ARMC4 mutations cause primary ciliary dyskinesia with randomization of
left/right body asymmetry. Am J Hum Genet 2013; 93: 357–367.
46 Hjeij R, Onoufriadis A, Watson CM, et al. CCDC151 mutations cause primary ciliary dyskinesia by disruption of
the outer dynein arm docking complex formation. Am J Hum Genet 2014; 95: 257–274.
47 Wallmeier J, Shiratori H, Dougherty GW, et al. TTC25 deficiency results in defects of the outer dynein arm
docking machinery and primary ciliary dyskinesia with left–right body asymmetry randomization. Am J Hum
Genet 2016; 99: 460–469.
48 Hjeij R, Aprea I, Poeta M, et al. Pathogenic variants in CLXN encoding the outer dynein arm docking
associated calcium-binding protein calaxin cause primary ciliary dyskinesia. Genet Med 2023; 25: 100798.
49 Leslie JS, Hjeij R, Vivante A, et al. Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality
defects and subtle ciliary beating abnormalities. Genet Med 2022; 24: 2249–2261.
50 Thomas L, Bouhouche K, Whitfield M, et al. TTC12 loss-of-function mutations cause primary ciliary dyskinesia
and unveil distinct dynein assembly mechanisms in motile cilia versus flagella. Am J Hum Genet 2020; 106:
153–169.
https://doi.org/10.1183/2312508X.10017922 129
51 Loges NT, Olbrich H, Becker-Heck A, et al. Deletions and point mutations of LRRC50 cause primary ciliary
dyskinesia due to dynein arm defects. Am J Hum Genet 2009; 85: 883–889.
52 Duquesnoy P, Escudier E, Vincensini L, et al. Loss-of-function mutations in the human ortholog of
Chlamydomonas reinhardtii ODA7 disrupt dynein arm assembly and cause primary ciliary dyskinesia. Am J
Hum Genet 2009; 85: 890–896.
53 Omran H, Kobayashi D, Olbrich H, et al. Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal
dyneins. Nature 2008; 456: 611–616.
54 Mitchison HM, Schmidts M, Loges NT, et al. Mutations in axonemal dynein assembly factor DNAAF3 cause
primary ciliary dyskinesia. Nat Genet 2012; 44: 381–389.
55 Tarkar A, Loges NT, Slagle CE, et al. DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat
Genet 2013; 45: 995–1003.
56 Horani A, Druley TE, Zariwala MA, et al. Whole-exome capture and sequencing identifies HEATR2 mutation as a
cause of primary ciliary dyskinesia. Am J Hum Genet 2012; 91: 685–693.
57 Paff T, Loges NT, Aprea I, et al. Mutations in PIH1D3 cause X-linked primary ciliary dyskinesia with outer and
inner dynein arm defects. Am J Hum Genet 2017; 100: 160–168.
58 Zariwala MA, Gee HY, Kurkowiak M, et al. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with
LRRC6. Am J Hum Genet 2013; 93: 336–345.
59 Knowles MR, Ostrowski LE, Loges NT, et al. Mutations in SPAG1 cause primary ciliary dyskinesia associated
with defective outer and inner dynein arms. Am J Hum Genet 2013; 93: 711–720.
60 Austin-Tse C, Halbritter J, Zariwala MA, et al. Zebrafish ciliopathy screen plus human mutational analysis
identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia. Am J Hum Genet 2013; 93: 672–686.
61 Höben IM, Hjeij R, Olbrich H, et al. Mutations in C11orf70 cause primary ciliary dyskinesia with randomization of
left/right body asymmetry due to defects of outer and inner dynein arms. Am J Hum Genet 2018; 102: 973–984.
62 Olbrich H, Schmidts M, Werner C, et al. Recessive HYDIN mutations cause primary ciliary dyskinesia without
randomization of left–right body asymmetry. Am J Hum Genet 2012; 91: 672–684.
63 Cindrić S, Dougherty GW, Olbrich H, et al. SPEF2- and HYDIN-mutant cilia lack the central pair-associated
protein SPEF2, aiding primary ciliary dyskinesia diagnostics. Am J Respir Cell Mol Biol 2020; 62: 382–396.
64 Bustamante-Marin XM, Shapiro A, Sears PR, et al. Identification of genetic variants in CFAP221 as a cause of
primary ciliary dyskinesia. J Hum Genet 2020; 65: 175–180.
65 El Khouri E, Thomas L, Jeanson L, et al. Mutations in DNAJB13, encoding an HSP40 family member, cause
primary ciliary dyskinesia and male infertility. Am J Hum Genet 2016; 99: 489–500.
66 Kott E, Legendre M, Copin B, et al. Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with
central-complex and radial-spoke defects. Am J Hum Genet 2013; 93: 561–570.
67 Jeanson L, Copin B, Papon JF, et al. RSPH3 mutations cause primary ciliary dyskinesia with central-complex
defects and a near absence of radial spokes. Am J Hum Genet 2015; 97: 153–162.
68 Castleman VH, Romio L, Chodhari R, et al. Mutations in radial spoke head protein genes RSPH9 and RSPH4A
cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. Am J Hum Genet 2009; 84: 197–209.
69 Edelbusch C, Cindrić S, Dougherty GW, et al. Mutation of serine/threonine protein kinase 36 (STK36) causes
primary ciliary dyskinesia with a central pair defect. Hum Mutat 2017; 38: 964–969.
70 Sha Y, Wei X, Ding L, et al. Biallelic mutations of CFAP74 may cause human primary ciliary dyskinesia and
MMAF phenotype. J Hum Genet 2020; 65: 961–969.
71 Biebach L, Cindrić S, Koenig J, et al. Recessive mutations in CFAP74 cause primary ciliary dyskinesia with
normal ciliary ultrastructure. Am J Respir Cell Mol Biol 2022; 67: 409–413.
72 Cho EH, Huh HJ, Jeong I, et al. A nonsense variant in NME5 causes human primary ciliary dyskinesia with
radial spoke defects. Clin Genet 2020; 98: 64–68.
73 Wirschell M, Olbrich H, Werner C, et al. The nexin–dynein regulatory complex subunit DRC1 is essential for
motile cilia function in algae and humans. Nat Genet 2013; 45: 262–268.
74 Olbrich H, Cremers C, Loges NT, et al. Loss-of-function GAS8 mutations cause primary ciliary dyskinesia and
disrupt the nexin-dynein regulatory complex. Am J Hum Genet 2015; 97: 546–554.
75 Merveille AC, Davis EE, Becker-Heck A, et al. CCDC39 is required for assembly of inner dynein arms and the
dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet 2011; 43: 72–78.
76 Becker-Heck A, Zohn IE, Okabe N, et al. The coiled-coil domain containing protein CCDC40 is essential for
motile cilia function and left–right axis formation. Nat Genet 2011; 43: 79–84.
77 Bustamante-Marin XM, Horani A, Stoyanova M, et al. Mutation of CFAP57, a protein required for the
asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia.
PLoS Genet 2020; 16: e1008691.
78 Imtiaz F, Allam R, Ramzan K, et al. Variation in DNAH1 may contribute to primary ciliary dyskinesia. BMC Med
Genet 2015; 16: 14.
79 Bonnefoy S, Watson CM, Kernohan KD, et al. Biallelic mutations in LRRC56, encoding a protein associated with
intraflagellar transport, cause mucociliary clearance and laterality defects. Am J Hum Genet 2018; 103: 727–739.
130 https://doi.org/10.1183/2312508X.10017922
80 Bustamante-Marin XM, Yin WN, Sears PR, et al. Lack of GAS2L2 causes PCD by impairing cilia orientation and
mucociliary clearance. Am J Hum Genet 2019; 104: 229–245.
81 Al Mutairi F, Alkhalaf R, Alkhorayyef A, et al. Homozygous truncating NEK10 mutation, associated with primary
ciliary dyskinesia: a case report. BMC Pulm Med 2020; 20: 141.
82 Wallmeier J, Al-Mutairi DA, Chen CT, et al. Mutations in CCNO result in congenital mucociliary clearance
disorder with reduced generation of multiple motile cilia. Nat Genet 2014; 46: 646–651.
83 Boon M, Wallmeier J, Ma L, et al. MCIDAS mutations result in a mucociliary clearance disorder with reduced
generation of multiple motile cilia. Nat Commun 2014; 5: 4418.
84 Wallmeier J, Frank D, Shoemark A, et al. De novo mutations in FOXJ1 result in a motile ciliopathy with
hydrocephalus and randomization of left/right body asymmetry. Am J Hum Genet 2019; 105: 1030–1039.
85 Wallmeier J, Bracht D, Alsaif HS, et al. Mutations in TP73 cause impaired mucociliary clearance and
lissencephaly. Am J Hum Genet 2021; 108: 1318–1329.
86 Ta-Shma A, Hjeij R, Perles Z, et al. Homozygous loss-of-function mutations in MNS1 cause laterality defects
and likely male infertility. PLoS Genet 2018; 14: e1007602.
87 Narasimhan V, Hjeij R, Vij S, et al. Mutations in CCDC11, which encodes a coiled-coil containing ciliary protein,
causes situs inversus due to dysmotility of monocilia in the left–right organizer. Hum Mutat 2015; 36: 307–318.
88 Sigg MA, Menchen T, Lee C, et al. Evolutionary proteomics uncovers ancient associations of cilia with signaling
pathways. Dev Cell 2017; 43: 744–762.e11.
89 Dougherty GW, Mizuno K, Nöthe-Menchen T, et al. CFAP45 deficiency causes situs abnormalities and
asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module. Nat Commun 2020;
11: 5520.
90 Ta-Shma A, Perles Z, Yaacov B, et al. A human laterality disorder associated with a homozygous WDR16
deletion. Eur J Hum Genet 2015; 23: 1262–1265.
91 Zariwala MA, Knowles MR, Leigh MW. Primary ciliary dyskinesia. In: GeneReviews. Seattle, University of
Washington, 1993.
92 Leigh MW, Horani A, Kinghorn B, et al. Primary ciliary dyskinesia (PCD): a genetic disorder of motile cilia.
Transl Sci Rare Dis 2019; 4: 51–75.
93 Olcese C, Patel MP, Shoemark A, et al. X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic
axonemal dynein assembly factor PIH1D3. Nat Commun 2017; 8: 14279.
94 Fassad MR, Patel MP, Shoemark A, et al. Clinical utility of NGS diagnosis and disease stratification in a
multiethnic primary ciliary dyskinesia cohort. J Med Genet 2020; 57: 322–330.
95 Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in
141,456 humans. Nature 2020; 581: 434–443.
96 Kuehni CE, Frischer T, Strippoli MPF, et al. Factors influencing age at diagnosis of primary ciliary dyskinesia in
European children. Eur Respir J 2010; 36: 1248–1258.
98 Shapiro AJ, Davis SD, Polineni D, et al. Diagnosis of primary ciliary dyskinesia. An official American Thoracic
Society Clinical Practice Guideline. Am J Respir Crit Care Med 2018; 197: e24–e39.
99 Lucas JS, Davis SD, Omran H, et al. Primary ciliary dyskinesia in the genomics age. Lancet Respir Med 2020; 8:
202–216.
100 Halbeisen FS, Shoemark A, Barbato A, et al. Time trends in diagnostic testing for primary ciliary dyskinesia in
Europe. Eur Respir J 2019; 54: 1900528.
101 Shoemark A, Dell S, Shapiro A, et al. ERS and ATS diagnostic guidelines for primary ciliary dyskinesia:
similarities and differences in approach to diagnosis. Eur Respir J 2019; 54: 1901066.
102 Rumman N, Jackson C, Collins S, et al. Diagnosis of primary ciliary dyskinesia: potential options for
resource-limited countries. Eur Respir Rev 2017; 26: 160058.
103 Majithia A, Fong J, Hariri M, et al. Hearing outcomes in children with primary ciliary dyskinesia – a
longitudinal study. Int J Pediatr Otorhinolaryngol 2005; 69: 1061–1064.
104 Prulière-Escabasse V, Coste A, Chauvin P, et al. Otologic features in children with primary ciliary dyskinesia.
Arch Otolaryngol Head Neck Surg 2010; 136: 1121–1126.
105 Sommer JU, Schäfer K, Omran H, et al. ENT manifestations in patients with primary ciliary dyskinesia: prevalence
and significance of otorhinolaryngologic co-morbidities. Eur Arch Otorhinolaryngol 2011; 268: 383–388.
106 Kreicher KL, Schopper HK, Naik AN, et al. Hearing loss in children with primary ciliary dyskinesia. Int J Pediatr
Otorhinolaryngol 2018; 104: 161–165.
107 Polineni D, Davis SD, Dell SD. Treatment recommendations in primary ciliary dyskinesia. Paediatr Respir Rev
2016; 18: 39–45.
108 Lucas JS, Alanin MC, Collins S, et al. Clinical care of children with primary ciliary dyskinesia. Expert Rev Respir
Med 2017; 11: 779–790.
https://doi.org/10.1183/2312508X.10017922 131
109 Marthin JK, Lucas JS, Boon M, et al. International BEAT-PCD consensus statement for infection prevention and
control for primary ciliary dyskinesia in collaboration with ERN-LUNG PCD Core Network and patient
representatives. ERJ Open Res 2021; 7: 00301-2021.
110 Knowles MR, Leigh MW, Carson JL, et al. Mutations of DNAH11 in patients with primary ciliary dyskinesia with
normal ciliary ultrastructure. Thorax 2012; 67: 433–441.
111 Knowles MR, Ostrowski LE, Leigh MW, et al. Mutations in RSPH1 cause primary ciliary dyskinesia with a unique
clinical and ciliary phenotype. Am J Respir Crit Care Med 2014; 189: 707–717.
112 Ostrowski LE, Yin W, Smith AJ, et al. Expression of a truncated form of ODAD1 associated with an unusually
mild primary ciliary dyskinesia phenotype. Int J Mol Sci 2022; 23: 1753.
113 Nyilas S, Bauman G, Sommer G, et al. Novel magnetic resonance technique for functional imaging of cystic
fibrosis lung disease. Eur Respir J 2017; 50: 1701464.
114 Nyilas S, Bauman G, Pusterla O, et al. Structural and functional lung impairment in primary ciliary dyskinesia.
Assessment with magnetic resonance imaging and multiple breath washout in comparison to spirometry. Ann
Am Thorac Soc 2018; 15: 1434–1442.
115 Halbeisen FS, Pedersen ESL, Goutaki M, et al. Lung function from school age to adulthood in primary ciliary
dyskinesia. Eur Respir J 2022; 60: 2101918.
116 Phillips GE, Thomas S, Heather S, et al. Airway response of children with primary ciliary dyskinesia to exercise
and β2-agonist challenge. Eur Respir J 1998; 11: 1389–1391.
117 Koh YY, Park Y, Jeong JH, et al. The effect of regular salbutamol on lung function and bronchial
responsiveness in patients with primary ciliary dyskinesia. Chest 2000; 117: 427–433.
118 Levine H, Bar-On O, Nir V, et al. Reversible bronchial obstruction in primary ciliary dyskinesia. J Clin Med 2022;
11: 6791.
119 Green K, Buchvald FF, Marthin JK, et al. Ventilation inhomogeneity in children with primary ciliary dyskinesia.
Thorax 2012; 67: 49–53.
120 Irving SJ, Ives A, Davies G, et al. Lung clearance index and high-resolution computed tomography scores in
primary ciliary dyskinesia. Am J Respir Crit Care Med 2013; 188: 545–549.
121 Boon M, Vermeulen FL, Gysemans W, et al. Lung structure–function correlation in patients with primary ciliary
dyskinesia. Thorax 2015; 70: 339–345.
122 Kinghorn B, McNamara S, Genatossio A, et al. Comparison of multiple breath washout and spirometry in children
with primary ciliary dyskinesia and cystic fibrosis and healthy controls. Ann Am Thorac Soc 2020; 17: 1085–1093.
123 Roehmel JF, Doerfler FJ, Koerner-Rettberg C, et al. Comparison of the lung clearance index in preschool
children with primary ciliary dyskinesia and cystic fibrosis. Chest 2022; 162: 534–542.
124 Leigh MW, Hazucha MJ, Chawla KK, et al. Standardizing nasal nitric oxide measurement as a test for primary
ciliary dyskinesia. Ann Am Thorac Soc 2013; 10: 574–581.
125 Raidt J, Krenz H, Tebbe J, et al. Limitations of nasal nitric oxide measurement for diagnosis of primary ciliary
dyskinesia with normal ultrastructure. Ann Am Thorac Soc 2022; 19: 1275–1284.
126 Shapiro AJ, Dell SD, Gaston B, et al. Nasal nitric oxide measurement in primary ciliary dyskinesia. A technical
paper on standardized testing protocols. Ann Am Thorac Soc 2020; 17: e1–e12.
127 Beydon N, Kouis P, Marthin JK, et al. Nasal nitric oxide measurement in children for the diagnosis of primary
ciliary dyskinesia: European Respiratory Society technical standard. Eur Respir J 2023; 61: 2202031.
128 Beydon N, Tamalet A, Escudier E, et al. Breath-holding and tidal breathing nasal NO to screen children for
primary ciliary dyskinesia. Pediatr Pulmonol 2021; 56: 2242–2249.
129 Buechel F, Usemann J, Aline A, et al. Feasibility of nasal NO screening in healthy newborns. Pediatr Pulmonol
2022; 57: 231–238.
130 Legendre M, Thouvenin G, Taytard J, et al. High nasal nitric oxide, cilia analyses, and genotypes in a
retrospective cohort of children with primary ciliary dyskinesia. Ann Am Thorac Soc 2022; 19: 1704–1712.
131 Shapiro AJ, Davis SD, Leigh MW, et al. Limitations of nasal nitric oxide testing in primary ciliary dyskinesia. Am
132 Raidt J, Wallmeier J, Hjeij R, et al. Ciliary beat pattern and frequency in genetic variants of primary ciliary
dyskinesia. Eur Respir J 2014; 44: 1579–1588.
133 Bricmont N, Alexandru M, Louis B, et al. Ciliary videomicroscopy: a long beat from the European Respiratory
Society guidelines to the recognition as a confirmatory test for primary ciliary dyskinesia. Diagnostics (Basel)
2021; 11: 1700.
134 Kempeneers C, Seaton C, Garcia Espinosa B, et al. Ciliary functional analysis: beating a path towards
standardization. Pediatr Pulmonol 2019; 54: 1627–1638.
135 Nikolaizik W, Hahn J, Bauck M, et al. Comparison of ciliary beat frequencies at different temperatures in
young adults. ERJ Open Res 2020; 6: 00477-2020.
136 Reula A, Pitarch-Fabregat J, Milara J, et al. High-speed video microscopy for primary ciliary dyskinesia
diagnosis: a study of ciliary motility variations with time and temperature. Diagnostics (Basel) 2021; 11: 1301.
132 https://doi.org/10.1183/2312508X.10017922
137 Bonhiver R, Bricmont N, Pirotte M, et al. Ciliary dyskinesia might be secondary to chronic inflammation in
cystic fibrosis. Rev Maladies Respir 2023; 40: 137.
138 Shoemark A, Burgoyne T, Kwan R, et al. Use of electron tomography to confirm the diagnosis of primary
ciliary dyskinesia. Paediatr Respir Epidemiol 2017; 50: PA1854.
139 Shoemark A, Burgoyne T, Kwan R, et al. Primary ciliary dyskinesia with normal ultrastructure:
three-dimensional tomography detects absence of DNAH11. Eur Respir J 2018; 51: 1701809.
140 Shapiro AJ, Leigh MW. Value of transmission electron microscopy for primary ciliary dyskinesia diagnosis in
the era of molecular medicine: genetic defects with normal and non-diagnostic ciliary ultrastructure.
Ultrastruct Pathol 2017; 41: 373–385.
141 Omran H, Loges NT. Immunofluorescence staining of ciliated respiratory epithelial cells. Methods Cell Biol
2009; 91: 123–133.
142 Frommer A, Hjeij R, Loges NT, et al. Immunofluorescence analysis and diagnosis of primary ciliary dyskinesia
with radial spoke defects. Am J Respir Cell Mol Biol 2015; 53: 563–573.
143 Olbrich H, Horváth J, Fekete A, et al. Axonemal localization of the dynein component DNAH5 is not altered in
secondary ciliary dyskinesia. Pediatr Res 2006; 59: 418–422.
144 Dougherty GW, Loges NT, Klinkenbusch JA, et al. DNAH11 localization in the proximal region of respiratory
cilia defines distinct outer dynein arm complexes. Am J Respir Cell Mol Biol 2016; 55: 213–224.
145 Hirst RA, Jackson CL, Coles JL, et al. Culture of primary ciliary dyskinesia epithelial cells at air–liquid interface
can alter ciliary phenotype but remains a robust and informative diagnostic aid. PLoS One 2014; 9: e89675.
146 Coles JL, Thompson J, Horton KL, et al. A revised protocol for culture of airway epithelial cells as a diagnostic
tool for primary ciliary dyskinesia. J Clin Med 2020; 9: 3753.
147 O’Connor MG, Horani A, Shapiro AJ. Progress in diagnosing primary ciliary dyskinesia: the North American
perspective. Diagnostics (Basel) 2021; 11: 1278.
148 Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint
consensus recommendation of the American College of Medical Genetics and Genomics and the Association
for Molecular Pathology. Genet Med 2015; 17: 405–424.
149 Martinů V, Bořek-Dohalská L, Varényiová Ž, et al. Evaluation of a clinical index as a predictive tool for primary
ciliary dyskinesia. Diagnostics (Basel) 2021; 11: 1088.
150 Djakow J, Rozehnalova E, Havlisova M, et al. Clinical index to evaluate the risk of primary ciliary dyskinesia in
children. Eur Respir J 2012; 40: 2844.
151 Behan L, Dimitrov BD, Kuehni CE, et al. PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia.
Eur Respir J 2016; 47: 1103–1112.
152 Leigh MW, Ferkol TW, Davis SD, et al. Clinical features and associated likelihood of primary ciliary dyskinesia in
children and adolescents. Ann Am Thorac Soc 2016; 13: 1305–1313.
153 Raidt J, Maitre B, Pennekamp P, et al. The disease-specific clinical trial network for primary ciliary dyskinesia:
PCD-CTN. ERJ Open Res 2022; 8: 00139-2022.
154 Dehlink E, Richardson C, Marsh G, et al. Are inhaled corticosteroids prescribed rationally in primary ciliary
dyskinesia? Eur Respir J 2018; 51: 1702221.
155 Kobbernagel HE, Buchvald FF, Haarman EG, et al. Efficacy and safety of azithromycin maintenance therapy in
primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3
156 Chang AB, Fortescue R, Grimwood K, et al. European Respiratory Society guidelines for the management of
children and adolescents with bronchiectasis. Eur Respir J 2021; 58: 2002990.
157 Rogers GB, Carroll MP, Zain NMM, et al. Complexity, temporal stability, and clinical correlates of airway
bacterial community composition in primary ciliary dyskinesia. J Clin Microbiol 2013; 51: 4029–4035.
158 Alanin MC, Nielsen KG, von Buchwald C, et al. A longitudinal study of lung bacterial pathogens in patients
with primary ciliary dyskinesia. Clin Microbiol Infect 2015; 21: 1093.e7.
159 Cohen-Cymberknoh M, Weigert N, Gileles-Hillel A, et al. Clinical impact of Pseudomonas aeruginosa
colonization in patients with primary ciliary dyskinesia. Respir Med 2017; 131: 241–246.
160 Maglione M, Bush A, Nielsen KG, et al. Multicenter analysis of body mass index, lung function, and sputum
microbiology in primary ciliary dyskinesia. Pediatr Pulmonol 2014; 49: 1243–1250.
161 Kouis P, Goutaki M, Halbeisen FS, et al. Prevalence and course of disease after lung resection in primary
ciliary dyskinesia: a cohort & nested case–control study. Respir Res 2019; 20: 212.
162 Hayes D, Reynolds SD, Tumin D. Outcomes of lung transplantation for primary ciliary dyskinesia and
Kartagener syndrome. J Heart Lung Transplant 2016; 35: 1377–1378.
163 Fokkens WJ, Lund VJ, Hopkins C, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020.
Rhinology 2020; 58: 1–464.
164 Barbato A, Frischer T, Kuehni CE, et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and
treatment approaches in children. Eur Respir J 2009; 34: 1264–1276.
https://doi.org/10.1183/2312508X.10017922 133
165 Mener DJ, Lin SY, Ishman SL, et al. Treatment and outcomes of chronic rhinosinusitis in children with
primary ciliary dyskinesia: where is the evidence? A qualitative systematic review. Int Forum Allergy Rhinol
2013; 3: 986–991.
166 Campbell R. Managing upper respiratory tract complications of primary ciliary dyskinesia in children. Curr Opin
Allergy Clin Immunol 2012; 12: 32–38.
167 Raidt J, Werner C. Chronic rhinosinusitis in non-cystic fibrosis bronchiectasis and primary ciliary dyskinesia. In:
Bachert C, Bals R, Bourdin A, et al., eds. The Nose and Sinuses in Respiratory Disorders. Sheffield, European
168 McLachlan RI, Ishikawa T, Osianlis T, et al. Normal live birth after testicular sperm extraction and
intracytoplasmic sperm injection in variant primary ciliary dyskinesia with completely immotile sperm and
structurally abnormal sperm tails. Fertil Steril 2012; 97: 313–318.
169 Wu H, Wang J, Cheng H, et al. Patients with severe asthenoteratospermia carrying SPAG6 or RSPH3 mutations
have a positive pregnancy outcome following intracytoplasmic sperm injection. J Assist Reprod Genet 2020; 37:
829–840.
170 Zhang X, Chen D, You Y, et al. Successful pregnancy in patient with Kartagener’s syndrome and infertility: case
report and published work review. Clin Exp Obstet Gynecol. 2018; 45: 791–793.
Disclosures: P. Pennekamp reports receiving grants or contracts from Ethris GmbH, outside the submitted
work. J. Raidt reports receiving support for the present manuscript from RA 3522/1 (CRU326). K. Wohlgemuth has
nothing to disclose. H. Olbrich reports receiving support for the present manuscript from OL450/3-1; DFG. H. Omran
reports receiving the following, outside the submitted work: grants from the Deutsche Forschungsgemeinschaft; and
consulting fees from Ethris GmbH and ReCode Therapeutics. H. Omran is a member of the medical advisory boards
of US PCD Foundation, and Kartagener Syndrom und Primäre Ciliäre Dyskinesie e.V.
Support statement: Work in the laboratory of H. Omran was funded by the Deutsche Forschungsgemeinschaft
(DFG; OM6/7, -8, -10, -11 (CRU326), -14, -16; RA 3522/1 (CRU326), OL450/3), Interdisziplinaeres Zentrum für
Klinische Forschung Muenster (IZKF; Om2/009/12, Om2/015/16, OM2/010/20), Care-for-Rare Foundation, Eva Luise
und Horst Köhler Stiftung, BESTCILIA (EU FP7, grant agreement no. 305404) and REGISTRY WAREHOUSE
(EU HORIZON2020, grant agreement no. 777295).
Acknowledgements: We thank the patients and their families, the Kartagener Syndrom und Primäre Ciliäre
Dyskinesie e.V. and the US PCD Foundation for their continuous support and collaboration.
134 https://doi.org/10.1183/2312508X.10017922
Chapter 10
Cystic fibrosis and other ion channel-related

diseases
1,2,3 1,2,3
Simon Y. Graeber and Marcus A. Mall
1
Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center,
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu
Berlin, Berlin, Germany. 2German Center for Lung Research (DZL), associated partner site, Berlin, Germany. 3Berlin
Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.
Corresponding author: Marcus A. Mall (marcus.mall@charite.de)
Cite as: Graeber SY, Mall MA. Cystic fibrosis and other ion channel-related diseases. In: Wagner TOF, Humbert M,
@ERSpublications
CF remains the most common fatal genetic lung disease worldwide, but new CFTR-directed therapies
provide substantial clinical improvement. Beyond CF, CFTR and other ion channels may be implicated in
other muco-obstructive lung diseases, including COPD. https://bit.ly/ERSM100
ISSN: 2312-5098.
Cystic fibrosis (CF) is the most common severe genetic disorder in Caucasian populations and is caused
by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes
an epithelial chloride channel. Although CF is a multisystem disease affecting many epithelial organs
including the lungs, pancreas and intestine, chronic lung disease remains the major cause of morbidity
and mortality. In the airways, CFTR dysfunction results in reduced airway surface liquid and impaired
mucociliary clearance leading to muco-obstructive lung disease. Recently developed CFTR modulators
restore CFTR function effectively in up to 90% of patients with the common F508del-CFTR mutation.
Mutation-agnostic approaches such as gene therapy or targeting of alternative ion channels involved in
airway surface hydration are currently under investigation. Beyond CF, other ion channels may be
implicated in the pathogenesis of chronic airways disease and emerging evidence suggests a role of
acquired CFTR dysfunction in COPD, suggesting that therapies developed for CF may also be
beneficial for a spectrum of other muco-obstructive lung diseases.
Introduction
Cystic fibrosis (CF) remains the most common fatal genetic lung disease worldwide. Although
it is a monogenetic disease caused by mutations in the cystic fibrosis transmembrane
conductance regulator (CFTR) gene, there is a large heterogeneity in the clinical manifestation
across patients with CF. In this chapter we discuss the pathophysiology of CF lung disease as
well as the clinical presentation and diagnostics of CF. Furthermore, we highlight the advances
in novel therapeutic options and discuss the potential role of acquired CFTR dysfunction and
other ion channels in other muco-obstructive lung diseases.
Pathophysiology of CF lung disease

CF is an autosomal recessive multisystem disease caused by mutations in the CFTR gene
located on chromosome 7 [1, 2]. CFTR is a cAMP-dependent epithelial anion channel
https://doi.org/10.1183/2312508X.10018022 135
responsible for the transport of chloride and bicarbonate and is expressed at the apical
membrane of epithelial cells lining the surface and submucosal glands of the conducting
airways, as well as the lumens of the gastrointestinal and biliary tracts, pancreatic duct, sweat
duct, and some other epithelial and nonepithelial tissues. Besides chronic progressive lung
disease, the majority of CF patients (80–90%) suffer from exocrine pancreatic insufficiency,
mostly already present at birth, which is often the first clinical symptom of the disease.
Although CF is a multi-organ disorder, the lung disease remains responsible for the majority of
morbidity and mortality [2]. In the airways, CFTR plays a key role in anion (chloride and
bicarbonate) and fluid secretion across the epithelium, and thereby in the regulation of the
airway surface liquid volume and pH, which are essential for proper mucus function and
mucociliary clearance (MCC), constituting the primary innate defence mechanism that protects
the lungs from inhaled pathogens, allergens and irritants (figure 1a) [3–7]. In health, the balance
between ion/fluid secretion via CFTR and alternative chloride channels, and absorption via the
amiloride-sensitive epithelial sodium channel (ENaC) facilitates proper mucus hydration to
ensure MCC (figure 1a), whereas the imbalance of these processes leads to airway surface
liquid depletion, mucus hyperconcentration and increased mucin crosslinking in CF [3, 4, 8–12].
As a consequence, airway mucus becomes highly viscoelastic and less transportable. This
abnormal CF mucus causes compression of the underlying periciliary layer, collapse of cilia and
mucus adherence to airway surfaces leading to impaired MCC and airway mucus plugging
(figure 1b) [5, 13–15]. The resulting host defence defect, together with the accumulation of
nutrient-rich mucus in the airways, set the stage for airway dysbiosis and chronic polymicrobial
infection with typical pathogens such as Haemophilus influenzae, Staphylococcus aureus,
Pseudomonas aeruginosa and Burkholderia cepacia, which provide a constant trigger for
chronic airway inflammation [16–18]. Further, emerging evidence suggests that mucus plugging
per se, probably via local hypoxia and release of interleukin-1α from hypoxic airway epithelial
cells, can trigger chronic airway inflammation [19–21]. This chronic neutrophilic inflammation
leading to a protease/anti-protease imbalance with high levels of free neutrophil elastase activity
in the airways is a key determinant of progressive structural lung damage causing bronchiectasis
and destruction of the lung parenchyma [22–24].
Clinical presentation of CF lung disease

Although lung disease continues to determine the majority of morbidity and mortality of
patients with CF, the first clinical symptoms are commonly related to gastrointestinal
manifestations that often occur right after birth. About 10% of newborns with CF present with
meconium ileus due to highly viscous meconium, and approximately 85% of CF infants present
with exocrine pancreatic insufficiency that causes maldigestion with diarrhoea and failure to
thrive [25, 26]. Respiratory symptoms, such as cough, chronic bronchitis and recurrent
pneumonia, can also occur in the first month of life, although they usually occur later in
childhood. However, studies in infants with CF have shown that airway mucus plugging and
other morphological changes of the lungs such as air trapping and bronchial wall thickening can
be detected along with elevated levels of neutrophil elastase in BAL (i.e. a key marker of
neutrophilic inflammation and lung disease severity) in the first months of life, even in the
absence of pulmonary symptoms [22, 27–29]. During preschool years, a chronic cough
develops in most children with CF and, due to mucus obstruction of the small airways,
ventilation inhomogeneity and hyperinflation of the lungs occur [30, 31]. Recent studies using
multiple-breath washout measurements as a sensitive effort-independent outcome measure of
lung function in infants and toddlers with CF showed that ventilation inhomogeneity occurs as
early as infancy and progresses over the first years of life [31–35]. From early childhood,
chronic rhinosinusitis develops, which can lead to chronic headaches and, especially in the
136 https://doi.org/10.1183/2312508X.10018022
CYSTIC FIBROSIS | S.Y. GRAEBER AND M.A. MALL
a) b)
Cl– Cl–
Class IV ENaC
CFTR
CFTR ENaC
Class III
Na+
Class VI Na+
H2O H2O H2O H2O

Class II
Class V
CFTR Class I
c) d)
Cl– Cl–
Ivacaftor
CFTR ENaC CFTR ENaC
Na+ Na+
H2O H2O H2O H2O

mRNA therapy
lipid nanoparticle
Elexacaftor
Tezacaftor
Gene editing
F508del
DNA therapy
viral vector
FIGURE 1 Pathophysiology of and therapeutic options for cystic fibrosis transmembrane conductance regulator
(CFTR) dysfunction in airway epithelium. a) In normal airway epithelia, the CFTR chloride channel is expressed in
the apical cell membrane where it plays an important role in chloride/fluid secretion. CFTR is expressed together
with the amiloride-sensitive epithelial sodium channel (ENaC) that constitutes the limiting pathway for sodium/
fluid absorption. Homeostasis of the airway surface liquid volume by balanced secretion and absorption of salt
and water is essential for proper mucociliary clearance, providing an important host defence mechanism of the
lung. b) Mutations in the CFTR gene lead to premature termination codons and lack of full-length protein (class I),
folding and trafficking defects resulting in lack of functional CFTR at the apical cell membrane (class II),
impaired channel gating resulting in reduced open probability of CFTR channels (class III), impaired channel
conductance (class IV), reduced levels of CFTR protein at the cell surface (class V) or reduced stability and
https://doi.org/10.1183/2312508X.10018022 137
shortened half-life of CFTR channels at the apical membrane (class VI). c) The CFTR correctors elexacaftor and
tezacaftor correct the folding defect of the common F508del-CFTR mutation. In combination with the
potentiator ivacaftor, which enhances the open probability of the CFTR channel in the apical membrane, CFTR
function is partially restored. d) Potential of gene therapy for cystic fibrosis, including mRNA replacement
therapy, DNA replacement therapy and gene editing. Figure partially created with BioRender.com
presence of nasal polyps, to severe obstruction of nasal breathing [36, 37]. Further, dysbiosis
and polymicrobial infection of the respiratory tract occurs, with H. influenzae, S. aureus and
P. aeruginosa as lead pathogens [16, 17]. With the progression of lung disease, patients with
CF present with progressive bronchiectasis, pulmonary exacerbations with an acute decrease in
lung function associated with cough and sputum production, tachydyspnoea, worsening of
auscultation findings, decrease in oxygen saturation, newly appearing morphological changes on
imaging, haemoptysis and/or weight loss [38]. In advanced disease, complications such as
atelectasis, pneumothoraces and allergic bronchopulmonary aspergillosis can occur. As chronic
hypoxaemia can lead to pulmonary arterial hypertension with right heart failure, most patients
with end-stage lung disease require continuous oxygen therapy [39]. Respiratory failure due to
end-stage lung disease remains the most common cause of death in patients with CF; however,
as treatment of lung disease and life expectancy have increased over the past decades,
extrapulmonary manifestations of CF occurring beyond infancy, including distal intestinal
obstruction syndrome, CF-related diabetes and CF liver disease, have gained importance, as
recently reviewed elsewhere [40].
Clinical and molecular diagnostics

Diagnostic testing for CF should be initiated if one or more clinical symptoms such as persistent
sinopulmonary or gastrointestinal symptoms, salt-loss syndrome or reproductive abnormalities are
present. In addition, many countries have established newborn screenings to detect patients with
CF presymptomatically [29, 41]. The European Cystic Fibrosis Society (ECFS) has developed
standardised criteria to establish a diagnosis of CF where at least one out of three diagnostic
criteria needs to be fulfilled and CFTR dysfunction must be proven. Diagnostic criteria are 1) a
positive newborn screening test, 2) siblings with a diagnosis of CF, or 3) at least one clinical
indication of CF. Evidence of CFTR dysfunction can be provided by 1) elevated sweat chloride
levels (>60 mmol·L−1), 2) detection of two CF-causing CFTR mutations in trans, or 3) detection
of CFTR dysfunction by either nasal potential difference or intestinal current measurement [42].
To date, more than 2000 variants in the CFTR gene have been identified, of which ∼400 have
been confirmed to be disease causing [43, 44]. The pathogenic CFTR variants have been
classified into six classes (I–VI) according to the dominant mechanism through which they
cause CFTR dysfunction, and can be detected by molecular diagnostics ranging from
PCR-based panel diagnostics for common mutations to next-generation whole exome and whole
genome sequencing (figure 1b) [39, 45–48]. Class I mutations lead to premature termination
codons (PTCs) and therefore no full-length protein. Class II mutations, including the deletion of
phenylalanine at position 508 of the protein (F508del), which is the most common CF-causing
mutation and is present on at least one allele in up to 90% of patients with CF worldwide, lead
to a folding and trafficking defect resulting in lack of functional CFTR at the apical cell
membrane. Class III mutations like G551D are expressed at the cell surface but cause impaired
channel gating, resulting in reduced open probability of CFTR channels. Class IV mutations
impair channel conductance and class V mutations show reduced levels of CFTR protein at the
cell surface. Class VI mutations reduce the stability and lead to a shortened half-life of CFTR
channels at the apical membrane. Classes I, II and III generally result in little or no CFTR
function and a severe phenotype including pancreatic insufficiency and severe lung disease.
138 https://doi.org/10.1183/2312508X.10018022
Classes IV, V and VI, however, are usually associated with residual CFTR function and patients
present with a milder phenotype including long-term pancreatic sufficiency [49]. Of note, many
CFTR mutations affect multiple of the aforementioned molecular mechanisms. For example, the
F508del mutation not only impairs folding, processing and trafficking of the CFTR protein, but
also shows defective gating and reduced stability when the protein reaches the apical membrane
[50, 51]. With the emergence of CFTR modulator drugs targeting specific CFTR mutations (see
next section), establishment of a molecular diagnosis with identification of the individual CFTR
genotype has become critical for treatment options of the underlying defect and should therefore
be achieved in every patient with CF.
Breakthroughs in therapies targeting the underlying molecular defects in CF

For decades, treatment of CF lung disease has been only symptomatic, i.e. by airway clearance
therapies to improve mucus clearance and antibiotics for the treatment of pulmonary exacerbations
and chronic Pseudomonas infection. Nevertheless, constant advances in symptomatic treatment
regimens and specialised multidisciplinary CF care have resulted in substantial quality of life and
life expectancy of patients with CF [39]. Importantly, the discovery of the CFTR gene in 1989
made it possible to unravel the molecular pathogenesis of CF, and subsequently to develop drugs
that target the root cause of the disease [1]. In fact, CF is the first successful example of
customised drug development for mutation-specific therapy of a rare genetic disease [2, 52, 53].
First, CFTR potentiators have been developed that increase the channel open probability of
CFTR gating mutations such as G551D that are expressed in the apical cell membrane [54]. The
potentiator ivacaftor enhances the opening of the CFTR channel and was approved for CF
patients with G551D and other gating mutations that are present in ∼3–4% of patients with CF
[54, 55]. Ivacaftor monotherapy improves CFTR function in these patients to a level of ∼50%
of normal CFTR activity, leading to substantial improvement in clinical outcomes including
spirometry, body mass index and quality of life [55, 56].
For patients with the most common F508del mutation, CFTR correctors have been developed to
correct the folding defect. The first-generation correctors lumacaftor and tezacaftor were
approved in dual combination with ivacaftor for patients homozygous for the F508del mutation
[57, 58]. The combinations of lumacaftor/ivacaftor and tezacaftor/ivacaftor improved CFTR
function in F508del homozygous patients to a level of 10–20% of normal CFTR activity
[59, 60], which is associated with modest improvement in lung function but substantial
reduction in exacerbation rates [57, 58]. Tezacaftor showed a better safety profile compared to
lumacaftor and in dual combination with ivacaftor also showed clinical benefits in patients with
one F508del mutation and a second residual function mutation [58, 61].
As F508del exhibits multiple folding defects, elexacaftor was developed as a next-generation

corrector, acting at a different site of the molecule to overcome the efficacy ceiling observed
with a single corrector. Recently, a triple combination therapy of elexacaftor and tezacaftor with
the potentiator ivacaftor demonstrated unprecedented improvements in lung function, body mass
index and self-reported respiratory symptoms as well as lung ventilation and mucus plugging
measured by multiple-breath washout and lung MRI in CF patients with at least one F508del
allele [62–64] (figure 1c). Further, it was found that elexacaftor/tezacaftor/ivacaftor (ETI)
improves F508del-CFTR function to levels of 40–50% of normal CFTR activity in the airways
and intestine of patients with one or two F508del alleles, which is superior to previous dual
drug combinations of lumacaftor/ivacaftor and tezacaftor/ivacaftor in F508del homozygous
patients, but in the same range as ivacaftor alone in CF patients with a G551D mutation [56, 59,
60]. ETI was also shown to be more effective than ivacaftor or tezacaftor/ivacaftor in patients
https://doi.org/10.1183/2312508X.10018022 139
compound heterozygous for F508del and a gating or residual function mutation, indicating that
treating both alleles is superior to treating only one CF allele [62, 63, 65]. Studies in the
real-world setting have confirmed results of clinical trials in a larger and more diverse patient
population and have shown that ETI reduces treatment burden, blood neutrophil counts and lung
transplantation rates in patients with CF [60, 64, 66–70]. Ongoing paediatric trials are crucial to
bring CFTR-directed therapeutics to young children and ideally infants as early in life as
possible, since early restoration of CFTR function may delay or even prevent irreversible
structural lung damage and thus have the greatest long-term benefit [71–80].
At a global level, the high costs of CFTR modulators are an important barrier to access,
especially for patients living in middle- and low-income countries [2, 81]. The successful
development of innovative therapies requires large investments; however, recent estimates
suggest that the current list price in the USA for ETI is more than 10-fold higher than the
estimated cost of production [82]. Transparency on how prices for these novel therapies are
determined, their impact on overall healthcare costs, adaptation of pricing as new data become
available, and alternative cost models for middle- and low-income countries will be important to
ensure all eligible patients can benefit from transformative CFTR-directed therapies [2].
Despite this major breakthrough in CFTR mutation-specific therapy for a growing number of
patients with CF, ∼15% of all patients carry CFTR genotypes that cannot be addressed with
current CFTR modulator drugs. It is therefore important that a robust drug development pipeline
exists that aims to close this gap, to address the underlying defect in all patients with CF
irrespective of CFTR genotype.
First, based on in vitro testing in cell lines, the US Food and Drug Administration (FDA) has
already expanded approval of ETI to an additional 177 non-F508del variants and emerging
evidence supports that additional CFTR variants exist that are responsive to ETI and this may
thus enhance personalised medicine of patients with ultra-rare CFTR genotypes. Recently, a
French compassionate programme showed that ∼25% of their patients with no F508del allele
and two CFTR variants that are currently not approved by the FDA for ETI treatment did
respond to treatment with ETI [83]. These results highlight the need for novel approaches to
make highly effective CFTR modulator therapies available to more patients with responsive
CFTR mutations. In this context, theratyping with preclinical patient-derived model systems, i.e.
intestinal organoids or primary nasal epithelial cells, has shown responsiveness of rare CFTR
mutations of unknown functional consequences to CFTR modulators in vitro [84–93].
Second, PTC suppressor drugs are currently under development to restore full-length CFTR
protein in patients with class I mutations, using similar high-throughput screening approaches to
those used to develop CFTR modulators. If successful, up to 13% of patients with at least one
PTC mutation may benefit from this approach [94].
Third, alternative ion channels that may compensate for CFTR dysfunction remain important
targets, especially for CF patients with large deletions in CFTR including promoter and intronic
regions of the gene. In this context, ENaC blockers that improve airway surface hydration via
inhibition of sodium/fluid absorption and activators of the alternative calcium-activated chloride
channel TMEM16A are currently being developed as a mutation-agnostic therapeutic approach
[95]. Further, based on genetic and functional studies in patients with CF, the constitutively active
chloride channel SLC26A9 may be a promising target to compensate for CFTR dysfunction
[9, 10]. These approaches, aiming to improve airway surface hydration and therefore MCC, may
also have a beneficial effect in a spectrum of other muco-obstructive lung diseases.
140 https://doi.org/10.1183/2312508X.10018022
Fourth, gene therapy as a mutation-agnostic approach to treat the underlying defect of CF in the
lungs is under development (figure 1d). The discovery of the CFTR gene raised hope that CF
may be curable with gene replacement therapy. Due to several hurdles, mainly related to gene
delivery to airway cells and limited durability of CFTR expression, previous gene therapy trials
have not been successful [96]. However, the development of new-generation viral vectors has
raised new hopes and a first clinical trial of an adeno-associated virus (AAV) gene therapy
composed of an AAV capsid variant (4D-A101) carrying a transgene cassette encoding human
CFTR with a deletion in the regulatory domain (CFTRΔR) is currently running (ClinicalTrials.
gov identifier: NCT05248230). Further, delivery of stable mRNA via lipid nanoparticles has
been introduced as a promising approach and first in vitro studies show the potential to reach
wild-type levels of CFTR mRNA in bronchial epithelial cells [97]. In addition, preclinical
studies with antisense oligonucleotide-based drugs for splicing modulation, which were recently
approved for various other genetic diseases, support the potential to treat patients with CF and
CFTR splicing and nonsense mutations [98–101]. Finally, the advances in gene editing have led
to successful correction of CFTR mutations in vitro using the CRISPR/Cas9 system [102].
However, the main challenge with these gene therapy approaches is to accomplish effective
delivery to airway epithelial cells in the chronically inflamed and mucus-obstructed airways in
vivo [103, 104]. Further, for all gene therapy approaches, it is unclear, so far, to what extent
repeated dosing is necessary and feasible.
The potential role of ion channels in other muco-obstructive lung diseases

Besides CF, a spectrum of chronic airways diseases including non-CF bronchiectasis, chronic
bronchitis, COPD and asthma are associated with hyperconcentrated mucus, impaired MCC and
airway mucus plugging, suggesting a potential role of dysregulated epithelial ion/fluid transport
in their pathogenesis. As mentioned earlier, next to CFTR, other key players involved in the
homeostatic regulation of the airway surface liquid are the amiloride-sensitive ENaC and the
alternative chloride channels TMEM16A and SLC26A9 (figure 2a).
ENaC plays a key role in fluid absorption across the airway epithelium [14, 15] and
overexpression of the β-subunit of ENaC in mice leads to airway surface dehydration, impaired
MCC and muco-obstructive lung disease with increased mortality [105]. Interestingly, patients
and mice with gain-of-function mutations in βENaC develop salt-sensitive hypertension due to
increased ENaC function in the kidney (Liddle syndrome), but no pulmonary phenotype
[106, 107]. Studies in mice carrying the Liddle mutation showed that gain of ENaC function is
inhibited in the airway epithelium under thin film conditions, which may prevent airway surface
dehydration and the onset of lung disease [108]. Nevertheless, a spectrum of other ENaC
gain-of-function mutations that have been identified, as well as proteolytic activation of ENaC
by proteases released from inflammatory cells and pathogens in the airways, may contribute to
the pathogenesis of a spectrum of muco-obstructive lung diseases [109–116].
TMEM16A is a calcium-activated chloride channel predominantly expressed in goblet cells in the

airways [117]. Channel activation can be regulated via different mechanisms, i.e. intracellular
calcium concentration, voltage or cell volume, as well as by several molecules including
calmodulin, protons, cholesterol and phosphatidylinositol 4,5-bisphosphate (PIP2) [118–121]. In
health, TMEM16A contributes to fluid secretion and regulation of mucin secretion [8, 122, 123].
In airway inflammation, TMEM16A is found to be upregulated to increase ion/fluid secretion
and maintain MCC. Therefore, activation of TMEM16A may improve airway mucus clearance
in CF and other muco-obstructive lung diseases [124]. Further, recent studies suggest that
dysregulation of TMEM16A is associated with chronic rhinosinusitis [125–127].
https://doi.org/10.1183/2312508X.10018022 141
a) b) Oxidative
Ozone P. aeruginosa
Arsenic stress
As Hypoxia
Cigarette
Cl– Cl– smoke Proteases IFN-J
TMEM16A
Cl– Na+ SLC26A9 Cl–
?
CFTR ENaC CFTR
H2O H2O H2O ? H2O
CFTR
FIGURE 2 Role of other ion channels and acquired cystic fibrosis transmembrane conductance regulator (CFTR)
dysfunction in airway surface liquid homeostasis. a) In addition to CFTR, the amiloride-sensitive epithelial
sodium channel (ENaC) and the alternative chloride channels transmembrane protein member 16A (TMEM16A)
and solute carrier family 26 member 9 (SLC26A9) contribute to the regulation of the airway surface liquid and
may therefore serve as potential therapeutic targets for mutation-agnostic therapies in patients with cystic
fibrosis and other muco-obstructive lung diseases. b) Potential role of acquired CFTR dysfunction caused by
cigarette smoke and other noxious stimuli resulting in reduced CFTR expression and/or CFTR function in COPD
and other muco-obstructive lung diseases. The mechanisms and pathways by which the different stimuli reduce
CFTR expression and/or function are largely unknown. P. aeruginosa: Pseudomonas aeruginosa; IFN: interferon.
Figure partially created with BioRender.com
SLC26A9 belongs to the solute carrier 26 family of anion transporters and is expressed at high
levels in the airway epithelium [128, 129], where it contributes to the regulation of the airway
surface liquid. Studies in mice suggest that SLC26A9 plays a role preventing mucus plugging in
allergic airway inflammation, which is supported by the finding of a polymorphism in the
3′ untranslated region (UTR) of SLC26A9 of asthmatic children reducing protein expression
in vitro [130, 131]. Further, mutations in the SLC26A9 gene were found in patients with non-CF
bronchiectasis [132]. As SLC26A9 is co-expressed with CFTR [133], variants in the SLC26A9
gene were found to be associated with response to CFTR modulator therapy in patients with CF
[134–139]. These data support that dysregulation of airway ion transport by ENaC, TMEM16A
and SLC26A9 may contribute to the pathogenesis of a spectrum of muco-obstructive lung
diseases, where these ion channels may also serve as potential therapeutic targets.
The potential role of acquired CFTR dysfunction in other lung diseases

In addition to these alternative ion channels, CFTR dysfunction may also be implicated in other
muco-obstructive lung diseases. Besides mutations in the CFTR gene, other extrinsic or intrinsic
factors can lead to acquired CFTR dysfunction, which has recently been implicated in the
pathogenesis of COPD (figure 2b) [140, 141]. The most common cause of acquired CFTR
142 https://doi.org/10.1183/2312508X.10018022
dysfunction in people without CF is probably cigarette smoking [142–147]. Exposure to

cigarette smoke has been shown to decrease both expression and function of CFTR [143, 144].
Further, environmental exposure to arsenic or ozone may also impair CFTR function and
contribute to disease severity of COPD [148, 149]. Chronic airway infection and inflammation
may also lead to impaired CFTR function in COPD and other muco-obstructive lung diseases.
For example, P. aeruginosa infection has been shown to reduce CFTR expression in airway
epithelial cells [150]. Further, interferon-γ and the protease neutrophil elastase, released in
chronic airway inflammation, can also reduce CFTR function in people without CF [151, 152].
In end-stage lung disease, hypoxia and oxidative stress can also lead to alteration of CFTR
expression and function [153, 154]. In COPD, a vicious cycle can occur in which neutrophilic
airway inflammation as well as hypoxia and oxidative stress hamper CFTR function, which in
turn aggravates mucociliary dysfunction and mucus plugging.
Above all, preventive strategies, i.e. primary prevention and smoking cessation, should remain
the first priority to combat COPD. However, once a vicious cycle of acquired CFTR dysfunction,
mucociliary dysfunction, infection and inflammation has been established, CFTR-directed
therapies and other ion channel modulators developed for the rare genetic disease CF may also
be useful in COPD and potentially other muco-obstructive lung diseases. Interestingly, in a
preclinical study in a ferret model of cigarette-smoke-induced COPD, treatment with the novel
CFTR potentiator GLPG2196 reversed acquired CFTR dysfunction, and improved MCC and
airway remodelling in vivo [155]. Furthermore, a recent phase 2 trial of the novel CFTR
potentiator icenticaftor (QBW251) in 92 patients with COPD found no change in the lung
clearance index but improvements in pre- and post-bronchodilator forced expiratory volume in
1 s and in sweat chloride, and icenticaftor was generally safe and well tolerated [156]. While
these studies are encouraging, larger clinical trials with CFTR modulators in patients with COPD
are needed to determine their benefit for patients suffering from this common complex disease.
Conclusions and outlook

The identification of the CFTR gene and unravelling of disease mechanisms has led to a
breakthrough therapy of the underlying molecular defect in CF patients with at least one copy of
the common F508del-CFTR mutation, accounting for approximately 85–90% of the global CF
population. Emerging data suggest that current CFTR modulator therapies restore CFTR function
to up to 50% of normal function, which is known to be associated with residual sinopulmonary
disease based on natural history studies of CF patients with residual function mutations.
Therefore, research efforts that focus on further improvement of pharmacological correction of
F508del-CFTR function, ideally towards wild-type CFTR levels, remain important. In addition,
paediatric trials aiming to bring CFTR-directed therapeutics to young children as early in their
lives as possible are a high clinical research priority, as early restoration of CFTR function may
prevent irreversible structural lung damage and thus have the greatest long-term benefit.
Beyond CF, emerging evidence suggests a role of acquired CFTR dysfunction in the
pathogenesis of COPD, suggesting that CFTR modulators that were developed for a rare genetic
disease may also be beneficial for this common complex disease that has emerged as the third
most common cause of death worldwide. Besides CFTR, ENaC and the alternative chloride
channels SLC26A9 and TMEM16A play important roles in airway surface liquid homeostasis
and their dysfunction has also been implicated in the pathogenesis of CF and other
muco-obstructive lung diseases such as asthma, bronchiectasis and COPD. These ion channels
may therefore serve as CFTR mutation-agnostic alternative therapeutic targets to improve airway
surface hydration and MCC in CF, as well as other muco-obstructive lung diseases with limited
https://doi.org/10.1183/2312508X.10018022 143
therapeutic options and high unmet medical need. In addition to pharmacological targeting of
these alternative targets, next-generation gene therapy approaches including inhaled CFTR
mRNA replacement, gene replacement with more effective vector systems and ultimately gene
editing to correct individual mutations provide promising strategies to restore CFTR function in
the lungs of all patients, independent of the CFTR genotype.
References
1 Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and
characterization of complementary DNA. Science 1989; 245: 1066–1073.
2 Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med
2020; 8: 65–124.
3 Hill DB, Button B, Rubinstein M, et al. Physiology and pathophysiology of human airway mucus. Physiol Rev
2022; 102: 1757–1836.
4 Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, not abnormal ion
composition, in the pathogenesis of cystic fibrosis airways disease. Cell 1998; 95: 1005–1015.
5 Mall MA, Hartl D. CFTR: cystic fibrosis and beyond. Eur Respir J 2014; 44: 1042–1054.
6 Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J
Clin Invest 2002; 109: 571–577.
7 Mall MA. Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: lessons from mouse
models. J Aerosol Med Pulm Drug Deliv 2008; 21: 13–24.
8 Benedetto R, Cabrita I, Schreiber R, et al. TMEM16A is indispensable for basal mucus secretion in airways and
intestine. FASEB J 2019; 33: 4502–4512.
9 Balazs A, Mall MA. Role of the SLC26A9 chloride channel as disease modifier and potential therapeutic target
in cystic fibrosis. Front Pharmacol 2018; 9: 1112.
10 Gong J, He G, Wang C, et al. Genetic evidence supports the development of SLC26A9 targeting therapies for
the treatment of lung disease. NPJ Genom Med 2022; 7: 28.
11 Li H, Salomon JJ, Sheppard DN, et al. Bypassing CFTR dysfunction in cystic fibrosis with alternative pathways
for anion transport. Curr Opin Pharmacol 2017; 34: 91–97.
12 Yuan S, Hollinger M, Lachowicz-Scroggins ME, et al. Oxidation increases mucin polymer cross-links to stiffen
airway mucus gels. Sci Transl Med 2015; 7: 276ra227.
13 Boucher RC. Muco-obstructive lung diseases. N Engl J Med 2019; 380: 1941–1953.
14 Mall MA. ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapies. Eur
Respir J 2020; 56: 2000946.
15 Shei RJ, Peabody JE, Kaza N, et al. The epithelial sodium channel (ENaC) as a therapeutic target for cystic
fibrosis. Curr Opin Pharmacol 2018; 43: 152–165.
16 Muhlebach MS, Zorn BT, Esther CR, et al. Initial acquisition and succession of the cystic fibrosis lung microbiome
is associated with disease progression in infants and preschool children. PLoS Pathog 2018; 14: e1006798.
17 Boutin S, Graeber SY, Stahl M, et al. Chronic but not intermittent infection with Pseudomonas aeruginosa is
associated with global changes of the lung microbiome in cystic fibrosis. Eur Respir J 2017; 50: 1701086.
18 Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis.
19 Fritzsching B, Zhou-Suckow Z, Trojanek JB, et al. Hypoxic epithelial necrosis triggers neutrophilic inflammation
via IL-1 receptor signaling in cystic fibrosis lung disease. Am J Respir Crit Care Med 2015; 191: 902–913.
20 Montgomery ST, Mall MA, Kicic A, et al. Hypoxia and sterile inflammation in cystic fibrosis airways:
mechanisms and potential therapies. Eur Respir J 2017; 49: 1600903.
21 Balazs A, Mall MA. Mucus obstruction and inflammation in early cystic fibrosis lung disease: Emerging role of
the IL-1 signaling pathway. Pediatr Pulmonol 2019; 54: Suppl. 3, S5–S12.
22 Sly PD, Gangell CL, Chen L, et al. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med
2013; 368: 1963–1970.
23 Gehrig S, Duerr J, Weitnauer M, et al. Lack of neutrophil elastase reduces inflammation, mucus
hypersecretion, and emphysema, but not mucus obstruction, in mice with cystic fibrosis-like lung disease. Am
24 McKelvey MC, Weldon S, McAuley DF, et al. Targeting proteases in cystic fibrosis lung disease. Paradigms,
progress, and potential. Am J Respir Crit Care Med 2020; 201: 141–147.
25 Plant BJ, Parkins MD. Extrapulmonary manifestations of cystic fibrosis. In: Mall MA, Elborn JS, eds. Cystic
Fibrosis (ERS Monograph). Sheffield, European Respiratory Society, 2014; pp. 219–235.
26 Sommerburg O, Schenk JP. Abdominelle Manifestationen bei Mukoviszidose: Klinische Übersicht [Abdominal
manifestations in cystic fibrosis: clinical review]. Radiologe 2020; 60: 781–790.
144 https://doi.org/10.1183/2312508X.10018022
27 Zuelzer WW, Newton WA Jr. The pathogenesis of fibrocystic disease of the pancreas; a study of 36 cases with
special reference to the pulmonary lesions. Pediatrics 1949; 4: 53–69.
28 Wielputz MO, Puderbach M, Kopp-Schneider A, et al. Magnetic resonance imaging detects changes in structure
and perfusion, and response to therapy in early cystic fibrosis lung disease. Am J Respir Crit Care Med 2014;
189: 956–965.
29 Sly PD, Brennan S, Gangell C, et al. Lung disease at diagnosis in infants with cystic fibrosis detected by
newborn screening. Am J Respir Crit Care Med 2009; 180: 146–152.
30 Esther CR Jr, Muhlebach MS, Ehre C, et al. Mucus accumulation in the lungs precedes structural changes and
infection in children with cystic fibrosis. Sci Trans Med 2019; 11: eaav3488.
31 Stahl M, Wielputz MO, Graeber SY, et al. Comparison of lung clearance index and magnetic resonance imaging
for assessment of lung disease in children with cystic fibrosis. Am J Respir Crit Care Med 2017; 195: 349–359.
32 Stahl M, Steinke E, Mall MA. Quantification of phenotypic variability of lung disease in children with cystic
fibrosis. Genes 2021; 12: 803.
33 Roehmel JF, Doerfler FJ, Koerner-Rettberg C, et al. Comparison of the lung clearance index in preschool
children with primary ciliary dyskinesia and cystic fibrosis. Chest 2022; 162: 534–542.
34 Stahl M, Graeber SY, Joachim C, et al. Three-center feasibility of lung clearance index in infants and preschool
children with cystic fibrosis and other lung diseases. J Cyst Fibros 2018; 17: 249–255.
35 Subbarao P, Stanojevic S, Brown M, et al. Lung clearance index as an outcome measure for clinical trials in
young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. Am J Respir Crit Care Med
2013; 188: 456–460.
36 Wucherpfennig L, Wuennemann F, Eichinger M, et al. Longitudinal MRI detects onset and progression of
chronic rhinosinusitis from infancy to school age in cystic fibrosis. Ann Am Thorac Soc 2023; 20: 687–697.
37 Sommerburg O, Wielputz MO, Trame JP, et al. Magnetic resonance imaging detects chronic rhinosinusitis in
infants and preschool children with cystic fibrosis. Ann Am Thorac Soc 2020; 17: 714–723.
38 Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on
exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The
Pulmozyme Study Group. N Engl J Med 1994; 331: 637–642.
39 Elborn JS. Cystic fibrosis. Lancet 2016; 388: 2519–2531.
40 Chin M, Brennan AL, Bell SC. Emerging nonpulmonary complications for adults with cystic fibrosis: adult cystic
fibrosis series. Chest 2022; 161: 1211–1224.
41 Sommerburg O, Hammermann J, Lindner M, et al. Five years of experience with biochemical cystic fibrosis
newborn screening based on IRT/PAP in Germany. Pediatr Pulmonol 2015; 50: 655–664.
42 De Boeck K, Derichs N, Fajac I, et al. New clinical diagnostic procedures for cystic fibrosis in Europe. J Cyst
Fibros 2011; 10: Suppl. 2, S53–S66.
43 Cystic Fibrosis Mutation Database. Date last updated: 25 April 2011. Date last accessed: 20 January 2023.
www.genet.sickkids.on.ca
44 The Clinical and Functional TRanslation of CFTR (CFTR2). Date last updated: 2011. Date last accessed: 20
January 2023. http://cftr2.org
45 Raraigh KS, Aksit MA, Hetrick K, et al. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis
informs variant-specific treatment. J Cyst Fibros 2022; 21: 463–470.
46 Morris-Rosendahl DJ, Edwards M, McDonnell MJ, et al. Whole-gene sequencing of CFTR reveals a high
prevalence of the intronic variant c.3874-4522A>G in cystic fibrosis. Am J Respir Crit Care Med 2020; 201:
1438–1441.
47 Richards CS, Bradley LA, Amos J, et al. Standards and guidelines for CFTR mutation testing. Genet Med 2002;
4: 379–391.
48 Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993;
73: 1251–1254.
49 Hirtz S, Gonska T, Seydewitz HH, et al. CFTR Cl− channel function in native human colon correlates with the
genotype and phenotype in cystic fibrosis. Gastroenterology 2004; 127: 1085–1095.
50 Lopes-Pacheco M, Pedemonte N, Veit G. Discovery of CFTR modulators for the treatment of cystic fibrosis.
Expert Opin Drug Discov 2021; 16: 897–913.
51 Veit G, Avramescu RG, Chiang AN, et al. From CFTR biology toward combinatorial pharmacotherapy: expanded
classification of cystic fibrosis mutations. Mol Biol Cell 2016; 27: 424–433.
52 Gentzsch M, Mall MA. Ion channel modulators in cystic fibrosis. Chest 2018; 154: 383–393.
53 Mall MA, Mayer-Hamblett N, Rowe SM. Cystic fibrosis: emergence of highly effective targeted therapeutics and
potential clinical implications. Am J Respir Crit Care Med 2020; 201: 1193–1208.
54 Van Goor F, Hadida S, Grootenhuis PDJ, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR
potentiator, VX-770. Proc Natl Acad Sci USA 2009; 106: 18825–18830.
55 Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR
mutation. N Engl J Med 2010; 363: 1991–2003.
https://doi.org/10.1183/2312508X.10018022 145
56 Graeber SY, Hug MJ, Sommerburg O, et al. Intestinal current measurements detect activation of mutant CFTR
in patients with cystic fibrosis with the G551D mutation treated with ivacaftor. Am J Respir Crit Care Med 2015;
192: 1252–1255.
57 Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous
for Phe508del CFTR. N Engl J Med 2015; 373: 220–231.
58 Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous
for Phe508del. N Engl J Med 2017; 377: 2013–2023.
59 Graeber SY, Dopfer C, Naehrlich L, et al. Effects of lumacaftor-ivacaftor therapy on cystic fibrosis
transmembrane conductance regulator function in Phe508del homozygous patients with cystic fibrosis. Am J
60 Graeber SY, Vitzthum C, Pallenberg ST, et al. Effects of elexacaftor/tezacaftor/ivacaftor therapy on CFTR function
in patients with cystic fibrosis and one or two F508del alleles. Am J Respir Crit Care Med 2022; 205: 540–549.
61 Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic
fibrosis. N Engl J Med 2017; 377: 2024–2035.
62 Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus
ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a
double-blind, randomised, phase 3 trial. Lancet 2019; 394: 1940–1948.
63 Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single
Phe508del allele. N Engl J Med 2019; 381: 1809–1819.
64 Graeber SY, Renz DM, Stahl M, et al. Effects of elexacaftor/tezacaftor/ivacaftor therapy on lung clearance index
and magnetic resonance imaging in patients with cystic fibrosis and one or two F508del alleles. Am J Respir
Crit Care Med 2022; 206: 311–320.
65 Barry PJ, Mall MA, Alvarez A, et al. Triple therapy for cystic fibrosis Phe508del-gating and -residual function
genotypes. N Engl J Med 2021; 385: 815–825.
66 Bower JK, Volkova N, Ahluwalia N, et al. Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor
in people with cystic fibrosis: interim results of a long-term registry-based study. J Cyst Fibros 2023; in press
[https://doi.org/10.1016/j.jcf.2023.03.002].
67 Dhote T, Martin C, Regard L, et al. Normalisation of circulating neutrophil counts after 12 months of
elexacaftor-tezacaftor-ivacaftor in patients with advanced cystic fibrosis. Eur Respir J 2023; 61: 2202096.
68 Nichols DP, Paynter AC, Heltshe SL, et al. Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor in people
with cystic fibrosis: a clinical trial. Am J Respir Crit Care Med 2022; 205: 529–539.
69 Martin C, Reynaud-Gaubert M, Hamidfar R, et al. Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in
lung transplant candidates with cystic fibrosis. J Cyst Fibros 2022; 21: 489–496.
70 Burgel PR, Durieu I, Chiron R, et al. Rapid improvement after starting elexacaftor-tezacaftor-ivacaftor in
patients with cystic fibrosis and advanced pulmonary disease. Am J Respir Crit Care Med 2021; 204: 64–73.
71 Chilvers MA, Davies JC, Milla C, et al. Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children
aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label,
extension study. Lancet Respir Med 2021; 9: 721–732.
72 Hoppe JE, Chilvers M, Ratjen F, et al. Long-term safety of lumacaftor-ivacaftor in children aged 2–5 years with
cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension
study. Lancet Respir Med 2021; 9: 977–988.
73 Mall MA, Brugha R, Gartner S, et al. Efficacy and safety of elexacaftor/tezacaftor/ivacaftor in children 6 through
11 years of age with cystic fibrosis heterozygous for F508del and a minimal function mutation: a phase 3b,
randomized, placebo-controlled study. Am J Respir Crit Care Med 2022; 206: 1361–1369.
74 McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of
lumacaftor and ivacaftor combination therapy in children aged 2–5 years with cystic fibrosis homozygous for
F508del-CFTR: an open-label phase 3 study. Lancet Respir Med 2019; 7: 325–335.
75 Rayment JH, Asfour F, Rosenfeld M, et al. A phase 3, open-label study of lumacaftor/ivacaftor in children 1 to
less than 2 years of age with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Care Med 2022;
206: 1239–1247.
76 Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24
months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med 2018; 6:
545–553.
77 Sawicki GS, Chilvers M, McNamara J, et al. A phase 3, open-label, 96-week trial to study the safety, tolerability,
and efficacy of tezacaftor/ivacaftor in children ⩾6 years of age homozygous for F508del or heterozygous for
F508del and a residual function CFTR variant. J Cyst Fibros 2022; 21: 675–683.
78 Walker S, Flume P, McNamara J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children
aged 6 through 11 years with cystic fibrosis. J Cyst Fibros 2019; 18: 708–713.
146 https://doi.org/10.1183/2312508X.10018022
79 Zemanick ET, Taylor-Cousar JL, Davies J, et al. A phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor
in children 6 through 11 years of age with cystic fibrosis and at least one F508del allele. Am J Respir Crit Care
Med 2021; 203: 1522–1532.
80 Stahl M, Steinke E, Seitz C, et al. Progression of lung disease detected by MRI and impact of NBS in preschool
children with CF. Pediatr Pulmonol 2018; 53: Suppl. 2, S226.
81 Guo J, Garratt A, Hill A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros
2022; 21: 456–462.
82 Guo J, Wang J, Zhang J, et al. Current prices versus minimum costs of production for CFTR modulators. J Cyst
Fibros 2022; 21: 866–872.
83 Burgel P-R, Sermet-Gaudelus I, Durieu I, et al. The French compassionate programme of elexacaftor/
tezacaftor/ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant. Eur
Respir J 2023; 61: 2202437.
84 Berkers G, van Mourik P, Vonk AM, et al. Rectal organoids enable personalized treatment of cystic fibrosis. Cell
Rep 2019; 26: 1701–1708.e3.
85 Dekkers JF, Gogorza Gondra RA, Kruisselbrink E, et al. Optimal correction of distinct CFTR folding mutants in
rectal cystic fibrosis organoids. Eur Respir J 2016; 48: 451–458.
86 Furstova E, Dousova T, Beranek J, et al. Response to elexacaftor/tezacaftor/ivacaftor in intestinal organoids
derived from people with cystic fibrosis. J Cyst Fibros 2022; 21: 243–245.
87 Ramalho AS, Fürstová E, Vonk AM, et al. Correction of CFTR function in intestinal organoids to guide
treatment of cystic fibrosis. Eur Respir J 2021; 57: 1902426.
88 Amatngalim GD, Rodenburg LW, Aalbers BL, et al. Measuring cystic fibrosis drug responses in organoids
derived from 2D differentiated nasal epithelia. Life Sci Alliance 2022; 5: e202101320.
89 Pedemonte N. Nasal epithelial cells as a gold-standard predictive model for personalized medicine in cystic
fibrosis. J Physiol 2022; 600: 1285–1286.
90 Pranke IM, Hatton A, Simonin J, et al. Correction of CFTR function in nasal epithelial cells from cystic fibrosis
patients predicts improvement of respiratory function by CFTR modulators. Sci Rep 2017; 7: 7375.
91 Reeves SR. Primary nasal epithelial cells from patients with cystic fibrosis hold promise for guiding precision
medicine and expanding treatment. Eur Respir J 2021; 58: 2102735.
92 Rodenburg LW, Delpiano L, Railean V, et al. Drug repurposing for cystic fibrosis: identification of drugs that
induce CFTR-independent fluid secretion in nasal organoids. Int J Mol Sci 2022; 23: 12657.
93 Sette G, Lo Cicero S, Blaconà G, et al. Theratyping cystic fibrosis in vitro in ALI culture and organoid models
generated from patient-derived nasal epithelial conditionally reprogrammed stem cells. Eur Respir J 2021; 58:
2100908.
94 De Boeck K, Zolin A, Cuppens H, et al. The relative frequency of CFTR mutation classes in European patients
with cystic fibrosis. J Cyst Fibros 2014; 13: 403–409.
95 Danahay HL, Lilley S, Fox R, et al. TMEM16A potentiation: a novel therapeutic approach for the treatment of
cystic fibrosis. Am J Respir Crit Care Med 2020; 201: 946–954.
96 Alton EW, Stern M, Farley R, et al. Cationic lipid-mediated CFTR gene transfer to the lungs and nose of
patients with cystic fibrosis: a double-blind placebo-controlled trial. Lancet 1999; 353: 947–954.
97 Ishimaru D, Boudko D, Meleshkevitch EA, et al. Functional rescue of CFTR by aerosolized delivery of optimized
CFTR mRNA using ReCode-LNPs in primary human bronchial epithelial cells derived from patients with cystic
fibrosis. Am J Respir Crit Care Med 2022; 205: A5488.
98 Kim YJ, Sivetz N, Layne J, et al. Exon-skipping antisense oligonucleotides for cystic fibrosis therapy. Proc Natl
Acad Sci USA 2022; 119: e2114858118.
99 Michaels WE, Pena-Rasgado C, Kotaria R, et al. Open reading frame correction using splice-switching antisense
oligonucleotides for the treatment of cystic fibrosis. Proc Natl Acad Sci USA 2022; 119: e2114886119.
100 Oren YS, Avizur-Barchad O, Ozeri-Galai E, et al. Antisense oligonucleotide splicing modulation as a novel cystic
fibrosis therapeutic approach for the W1282X nonsense mutation. J Cyst Fibros 2022; 21: 630–636.
101 Oren YS, Irony-Tur Sinai M, Golec A, et al. Antisense oligonucleotide-based drug development for cystic
fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation. J Cyst Fibros 2021; 20: 865–875.
102 Geurts MH, de Poel E, Amatngalim GD, et al. CRISPR-based adenine editors correct nonsense mutations in a
cystic fibrosis organoid biobank. Cell Stem Cell 2020; 26: 503–510.e7.
103 Donnelley M, Parsons D, Prichard I. Perceptions of airway gene therapy for cystic fibrosis. Expert Opin Biol Ther
2023; 23: 103–113.
104 Sui H, Xu X, Su Y, et al. Gene therapy for cystic fibrosis: challenges and prospects. Front Pharmacol 2022; 13:
1015926.
105 Mall M, Grubb BR, Harkema JR, et al. Increased airway epithelial Na+ absorption produces cystic fibrosis-like
lung disease in mice. Nat Med 2004; 10: 487–493.
106 Hansson JH, Nelson-Williams C, Suzuki H, et al. Hypertension caused by a truncated epithelial sodium
channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 1995; 11: 76–82.
https://doi.org/10.1183/2312508X.10018022 147
107 Tetti M, Monticone S, Burrello J, et al. Liddle syndrome: review of the literature and description of a new case.
Int J Mol Sci 2018; 19: 812.
108 Mall MA, Button B, Johannesson B, et al. Airway surface liquid volume regulation determines different airway
phenotypes in Liddle compared with betaENaC-overexpressing mice. J Biol Chem 2010; 285: 26945–26955.
109 Rauh R, Soell D, Haerteis S, et al. A mutation in the beta-subunit of ENaC identified in a patient with cystic
fibrosis-like symptoms has a gain-of-function effect. Am J Physiol Lung Cell Mol Physiol 2013; 304: L43–L55.
110 Caldwell RA, Boucher RC, Stutts MJ. Neutrophil elastase activates near-silent epithelial Na+ channels and
increases airway epithelial Na+ transport. Am J Physiol Lung Cell Mol Physiol 2005; 288: L813–L819.
111 Hill AT, Campbell EJ, Hill SL, et al. Association between airway bacterial load and markers of airway
inflammation in patients with stable chronic bronchitis. Am J Med 2000; 109: 288–295.
112 Azad AK, Rauh R, Vermeulen F, et al. Mutations in the amiloride-sensitive epithelial sodium channel in
patients with cystic fibrosis-like disease. Hum Mutat 2009; 30: 1093–1103.
113 Ghosh A, Boucher RC, Tarran R. Airway hydration and COPD. Cell Mol Life Sci 2015; 72: 3637–3652.
114 Mutesa L, Azad AK, Verhaeghe C, et al. Genetic analysis of Rwandan patients with cystic fibrosis-like
symptoms: identification of novel cystic fibrosis transmembrane conductance regulator and epithelial sodium
channel gene variants. Chest 2009; 135: 1233–1242.
115 Wang W, Ji HL. Epithelial sodium and chloride channels and asthma. Chin Med J (Engl) 2015; 128: 2242–2249.
116 Zhao R, Liang X, Zhao M, et al. Correlation of apical fluid-regulating channel proteins with lung function in
human COPD lungs. PLoS One 2014; 9: e109725.
117 Caputo A, Caci E, Ferrera L, et al. TMEM16A, a membrane protein associated with calcium-dependent chloride
channel activity. Science 2008; 322: 590–594.
118 Liu Y, Zhang H, Men H, et al. Volume-regulated Cl− current: contributions of distinct Cl− channels and
localized Ca2+ signals. Am J Physiol Cell Physiol 2019; 317: C466–C480.
119 Le SC, Jia Z, Chen J, et al. Molecular basis of PIP2-dependent regulation of the Ca2+-activated chloride
channel TMEM16A. Nat Commun 2019; 10: 3769.
120 Ma K, Wang H, Yu J, et al. New insights on the regulation of Ca2+-activated chloride channel TMEM16A. J Cell
Physiol 2017; 232: 707–716.
121 Yu K, Jiang T, Cui Y, et al. A network of phosphatidylinositol 4,5-bisphosphate binding sites regulates gating of
the Ca2+-activated Cl− channel ANO1 (TMEM16A). Proc Natl Acad Sci USA 2019; 116: 19952–19962.
122 Ousingsawat J, Martins JR, Schreiber R, et al. Loss of TMEM16A causes a defect in epithelial Ca2+-dependent
chloride transport. J Biol Chem 2009; 284: 28698–28703.
123 Rock JR, O’Neal WK, Gabriel SE, et al. Transmembrane protein 16A (TMEM16A) is a Ca2+-regulated Cl−
secretory channel in mouse airways. J Biol Chem 2009; 284: 14875–14880.
124 Huang F, Zhang H, Wu M, et al. Calcium-activated chloride channel TMEM16A modulates mucin secretion and
airway smooth muscle contraction. Proc Natl Acad Sci USA 2012; 109: 16354–16359.
125 Kondo M, Tsuji M, Hara K, et al. Chloride ion transport and overexpression of TMEM16A in a guinea-pig
asthma model. Clin Exp Allergy 2017; 47: 795–804.
126 Zhang Y, Wang X, Wang H, et al. TMEM16A-mediated mucin secretion in IL-13-induced nasal epithelial cells
from chronic rhinosinusitis patients. Allergy Asthma Immunol Res 2015; 7: 367–375.
127 Salomon JJ, Albrecht T, Graeber SY, et al. Chronic rhinosinusitis with nasal polyps is associated with impaired
TMEM16A-mediated epithelial chloride secretion. J Allergy Clin Immunol 2021; 147: 2191–2201.e2.
128 Liu X, Li T, Riederer B, et al. Loss of Slc26a9 anion transporter alters intestinal electrolyte and HCO− 3 transport
and reduces survival in CFTR-deficient mice. Pflugers Arch 2015; 467: 1261–1275.
129 Lohi H, Kujala M, Makela S, et al. Functional characterization of three novel tissue-specific anion exchangers
SLC26A7, -A8, and -A9. J Biol Chem 2002; 277: 14246–14254.
130 Anagnostopoulou P, Dai L, Schatterny J, et al. Allergic airway inflammation induces a pro-secretory epithelial
ion transport phenotype in mice. Eur Respir J 2010; 36: 1436–1447.
131 Anagnostopoulou P, Riederer B, Duerr J, et al. SLC26A9-mediated chloride secretion prevents mucus
obstruction in airway inflammation. J Clin Invest 2012; 122: 3629–3634.
132 Bakouh N, Bienvenu T, Thomas A, et al. Characterization of SLC26A9 in patients with CF-like lung disease.
Hum Mutat 2013; 34: 1404–1414.
133 Bertrand CA, Mitra S, Mishra SK, et al. The CFTR trafficking mutation F508del inhibits the constitutive activity
of SLC26A9. Am J Physiol Lung Cell Mol Physiol 2017; 312: L912–L925.
134 Li W, Soave D, Miller MR, et al. Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of
modifier genes on early cystic fibrosis-related morbidities. Hum Genet 2014; 133: 151–161.
135 Miller MR, Soave D, Li W, et al. Variants in solute carrier SLC26A9 modify prenatal exocrine pancreatic damage
in cystic fibrosis. J Pediatr 2015; 166: 1152–1157.e6.
136 Pereira SV, Ribeiro JD, Bertuzzo CS, et al. Association of clinical severity of cystic fibrosis with variants in the
SLC gene family (SLC6A14, SLC26A9, SLC11A1 and SLC9A3). Gene 2017; 629: 117–126.
148 https://doi.org/10.1183/2312508X.10018022
137 Pereira SVN, Ribeiro JD, Bertuzzo CS, et al. Interaction among variants in the SLC gene family (SLC6A14,
SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis. Pediatr Pulmonol
2018; 53: 888–900.
138 Soave D, Miller MR, Keenan K, et al. Evidence for a causal relationship between early exocrine pancreatic
disease and cystic fibrosis-related diabetes: a Mendelian randomization study. Diabetes 2014; 63: 2114–2119.
139 Strug LJ, Gonska T, He G, et al. Cystic fibrosis gene modifier SLC26A9 modulates airway response to
CFTR-directed therapeutics. Hum Mol Genet 2016; 25: 4590–4600.
140 Dransfield M, Rowe S, Vogelmeier CF, et al. Cystic fibrosis transmembrane conductance regulator: roles in
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2022; 205: 631–640.
141 Mall MA, Criner GJ, Miravitlles M, et al. Cystic fibrosis transmembrane conductance regulator in COPD: a role in
respiratory epithelium and beyond. Eur Respir J 2023; 61: 2201307.
142 Banks C, Freeman L, Cho DY, et al. Acquired cystic fibrosis transmembrane conductance regulator dysfunction.
World J Otorhinolaryngol Head Neck Surg 2018; 4: 193–199.
143 Cantin AM, Hanrahan JW, Bilodeau G, et al. Cystic fibrosis transmembrane conductance regulator function is
suppressed in cigarette smokers. Am J Respir Crit Care Med 2006; 173: 1139–1144.
144 Clunes LA, Davies CM, Coakley RD, et al. Cigarette smoke exposure induces CFTR internalization and
insolubility, leading to airway surface liquid dehydration. FASEB J 2012; 26: 533–545.
145 Dransfield MT, Wilhelm AM, Flanagan B, et al. Acquired cystic fibrosis transmembrane conductance regulator
dysfunction in the lower airways in COPD. Chest 2013; 144: 498–506.
146 Raju SV, Solomon GM, Dransfield MT, et al. Acquired cystic fibrosis transmembrane conductance regulator
dysfunction in chronic bronchitis and other diseases of mucus clearance. Clin Chest Med 2016; 37: 147–158.
147 Sloane PA, Shastry S, Wilhelm A, et al. A pharmacologic approach to acquired cystic fibrosis transmembrane
conductance regulator dysfunction in smoking related lung disease. PLoS One 2012; 7: e39809.
148 Mazumdar M, Christiani DC, Biswas SK, et al. Elevated sweat chloride levels due to arsenic toxicity. N Engl J
Med 2015; 372: 582–584.
149 Qu F, Qin XQ, Cui YR, et al. Ozone stress down-regulates the expression of cystic fibrosis transmembrane
conductance regulator in human bronchial epithelial cells. Chem Biol Interact 2009; 179: 219–226.
150 Trinh NT, Bilodeau C, Maille E, et al. Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis
transmembrane conductance regulator function and rescue in airway epithelial cells. Eur Respir J 2015; 45:
1590–1602.
151 Galietta LJ, Folli C, Marchetti C, et al. Modification of transepithelial ion transport in human cultured bronchial
epithelial cells by interferon-gamma. Am J Physiol Lung Cell Mol Physiol 2000; 278: L1186–L1194.
152 Le Gars M, Descamps D, Roussel D, et al. Neutrophil elastase degrades cystic fibrosis transmembrane
conductance regulator via calpains and disables channel function in vitro and in vivo. Am J Respir Crit Care
Med 2013; 187: 170–179.
153 Guimbellot JS, Fortenberry JA, Siegal GP, et al. Role of oxygen availability in CFTR expression and function.
Am J Respir Cell Mol Biol 2008; 39: 514–521.
154 Zhang Z, Leir SH, Harris A. Oxidative stress regulates CFTR gene expression in human airway epithelial cells
through a distal antioxidant response element. Am J Respir Cell Mol Biol 2015; 52: 387–396.
155 Kaza N, Lin VY, Stanford D, et al. Evaluation of a novel CFTR potentiator in COPD ferrets with acquired CFTR
dysfunction. Eur Respir J 2022; 60: 2101581.
156 Rowe SM, Jones I, Dransfield MT, et al. Efficacy and safety of the CFTR potentiator icenticaftor (QBW251) in
COPD: results from a phase 2 randomized trial. Int J Chron Obstruct Pulmon Dis 2020; 15: 2399–2409.
Disclosures: S.Y. Graeber has been supported by grants from the Christiane Herzog Stiftung (Stuttgart, Germany)
and the Mukoviszidose Institut gGmbH (Bonn, Germany), the research and development arm of the German Cystic
Fibrosis Association Mukoviszidose e.V. (2101 C-H-P). S.Y. Graeber has received personal fees for participation in
advisory boards and lectures from Chiesi GmbH and Vertex Pharmaceuticals relating to the development of novel
therapies for cystic fibrosis. M.A. Mall has been supported by grants from the German Research Foundation (CRC
1449 – project 431232613; sub-projects A01, C04, Z02; and project 450557679), the German Federal Ministry of
Education and Research (82DZL009B1) and Vertex Pharmaceuticals. M.A. Mall has received personal fees for
participation in advisory boards, consultancy and lectures from Boehringer Ingelheim, Arrowhead Pharmaceuticals,
Vertex Pharmaceuticals, Enterprise Therapeutics, Kither Biotech and Antabio relating to the development of novel
therapies for cystic fibrosis.
https://doi.org/10.1183/2312508X.10018022 149
Chapter 11
Bronchiectasis: from orphan disease

to precision medicine
1,2
Hayoung Choi and James D. Chalmers1
1
Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee,
UK. 2Division of Pulmonary, Allergy, and Critical Care Medicine, Dept of Internal Medicine, Hallym University
Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
Corresponding author: James D. Chalmers ( jchalmers@dundee.ac.uk)
Cite as: Choi H, Chalmers JD. Bronchiectasis: from orphan disease to precision medicine. In: Wagner TOF, Humbert M,
Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory
Society, 2023; pp. 150–164 [https://doi.org/10.1183/2312508X.10018122].
@ERSpublications
Although bronchiectasis was once an orphan disease, advancements in bronchiectasis research based on
phenotyping, endotyping and genotyping have been guiding our understanding and management of this
disease to the era of precision medicine https://bit.ly/ERSM100
ISSN: 2312-5098.
Bronchiectasis is a chronic lung disease characterised radiologically by permanent bronchial dilation

and clinically by the presence of cough, sputum and recurrent chest infection. Once bronchiectasis is
diagnosed, an initial clinical investigation should be conducted to identify the treatable underlying
causes, including allergic bronchopulmonary aspergillosis, immunodeficiency and nontuberculous
mycobacterial lung disease. Uncommon genetic diseases, including primary ciliary dyskinesia and
cystic fibrosis, are also important causes of bronchiectasis and may be identified even in adults with
bronchiectasis. The identified treatable cause can be a therapeutic target in the management of
bronchiectasis. For cases of bronchiectasis without a treatable cause, management includes improving
airway clearance, controlling infection and preventing complications. These features can be highly
individualised, and so a precision medicine approach incorporating phenotypes and endotypes is
recommended. Such an approach can guide the administration of therapy that can effectively reduce
symptom burden and prevent exacerbations.
Introduction
Bronchiectasis not caused by cystic fibrosis (CF) (hereafter referred to as bronchiectasis) is
characterised by permanent dilation of the bronchi on chest CT and compatible symptoms,
including cough, sputum and recurrent chest infections [1, 2]. Bronchiectasis is highly
heterogeneous because it represents the final common pathway of a number of infectious,
genetic, autoimmune and allergic disorders [1, 3]. Bronchiectasis was considered an orphan
disease and was relatively neglected in terms of research [4], but has experienced a renaissance
over the past 10 years. Significant advances in our understanding of bronchiectasis have arisen
through epidemiological studies, large-scale multicentre registries, translational research and
clinical trials [5–9]. In this chapter, we will examine the general aspects of bronchiectasis, with
greater focus on the rare diseases related to bronchiectasis.
150 https://doi.org/10.1183/2312508X.10018122
BRONCHIECTASIS | H. CHOI AND J.D. CHALMERS
Epidemiology
Part of the increasing profile of bronchiectasis is a reflection of its increasing prevalence
worldwide. QUINT et al. [10] reported that the prevalence of bronchiectasis in the UK was up to
566 per 100 000 of the population and showed an increasing trend from 2004 to 2013 of ∼40%.
Similar data have been reported in other European countries, the USA and Asian countries
[11–13]. Moreover, the prevalence of bronchiectasis may have increased further since the time
these statistics were reported, as there have been few reports since 2013. Bronchiectasis is
associated with increased mortality compared with the general population and is also associated
with increased hospitalisation and high healthcare costs [10, 14–17].
Pathophysiology
A traditional “vicious cycle” model explains the pathophysiology of bronchiectasis using key
components: failed mucus clearance, chronic bacterial infection and airway inflammation [18].
This model has evolved into a “vicious vortex” model that emphasises the complex pathways
that connect the three components of bronchiectasis [19]. Each key component has recently
been better understood through the findings of translational research, demonstrating that, in
bronchiectasis, mucus is hyperconcentrated with an excess of the pro-inflammatory mucin
MUC5AC [20], the lung microbiome shows reduced diversity and increased relative abundance
of proteobacteria in severe disease [21, 22], and patients typically have neutrophilic
inflammation dominated by a process called neutrophil extracellular trap formation, which
contributes to immune dysregulation and failure of pathogen clearance [23, 24]. Bronchiectasis
is a heterogeneous disease, however, and as a result, the pathophysiology is both complex and
different among individuals. Several rare diseases of mucociliary clearance, lung structure and
immune dysfunction can cause bronchiectasis, and these are discussed in the next section.
Table 1 summarises other rare diseases that can cause bronchiectasis.
Rare diseases that can cause bronchiectasis

Primary ciliary dyskinesia
Primary ciliary dyskinesia (PCD) is a rare multisystem disease caused by genetic mutations that
result in defects in motile cilia [38]. PCD was determined to be the aetiology of bronchiectasis
in <1% of Indian, 1.7% of European and 3.9% of Australian cohorts of adult patients with
bronchiectasis but is likely to be grossly underdiagnosed [8, 39, 40]. Although no symptom or
sign is 100% specific for PCD, careful history taking allows PCD to be suspected in patients
with bronchiectasis. Potential clues that clinicians should ask about include chronic
rhinosinusitis, recurrent episodes of otitis media, neonatal respiratory failure or distress,
infertility and organ laterality defects (situs inversus) [38, 41, 42]. An early age of onset of
symptoms also makes a genetic cause of bronchiectasis more likely.
A recent genome-sequencing study highlighted the underdiagnosis of PCD in patients with

bronchiectasis. Whole-genome sequencing revealed pathogenic variants in motile ciliopathy
genes in 12% (17 out of 142) of patients with severe bronchiectasis. However, the British
Thoracic Society (BTS) audit data showed that <2% of 4898 patients with bronchiectasis were
tested for PCD and <1% received genetic testing [43]. In addition to a detailed clinical history,
chest CT findings may aid the diagnosis of PCD (figure 1d). Radiologically, the upper lobes are
usually spared, whereas bronchiectasis is prevalent mainly in the middle and lower lobes, in
addition to mucus plugging and peribronchial thickening [44]. Several diagnostic tests are used
to diagnose PCD. Measurement of nasal nitric oxide (NO) levels is widely used as a screening
test, with an NO level of <77 nL·min−1 recommended as the cut-off for discriminating PCD
from non-PCD cases [45, 46]. Nasal NO is not sufficient to rule in or rule out a diagnosis of
https://doi.org/10.1183/2312508X.10018122 151
TABLE 1 Rare diseases associated with the development of bronchiectasis
Aetiology Key features Diagnostic test First author [ref.]
Aspiration Bronchiectasis most abundant in Swallowing assessment, PICCIONE [25]

the posterior segments of the endoscopy and
lower lobes motility testing
Often related to neurological
abnormality or
gastro-oesophageal reflux
α1-Antitrypsin Early-onset (patients in their 30s Levels and function of BRODE [26]
deficiency and 40s) panacinar emphysema α1-antitrypsin
most pronounced in the
lung bases
PFT findings consistent with COPD
ZZ genotype affects liver disease,
including elevated transaminases
and cirrhosis, in older children and
adults (figure 1b)
Airway obstruction Usually localised bronchiectasis Chest CT and DENNEY [27]
Obstruction due to foreign body or bronchoscopy
external compression
Ataxia telangiectasia A rare childhood neurological Serum α-fetoprotein ROTHBLUM-OVIATT [28],
disorder characterised by level and genetic BOTT [29]
cerebellar degeneration, analysis (ATM gene)
telangiectasia, immunodeficiency,
cancer susceptibility and
radiation sensitivity
Bronchiolitis obliterans The end product of a large Chest CT JOSÉ [30], LEE [31]
number of respiratory conditions,
including infections (usually most
common), graft-versus-host disease
and autoimmune diseases
Marfan syndrome The development of bronchiectasis Clinical characteristics TUN [32]
potentially due to an intrinsic and genetic analysis
bronchial wall defect from FBN1 (FBN1 gene)
degeneration or a higher risk of
recurrent lung infections if chest
wall deformities are present
Polycystic kidney The development of bronchiectasis Renal ultrasonography MOUA [33]
disease potentially due to polycystins also and genetic analysis
expressed in the cilia of both (PKD1 or PKD2 gene)
human airway epithelial and
airway smooth muscle cells
Rheumatoid arthritis, Bronchiectasis can precede the Serum autoantibody CHALMERS [1],
Sjögren syndrome, development of other features of evaluation DUARTE [34],
systemic lupus connective tissue disease DE SOYZA [35]
erythematous An inflammatory process in the
lungs can provoke autoimmune
responses, such as the generation
of citrullinated peptide antibodies
against antigens released from
activated neutrophils
Rheumatoid arthritis-related
bronchiectasis showed a worse
prognosis than bronchiectasis of
other aetiologies
Continued
152 https://doi.org/10.1183/2312508X.10018122
TABLE 1 Continued
Aetiology Key features Diagnostic test First author [ref.]
Yellow nail syndrome Middle-age onset Clinical characteristics VIGNES [36],

A rare condition defined by the Genetic analysis (FOXC2 WOODFIELD [37]
presence of two of the following: gene) in some patients
1) slow-growing, hard, yellow and
dystrophic nails; 2) lymphoedema;
or 3) respiratory tract disease
Most common respiratory
manifestations are pleural effusion
and bronchiectasis
In a case–control study,
bronchiectasis in yellow nail
syndrome was less severe than
idiopathic bronchiectasis
ATM: ataxia telangiectasia, mutated; FBN1: fibrillin-1; PKD1/2: polycystin 1/2; FOXC2: forkhead box protein C2.
a) b)
c) d)
FIGURE 1 Typical radiological features of diseases that can cause bronchiectasis. a) Nontuberculous
mycobacterial lung disease. Bronchiectasis is most prevalent in the right middle lobe or lingula plus multifocal
nodular or cavitary opacities and multiple small nodules. b) α1-Antitrypsin deficiency (PI ZZ genotype), showing
panlobular emphysema and bronchiectasis of basal predominance. c) Tracheobronchomegaly, demonstrating an
increased transverse diameter of the trachea and combined bronchiectasis. d) Primary ciliary dyskinesia, with
dextrocardia and bronchiectasis prevalent mainly in the middle and lower lobes, plus mucus plugging and
peribronchial thickening.
https://doi.org/10.1183/2312508X.10018122 153
PCD, as normal nasal NO levels have been observed in patients with PCD related to specific
genes or variants [38, 47]. International guidelines recommend that PCD diagnosis should be
confirmed using a combination of high-speed videomicroscopy, identification of defects using
electron microscopy and pathogenic mutations in known PCD genes [45, 46].
There is currently no specific treatment for PCD. However, it is still important to diagnose PCD
in patients with bronchiectasis to enable the initiation of more specific management strategies.
Most importantly, patients should practice more intensified airway clearance techniques (ACTs),
taught and regularly reviewed by a specialist respiratory physiotherapist. Other management
strategies include upper airway management, cardiac examination, fertility counselling and
genetic counselling. In the future, it is likely that small-molecule and gene therapy to correct
genetic defects will become available [48]. PCD is reviewed in greater depth in another chapter
of this Monograph [49].
CF
CF is dealt with in another chapter of this Monograph [50] and is typically excluded from the list
of causes of “non-CF” bronchiectasis. Nevertheless, it is important to remember that in children
and even adults presenting with unexplained bronchiectasis, CF is among the potential causes.
Milder and atypical genotypes mean that some patients reach adulthood without being suspected
of having CF. Features that may suggest CF include upper airway involvement, upper lobe
bronchiectasis, involvement of organs beyond the chest, infection with Pseudomonas aeruginosa
or Staphylococcus aureus, and an early age of onset of symptoms [51]. It is essential to identify
CF because of the availability of specific therapies, as discussed elsewhere [50].
Nontuberculous mycobacteria
Nontuberculous mycobacteria (NTM) are ubiquitous in the environment, most commonly in
water and soil; they enter the body through inhalation or aspiration and cause lung disease in
susceptible hosts [52, 53]. The relationship between NTM lung disease and bronchiectasis is
well known. However, the cause–effect correlation between the two diseases is like the chicken
and egg question [54]. In international bronchiectasis registry studies, NTM lung disease was
determined to be the aetiology of bronchiectasis in 4.0% of Korean and 8.5% of Australian
patients [9, 40]. Surprisingly, in a US bronchiectasis registry study, 63% of patients had a
history of NTM disease or NTM isolated at baseline evaluation [7]. However, this rate should
be interpreted cautiously, because the cohort of patients in this US study was enrolled from
tertiary referral institutions with an interest in NTM lung disease. True differences in the
geographical distribution of NTM infections are also possible. Demographic data, comorbidities
and radiological findings may serve as clinical clues in cases of suspected NTM lung disease in
patients with bronchiectasis. NTM lung disease is disproportionally more prevalent in females,
and its incidence increases with age [55]. In addition to bronchiectasis, NTM lung disease
affects patients with pre-existing structural pulmonary diseases (e.g. tuberculosis and COPD) [56].
The typical radiological features of NTM pulmonary disease are bronchiectasis that is most
prevalent in the right middle lobe or lingula, plus multifocal nodular or cavitary opacities and
multiple small nodules (figure 1a) [56, 57].
As NTM lung disease is a treatable cause, sputum cultures for mycobacteria should be
considered for all patients with bronchiectasis [58, 59]. If NTM are isolated, the patient should
be assessed as to whether they meet the diagnostic criteria for NTM lung disease according to
the international guidelines, which comprise consistent clinical symptoms, typical chest imaging
findings and compatible microbiological test results as follows: 1) the same NTM species
isolated in two or more sputum cultures, 2) NTM species isolated in at least one bronchial wash
154 https://doi.org/10.1183/2312508X.10018122
or lavage, or 3) biopsy with mycobacterial histopathological features plus positive culture for
NTM (or at least one sputum or bronchial wash that is culture positive for NTM) [52, 53].
Although confirming a diagnosis of NTM lung disease is straightforward, treatment of NTM
lung disease may be challenging. Not all NTM infections require antibiotic treatment, and the
decision must weigh up the benefits and therapeutic difficulties, linked to the high prevalence of
treatment discontinuation due to side-effects, and the risk of treatment failure and relapse. The
treatment of NTM lung disease requires the administration of a combination of antibiotics for a
long period, and should be decided based on clinical symptoms, progression of radiological
signs and knowledge of the infecting NTM species.
Tracheobronchomegaly
Tracheobronchomegaly, also known as Mounier–Kuhn syndrome, is a rare congenital anomaly
characterised by dilated trachea and major bronchi on radiological examination and usually
presents as recurrent lower respiratory infections [60]. The underlying pathology of
tracheobronchomegaly is atrophy or absence of elastic fibres and smooth muscle cells from the
trachea down to the main bronchi [61]. Diagnosis of tracheobronchomegaly can be aided by a
CT scan and bronchoscopy. Radiologically, CT of patients with tracheobronchomegaly shows an
increase in the transverse diameter of the trachea (usually >3 cm) and main bronchi (figure 1c)
[62, 63]. Furthermore, dynamic radiographic studies or bronchoscopy show that the trachea and
main bronchi distend on deep inspiration and collapse on expiration. Although there is no
specific therapy for tracheobronchomegaly, we suggest that general bronchiectasis management
strategies, including ACTs, would be beneficial.
Allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is an immunologically mediated lung disease
caused by sensitisation to Aspergillus fumigatus [64]. Sensitisation to other fungi may also
occur, which is referred to as allergic bronchopulmonary mycosis. ABPA is reported to most
commonly complicate asthma or CF, although the orphan nature of bronchiectasis is such that
the relationship between ABPA and bronchiectasis has not been well studied. The typical
clinical manifestations of ABPA include symptoms of poorly controlled asthma such as
breathlessness, cough and wheeze, recurrent pulmonary opacities and bronchiectasis [65].
Expectoration of brownish mucus plugs is a characteristic symptom observed in approximately
one-third of patients with ABPA [66, 67].
Multicentre bronchiectasis registry studies have shown that the prevalence of ABPA among
patients with bronchiectasis varies geographically, with 3.9% reported in Australia, 4.5% in
European countries and 8.9% in India [8, 39, 40]. Bronchiectasis with ABPA is more
commonly central or affects the upper lobes, whereas bronchiectasis of other aetiologies is
predominantly peripheral and affects the lower lobes [64]. High-attenuation mucus plugging in
the bronchi is a typical radiological abnormality in ABPA [66, 68]. Although the mucoid
impaction is usually hypodense on chest CT, the high-attenuation mucus is visibly denser than
the paraspinal skeletal muscles, which is pathognomonic for ABPA.
In addition to medical history and imaging abnormalities indicating ABPA, immunological and
microbiological tests are essential for the diagnosis of ABPA. The generally recommended tests
are a total serum IgE test, an Aspergillus-specific IgG test and an Aspergillus-specific IgE test
(or skin prick tests for Aspergillus) [69]. The European Respiratory Society (ERS) and BTS
bronchiectasis guidelines recommend routine screening of all patients for ABPA at the time of
diagnosis [58, 59]. This is because establishing the diagnosis of ABPA, which is a treatable
cause of bronchiectasis, can facilitate aetiology-directed therapy. Systemic corticosteroids, which
https://doi.org/10.1183/2312508X.10018122 155
help suppress immune hyperreactivity through their anti-inflammatory properties, are the
mainstay of ABPA treatment [66]. Antifungal agents are also widely used for the treatment of
ABPA. The role of these agents has not been fully determined, although they are presumed to
aid in suppressing the inflammatory response by reducing the fungal burden and mitigating the
antigenic stimulus [70]. A randomised controlled trial (RCT) also showed that the addition of
itraconazole could lead to a clinical improvement in patients with corticosteroid-dependent
ABPA [71]. Due to the large variability in systemic absorption of itraconazole and the lack of
an analytical method to measure its blood level, in some cases, voriconazole is also considered
for the management of ABPA, despite its higher cost [72]. Although the optimal treatment
regimen for ABPA is still under investigation [73, 74], early diagnosis of ABPA and prompt
initiation of treatment in the acute stage are of paramount importance for preventing further lung
damage in patients with bronchiectasis.
Immunodeficiency
Patients with primary (PID) or secondary immunodeficiency have a high risk for bronchiectasis,
not only because their immune systems cannot effectively defend their lungs against infections
but also because they may have a dysregulated inflammatory response [75, 76]. Recurrent
infections, particularly in multiple locations and by unusual organisms, can be clues for PID
when recording the medical history of patients with bronchiectasis.
PID was reported as the aetiology of bronchiectasis in 3.7% of Australian, 4.2% of Spanish and
5.8% of European adult patients in a multicentre cohort [39, 40, 77]. ERS and BTS
bronchiectasis guidelines recommend measuring the serum IgA, IgM and IgG levels of all
patients at the time of screening [58, 59]. In addition, BTS guidelines recommend the
measurement of antibody levels to assess a patient’s functional antibody response; if they are
low, the patient should be immunised using the 23-valent carbohydrate pneumococcal vaccine,
and the post-vaccination antibody levels should be checked 4–8 weeks later. Antibody levels
below the protective threshold are indicative of specific polysaccharide antibody deficiency [58].
However, as a wide array of immunodeficiencies exist, some immunodeficiency diseases can be
identified only through in-depth immune function tests aided by genetic confirmation [78], which
requires cooperation with immunologists. Moreover, extrapulmonary manifestations of PID can
be heterogeneous (e.g. cancer, gastrointestinal, haematological and rheumatological disorders), so
the involvement of a multidisciplinary team for coordinated action may often be necessary [79].
Despite the low prevalence of PID among adults with bronchiectasis, establishment of the
diagnosis of PID is important because it can alter the course of management in the subset of
patients with PID. It is well known that Ig substitution decreases the risk for bacterial
pneumonia and mortality in patients with PID [80, 81]. In a French single-centre, observational
study of 98 patients who underwent four or more PFTs and were followed up for a median of
9.5 years, patients with PID-related bronchiectasis (20.4%) who received Ig replacement and
patients with bronchiectasis of other aetiologies (79.6%) showed similar clinical outcomes, including
exacerbation rate, number of hospitalisations, lung function decline and mortality rate [82]. The
results of this study indicate that PID is one of the treatable causes of bronchiectasis.
Inflammatory bowel disease-associated bronchiectasis

A rare complication of Crohn’s disease and particularly ulcerative colitis is the development of
bronchiectasis [1, 83]. Patients typically have copious sputum production with no evidence
of airway infection, the so-called “sterile bronchorrhoea”. Bronchoscopy may show ulceration of
the bronchial walls and copious secretions. Patients typically have a history of inflammatory
bowel disease (IBD), and a relationship with bowel surgery and particularly previous colectomy
156 https://doi.org/10.1183/2312508X.10018122
has been reported. An awareness of IBD-associated bronchiectasis as a distinct rare disease is

important because patients are typically treated repeatedly with ineffective courses of antibiotics,
which fail to improve the sputum production. IBD-associated disease is highly sensitive to
corticosteroids, and high-dose inhaled corticosteroids are usually effective in reducing symptoms
or even achieving complete remission of symptoms.
Investigation of bronchiectasis
The aim of initial investigation in cases of bronchiectasis is to assess the possible underlying
aetiology, the severity of the disease and the presence of treatable traits. International bronchiectasis
guidelines recommend the use of a set of tests for the initial evaluation of bronchiectasis, which
generally includes a differential blood count, immunoglobulin tests (IgG, IgA and IgM), total IgE
level, A. fumigatus-specific IgE and IgG/preceptins, bacterial and mycobacterial sputum cultures,
and spirometry [58, 59, 84–88]. As mentioned earlier, some of these tests aid in defining the
underlying aetiology of bronchiectasis. In contrast, bacterial culture results, particularly isolation of
P. aeruginosa, and lung function provide important information necessary for predicting the
long-term outcomes of patients with bronchiectasis [89–91]. Furthermore, isolation of
P. aeruginosa may guide chronic bacterial infection-targeted therapy, such as eradication treatment
or long-term inhaled antibiotics in the case of failed eradication [58, 59, 92].
Some aspects of the initial aetiological evaluation of bronchiectasis need to be discussed. First,
regarding the recommendation of utilising a set of initial tests, a previous study indicated that a
standardised aetiological algorithm for bronchiectasis could reduce the frequency of diagnosis of
idiopathic bronchiectasis from 42% to 29% [93]. However, the standardised approach should be
tailored according to the differences in the prevalence of underlying causes of bronchiectasis in
different regions; for example, measurement of the serum level of α1-antitrypsin is
recommended by the Pulmonology Portuguese Society Bronchiectasis Study Group but is not
recommended in the UK (estimated prevalence of α1-antitrypsin deficiency: 1 in 2191 in
Portugal, 1 in 4440 in England and 1 in 15 388 in Scotland) [87, 94]. Second, who should
receive more extensive diagnostic work-up beyond a set of tests for initial evaluation? Patients
with bronchiectasis who present with symptoms suggesting a rare aetiology such as PCD should
be investigated. PCD testing requires considerable expertise, which is not available in all
hospitals, and therefore testing is limited by available resources [58, 59]. Third, the availability
of the specific therapeutic approach should also be considered as a criterion for prioritised
diagnostic work-up. For example, the availability of targeted CF transmembrane conductance
regulator modulator treatment for defined CF genotypes has a dramatic impact on the individual
patient, although CF is a very rare aetiology of bronchiectasis and comprises only ∼1% of
cases [51]. Prospective bronchiectasis registry studies have shown that, even after diagnostic
work-up, 21–42% of bronchiectasis cases have an idiopathic aetiology [9]. Moreover,
considering that there is no available specific treatment for bronchiectasis with a postinfective or
post-tuberculosis aetiology, initiation of aetiology-targeted treatment is not possible for a large
proportion of patients with bronchiectasis. The phenotypes, endotypes and treatable traits of
bronchiectasis will be discussed in the next section from this perspective.
Management of bronchiectasis: treatable traits

The key goals of the management of bronchiectasis are to reduce symptoms, improve quality of
life, prevent exacerbations and hospitalisations, and, where possible, reduce mortality. As the
key components of the disease include impaired mucus clearance, airway infection and
inflammation, treatments are focused on each of these aspects, including airway physiotherapy,
mucoactive drugs, antibiotic treatments and anti-inflammatories. Bronchiectasis management is
https://doi.org/10.1183/2312508X.10018122 157
challenging because the disease is so heterogeneous and patients present with very diverse
symptoms and severity of disease, and therefore treatment needs. A personalised management
approach based on the patient’s clinical features, also known as treatable traits, is recommended.
Treatable causes
As discussed in the section Rare diseases that can cause bronchiectasis, an underlying cause,
such as ABPA and NTM lung disease, can guide the treatment of bronchiectasis. We
recommend that general management for bronchiectasis be provided along with
aetiology-specific treatment to patients with bronchiectasis. For example, ACTs aid the
improvement of respiratory symptoms and health-related quality of life, even in patients who are
receiving antibiotic therapy for NTM lung disease [95, 96].
Phenotypes and endotypes

Management of bronchiectasis without a treatable aetiology is a challenging aspect of
bronchiectasis management. How should such cases be classified beyond just saying they are
cases of idiopathic or postinfective bronchiectasis? Phenotypes and endotypes are useful in this
context. Phenotypes are defined as observable characteristics related to clinically meaningful
outcomes [97]. Most well-characterised phenotypes in bronchiectasis are “chronic Pseudomonas
infection”, associated with increased exacerbations, hospital admissions and mortality [98], or
“frequent exacerbator”, which denotes frequent past exacerbations that are strong predictors of
future exacerbation [99]. Phenotypes can aid the identification of the clinical problem and the
determination of related outcomes. Endotypes are defined as specific pathophysiological
processes or biomarkers [100]. From this perspective, clinicians can determine which of the
three components of bronchiectasis pathophysiology (failed mucus clearance, chronic bacterial
infection and airway inflammation) is the key mechanism underlying symptom burden and
exacerbation in patients with bronchiectasis. The recognised endotypes may serve as treatable
traits that guide bronchiectasis management, which is discussed in the next section.
Treatable traits-targeted management

The recent progress in bronchiectasis research, including RCTs, has provided a higher level of
evidence for the management of bronchiectasis in clinical practice. In this section, we briefly
introduce bronchiectasis research from the perspective of the treatable traits concept.
First, the most widely used nonpharmacological technique for failed mucus clearance-targeted
therapy for bronchiectasis is ACTs. This is because bronchiectasis guidelines recommend that
all patients with bronchiectasis should receive instructions on ACTs [58, 59]. Although existing
evidence regarding the efficacy of physiotherapy is regarded as weak, MUNOZ et al. [101]
performed an RCT of 22 patients who performed the ELTGOL technique (slow expiration with
the glottis opened in the lateral posture) twice a day over 1 year compared with 22 patients who
performed placebo exercises. Sputum volume as the primary study outcome was higher in the
ELTGOL group than in the placebo group. Furthermore, patients in the ELTGOL group had a
clinically significant improvement in health-related quality of life ( p<0.001) and fewer
exacerbations than the placebo group ( p=0.042). Although evidence is weak, a proportion of
patients will benefit from the use of mucoactive therapies such as hypertonic saline or
carbocisteine/N-acetylcysteine [58, 59]. RCTs of these therapies are ongoing.
In patients with airway infections, inhalation of antibiotics is recommended by ERS guidelines

for the management of patients with three or more exacerbations per year and infection with
P. aeruginosa [59]. Although individual trials have shown conflicting results regarding the
efficacy of inhaled antibiotics, a meta-analysis of 16 trials with 2597 patients showed that
158 https://doi.org/10.1183/2312508X.10018122
inhaled antibiotics significantly reduced the frequency of all exacerbations (rate ratio (RR) 0.81,
95% CI 0.67–0.97; p=0.020) and severe exacerbations (RR 0.43, 95% CI, 0.24–0.78; p=0.005)
[92]. Furthermore, the time to first exacerbation was significantly prolonged (hazard ratio (HR)
0.83, 95% CI 0.69–0.99; p=0.015).
Third, the most typical example of airway inflammation-targeted therapy for bronchiectasis is
long-term administration of macrolides. An individual patient meta-analysis, which included three
Bronchiectasis diagnosis
• Based on chest CT and clinical symptoms/signs
Medical history
• Including exacerbation and comorbidities
A set of tests for initial investigation

Investigation
More extensive diagnosis work-up

• When rare underlying causes are suspected
Sputum microbiology and spirometry
Bronchiectasis severity and clinical phenotype assessment
Does a patient have a treatable underlying cause?
Yes No
Treat underlying cause Investigate treatable traits

• CF, PCD, ABPA, NTM lung • Phenotypes and
disease, etc. endotypes
Treatable traits-targeted management

Management
Failed mucus clearance Chronic bacterial infection Airway inflammation
• Airway clearance • Inhaled antibiotics

technique • Eradication antibiotics
• Mucoactive therapy Neutrophilic Eosinophilic
endotype endotype
• Long-term macrolide • Inhaled corticosteroid

• Dipeptidyl peptidase-1 • Anti-IL-5 or anti-IL-5
inhibitor (under receptor monoclonal
development) antibodies
FIGURE 2 Suggested algorithm for the management of bronchiectasis. CF: cystic fibrosis; PCD: primary ciliary
dyskinesia; ABPA: allergic bronchopulmonary aspergillosis; NTM: nontuberculous mycobacteria; IL: interleukin.
https://doi.org/10.1183/2312508X.10018122 159
trials (n=341), showed that macrolides reduced the frequency of exacerbation (incidence RR 0.49,
95% CI 0.36–0.66; p<0.001) and prolonged the time to first exacerbation (HR 0.46, 95% CI 0.34–
0.61; p<0.001) in patients with bronchiectasis [102]. Moreover, molecular studies revealed that
neutrophilic inflammation can reflect disease activity, stratify patients according to the expected
outcomes and serve as a direct therapeutic target [23, 24, 103]. A novel drug that directly targets
neutrophilic inflammation through inhibition of dipeptidyl peptidase-1 in bronchiectasis is
currently under development [104]. In addition, although bronchiectasis is classically regarded as a
neutrophilic disorder, ∼20% of the population in a recent European multicohort study had
eosinophilic inflammation, a subtype that may respond to targeted therapy with corticosteroids or
biological drugs currently used for asthma [105]. This result may be a milestone finding that
ushers in an era of targeting eosinophilic inflammation in the treatment of bronchiectasis.
There is no one-size-fits-all therapeutic strategy for the management of bronchiectasis.

Appropriate targeting of treatable traits may guarantee optimal treatment outcomes in patients
with bronchiectasis. For example, an RCT indicated that inhaled mannitol did not significantly
reduce exacerbation rates, which was the primary outcome of the study [106]. Interestingly, a
post-hoc analysis by GAO et al. [107] showed that inhaled mannitol treatment improved the time
to first exacerbation (HR 0.56, 95% CI 0.40–0.77; p<0.001) only in highly symptomatic
patients (symptom burden was measured using the St George’s Respiratory Questionnaire);
however, no benefit was evident in patients with lower symptom burdens.
Idiopathic disease in the future: precision medicine

Non-CF bronchiectasis may not be the right name for describing a group of various disorders that
present with bronchiectasis. Investigating the aetiology permits accurate naming of some diseases,
particularly the rare diseases mentioned earlier. In the future, idiopathic and postinfective
bronchiectasis, which account for a large proportion of bronchiectasis cases, will probably be broken
down into several subtypes through phenotyping, endotyping and genotyping. Consequently, the
right name for each subtype of bronchiectasis will guide treatable traits-targeted management.
Figure 2 depicts a suggested algorithm for the investigation and management of bronchiectasis.
Conclusion
Bronchiectasis has been suggested as the most common chronic respiratory disease after asthma
and COPD, with a very high socioeconomic burden according to the current epidemiological
data. Once bronchiectasis is diagnosed, a set of tests for initial investigation should be
performed to identify the treatable underlying causes. Although the prevalence of each aetiology
of bronchiectasis may be low compared with the overall prevalence of bronchiectasis, defining
PCD, NTM lung disease, ABPA or immunodeficiency as the underlying aetiology allows
identification of the treatable cause in cases of bronchiectasis. For cases of bronchiectasis
without a treatable cause, phenotypes and endotypes may facilitate the recognition of problems
and related pathophysiological mechanisms that indicate treatable traits. Bronchiectasis
management that appropriately targets one or more of the three key treatable traits (failed mucus
clearance, chronic bacterial infection and airway inflammation) can be effective in reducing
symptom burden and preventing exacerbations.
References
1 Chalmers JD, Chang AB, Chotirmall SH, et al. Bronchiectasis. Nat Rev Dis Primers 2018; 4: 45.
2 Aliberti S, Goeminne PC, O’Donnell AE, et al. Criteria and definitions for the radiological and clinical diagnosis
of bronchiectasis in adults for use in clinical trials: international consensus recommendations. Lancet Respir
Med 2022; 10: 298–306.
160 https://doi.org/10.1183/2312508X.10018122
3 O’Donnell AE. Bronchiectasis – a clinical review. N Engl J Med 2022; 387: 533–545.
4 Keistinen T, Saynajakangas O, Tuuponen T, et al. Bronchiectasis: an orphan disease with a poorly-understood
prognosis. Eur Respir J 1997; 10: 2784–2787.
5 Chalmers JD. Bronchiectasis from 2012 to 2022. Clin Chest Med 2022; 43: 1–6.
6 Chalmers JD, Aliberti S, Polverino E, et al. The EMBARC European Bronchiectasis Registry: protocol for an
international observational study. ERJ Open Res 2016; 2: 00081-2015.
7 Aksamit TR, O’Donnell AE, Barker A, et al. Adult patients with bronchiectasis: a first look at the US
bronchiectasis research registry. Chest 2017; 151: 982–992.
8 Dhar R, Singh S, Talwar D, et al. Bronchiectasis in India: results from the European Multicentre Bronchiectasis
Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India Registry. Lancet Glob
Health 2019; 7: e1269–e1279.
9 Lee H, Choi H, Chalmers JD, et al. Characteristics of bronchiectasis in Korea: first data from the Korean
Multicentre Bronchiectasis Audit and Research Collaboration registry and comparison with other international
registries. Respirology 2021; 26: 619–621.
10 Quint JK, Millett ER, Joshi M, et al. Changes in the incidence, prevalence and mortality of bronchiectasis in
the UK from 2004 to 2013: a population-based cohort study. Eur Respir J 2016; 47: 186–193.
11 Choi H, Yang B, Nam H, et al. Population-based prevalence of bronchiectasis and associated comorbidities in
South Korea. Eur Respir J 2019; 54: 1900194.
12 Weycker D, Hansen GL, Seifer FD. Prevalence and incidence of noncystic fibrosis bronchiectasis among US
adults in 2013. Chron Respir Dis 2017; 14: 377–384.
13 Ringshausen FC, Rademacher J, Pink I, et al. Increasing bronchiectasis prevalence in Germany, 2009–2017: a
population-based cohort study. Eur Respir J 2019; 54: 1900499.
14 Seitz AE, Olivier KN, Adjemian J, et al. Trends in bronchiectasis among Medicare beneficiaries in the United
States, 2000 to 2007. Chest 2012; 142: 432–439.
15 Sanchez-Munoz G, Lopez de Andres A, Jimenez-Garcia R, et al. Time trends in hospital admissions for
bronchiectasis: analysis of the Spanish national hospital discharge data (2004 to 2013). PLoS One 2016; 11:
e0162282.
16 Choi H, Yang B, Kim YJ, et al. Increased mortality in patients with non cystic fibrosis bronchiectasis with
respiratory comorbidities. Sci Rep 2021; 11: 7126.
17 Diel R, Chalmers JD, Rabe KF, et al. Economic burden of bronchiectasis in Germany. Eur Respir J 2019; 53:
1802033.
18 Cole PJ. Inflammation: a two-edged sword – the model of bronchiectasis. Eur J Respir Dis Suppl 1986; 147:
6–15.
19 Flume PA, Chalmers JD, Olivier KN. Advances in bronchiectasis: endotyping, genetics, microbiome, and
disease heterogeneity. Lancet 2018; 392: 880–890.
20 Ramsey KA, Chen ACH, Radicioni G, et al. Airway mucus hyperconcentration in non-cystic fibrosis
bronchiectasis. Am J Respir Crit Care Med 2020; 201: 661–670.
21 Dicker AJ, Lonergan M, Keir HR, et al. The sputum microbiome and clinical outcomes in patients with
bronchiectasis: a prospective observational study. Lancet Respir Med 2021; 9: 885–896.
22 Mac Aogain M, Narayana JK, Tiew PY, et al. Integrative microbiomics in bronchiectasis exacerbations. Nat Med
2021; 27: 688–699.
23 Chalmers JD, Moffitt KL, Suarez-Cuartin G, et al. Neutrophil elastase activity is associated with exacerbations
and lung function decline in bronchiectasis. Am J Respir Crit Care Med 2017; 195: 1384–1393.
24 Keir HR, Shoemark A, Dicker AJ, et al. Neutrophil extracellular traps, disease severity, and antibiotic response
in bronchiectasis: an international, observational, multicohort study. Lancet Respir Med 2021; 9: 873–884.
25 Piccione JC, McPhail GL, Fenchel MC, et al. Bronchiectasis in chronic pulmonary aspiration: risk factors and
clinical implications. Pediatr Pulmonol 2012; 47: 447–452.
26 Brode SK, Ling SC, Chapman KR. Alpha-1 antitrypsin deficiency: a commonly overlooked cause of lung
disease. CMAJ 2012; 184: 1365–1371.
27 Denney MK, Berkas EM, Snider TH, et al. Foreign body bronchiectasis. Dis Chest 1968; 53: 613–616.
28 Rothblum-Oviatt C, Wright J, Lefton-Greif MA, et al. Ataxia telangiectasia: a review. Orphanet J Rare Dis 2016;
11: 159.
29 Bott L, Lebreton J, Thumerelle C, et al. Lung disease in ataxia-telangiectasia. Acta Paediatr 2007; 96:
1021–1024.
30 José RJ, Dickey BF, Sheshadri A. Airway disease in hematologic malignancies. Expert Rev Respir Med 2022; 16:
303–313.
31 Lee E, Shim JY, Kim HY, et al. Clinical characteristics and etiologies of bronchiectasis in Korean children: a
multicenter retrospective study. Respir Med 2019; 150: 8–14.
32 Tun MH, Borg B, Godfrey M, et al. Respiratory manifestations of Marfan syndrome: a narrative review. J Thorac
Dis 2021; 13: 6012–6025.
https://doi.org/10.1183/2312508X.10018122 161
33 Moua T, Zand L, Hartman RP, et al. Radiologic and clinical bronchiectasis associated with autosomal
dominant polycystic kidney disease. PLoS One 2014; 9: e93674.
34 Duarte AC, Porter J, Leandro MJ. Bronchiectasis in rheumatoid arthritis. A clinical appraisial. Joint Bone Spine
2020; 87: 419–424.
35 de Soyza A, McDonnell MJ, Goeminne PC, et al. Bronchiectasis rheumatoid overlap syndrome is an
independent risk factor for mortality in patients with bronchiectasis: a multicenter cohort study. Chest 2017;
151: 1247–1254.
36 Vignes S, Baran R. Yellow nail syndrome: a review. Orphanet J Rare Dis 2017; 12: 42.
37 Woodfield G, Nisbet M, Jacob J, et al. Bronchiectasis in yellow nail syndrome. Respirology 2017; 22: 101–107.
38 Goutaki M, Shoemark A. Diagnosis of primary ciliary dyskinesia. Clin Chest Med 2022; 43: 127–140.
39 Lonni S, Chalmers JD, Goeminne PC, et al. Etiology of non-cystic fibrosis bronchiectasis in adults and its
correlation to disease severity. Ann Am Thorac Soc 2015; 12: 1764–1770.
40 Visser SK, Bye PTP, Fox GJ, et al. Australian adults with bronchiectasis: the first report from the Australian
Bronchiectasis Registry. Respir Med 2019; 155: 97–103.
41 Vanaken GJ, Bassinet L, Boon M, et al. Infertility in an adult cohort with primary ciliary dyskinesia:
phenotype–gene association. Eur Respir J 2017; 50: 1700314.
42 Hirokawa N, Tanaka Y, Okada Y, et al. Nodal flow and the generation of left-right asymmetry. Cell 2006; 125:
33–45.
43 Shoemark A, Griffin H, Wheway G, et al. Genome sequencing reveals underdiagnosis of primary ciliary
dyskinesia in bronchiectasis. Eur Respir J 2022; 60: 2200176.
44 Rademacher J, Dettmer S, Fuge J, et al. The primary ciliary dyskinesia computed tomography score in adults
with bronchiectasis: a derivation und validation study. Respiration 2021; 100: 499–509.
46 Shapiro AJ, Davis SD, Polineni D, et al. Diagnosis of primary ciliary dyskinesia. An Official American Thoracic
47 Shoemark A, Moya E, Hirst RA, et al. High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary
dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations. Thorax
2018; 73: 157–166.
48 Contarini M, Shoemark A, Rademacher J, et al. Why, when and how to investigate primary ciliary dyskinesia in
adult patients with bronchiectasis. Multidiscip Respir Med 2018; 13: Suppl. 1, 26.
49 Pennekamp P, Raidt J, Wohlgemuth K, et al. Primary ciliary dyskinesia. In: Wagner TOF, Humbert M,
50 Graeber SY, Mall MA. Cystic fibrosis and other ion channel-related diseases. In: Wagner TOF, Humbert M,
51 Shteinberg M, Haq IJ, Polineni D, et al. Cystic fibrosis. Lancet 2021; 397: 2195–2211.
52 Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an
official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline. Clin Infect Dis 2020; 71: e1–e36.
53 Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and
prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175: 367–416.
54 Yang B, Ryu J, Kim T, et al. Impact of bronchiectasis on incident nontuberculous mycobacterial pulmonary
disease: a 10-year National Cohort Study. Chest 2021; 159: 1807–1811.
55 Prevots DR, Shaw PA, Strickland D, et al. Nontuberculous mycobacterial lung disease prevalence at four
integrated health care delivery systems. Am J Respir Crit Care Med 2010; 182: 970–976.
56 Stout JE, Koh WJ, Yew WW. Update on pulmonary disease due to non-tuberculous mycobacteria. Int J Infect
Dis 2016; 45: 123–134.
57 Dettmer S, Ringshausen FC, Fuge J, et al. Computed tomography in adults with bronchiectasis and
nontuberculous mycobacterial pulmonary disease: typical imaging findings. J Clin Med 2021; 10: 2736.
58 Hill AT, Sullivan AL, Chalmers JD, et al. British Thoracic Society Guideline for bronchiectasis in adults. Thorax
2019; 74: Suppl. 1, 1–69.
59 Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society guidelines for the management
of adult bronchiectasis. Eur Respir J 2017; 50: 1700629.
60 Schwartz M, Rossoff L. Tracheobronchomegaly. Chest 1994; 106: 1589–1590.
61 van Schoor J, Joos G, Pauwels R. Tracheobronchomegaly – the Mounier–Kuhn syndrome: report of two cases
and review of the literature. Eur Respir J 1991; 4: 1303–1306.
62 Govindaraj V, Mohapatra MM, Kumar BN, et al. Tracheobronchomegaly as a cause of bronchiectasis in an
adult. Case Rep Pulmonol 2016; 2016: 5049406.
162 https://doi.org/10.1183/2312508X.10018122
63 Satia I, Dua B, Singh N, et al. Tracheobronchomegaly, cough and recurrent chest infection: Mounier–Kuhn
syndrome. ERJ Open Res 2020; 6: 00138-2020.
64 Shah A, Panjabi C. Allergic aspergillosis of the respiratory tract. Eur Respir Rev 2014; 23: 8–29.
65 Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2002; 110: 685–692.
66 Agarwal R, Muthu V, Sehgal IS, et al. Allergic bronchopulmonary aspergillosis. Clin Chest Med 2022; 43: 99–125.
67 Agarwal R, Gupta D, Aggarwal AN, et al. Clinical significance of hyperattenuating mucoid impaction in allergic
bronchopulmonary aspergillosis: an analysis of 155 patients. Chest 2007; 132: 1183–1190.
68 Agarwal R. High attenuation mucoid impaction in allergic bronchopulmonary aspergillosis. World J Radiol
2010; 2: 41–43.
69 Greenberger PA. When to suspect and work up allergic bronchopulmonary aspergillosis. Ann Allergy Asthma
Immunol 2013; 111: 1–4.
70 Malo JL. Antifungal therapy for allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2003; 111:
934–935.
71 Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary
aspergillosis. N Engl J Med 2000; 342: 756–762.
72 Agarwal R, Dhooria S, Sehgal IS, et al. A randomised trial of voriconazole and prednisolone monotherapy in
acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Eur Respir J 2018; 52: 1801159.
73 Agarwal R, Dhooria S, Singh Sehgal I, et al. A randomized trial of itraconazole vs prednisolone in acute-stage
allergic bronchopulmonary aspergillosis complicating asthma. Chest 2018; 153: 656–664.
74 Agarwal R, Muthu V, Sehgal IS, et al. A randomised trial of prednisolone versus prednisolone and itraconazole
in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Eur Respir J 2022; 59: 2101787.
75 Wall LA, Wisner EL, Gipson KS, et al. Bronchiectasis in primary antibody deficiencies: a multidisciplinary
approach. Front Immunol 2020; 11: 522.
76 Holmes AH, Pelton S, Steinbach S, et al. HIV related bronchiectasis. Thorax 1995; 50: 1227.
77 Martinez-Garcia MA, Villa C, Dobarganes Y, et al. RIBRON: the Spanish online bronchiectasis registry.
Characterization of the first 1912 patients. Arch Bronconeumol 2021; 57: 28–35.
78 Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases: an update on the classification
from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency
2015. J Clin Immunol 2015; 35: 696–726.
79 Barrios Y, Franco A, Alonso-Larruga A, et al. Success with multidisciplinary team work: experience of a primary
immunodeficiency unit. J Investig Allergol Clin Immunol 2020; 30: 208–210.
80 Aguilar C, Malphettes M, Donadieu J, et al. Prevention of infections during primary immunodeficiency. Clin
Infect Dis 2014; 59: 1462–1470.
81 Orange JS, Grossman WJ, Navickis RJ, et al. Impact of trough IgG on pneumonia incidence in primary
immunodeficiency: a meta-analysis of clinical studies. Clin Immunol 2010; 137: 21–30.
82 Goussault H, Salvator H, Catherinot E, et al. Primary immunodeficiency-related bronchiectasis in adults:
comparison with bronchiectasis of other etiologies in a French reference center. Respir Res 2019; 20: 275.
83 Camus P, Colby TV. The spectrum of airway involvement in inflammatory bowel disease. Clin Chest Med 2022;
43: 141–155.
84 Choi H, Lee H, Ra SW, et al. Developing a diagnostic bundle for bronchiectasis in South Korea: a modified
Delphi consensus study. Tuberc Respir Dis (Seoul) 2022; 85: 56–66.
85 Al-Jahdali H, Alshimemeri A, Mobeireek A, et al. The Saudi Thoracic Society guidelines for diagnosis and
management of noncystic fibrosis bronchiectasis. Ann Thorac Med 2017; 12: 135–161.
86 Martinez-Garcia MA, Maiz L, Olveira C, et al. Spanish guidelines on treatment of bronchiectasis in adults. Arch
Bronconeumol 2018; 54: 88–98.
87 Pulmonology Portuguese Society Bronchiectasis Study Group. Recommendations for aetiological diagnosis of
bronchiectasis. Rev Port Pneumol (2006) 2016; 22: 222–235.
88 Chang AB, Bell SC, Torzillo PJ, et al. Chronic suppurative lung disease and bronchiectasis in children and
adults in Australia and New Zealand Thoracic Society of Australia and New Zealand guidelines. Med J Aust
2015; 202: 130.
89 Araujo D, Shteinberg M, Aliberti S, et al. The independent contribution of Pseudomonas aeruginosa infection
to long-term clinical outcomes in bronchiectasis. Eur Respir J 2018; 51: 1701953.
90 Chalmers JD, Goeminne P, Aliberti S, et al. The bronchiectasis severity index. An international derivation and
validation study. Am J Respir Crit Care Med 2014; 189: 576–585.
91 Martinez-Garcia MA, Vendrell M, Giron R, et al. The multiple faces of non-cystic fibrosis bronchiectasis. A
cluster analysis approach. Ann Am Thorac Soc 2016; 13: 1468–1475.
92 Laska IF, Crichton ML, Shoemark A, et al. The efficacy and safety of inhaled antibiotics for the treatment of
bronchiectasis in adults: a systematic review and meta-analysis. Lancet Respir Med 2019; 7: 855–869.
93 Araujo D, Shteinberg M, Aliberti S, et al. Standardised classification of the aetiology of bronchiectasis using an
objective algorithm. Eur Respir J 2017; 50: 1701289.
https://doi.org/10.1183/2312508X.10018122 163
94 Blanco I, Bueno P, Diego I, et al. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers
worldwide: an update. Int J Chron Obstruct Pulmon Dis 2017; 12: 561–569.
95 Lee AL, Burge AT, Holland AE. Airway clearance techniques for bronchiectasis. Cochrane Database Syst Rev
2015; 11: CD008351.
96 Lee AL, Burge AT, Holland AE. Positive expiratory pressure therapy versus other airway clearance techniques
for bronchiectasis. Cochrane Database Syst Rev 2017; 9: CD011699.
97 Chalmers JD. Phenotypes and endotypes. Bronchiectasis 2018; 81: 133–152.
98 Finch S, McDonnell MJ, Abo-Leyah H, et al. A comprehensive analysis of the impact of Pseudomonas
aeruginosa colonization on prognosis in adult bronchiectasis. Ann Am Thorac Soc 2015; 12: 1602–1611.
100 Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous
disease. Lancet 2008; 372: 1107–1119.
101 Munoz G, de Gracia J, Buxo M, et al. Long-term benefits of airway clearance in bronchiectasis: a randomised
placebo-controlled trial. Eur Respir J 2018; 51: 1701926.
102 Chalmers JD, Boersma W, Lonergan M, et al. Long-term macrolide antibiotics for the treatment of
bronchiectasis in adults: an individual participant data meta-analysis. Lancet Respir Med 2019; 7: 845–854.
103 Giam YH, Shoemark A, Chalmers JD. Neutrophil dysfunction in bronchiectasis: an emerging role for
immunometabolism. Eur Respir J 2021; 58: 2003157.
104 Chalmers JD, Haworth CS, Metersky ML, et al. Phase 2 trial of the DPP-1 inhibitor brensocatib in
bronchiectasis. N Engl J Med 2020; 383: 2127–2137.
105 Shoemark A, Shteinberg M, de Soyza A, et al. Characterization of eosinophilic bronchiectasis: a European
multicohort study. Am J Respir Crit Care Med 2022; 205: 894–902.
106 Bilton D, Tino G, Barker AF, et al. Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised,
controlled trial. Thorax 2014; 69: 1073–1079.
107 Gao YH, Abo Leyah H, Finch S, et al. Relationship between symptoms, exacerbations, and treatment response
in bronchiectasis. Am J Respir Crit Care Med 2020; 201: 1499–1507.
Disclosures: H. Choi reports receiving consultancy and speaker fees from Boryung Pharmaceutical Co., Ltd, outside
the submitted work. J.D. Chalmers reports receiving the following, outside the submitted work: research grants
from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed; and
consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen,
Novartis and Zambon.
164 https://doi.org/10.1183/2312508X.10018122
Chapter 12
α1-Antitrypsin deficiency and other rare forms

of emphysema
1 1,2
Joanna Chorostowska-Wynimko , Sabina Janciauskiene , Magdalena Pelc1,
Pavel Strnad3 and David Parr 4
1
Dept of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
2
Dept of Internal Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH),
Hannover Medical School, Hannover, Germany. 3Medical Clinic III, Gastroenterology, Metabolic Diseases and
Intensive Care, University Hospital RWTH Aachen, Aachen, Germany. 4Dept of Respiratory Medicine, University
Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
Corresponding author: Joanna Chorostowska-Wynimko ( j.chorostowska@igichp.edu.pl)
Cite as: Chorostowska-Wynimko J, Janciauskiene S, Pelc M, et al. α1-Antitrypsin deficiency and other rare forms of
emphysema. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS
Monograph). Sheffield, European Respiratory Society, 2023; pp. 165–179 [https://doi.org/10.1183/2312508X.10018222].
@ERSpublications
It is strongly recommended that α1-antitrypsin deficiency testing is included in the routine diagnostics of all
patients with COPD and other chronic obstructive respiratory disorders, irrespective of age, smoking history
or disease phenotype https://bit.ly/ERSM100
ISSN: 2312-5098.
α1-Antitrypsin deficiency (AATD) is the major single-gene disorder linked to high-risk emphysema.
AATD is inherited in an autosomal-recessive pattern with codominant expression of the alleles. It results
from carrying biallelic pathogenic variants of the SERPINA1 gene encoding α1-antitrypsin (AAT). AAT
is the key serum protease inhibitor, and its depletion in quantity and/or serum activity leads to protease–
antiprotease imbalance, as well as disrupted regulation of inflammatory and antimicrobial responses. The
sequelae of these effects are the degradation of lung tissue with eventual progression to emphysema and
COPD. Other lung phenotypes include bronchial asthma and bronchiectasis. While augmentation
therapy with human AAT protein is the only currently approved specific treatment for AATD-related
emphysema, optimised treatment, both pharmacological and nonpharmacological, as well as
recommended lifestyle changes, including a smoke-free environment, should be in line with the
currently accepted clinical guidelines for lung disease. Some AAT protein variants (PI*Z) confer an
increased risk of liver pathology, mainly liver cirrhosis resulting from hepatocytic accumulation of the
abnormal AAT protein. Regular follow-up in a highly specialised AATD clinical centre is
recommended. Other monogenic syndromes leading to a high risk of emphysema involvement are
mainly linked to genes regulating connective tissue metabolism or telomerase functional activity.
Introduction
a1-Antitrypsin deficiency (AATD; ORPHA:60, OMIM 613490) is a genetically determined
condition, resulting from carriage of biallelic pathogenic variants of the SERPINA1 gene encoding
α1-antitrypsin (AAT). It is listed among the three most common genetic disorders in Caucasians,
affecting approximately 1 in 2000–5000 individuals [1]. However, it remains severely
underrecognised worldwide. AATD predisposes towards progressive obstructive lung disease, mostly
emphysema and COPD, as well as chronic liver disorder, mainly hepatitis, cirrhosis and cancer.
https://doi.org/10.1183/2312508X.10018222 165
Molecular background of AATD

AATD is caused by biallelic pathogenic variants in the SERPINA1 gene occurring in the
homozygous or compound heterozygous state. Currently, around 200 known molecular variants
have been identified in SERPINA1 with 121 rated as disease causing or probably disease
causing for AATD of variable degree, according to the ClinVar database (www.ncbi.nlm.nih.
gov/clinvar/) and Human Gene Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) (table 1).
The normal (wild-type) alleles, referred to as M (M1–4, written as PI*M), yield normal levels
of fully active AAT protein in the peripheral blood. Deficiency alleles are caused mainly by
missense mutations, such as the most commonly observed PI*Z (c.1096G>A p.Glu366Lys) and
PI*S (c.863A>T p.Glu288Val), as well as small deletions such as PI*Mmalton (c.226_228del p.
Phe76del). They result in low AAT plasma levels (<20% of normal) and depleted inhibitory
AAT activity. Dysfunctional variants, which are relatively rare, such as PI*F (c.739C>T p.
Arg247Cys) or PI*MMineral Springs (c.272G>A p.Gly91Glu) affect the AAT enzymatic activity
but not necessarily the plasma levels, which may be within the normal range. In contrast, very
rare null alleles (PI*Q0), which completely prevent AAT synthesis or produce protein that is
swiftly degraded intracellularly, usually result in an AAT serum level below the detection limit
of the assay (<1% of normal) (table 2).
TABLE 1 Pathogenic mechanisms leading to functional α1-antitrypsin (AAT) deficiency
Type of Mechanism Clinical significance Variants (examples)

AAT defect
Deficiency Abnormal protein conformation High risk for liver disease due to Most common severe
resulting in reduced AAT (polymer accumulation variant: c.1096G>A
enzymatic selectivity; AAT in hepatocytes) p.Glu366Lys (“Z”)
polymerisation, reduced AAT Mild to high risk of lung disease Most common mild
hepatocytic secretion (severity of AAT serum variants: c.863A>T
Slower polymerisation rate; deficiency resulting from AAT p.Glu288Val (“S”) and
lower intracellular retention intracellular accumulation by c.187C>T p.Arg63Cys (“I”)
of AAT (mutations less hepatocytes) Rare variants: c.226_228del
disruptive to the protein p.Phe76del (“Mmalton”)
structure and folding)
Dysfunction Reduced binding affinity of AAT Increased risk for lung disease: Rare variants: c.739C>T
to target proteases impaired neutrophil elastase p.Arg247Cys (“F”) and
AAT propensity for inhibition; AAT plasma c.1145T>G p.Met382Arg
polymerisation, variable deficiency, variable (variant (“Pittsburgh”)
(variant specific) specific)
AAT serum levels normal/close
to normal
Increased risk for liver disease
(mild impairment of hepatic
secretion)
Other variant-specific clinical
consequences (e.g. Pittsburgh
variant: gain of antithrombin
activity)
Lack of Loss of functional SERPINA1 Severe AAT deficiency (no Rare null variants:
protein allele (e.g. gross deletion hepatocytic synthesis) c.611_612delCA
product with complete loss of High risk for lung disease p.(Thr204Serfs*11)
gene-coding sequence) (severe, early-onset (“Q0cork”)
Lack of AAT polymerisation emphysema)
No risk for liver disease
Data from [2–4].
166 https://doi.org/10.1183/2312508X.10018222
https://doi.org/10.1183/2312508X.10018222
TABLE 2 Range of α1-antitrypsin (AAT) concentration in serum according to the deficient SERPINA1 variants
Genotype Mean AAT serum concentration # Median AAT serum concentration # Pathogenic variant(s) First author
[ref.]
μM mg·dL–1 μM mg·dL–1 Deficient Null
PI*MM 33 (20–53) [5] 179.3 (108.7–288) [5] 27 (18.8–46.7) [5] 147 (102–254) [5] STOLLER [5],
23.9 (19.3–30.2) [6] 129.8 (105–164) [6] 27.4 (18.4–50.2) [7] 149 (100–273) [7] FERRAROTTI [6],
DONATO [7]
PI*MS 33 (18–52) [5] 179.3 (97.8–282.6) [5] 23 (15.8–40.1) [5] 125 (86–218) [5] c.863A>T STOLLER [5],
20 (16.2–25.2) [6] 108.5 (88–137) [6] 23.2 (15.5–41.4) [7] 126 (84–225) [7] p.Glu288Val FERRAROTTI [6],
DONATO [7]
PI*MZ 25.4 (15–42) [5] 138 (81.5–228.3) [5] 16.6 (11.4–27.8) [5] 90 (62–151) [5] c.1096G>A STOLLER [5],
14.8 (12.1–18.4) [6] 80.5 (66–100) [6] 16.4 (11.2–28.7) [7] 89 (61–156) [7] p.Glu366Lys FERRAROTTI [6],
a1-ANTITRYPSIN DEFICIENCY | J. CHOROSTOWSKA-WYNIMKO ET AL.

DONATO [7]
PI*SS 28 (20–48) [5] 152.2 (108.7–260.9) [5] 17.5 (7.9–28.3) [5] 95 (43–154) [5] c.863A>T STOLLER [5],
15.6 (13.4–19.5) [6] 84.9 (73–106) [6] 17.5 (9.0–33.3) [7] 95 (49–181) [7] p.Glu288Val FERRAROTTI [6],
homozygous DONATO [7]
PI*SZ 16.5 (10–23) [5] 89.7 (54.3–25) [5] 11.4 (6.1–19.9) [5] 62 (33–108) [5] c.863A>T STOLLER [5],
10.2 (9–12.1) [6] 55.5 (49–66) [6] 11.8 (7.7–19.9) [7] 64 (42–108) [7] p.Glu288Val, FERRAROTTI [6],
c.1096G>A DONATO [7]
p.Glu366Lys
PI*ZZ 5.3 (3.4–7) [5] 28.8 (18.5–38) [5] ⩽5.3 (⩽5.3–9.6) [5] ⩽29 (⩽29–52) [5] c.1096G>A STOLLER [5],
5.9 [6] 32 [6] 4.6 (2.8–10.5) [7] 25 (15–57) [7] p.Glu366Lys FERRAROTTI [6],
homozygous DONATO [7]
PI*Q0BresciaQ0Brescia Undetectable Undetectable Undetectable Undetectable c.841G>T p.Glu281* FERRAROTTI [8]
homozygous
PI*Q0CasablancaQ0Casablanca <1.84 <10 <1.84 <10 c.288_291del RENOUX [9]
p.His97Metfs*7
homozygous
PI*Q0LampedusaQ0Lampedusa <1.84 <10 <1.84 <10 c.787del FERRAROTTI [8]
p.Val263Cysfs*3
homozygous
Continued
167
168

TABLE 2 Continued
Genotype Mean AAT serum concentration # Median AAT serum concentration # Pathogenic variant(s) First author
[ref.]
μM mg·dL–1 μM mg·dL–1 Deficient Null
PI*Q0AchicourtQ0Clayton <1.84 <10 <1.84 <10 c.917+1G>A p.?, RENOUX [9]

c.1158dup
p.Glu387Argfs*14
PI*ZQ0Brescia 3.7 20 3.7 20 c.1096G>A c.841G>T p.Glu281* FERRAROTTI [8]
p.Glu366Lys
PI*ZQ0Saint-Avold 3.9 21 3.9 21 c.1096G>A c.918-1G>A p.? RENOUX [9]
p.Glu366Lys
PI*SQ0Cosenza 12 (11–13.1) 65.5 (60–71) (11–13.1) (60–71) c.863A>T c.985C>T p.Gln329* FERRAROTTI [8]
p.Glu288Val
PI*SQ0Oliveira do Douro 9.9 59 9.9 59 c.863A>T c.914_915del SILVA [10]
p.Glu288Val p.Arg305Lysfs*17
PI*SQ0Torino 13.1 71 13.1 71 c.863A>T c.963T>A p.Tyr321* FERRAROTTI [8]
p.Glu288Val
PI*MQ0Amiens 17.9 (14–21.7) 97 (76–118) (14–21.7) (76–118) c.1065+1G>A p.? RENOUX [9]
PI*MQ0Brescia 14.7 (12.9–19.9) 79.8 (70–108) 13 (12.9–19.9) 70.5 (70–108) c.841G>T p.Glu281* FERRAROTTI [8]
PI*MQ0Cork 12.9 70 12.9 70 c.611_612del FERRAROTTI [8]
p.Thr204Serfs*11
PI*MQ0Cosenza 15.2 (14.7–15.6) 82.5 (80–85) (14.7–15.6) (80–85) c.985C>T p.Gln329* FERRAROTTI [8]
PI*MQ0Dublin 14.7 (11.8–20.4) 79.8 (64–111) 13.2 (11.8–20.4) 72 (64–111) c.1182del FERRAROTTI [8]
https://doi.org/10.1183/2312508X.10018222
p.Phe394Leufs*4
PI*MQ0Lampedusa 13.8 (11.4–18.4) 75 (62–100) 13.6 (11.4–18.4) 74 (62–100) c.787del FERRAROTTI [8]
p.Val263Cysfs*3
PI*MQ0Perugia 15 (14.7–15.3) 81.5 (80–83) (14.7–15.3) (80–83) c.787del FERRAROTTI [8]
p.Val263Cysfs*3
PI*MQ0Pordenone 14.4 (8.6–23.9) 78.4 (47–130) 14.4 (8.6–23.9) 78 (47–130) c.1052del FERRAROTTI [8]
p.Leu351Argfs*12
PI*MQ0Saint-Etienne 13.6 74 13.6 74 c.559A>T p.Lys187* RENOUX [9]
PI*MQ0Vila Real 12.3 67 12.3 67 c.1192_1195del SILVA [10]
p.Met398Leufs*15
#
: The 5th–95th percentiles of AAT concentration for genotypes PI*MM, PI*MS, PI*MZ, PI*SS, PI*SZ and PI*ZZ are given in parentheses. For rare null variants, the data
represent individual case reports or small series of patients and the range of serum AAT level is given in parentheses; where the source did not state the calculation
method, the same value is given in both columns. Concentration values were mathematically converted to μM or mg·dL−1 (1 mg·dL−1=5.434783 μM) using www.endmemo.
com/medical/unitconvert/alpha1-Antitrypsin.php).
AATD is inherited in an autosomal-recessive pattern with codominant expression of alleles. The

recessive pattern means that both genes in a pair must be abnormal in order to cause disease,
while codominance indicates that both alleles of the SERPINA1 gene are active in an individual.
Therefore, in heterozygotes (e.g. PI*SZ), each gene produces a different AAT protein. This
determines the phenotypic differences between the heterozygote and the corresponding
homozygotes (carrying identical alleles PI*ZZ or PI*SS). Consequently, the PI*SS genotype is
not associated with an increased risk of emphysema, PI*SZ heterozygotes are at somewhat
increased risk, particularly if they smoke, and PI*ZZ homozygosity is the most common cause
of severe AAT deficiency [11].
Although the wide molecular spectrum of SERPINA1 variation is evident, the clinical guidance is
currently established only for the most common or severe forms of AATD [12]. Most of the
clinical cases of AATD-related emphysema are associated with the homozygous Pi*ZZ genotype,
while ∼5% of AATD individuals have other deficiency alleles associated with low circulating
levels of AAT or null alleles, which do not express measurable levels of AAT protein [10].
Pathological mechanisms behind severe AATD-related lung emphysema

AAT is a major serine protease inhibitor from the serpin superfamily (with a serine residue at
their active site), which suppresses activity of proteolytic enzymes, such as neutrophil elastase,
proteinase-3 and cathepsin G, the main target proteases inhibited by AAT. Although produced
mainly by the liver, and to a much lesser extent by other cells (monocytes, granulocytes,
macrophages, pulmonary epithelial and alveolar cells), and circulating in the whole body, the
antiproteolytic properties of AAT appear to be most critical for protection of the fragile alveolar
tissue of the lower airways against excessive destruction by neutrophil elastase [13].
An imbalance between lung protease and antiprotease activity is proposed as the major
mechanism resulting in emphysema related to AATD. According to the protease–antiprotease
hypothesis, inflammation-induced active proteases, if not opposed by their cognate inhibitors,
will degrade lung connective tissue, particularly elastin, induce structural damage causing
narrowing of airways and cause destruction of lung parenchyma resulting in emphysema [14].
These inhibitors not only neutralise protease activity but also display antimicrobial and
immunomodulatory functions [15].
The protease–antiprotease hypothesis is supported by at least three main findings:

1) intrapulmonary instillation of proteases in experimental animal models results in typical
features of the emphysema [16], 2) gene targeting of specific proteases protects against cigarette
smoke-induced emphysema [17], and 3) the inherited severe deficiency of AAT favours
proteolysis and increases the risk of developing early-onset emphysema, especially in cigarette
smokers [13].
Apart from the protease–antiprotease imbalance, other mechanisms, such as AAT regulation
of inflammatory responses via protease noninhibitory functions, have also been proposed.
AATD individuals carrying the Z allele of AAT produce significant amounts of circulating
Z-AAT polymers that act as chemoattractants leading to colocalisation of neutrophils and
polymeric Z-AAT in the alveolar wall [18–20]. Moreover, cigarette smoke seems to enhance
Z-AAT oxidation and polymerisation [21]. Hence, cigarette smoke-induced pro-inflammatory
cytokine production and protease activation, together with impaired antiprotease activity and
increased polymerisation of Z-AAT, may ultimately promote emphysema development.
Moreover, AAT can directly interact with inflammatory molecules, such as reactive oxygen
https://doi.org/10.1183/2312508X.10018222 169
species, free haem, defensins, interleukin-8 and leukotriene B, and neutralise their effects
[2, 3]. In contrast, the interactions with inflammatory substances (including proteases) may
eliminate the functional activity of AAT and result in an acquired further deficiency of
AAT [15]. Inflammatory stimuli such as cigarette smoke, air pollution and recurrent bacterial
colonisation, factors known to accelerate lung disease progression, may also promote AAT
inactivation. The combination of acquired and inherited AATD in some individuals may
strongly increase the risk for lung disease development.
Molecular diagnostics of AATD

AATD cannot be diagnosed unequivocally based on clinical symptoms alone. A range of both
quantitative and qualitative tests must be applied in a stepwise algorithm to confirm its presence
and provide precise clinical and genetic counselling (figure 1). Currently, establishing the
diagnosis of severe AATD includes demonstration of a low serum concentration of AAT
(<50 mg·dL−1 or <11 μM) in a quantitative test. Nephelometry is considered the most reliable
and is therefore the most commonly used laboratory method. A serum AAT level <110 mg·dL−1
or 24.4 μM (normal serum AAT level 90–220 mg·dL−1) calls for further diagnostic evaluation [6].
Of note, with AAT being an acute-phase reactant, its serum concentration becomes markedly
elevated during inflammation, injury or infection. Therefore, at the time of quantitative AAT
testing, the recommendation is to simultaneously confirm that C-reactive protein levels are
Clinical symptoms suggestive of AATD
• COPD, emphysema, persistent airflow obstruction (e.g. asthma) and/or bronchiectasis without evident
aetiology
AND/OR
• Liver disease at any age, otherwise unexplained
• Necrotising panniculitis
• ANCA-associated systemic vasculitis
AAT serum concentration measurement
AAT serum concentration <100–110 mg·dL–1 + CRP levels within normal limits
AAT protein phenotyping SERPINA1 genotyping
Known pathogenic No pathogenic Known pathogenic No common

phenotype, e.g. phenotype genotype, e.g. pathogenic
PI*ZZ, PI*SZ detected PI*ZZ, PI*SZ or PI*SS allele detected
Sequencing of SERPINA1 to verify variants detected

by other methods or in search of rare pathogenic molecular variants
Genetic counselling and clinical management
FIGURE 1 Diagnostic algorithm for α1-antitrypsin deficiency (AATD) detection. AAT: α1-antitrypsin; CRP: C-reactive
protein. Data from [11, 12].
170 https://doi.org/10.1183/2312508X.10018222
within normal limits to prevent false-negative results in mutation-positive patients. Other factors
affecting AAT levels to be considered are cigarette smoke and oestrogen levels [22]. The next
diagnostic step involves qualitative testing to detect a functionally deficient AAT protein using
protein phenotyping through isoelectric focusing and/or identifying pathogenic or probable
pathogenic biallelic variants in SERPINA1 at the DNA level, by simple genotyping or
sequencing of the whole SERPINA1 coding region [11, 23]. A combination of at least two
different methods is currently recommended for accurate AATD diagnosis (figure 1) [12]. Genetic
results should always be compared with the AAT concentration in order to confirm genotype–
phenotype correlations and avoid any misinterpretation.
The diversity of variants and genetic modifications that needs to be identified to provide a
definitive diagnosis of AATD implies the need for an expert, highly specialised diagnostic
laboratory equipped with techniques enabling phenotyping and genotyping but also sequencing
of the SERPINA1 gene and suitably qualified and experienced personnel [24]. Moreover, the
number of identified variants, their high (dys)functional variability and wide spectrum of
clinical presentations accentuates the importance of highly specialised clinical centres providing
expert healthcare for AATD patients and their families, embracing genetic and clinical
diagnostics, treatment and genetic counselling [11, 25].
As for any inherited condition, genetic counselling should be provided to all those diagnosed with,
as well as those at risk of, AATD, both before and after genetic testing [11]. Familial testing should
also be offered to siblings, parents and adult children with appropriate pre- and post-genetic test
counselling (table 3). Early detection of AATD is considered the best practice [5].
AATD-related lung diseases

Four out of the first six electrophoretic strips that were identified as lacking AAT were observed
to have originated from subjects with emphysema, which led to recognition of the clinical
TABLE 3 Recommendations for genetic testing for α1-antitrypsin deficiency (AATD)

Respiratory disorders Emphysema (in particular, early onset)
COPD
Asthma with incompletely reversible airflow obstruction
Bronchiectasis (provisional recommendation)
Asymptomatic individuals with persistent obstructive pulmonary
dysfunction with smoking and/or occupational exposure
Asymptomatic individuals with persistent obstructive pulmonary
dysfunction and no other risk factors (provisional recommendation)
Liver disorders Individuals with unexplained liver disease (newborns, children, adults)
Other Necrotising panniculitis
ANCA-associated systemic vasculitis (provisional recommendation)
Familial screening/ Individuals (adults and adolescents) with a family member with clinically
predispositional testing significant AATD (e.g. homozygosity (PI*ZZ) or heterozygosity
(PI*SZ, PI*MmaltonZ)):
Siblings
Parents
Offspring (provisional recommendation)
Other relatives (provisional recommendation)
Individuals with family history of persistent chronic obstructive lung
disease or liver disease
Data from [11, 12, 26].
https://doi.org/10.1183/2312508X.10018222 171
syndrome associated with AATD [27]. Since then, a variety of clinical lung diseases have been
associated with AATD, including COPD (with emphysematous and bronchitic phenotypes),
asthma ( possibly independent of the COPD risk) and bronchiectasis. COPD is common in
AATD and is almost universal after 5 years of cigarette smoking, but nonsmoking individuals
are also susceptible to developing COPD, albeit at an older age than smoking individuals.
However, the estimated survival of nonsmoking, nonindex (i.e. asymptomatic) individuals with
severe AATD is similar to that of the general population [28]. This demonstrates that the
penetration of AATD is far from complete. At the same time, underdiagnosis of both AATD
and AATD-related lung disease prevents a reliable estimation.
The classical description of predominantly basal panlobular emphysema, used previously as a

guide for AATD testing, has been replaced by the understanding that AATD phenotypes are
more heterogeneous [26, 29]. The distinctive anatomical patterns of centrilobular and panlobular
emphysema were noted to coexist in early pathological studies that pre-dated awareness of
AATD, but with advances in noninvasive clinical assessment through CT imaging, it has been
possible to demonstrate that patients with AATD often have coexisting panlobular and
centrilobular emphysema [30, 31]. When the latter occurs, it typically involves the upper parts
of the lung. This distribution of emphysema is present in approximately one-third of PI*ZZ
patients and has been shown to influence the pattern of physiological impairment [32]. In
PI*SZ deficiency, the type of emphysema is more comparable to COPD without AATD [33].
It is now recommended that all individuals with COPD, regardless of phenotype, should be
tested. Furthermore, asthma is the most common misdiagnosis in AATD individuals and may be
more prevalent in PI*MZ and PI*ZZ AATD; it presents with indistinguishable symptoms of
breathlessness and wheeze, so testing is also recommended in these patients [34]. The
importance of AATD testing in bronchiectasis remains contentious, despite the high prevalence
of bronchiectasis identified on HRCT imaging of patients with PI*ZZ deficiency [31, 35, 36].
While preliminary testing for AATD by means of AAT serum measurement has a low detection
rate, it is justifiable to test further if initial screening fails to identify an underlying cause,
particularly when there is coexisting emphysema.
The clinical presentation of AATD-associated lung disease is usually with progressively

worsening breathlessness, wheeze with airway reactivity and, with variable frequency in different
populations, chronic cough and sputum production [37]. The natural history was best
characterised in a longitudinal study over four decades of 127 PI*ZZ infants identified from
200 000 live births in Sweden between 1972 and 1974, but more comprehensive clinical
measurements collected over shorter periods provide greater insight into the best methods for
disease monitoring and outcome assessment for clinical interventions [34]. While spirometry is
the conventional method for the diagnosis of COPD, routine clinical assessment of disease
severity/stage and disease progression, it is a nonspecific measure that fails to capture the
heterogeneity of lung disease and is subject to variability that makes it insensitive to clinical
progression or therapeutic interventions. Gas transfer is usually also impaired in the presence of
emphysema but is likewise subject to poor specificity and sensitivity. Furthermore, the differential
impairment between spirometry and gas-transfer measures that is associated with phenotypic
variability, and the potential for discordant decline between these two methods, support the use of
full PFTs for routine clinical monitoring in order to ensure reliable detection and characterisation
of disease progression [32]. The gold-standard method for clinical assessment is now accepted to
be CT imaging, which, in addition to accurately elucidating clinical phenotype, is capable of
detecting other pathologies and lends itself to quantitative assessment for the purpose of outcome
assessment in interventional studies and, potentially, future routine clinical practice [38–42].
172 https://doi.org/10.1183/2312508X.10018222
Augmentation therapy, provided as weekly intravenous infusions of AAT protein (60 mg·kg−1), is
the only specific treatment currently recommended for adults with emphysema and documented
severe AATD accompanied by a blood AAT concentration of <11 μM. In particular, it should be
offered to patients with progressive respiratory disease. The effects of augmentation on
exacerbations of AATD lung disease remain uncertain [12]. A 2-year randomised, double-blinded,
placebo-controlled trial demonstrated the disease-modifying effect of augmentation therapy
measured as a 38% reduction in the annual rate of decline in lung density quantified with CT
imaging when measured at total lung capacity and functional residual capacity combined, or as a
26% reduction when measured at total lung capacity [42]. A subsequent 2-year open-label study
with a standard dose (60 mg·kg−1) of AAT resulted in a 38% reduction in lung density decline in
patients who had been treated for 4 years (the early-start treatment group) [43]. No effect on lung
function and quality of life was observed, as predicted from previous estimates of the magnitude
and duration of study that would be required to demonstrate an effect on these measures [44].
Augmentation is considered safe, and adverse event rates are similar for real-life practice and
clinical trials [42]. The main contraindications to i.v. supplementation of AAT are hypersensitivity
to the active substance and IgA deficiency. There are no data to support augmentation treatment in
individuals with severe AATD but without symptoms of respiratory disease or in subjects with
intermediate AATD (e.g. PI*MZ), irrespective of lung involvement [12].
Besides augmentation therapy, the pharmacotherapy of AATD-related emphysema follows

standard guidelines for COPD. In view of AATD status, prophylactic and vigorous management
of respiratory infection is of crucial importance. Therefore, yearly vaccination against influenza
and severe acute respiratory syndrome coronavirus 2 as well as periodic vaccination against
pneumococci are strongly recommended. Lung transplantation, surgical lung volume reduction
and endobronchial valve placement are potential options for patients with severe AATD-related
emphysema. While there are contradictory data regarding the long-term benefit in AATD
patients, quality of life significantly improves in the short term. However, careful patient
selection is currently advocated through a multidisciplinary team approach [12].
Nonpharmacological therapies include respiratory rehabilitation and a balanced diet in all patients,
as well as long-term oxygen therapy in those with chronic respiratory failure. Avoidance of
exposure to tobacco smoke or inhaled irritants is an important part of treatment as well as
lifestyle, and is recommended to healthy individuals with intermediate and severe AATD and
heterozygotes (PI*MZ). Both active and passive smoking is strongly contraindicated [12].
AATD-related liver disease

AATD-related liver disease is greatly underdiagnosed and has a biphasic pattern [4]. A small
subset of newborns with Pi*ZZ genotype (⩽10%) display neonatal cholestasis. While most
recover, others develop end-stage liver disease that requires liver transplantation [45, 46].
A second peak of AATD-related liver disease occurs in late adulthood [45, 46]. Notably, there
is no correlation between the extent of lung and liver disease. Also, it remains unknown
whether subjects with paediatric AATD-related liver disease are at higher risk of liver-related
complications later in life. Consequently, AATD individuals need careful evaluation of both
organs throughout life.
In adults, the PI*ZZ genotype confers an approximate 20-fold increased risk of liver cirrhosis
and an even higher risk of liver cancer [47, 48]. Approximately 85% of PI*ZZ subjects have
normal liver transaminases. Recurrently elevated values should trigger a thorough clinical
work-up [49]. To estimate the liver-related risks, an obligatory, baseline, noninvasive
https://doi.org/10.1183/2312508X.10018222 173
assessment of liver fibrosis with liver stiffness measurement via transient elastography is
recommended in all PI*ZZ subjects [50, 51]. Alternatively, the aspartate transaminase/platelet
ratio index can be used as an inexpensive, widely available tool [50, 51]. Liver biopsy should
be considered in indeterminate cases and/or to exclude additional comorbidities in subjects with
recurrently elevated liver enzymes.
At the initial evaluation, at least two-thirds of subjects will present with no or minimal liver
fibrosis and normal liver enzymes, and these individuals require only basal liver monitoring
(i.e. liver enzyme evaluation once or twice a year and assessment of liver fibrosis approximately
every 3 years). PI*ZZ subjects have a strongly increased risk of liver cancer [48, 52]. However,
hepatocellular carcinoma seems to develop almost exclusively in patients with advanced liver
fibrosis and therefore these individuals should undergo liver ultrasound screening every
6 months [52]. Additionally, they should be offered participation in clinical trials and thorough
counselling, focusing on a healthy lifestyle and weight loss where appropriate, as well as
avoidance of hepatotoxic agents such as alcohol or certain drugs. Among the investigative
compounds, fazirsiran is the only one with available positive human data. It constitutes a small
inhibitory RNA, resulting in double-stranded RNA inactivation of the AAT mRNA, thereby
blocking AAT synthesis [53]. Due to a chemical modification with N-acetylgalactosamine,
fazirsiran is specifically taken up by hepatocytes and is therefore organ specific [53]. In an
open-label, phase II trial, fazirsiran demonstrated an ∼85% decrease in hepatic as well as serum
AAT levels that was accompanied by an encouraging improvement in multiple liver injury
markers, as well as an encouraging safety profile [54].
The PI*SZ and PI*MZ genotypes confer approximately 3-fold and 2-fold increased risk of liver
cirrhosis at the population level, respectively [49, 55]. However, the risk is substantially increased
in the presence of additional risk factors, such as obesity, diabetes or metabolic syndrome
[49, 55]. Subjects with additional risk factors or with recurrently elevated liver enzymes may
therefore require regular liver monitoring, especially in the presence of significant liver fibrosis.
Other disease manifestations of AATD

A significant number of extrapulmonary manifestations linked to AATD confirm its systemic
nature. These include well-documented associations with panniculitis and ANCA-associated
vasculitis, as well as speculative connections with cholelithiasis, aneurysmal disease, chronic
inflammatory demyelinating polyneuropathy, Guillain–Barré syndrome, multiple sclerosis,
diabetes mellitus and others [3, 4, 56].
Other rare diseases conferring increased risk of pulmonary emphysema

While the SERPINA1 gene is the only well-proven single-gene disorder causing emphysema,
some other genes with a similar Mendelian inheritance pattern have been reported as a cause or
possible cause, mostly as part of monogenic syndromes affecting genes that regulate the
function of connective tissue and telomerases (table 4).
In addition, genome-wide association studies (GWAS) have explored potential connections

between the emphysema phenotype and specific genomic regions. A number of loci (e.g. HHIP,
CHRNA3, AGER and DLC1) have been identified as potential high-risk variants [66, 67].
However, it is important to note that emphysema is a complex disease driven by the interaction
between both genetic and environmental factors. Meanwhile, GWAS is not reliable in detecting
rare variants of medium/high penetrance, in particular those with low frequency that probably
play a role in emphysema development.
174 https://doi.org/10.1183/2312508X.10018222
https://doi.org/10.1183/2312508X.10018222
TABLE 4 Other rare diseases conferring increased risk of pulmonary emphysema
Syndrome Gene/pathogenic Inheritance Pathogenic mechanism Clinical phenotype/systemic First author

variant abnormalities [ref.]
LTBP4-related cutis LTBP4 Autosomal recessive Disrupted activity of Respiratory (emphysema (∼100%), atelectasis, CALLEWAERT [57]
laxa type I/Urban– LTBP4 protein PH), gastrointestinal (diverticula), urinary
Rifkin–Davis (diverticula), musculoskeletal (hypotonia/
syndrome motor delay), cardiovascular, hernias
(inguinal, umbilical)
TERT (rare variants, Autosomal dominant Disrupted telomerase Emphysema alone or combined with fibrosis CALLEWAERT [58]
e.g. p.Arg599Gln, activity, shorter (UIP), increased risk of pneumothorax
p.Thr726Met, telomere length (smokers only), predominantly in females
p.His925Gln)
PTPN6 (also known Autosomal dominant Disrupted phosphatase Early-onset panacinar emphysema (lower lobe BOSSÉ [59]

as SHP-1; activity of SHP-1 predominance, age- and
p.Ala455Thr) smoking-dependent expressivity)
Marfan syndrome FBN1 Autosomal dominant (both Disrupted FBN1 activity, Respiratory (emphysema, spontaneous TUN [60]
homozygosity and increased TGF-β pneumothorax, bronchiectasis,
heterozygosity are activity sleep-disordered breathing), cardiovascular
pathogenic) (aortic dilation), skeletal and ocular
abnormalities, dysmorphism
ELN-related cutis laxa ELN Autosomal dominant Disrupted activity of Connective tissue (generalised cutis laxa: CALLEWAERT [61]
type I tropoelastin loose, redundant skin folds), respiratory
(severe emphysema), vascular (aortic root
dilation), inguinal hernia, facial
dysmorphism (ptosis, long philtrum, large
ears, husky voice, beaked nose)
FBLN5-related cutis FBLN5 Autosomal recessive, Disrupted activity of Connective tissue (cutis laxa), respiratory (early VAN MALDERGEM [62]
laxa autosomal dominant FBLN5 childhood-onset pulmonary emphysema),
(less common) vascular (peripheral pulmonary artery
stenosis, supravalvar aortic stenosis),
gastrointestinal (pyloric stenosis), inguinal
hernias, hollow viscus diverticula (intestine,
bladder)
Continued
175
176

TABLE 4 Continued
Syndrome Gene/pathogenic Inheritance Pathogenic mechanism Clinical phenotype/systemic First author

variant abnormalities [ref.]
EFEMP2-related EFEMP2 Autosomal recessive Disrupted activity of Connective tissue (cutis laxa), respiratory LOEYS [63]
cutis laxa fibulin-4 (emphysema <25% cases), musculoskeletal
(diaphragmatic abnormalities 25–90%),
vascular (aortic aneurysms >90%),
dysmorphic facial features (long philtrum,
large ears, beaked nose), skeletal
abnormalities
Proteus syndrome AKT1 (p.Glu17Lys) Somatic heterozygotic Constitutive activation Skeletal (asymmetric skeletal distortion), BIESECKER [64]
mosaicism (de novo of AKT1 kinase and connective tissue (cerebriform connective
pathogenic variant), activation of PIK3CA/ tissue nevi, linear verrucous epidermal
germline pathogenic AKT pathway nevus), adipose dysregulation, dysmorphic
(lethal) facial features (dolichocephaly, long face,
downslanting palpebral fissures), respiratory
(bullous pulmonary degeneration), vascular
malformations, tumours (e.g. mesothelioma,
breast cancer), tissue overgrowth (spleen,
liver, thymus, gastrointestinal tract)
https://doi.org/10.1183/2312508X.10018222
Congenital lobar Idiopathic (50%), Respiratory (normal acinus structure at birth, MUKHTAR [65]
emphysema/ absent or defective no or abnormal acinar maturation leading
congenital lobar bronchial cartilage to alveolar overinflation and abnormal
overinflation (25%) alveoli number (hypoalveolar/polyalveolar
form), internal/external bronchial
obstruction, parenchymal disease)), cardiac,
renal, musculoskeletal malformations
LTBP4: latent transforming growth factor β-binding protein 4; ELN: ellastine; FBLN5: fibulin-5; EFEMP2: epidermal growth factor-containing fibulin-like extracellular matrix
protein 2; TERT: telomerase; UIP: usual interstitial pneumonia; PTPN6: protein tyrosine phosphatase nonreceptor type 6; SHP-1: Src homology 2 domain tyrosine
phosphatase-1; FBN1: fibrillin-1; TGF-β: transforming growth factor-β; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α; AKT1: protein kinase B.
Conclusion
AATD is the major genetic cause of emphysema, and is one of the three most common rare
diseases in Caucasians. However, it remains largely undiagnosed. It is estimated that <10% of
individuals with severe AATD have been identified [1], despite recommendations by the World
Health Organization and the two major respiratory societies, the European Respiratory Society
and the American Thoracic Society, for routine AATD profiling in patients with chronic
obstructive respiratory diseases [12, 26, 68]. In Europe, the estimated delay from first respiratory
symptoms to diagnosis of AATD remains at ∼7 years [69].
Meanwhile, the benefit of early specific treatment of severe AAT deficiency is well evidenced [43].
It is strongly recommended that AATD testing is included in the routine diagnostic work-up of
all patients with COPD and other chronic obstructive respiratory disorders, irrespective of their
age, smoking history or disease phenotype [12].
References
1 Blanco I, Bueno P, Diego I, et al. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers
worldwide: an update. Int J Chron Obstruct Pulmon Dis 2017; 12: 561–569.
2 Lechowicz U, Rudzinski P, Jezela-Stanek A, et al. Post-translational modifications of circulating alpha-1-
antitrypsin protein. Int J Mol Sci 2020; 21: 9187.
3 Janciauskiene S, Welte T. Well-known and less well-known functions of alpha-1 antitrypsin. its role in chronic
obstructive pulmonary disease and other disease developments. Ann Am Thorac Soc 2016; 13: Suppl. 4,
S280–S288.
4 Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med 2020; 382: 1443–1455.
5 Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 antitrypsin deficiency. In: Adam MP, Mirzaa GM, Pagon RA, et al.
eds. GeneReviews. Seattle, University of Washington, 2020.
6 Ferrarotti I, Thun GA, Zorzetto M, et al. Serum levels and genotype distribution of α1-antitrypsin in the general
population. Thorax 2012; 67: 669–674.
7 Donato LJ, Jenkins SM, Smith C, et al. Reference and interpretive ranges for α1-antitrypsin quantitation by
phenotype in adult and pediatric populations. Am J Clin Pathol 2012; 138: 398–405.
8 Ferrarotti I, Carroll TP, Ottaviani S, et al. Identification and characterisation of eight novel SERPINA1 Null
mutations. Orphanet J Rare Dis 2014; 9: 172.
9 Renoux C, Odou MF, Tosato G, et al. Description of 22 new alpha-1 antitrypsin genetic variants. Orphanet J Rare
Dis 2018; 13: 161.
10 Silva D, Oliveira DJ, Guimaraes M, et al. Alpha-1-antitrypsin (SERPINA1) mutation spectrum: three novel variants
and haplotype characterization of rare deficiency alleles identified in Portugal. Respir Med 2016; 116: 8–18.
11 Chorostowska-Wynimko J, Jezela-Stanek A. Genetic counselling. In: Strnad P, Brantly ML, Bals R, eds.
α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 143–149.
12 Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of
pulmonary disease in α1-antitrypsin deficiency. Eur Respir J 2017; 50: 1700610.
13 Janciauskiene S, Wrenger S, Immenschuh S, et al. The multifaceted effects of alpha1-antitrypsin on neutrophil
functions. Front Pharmacol 2018; 9: 341.
14 Pandey KC, De S, Mishra PK. Role of proteases in chronic obstructive pulmonary disease. Front Pharmacol 2017;
8: 512.
15 Taggart C, Mall MA, Lalmanach, et al. Protean proteases: at the cutting edge of lung diseases. Eur Respir J 2017;
49: 1501200.
16 Wood AM, Stockley RA. Alpha one antitrypsin deficiency: from gene to treatment. Respiration 2007; 74: 481–492.
17 Hautamaki RD, Kobayashi DK, Senior RM, et al. Requirement for macrophage elastase for cigarette
smoke-induced emphysema in mice. Science 1997; 277: 2002–2004.
18 Tan L, Dickens JA, Demeo DL, et al. Circulating polymers in α1-antitrypsin deficiency. Eur Respir J 2014; 43:
1501–1504.
19 Mulgrew AT, Taggart CC, Lawless MW, et al. Z α1-antitrypsin polymerizes in the lung and acts as a neutrophil
chemoattractant. Chest 2004; 125: 1952–1957.
20 Sark AD, Fromme M, Olejnicka B, et al. The relationship between plasma alpha-1-antitrypsin polymers and lung
or liver function in ZZ alpha-1-antitrypsin-deficient patients. J Biomolecules 2022; 12: 380.
21 Alam S, Li Z, Atkinson C, et al. Z α1-antitrypsin confers a proinflammatory phenotype that contributes to
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 189: 909–931.
https://doi.org/10.1183/2312508X.10018222 177
22 Sanders CL, Ponte A, Kueppers F. The effects of inflammation on alpha 1 antitrypsin levels in a national
screening cohort. COPD 2018; 15: 10–16.
23 Foil KE. Variants of SERPINA1 and the increasing complexity of testing for alpha-1 antitrypsin deficiency. Ther
Adv Chronic Dis 2021; 12: Suppl., 20406223211015954.
24 Ferrarotti I, Poplawska-Wisniewska B, Trevisan MT, et al. How can we improve the detection of
alpha1-antitrypsin deficiency? PLoS One 2015; 10: e0135316.
25 Chorostowska-Wynimko J, Wencker M, Horváth I. The importance of effective registries in pulmonary diseases
and how to optimize their output. Chron Respir Dis 2019; 16: 1479973119881777.
26 American Thoracic Society/European Respiratory Society. American Thoracic Society/European Respiratory
Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin
deficiency. Am J Respir Crit Care Med 2003; 168: 818–900.
27 Ericsson S. Studies in alpha-1 antitrypsin deficiency. Acta Med Scand Suppl 1965; 432: 1–85.
28 Tanash HA, Ekström M, Rönmark E, et al. Survival in individuals with severe alpha 1-antitrypsin deficiency
(PiZZ) in comparison to a general population with known smoking habits. Eur Respir J 2017; 50: 1700198.
29 Brantley ML, Paul LD, Miller BH, et al. Clinical features and history of the destructive lung disease associated
with alpha-1 antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis 1988; 139: 327–336.
30 Thurlbeck WM. The incidence of pulmonary emphysema with observations on the relative incidence and spatial
distribution of various types of emphysema. Am Rev Respir Dis 1963; 87: 207–215.
31 Parr DG, Guest PG, Reynolds JH, et al. Prevalence and impact of bronchiectasis in α1-antitrypsin deficiency. Am
32 Parr DG, Stoel BC, Stolk J, et al. Pattern of emphysema distribution in α1-antitrypsin deficiency influences lung
function impairment. Am J Respir Crit Care Med 2004; 170: 1172–1178.
33 Green CE, Vayalapra S, Hampson JA, et al. PiSZ alpha-1 antitrypsin deficiency (AATD): pulmonary phenotype
and prognosis relative to PiZZ AATD and PiMM COPD. Thorax 2015; 70: 939–945.
34 Bernspång E, Sveger T, Piitulainen E. Respiratory symptoms and lung function in 30-year-old individuals with
alpha-1-antitrypsin deficiency. Respir Med 2007; 101: 1971–1976.
35 Cuvelier A, Muir JF, Hellot MF, et al. Distribution of α1-antitrypsin alleles in patients with bronchiectasis. Chest
2000; 117: 415–419.
36 Carreto L, Morrison M, Donovan J, et al. Utility of routine screening for alpha-1 antitrypsin deficiency in
patients with bronchiectasis. Thorax 2020; 75: 592–593.
37 Dowson L, Guest PJ, Stockley RA. The relationship of chronic sputum expectoration to physiologic, radiologic
and health status characteristics in α1-antitrypsin deficiency (Pi Z). Chest 2002; 122: 1247–1255.
38 Campos MA, Diaz A. The role of computed tomography for the evaluation of lung disease in alpha-1 antitrypsin
deficiency. Chest 2018; 153: 1240–1248.
39 Subramanian DR, Edgar R, Ward H, et al. Prevalence and radiological outcomes of lung nodules in alpha-1
antitrypsin deficiency. Respir Med 2013; 107: 863–869.
40 Crossley D, Renton M, Muhhamad K, et al. CT densitometry in emphysema: a systematic review of its clinical
utility. Int J Chron Obst Pulm Dis 2018; 13: 547–563.
41 Parr DG. Imaging. In: Kolb M, Vogelmeier CF, eds. Outcomes of Clinical Trials (ERS Monograph). Sheffield,
42 Chapman KR, Burdon JGW, Piitulainen E, et al. Intravenous augmentation treatment and lung density in α1
antitrypsin deficiency (RAPID): a randomised, double blind, placebo-controlled trial. Lancet 2015; 386: 360–368.
43 McElvaney NG, Burdon J, Holmes M, et al. Long-term efficacy and safety of α1 proteinase inhibitor treatment
for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet
Respir Med 2017; 5: 51–60.
44 Schuchter MD, Stoller JK, Barker AF, et al. Feasibility of a clinical trial of augmentation therapy for
α1-antitrypsin deficiency. Am J Respir Crit Care Med 2000; 161: 796–801.
45 Chu AS, Chopra KB, Perlmutter DH. Is severe progressive liver disease caused by alpha-1-antitrypsin deficiency
more common in children or adults? Liver Transpl 2016; 22: 886–894.
46 Townsend SA, Edgar RA, Ellis PR, et al. Systematic review: the natural history of alpha-1 antitrypsin deficiency,
and associated liver disease. Aliment Pharmacol Ther 2018; 47: 877–885.
47 Fromme M, Schneider CV, Pereira V, et al. Hepatobiliary phenotypes of adults with alpha-1 antitrypsin
deficiency. Gut 2022; 71: 415–423.
48 Hiller AM, Ekström M, Piitulainen E, et al. Cancer risk in severe alpha-1-antitrypsin deficiency. Eur Respir J 2022;
60: 2103200.
49 Fromme M, Schneider CV, Trautwein C, et al. Alpha-1 antitrypsin deficiency: a re-surfacing adult liver disorder.
J Hepatol 2022; 76: 946–958.
50 Clark VC, Marek G, Liu C, et al. Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a
non-cirrhotic cohort. J Hepatol 2018; 69: 1357–1364.
178 https://doi.org/10.1183/2312508X.10018222
51 Kümpers J, Fromme M, Schneider CV, et al. Assessment of liver phenotype in adults with severe alpha-1
antitrypsin deficiency (Pi*ZZ genotype). J Hepatol 2019; 71: 1272–1274.
52 Fromme M, Strnad P. Liver cancer in severe alpha-1 antitrypsin deficiency: who is at risk? Eur Resp J 2022; 60:
2200718.
53 Gardin A, Remih K, Gonzales E, et al. Modern therapeutic approaches to liver-related disorders. J Hepatol 2022;
76: 1392–1409.
54 Strnad P, Mandorfer M, Choudhury G, et al. Fazirsiran for liver disease associated with alpha1-antitrypsin
deficiency. N Engl J Med 2022; 387: 514–524.
55 Schneider CV, Hamesch K, Gross A, et al. Liver phenotypes of European adults heterozygous or homozygous for
Pi∗Z variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and noncarriers. Gastroenterology 2020; 159: 534–548.e11.
56 Tejwani V, Stoller JK. The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency. Ther Adv
Chronic Dis 2021; 12: Suppl., 2040622321995691.
57 Callewaert BL, Urban Z. LTBP4-related cutis laxa. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews.
Seattle, University of Washington, 2023.
58 Stanley SE, Chen JJL, Podlevsky JD, et al. Telomerase mutations in smokers with severe emphysema. J Clin
Invest 2015; 125: 563–570.
59 Bossé Y, Lamontagne M, Gaudreault N, et al. Early-onset emphysema in a large French–Canadian family: a
genetic investigation. Lancet Resp 2019; 7: 427–436.
60 Tun MH, Borg B, Godfrey M, et al. Respiratory manifestations of Marfan syndrome: a narrative review. J Thorac
Dis 2021; 13: 6012–6025.
61 Callewaert BL, Urban Z. ELN-related cutis laxa. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews.
Seattle, University of Washington, 2022.
62 van Maldergem L, Loeys B. FBLN5-related cutis laxa. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds.
GeneReviews. Seattle, University of Washington, 2018.
63 Loeys B, De Paepe A, Urban Z. EFEMP2-related cutis laxa. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds.
GeneReviews. Seattle, University of Washington, 2020.
64 Biesecker LG, Sapp JC. Proteus syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al. eds. GeneReviews. Seattle,
University of Washington, 2019.
65 Mukhtar S, Trovela DAV. Congenital lobar emphysema. In: StatPearls. Treasure Island, StatPearls Publishing,
2022.
66 Hobbs BD, de Jong K, Lamontagne M, et al. Genetic loci associated with chronic obstructive pulmonary disease
overlap with loci for lung function and pulmonary fibrosis. Nat Genet 2017; 49: 426–432.
67 Cho MH, Castaldi PJ, Hersh CP, et al. A genome-wide association study of emphysema and airway quantitative
imaging phenotypes. Am J Respir Crit Care Med 2015; 192: 559–569.
68 World Health Organization. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World
Health Organ 1997; 75: 397–415.
69 Köhnlein T, Janciauskiene S, Welte T. Diagnostic delay and clinical modifiers in alpha-1 antitrypsin deficiency.
Ther Adv Respir Dis 2010; 4: 279–287.
Disclosures: J. Chorostowska-Wynimko reports the following, outside the submitted work: receipt of grants or
contracts from AstraZeneca, Pfizer, CSL Behring, Grifols and Mereo Biopharma; consulting fees from CSL Behring,
Grifols, Mereo Biopharma, Amgen and Pfizer; payment or honoraria for lectures, presentations, speakers’ bureaus,
manuscript writing or educational events from AstraZeneca, MSD, Pfizer, Takeda, Amgen, Grifols, CSL Behring,
Novartis, Chiesi, Celon Pharma and Adamed; support for attending meetings and/or travel from MSD, Amgen and
Pfizer; participation on a data safety monitoring boards or advisory boards for CSL Behring, Grifols and Mereo
Biopharma; and a leadership or fiduciary role for the European Respiratory Society, the Polish Respiratory Society,
the International Respiratory Coalition, the Polish Coalition for Respiratory Disorders, the Polish Coalition for
Treatment of Asthma, and the Polish Foundation for Patients with Alpha-1 Antitrypsin Deficiency. S. Janciauskiene
reports the following, outside the submitted work: support for attending meetings from CSL Behring; payment or
honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi
GmbH; and a supporting role for Alpha1-Deutschland. M. Pelc has nothing to disclose. P. Strnad reports the
following, outside the submitted work: grants or contracts from Arrowhead Pharmaceuticals, Dicerna
Pharmaceuticals and Vertex Pharmaceuticals; consulting fees from Albireo, Alnylam, CSL Behring, Grifols Inc.,
Sanofi, Dicerna Pharmaceuticals, Intellia, Takeda Pharmaceuticals and Ono Pharmaceuticals; payment or honoraria
for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from CSL Behring and
Grifols Inc.; payment for expert testimony from Takeda Pharmaceuticals; support for attending meetings and/or
travel from Gilead and Vertex; participation on a data safety monitoring boards or advisory boards for Dicerna
Pharmaceuticals, Albireo, Takeda Pharmaceuticals and Intellia; a leadership or fiduciary role for
Alpha1-Deutschland and Alpha1 global; and receipt of equipment, materials, drugs, medical writing, gifts or other
services from Takeda Pharmaceuticals. D. Parr reports the following, outside the submitted work: consulting fees
from Mereo Biopharma; and a leadership or fiduciary role for EARCO: Alpha-1 Foundation.
https://doi.org/10.1183/2312508X.10018222 179
Chapter 13
Pulmonary arterial hypertension

Sarah Cullivan and Sean Gaine
National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland.
Corresponding author: Sarah Cullivan (sarahkcullivan@gmail.com)
Cite as: Cullivan S, Gaine S. Pulmonary arterial hypertension. In: Wagner TOF, Humbert M, Wijsenbeek M, et al.,
eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023;
pp. 180–191 [https://doi.org/10.1183/2312508X.10018322].
@ERSpublications
Significant advances have been made in the diagnosis and treatment of pulmonary arterial hypertension in
recent years. It is a paradigm for successful management of a rare respiratory disease. https://bit.ly/ERSM100
ISSN: 2312-5098.
Pulmonary arterial hypertension (PAH) is a progressive condition that is characterised by inflammation,

remodelling and progressive luminal narrowing in the pulmonary vasculature. Diagnosis requires right
heart catheterisation and demonstration of a mean pulmonary artery pressure >20 mmHg, pulmonary
vascular resistance >2 Wood units and a pulmonary artery wedge pressure ⩽15 mmHg. In the preceding
decades, our understanding of the epidemiology, pathology and pathobiology of PAH has expanded.
There is a greater appreciation of the importance of multidisciplinary care and individualised,
goal-orientated treatment decisions. While current PAH therapies focus on three specific pathways,
there are several promising emerging therapies on the horizon.
Introduction
Pulmonary arterial hypertension (PAH) is a progressive condition of the pulmonary vasculature
that is associated with substantial morbidity and mortality. The median survival of PAH in the
1990s was only 2.8 years. Since then, considerable progress has been made in the diagnosis,
management and treatment of this rare disease. The haemodynamic definition of PAH has
recently been revisited, and a lower diagnostic threshold has been chosen to define PAH. A
mean pulmonary artery pressure (mPAP) >20 mmHg ( previously ⩾25 mmHg), pulmonary
vascular resistance (PVR) >2 Wood units (WU; previously >3 WU) and a pulmonary artery
wedge pressure (PAWP) ⩽15 mmHg at right heart catheterisation (RHC) are required to
diagnose PAH. Recent guidelines recommend careful patient phenotyping, nuanced risk
assessment and goal-orientated treatment decisions.
Clinical classification
Group 1 PAH is a rare and progressive condition of the pulmonary vasculature. The first
reported case of PAH was published by von Romberg in 1891 with the description of thickened
pulmonary arteries in an autopsy specimen of a 24-year-old [1]. More recently, the epidemic of
anorexigen-associated PAH (APAH) in the 1960s drew international attention to the condition
and prompted the first World Symposium on Pulmonary Hypertension in 1973 [2]. This
meeting of global leaders provided a definition for PH and a consensus on classification [3].
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PULMONARY ARTERIAL HYPERTENSION | S. CULLIVAN AND S. GAINE
The clinical classification of PH has been updated at a number of subsequent World Symposia
and now categorises conditions associated with PH into five distinct groups: group 1 PAH,
group 2 PH associated with left heart disease, group 3 PH associated with lung disease and/or
hypoxia, group 4 PH associated with pulmonary artery obstructions, and group 5 PH with
unclear and/or multifactorial mechanisms [4]. This chapter focuses on group 1 PAH and
associated subgroups (table 1).
The annual incidence of PAH is estimated at six cases per million of the population [5]. While
the idiopathic form of the condition was classically considered a disease of young females, it is
increasingly being identified in older patients of both sexes. Therefore, detailed clinical
assessment and careful phenotyping are required to assign PH to an appropriate clinical group.
Within group 1 PAH, idiopathic PAH (IPAH) is typically the most common subgroup, followed
by PAH associated with connective tissue disease (CTD-PAH) [4]. Typically, <10% of patients
with IPAH are acute responders at vasoreactivity testing during RHC. Around half of the acute
responders will maintain long-term clinical improvements with calcium-channel blockers, and
these patients usually have an excellent prognosis [6, 7]. Therefore, vasoreactivity testing is
recommended in all patients with IPAH, hereditary PAH (HPAH) and APAH at the time of
diagnosis to ensure that this small subset of patients is identified and treated accordingly.
HPAH is a subgroup of PAH that occurs in a familial context or due to a mutation in a PAH
susceptibility gene such as BMPR2 (bone morphogenetic protein receptor type 2) [8, 9]. BMPR2
gene mutations are inherited in an autosomal-dominant pattern and demonstrate incomplete
penetrance and a female preponderance (table 2) [4]. Mutations in the kinase insert domain receptor
(KDR) gene were identified recently in association with HPAH and IPAH. These mutations
typically result in late-onset PAH in older adults and are strongly associated with reductions in DLCO
[8]. A number of drugs and toxins are also associated with PAH, including the drugs aminorex,
fenfluramine, dasatinib and methamphetamines [3]. Therefore, a detailed family history and
questioning regarding drug and toxin exposures are important components of PH consultations.
Systemic sclerosis (SSc) is the predominant CTD in many PAH cohorts, particularly in Europe
and the USA [15]. The prevalence of PAH in individuals with SSc is high, and it is estimated
TABLE 1 Clinical classification of group 1 pulmonary arterial hypertension (PAH)
Subgroup Description
1.1 Idiopathic PAH

1.1.1 Nonresponders at vasoreactivity testing
1.1.2 Acute responders at vasoreactivity testing
1.2 Heritable PAH
1.3 PAH associated with drugs and toxins
1.4 PAH associated with:
1.4.1 Connective tissue disease
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.5 PAH with features of venous/capillary involvement
1.6 Persistent PH of the newborn
https://doi.org/10.1183/2312508X.10018322 181
TABLE 2 Examples of pulmonary arterial hypertension (PAH) susceptibility genes
Gene(s) Overview First author

[ref.]
BMPR2 BMPR2 is a member of the TGF-β receptor superfamily and is important EYRIES [10]
for vascular homeostasis; it is inherited in an autosomal-dominant
manner, with incomplete penetrance
ACVRL1 and ENG These genes are members of the TGF-β receptor superfamily and are GIRERD [11, 12]
associated with IPAH, HPAH and hereditary haemorrhagic
telangiectasia
SMAD9 SMAD9 is an important gene in the BMP signalling pathway, and GIRERD [12]
encodes SMAD9 (also known as SMAD8)
GDF2 This gene encodes the BMP9 ligand, which is a mediator in the BMP EYRIES [10]
signalling pathway; mutations are associated with paediatric and
adult PAH
TBX4 TBX4 is associated with small patella syndrome, and mutations in this GIRERD [12],
gene may result in paediatric and adult PAH KERSTJENS-
FREDERIKSE [13]
CAV1 This gene encodes the protein caveolin 1, which is responsible for the GIRERD [12]
integrity of caveolae in the plasma membranes of endothelial cells;
mutations in this gene are associated with IPAH, HPAH and
lipodystrophy
KCNK3 Mutations in KCNK3 result in adult PAH; this gene encodes a potassium GIRERD [12]
channel, which is important for regulation of the plasma membrane
resting potential
EIF2AK4 Mutations in this gene are associated with paediatric and adult EYRIES [14]
pulmonary veno-occlusive disease/pulmonary capillary
haemangiomatosis; it has autosomal recessive inheritance, with near
complete penetrance
KDR Mutations in KDR are associated with older-onset adult PAH SWIETLIK [8]
BMPR2: bone morphogenetic protein (BMP) receptor 2 gene; TGF-β: transforming growth factor-β; ACVRL1:
activin A receptor-like type 1 gene (also called ALK1); ENG: endoglin gene; IPAH: idiopathic PAH; HPAH:
hereditary PAH; SMAD9: small mothers against decapentaplegic family member 9 gene; GDF2: growth and
differentiation factor 2 gene; TBX4: T-box 4 gene; CAV1: caveolin 1 gene; KCNK3: potassium-channel two-pore
domain subfamily K member 3 gene; EIF2AK4: eukaryotic translation initiation factor 2α kinase 4 gene; KDR:
kinase insert domain receptor gene.
that 5–19% of patients with SSc may develop precapillary PAH during their disease course [4].
Therefore, annual evaluation of the risk of PAH is recommended using a combination of
clinical features, echocardiography, DLCO and N-terminal pro-B-type natriuretic peptide
(NT-proBNP) screening. This is particularly important in those with a diagnosis of SSc of
>3 years’ duration, FVC ⩾40% and DLCO <60% [4]. Additional important CTDs that are
associated with PAH include systemic lupus erythematosus, mixed CTD and Sjögren
syndrome [4]. While immunosuppressive therapies are generally ineffective in SSc-PAH, they
have an important role in the management of other CTD cohorts [4, 16].
Additional important PAH subgroups outlined in table 1 include infectious aetiologies such as
HIV and schistosomiasis, PAH-associated portal hypertension, PAH associated with congenital
heart disease (CHD-PAH) and PAH with features of venous/capillary involvement.
Schistosomiasis and HIV are important chronic infectious diseases that are associated with
PAH. These patients often have notable demographic differences from other PAH subgroups,
and PAH associated with schistosomiasis is not uncommon in regions of Africa and South
America [4, 17]. Treatment should be tailored to manage the underlying infections, while
182 https://doi.org/10.1183/2312508X.10018322
taking potential drug–drug interactions into consideration. For patients with PAH associated
with HIV, initial monotherapy is advised, which can be followed by sequential combination
therapy if required.
PAH associated with portal hypertension is estimated to affect 1–2% of patients with portal
hypertension, and may occur with or without concomitant liver disease. It is often detected
during assessment for liver transplantation, as severe portal hypertension is considered a
contraindication to liver transplantation due to the high associated perioperative mortality. The
International Liver Transplant Society recommends an mPAP <35 mmHg and a PVR <5 WU
for potential liver-transplant candidates [18]. A higher mPAP threshold of 35–44 mmHg may be
tolerated by some centres in subjects treated with PAH-specific therapy if there is evidence of
improvement in the PVR to <3 WU on therapy [18].
CHD-PAH is a heterogeneous subgroup that can affect up to 7% of adult patients with CHD. This
subgroup can be further subdivided into four clinical cohorts [4]: 1) Eisenmenger syndrome,
2) PAH associated with prevalent systemic-to-pulmonary shunts (correctable and noncorrectable),
3) PAH associated with small/coincidental defects, and 4) PAH after defect correction. RHC with
compartmental oximetry is recommended for these patients to confirm PAH and to calculate the
ratio of pulmonary/systemic blood flow, as this will guide subsequent management decisions.
PAH with features of venous/capillary involvement encompasses both pulmonary capillary

haemangiomatosis (PCH) and pulmonary veno-occlusive disease (PVOD). PVOD is a rare
subgroup of PAH, with an estimated incidence of less than one case per million of the
population [4]. It is characterised by diffuse involvement of venules and septal veins; however,
capillary and pulmonary artery involvement may also occur. Identified risk factors include
certain chemotherapies, organic solvents such as trichloroethylene, and CTDs such as SSc.
Biallelic mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene
have been associated with heritable PVOD. A comprehensive assessment including careful
evaluation of PFTs, radiology and genetic tests is frequently required to define the disease.
Unfortunately, PVOD often has a poor prognosis, and therefore early referral for lung transplant
assessment is recommended for eligible subjects [19].
Pathology and pathobiology

In health, the pulmonary circulation is a high-flow, low-pressure circuit. In PAH, there is
progressive luminal narrowing due to pulmonary vascular remodelling, and this results in
increased PVR and right ventricular afterload. The histopathological changes of PAH incorporate
all three layers of the pulmonary artery wall: the intima, media and surrounding adventitia.
Endothelial-to-mesenchymal transition, onion-skin lesions and colander-like lesions consisting

of organised thrombosis may be observed in the intima of pulmonary arteries in PAH [20].
Plexiform lesions are typically considered the histological hallmark of PAH; however, a
nonplexiform vasculopathy may also be observed [21]. This is characterised by vascular
rarefaction and microvascular remodelling, and may be more common in men with lower DLCO
[21]. Hyperplastic smooth muscle cells are often observed in the media of pulmonary arteries,
and perivascular inflammation and ectopic lymphoid tissues have also been reported. Changes
are not limited to the arterial system, and abnormalities in pulmonary capillaries, veins and
bronchial vessels are also described [22, 23].
Immense progress has been made to elucidate the mechanisms driving the pathology of PAH.
Imbalances in the transforming growth factor-β (TGF-β) and bone morphogenetic protein
https://doi.org/10.1183/2312508X.10018322 183
(BMP) pathways have been implicated in the pathobiology of PAH. Attenuated signalling via
the BMP pathway and increased signalling via the TGF-β pathway are frequently observed, and
result in a pro-proliferative environment. This pathway is the target of novel therapies such as
sotatercept, an activin receptor type IIA–Fc fusion protein [24]. An imbalance of vasoactive
mediators is also observed in PAH, with reduced nitric oxide and prostacyclin signalling, and
increased endothelin and thromboxane levels in the pulmonary circulation [22]. This imbalance
favours vasoconstriction and remodelling in the pulmonary vasculature.
Diagnostic considerations
A diagnosis of PAH requires careful clinical assessment and a number of key investigations
(table 3). Patients with PAH often present with unexplained dyspnoea, and a high index of
suspicion is required to identify the disease at an early stage. Clinical assessment may suggest
the underlying aetiology of PAH, for example by highlighting a family history of PAH, diet pill
exposure or a history of CHD. Similarly, clinical examination can reveal useful signs such as
sclerodactyly, digital ulceration and telangiectasia in a patient with SSc-PAH. The revised
European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines provide
a comprehensive overview of investigations for PAH, which should include serology, PFTs,
radiology, echocardiography and RHC (table 3) [4].
As highlighted in table 3, PFTs can assess underlying lung disease, and DLCO has evolved as a
valuable prognostic biomarker in PAH [25, 26]. Marked reductions in DLCO can be observed in
subjects with PAH with features of venous/capillary involvement (PVOD/PCH), PAH
associated with scleroderma and a cluster of patients with IPAH. These individuals with IPAH
and severe reductions in DLCO are often male and older, and have a history of tobacco exposure
and comorbidities [27].
Similarly, chest imaging and ventilation–perfusion scintigraphy are important to exclude group 3
and group 4 PH and can evaluate for signs of PVOD. PVOD may be suggested by septal-line
thickening, centrilobular ground-glass opacities and mediastinal adenopathy on imaging, and is
typically characterised by marked reductions in DLCO. It is important to note that characteristic
radiographic changes can be minimal or absent in up to one-quarter of cases [28].
Echocardiography is an important tool to screen for PH in symptomatic patients. The peak

tricuspid regurgitation velocity (TRV) is a central variable to evaluate the probability of
PH [29]. A peak TRV ⩽2.8 m·s−1 in the absence of other PH signs on echocardiography
suggests a low probability of PH, while a peak TRV >3.4 m·s−1 indicates a high probability of
PH and patients should be considered for RHC [4]. The peak TRV thresholds have not been
amended in the revised guidelines due to a lack of supporting evidence, despite recent revisions
in the haemodynamic definition of PH. However, consideration of additional echocardiographic
variables is recommended to evaluate the probability of PH. These include careful examination
of the right ventricle, pulmonary artery, right atrium and inferior vena cava. The tricuspid
annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/sPAP) ratio is a
new addition to these parameters. This reflects right ventricular and pulmonary artery coupling,
and a ratio of <0.55 mm·mmHg−1 may suggest PH and warrants further investigation [4].
Detailed assessment of left heart parameters is also important in order to exclude group 2 PH.
RHC is required to diagnose PAH. A precapillary pattern is observed at RHC, which is characterised
by an mPAP >20 mmHg, PVR >2 WU and PAWP ⩽15 mmHg [4]. Vasoreactivity testing, exercise
testing and a fluid challenge can be considered on a case-by-case basis during RHC (table 3).
184 https://doi.org/10.1183/2312508X.10018322
TABLE 3 Diagnostic considerations in pulmonary arterial hypertension (PAH)
Investigation Results
Blood tests Blood counts, renal profile, liver function, uric acid, iron status, BNP/
NT-proBNP, hepatitis and HIV serology, autoimmune serology
ECG Can suggest PH, e.g. P pulmonale, right bundle branch block or right
ventricular hypertrophy
Echocardiography Peak tricuspid regurgitation velocity and assessment of the inferior vena
cava, right atrium, pulmonary artery and right ventricle can assess the
probability of PH (low/intermediate/high)
Signs of left heart disease can be examined, including left atrial
enlargement
Can indicate congenital heart disease
PFTs Important to exclude underlying obstructive and/or restrictive lung disease
DLCO provides additional prognostic information in PAH
Chest CT HRCT and CTPA can look for signs of proximal chronic thromboembolic PH
and evaluate the underlying pulmonary parenchyma
Ventilation/perfusion lung scan Important to exclude chronic thromboembolic PH
Abdominal Doppler ultrasound Can assess for underlying liver disease and portal hypertension
Right heart catheterisation
Precapillary pattern mPAP >20 mmHg
PVR >2 WU
PAWP ⩽15 mmHg
Vasoreactivity testing Should be considered in all cases of IPAH, HPAH and PAH associated with
drugs or toxins
Inhaled nitric oxide, inhaled iloprost and intravenous epoprostenol can be
used during RHC to assess for responsiveness
An acute response is suggested by a reduction in mPAP of ⩾10 mmHg, to
an absolute value of mPAP ⩽40 mmHg, with an increased or unchanged
CO
Exercise PH Defined as mPAP/CO slope >3 mmHg·L−1·min−1 between rest and exercise
Incremental exercise tests (step or ramp protocol) with repeated
haemodynamic measurements can be used
Fluid challenge May expose left ventricular dysfunction in patients with PAWP <15 mmHg
Approximately 500 mL of saline is infused over 5–10 min during RHC
Miscellaneous Additional investigations such as atrial blood gas, genetic counselling and
testing, cardiac MRI, cardiopulmonary exercise testing and sleep studies
can provide valuable information and should be considered on a
case-by-case basis
BNP/NT-proBNP: B-type natriuretic peptide/N-terminal pro-B-type natriuretic peptide; CTPA: CT pulmonary
angiogram; mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; PAWP: pulmonary
artery wedge pressure; IPAH: idiopathic PAH; HPAH: hereditary PAH; RHC: right heart catheterisation;
CO: cardiac output.
Risk stratification
Comprehensive risk assessment in PAH is important to guide goal-directed treatment decisions.
The National Institute of Health equation was published in 1991 and was one of the first risk
assessment tools for PAH. It comprised three haemodynamic variables (mPAP, cardiac index
and mean right atrial pressure) and estimated the 1-, 3- and 5-year survival of incident patients
with IPAH [30]. Since then, a number of additional risk assessment tools have been developed
to facilitate risk assessment in PAH.
The ESC/ERS risk stratification table was revised in the 2022 guidelines (table 4) [4]. This
recommends multiparametric risk assessment at the time of diagnosis to divide patients into
https://doi.org/10.1183/2312508X.10018322 185
TABLE 4 European Society of Cardiology/European Respiratory Society multiparametric risk assessment for
pulmonary arterial hypertension
At diagnosis At first follow-up visit
Clinical Progression of symptoms WHO functional class

Syncope
WHO functional class
Clinical signs of right heart failure
Exercise 6MWD 6MWD
CPET:
Peak V′O2
V′E/V′CO2 slope
Laboratory BNP/NT-proBNP BNP/NT-proBNP
Imaging Echocardiogram:
Right atrial area
Pericardial effusion
TAPSE/sPAP
Cardiac MRI:
RV EF
Stroke volume index
RV end-systolic volume index
Haemodynamic Right atrial pressure
Cardiac index
SvO2
Stroke volume index
WHO: World Health Organization; 6MWD: 6-min walk distance; CPET: cardiopulmonary exercise testing, V′O2:
oxygen uptake, V′E: minute ventilation; V′CO2: carbon dioxide production; BNP: B-type natriuretic peptide;
NT-proBNP: N-terminal pro-B-type natriuretic peptide; TAPSE/sPAP: tricuspid annular plane systolic excursion/
systolic pulmonary arterial pressure; RV: right ventricular; EF: ejection fraction; SvO2: mixed venous oxygen
saturation. Data from [4].
low-, intermediate- and high-risk strata. Patients with a low-risk profile have an estimated
1-year mortality of <5%, while those in the high-risk category have a 1-year mortality of
>20% [4]. At subsequent visits, a noninvasive strategy can be employed, using World Health
Organization functional class, 6-min walk distance and NT-proBNP (table 4). Additional
variables should be considered as indicated, including right heart imaging such as
echocardiography and cardiac MRI, and haemodynamic assessment (table 4). Patients are then
divided into low risk, intermediate–low risk, intermediate–high risk and high risk, in a new
four-strata model [4]. Substratifying the intermediate-risk group in this way allows a more
nuanced approach to risk assessment, as 60–70% of patients typically fall into this risk
category [4].
Another important risk stratification tool is the Registry to Evaluate Early and Long-Term
Pulmonary Arterial Hypertension Disease Management (REVEAL) risk equation and scores,
which were first published in 2010 [31]. These comprise 12–14 weighted variables and divide
patients into five risk strata to estimate the likelihood of survival at 12 months [32–35].
Interestingly, the REVEAL scores incorporate nonmodifiable factors such as PAH type, sex, age
and DLCO. DLCO provides valuable information in patients with pulmonary vascular disease, as
patients with PAH and severe reductions in DLCO often have a specific phenotype. Individuals
with IPAH and marked reductions in DLCO to <45% are often older, male, have comorbidities
and a history of tobacco exposure, and have significantly worse outcomes [25, 26].
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Treatment
The treatment of PAH requires careful consideration of individual patient characteristics and
needs by a multidisciplinary team. General and supportive measures that should be considered
in all patients include vaccinations, supplemental oxygen therapy (if arterial oxygen tension
<8 kPa), diuretics and psychosocial support. Exercise training and rehabilitation are safe and
efficacious in stable PAH and have beneficial effects on exercise capacity, muscular function
and quality of life [36–38]. Reliable contraception should be discussed with female patients of
child-bearing age, considering the negative implications of pregnancy in PAH. Comorbidities
should also be addressed, and anaemia and iron deficiency should be corrected.
Regarding PAH-specific therapy, there are currently three central treatment pathways: the
prostacyclin, endothelin and nitric oxide pathways (figure 1). The first approved drug for PAH was
the synthetic prostacyclin analogue epoprostenol [39]. This revolutionised the field and reduced
mortality for a disease that had previously had a median survival of 2.8 years [40]. Since then,
additional therapies have become available. Figure 1 provides an overview of current and future
treatment pathways in PAH. The aim of therapy is to augment the nitric oxide and prostacyclin
pathways and inhibit the endothelin pathway in order to promote vasodilation and mitigate
pulmonary vascular remodelling, and to rebalance the activin II receptor and BMP pathways.
The revised ESC/ERS guidelines emphasise the importance of considering comorbidities when
choosing a treatment regimen [4]. Patients with significant cardiopulmonary comorbidities
Activin II
Nitric oxide Endothelin Prostacyclin
receptor and
pathway pathway pathway
BMP pathway
Reduced Increased Reduced Rebalances pro/

endogenous endothelin prostacyclin antiproliferative
nitric oxide signalling signalling signalling
• Sildenafil • Macitentan • Selexipag (oral) • Sotatercept

• Tadalafil • Ambrisentan • Iloprost, treprostinil,
• Riociguat • Bosentan epoprostenol
FIGURE 1 Current and future treatment pathways in pulmonary arterial hypertension. BMP: bone morphogenetic
protein.
https://doi.org/10.1183/2312508X.10018322 187
should be considered for initial oral monotherapy, irrespective of their risk status [26]. Addition
PAH therapies can subsequently be prescribed on a case-by-case basis, in an individualised
approach [4, 26]. This underscores the importance of careful phenotyping at the time of PAH
diagnosis, as patients with the diagnosis may differ significantly in treatment regimens based on
individual characteristics [26, 41]. Initial double combination therapy with an endothelin
receptor antagonist and a phosphodiesterase type 5 inhibitor is advised for subjects with low-
and intermediate-risk PAH, without significant comorbidities (figure 2). Additional parenteral
prostacyclin should be considered in high-risk disease.
At the first follow-up visit and each subsequent visit, risk assessment should be repeated using
the four-strata model, and therapy escalated if a low-risk profile is not achieved. Monotherapy
with high-dose calcium-channel blockers is only prescribed for a subset of patients with IPAH
who are long-term responders to calcium-channel blockers.
Figure 2 highlights suggested initial treatment for subjects with a new diagnosis of IPAH,
HPAH, APAH and CTD-PAH and negative vasoreactivity testing. The vasodilatory properties
of these drugs may result in systemic side-effects, including hypotension, flushing and
light-headedness. Liver function monitoring may be required for patients prescribed an
endothelin receptor antagonist, and ocular side-effects may occur in patients prescribed
phosphodiesterase type 5 inhibitors. Prostacyclin side-effects are common, particularly during
drug titrations, and include gastrointestinal disturbance, headache, jaw sensitivity and
thrombocytopenia.
Confirmed
PAH
Low- or Significant
intermediate-risk High-risk strata cardiovascular
strata comorbidities
Initial oral monotherapy

Initial double Initial triple therapy (ERA or PD5i)
combination therapy including parenteral +/–
(PD5i and an ERA) prostacyclin Sequential combination
therapy
FIGURE 2 Treatment algorithm for pulmonary arterial hypertension (PAH) at the time of diagnosis.
PD5i: phosphodiesterase type 5 inhibitor; ERA: endothelin receptor antagonist.
188 https://doi.org/10.1183/2312508X.10018322
There are a number of emerging therapies in clinical development, and one such promising
agent is sotatercept. Sotatercept is a novel, first-in-class fusion protein that rebalances the pro-
and antiproliferative signalling pathways in PAH. It binds and sequesters TGF-β superfamily
ligands and augments signalling via the BMPR2 pathway [24]. Treatment with sotatercept in
patients with PAH has resulted in significant reductions in PVR and is a promising fourth
pathway in PAH therapy (figure 1).
The implications of the new haemodynamic definition of PAH on treatment and the role of
PAH-specific therapy for patients with an mPAP between 21 and 24 mmHg and a PVR between
2 and 3 WU are unknown and will be the focus of future studies. As PAH remains an incurable
disease, timely referral for lung transplant assessment should be considered in all eligible
patients. Furthermore, palliative care consultation should be considered for patients with
persistent cardiorespiratory symptoms or to support end-of-life care in advanced disease.
As PAH is a rare condition, it is recommended that cases are managed in specialised PH

centres. A core multidisciplinary team consisting of two PH specialists, two PH nurse
specialists, at least two cardiothoracic surgeons, an interventionalist, a data manager and a study
nurse is recommended in the revised ESC/ERS guidelines [4]. The European Reference
Network on rare respiratory diseases (ERN-LUNG) has a PH core network that provides
specific guidance and recommendations regarding this. Patients should also be linked in with
PH patient associations, which can provide invaluable educational and emotional support.
Conclusion
PAH has become a paradigm for a successful approach to the management of a rare disease.
Our understanding of the epidemiology, pathology and pathobiology of PAH has evolved in
recent years. The haemodynamic definition of PAH has been revised, and risk assessment has
been refined. There is a greater appreciation of patient phenotyping, risk assessment and shared
decision making. Furthermore, there are a number of promising emerging therapies on the
horizon. Expert PH centres and holistic, person-centred care that moves beyond medication is an
important component of modern care.
References
1 Romberg E. Über sklerose der lungenarterie. Dtsch Arch Klin Med 1891; 48: 197–206.
2 Kay JM, Smith P, Heath D. Aminorex and the pulmonary circulation. Thorax 1971; 26: 262–270.
3 Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of
pulmonary hypertension. Eur Respir J 2019; 53: 1801913.
4 Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of
pulmonary hypertension. Eur Respir J 2022; 43: 3618–3731.
5 Leber L BA, Muller A. Epidemiology of pulmonary arterial hypertension and chronic thromboembolic
pulmonary hypertension: identification of the most accurate estimates from a systematic literature review. Pulm
Circ 2021; 11: 2045894020977300.
6 Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary
arterial hypertension. Circulation 2005; 111: 3105–3111.
7 Montani D, Savale L, Natali D, et al. Long-term response to calcium-channel blockers in non-idiopathic
pulmonary arterial hypertension. Eur Heart J 2010; 31: 1898–1907.
8 Swietlik EM, Greene D, Zhu N, et al. Bayesian inference associates rare KDR variants with specific phenotypes in
pulmonary arterial hypertension. Circ Genom Precis Med 2020; 14: e003155.
9 Montani D, Girerd B, Jaïs X, et al. Screening for pulmonary arterial hypertension in adults carrying a BMPR2
mutation. Eur Respir J 2021; 58: 2004229.
10 Eyries M, Montani D, Nadaud S, et al. Widening the landscape of heritable pulmonary hypertension mutations
in paediatric and adult cases. Eur Respir J 2019; 53: 1801371.
https://doi.org/10.1183/2312508X.10018322 189
11 Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying
an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181: 851–861.
12 Girerd B, Weatherald J, Montani D, et al. Heritable pulmonary hypertension: from bench to bedside. Eur Respir
Rev 2017; 26: 170037.
13 Kerstjens-Frederikse WS, Bongers EM, Roofthooft MT, et al. TBX4 mutations (small patella syndrome) are
associated with childhood-onset pulmonary arterial hypertension. J Med Genet 2013; 50: 500–506.
14 Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive
form of pulmonary hypertension. Nat Genet 2014; 46: 65–69.
15 Avouac J, Airò P, Meune C, et al. Prevalence of pulmonary hypertension in systemic sclerosis in European
Caucasians and metaanalysis of 5 studies. J Rheumatol 2010; 37: 2290–2298.
16 Sanchez O, Sitbon O, Jaïs X, et al. Immunosuppressive therapy in connective tissue diseases-associated
pulmonary arterial hypertension. Chest 2006; 130: 182–189.
17 Kolaitis NA, Lammi M, Mazimba S, et al. HIV-associated pulmonary arterial hypertension: a report from the
pulmonary hypertension association registry. Am J Respir Crit Care Med 2022; 205: 1121–1124.
18 Krowka MJ, Fallon MB, Kawut SM, et al. International Liver Transplant Society Practice Guidelines: diagnosis
and management of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation 2016; 100:
1440–1452.
19 Montani D, Lau EM, Dorfmüller P, et al. Pulmonary veno-occlusive disease. Eur Respir J 2016; 47: 1518–1534.
20 Piera-Velazquez S, Jimenez SA. Endothelial to mesenchymal transition: role in physiology and in the
pathogenesis of human diseases. Physiol Rev 2019; 99: 1281–1324.
21 Nossent EJ, Smits J, Seegers C, et al. A new clinical phenotype with non-plexiform vasculopathy and distinctive
microvessel remodeling among idiopathic pulmonary arterial hypertension patients. In: D96 Embarcadero:
Machines and Deep Phenotyping of The Pulmonary Circulation, 18 May 2022. New York, American Thoracic
Society, Abstract 5302.
22 Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the
art and research perspectives. Eur Respir J 2019; 53: 1801887.
23 Ghigna M-R, Dorfmüller P. Pulmonary vascular disease and pulmonary hypertension. Diagn Histopathol 2019;
25: 304–312.
24 Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the treatment of pulmonary arterial hypertension.
N Engl J Med 2021; 384: 1204–1215.
25 Trip P, Nossent EJ, de Man FS, et al. Severely reduced diffusion capacity in idiopathic pulmonary arterial
hypertension: patient characteristics and treatment responses. Eur Respir J 2013; 42: 1575–1585.
26 Hoeper MM, Pausch C, Grünig E, et al. Idiopathic pulmonary arterial hypertension phenotypes determined by
cluster analysis from the COMPERA registry. J Heart Lung Transplant 2020; 39: 1435–1444.
27 Eyries M, Montani D, Girerd B, et al. Familial pulmonary arterial hypertension by KDR heterozygous loss of
function. Eur Respir J 2020; 55: 1902165.
28 Montani D, Achouh L, Dorfmüller P, et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and
hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008; 87:
220–233.
29 Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur Respir J 2015; 46: 903–975.
30 d’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from
a national prospective registry. Ann Intern Med 1991; 115: 343–349.
31 Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights
from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management
(REVEAL). Circulation 2010; 122: 164–172.
32 Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL registry risk score calculator in patients newly
diagnosed with pulmonary arterial hypertension. Chest 2012; 141: 354–362.
33 Cogswell R, Pritzker M, de Marco T. Performance of the REVEAL pulmonary arterial hypertension prediction
model using non-invasive and routinely measured parameters. J Heart Lung Transplant 2014; 33: 382–387.
34 Benza RL, Kanwar MK, Raina A, et al. Development and validation of an abridged version of the REVEAL 2.0
risk score calculator, REVEAL Lite 2, for use in patients with pulmonary arterial hypertension. Chest 2021; 159:
337–346.
35 Kanwar MK, Gomberg-Maitland M, Hoeper M, et al. Risk stratification in pulmonary arterial hypertension using
Bayesian analysis. Eur Respir J 2020; 56: 2000008.
36 Grünig E, Eichstaedt C, Barberà JA, et al. ERS statement on exercise training and rehabilitation in patients with
severe chronic pulmonary hypertension. Eur Respir J 2019; 53: 1800332.
37 Ehlken N, Lichtblau M, Klose H, et al. Exercise training improves peak oxygen consumption and
haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-
embolic pulmonary hypertension: a prospective, randomized, controlled trial. Eur Heart J 2016; 37: 35–44.
190 https://doi.org/10.1183/2312508X.10018322
38 Grünig E, MacKenzie A, Peacock AJ, et al. Standardized exercise training is feasible, safe, and effective in
pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European
multicentre randomized controlled trial. Eur Heart J 2021; 42: 2284–2295.
39 Sitbon O, Vonk Noordegraaf A. Epoprostenol and pulmonary arterial hypertension: 20 years of clinical
experience. Eur Respir Rev 2017; 26: 160055.
40 Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol ( prostacyclin) with
conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334: 296–301.
41 Peacock AJ, Ling Y, Johnson MK, et al. Idiopathic pulmonary arterial hypertension and co-existing lung disease:
is this a new phenotype? Pulm Circ 2020; 10: 2045894020914851.
Disclosures: S. Cullivan has nothing to declare. S. Gaine has received honoraria and speaker’s fees from Actelion
and Janssen Pharmaceuticals, and is an advisory board member for United Therapeutics, outside the submitted
work.
https://doi.org/10.1183/2312508X.10018322 191
Chapter 14
Chronic thromboembolic pulmonary

hypertension
Marion Delcroix 1,2, Laurent Godinas1,2, Rozenn Quarck 1,2
, Catharina Belge1,2,
Bart Meyns3,4, Geert Maleux5 and Tom Verbelen 3,4
1
Clinical Dept of Respiratory Diseases, University Hospitals of Leuven, Leuven, Belgium. 2Laboratory of Respiratory
Diseases and Thoracic Surgery (BREATHE), Dept of Chronic Diseases and Metabolism (CHROMETA), KU Leuven –
University of Leuven, Leuven, Belgium. 3Clinical Dept of Cardiac Surgery, University Hospitals of Leuven, Leuven,
Belgium. 4Dept of Cardiovascular Sciences, KU Leuven – University of Leuven, Leuven, Belgium. 5Clinical Dept of
Radiology, University Hospitals of Leuven, Leuven, Belgium.
Corresponding author: Marion Delcroix (marion.delcroix@uzleuven.be)
Cite as: Delcroix M, Godinas L, Quarck R, et al. Chronic thromboembolic pulmonary hypertension. In: Wagner TOF,
@ERSpublications
Chronic thromboembolic PH is a rare and underdiagnosed complication of pulmonary embolism. It requires
a specific therapeutic approach combining life-long anticoagulation with surgery, angioplasty and/or PH
drugs. https://bit.ly/ERSM100
ISSN: 2312-5098.
Chronic thromboembolic PH (CTEPH) is a rare complication of acute pulmonary embolism (PE), in

which the increased pulmonary vascular resistance results from persistent large-vessel fibrothrombotic
obstruction combined with a secondary microvasculopathy. Symptoms such as exertional dyspnoea are
nonspecific, and the diagnosis requires dedicated pulmonary perfusion imaging. Consequently, CTEPH
is underdiagnosed and frequently misdiagnosed as acute PE. It should be suspected immediately when
signs of PH and chronic pulmonary arterial obstructions are observed at echocardiography or at CT
pulmonary angiography. The treatment is essentially surgical and consists of removing the intravascular
material and the internal layer of the involved pulmonary arteries, called pulmonary endarterectomy.
When patients are inoperable because of a disease that is too distal, a haemodynamic severity
disproportionate to imaging abnormalities or severe comorbidities, medical therapy with PH drugs,
targeting the microvasculopathy, and balloon pulmonary angioplasty, targeting (sub)segmental lesions,
are recommended. The combination of these therapeutic approaches aiming to normalise pulmonary
haemodynamics is currently recommended.
Introduction
Chronic thromboembolic PH (CTEPH) is classified under the fourth group of the PH clinical
classification together with other causes of pulmonary artery obstruction, which are to be
considered in its differential diagnosis [1, 2]. It is a rare complication of acute pulmonary embolism
(PE), due to incomplete resolution of pulmonary emboli with residual fibrothrombotic thickenings
and partial to complete large-vessel obstruction. A decrease in the proportion of permeable
pulmonary vessels >50% [3–5] induces an increase in pulmonary vascular resistance (PVR) and in
pulmonary arterial pressure (PAP), which themselves can induce a microvasculopathy leading to
192 https://doi.org/10.1183/2312508X.10018422
CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION | M. DELCROIX ET AL.
progressive deterioration in the absence of new episodes of acute PE. Surgical and percutaneous
techniques have been developed to resolve the pulmonary artery obstructions, and PH drugs are
used to target the microvasculopathy. In this chapter, we provide an updated summary of the
epidemiology, pathophysiology and management of CTEPH.
Definitions
Chronic thromboembolic pulmonary disease (CTEPD) has been proposed as an overarching
term to characterise symptomatic patients who present with mismatched perfusion defects on a
ventilation/perfusion (V′/Q′) lung scan and specific signs of chronic clots on CT pulmonary
angiography (CTPA) or digital subtraction angiography (DSA), whether or not they have PH at
rest [6]. For patients with PH at rest, the historical term CTEPH is still of use. CTEPH is a
precapillary PH and as such is haemodynamically defined by mean PAP (mPAP) >20 mmHg,
wedge pressure ⩽15 mmHg and PVR >2 Wood units (WU) [1, 2].
Epidemiology
CTEPH is a rare form of PH but encompasses about one-third of patients referred to PH
centres [7]. In most of them, a history of PE is found [8]. Although, after acute PE, up to 50% of
patients have persistent perfusion defects [9] and ∼30% have new-onset or worsened exercise
dyspnoea [10], only a small proportion, estimated to be between 0.8% and 3%, will be diagnosed
with CTEPH [11–13]. The observed incidence of CTEPH is around six cases per million of the
population, but could be three times higher, as estimated from PE incidence [7, 14].
Consequently, the latest recommendations from the 2019 European Society of Cardiology (ESC)
PE guidelines [15] and from the 2022 ESC/European Respiratory Society (ERS) PH guidelines
[1, 2], which encourage “routine clinical evaluation of patients 3–6 months after the acute PE
episode” and “further diagnostic evaluation in patients with persistent or new-onset dyspnoea/
exercise limitation after PE”, will potentially increase the proportion of diagnosed cases and
reduce the time from symptoms to CTEPH diagnosis (historically averaging 14 months [8]). If
access to echocardiography is restricted, it is proposed that CTEPH is excluded by a combination
of normal ECG and normal N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels [16, 17].
As the prognosis of untreated CTEPH is poor and is inversely related to the level of mPAP [18, 19]
and to the diagnostic delay [20], and as the treatment of CTEPH is specific and very efficient, a
proper and early diagnosis is of utmost importance.
Pathophysiology
CTEPH is characterised by the persistence and fibrotic organisation of thrombi within the
pulmonary arteries. Multiple causes for the incomplete resolution of clots have been proposed,
but there is still uncertainty about the sequence of events and the interplay of the mechanisms.
Among others, increased thrombosis, inefficient fibrinolysis, inflammation and deficient
angiogenesis have been investigated. Thrombophilic risk factors are different from those
reported in acute PE, with a predominance of antiphospholipid syndrome (in ∼10% of patients
[8, 21]) and of increased factor VIII [8, 22–24]. Fibrin abnormalities and fibrinogen
polymorphism associated with plasmin resistance have been observed [25–27]. Increased
prevalence of inflammatory diseases [22], indwelling catheters and pacemaker leads [28, 29],
and elevated inflammatory biomarkers [30–33] are also reported. Evidence of dysregulated
angiogenesis is also accumulating [33–35], and involvement of the transforming growth factor-β
pathway has emerged recently [36, 37]. Among other associated conditions, splenectomy,
myelodysplastic syndromes including essential thrombocytosis, ventriculo-atrial derivations for
hydrocephaly, cancer, thyroid replacement therapy and non-O blood groups are found [8, 22].
https://doi.org/10.1183/2312508X.10018422 193
A secondary microvasculopathy frequently aggravates the disease. It is observed in both the

occluded and nonoccluded lung area [38]: in the nonoccluded zones, vascular remodelling is
induced by the increased high-pressure blood flow derived from the occluded zones, while in
the occluded zones, remodelling seems to be induced by collateral revascularisation originating
from high-pressure systemic circulation via the bronchial arteries [39]. The microvasculopathy is
responsible for discordances between haemodynamic severity and the degree of vascular
obstruction at imaging [5].
With time, the increased resistance of the pulmonary circulation will induce right ventricle (RV)
hypertrophy, also called adaptive RV remodelling, followed by progressive RV dilation and
failure, known as maladaptive RV remodelling. PAP, PVR and cardiac output are generally
lower than in idiopathic pulmonary arterial hypertension (IPAH) [40]. The systolic–diastolic
pressure gradient (or pulse pressure) is frequently increased as a result of the reflected pressure
waves on proximal vessel obstructions. These reflected waves are also responsible for a more
dilated and stiffer RV than in IPAH [41, 42].
Regarding gas exchange, CTEPH is characterised by hypoxaemia due to a combination of low

mixed venous oxygen pressure caused by low cardiac output and increased oxygen extraction,
V′/Q′ mismatch, slightly impaired diffusion capacity and, in some cases, a shunt through an
open foramen ovale [43, 44]. The associated hypocapnia is due to exceeding ventilation.
Diagnosis
As in other forms of PH, symptoms of CTEPH are nonspecific and include exertional dyspnoea,
oedema, fatigue, chest pain, syncope and dizziness [8]. Haemoptysis is more frequent than in
IPAH and is related to the hypertrophic bronchial circulation [45]. The presence of some risk
factors or associated conditions, described in the previous section, can increase the pretest
probability of CTEPH. Echocardiography is used to detect PH by determining its probability as
low, intermediate or high (figure 1) [1, 2]. A planar V′/Q′ scan, single-photon emission CT or
other imaging techniques of perfusion (dual-energy CT and subtraction iodine mapping) are
also required [6, 46–50]. Patients follow two trajectories: some are identified by V′/Q′ scan
showing mismatched perfusion defects during the work-up of unexplained PH, while others are
diagnosed in the follow-up of acute PE. CTPA is used for the anatomic evaluation of chronic
obstruction in CTEPH, as is DSA [51]. It is, however, an underutilised tool for the diagnosis of
CTEPH as chronic clots are frequently misinterpreted as acute PE, even if they have other
characteristics [15, 52–54], or are even completely overlooked, especially in the most distal
forms of CTEPH. Chronic clots present as webs, mostly located at the vascular divisions, and as
retracted and parietalised thrombi with obtuse angles to the vessel wall. They are accompanied
by hypertrophied bronchial arterial collaterals originating from the descending aorta and
intercostal and subdiaphragmatic arteries, by mosaic perfusion of the lung parenchyma, and by
peripheral scars. Acute clots are mostly located centrally in the vessels and surrounded by the
contrast medium. DSA is used when CTPA is inconclusive, and may show webs, partial
occlusions, complete occlusions with pouching, and tortuous lesions (figure 2) [55]. The new
University of California San Diego surgical classification describes the level of obstruction from
I to IV, corresponding to the main, lobar, segmental and subsegmental arteries, respectively, but
this can only be confirmed at surgery [56, 57].
CTEPH must be distinguished from other causes of pulmonary artery obstruction such as intima
sarcoma, large-vessel arteritis such as Takayasu disease, IgG4-related disease, intravascular
leiomyomatosis, anthracosilicosis and mediastinal fibrosis (figure 3) [1, 2].
194 https://doi.org/10.1183/2312508X.10018422
PE follow-up PH follow-up
Echocardiographic intermediate/high probability of PH
Detection
Perfusion imaging (V'/Q' scan, other)
Referral to CTEPH centre
Treatment assessment
CTPA with/without DSA
RHC
FIGURE 1 Diagnosis of chronic thromboembolic PH (CTEPH). PE: pulmonary embolism; V′/Q′: ventilation/
perfusion ratio; CTPA: CT pulmonary angiography; DSA: digital subtraction angiography; RHC: right heart
catheterisation.
a) b) c)
FIGURE 2 Digital subtraction angiography (DSA) in patients with chronic thromboembolic PH. a) DSA of the left
pulmonary arteries in a patient with proximal and operable disease. The blue arrow shows the proximal
involvement of the left lower lobe artery. b) DSA of the left pulmonary arteries in a patient with splenectomy
and subsegmental disease. The red arrows show the spindly aspect of subsegmental vessels. Note the lack of
perfusion downstream. c) DSA of the left pulmonary arteries in a patient with suspected microvasculopathy and
relatively minor macroscopic involvement of the pulmonary vasculature. The dotted red arrows represent the
subpleural perfusion defects.
https://doi.org/10.1183/2312508X.10018422 195
196

a) Intima sarcoma b) Intravascular c) Multiple congenital d) Takayasu disease
leiomyomatosis stenosis
https://doi.org/10.1183/2312508X.10018422
FIGURE 3 Mimics of chronic thromboembolic PH: a) intima sarcoma (left four panels), b) intravascular leiomyomatosis, c) multiple congenital stenosis, and d) Takayasu
disease. The upper panels show CT scans of each disease.
Surgical treatment
In contrast to other forms of PH, CTEPH can be treated very efficiently by a surgical approach,
called pulmonary endarterectomy (PEA) (figure 4) [58, 59]. This has the potential to nearly
normalise pulmonary haemodynamics in 70–75% of operated patients [60, 61]. However,
postoperative PAP can still show a steeper increase with exercise [62] compared with normal
individuals in which the pressure/flow slope does not exceed 3 mmHg·L−1·min−1 [1, 2].
The evaluation of operability is a complex and unstandardised process needing expert input
from PEA surgeons, PH specialists, chest radiologists and interventional cardiologists/
radiologists, together forming the CTEPH team. Among other criteria, the surgeon’s skills and
experience are of the utmost importance in allowing them to reach up to subsegmental arteries,
and to take proper therapeutic decisions in case of an imbalance between the haemodynamic
severity and the obstructive lesions. Therefore, education in high-volume centres and standards
of >50 procedures per year have been proposed, although this may not be reachable in small
countries [1, 2, 6, 60]. In addition, comorbidities, such as severe COPD and malignancies, can
influence the treatment decision. Advanced age has not been reported as a contraindication to
PEA, as surgery can be very successful in these patients [63]. In the presence of coronary or
valvular heart diseases, concomitant repair is proposed. More recently, a percutaneous
interventional approach (balloon pulmonary angioplasty (BPA)), targeting segmental/
Proximal PA fibrotic Distal PA fibrotic Microvasculopathy

obstructions obstructions
PEA PEA/ BPA CTEPH drug

BPA therapy
1 2
Multimodal CTEPH treatment
FIGURE 4 Chronic thromboembolic PH (CTEPH) therapeutic approaches and their target. 1: Fibro-thrombotic
occlusion before BPA; 2: balloon inflation; 3: unobstructed vessel lumen with the occluding material pushed to
the side. PA: pulmonary artery; PEA: pulmonary endarterectomy; BPA: balloon pulmonary angioplasty.
Reproduced from [42] with permission.
https://doi.org/10.1183/2312508X.10018422 197
subsegmental lesions, has been introduced and somewhat overlaps with surgery for distal
lesions, taking predominance depending on the interventionalist’s experience (figure 4) [64]. An
absence of venous thromboembolism history, signs of RV failure, significant concomitant lung
or left heart disease, functional class IV, inconsistency on imaging modalities, no disease
appreciable in lower lobes, PVR >1200 dyn·s·cm–5 (15 WU; out of proportion to site and
number of obstructions on imaging), and higher diastolic PAP are associated with a higher
operative risk with a less predictable long-term outcome [57].
The results of surgery are impressive, with a 65% reduction in PVR [60] and an excellent 3-year
survival of 90% [65]. In-hospital mortality was 4.7% in the European CTEPH registry, which
included both high- and intermediate-volume centres [60]. Currently, high-volume centres report
surgical mortalities of <2% (unpublished data). The following complications are frequently
reported but usually resolve during the first postoperative days: infections (mostly respiratory),
neurological complications, lung reperfusion injury, haemoptysis and other bleedings, and
pericardial effusions [60]. A few patients need postoperative extracorporeal membrane oxygenation,
and the median duration of mechanical ventilation is 1 day. Predictors of mortality are low surgeon
and centre experience, functional class IV, an absence of venous thromboembolism history, a
history of cancer, high pre- and postoperative PVR, and additional cardiac interventions [60, 65].
Technically, PEA consists of the extraction of the obstructive fibrothrombotic material together
with the internal layer of the pulmonary arteries (intima and part of the media [33]) from the
right and left pulmonary arteries to their segmental/subsegmental branches. It is performed
through a median sternotomy, under cardiopulmonary bypass with periods of deep hypothermic
cardiac arrest for proper visualisation of the operation field [56, 59].
A similar therapeutic approach can be proposed for highly symptomatic and well-selected
patients with CTEPD without PH with acceptable morbidity and no mortality [66–68].
Medical treatment
As a significant proportion of patients are not operable, for technical or medical reasons, and
some refuse surgery, an alternative approach is to target the microvasculopathy of the
still-perfused areas with PH drugs. This approach is also relevant for patients with persistent or
recurrent PH after PEA due to unreachable distal obstructions combined with microvasculopathy.
PH drugs have been evaluated in CTEPH, but so far, only the guanylate cyclase stimulator
riociguat, the endothelin receptor antagonist macitentan and the prostacyclin analogue treprostinil
have proven efficacy. Riociguat improved exercise capacity, functional class, PVR, the RV strain
plasma biomarker NT-proBNP and quality of life in patients with inoperable CTEPH and
persistent/recurrent postoperative PH [69]. Macitentan improved PVR and exercise capacity in
patients with inoperable CTEPH of whom 60% were already receiving PH drugs [70]. S.c.
administration of treprostinil improved exercise capacity in patients with inoperable CTEPH and
persistent/recurrent postoperative PH [71]. However, many patients worldwide are treated with
generic phosphodiesterase 5 inhibitors and endothelin receptor antagonists depending on drug
availability and cost [64, 65]. Globally, PH drugs used in monotherapy decrease PVR by ∼30%.
Despite the absence of evidence, PH drugs are sometimes used preoperatively in patients with
high PVR in order to decrease the operative risk known to increase with high PVR [60], and
when the waiting time for PEA is prolonged. Frequently patients referred to CTEPH centres are
already receiving PH drugs. However, no benefit of this has been proven, and in the European
CTEPH registry, there was even an unfavourable effect of PH drugs on survival, possibly
related to delayed surgery [65].
198 https://doi.org/10.1183/2312508X.10018422
Life-long therapeutic anticoagulation is required to prevent PE recurrence and local thrombosis,

which could induce disease recurrence or haemodynamic deterioration [1, 2].
Interventional treatment
BPA was generalised as a therapeutic approach on the basis of pioneering work from Japanese
investigators ∼10 years ago [72–74]. Since then, many single-centre reports have confirmed the
efficacy and safety of the procedure. A recent meta-analysis of 40 studies confirmed that BPA
represents a safe and effective treatment option for select individuals with CTEPH with
significant improvements in haemodynamic parameters, improved exercise tolerance and a
relatively low risk of major complications [75]. However, there is no standardisation of the
technique across centres: some perform more sessions, some use smaller balloons, and others
treat lesions in many lobes in a single session. An ERS technical standard paper is under
preparation to optimise the interventional protocol.
Complications can occur during the procedure, such as pulmonary vascular injury with or
without haemoptysis (due to wire perforation, balloon overdilation or high-pressure contrast
injection), vascular dissection, an allergic reaction to the contrast medium, or an adverse
reaction to conscious sedation or local anaesthesia, or after the procedure, such as lung injury
(radiographic opacity with or without haemoptysis, with or without hypoxaemia), renal
dysfunction and access site problems [57]. Similarly to PEA, the operator experience influences
outcome and a standard of 30 patients or 100 procedures per year has been proposed [1, 2, 76].
Baseline mPAP is the strongest predictor of lung injury [76, 77]. The role of medical therapy
before BPA is currently under debate. A French study showed a significant reduction in
complications when riociguat was administrated before BPA [78]. Associated with PH drugs,
BPA can reduce PVR by nearly 50%. Persistent clinical and haemodynamic benefits have been
reported for up to 5 years postprocedure with a survival rate of 98% [79].
BPA can also be proposed for highly symptomatic patients with CTEPD without PH and distal
lesions with acceptable morbidity and no mortality [80].
Multimodal approach
Due to the heterogeneous disease distribution, proximal disease (in the right lung) can coexist
with distal disease (on the left side), and PEA and BPA can be complementary. Most
frequently, BPA will be performed after PEA if persistent or recurrent PH is observed. The
results are good [81, 82], but some authors reported a higher rate of complications and more
difficult procedures due to the previous surgical treatment [83, 84]. As alluded to in previous
sections, PH drugs can be used before PEA or BPA, but are most frequently used after. Besides
a normalised functional capacity, the therapeutic target of multimodal therapy is currently
unclear. Despite the historical reports suggesting that mPAP <30 mmHg is safe in the long term
[18, 85], many BPA interventionalists are willing to normalise mPAP and/or imaging.
Conclusion
CTEPH is a precapillary PH caused by fibrothrombotic obstruction of large pulmonary arteries
combined with microvasculopathy. It is frequently related to a previous episode of acute PE, but
only a small percentage of patients with acute PE will later be diagnosed with CTEPH. Its
diagnosis is based on the concomitant observation of PH, mismatched perfusion defects and
typical obstructive lesions on CTPA, in patients with exercise limitation. CTEPH is frequently
misdiagnosed as acute PE, and a systematic approach is needed to recognise signs suggestive of
CTEPH on the initial CTPA. A closer follow-up after acute PE to monitor symptom resolution
https://doi.org/10.1183/2312508X.10018422 199
should help to reduce CTEPH diagnostic delay. Three therapeutic approaches are used, each
targeting a specific site of the disease: PEA for proximal arteries, BPA for distal arteries and
PH drugs for the microvasculopathy. This combination aims to normalise pulmonary
haemodynamics and resolve symptoms. This can only be achieved if treatment selection is
performed in CTEPH centres with expertise in these three approaches.
References
1 Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of
2 Humbert M, Kovacs G, Hoeper MM, et al. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur Heart J 2022; 43: 3618–3731.
3 Dalen JE, Haynes FW, Hoppin FG, et al. Cardiovascular responses to experimental pulmonary embolism. Am J
Cardiol 1967; 20: 3–9.
4 Dexter L, Smith GT. Quantitative studies of pulmonary embolism. Am J Med Sci 1964; 247: 641–648.
5 Azarian R, Wartski M, Collignon MA, et al. Lung perfusion scans and hemodynamics in acute and chronic
pulmonary embolism. J Nucl Med 1997; 38: 980–983.
6 Delcroix M, Torbicki A, Gopalan D, et al. ERS statement on chronic thromboembolic pulmonary hypertension.
Eur Respir J 2021; 57: 2002828.
7 Delcroix M, Kerr K, Fedullo P. Chronic thromboembolic pulmonary hypertension. epidemiology and risk factors.
Ann Am Thorac Soc 2016; 13: Suppl. 3, S201–S206.
8 Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from
an international prospective registry. Circulation 2011; 124: 1973–1981.
9 Nijkeuter M, Hovens MMC, Davidson BL, et al. Resolution of thromboemboli in patients with acute pulmonary
embolism: a systematic review. Chest 2006; 129: 192–197.
10 Klok FA, Kralingen KWV, van Dijk APJ, et al. Prevalence and potential determinants of exertional dyspnea after
acute pulmonary embolism. Respir Med 2010; 104: 1744–1749.
11 Ende-Verhaar YM, Cannegieter SC, Noordegraaf AV, et al. Incidence of chronic thromboembolic pulmonary
hypertension after acute pulmonary embolism: a contemporary view of the published literature. Eur Respir J
2017; 49: 1601792.
12 Valerio L, Mavromanoli AC, Barco S, et al. Chronic thromboembolic pulmonary hypertension and impairment
after pulmonary embolism: the FOCUS study. Eur Heart J 2022; 43: 3387–3398.
13 Coquoz N, Weilenmann D, Stolz D, et al. Multicentre observational screening survey for the detection of CTEPH
following pulmonary embolism. Eur Respir J 2018; 51: 1702505.
14 Kramm T, Wilkens H, Fuge J, et al. Incidence and characteristics of chronic thromboembolic pulmonary
hypertension in Germany. Clin Res Cardiol 2018; 107: 548–553.
15 Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute
pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J
2019; 2019: 543–603.
16 Klok FA, Surie S, Kempf T, et al. A simple non-invasive diagnostic algorithm for ruling out chronic thromboembolic
pulmonary hypertension in patients after acute pulmonary embolism. Thromb Res 2011; 128: 21–26.
17 Boon GJAM, Ende-Verhaar YM, Bavalia R, et al. Non-invasive early exclusion of chronic thromboembolic
pulmonary hypertension after acute pulmonary embolism: the InShape II study. Thorax 2021; 76: 1002–1009.
18 Riedel M, Stanek V, Widimsky J, et al. Longterm follow-up of patients with pulmonary thromboembolism: late
prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81: 151–158.
19 Lewczuk J, Piszko P, Jagas J, et al. Prognostic factors in medically treated patients with chronic pulmonary
embolism. Chest 2001; 119: 818–823.
20 Klok FA, Barco S, Konstantinides SV, et al. Determinants of diagnostic delay in chronic thromboembolic
pulmonary hypertension: results from the European CTEPH Registry. Eur Respir J 2018; 52: 1801687.
21 Cheng CY, Zhang YX, Denas G, et al. Prevalence of antiphospholipid (aPL) antibodies among patients with
chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis. Intern Emerg Med
2019: 14, 521–527.
22 Bonderman D, Wilkens H, Wakounig S, et al. Risk factors for chronic thromboembolic pulmonary hypertension.
Eur Respir J 2009; 33: 325–331.
23 Wolf M, Boyer-Neumann C, Parent F, et al. Thrombotic risk factors in pulmonary hypertension. Eur Respir J
2000; 15: 395–399.
24 Bonderman D, Turecek P, Jakowitsch J, et al. High prevalence of elevated clotting factor VIII in chronic
thromboembolic pulmonary hypertension. Thromb Haemostasis 2003; 90: 372–376.
200 https://doi.org/10.1183/2312508X.10018422
25 Suntharalingam J, Goldsmith K, van Marion V, et al. Fibrinogen Aα Thr312Ala polymorphism is associated with
chronic thromboembolic pulmonary hypertension. Eur Respir J 2008; 31: 736–741.
26 Morris TA, Marsh JJ, Chiles PG, et al. Fibrin derived from patients with chronic thromboembolic pulmonary
hypertension is resistant to lysis. Am J Respir Crit Care 2006; 173: 1270–1275.
27 Morris TA, Marsh JJ, Chiles PG, et al. High prevalence of dysfibrinogenemia among patients with chronic
thromboembolic pulmonary hypertension. Blood 2009; 114: 1929–1936.
28 Bonderman D, Jakowitsch J, Adlbrecht C, et al. Medical conditions increasing the risk of chronic
thromboembolic pulmonary hypertension. Thromb Haemost 2005; 93: 512–516.
29 Jevnikar M, Montani D, Savale L, et al. Chronic thromboembolic pulmonary hypertension and totally
implantable central venous access systems. Eur Respir J 2020; 57: 2002208.
30 Quarck R, Nawrot T, Meyns B, et al. C-reactive protein: a new predictor of adverse outcome in pulmonary
arterial hypertension. J Am Coll Cardiol 2009; 53: 1211–1218.
31 Zabini D, Heinemann A, Foris V, et al. Comprehensive analysis of inflammatory markers in chronic
thromboembolic pulmonary hypertension patients. Eur Respir J 2014; 44: 951–962.
32 Soon E, Holmes AM, Treacy CM, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic
and familial pulmonary arterial hypertension. Circulation 2010; 122: 920–927.
33 Quarck R, Wynants M, Verbeken E, et al. Contribution of inflammation and impaired angiogenesis to the
pathobiology of chronic thromboembolic pulmonary hypertension. Eur Respir J 2015; 46: 431–443.
34 Alias S, Redwan B, Panzenbock A, et al. Defective angiogenesis delays thrombus resolution: a potential
pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension. Arterioscler Thromb
Vasc Biol 2014; 34: 810–819.
35 Hobohm L, Kölmel S, Niemann C, et al. Role of angiopoietin-2 in venous thrombus resolution and chronic
thromboembolic disease. Eur Respir J 2021; 58: 2004196.
36 Bochenek ML, Leidinger C, Rosinus NS, et al. Activated endothelial TGFβ1 signaling promotes venous thrombus
nonresolution in mice via endothelin-1: potential role for chronic thromboembolic pulmonary hypertension.
Circ Res 2020; 126: 162–181.
37 Sharma S, Hofbauer TM, Ondracek AS, et al. Neutrophil extracellular traps promote fibrous vascular occlusions
in chronic thrombosis. Blood 2021; 137: 1104–1116.
38 Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel
thromboembolic pulmonary hypertension. Chest 1993; 103: 685–692.
39 Dorfmüller P, Günther S, Ghigna MR, et al. Microvascular disease in chronic thromboembolic pulmonary
hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J 2014; 44: 1275–1288.
40 Braams NJ, van Leeuwen JW, Noordegraaf AV, et al. Right ventricular adaptation to pressure-overload:
differences between chronic thromboembolic pulmonary hypertension and idiopathic pulmonary arterial
hypertension. J Heart Lung Transplant 2021; 40: 458–466.
41 Fukumitsu M, Westerhof BE, Ruigrok D, et al. Early return of reflected waves increases right ventricular wall
stress in chronic thromboembolic pulmonary hypertension. Am J Physiol Heart Circ 2020; 319: H1438–H1450.
42 Simonneau MD, Fadel E, Vonk Noordegraaf A, et al. Highlights from the International Chronic Thromboembolic
Pulmonary Hypertension Congress 2021. Eur Respir Rev 2023; 32: 220132.
43 Dantzker DR, Bower JS. Mechanisms of gas exchange abnormality in patients with chronic obliterative
pulmonary vascular disease. J Clin Invest 1979; 64: 1050–1055.
44 d’Alonzo GE, Bower JS, Dantzker DR. Differentiation of patients with primary and thromboembolic pulmonary
hypertension. Chest 1984; 85: 457–461.
45 Lang I, Simonneau G, Pepke-Zaba J, et al. Factors associated with diagnosis and operability of chronic
thromboembolic pulmonary hypertension. Thromb Haemostasis 2013; 110: 83–91.
46 Helmersen D, Provencher S, Hirsch AM, et al. Diagnosis of chronic thromboembolic pulmonary hypertension: a
Canadian Thoracic Society clinical practice guideline update. Can J Respir Crit Care Sleep Med 2019; 3: 177–198.
47 Dournes G, Verdier D, Montaudon M, et al. Dual-energy CT perfusion and angiography in chronic
thromboembolic pulmonary hypertension: diagnostic accuracy and concordance with radionuclide scintigraphy.
Eur Radiol 2014; 24: 42–51.
48 Masy M, Giordano J, Petyt G, et al. Dual-energy CT (DECT) lung perfusion in pulmonary hypertension:
concordance rate with V/Q scintigraphy in diagnosing chronic thromboembolic pulmonary hypertension
(CTEPH). Eur Radiol 2018; 28: 5100–5110.
49 Hong YJ, Kim JY, Choe KO, et al. Different perfusion pattern between acute and chronic pulmonary
thromboembolism: evaluation with two-phase dual-energy perfusion CT. Am J Roentgenol 2013; 200: 812–817.
50 Grob D, Oostveen LJ, Prokop M, et al. Imaging of pulmonary perfusion using subtraction CT angiography is
feasible in clinical practice. Eur Radiol 2019; 29: 1408–1414.
51 Remy-Jardin M, Ryerson CJ, Schiebler ML, et al. Imaging of pulmonary hypertension in adults: a position paper
from the Fleischner Society. Eur Respir J 2021; 57: 2004455.
https://doi.org/10.1183/2312508X.10018422 201
52 Guérin L, Couturaud F, Parent F, et al. Prevalence of chronic thromboembolic pulmonary hypertension after
acute pulmonary embolism. Thromb Haemostasis 2014; 112: 598–605.
53 Ruggiero A, Screaton NJ. Imaging of acute and chronic thromboembolic disease: state of the art. Clin Radiol
2017; 72: 375–388.
54 Braams NJ, Boon GJAM, de Man FS, et al. Evolution of CT findings after anticoagulant treatment for acute
pulmonary embolism in patients with and without an ultimate diagnosis of chronic thromboembolic
55 Kawakami T, Ogawa A, Miyaji K, et al. Novel angiographic classification of each vascular lesion in chronic
thromboembolic pulmonary hypertension based on selective angiogram and results of balloon pulmonary
angioplasty. Circ Cardiovasc Interv 2016; 9: e003318.
56 Madani M, Mayer E, Fadel E, et al. Pulmonary endarterectomy. Patient selection, technical challenges, and
outcomes. Ann Am Thorac Soc 2016; 13: Suppl. 3, S240–S247.
57 Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2019; 53:
1801915.
58 Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned
in 1,500 cases. Ann Thorac Surg 2003; 76: 1457–1464.
59 Madani MM, Auger WR, Pretorius V, et al. Pulmonary endarterectomy: recent changes in a single institution’s
experience of more than 2,700 patients. Ann Thorac Surg 2012; 94: 97–103.
60 Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic
thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac
Cardiovasc Surg 2011; 141: 702–710.
61 Hsieh WC, Jansa P, Huang WC, et al. Residual pulmonary hypertension after pulmonary endarterectomy: a
meta-analysis. J Thorac Cardiovasc Surg 2018; 156: 1275–1287.
62 Claessen G, Gerche AL, Dymarkowski S, et al. Pulmonary vascular and right ventricular reserve in patients with
normalized resting hemodynamics after pulmonary endarterectomy. J Am Heart Assoc 2015; 4: e001602.
63 Berman M, Hardman G, Sharples L, et al. Pulmonary endarterectomy: outcomes in patients aged >70. Eur J
Cardiothorac Surg 2012; 41: e154–e160.
64 Guth S, d’Armini AM, Delcroix M, et al. Current strategies for managing chronic thromboembolic pulmonary
hypertension: results of the worldwide prospective CTEPH Registry. ERJ Open Res 2021; 7: 00850-2020.
65 Delcroix M, Lang I, Pepke-Zaba J, et al. Long-term outcome of patients with chronic thromboembolic
pulmonary hypertension: results from an international prospective registry. Circulation 2016; 133: 859–871.
66 Taboada D, Pepke-Zaba J, Jenkins DP, et al. Outcome of pulmonary endarterectomy in symptomatic chronic
thromboembolic disease. Eur Respir J 2014; 44: 1635–1645.
67 van Kan C, van der Plas MN, Reesink HJ, et al. Hemodynamic and ventilatory responses during exercise in
chronic thromboembolic disease. J Thorac Cardiovasc Surg 2016; 152: 763–771.
68 Guth S, Wiedenroth CB, Rieth A, et al. Exercise right heart catheterisation before and after pulmonary
endarterectomy in patients with chronic thromboembolic disease. Eur Respir J 2018; 52: 1800458.
69 Ghofrani HA, d’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic
pulmonary hypertension. New Engl J Medicine 2013; 369: 319–329.
70 Ghofrani HA, Simonneau G, d’Armini AM, et al. Macitentan for the treatment of inoperable chronic
thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised,
double-blind, placebo-controlled study. Lancet Respir Med 2017; 5: 785–794.
71 Sadushi-Kolici R, Jansa P, Kopec G, et al. Subcutaneous treprostinil for the treatment of severe non-operable
chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled
72 Sugimura K, Fukumoto Y, Satoh K, et al. Percutaneous transluminal pulmonary angioplasty markedly improves
pulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonary
hypertension. Circ J 2012; 76: 485–488.
73 Kataoka M, Inami T, Hayashida K, et al. Percutaneous transluminal pulmonary angioplasty for the treatment of
chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012; 5: 756–762.
74 Mizoguchi H, Ogawa A, Munemasa M, et al. Refined balloon pulmonary angioplasty for inoperable patients with
chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012; 5: 748–755.
75 Kennedy MK, Kennedy SA, Tan KT, et al. Balloon pulmonary angioplasty for chronic thromboembolic
pulmonary hypertension: a systematic review and meta-analysis. Cardiovasc Intervent Radiol 2023; 46: 5–18.
76 Brenot P, Jais X, Taniguchi Y, et al. French experience of balloon pulmonary angioplasty for chronic
thromboembolic pulmonary hypertension. Eur Respir J 2019; 53: 1802095.
77 Ejiri K, Ogawa A, Fujii S, et al. Vascular injury is a major cause of lung injury after balloon pulmonary
angioplasty in patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2018; 11:
e005884.
202 https://doi.org/10.1183/2312508X.10018422
78 Jaïs X, Brenot P, Bouvaist H, et al. Balloon pulmonary angioplasty versus riociguat for the treatment of
inoperable chronic thromboembolic pulmonary hypertension (RACE): a multicentre, phase 3, open-label,
randomised controlled trial and ancillary follow-up study. Lancet Respir Med 2022; 10: 961–971.
79 Aoki T, Sugimura K, Tatebe S, et al. Comprehensive evaluation of the effectiveness and safety of balloon
pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and
procedure-related complications. Eur Heart J 2017; 38: 3152–3159.
80 Wiedenroth CB, Olsson KM, Guth S, et al. Balloon pulmonary angioplasty for inoperable patients with chronic
thromboembolic disease. Pulm Circ 2018; 8: 2045893217753122.
81 Araszkiewicz A, Darocha S, Pietrasik A, et al. Balloon pulmonary angioplasty for the treatment of residual or
recurrent pulmonary hypertension after pulmonary endarterectomy. Int J Cardiol 2019; 278: 232–237.
82 Shimura N, Kataoka M, Inami T, et al. Additional percutaneous transluminal pulmonary angioplasty for residual
or recurrent pulmonary hypertension after pulmonary endarterectomy. Int J Cardiol 2015; 183: 138–142.
83 Ito R, Yamashita J, Sasaki Y, et al. Efficacy and safety of balloon pulmonary angioplasty for residual pulmonary
hypertension after pulmonary endarterectomy. Int J Cardiol 2021; 334: 105–109.
84 Hug KP, Coghlan JG, Cannon J, et al. Serial right heart catheter assessment between balloon pulmonary
angioplasty sessions identify procedural factors that influence response to treatment. J Heart Lung Transplant
2021; 40: 1223–1234.
85 Cannon JE, Su L, Kiely DG, et al. Dynamic risk stratification of patient long-term outcome after pulmonary
endarterectomy: results from the United Kingdom national cohort. Circulation 2016; 133: 1761–1771.
Disclosures: M. Delcroix reports receiving the following, outside the submitted work: research grants from Janssen,
and speaker and consultant fees from Altavant, Acceleron, AOP, Daiichi Sankyo, Bayer, Ferrer, Gossamer and MSD,
all paid to her institution. M. Delcroix is the holder of the Janssen Chair for Pulmonary Hypertension at the KU
Leuven. L. Godinas reports receiving consultant fees and travel fees from Janssen and MSD, outside the submitted
work. C. Belge reports receiving the following, outside the submitted work: speaker fees, fees for participation at
Advisory Boards and support for attending meetings and/or travel from Janssen and MSD, all paid to her
institution. T. Verbelen reports receiving speaker fees from Medtronic, outside the submitted work. The remaining
authors have nothing to declare.
https://doi.org/10.1183/2312508X.10018422 203
Chapter 15
Pulmonary hypertension in orphan lung

diseases
1,2,3
David Montani , Mithum Kularatne1,2,3,4, Etienne-Marie Jutant 5
and
1,2,3
Marc Humbert
1
Assistance Publique – Hôpitaux de Paris (AP-HP), Dept of Respiratory and Intensive Care Medicine, Pulmonary
Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France. 2Université Paris-Saclay, Faculty
of Medicine, Le Kremlin-Bicêtre, France. 3INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and
Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France. 4University of Calgary, Calgary, Canada.
5
Respiratory Dept, CHU de Poitiers, INSERM CIC 1402, IS-ALIVE Research Group, University of Poitiers, Poitiers,
France. 6European Reference Network for Rare Diseases of the respiratory system (ERN-LUNG), Frankfurt, Germany.
Corresponding author: David Montani (davidmontani@gmail.com)
Cite as: Montani D, Kularatne M, Jutant E, et al. Pulmonary hypertension in orphan lung diseases. In: Wagner TOF,
European Respiratory Society, 2023; pp. 204–223 [https://doi.org/10.1183/2312508X.10018522].
@ERSpublications
This chapter raises awareness of the link between orphan lung diseases and pulmonary hypertension https://
bit.ly/ERSM100
ISSN: 2312-5098.
PH may develop in the clinical course of certain orphan lung diseases and is typically associated with
decreased survival. PH is usually related to the degree of pulmonary parenchymal involvement, but
disproportionate involvement of the pulmonary vasculature can occur, particularly in diseases such as
sarcoidosis, pulmonary Langerhans cell histiocytosis, neurofibromatosis type 1, combined pulmonary
fibrosis and emphysema, and lymphangioleiomyomatosis. TBX4 syndrome is a genetic disorder
typically affecting development of the lower extremities and lungs, but pulmonary vascular involvement
can be observed and typically coexists with specific parenchymal findings. Pulmonary veno-occlusive
disease/pulmonary capillary haemangiomatosis (PVOD/PCH) is a characteristic form of PH with
preferential involvement of the pulmonary venous compartment. Its heritable form is associated with
autosomal-recessive transmission due to mutations in the eukaryotic translation initiation factor 2α
kinase 4 (EIF2AK4) gene. PVOD/PCH is associated with a poor response to pulmonary arterial
hypertension-specific therapy and results in a poor prognosis, necessitating early recognition and
referral for lung transplantation.
Introduction
PH is defined in the most recent European Respiratory Society (ERS)/European Society of
Cardiology (ESC) guidelines for the diagnosis and treatment of PH as an elevated mean
pulmonary arterial pressure (mPAP) >20 mmHg, as measured invasively by right heart
catheterisation (RHC) [1]. This threshold is based on invasive physiological studies showing that,
in the general population, mPAP is equivalent to 14 mmHg (±3.3 mmHg) with two standard
deviations denoting the upper limit of normal of 20 mmHg [2]. Pre-capillary PH is defined with
two additional parameters: 1) increased pulmonary vascular resistance (PVR) >2 Wood units
(WU), and 2) normal pulmonary arterial wedge pressure (PAWP) ⩽15 mmHg [1]. This classification
204 https://doi.org/10.1183/2312508X.10018522
PULMONARY HYPERTENSION | D. MONTANI ET AL.
comprises the following subgroups of PH: pulmonary arterial hypertension (PAH), PH associated
with left heart disease, PH associated with lung disease and/or hypoxia, PH associated with
pulmonary arterial obstructions, and PH with unclear and/or multifactorial mechanisms (table 1).
Although in the majority of cases PH associated with parenchymal lung disease is associated
with modest increases in mPAP [3], in some cases the haemodynamic abnormalities may be out
of proportion to the severity of the lung disease, suggesting direct pulmonary vascular
involvement. The threshold for out-of-proportion PH has recently been defined as >5 WU in the
most recent guidelines based on studies in patients with COPD and ILD [1].
The clinical classification of PH was revised recently in the 2022 ERS/ESC guidelines and is
presented in table 1 [1]. Group 1 includes all forms of PAH including idiopathic and heritable,
PAH associated with drugs and toxins, and PAH associated with other medical conditions
(specifically connective tissue disease, HIV infection, portal hypertension, congenital heart
TABLE 1 Classification of PH based on European Respiratory Society/European Society of Cardiology guidelines

Group 1: PAH
1.1 Idiopathic
1.1.1 Nonresponders at vasoreactivity testing
1.1.2 Acute responders at vasoreactivity testing
1.2 Heritable
1.3 Associated with drugs and toxins
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.5 PAH with features of venous/capillary (PVOD/PCH) involvement
1.6 Persistent PH of the newborn
Group 2: PH associated with left heart disease
2.1 Heart failure
2.2 Valvular heart disease
2.3 Congenital/acquired cardiovascular conditions leading to post-capillary PH
Group 3: PH associated with lung diseases and/or hypoxia
3.1 Obstructive lung disease or emphysema
3.2 Restrictive lung disease
3.3 Lung disease with mixed restrictive/obstructive pattern
3.4 Hypoventilation syndromes
3.5 Hypoxia without lung disease
3.6 Developmental lung disorders
Group 4: PH associated with pulmonary artery obstructions
4.1 Chronic thromboembolic PH
4.2 Other pulmonary artery obstructions
Group 5: PH with unclear and/or multifactorial mechanisms
5.1 Haematological disorders
5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis and neurofibromatosis type 1
5.3 Metabolic disorders
5.4 Chronic renal failure with or without haemodialysis
5.5 Pulmonary tumour thrombotic microangiopathy
5.6 Fibrosing mediastinitis
PAH: pulmonary arterial hypertension; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillary
haemangiomatosis. Reproduced and modified from [1] with permission.
https://doi.org/10.1183/2312508X.10018522 205
disease and schistosomiasis). Group 1.5 contains a rare condition involving predominant
pulmonary venous or capillary involvement, termed “PAH with features of venous/capillary
involvement” [1]. This category includes pulmonary veno-occlusive disease (PVOD) and
pulmonary capillary haemangiomatosis (PCH), which have recently been demonstrated to be
two presentations of the same clinical entity [4–7]. Group 2 includes causes of post-capillary
PH due to left heart disease, which is defined haemodynamically by an increase in PAWP
>15 mmHg with a normal PVR [8]. Group 3 comprises PH associated with lung diseases and/or
hypoxia and contains diseases that result in PH predominantly as a result of chronic
hypoxaemia due to chronic lung disease, impaired control of breathing or residence at high
altitude. Group 3 also includes combined pulmonary fibrosis and emphysema (CPFE)
characterised by both obstructive and restrictive features, which more frequently have findings
of severe PH on haemodynamic evaluation and lymphangioleiomyomatosis (LAM) [9–11].
Group 4 PH is associated with pulmonary artery obstructions and predominantly comprises
chronic thromboembolic PH [12]. Finally, group 5 PH contains a group of heterogeneous
medical conditions that cause PH through unclear and/or multifactorial mechanisms and
includes entities such as haematological disorders, systemic and metabolic disorders, chronic
renal failure, pulmonary tumour thrombotic microangiopathy and fibrosing mediastinitis.
The goal in the primary evaluation of patients who have evidence of PH in the context of
orphan lung diseases is to rule out other, more common causes of PH such as post-capillary PH
and chronic thromboembolic PH, as well as to screen patients for PAH associated with other
medical conditions. Pre-capillary PH due to orphan lung diseases is found in several different
categories within this classification including group 1 (1.2: small patella syndrome; 1.5: PVOD/
PCH), group 3 (syndrome of CPFE, as well as LAM), and group 5 (sarcoidosis, pulmonary
Langerhans cell histiocytosis (PLCH) and neurofibromatosis type 1 (NF1)). These are discussed
in the following sections.
PAH with features of venous/capillary (PVOD/PCH) involvement (group 1.5)

PVOD and PCH are rare causes of PH that are difficult to differentiate from PAH due to similar
characteristics. However, due to the significant difference in management strategies, attempting
to make this distinction is critical [13, 14]. The true prevalence of PVOD is challenging to
establish due to this difficulty in differentiation, and histological studies have suggested that
3–12% of cases initially diagnosed as idiopathic PAH (IPAH) are, in fact, PVOD [15, 16]. IPAH
is characterised by a female preponderance compared with PVOD, which has a male/female
ratio of ∼1 [5, 17]. Although previously thought to be two different conditions, it is now well
established that PVOD and PCH are two presentations of the same disease with numerous
common traits and overlapping features [14]. Histological examination of lung tissue in PVOD
shows extensive and diffuse occlusion of pulmonary veins by fibrous tissue and intimal
thickening preferentially involving venules and small veins in lobular septa (figure 1a), and
localised capillary proliferations, which may obstruct veins and venular walls in patients with
PCH [4, 15, 18, 19]. A clinicopathological study of 35 lung specimens from patients diagnosed
with PVOD or PCH found capillary lesions in 75% of cases diagnosed as PVOD and
significant venous involvement in 80% of cases diagnosed as PCH [18]. It has been postulated
that capillary haemangiomatosis may occur as a result of an angioproliferative process
associated with venous obstruction, as observed with PVOD. Additionally, a common genetic
background was identified in families with PVOD or PCH, confirming that the two terms
describe the same clinical entity [7, 20]. In the most recent clinical classification, PVOD/PCH
was categorised as group 1.5, PAH with features of venous/capillary (PVOD/PCH) involvement
(table 1) [1].
206 https://doi.org/10.1183/2312508X.10018522
a)
b)
Lesions of PVOD Pulmonary artery
Pulmonary artery
Bronchus
Pulmonary capillaries
Pulmonary
vein c)
Pulmonary vein
Pulmonary
capillaries
FIGURE 1 Pathological features and radiological abnormalities associated with pulmonary veno-occlusive
disease (PVOD). a) All three compartments of the pulmonary microcirculation are affected including intimal
fibrosis of small pre-septal venules, capillary haemangiomatosis, and arterial lesions with intimal fibrosis and
medial hypertrophy. b, c) HRCT features of PVOD with septal lines and centrilobular ground-glass opacities (b)
and lymph node enlargement (c). Reproduced and modified from [13] with permission.
The genetic basis of PVOD/PCH was identified in 2014 as biallelic mutations of the eukaryotic
translation initiation factor 2α kinase 4 gene (EIF2AK4), which was found in 100% of familial
PVOD/PCH, as well as in 25% of sporadic PVOD/PCH [7, 20, 21]. Heritable PVOD/PCH is an
autosomal-recessive disease with a male/female ratio of 1 and is characterised by a lower age at
diagnosis compared with sporadic PVOD/PCH patients [7]. Certain risk factors have been
highlighted for the development of sporadic PVOD/PCH, notably chemotherapeutic regimens
including alkylating agents such as cyclophosphamide and mitomycin [22–24]. PVOD/PCH has
been reported as a complication of solid-organ or haematological malignancies, bone marrow
transplantation, peripheral blood stem-cell transplant and radiotherapy. Occupational exposure to
trichloroethylene, a chemical solvent, has also been described [25]. Additionally, there appears
to be a relationship with tobacco exposure, with an increased proportion of smokers with
PVOD/PCH compared with PAH [5]. This difference was not explained by a gendered
difference in smoking rates, as increased tobacco exposure was seen in both males and females.
Furthermore, this association is also strengthened by the association between PVOD/PCH and
PLCH, a pulmonary disease occurring almost exclusively in smokers. There have also been
increasing descriptions of venous involvement in a number of diseases associated with PH,
specifically systemic sclerosis [26, 27], PLCH [28] and inflammatory diseases such as
sarcoidosis [29]. It is difficult to establish whether these associations are related to the
underlying disease or whether their treatment leads to the onset of PVOD/PCH.
Patients with PVOD/PCH have a poorer prognosis compared with patients with PAH,
highlighting the importance of differentiating the two conditions. A definitive diagnosis requires
either histological examination of lung biopsy samples or identification of biallelic mutation in
the EIF2AK4 gene, particularly in patients with a family history. Lung biopsies are associated
with a high risk of mortality in patients with established pulmonary vasculopathy and as a result
are contraindicated. Therefore, the treatment decision is usually based on clinical and
pathological grounds, and definitive diagnosis is only obtained at autopsy or by examination of
https://doi.org/10.1183/2312508X.10018522 207
explant specimens. PVOD/PCH is difficult to differentiate from PAH on clinical grounds alone,
as the physical examination findings in both conditions are often identical. Both diseases are
characterised by the insidious development of symptoms, marked by progressive dyspnoea and
asthenia, and progress into symptoms related to right heart failure as the disease progresses. As
the symptoms are nonspecific, the diagnosis is often made later in the course of the disease.
Findings such as Raynaud’s phenomenon and digital clubbing are more commonly associated
with IPAH but have also been observed with PVOD/PCH [5]. Respiratory examination may
reveal evidence of crackles and pleural effusions suggestive of acute pulmonary oedema, which
may occur after initiation of PAH-specific therapy. Despite the venular involvement,
measurement of PAWP is typically normal, as the pressure measurements recorded when the
catheter is wedged in a pulmonary artery branch are reflective of larger veins, which are
typically not involved in PVOD/PCH. Thus, PAWP measured in PVOD/PCH does not reflect
the true capillary pressure, making the term pulmonary capillary wedge pressure obsolete [5, 30].
Due to the involved vascular regions in PVOD/PCH, capillary pressure is increased, explaining
the development of acute pulmonary oedema after the initiation of PAH-specific therapy. As a
result, despite anatomical obstruction predominantly affecting the post-capillary vessels, the
haemodynamic pattern on RHC is pre-capillary PH. Interestingly, a similar proportion (12%) of
patients with PVOD/PCH have an acute vasodilator response compared with those with IPAH,
but in contrast to IPAH, an acute vasodilator response is not associated with a better prognosis,
nor has a long-term response to calcium-channel blockers been reported [31].
Due to the challenges in diagnosing patients with PVOD/PCH, a noninvasive approach to

screen patients with PH has been proposed [13, 30, 32]. This approach includes assessment of
HRCT of the chest, arterial blood gas analysis, DLCO testing and, in rare cases, BAL. On HRCT
scans of the chest, the findings of diffuse centrilobular ground-glass opacities, septal thickening
and mediastinal lymphadenopathy are common and highly suggestive of PVOD/PCH in patients
with pre-capillary PH (figure 1b, c) [33, 34]. Arterial blood gas analysis reveals a significantly
lower resting arterial oxygen tension (PaO2), and DLCO testing reveals significant impairment of
diffusion compared with IPAH [17, 30]. If performed, BAL in patients with PVOD/PCH reveals
haemosiderin-laden macrophages and a relative high average Golde score (usually <100) [35].
The response to PAH-specific therapy and the overall prognosis of PVOD/PCH are poor.
Approximately 50% of patients with PVOD/PCH may experience life-threatening deterioration
related to severe pulmonary oedema after initiating PAH-specific therapy [5, 30], which is due
to increased pulmonary blood flow with fixed post-capillary obstruction. Although pulmonary
oedema has been seen with all PAH-specific therapies [5], clinical, functional and
haemodynamic improvements have been reported following the cautious use of intravenous
epoprostenol as a bridge to lung transplantation in selected patients [30]. Some isolated cases or
small case series have shown some moderate clinical and haemodynamic improvements [36–41].
Additionally, the existence of an inflammatory background in certain PVOD/PCH patients
may prompt some practitioners to introduce immunosuppressive therapies. However, the data in
this area are scarce and this is not currently recommended by international guidelines [1].
Recently, a case series of three patients with idiopathic or heritable PVOD with features of
undetermined immune diseases revealed clinical and haemodynamic stabilisation or
improvement following immunosuppressive therapy with glucocorticoids and mycophenolate
mofetil [42]. However, it has not been established whether and how frequently
immunosuppressive therapy can impact patients with PVOD/PCH, even in the absence of
immune dysregulation. Due to the overall poor response to PAH-specific therapy and a lack
of other treatment options, early referral to lung transplant evaluation remains the treatment of
choice for patients with PVOD/PCH.
208 https://doi.org/10.1183/2312508X.10018522
PAH associated with small patella syndrome (group 1.2)

TBX4 syndrome is an autosomal-dominant condition that variably involves the lower limbs,
pulmonary parenchyma and pulmonary vasculature in affected patients. The T-box 4 gene
(TBX4) is a member of the T-box gene family encoding transcription factors that play a
dominant role in the development of various organs [43–45].
TBX4 syndrome has historically been described as dysplasia of the lower limbs with hypoplasia
or aplasia of the patella, ossification of the ischia and inferior pubic rami, and abnormalities of
the lower extremities, characteristically a large gap between the first and second toes and flat
feet, supporting the classic name small patella syndrome (SPS) or coxo-podo-patellar syndrome [46].
In 2013, involvement of mutations in the TBX4 gene was shown to be associated with the
development of pulmonary vasculopathy [47]. Indeed, TBX4 plays a significant role in the
normal development and branching of the lungs, with mutations in this gene resulting in
findings such as tracheal and bronchial diverticula, thickened and irregular bronchial walls,
peribronchial cysts and emphysema-like lesions (figure 2a, b) [48, 49].
Mutations in TBX4 can cause the development of PAH and in the current classification is
identified within group 1.2, heritable PAH (table 1) [2]. The presentation of PAH in patients
with TBX4 mutations has a female preponderance, as observed in IPAH or heritable PAH [49].
PAH presents with a bimodal distribution with an initial peak during early childhood [47–49]
and a second peak in late adulthood [49]. TBX4 mutations represent ∼6% of paediatric PAH
a) b)
c) d)
FIGURE 2 HRCT of the chest and pathological assessment of pulmonary arterial hypertension patients carrying a
TBX4 mutation. a) HRCT images showing the presence of paraseptal emphysema in both lungs and a large,
multi-loculated diverticula (arrow) directly connected to the posterior wall of the trachea (arrowhead). b) HRCT
with coronal oblique reformation of the chest, viewed as a minimum intensity projection, showing the presence
of bronchial wall irregularities and numerous adenolectases (arrows) in segmental and subsegmental bronchi of
the left upper lobe. c) Pulmonary vascular remodelling with small pulmonary arteries that appear thickened
with marked intimal fibrosis and a plexiform lesion. d) Parenchymal alterations with patchy peribronchiolar
fibrosis. Scale bars: c) 200 μm; d) 500 μm. Reproduced and modified from [49] with permission.
https://doi.org/10.1183/2312508X.10018522 209
cases and 3% of adult-onset PAH cases [49–51]. However, due to the implication of TBX4
mutations in the development of the lower limbs and lung tissues, PAH patients with TBX4
mutations may present with anomalies consistent with SPS and/or characteristic pulmonary
parenchymal abnormalities [48, 49, 52]. Haemodynamic findings at the time of diagnosis reveal
severe pre-capillary PH. Clinical findings of SPS can be found in the majority of cases but are
often missed, thus requiring rigorous examination of the lower limbs, and HRCT of the chest
must be examined meticulously, as bronchial and parenchymal lesions can be seen in 60% and
90% of cases, respectively [49]. Penetrance of SPS, lung abnormalities and PAH are
incomplete, and different phenotypes may be present, despite the same mutation, ranging from
an asymptomatic clinical picture to findings of SPS, lung parenchymal abnormalities and PAH
[49, 53, 54]. Pathological evaluations of lung tissues from patients with TBX4 mutations with
PAH reveal typical vasculopathy but also distal lung development abnormalities associated with
the presence of cholesterol cleft inclusions in the perivascular connective tissue; the significance
of the latter finding is unknown (figure 2c, d) [48, 49].
Similar to other forms of heritable PAH, initiation of PAH therapy can result in clinical
improvement and, to a lesser extent, haemodynamic improvement. The prognosis is poor, and
lung transplantation (LTx) remains the only curative option to date [49].
PH in CPFE (group 3)
The syndrome of CPFE was only recently described as a distinct entity characterised by diffuse
destruction of the lung parenchyma in 2005 [10]. CPFE is more common in male smokers and
results from the combined effects of emphysema involving the upper lobes and lung fibrosis
involving the lower lobes (figure 3a, b) [10, 55–58]. Despite considerable parenchymal
involvement, PFTs are typically well preserved except for a severe reduction in DLCO and the
presence of severe hypoxaemia [58, 59]. Pre-capillary PH is common in this patient population
with a prevalence of 47–90%, depending on whether the diagnosis was established using
echocardiography or through RHC. This prevalence is higher than in either COPD or idiopathic
pulmonary fibrosis alone [10, 11, 60]. Haemodynamic impairment is typically severe and
develops quickly after diagnosis, and appears to be correlated to the degree of emphysema seen
on HRCT [11, 59, 60]. CPFE is placed in the current clinical classification within subgroup 3.3
comprising lung disease with mixed restrictive/obstructive pattern [2].
The mechanism for the development of PH in patients with CPFE is assumed to be associated
with the destruction of alveolae due to emphysema and the thickening of alveolar membranes
from fibrosis leading to a reduction in lung perfusion and loss of the pulmonary capillary bed
[9, 61]. However, histopathological studies have described the presence of true pulmonary
vasculopathy in patients with CPFE-related PH. Vascular remodelling has been seen with
intimal fibrosis, medial hypertrophy of small pulmonary arteries and in situ thrombosis but with
an absence of plexiform lesions [62–64]. In addition, venular involvement may be seen, but
without significant involvement of the capillaries [63]. Interestingly, vascular lesions can be
seen in areas of the lung free from parenchymal involvement [62]. CPFE can also be seen in
patients with connective tissue diseases with a similar prevalence of PH [65].
In one retrospective study on pulmonary haemodynamics at the time of diagnosis, patients with
CPFE had moderate to severe haemodynamic impairment with a mPAP of 40±9 mmHg, PVR
of 6.5±2.6 WU and cardiac index of 2.5±0.7 L·min−1·m−2 [60]. The majority of patients (85%)
were in functional class III or IV with an impaired 6-min walk distance (6MWD) of
244±126 m. Univariate analysis identified that DLCO <22%, cardiac index <2.4 L·min−1·m−2
210 https://doi.org/10.1183/2312508X.10018522
a) b)
c) d)
FIGURE 3 HRCT of the chest of patients with group 3 PH. a, b) HRCT images in a patient with PH associated
with combined pulmonary fibrosis and emphysema showing predominant emphysema in the upper lobes (a)
and pulmonary fibrosis in the lower lobes (b). c, d) HRCT images showing moderate (c) and severe (d) diffuse
cystic lung disease in patients with PH-associated lymphangioleiomyomatosis.
and PVR >6.1 WU were associated with an increased risk of death [60]. The prognosis of CPFE
is highly associated with the presence of PH, with a 1-year survival of 60±10% in patients with
CPFE and PH [60].
Although case reports suggest an improvement in pulmonary haemodynamics with the use of
PAH-specific therapy in CPFE [60, 66–68], its use is not recommended due to the lack of
evidence of benefit and the risk of worsening hypoxaemia due to ventilation–perfusion
mismatching [9, 69]. Supportive care including oxygen therapy should be initiated if chronic
respiratory failure develops, and referral for LTx assessment should be considered.
PH associated with LAM (group 3)

LAM is a rare multisystem disorder typically affecting young women, with an estimated
prevalence of one to nine per 1 million of the population [70–72]. It typically occurs
sporadically, but in 30% of patients, it occurs in the context of tuberous sclerosis complex
(TSC) associated with mutations in the TSC1 and TSC2 genes. These genes encode the proteins
hamartin and tuberin, respectively [73–75]. Our current understanding of the development of
LAM is consistent with Knudson’s “two-hit” hypothesis for tumour development: there is an
initial mutation in either TSC1 or TSC2, followed by a second hit represented by loss of
heterozygosity, leading to the loss of function of the TSC1 or TSC2 gene product [76]. The
hamartin–tuberin complex plays a major role in the inhibition of the mammalian target of
rapamycin (mTOR) pathway. Thus, via a dysregulated mTOR pathway, there is abnormal
proliferation of smooth muscle-like cells, or LAM cells, along the lymphatics within the lungs
https://doi.org/10.1183/2312508X.10018522 211
and the abdomen, leading to diffuse cystic lung disease (figure 3c, d), benign renal tumours,
pneumothoraces, pleural and peritoneal chylous effusions and abdominal lymphangioleiomyomas
[75, 77]. Within the lungs, the secretion of metalloprotease by LAM cells leads to the formation
and progression of cysts, which are responsible for airflow obstruction, reduced DLCO and the
development of chronic respiratory insufficiency [78–80]. In LAM, serum levels of vascular
endothelial growth factor D, a factor involved in the expansion of lymphatic vessels, has been
shown to be elevated compared with both healthy controls and patients with other cystic lung
diseases [81]. The mTOR inhibitor sirolimus has been shown to be effective in treating the
extrathoracic lesions associated with LAM, as well as improving patients’ quality of life
[82–84]. Referral for LTx assessment is necessary for patients who develop advanced
respiratory disease due to LAM [84–90].
PH can complicate the disease course in 7% of patients with LAM, regardless of stage of
disease, but rates can be as high as 45% in patients at the time of LTx [80, 88, 91, 92]. As a
result, the ERS guidelines for the diagnosis and management of LAM state that in patients with
nonsevere LAM, screening for PH is not recommended due to the relatively low frequency of
PH in this population [84]. However, in patients who are being considered for LTx, an
estimation of the pulmonary artery pressure should be performed [86]. In the most recent
clinical classification, LAM was recategorised into group 3, PH associated with lung disease
and/or hypoxia, from its previous location in group 5, PH with unclear and/or multifactorial
mechanisms [2]. There are two main hypotheses that can explain the development of PH in
patients with LAM. The first explanation is related to the development of hypoxic pulmonary
vasoconstriction in the context of severe parenchymal lung disease due to cysts [80, 92]. There are
several studies that outline a significant correlation between the haemodynamic severity at RHC
and the degree of lung function impairment and PaO2 levels [91–94]. Studies have shown that
treatment with sirolimus results in an improvement in pulmonary haemodynamics in parallel
with improvements with FVC, forced expiratory volume in 1 s (FEV1) and PaO2 [92, 94]. The
second explanation is related to upregulated mTOR secretion by LAM cells, activation of
mTOR complexes 1 and 2 by hypoxia, which leads to vascular smooth muscle cell proliferation,
and PH [93, 95, 96].
In one retrospective multicentre study, 20 patients with LAM and pre-capillary PH confirmed by
RHC were described [93]. The mean patient age at the time of diagnosis was 49 years, with a
mean time between diagnosis of LAM and PH of 9.2 years. Haemodynamic evaluation revealed
moderate PH with a mPAP of 32±6 mmHg, cardiac index of 3.5±1.1 L·min−1·m−2 and PVR of
4.7±2.3 WU, with only four patients (20%) having mPAP measured as >35 mmHg. PFTs
revealed a decreased FEV1 of 42±25% and a DLCO of 29±13% with evidence of hypoxaemia on
arterial blood gas testing (PaO2 7.4±1.3 kPa on room air) [93]. This study revealed that, in the
majority of cases, PH was only mild or moderate and was correlated to the degree of pulmonary
involvement [93]. Only six patients received oral PAH-specific therapy, which resulted in a
decrease in mPAP and PVR. This study showed that the overall survival was 94% at 2 years [93].
In conclusion, patients with advanced lung involvement secondary to LAM are relatively likely
to have findings of mild to moderate PH on haemodynamic evaluation. The mechanisms
responsible for the development of PH appear to be a combination of chronic hypoxaemia and
pulmonary capillary destruction by the cystic lung lesions. By improving lung function and the
degree of hypoxaemia, sirolimus may improve the pulmonary haemodynamics. In some
patients, pulmonary vascular involvement may occur, potentially related to the activation of
mTOR in a mechanism similar to that proposed in patients with PH and NF1. Further studies
are needed to determine whether PAH-specific therapy is appropriate in this patient population.
212 https://doi.org/10.1183/2312508X.10018522
PH associated with sarcoidosis (group 5.2)

Sarcoidosis is characterised by multisystem granulomatous inflammation of unknown aetiology
with frequent pulmonary involvement [97–99]. The estimated prevalence of PH in sarcoidosis is
2.5–15% in unselected patients, but the actual prevalence can vary widely depending on the
population being studied [100–104]. In patients with persistent dyspnoea, PH prevalence has
been estimated to be 47–53.8% and is as high as 74% in patients with advanced lung disease
listed for transplantation [105, 106]. PH is more common among patients with radiological
stage 4 pulmonary sarcoidosis, characterised by pulmonary fibrosis, which accounts for 66–74%
of all sarcoidosis-associated PH (SaPH) [100, 107–109]. However, the reported prevalence of
PH in sarcoidosis in these studies is limited, as haemodynamic assessment was not performed
in many of these studies, instead relying on echocardiography to detect PH and ascertain its
mechanism despite its low accuracy in diagnosis [102, 110, 111].
There are multiple pathological processes underlying SaPH, and these processes fall within
different groups within the current clinical classification of PH [1, 2]. Advanced interstitial
fibrosis with loss of the pulmonary vascular bed combined with alveolar hypoxaemia can
promote the development of mild or moderate PH in some patients [99, 103, 112, 113].
Although PH is often seen in the context of more advanced parenchymal disease in sarcoidosis
[110, 113, 114], in some cases there is a discrepancy between the severity of PH on
haemodynamic evaluation and the severity of the parenchymal involvement. In this
circumstance, other mechanisms beyond loss of the pulmonary vascular bed by interstitial
fibrosis must be invoked to explain the development of PH [103, 115]. In these cases, direct
pulmonary vascular involvement from sarcoidosis must be considered, such as distal arterial or
venous infiltration by granulomas [99, 115–118]. Indeed, many studies have reported pulmonary
venular lesions similar to those seen in PVOD) [113, 115, 116]. Post-capillary PH may develop
due to direct myocardial involvement from sarcoidosis or due to the development of heart
failure with preserved ejection fraction in patients with ischaemic or hypertensive heart disease
secondary to diabetes mellitus or hypertension, resulting in long-term treatment with
corticosteroids [110, 112, 119]. Additionally, hepatic involvement may lead to portopulmonary
hypertension [120], and intrathoracic lymphadenopathy or fibrosing mediastinitis can cause
extrinsic compression of the proximal pulmonary arteries and veins leading to PH (figure 4a, b)
[107, 115, 121–123]. In summary, sarcoidosis may lead to PH in various ways and is best
classified within group 5, PH with unclear and/or multifactorial mechanisms (table 1) [1, 2].
The presence of PH in sarcoidosis has been demonstrated to be correlated with the severity of the
disease, particularly in mild and moderate PH [103, 105, 110, 114], and has been associated with
oxygen desaturation during the 6-min walk test and low DLCO on PFTs [108, 109, 112, 114].
Cardiac biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) have not
been demonstrated to predict PH in patients but can be seen to be elevated in patients with
cardiac sarcoidosis [124]. PH may be present in patients with any stage of pulmonary sarcoidosis
[103, 115], and if suspected, referral for RHC is required to establish the diagnosis [112]. Patients
with SaPH are recognised to have a worse prognosis compared with patients without pre-capillary
PH [110, 125, 126], with 5-year survival estimated at 55% [107]. Features associated with
increased mortality include higher levels of mPAP and African American ethnicity, as well as
chronic hypoxaemic respiratory failure requiring oxygen supplementation [125].
While immunosuppressive therapy is commonly used in the treatment of sarcoidosis, studies

have not clearly demonstrated efficacy in the management of pulmonary vascular disease in
sarcoidosis [99, 127, 128], and in certain subgroups of SaPH, immunosuppressive therapy can
be considered, such as PH secondary to extrinsic pulmonary vascular compression by
https://doi.org/10.1183/2312508X.10018522 213
a) b)
c) d)
e) f)
FIGURE 4 HRCT of the chest of patients with group 5 PH. a, b) HRCT images in a patient with
sarcoidosis-associated PH showing parenchymal micronodules (a) and mediastinal and hilar lymphadenopathy
with extrinsic compression of the bilateral pulmonary arteries (b). c, d) HRCT images in a patient with
pulmonary Langerhans cell histiocytosis-associated PH showing cavitary nodules and cysts predominantly in the
middle and upper regions of the lungs (c) and dilation of the pulmonary artery (d). e, f) HRCT images of
patients with neurofibromatosis type 1-associated PH, with multiple diffuse centimetric cysts (e). Note the dorsal
kyphoscoliosis and laterothoracic meningocele (f ).
metabolically active mediastinal lymphadenopathy [107]. Oxygen therapy should be prescribed

if chronic hypoxaemia is present to prevent hypoxic pulmonary vasoconstriction. Currently, the
use of PAH-specific therapy is not recommended in patients with SaPH; however, in routine
clinical practice, patients with severe pre-capillary PH are often treated with one or a
combination of medications off label [129]. The majority of studies assessing the use of such
treatments are open-label observational studies [107, 108, 127, 130–136], but a multicentre,
double-blinded, randomised trial comparing bosentan with placebo in 35 patients with
sarcoidosis and pre-capillary PH was performed [133]. In this study, treatment with bosentan
resulted in improvement of pulmonary haemodynamics (mPAP and PVR) but did not have an
effect on the exercise capacity as measured by 6MWD or functional class compared with
placebo. Three studies comprising a meta-analysis, a large retrospective cohort study and a
214 https://doi.org/10.1183/2312508X.10018522
publication outlining the experience within the French Pulmonary Hypertension Registry
between 2004 and 2015 again confirmed these findings, showing haemodynamic improvement
with PAH-specific therapy, without improvement in either functional class, exercise capacity or
quality of life [107, 108, 137]. An ongoing randomised placebo-controlled trial of the oral
prostacyclin analogue selexipag in SaPH is currently ongoing (ClinicalTrials.gov indicator
NCT03942211).
There are significant risks with the use of PAH-specific therapy in patients with SaPH. These
include the deterioration of gas exchange due to the release of protective hypoxic pulmonary
vasoconstriction and resulting worsening mismatch in ventilation and perfusion [69].
Additionally, patients with a predominant venular involvement similar to PVOD are at risk of
developing pulmonary oedema after initiation of PAH-specific therapy [130, 138]. Based on the
lack of evidence of efficacy and the risks inherent to a trial of therapy off label, the use of
PAH-specific therapy is currently not supported by the guidelines and should only be
considered in experienced PH centres. Given the poor prognosis of patients with SaPH and the
lack of effective medical therapy, early consideration and referral for LTx should occur. These
patients should be considered carefully, as the presence of PH prior to LTx places them at
increased risk for perioperative mortality [105, 139] and primary graft dysfunction [139]
post-transplantation.
PH associated with PLCH (group 5.2)

Langerhans cell histiocytosis is a disease characterised by clonal expansion of myeloid
precursors that infiltrate organs and differentiate into Langerhans cells [140]. This disease is
usually isolated to pulmonary involvement (PLCH), but in rare cases, extrapulmonary
manifestations can be seen [140]. PLCH typically affects younger patients who are active
smokers and is a rare cause of diffuse parenchymal lung disease [141]. PH can develop during
the course of the disease, and severe PH is frequently identified in advanced lung disease
[141–144]. The prevalence of severe PH ( previously defined as mPAP ⩾35 mmHg) was
reported to be 44–100% in patients referred for LTx for PLCH [142, 143]. This prevalence is
significantly higher than the rates reported in patients with other chronic lung diseases such as
COPD or idiopathic pulmonary fibrosis referred for LTx assessment [143].
Despite involvement of the lung parenchyma, PLCH is designated as group 5, PH with unclear
and/or multifactorial mechanisms [2]. This is due to the discrepancy between the
haemodynamic severity and the degree of parenchymal lung involvement with a lack of
correlation between haemodynamic parameters and findings on PFTs. These data suggest that
there is direct pulmonary vascular involvement that occurs independently of the parenchymal
lung disease [142, 143]. Histopathological studies have revealed diffuse proliferative
vasculopathy with intimal fibrosis and medial hypertrophy involving the small- to medium-sized
pulmonary vessels and septal veins. This vascular involvement appears to preferentially affect
the pulmonary veins, with less involvement of the muscular pulmonary arteries (figure 4c, d)
[142, 145, 146]. In up to one-third of patients, significant venous involvement in a pattern
similar to PVOD is present [28, 142]. Less commonly, vascular lesions may be due to direct
infiltration with Langerhans cells [142, 146]. Additionally, vascular lesions can be seen in areas
without nearby parenchymal lesions [142, 146], and vascular lesions adjacent to areas of
parenchymal involvement appear to be less severe [146]. Finally, while exercise limitation in
patients with PLCH is often multifactorial with both ventilatory and cardiocirculatory limitation
[147, 148], the primary cause of limitation in patients with PLCH and PH appears to be
haemodynamic impairment [149].
https://doi.org/10.1183/2312508X.10018522 215
Data on the use of PAH-specific therapies in the treatment of PLCH-related PH is very limited.
Some case reports have detailed improvements in haemodynamics, 6MWD and functional class
without significant deterioration in gas exchange or the development of pulmonary oedema
mostly with monotherapy regimens of phosphodiesterase type 5 inhibitors, endothelin receptor
antagonists or prostaglandins [150–157]. Unfortunately, no prospective randomised controlled
trials are available to ensure the safety and efficacy of PAH-specific therapy in patients with
PLCH-related PH. In one retrospective study of 29 patients with PLCH and PH, the majority of
patients (66%) had severe haemodynamic impairments with a mPAP of ⩾40 mmHg [158].
PAH-specific therapies caused haemodynamic improvements in both mPAP and PVR.
Two-thirds of patients had an improvement in functional class and 45% of patients attained a
>10% improvement in their 6MWD. Baseline functional class was the only predictor of death in
these patients, and, unfortunately, the use of PAH-specific therapy did not translate into an
improvement in survival [158]. While this study showed that PAH-specific therapy was safe,
without the development of gas-exchange abnormalities or pulmonary oedema, other studies
have reported the development of severe acute pulmonary oedema following administration of
i.v. epoprostenol [28, 142, 146].
Cladribine, a cytotoxic agent used in the treatment of progressive PLCH, has not been
rigorously evaluated, but one patient treated with this medication against a background of
bosentan therapy showed an improvement in functional status, lung function and 6MWD, as
well the degree of parenchymal involvement on HRCT [159]. Mutations in the
mitogen-activated protein kinase (MAPK) pathways, including BRAFV600E mutation, have been
found in up to 50% of patients with Langerhans cell histiocytosis. This new breakthrough may
lead to new treatment options with medications targeting the MAPK pathway. Unfortunately,
there are no data regarding the use of such treatments in PLCH and more specifically in
PLCH-associated PH. In patients with advanced or end-stage PLCH with or without associated
PH, LTx remains the only effective treatment option [143]. However, recurrence of PLCH
post-transplant has been reported, with the risk of recurrence associated with the presence of
extrapulmonary disease prior to transplantation [143, 160, 161].
PH associated with neurofibromatosis type 1 (group 5.2)

NF1, also known as von Recklinghausen disease, is a common autosomal-dominant disease
with a prevalence of 1 in 3000–6000 and almost complete penetrance by the age of 5 years
[162]. The condition is caused by mutation in the neurofibromin 1 (NF1) gene, which encodes a
cytoplasmic protein involved in tumour suppression called neurofibromin. Neurofibromin is a
guanosine triphosphatase (GTPase)-activating protein that serves as a negative regulator of RAS
signal transmission [163]. The loss of neurofibromin is associated with activation of several
transcription pathways. The diagnosis of NF1 is clinical and is based on the presence of at least
two out of seven clinical criteria (café-au-lait spots, cutaneous or s.c. neurofibromas or
plexiform neurofibromas, optic pathway glioma, freckling in the axillary of inguinal region,
Lisch nodules or choroidal abnormalities, bone dysplasia or a first-degree family history of
NF1) [164]. Respiratory involvement in NF1 includes the presence of cysts, bullae, intrathoracic
meningoceles, airway plexiform neurofibromas, interstitial infiltrates or ILD, and PH [162]. PH
was previously thought to be associated with advanced parenchymal involvement, but several
case reports and a case series revealed PH in patients with mild or absent lung involvement
related to NF1 (figure 4e, f ) [165]. A case series from the French Pulmonary Hypertension
Network of 49 patients with PH associated with NF1 revealed a female preponderance (female/
male ratio 3.9), while NF1 was equally found in females and males, with a median age of
diagnosis of 62 years [166]. PFTs revealed significant impairment of DLCO to 30% and
216 https://doi.org/10.1183/2312508X.10018522
hypoxaemia with a median PaO2 of 56 mmHg. Haemodynamic abnormalities were severe, with a
mPAP of 45 mmHg and PVR of 10.7 WU, and was associated with severe function impairment,
with >90% of patients presenting in New York Heart Association stage III or IV. Chest CT
scans revealed pulmonary parenchymal lesions in one-third of cases including cysts,
ground-glass opacities, emphysema and interstitial abnormalities that were moderate and
insufficient to explain the severity of PH. Histopathological data revealed intense pulmonary
vascular remodelling and, along with the female predominance and disproportionate PH
compared with the parenchymal involvement, suggested direct pulmonary vascular involvement
in NF1. In these patients, the response to PAH-specific therapy was poor, with a 5-year
transplant-free survival of only 42%, and thus referral for LTx assessment should be considered
early after diagnosis of PH associated with NF1.
Further research is needed to evaluate the role of the NF1 mutation and its effect on RAS and
mTOR signalling leading to the development of pulmonary vascular remodelling. As a result,
NF1 is classified as subgroup 5.2, PH associated with systemic disorders.
Conclusion
PH may occur in several orphan lung diseases including PLCH, NF1, sarcoidosis, LAM and
CPFE. PH may be a consequence of hypoxic pulmonary vasoconstriction and loss of the
pulmonary vascular bed, resulting in haemodynamic severity in proportion to the degree of
parenchymal involvement. However, in certain cases, particularly with sarcoidosis, NF1 and
PLCH, specific pulmonary vascular involvement may occur and result in severe
“out-of-proportion” pre-capillary PH, which is usually associated with a poor prognosis.
Additionally, in the last decade, mutations in the TBX4 gene responsible for SPS have been
identified as of interest in heritable PAH. In this condition, PAH is typically, but not always,
associated with characteristic phenotypic traits associated with this syndrome. Finally, PVOD is
a rare pulmonary vascular disease, presenting similarly to IPAH, but differentiation is critical,
allowing important differences in diagnosis, management and outcomes.
References
2 Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification
of pulmonary hypertension. Eur Respir J 2019; 53: 1801913.
3 Weitzenblum E, Hirth C, Ducolone A, et al. Prognostic value of pulmonary artery pressure in chronic
obstructive pulmonary disease. Thorax 1981; 36: 752–758.
4 Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension.
J Am Coll Cardiol 2004; 43: S25–S32.
5 Montani D, Achouh L, Dorfmüller P, et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic,
and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008;
87: 220–233.
6 Montani D, Girerd B, Jaïs X, et al. Clinical phenotypes and outcomes of heritable and sporadic pulmonary
veno-occlusive disease: a population-based study. Lancet Respir Med 2017; 5: 125–134.
7 Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive
form of pulmonary hypertension. Nat Genet 2014; 46: 65–69.
8 Vachiéry JL, Tedford RJ, Rosenkranz S, et al. Pulmonary hypertension due to left heart disease. Eur Respir J
2019; 53: 1801897.
9 Nathan SD, Barbera JA, Gaine SP, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur
Respir J 2019; 53: 1801914.
10 Cottin V, Nunes H, Brillet PY, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised
entity. Eur Respir J 2005; 26: 586–593.
11 Mejía M, Carrillo G, Rojas-Serrano J, et al. Idiopathic pulmonary fibrosis and emphysema. Chest 2009; 136:
10–15.
https://doi.org/10.1183/2312508X.10018522 217
12 Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2019; 53:
1801915.
13 Montani D, Lau EM, Dorfmüller P, et al. Pulmonary veno-occlusive disease. Eur Respir J 2016; 47: 1518–1534.
14 Weatherald J, Dorfmüller P, Perros F, et al. Pulmonary capillary haemangiomatosis: a distinct entity? Eur
Respir Rev 2020; 29: 190168.
15 Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension. A qualitative and
quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood
Institute, Primary Pulmonary Hypertension Registry. Circulation 1989; 80: 1198–1206.
16 Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156
clinically diagnosed cases. Circulation 1970; 42: 1163–1184.
17 Holcomb BW Jr, Loyd JE, Ely EW, et al. Pulmonary venoocclusive disease: a case series and new observations.
Chest 2000; 118: 1671–1679.
18 Lantuejoul S, Sheppard MN, Corrin B, et al. Pulmonary veno-occlusive disease and pulmonary capillary
hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol 2006; 30: 850–857.
19 Havlik DM, Massie LW, Williams WL, et al. Pulmonary capillary hemangiomatosislike foci. An autopsy study of 8
cases. Am J Clin Pathol 2000; 113: 655–662.
20 Best DH, Sumner KL, Austin ED, et al. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest 2014;
145: 231–236.
21 Tenorio J, Navas P, Barrios E, et al. A founder EIF2AK4 mutation causes an aggressive form of pulmonary
arterial hypertension in Iberian Gypsies. Clin Genet 2015; 88: 579–583.
22 Günther S, Perros F, Rautou PE, et al. Understanding the similarities and differences between hepatic and
pulmonary veno-occlusive disease. Am J Pathol 2019; 189: 1159–1175.
23 Perros F, Günther S, Ranchoux B, et al. Mitomycin-induced pulmonary veno-occlusive disease: evidence from
human disease and animal models. Circulation 2015; 132: 834–847.
24 Ranchoux B, Günther S, Quarck R, et al. Chemotherapy-induced pulmonary hypertension: role of alkylating
agents. Am J Pathol 2015; 185: 356–371.
25 Montani D, Lau EM, Descatha A, et al. Occupational exposure to organic solvents: a risk factor for pulmonary
veno-occlusive disease. Eur Respir J 2015; 46: 1721–1731.
26 Dorfmüller P, Humbert M, Perros F, et al. Fibrous remodeling of the pulmonary venous system in pulmonary
arterial hypertension associated with connective tissue diseases. Hum Pathol 2007; 38: 893–902.
27 Dorfmuller P, Montani D, Humbert M. Beyond arterial remodelling: pulmonary venous and cardiac
involvement in patients with systemic sclerosis-associated pulmonary arterial hypertension. Eur Respir J 2010;
35: 6–8.
28 Hamada K, Teramoto S, Narita N, et al. Pulmonary veno-occlusive disease in pulmonary Langerhans’ cell
granulomatosis. Eur Respir J 2000; 15: 421–423.
29 Hoffstein V, Ranganathan N, Mullen JB. Sarcoidosis simulating pulmonary veno-occlusive disease. Am Rev
Respir Dis 1986; 134: 809–811.
30 Montani D, Price LC, Dorfmuller P, et al. Pulmonary veno-occlusive disease. Eur Respir J 2009; 33: 189–200.
31 Montani D, Savale L, Natali D, et al. Long-term response to calcium-channel blockers in non-idiopathic
pulmonary arterial hypertension. Eur Heart J 2010; 31: 1898–1907.
32 Ogawa A, Takahashi Y, Matsubara H. Clinical prediction score for identifying patients with pulmonary
veno-occlusive disease/pulmonary capillary hemangiomatosis. J Cardiol 2018; 72: 255–260.
33 Resten A, Maitre S, Humbert M, et al. Pulmonary hypertension: CT of the chest in pulmonary venoocclusive
disease. Am J Roentgenol 2004; 183: 65–70.
34 Ali N, Loughborough WW, Rodrigues JCL, et al. Computed tomographic and clinical features of pulmonary
veno-occlusive disease: raising the radiologist’s awareness. Clin Radiol 2019; 74: 655–662.
35 Rabiller A, Jaïs X, Hamid A, et al. Occult alveolar haemorrhage in pulmonary veno-occlusive disease. Eur
Respir J 2006; 27: 108–113.
36 Barreto AC, Franchi SM, Castro CRP, et al. One-year follow-up of the effects of sildenafil on pulmonary arterial
hypertension and veno-occlusive disease. Braz J Med Biol Res 2005; 38: 185–195.
37 Kuroda T, Hirota H, Masaki M, et al. Sildenafil as adjunct therapy to high-dose epoprostenol in a patient with
pulmonary veno-occlusive disease. Heart Lung Circ 2006; 15: 139–142.
38 Luo Q, Jin Q, Zhao Z, et al. Targeted therapy in pulmonary veno-occlusive disease: time for a rethink? BMC
Pulm Med 2019; 19: 257.
39 Palazzini M, Manes A. Pulmonary veno-occlusive disease misdiagnosed as idiopathic pulmonary arterial
hypertension. Eur Respir Rev 2009; 18: 177–180.
40 Sourla E, Paspala A, Boutou A, et al. A case of pulmonary veno-occlusive disease: diagnostic dilemmas and
therapeutic challenges. Ther Adv Respir Dis 2013; 7: 119–123.
41 Ye X, Yan C, Zhang X, et al. Lengthy diagnostic challenge in a rare case of pulmonary veno-occlusive disease:
case report and review of the literature. Intern Med 2011; 50: 1323–1327.
218 https://doi.org/10.1183/2312508X.10018522
42 Bergbaum C, Samaranayake CB, Pitcher A, et al. A case series on the use of steroids and mycophenolate
mofetil in idiopathic and heritable pulmonary veno-occlusive disease: is there a role for immunosuppression?
Eur Respir J 2021; 57: 2004354.
43 Papaioannou VE. The T-box gene family: emerging roles in development, stem cells and cancer. Development
2014; 141: 3819–3833.
44 Arora R, Metzger RJ, Papaioannou VE. Multiple roles and interactions of Tbx4 and Tbx5 in development of the
respiratory system. PLoS Genet 2012; 8: e1002866.
45 Takeuchi JK. Tbx5 and Tbx4 trigger limb initiation through activation of the Wnt/Fgf signaling cascade.
Development 2003; 130: 2729–2739.
46 Bongers EMHF, Duijf PHG, van Beersum SEM, et al. Mutations in the human TBX4 gene cause small patella
syndrome. Am J Hum Genet 2004; 74: 1239–1248.
47 Kerstjens-Frederikse WS, Bongers EMHF, Roofthooft MTR, et al. TBX4 mutations (small patella syndrome) are
associated with childhood-onset pulmonary arterial hypertension. J Med Genet 2013; 50: 500–506.
48 Galambos C, Mullen MP, Shieh JT, et al. Phenotype characterisation of TBX4 mutation and deletion carriers
with neonatal and paediatric pulmonary hypertension. Eur Respir J 2019; 54: 1801965.
49 Thoré P, Girerd B, Jaïs X, et al. Phenotype and outcome of pulmonary arterial hypertension patients carrying
a TBX4 mutation. Eur Respir J 2020; 55: 1902340.
50 Levy M, Eyries M, Szezepanski I, et al. Genetic analyses in a cohort of children with pulmonary hypertension.
Eur Respir J 2016; 48: 1118–1126.
51 Zhu N, Pauciulo MW, Welch CL, et al. Novel risk genes and mechanisms implicated by exome sequencing of
2572 individuals with pulmonary arterial hypertension. Genome Med 2019; 11: 69.
52 Jansen SMA, van den Heuvel L, Meijboom LJ, et al. Correspondence regarding “T-box protein 4 mutation
causing pulmonary arterial hypertension and lung disease”: a single-centre case series. Eur Respir J 2020; 55:
1902272.
53 Zhu N, Gonzaga-Jauregui C, Welch CL, et al. Exome sequencing in children with pulmonary arterial
hypertension demonstrates differences compared with adults. Circ Genomic Precis Med 2018; 11: e001887.
54 Navas P, Tenorio J, Quezada CA, et al. Análisis de los genes BMPR2, TBX4 y KCNK3 y correlación
genotipo-fenotipo en pacientes y familias españolas con hipertensión arterial pulmonar. [Molecular analysis
of BMPR2, TBX4, and KCNK3 and genotype–phenotype correlations in Spanish patients and families with
idiopathic and hereditary pulmonary arterial hypertension.] Rev Esp Cardiol 2016; 69: 1011–1019.
55 Wiggins J, Strickland B, Turner-Warwick M. Combined cryptogenic fibrosing alveolitis and emphysema: the
value of high resolution computed tomography in assessment. Respir Med 1990; 84: 365–369.
56 Papaioannou AI, Kostikas K, Manali ED, et al. Combined pulmonary fibrosis and emphysema: the many
aspects of a cohabitation contract. Respir Med 2016; 117: 14–26.
57 Brillet PY, Cottin V, Letoumelin P, et al. Syndrome emphysème des sommets et fibrose pulmonaire des bases
combinés (syndrome emphysème/fibrose): aspects tomodensitométriques et fonctionnels. [Combined apical
emphysema and basal fibrosis syndrome (emphysema/fibrosis syndrome): CT imaging features and pulmonary
function tests.] J Radiol 2009; 90: 43–51.
58 Hage R, Gautschi F, Steinack C, et al. Combined pulmonary fibrosis and emphysema (CPFE) clinical features
and management. Int J Chron Obstruct Pulmon Dis 2021; 16: 167–177.
59 Cottin V. The impact of emphysema in pulmonary fibrosis. Eur Respir Rev 2013; 22: 153–157.
60 Cottin V, Le Pavec J, Prevot G, et al. Pulmonary hypertension in patients with combined pulmonary fibrosis
and emphysema syndrome. Eur Respir J 2010; 35: 105–111.
61 Behr J, Ryu JH. Pulmonary hypertension in interstitial lung disease. Eur Respir J 2008; 31: 1357–1367.
62 Sugino K, Ota H, Fukasawa Y, et al. Pathological characteristics in idiopathic nonspecific interstitial pneumonia
with emphysema and pulmonary hypertension. Respirol Case Rep 2013; 1: 39–42.
63 Sato T, Tsujino I, Tanino M, et al. Broad and heterogeneous vasculopathy in pulmonary fibrosis and
emphysema with pulmonary hypertension. Respirol Case Rep 2013; 1: 10–13.
64 Hirano ACG, Targueta EP, Ferraz de Campos FP, et al. Severe pulmonary hypertension due to combined
pulmonary fibrosis and emphysema: another cause of death among smokers. Autopsy Case Rep 2017; 7: 15–26.
65 Cottin V, Nunes H, Mouthon L, et al. Combined pulmonary fibrosis and emphysema syndrome in connective
tissue disease. Arthritis Rheum 2011; 63: 295–304.
66 Cottin V. Clinical case: combined pulmonary fibrosis and emphysema with pulmonary hypertension – clinical
management. BMC Res Notes 2013; 6: Suppl. 1, S2.
67 Mercurio V, Carlomagno G, Fazio S. Response to pulmonary vasodilator treatment in a former smoker with
combined interstitial lung disease complicated by pulmonary hypertension: case report and review of the
literature. Heart Lung 2012; 41: 512–517.
68 Roccia F, Campolo B, Gallelli L, et al. Effects of ambrisentan in a patient affected by combined pulmonary
fibrosis and emphysema and by severe pulmonary hypertension: clinical, functional, and biomolecular
findings. Clin Drug Investig 2013; 33: 451–457.
https://doi.org/10.1183/2312508X.10018522 219
69 Blanco I, Gimeno E, Munoz PA, et al. Hemodynamic and gas exchange effects of sildenafil in patients with
chronic obstructive pulmonary disease and pulmonary hypertension. Am J Respir Crit Care Med 2010; 181:
270–278.
70 Johnson SR, Taveira-DaSilva AM, Moss J. Lymphangioleiomyomatosis. Clin Chest Med 2016; 37: 389–403.
71 O’Mahony AM, Lynn E, Murphy DJ, et al. Lymphangioleiomyomatosis: a clinical review. Breathe 2020; 16:
200007.
72 Elia D, Torre O, Cassandro R, et al. Ultra-rare cystic disease. Eur Respir Rev 2020; 29: 190163.
73 Yu J, Astrinidis A, Henske EP. Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic
lymphangiomyomatosis. Am J Respir Crit Care Med 2001; 164: 1537–1540.
74 Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of
sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000; 97: 6085–6090.
75 Harari S, Torre O, Moss J. Lymphangioleiomyomatosis: what do we know and what are we looking for? Eur
Respir Rev 2011; 20: 34–44.
76 Nordling CO. A new theory on the cancer-inducing mechanism. Br J Cancer 1953; 7: 68–72.
77 Torre O, Elia D, Caminati A, et al. New insights in lymphangioleiomyomatosis and pulmonary Langerhans cell
histiocytosis. Eur Respir Rev 2017; 26: 170042.
78 Cottin V, Archer F, Leroux C, et al. Milestones in lymphangioleiomyomatosis research. Eur Respir Rev 2011; 20:
3–6.
79 Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients
at enrollment. Am J Respir Crit Care Med 2006; 173: 105–111.
80 Taveira-DaSilva AM, Steagall WK, Rabel A, et al. Reversible airflow obstruction in lymphangioleiomyomatosis.
Chest 2009; 136: 1596–1603.
81 Glasgow CG, Avila NA, Lin JP, et al. Serum vascular endothelial growth factor-D levels in patients with
lymphangioleiomyomatosis reflect lymphatic involvement. Chest 2009; 135: 1293–1300.
82 McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J
Med 2011; 364: 1595–1606.
83 Bissler JJ, Elwing JM, Schmithorst VJ, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or
lymphangioleiomyomatosis. N Engl J Med 2008; 58: 140–151.
84 Johnson SR, Cordier JF, Lazor R, et al. European Respiratory Society guidelines for the diagnosis and
management of lymphangioleiomyomatosis. Eur Respir J 2010; 35: 14–26.
85 Reynaud-Gaubert M, Mornex JF, Mal H, et al. Lung transplantation for lymphangioleiomyomatosis: the French
experience. Transplantation 2008; 86: 515–520.
86 Benden C, Rea F, Behr J, et al. Lung transplantation for lymphangioleiomyomatosis: the European experience.
J Heart Lung Transplant 2009; 28: 1–7.
87 Boehler A, Speich R, Russi EW, et al. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 1996;
335: 1275–1280.
88 Khawar MU, Yazdani D, Zhu Z, et al. Clinical outcomes and survival following lung transplantation in patients
with lymphangioleiomyomatosis. J Heart Lung Transplant 2019; 38: 949–955.
89 Salman J, Ius F, Sommer W, et al. Long-term results of bilateral lung transplantation in patients with
end-stage pulmonary lymphangioleiomyomatosis. Prog Transplant 2019; 29: 115–121.
90 Kurosaki T, Otani S, Miyoshi K, et al. Favorable survival even with high disease-specific complication rates in
lymphangioleiomyomatosis after lung transplantation – long-term follow-up of a Japanese center. Clin Respir J
2020; 14: 116–123.
91 Freitas CSG, Baldi BG, Jardim C, et al. Pulmonary hypertension in lymphangioleiomyomatosis: prevalence,
severity and the role of carbon monoxide diffusion capacity as a screening method. Orphanet J Rare Dis 2017;
12: 74.
92 Xu KF, Xu W, Liu S, et al. Lymphangioleiomyomatosis. Semin Respir Crit Care Med 2020; 41: 256–268.
93 Cottin V, Harari S, Humbert M, et al. Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in
20 patients. Eur Respir J 2012; 40: 630–640.
94 Wu X, Xu W, Wang J, et al. Clinical characteristics in lymphangioleiomyomatosis-related pulmonary
hypertension: an observation on 50 patients. Front Med 2019; 13: 259–266.
95 Goncharova EA, Goncharov DA, Eszterhas A, et al. Tuberin regulates p70 S6 kinase activation and ribosomal
protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary
lymphangioleiomyomatosis (LAM). J Biol Chem 2002; 277: 30958–30967.
96 Krymskaya VP, Snow J, Cesarone G, et al. mTOR is required for pulmonary arterial vascular smooth muscle
cell proliferation under chronic hypoxia. FASEB J 2011; 25: 1922–1933.
97 Culver DA, Judson MA. New advances in the management of pulmonary sarcoidosis. BMJ 2019; 367: l5553.
98 Baughman RP, Wells A. Advanced sarcoidosis. Curr Opin Pulm Med 2019; 25: 497–504.
99 Corte TJ, Wells AU, Nicholson AG, et al. Pulmonary hypertension in sarcoidosis: a review. Respirology 2011; 16:
69–77.
220 https://doi.org/10.1183/2312508X.10018522
100 Huitema MP, Bakker ALM, Mager JJ, et al. Prevalence of pulmonary hypertension in pulmonary sarcoidosis:
the first large European prospective study. Eur Respir J 2019; 54: 1900897.
101 Pabst S, Hammerstingl C, Grau N, et al. Pulmonary arterial hypertension in patients with sarcoidosis: the
Pulsar single center experience. Adv Exp Med Biol 2013; 755: 299–305.
102 Pabst S, Grohé C, Skowasch D. Prevalence of sarcoidosis-associated pulmonary hypertension: cumulative
analysis of two PULSAR studies. Eur Respir J 2020; 55: 1902223.
103 Handa T, Nagai S, Miki S, et al. Incidence of pulmonary hypertension and its clinical relevance in patients with
sarcoidosis. Chest 2006; 129: 1246–1252.
104 Głuskowski J, Hawryłkiewicz I, Zych D, et al. Pulmonary haemodynamics at rest and during exercise in
patients with sarcoidosis. Respiration 1984; 46: 26–32.
105 Shorr AF, Helman DL, Davies DB, et al. Pulmonary hypertension in advanced sarcoidosis: epidemiology and
clinical characteristics. Eur Respir J 2005; 25: 783–788.
106 Arcasoy SM, Christie JD, Pochettino A, et al. Characteristics and outcomes of patients with sarcoidosis listed
for lung transplantation. Chest 2001; 120: 873–880.
107 Boucly A, Cottin V, Nunes H, et al. Management and long-term outcomes of sarcoidosis-associated pulmonary
hypertension. Eur Respir J 2017; 50: 1700465.
108 Parikh KS, Dahhan T, Nicholl L, et al. Clinical features and outcomes of patients with sarcoidosis-associated
pulmonary hypertension. Sci Rep 2019; 9: 4061.
109 Shlobin OA, Kouranos V, Barnett SD, et al. Physiological predictors of survival in patients with
sarcoidosis-associated pulmonary hypertension: results from an international registry. Eur Respir J 2020; 55:
1901747.
110 Baughman RP, Engel PJ, Taylor L, et al. Survival in sarcoidosis-associated pulmonary hypertension: the
importance of hemodynamic evaluation. Chest 2010; 138: 1078–1085.
111 Huitema MP, Bakker ALM, Mager JJ, et al. Predicting pulmonary hypertension in sarcoidosis; value of PH
probability on echocardiography. Int J Cardiovasc Imaging 2020; 36: 1497–1505.
112 Bourbonnais JM, Samavati L. Clinical predictors of pulmonary hypertension in sarcoidosis. Eur Respir J 2008;
32: 296–302.
113 Sulica R, Teirstein AS, Kakarla S, et al. Distinctive clinical, radiographic, and functional characteristics of
patients with sarcoidosis-related pulmonary hypertension. Chest 2005; 128: 1483–1489.
114 Baughman RP, Shlobin OA, Wells AU, et al. Clinical features of sarcoidosis associated pulmonary hypertension:
results of a multi-national registry. Respir Med 2018; 139: 72–78.
115 Nunes H, Humbert M, Capron F, et al. Pulmonary hypertension associated with sarcoidosis: mechanisms,
haemodynamics and prognosis. Thorax 2006; 61: 68–74.
116 Takemura T, Matsui Y, Saiki S, et al. Pulmonary vascular involvement in sarcoidosis: a report of 40 autopsy
cases. Hum Pathol 1992; 23: 1216–1223.
117 Smith LJ, Lawrence JB, Katzenstein AA. Vascular sarcoidosis: a rare cause of pulmonary hypertension. Am J
Med Sci 1983; 285: 38–44.
118 Barst RJ, Ratner SJ. Sarcoidosis and reactive pulmonary hypertension. Arch Intern Med 1985; 145: 2112–2114.
119 Masri SC, Bellumkonda L. Sarcoid heart disease: an update on diagnosis and management. Curr Cardiol Rep
2020; 22: 177.
120 Salazar A, Mañá J, Sala J, et al. Combined portal and pulmonary hypertension in sarcoidosis. Respiration
1994; 61: 117–119.
121 Hamilton-Craig CR, Slaughter R, McNeil K, et al. Improvement after angioplasty and stenting of pulmonary
arteries due to sarcoid mediastinal fibrosis. Heart Lung Circ 2009; 18: 222–225.
122 Toonkel RL, Borczuk AC, Pearson GD, et al. Sarcoidosis-associated fibrosing mediastinitis with resultant
pulmonary hypertension: a case report and review of the literature. Respiration 2010; 79: 341–345.
123 Seferian A, Steriade A, Jaïs X, et al. Pulmonary hypertension complicating fibrosing mediastinitis. Medicine
(Baltimore) 2015; 94: e1800.
124 Handa T, Nagai S, Ueda S, et al. Significance of plasma NT-proBNP levels as a biomarker in the assessment of
cardiac involvement and pulmonary hypertension in patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung
Dis 2010; 27: 27–35.
125 Shorr AF, Davies DB, Nathan SD. Predicting mortality in patients with sarcoidosis awaiting lung
transplantation. Chest 2003; 124: 922–928.
126 Jeny F, Uzunhan Y, Lacroix M, et al. Predictors of mortality in fibrosing pulmonary sarcoidosis. Respir Med
2020; 169: 105997.
127 Baughman RP, Engel PJ, Meyer CA, et al. Pulmonary hypertension in sarcoidosis. Sarcoidosis Vasc Diffuse Lung
Dis 2006; 23: 108–116.
128 Diaz-Guzman E, Farver C, Parambil J, et al. Pulmonary hypertension caused by sarcoidosis. Clin Chest Med
2008; 29: 549–563.
https://doi.org/10.1183/2312508X.10018522 221
129 Bandyopadhyay D, Humbert M. An update on sarcoidosis-associated pulmonary hypertension. Curr Opin Pulm
Med 2020; 26: 582–590.
130 Fisher KA, Serlin DM, Wilson KC, et al. Sarcoidosis-associated pulmonary hypertension: outcome with
long-term epoprostenol treatment. Chest 2006; 130: 1481–1488.
131 Milman N, Burton CM, Iversen M, et al. Pulmonary hypertension in end-stage pulmonary sarcoidosis:
therapeutic effect of sildenafil? J Heart Lung Transplant 2008; 27: 329–334.
132 Foley RJ, Metersky ML. Successful treatment of sarcoidosis-associated pulmonary hypertension with bosentan.
Respiration 2008; 75: 211–214.
133 Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary
hypertension. Sarcoidosis Vasc Diffuse Lung Dis 2009; 26: 110–120.
134 Barnett CF, Bonura EJ, Nathan SD, et al. Treatment of sarcoidosis-associated pulmonary hypertension: a
two-center experience. Chest 2009; 135: 1455–1461.
135 Keir GJ, Walsh SLF, Gatzoulis MA, et al. Treatment of sarcoidosis-associated pulmonary hypertension: a single
centre retrospective experience using targeted therapies. Sarcoidosis Vasc Diffuse Lung Dis 2014; 31: 82–90.
136 Judson MA, Highland KB, Kwon S, et al. Ambrisentan for sarcoidosis associated pulmonary hypertension.
Sarcoidosis Vasc Diffuse Lung Dis 2011; 28: 139–145.
137 Dobarro D, Schreiber BE, Handler C, et al. Clinical characteristics, haemodynamics and treatment of
pulmonary hypertension in sarcoidosis in a single centre, and meta-analysis of the published data. Am J
Cardiol 2013; 111: 278–285.
138 Montani D, Jaïs X, Price LC, et al. Cautious epoprostenol therapy is a safe bridge to lung transplantation in
pulmonary veno-occlusive disease. Eur Respir J 2009; 34: 1348–1356.
139 Diamond JM, Lee JC, Kawut SM, et al. Clinical risk factors for primary graft dysfunction after lung
transplantation. Am J Respir Crit Care Med 2013; 187: 527–534.
140 Rodriguez-Galindo C, Allen CE. Langerhans cell histiocytosis. Blood 2020; 135: 1319–1331.
141 Tazi A. Adult pulmonary Langerhans’ cell histiocytosis. Eur Respir J 2006; 27: 1272–1285.
142 Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit
Care Med 2000; 161: 216–223.
143 Dauriat G, Mal H, Thabut G, et al. Lung transplantation for pulmonary Langerhans’ cell histiocytosis: a
multicenter analysis. Transplantation 2006; 81: 746–750.
144 Harari S, Comel A. Pulmonary Langerhans cell histiocytosis. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18:
253–262.
145 Taniyama D, Kamata H, Miyamoto K, et al. Autopsy findings in a case of pulmonary Langerhans cell
histiocytosis-associated pulmonary hypertension. Am J Case Rep 2017; 18: 1401–1406.
146 Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and clinical characteristics of pulmonary
hypertension complicating pulmonary Langerhans cell histiocytosis. Mayo Clin Proc 2004; 79: 1269–1275.
147 Heiden GI, Sobral JB, Freitas CSG, et al. Mechanisms of exercise limitation and prevalence of pulmonary
hypertension in pulmonary Langerhans cell histiocytosis. Chest 2020; 158: 2440–2448.
148 Rolland-Debord C, Fry S, Giovannelli J, et al. Physiologic determinants of exercise capacity in pulmonary
Langerhans cell histiocytosis: a multidimensional analysis. PLoS One 2017; 12: e0170035.
149 Crausman RS, Jennings CA, Tuder RM, et al. Pulmonary histiocytosis X: pulmonary function and exercise
pathophysiology. Am J Respir Crit Care Med 1996; 153: 426–435.
150 Fukuda Y, Miura S, Fujimi K, et al. Effects of treatment with a combination of cardiac rehabilitation and
bosentan in patients with pulmonary Langerhans cell histiocytosis associated with pulmonary hypertension.
Eur J Prev Cardiol 2014; 21: 1481–1483.
151 Kiakouama L, Cottin V, Etienne-Mastroïanni B, et al. Severe pulmonary hypertension in histiocytosis X:
long-term improvement with bosentan. Eur Respir J 2010; 36: 202–204.
152 Kinoshita Y, Watanabe K, Sakamoto A, et al. Pulmonary Langerhans cell histiocytosis-associated pulmonary
hypertension showing a drastic improvement following smoking cessation. Intern Med 2016; 55: 491–495.
153 May A, Kane G, Yi E, et al. Dramatic and sustained responsiveness of pulmonary Langerhans cell
histiocytosis-associated pulmonary hypertension to vasodilator therapy. Respir Med Case Rep 2015; 14: 13–15.
154 Held M, Jany B, Warth A, et al. Pulmonale Hypertonie und Langerhanszell-Granulomatose – erfolgreiche
langfristige Therapie mit Sildenafil und Iloprost. [Pulmonary hypertension and Langerhans cell
granulomatosis: successful treatment with sildenafil and iloprost.] Dtsch Med Wochenschr 2013; 138: 524–527.
155 Nemoto K, Oh-ishi S, Inui T, et al. Long-term improvement during tadalafil therapy in a patient with
pulmonary hypertension secondary to pulmonary Langerhans cell histiocytosis. Respir Med Case Rep 2016; 18:
54–57.
156 Yoshida T, Konno S, Tsujino I, et al. Severe pulmonary hypertension in adult pulmonary Langerhans cell
histiocytosis: the effect of sildenafil as a bridge to lung transplantation. Intern Med 2014; 53: 1985–1990.
157 Miyashita T, Yamazaki S, Ohta H, et al. Secondary pulmonary hypertension due to pulmonary Langerhans cell
histiocytosis accompanied with panhypopituitarism. Respirol Case Rep 2021; 9: e00697.
222 https://doi.org/10.1183/2312508X.10018522
158 Le Pavec J, Lorillon G, Jaïs X, et al. Pulmonary Langerhans cell histiocytosis-associated pulmonary
hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest 2012;
142: 1150–1157.
159 Grobost V, Khouatra C, Lazor R, et al. Effectiveness of cladribine therapy in patients with pulmonary
Langerhans cell histiocytosis. Orphanet J Rare Dis 2014; 9: 191.
160 Etienne B, Bertocchi M, Gamondes JP, et al. Relapsing pulmonary Langerhans cell histiocytosis after lung
161 Yazicioglu A, Turkkan S, Demirag F, et al. Recurrence pattern of pulmonary Langerhans cell histiocytosis after
lung transplantation: a case report. Transplant Proc 2016; 48: 3231–3233.
162 Jutant EM, Girerd B, Jaïs X, et al. Pulmonary hypertension associated with neurofibromatosis type 1. Eur
Respir Rev 2018; 27: 180053.
163 Reynolds R, Browning G, Nawroz I, et al. Von Recklinghausen’s neurofibromatosis: neurofibromatosis type 1.
Lancet 2003; 361: 1552–1554.
164 National Institutes of Health Consensus Development Conference Statement: neurofibromatosis.
Neurofibromatosis 1988; 1: 172–178.
165 Montani D, Coulet F, Girerd B, et al. Pulmonary hypertension in patients with neurofibromatosis type I.
Medicine (Baltimore) 2011; 90: 201–211.
166 Jutant EM, Jaïs X, Girerd B, et al. Phenotype and outcomes of pulmonary hypertension associated with
neurofibromatosis type 1. Am J Respir Crit Care Med 2020; 202: 843–852.
Disclosures: D. Montani reports receiving the following, outside the submitted work: grants or contracts from
Acceleron, Janssen and Merck MSD; consulting fees from Acceleron, Merck MSD and Janssen; and payment or
honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Bayer,
Janssen and Merck MSD. M. Kalaratne has nothing to disclose. E.-M. Jutant reports receiving the following, outside
the submitted work: consulting fees from Chiesi; payment or honoraria for lectures, presentations, speakers’
bureaus, manuscript writing or educational events from Chiesi and GSK; and support for attending meetings
and/or travel from Janssen. M. Humbert reports receiving the following, outside the submitted work: grants or
contracts from Acceleron, AOP Orphan, Janssen, Merc and Shou Ti; consulting fees from Acceleron, Aerovate,
Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti and United Therapeutics; and
payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events
from Janssen and Merck. M. Humbert reports participation on a data safety monitoring board or advisory board
for Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work.
https://doi.org/10.1183/2312508X.10018522 223
Chapter 16
Hepatopulmonary syndrome: a liver-induced

oxygenation defect
Laurent Savale 1,2,3, Fabien Robert1,2, Ly Tu1,2, Marie-Caroline Certain1,2,3,
Audrey Baron1,2,3, Audrey Coilly2,4,5, Léa Duhaut2,4,5, Marc Humbert 1,2,3,
Christophe Guignabert 1,2 and Olivier Sitbon 1,2,3
1
INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue,
Le Plessis-Robinson, France. 2Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France. 3Assistance
Publique – Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, European Reference
Network on Rare Respiratory Diseases (ERN-LUNG), Hôpital Bicêtre, Le Kremlin-Bicêtre, France. 4AP-HP Hôpital Paul
Brousse, Centre Hépato-Biliaire, Villejuif, France. 5UMR-S 1193, Université Paris-Saclay, Villejuif, France.
Corresponding author: Laurent Savale (laurent.savale@aphp.fr)
Cite as: Savale L, Robert F, Tu L, et al. Hepatopulmonary syndrome: a liver-induced oxygenation defect. In: Wagner TOF,
@ERSpublications
Hepatopulmonary syndrome is an underdiagnosed devastating complication of chronic liver disease that can
lead to a decision for liver transplantation, regardless of the severity of liver disease. Its detection and
diagnostic approach must be rigorous. https://bit.ly/ERSM100
ISSN: 2312-5098.
A diagnosis of hepatopulmonary syndrome (HPS) is based on the clinical triad of liver disease and/or
portal hypertension, intrapulmonary vascular dilation and abnormal arterial oxygenation. HPS is clearly
identified as a significant comorbidity affecting both the functional status and prognosis of patients with
chronic liver disease. Although substantial progress has been made in the description of the clinical
characteristics and outcomes, no specific targeted therapy has been shown to have a long-term effect on
the evolution of HPS. Liver transplantation, which remains the only option to reverse HPS, must be
considered an essential option in the management of severe HPS (arterial oxygen tension <60 mmHg),
regardless of the severity of the underlying liver disease. Progress in our understanding of the
pathophysiological mechanisms involved in HPS and in the regulatory mechanisms between the liver
and the lung circulation is needed to identify potential targeted therapies in the future.
Introduction
The pulmonary circulation can be severely affected by pathogenic processes arising within the
liver and the portal venous system. Two distinct vascular disorders associated with liver disease
and/or portal hypertension have been described: hepatopulmonary syndrome (HPS), which is
characterised by an alteration of the pulmonary capillary bed, and portopulmonary hypertension,
which is characterised by an obstructive remodelling of the distal pulmonary vascular bed [1–3].
Severe arterial hypoxaemia is the most dramatic manifestation of HPS, explained primarily by
intrapulmonary vascular dilations (IPVDs) and alterations in the neoangiogenic processes [2].
The risk of patients with portal hypertension developing HPS underlines the complex
224 https://doi.org/10.1183/2312508X.10006023
HEPATOPULMONARY SYNDROME | L. SAVALE ET AL.
physiological interactions between the portal and the pulmonary circulation. This vascular
complication is clearly identified as a significant comorbidity affecting both the functional status
and the prognosis of patients with chronic liver disease. Although substantial progress has been
made in the description of the clinical characteristics and outcomes, no specific targeted therapy
has been shown to have a long-term effect on the evolution of HPS. Currently, liver
transplantation remains the only option to reverse HPS [4].
This chapter aims to provide an overview of our current understanding of the molecular signalling
pathways involved in HPS and presents a comprehensive approach to disease management.
Histological features and pathophysiology of HPS

Histological features
Very few histological data are available in humans to precisely describe the structural
abnormalities that characterise HPS. Although this syndrome was first described in the 1800s,
the only available histological descriptions are based on autopsy analyses performed in the
1950s to 1970s [5–7]. HPS is a pulmonary vascular disease that appears to primarily induce a
disturbance of the pulmonary capillary bed homeostasis with a preferential localisation of
features in the lower lobes. The structural modifications observed are characterised mainly by
pulmonary capillary vasodilation combined with neoangiogenesis phenomena, which can result
in the development of arteriovenous communications in the most severely affected patients. In
the vast majority of cases, these vascular abnormalities are microscopic, although macroscopic
abnormalities can be observed on imaging examinations, such as CT or a pulmonary angiogram
in the most severe patients [8, 9].
Consequences for gas exchange

The main consequence of these structural abnormalities of the pulmonary capillary bed that
characterise HPS is the abnormal arterial oxygenation induced by different pathophysiological
mechanisms [2, 10]. Abnormal arterial oxygenation in HPS is induced mainly by a ventilation/
perfusion (V′/Q′) mismatch due to overperfusion of the alveolar vascular bed without ventilation
abnormalities. In addition, pulmonary hypoxic vasoconstriction is disturbed in cirrhotic patients,
which aggravates this phenomenon. Other mechanisms involved in abnormal arterial
oxygenation are increased intrapulmonary shunt and oxygen diffusion impairment [11].
Pulmonary or pleural arteriovenous communications in severe forms of HPS can develop,
leading to true shunting-induced hypoxaemia. Diffusion impairment could be due to a
lengthening of the time necessary for the oxygen to reach the red blood cells in the centre of the
dilated capillary, combined with a shortened transit time of the red blood cells in the lung
vessels due to the high cardiac output commonly observed in cirrhosis.
Pathophysiological mechanisms
Most data concerning the pathophysiological hypothesis are based on experimental observations
in an animal model of HPS induced by common bile duct ligation (CBDL) in rodents (rats and
mice) [12]. The CBDL model recapitulates the main characteristics of HPS including portal
hypertension induced by biliary cirrhosis and hypoxaemia due to pulmonary capillary
vasodilation/intrapulmonary shunt. To date, the main mechanisms that have been highlighted in
the progression of the disease are: 1) vasodilation and vascular tone disturbance,
2) inflammatory processes due to bacterial translocation, endotoxaemia induced by liver disease
and monocyte/macrophage recruitment in the pulmonary circulation, and 3) an impairment of
angiogenesis (figure 1).
https://doi.org/10.1183/2312508X.10006023 225
Liver disease and/or portal hypertension

(cirrhosis, extrahepatic portal hypertension, congenital portosystemic shunt, acute liver failure)
Bacterial translocation
Endotoxaemia
Angiogenic factors Shear stress
(e.g. PGF, PDGF, VEGF) Endothelin Pro-inflammatory
cytokines
+ +
ETB-R iNOS
IVPM
+
eNOS
ECs
+
+
SMCs NO
Arteriovenous
Angiogenesis Vasodilation
communications
Increased
Vc/Qc Diffusion
intrapulmonary
mismatch limitation
shunt
Abnormal arterial oxygenation
A–aDO ≥15 mmHg

2
(or >20 mmHg in patients >64 years)
FIGURE 1 Main mechanisms of pathophysiology and abnormal arterial oxygenation in hepatopulmonary

syndrome. The alveolar–arterial oxygen gradient (A–aDO2) is calculated as described in the text. PGF: placental
growth factor; PDGF: platelet-derived growth factor; VEGF: vascular endothelial growth factor; IVPM: intravascular
pulmonary macrophages; ECs: endothelial cells; SMCs: smooth muscle cells; eNOS: endothelial nitric oxide
synthase; ETB-R: endothelin B receptor; NO: nitric oxide; iNOS: inducible nitric oxide synthase; V′/Q′: ventilation/
perfusion ratio.
Pulmonary vasodilation
Increased production of nitric oxide (NO) is likely to play a central role in IPVDs and decreases
pulmonary vascular tone [13–16]. In humans, higher levels of expired NO were reported in
HPS patients than in cirrhotic patients without HPS [17, 18]. This finding is normalised after
liver transplantation [18], or after an acute intervention with some NO inhibitors [19]. In CBDL
rats, HPS development is related to increased pulmonary NO production mediated by
overexpression of both endothelial and inducible NO synthase (eNOS and iNOS, respectively) [16].
While biomechanical forces on the endothelium, including shear stress from disturbed
turbulent blood flow, could activate eNOS, iNOS, which produces large amounts of NO, is
induced in infiltrated pulmonary monocytes/macrophages in response to inflammatory mediators
such as lipopolysaccharide and cytokines. Moreover, an increased level of endothelin 1 (ET-1)
226 https://doi.org/10.1183/2312508X.10006023
in HPS combined with overexpression of its receptor, ETB-R, has been shown to contribute to
the upregulation of eNOS [20–24]. The role of NO is underlined by the efficacy of targeted
treatment decreasing the production of NO in the CBDL model of HPS [20, 25].
In addition, the expression of haem oxygenase 1 (HO-1), a stress response enzyme that
degrades haem to carbon monoxide, free iron and biliverdin, has been demonstrated to increase
in pulmonary intravascular monocytes/macrophages, suggesting its contribution to the
development of HPS [26]. Consistent with this notion, treatment with an HO-1 inhibitor
reverses HPS in the CBDL model by decreasing the carboxyhaemoglobin level [27].
Bacterial translocation, endotoxaemia and intravascular monocyte/macrophage recruitment

In the CBDL model, HPS development is systematically associated with a pronounced
infiltration of pulmonary intravascular macrophages in the damaged lungs that adhere to the
pulmonary vascular endothelium. Intravascular monocyte depletion using gadolinium or
clodronate prevents and reverses HPS, suggesting an active role for these macrophages in the
development of HPS [28]. The source has been suggested to be the splenic monocyte
reservoir [29], and the trigger could be bacterial translocation and endotoxaemia that can
directly atack the pulmonary circulation via portosystemic shunts by inducing local production
of molecules implicated in chemotaxis, recruitment of monocytes and adhesion at endothelial
cells [30]. Intrapulmonary macrophages are indeed a source of various types of
pro-inflammatory cytokines and other mediators that lead to vasodilation and angiogenesis [31].
Many drugs targeting inflammation or bacterial translocation have been tested in the CBDL
model, and most have demonstrated a beneficial effect on IPVDs and gas exchange [31–37].
Increased pulmonary angiogenic function

Several studies in experimental models support the notion that pro-angiogenic factors may be
involved in HPS development. Scanning electron microscopy has demonstrated an increase in
capillary density [38, 39], and the serum of CBDL rats was shown to promote the in vitro
proliferation, migration and tube formation of endothelial cells [40]. Consistent with this notion,
vascular endothelial growth factor, platelet-derived growth factor and placental growth factor
(PGF) have been reported as potential factors implicated in pulmonary angiogenesis [30, 41].
However, a mechanistic understanding of how these factors contribute to disease initiation,
perpetuation and worsening is lacking. In humans, the risk of HPS is associated with
polymorphisms in genes involved in the regulation of angiogenesis, such as endoglin and von
Willebrand factor (VWF) [42]. In a recent prospective study, higher levels of circulating
proteins involved in angiogenic processes, such as VWF, angiopoietin 2, tyrosine protein kinase
Kit (c-KIT), vascular cell adhesion molecule 1 (VCAM-1) and angiopoietin 1 receptor (TIE2),
were observed, while levels of antiangiogenic markers such as angiostatin and endostatin tended
to be lower [41]. Blocking the PGF pathway with an anti-PGF antibody improves HPS in
CBDL mice by decreasing pulmonary angiogenesis but also decreases monocyte infiltration [38].
The bone morphogenetic protein 9 (BMP9)-mediated signalling pathway is a main player in

maintaining the vasomotor balance and vascular-tissue homeostasis in lungs by providing protection
to the vascular endothelium. BMP9 (produced mainly by the liver) and BMP10 (synthesised mainly
by the liver and the right atrium) bind with high affinity to activin receptor-like kinase 1 (ALK1),
BMP type II receptor (BMPR-II) and endoglin, which are particularly highly expressed in lung
vascular endothelial cells [43, 44]. It is now well accepted that alterations in the BMP9 signalling
pathway play a central role in the pathogenesis of pulmonary arterial hypertension and hereditary
haemorrhagic telangiectasia, which is characterised by arteriovenous malformations similar to those
observed in HPS [43, 45–47]. Thus, the BMP9 signalling pathway might be involved in the
https://doi.org/10.1183/2312508X.10006023 227
pathophysiology of HPS. Consistent with this notion, a lower level of circulating BMP9 in these
patients than in cirrhotic patients without HPS has been described recently [48]. Interestingly,
pulmonary vascular abnormalities similar to those described in HPS have been observed after
bidirectional cavopulmonary anastomosis, a surgical procedure that has been performed in children
with a single ventricle. In addition, pulmonary arteriovenous malformations induced by this
procedure can be reversed by redirecting hepatic vein flow from a normal liver to the pulmonary
vascular bed. This observation highlights the fact that deprivation of liver-derived factors, of which
BMP9 could be part, contribute to the pulmonary circulation disorders that characterise HPS [49].
Prevalence of HPS and impact on survival

A wide variability in the prevalence of HPS has been reported, ranging from 5% to >30% in
cirrhotic patients with various levels of severity [50–52]. Several factors may explain these
discrepancies. First, the populations studied are not always similar. Moreover, the threshold to
define gas-exchange abnormalities is not consistent from one study to another. Finally, one of
the main explanations is probably related to the fact that a large proportion of patients with HPS
are pauci- or asymptomatic. Severe forms resulting in a functional impact are less frequent.
Therefore, a high prevalence is reported when screening is performed systematically in all
patients, and a lower prevalence is reported when the diagnostic approach only targets
symptomatic patients. Neither aetiology nor severity of liver disease was identified as a risk
factor [53].
The presence of pulmonary vascular dilation is also observed in a high proportion of cirrhotic
patients, but approximately half of them have normal gas exchange and do not meet the
diagnostic criteria for HPS [54].
HPS has a clinically significant negative impact on functional status, health-related quality of
life and survival, regardless of the degree of abnormal oxygenation [41, 51–53, 55]. A recent
prospective study reported a lower probability of HPS patients being alive than liver disease controls
at 1 year (87% versus 92%), 2 years (73% versus 83%) and 3 years (63% versus 81%) [41].
Diagnostic approach and clinical investigations

As described in the following sections, the diagnosis of HPS is based on the clinical triad of
liver disease and/or portal hypertension, IPVDs and abnormal arterial oxygenation. The impact
of HPS on patient management is major, and the diagnostic approach and evaluation of HPS
severity must be rigorous (table 1).
Liver disease
Most often, HPS occurs in patients with cirrhosis. However, HPS can be also observed in other
pathological hepatic conditions including acute liver failure, extrahepatic portal hypertension
and congenital portosystemic shunts [56]. The risk of developing HPS is therefore not directly
correlated to the severity of the underlying liver disease, although a recent study suggested that
the risk of acute-on-chronic liver failure is higher in cirrhotic patients with HPS [57]. There is
only one case–control study comparing cirrhotic patients with and without HPS, which showed
that the signs of portal hypertension (hepatofugal flow and portal thrombosis on Doppler
ultrasound, significant portosystemic shunts and obstructed intrahepatic portal branches on
histology) were more marked in patients with HPS [58]. No predisposing factor has been
identified to date, such as the aetiology of the underlying liver disease, sex or environmental
factors. In some cases, hypoxaemia and the discovery of pulmonary intravascular dilations lead
to the diagnosis of an unknown liver disease.
228 https://doi.org/10.1183/2312508X.10006023
TABLE 1 Pulmonary investigations in hepatopulmonary syndrome (HPS)
Investigation Objectives Characteristics in HPS
Room air arterial blood To detect abnormal arterial A–aDO2 ⩾15 mmHg, or >20 mmHg in
gas analysis in an oxygenation patients >64 years#
upright position To assess the severity of HPS PaO2 >80 mmHg indicates mild HPS,
60–80 mmHg indicates moderate
HPS, 50–60 mmHg indicates severe
HPS and <50 mmHg indicates very
severe HPS
Orthodeoxia (not observed in all
patients): decrease in PaO2 of
>5 mmHg in sitting position
Contrast-enhanced To detect intrapulmonary Passage of microbubbles from the right
echocardiography vascular dilations cavities to the left cavities visualised
after three cardiac cycles#
Technetium-labelled To detect intrapulmonary Macroaggregated albumin particles in
macroaggregated vascular dilations extrathoracic organs#
albumin scan
PFTs To detect associated pulmonary Normal volumes and flows in
disease that could contribute isolated HPS
to gas-exchange abnormalities Decreased DLCO: nonspecific for HPS
Thoracic CT To detect associated pulmonary Normal in most cases of isolated HPS
disease that could contribute Pulmonary vascular dilations in the
to gas-exchange abnormalities subpleural areas of the lower lobes
sometimes observed in the most
severe cases
A–aDO2: alveolar–arterial oxygen gradient; PaO2: arterial oxygen tension. #: diagnostic criteria.
Clinical characteristics
Because hypoxaemia in HPS is exclusively due to vascular impairment without alteration of the
ventilatory mechanics, a large number of patients remain pauci-symptomatic for a long period.
Dyspnoea is most often significant in patients at an advanced stage of the disease. This explains
why HPS remains an underdiagnosed pathology when it is not systematically screened in an
at-risk population. The main symptoms suggestive of HPS are the presence of platypnoea,
defined as increased dyspnoea in the upright position, and orthodeoxia, defined as a decrease in
arterial oxygen tension (PaO2) >5 mmHg or oxygen saturation >4% when moving from the
supine to the sitting position [4]. These phenomena are explained by the predominance of
IPVDs in the lower lobes. However, they are described in only 25% of HPS patients [59]. Other
less specific clinical signs observed in patients with advanced HPS are cyanosis, digital
clubbing and abundant cutaneous telangiectasia [2].
Abnormal arterial oxygenation

Hyperventilation is frequently observed in cirrhotic patients, resulting in a low arterial carbon
dioxide tension (PaCO2) and respiratory alkalosis. For this reason, pulse oximetry is not
sufficiently sensitive to screen for HPS in liver transplantation candidates [60]. Similarly, PaO2
by itself can underestimate the gas-exchange abnormality in cirrhotic patients. Therefore, to
avoid underestimation of the gas-exchange abnormalities, it is recommended that the alveolar–
arterial oxygen gradient (A–aDO2) is determined while breathing room air to better appreciate
oxygenation by integrating the PaCO2 level. A–aDO2 is calculated as:
A–aDO2=((Patm–PH2O)×0.21–PaCO2/0.8)–PaO2
https://doi.org/10.1183/2312508X.10006023 229
where Patm is atmospheric pressure and PH2O is the water vapour pressure. There is currently a
consensus that an abnormal A–aDO2 can be defined as a value ⩾15 mmHg in people ⩽64 years
of age and >20 mmHg in patients >64 years of age on arterial blood gas while breathing room
air in the seated position at rest [4]. As explained, the vertical position can be associated with
more severe hypoxaemia than the prone position due to the preferential location of vascular
disorders in the lower lobes. PaO2 is used to distinguish mild (>80 mmHg), moderate
(60–80 mmHg), severe (50–60 mmHg) and very severe (<50 mmHg) forms of HPS.
The 100% inspiratory oxygen fraction (FIO2) test is most frequently normal in patients with HPS
but can be altered in the most severe form of HPS associated with true shunting, probably due
to the development of arteriovenous communications.
IPVDs
Dilation of the pulmonary capillary bed corresponds to the princeps anomaly of HPS and must
therefore be the subject of particular attention in the diagnostic approach (figure 2).
Contrast-enhanced echocardiography is the reference tool for detecting the presence of
IPVDs [4]. Agitated saline is injected via a peripheral vein and the path of the microbubbles is
observed via an apical four-chamber view during at least 10 continuous cardiac cycles. The
diameter of the microbubbles generated by the agitated saline solution is larger than the normal
diameter of pulmonary capillaries (normal diameter 8–15 μm). Therefore, in the physiological
state, no passage of microbubbles from the right cavities to the left cavities is observed, the
bubbles being trapped in the pulmonary circulation. In the case of IPVDs, a more or less
significant passage of microbubbles from the right cavities to the left cavities is visualised. In
contrast, an immediate opacification (fewer than three cycles) of the left atrium or ventricle is
representative of an intracardiac shunt. The negative and positive predictive value of
contrast-enhanced echocardiography to detect IPVDs is acceptable if the test is performed under
optimal conditions [54]. The semi-supine position can increase the sensitivity of the test. In
patients with poor echogenicity, an alternative is to perform transoesophageal echocardiography
after eliminating oesophageal varices that would contraindicate the examination.
Technetium-labelled macroaggregated albumin scans are an alternative tool to detect

intrapulmonary shunts [61]. Similar to the microbubbles described above, macroaggregated
albumin particles are trapped in the pulmonary microcirculation under physiological conditions.
In the case of IPVDs, some of the particles pass into the systemic circulation through the
pulmonary circulation and are finally trapped in different organs. A clear consensus to define a
a) Cycle 1 b) Cycle 3 c) Cycle 5
RV LV RV LV
RV LV
RA LA RA LA
RA LA PV
PV PV
FIGURE 2 Contrast-enhanced echocardiography to detect intrapulmonary vascular dilations. a) Passage of

microbubbles in the right cavities. b) Arrival of microbubbles in the left cavities through the pulmonary veins in
the third cardiac cycle (red arrow). c) Filling of the right cavities by microbubbles. RV: right ventricle; LV: left
ventricle; RA: right atrium; LA: left atrium; PV: pulmonary vein.
230 https://doi.org/10.1183/2312508X.10006023
significant intrapulmonary shunt is lacking. It has been suggested that an uptake of

microparticles in the brain compared with the lungs of >6% could be considered abnormal, but
a clear cut-off needs to be properly determined. Technetium-labelled macroaggregated albumin
scans have two main limitations. First, the ability to detect IPVDs is lower than that of
contrast-enhanced echocardiography. Second, they do not allow us to distinguish
intrapulmonary and intracardiac shunts. This examination can be useful in nonechogenic
patients or in cases of cofactors implicated in gas-exchange disturbance to better assess the role
of IPVDs in hypoxaemia and to quantify the shunt.
Other investigations
One of the key points in the investigation of HPS is to detect other associated conditions that
could be involved in the abnormal arterial oxygenation. PFTs are mandatory to exclude an
associated obstructive or restrictive pathology. Pulmonary volumes and flows are normal in
isolated HPS. Diffusion impairment marked by low DLCO is observed in a very large number of
cirrhotic patients but is not specific to HPS.
It is also recommended to perform a thoracic CT in all patients to detect an associated

respiratory pathology. In the case of isolated HPS, the CT is most often normal [4]. However,
pulmonary vascular dilations in the subpleural areas of the lower lobes can be visible in the
most severe cases (figure 3).
An association between HPS and portopulmonary hypertension has been classically reported
and is probably underestimated [62]. Echocardiographic screening of PH is required in all HPS
patients, and right heart catheterisation must be performed in cases of an intermediate or high
probability of PH to confirm the diagnosis [63]. The effect of pulmonary arterial
hypertension-targeted therapies on gas-exchange abnormalities in HPS patients has not been
clearly studied; some authors have suggested that the vasodilatory effect of these drugs could be
deleterious, but this hypothesis remains to be demonstrated [64].
Management of HPS
Medical treatment
No medical treatment has been able to exert prolonged efficacy in HPS. This finding contrasts
with the results obtained in the preclinical model of HPS, with a wide variety of treatments
targeting NO overproduction, inflammation, bacterial translocation and angiogenesis. In
humans, a few clinical cases or case series have described the potential effects of some of these
therapies but without a sufficient level of proof.
Some clinical trials have been conducted in HPS, but all were limited by difficulties in
including patients and failed to demonstrate convincing efficacy in the small numbers of
patients. A phase II clinical trial has been performed with norfloxacin [65]. In this study, each
HPS and pre-HPS subject was treated with norfloxacin for a 4-week period. To ensure that any
observed improvement was indeed due to norfloxacin, each subject was also treated with a
separate 4-week course of an identical placebo. Only nine patients were recruited. Their A–aDO2
decreased by 0.8±4.8 and 3.4±12.4 mmHg while the patients were on norfloxacin and placebo,
respectively (nonsignificant). An open-label, prospective, nonrandomised clinical trial to study
the efficacy and safety of pentoxifylline therapy was performed >10 years ago with nine
enrolled patients. There were eight complete responders, defined by an increase in PaO2 of
>10 mmHg from the baseline level or a PaO2 of ⩾80 mmHg [66]. Another pilot study performed
in nine other patients did not show improvement in arterial oxygenation, and tolerance of
https://doi.org/10.1183/2312508X.10006023 231
a) b)
c) d)
FIGURE 3 Thoracic CT showing pulmonary vascular dilations in a severe form of hepatopulmonary syndrome.
a) Pseudo-appearance of subpleural reticulations on parenchymal section. The inset is shown in c. b) Pulmonary
vascular dilations (arrows) in the subpleural areas of the lower lobes detected after injection. The inset is shown
in d.
pentoxifylline was limited by gastrointestinal toxicity [67]. Finally, the benefit/risk ratio of these
drugs is not convincing. To target angiogenesis, the efficacy on A–aDO2 and the adverse effect
profile of sorafenib, a tyrosine kinase inhibitor, were recently evaluated in a randomised,
double-blinded, placebo-controlled parallel trial. A total of 28 patients with HPS were enrolled.
No statistically significant difference in the median change in A–aDO2 from baseline to
12 weeks between the patients allocated to sorafenib and those allocated to placebo was found [68].
Liver transplantation
To date, liver transplantation remains the only curative treatment for HPS [4]. Very interestingly,
in almost all patients, the resolution of the triggering factor leads to a reversibility of abnormal
arterial oxygenation after a somewhat long delay, which can take several months. The same
observation has been reported after the closure of congenital portosystemic shunts [69].
Given the absence of effective medical therapies and the prognostic impact of HPS, liver
transplantation is considered an essential option in the management of severe HPS
(PaO2 <60 mmHg), regardless of the severity of the underlying liver disease. The positive effect
of liver transplantation on the survival of patients who develop severe HPS has mainly been
demonstrated by retrospective studies. While the 5-year survival without liver transplantation
232 https://doi.org/10.1183/2312508X.10006023
was ∼20%, all recent studies in transplanted HPS patients reported a survival of >85% at
5 years, which is quite similar to the post-transplantation survival of patients without HPS
[70–73]. Because mortality associated with HPS is not necessarily related to the severity of liver
disease as measured by MELD (Model for End-stage Liver Disease) scores, a MELD exception
for HPS patients with a PaO2 <60 mmHg has been granted in most countries, with priority levels
that may differ depending on the system. Some studies reported a higher rate of post-transplant
mortality in patients with PaO2 <50 mmHg [74]. However, the excess mortality observed in
patients with severe hypoxaemia does not contraindicate transplantation in these patients.
Indeed, survival remains much higher than that without transplantation and is acceptable after
transplantation compared with other indications.
Management after liver transplantation

A temporary worsening of gas exchange is frequently observed in the postoperative period,
which can lead to prolonged intubation and a long stay in intensive care [75], although survival
rates and post-transplant oxygenation improved in adult patients with HPS who underwent liver
transplantation after MELD exception implementation [76]. This transitory aggravation is
mainly due to V′/Q′ mismatch worsening related to the repercussions of abdominal surgery on
the pulmonary bases (atelectasis and diaphragmatic dysfunction related to the subcostal incision,
vasoconstriction predominant at the apex), while vascular lesions due to HPS have not yet
regressed. Severe and early post-transplantation hypoxaemia in HPS, defined as the need for
100% FIO2 to maintain an oxygen saturation >88%, is not uncommon and occurs in 5–12% of
patients [77]. The management of this transient aggravation is based mainly on the treatment of
potential aggravating factors, the positioning of patients (strict dorsal decubitus or alternate
lateral decubitus, or the Trendelenburg position) and the use of inhaled NO to improve the V′/Q′
ratio. In the case of deep refractory hypoxaemia, temporary implantation of venovenous
extracorporeal membrane oxygenation can be considered with success, as described by case
reports in the literature and in our own experience [78]. Thanks to priority access to
transplantation for HPS and improvements in the management of these patients, post-transplant
survival is now globally similar to that for the whole liver transplant population.
After the immediate postoperative period, a gradual improvement in gas exchange is described
in almost all patients. A delay of 1 year to achieve normalisation of the gas exchange at rest and
during exercise can be observed in some cases. This time is variable from one patient to another
and depends on the severity of hypoxaemia before liver transplantation [75]. Rare cases of HPS
recurrence at a distance from the liver transplantation have been observed, always related to a
recurrence of the initial liver disease on the graft [79].
Conclusion
HPS remains a major complication of liver diseases affecting both the functional status and
prognosis of patients. Currently, liver transplantation remains the only option to reverse HPS.
Progress in our understanding of the pathophysiological mechanisms involved in HPS and of
the complex interaction and regulatory mechanisms between the liver and the lung circulation is
mandatory to identify potential targeted therapies.
References
1 Del Valle K, DuBrock HM. Hepatopulmonary syndrome and portopulmonary hypertension: pulmonary vascular
complications of liver disease. Compr Physiol 2021; 11: 3281–3302.
2 Rodríguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome – a liver-induced lung vascular disorder. N Engl J
Med 2008; 358: 2378–2387.
3 Savale L, Watherald J, Sitbon O. Portopulmonary hypertension. Semin Respir Crit Care Med 2017; 38: 651–661.
https://doi.org/10.1183/2312508X.10006023 233
4 Krowka MJ, Fallon MB, Kawut SM, et al. International liver transplant society practice guidelines: diagnosis and
management of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation 2016; 100:
1440–1452.
5 Berthelot P, Walker JG, Sherlock S, et al. Arterial changes in the lungs in cirrhosis of the liver – lung spider
nevi. N Engl J Med 1966; 274: 291–298.
6 Kennedy TC, Knudson RJ. Exercise-aggravated hypoxemia and orthodeoxia in cirrhosis. Chest 1977; 72: 305–309.
7 Hoffbauer FW, Rydell R. Multiple pulmonary arteriovenous fistulas in juvenile cirrhosis. Am J Med 1956; 21: 450–460.
8 Saad NEA, Lee DE, Waldman DL, et al. Pulmonary arterial coil embolization for the management of persistent
type I hepatopulmonary syndrome after liver transplantation. J Vasc Interv Radiol 2007; 18: 1576–1580.
9 Luo BW, Du ZY. Advances in diagnostic imaging of hepatopulmonary syndrome. Front Med (Lausanne) 2021; 8:
817758.
10 Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet
2004; 363: 1461–146.
11 Martínez GP, Barberà JA, Visa J, et al. Hepatopulmonary syndrome in candidates for liver transplantation.
J Hepatol 2001; 34: 651–657.
12 Fallon MB, Abrams GA, McGrath JW, et al. Common bile duct ligation in the rat: a model of intrapulmonary
vasodilatation and hepatopulmonary syndrome. Am J Physiol 1997; 272: G779–G784.
13 Ros J, Jiménez W, Lamas S, et al. Nitric oxide production in arterial vessels of cirrhotic rats. Hepatology 1995;
21: 554–560.
14 Martin PY, Ginès P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and
water retention in cirrhosis. N Engl J Med 1998; 339: 533–541.
15 Fallon MB, Abrams GA, Luo B, et al. The role of endothelial nitric oxide synthase in the pathogenesis of a rat
model of hepatopulmonary syndrome. Gastroenterology 1997; 113: 606–614.
16 Nunes H, Lebrec D, Mazmanian M, et al. Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats. Am
17 Rolla G, Brussino L, Colagrande P, et al. Exhaled nitric oxide and oxygenation abnormalities in hepatic cirrhosis.
Hepatology 1997; 26: 842–847.
18 Rolla G, Brussino L, Colagrande P, et al. Exhaled nitric oxide and impaired oxygenation in cirrhotic patients
before and after liver transplantation. Ann Intern Med 1998; 129: 375–378.
19 Gómez FP, Barberà JA, Roca J, et al. Effects of nebulized N G-nitro-L-arginine methyl ester in patients with
hepatopulmonary syndrome. Hepatology 2006; 43: 1084–1091.
20 Ling Y, Zhang J, Luo B, et al. The role of endothelin-1 and the endothelin B receptor in the pathogenesis of
hepatopulmonary syndrome in the rat. Hepatology 2004; 39: 1593–1602.
21 Luo B, Liu L, Tang L, et al. Increased pulmonary vascular endothelin B receptor expression and responsiveness
to endothelin-1 in cirrhotic and portal hypertensive rats: a potential mechanism in experimental
hepatopulmonary syndrome. J Hepatol 2003; 38: 556–563.
22 Luo B, Tang L, Wang Z, et al. Cholangiocyte endothelin 1 and transforming growth factor β1 production in rat
experimental hepatopulmonary syndrome. Gastroenterology 2005; 129: 682–695.
23 Tang L, Luo B, Patel RP, et al. Modulation of pulmonary endothelial endothelin B receptor expression and
signaling: implications for experimental hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol 2007;
292: L1467–L1472.
24 Zhang M, Luo B, Chen SJ, et al. Endothelin-1 stimulation of endothelial nitric oxide synthase in the
pathogenesis of hepatopulmonary syndrome. Am J Physiol 1999; 277: G944–G952.
25 Zhang J, Ling Y, Tang L, et al. Attenuation of experimental hepatopulmonary syndrome in endothelin B
receptor-deficient rats. Am J Physiol Gastrointest Liver Physiol 2009; 296: G704–G708.
26 Imamura M, Luo B, Limbird J, et al. Hypoxic pulmonary hypertension is prevented in rats with common bile
duct ligation. J Appl Physiol 2005; 98: 739–747.
27 Zhang J, Ling Y, Luo B, et al. Analysis of pulmonary heme oxygenase-1 and nitric oxide synthase alterations in
experimental hepatopulmonary syndrome. Gastroenterology 2003; 125: 1441–1451.
28 Thenappan T, Goel A, Marsboom G, et al. A central role for CD68+ macrophages in hepatopulmonary syndrome:
reversal by macrophage depletion. Am J Respir Crit Care Med 2011; 183: 1080–1091.
29 Wu W, Zhang J, Yang W, et al. Role of splenic reservoir monocytes in pulmonary vascular monocyte
accumulation in experimental hepatopulmonary syndrome. J Gastroenterol Hepatol 2016; 31: 1888–1894.
30 Raevens S, Coulon S, van Steenkiste C, et al. Role of angiogenic factors/cell adhesion markers in serum of
cirrhotic patients with hepatopulmonary syndrome. Liver Int 2015; 35: 1499–1507.
31 Sztrymf B, Rabiller A, Nunes H, et al. Prevention of hepatopulmonary syndrome and hyperdynamic state by
pentoxifylline in cirrhotic rats. Eur Respir J 2004; 23: 752–758.
32 Sztrymf B, Libert JM, Mougeot C, et al. Cirrhotic rats with bacterial translocation have higher incidence and
severity of hepatopulmonary syndrome. J Gastroenterol Hepatol 2005; 20: 1538–1544.
234 https://doi.org/10.1183/2312508X.10006023
33 Rabiller A, Nunes H, Lebrec D, et al. Prevention of Gram-negative translocation reduces the severity of
hepatopulmonary syndrome. Am J Respir Crit Care Med 2002; 166: 514–517.
34 Zhu J, Qiu J, Chen K, et al. Tea polyphenols and levofloxacin alleviate the lung injury of hepatopulmonary
syndrome in common bile duct ligation rats through endotoxin–TNF signaling. Biomed Pharmacother 2021; 137:
111263.
35 Zhang J, Ling Y, Tang L, et al. Pentoxifylline attenuation of experimental hepatopulmonary syndrome. J Appl
Physiol 2007; 102: 949–955.
36 Liu L, Liu N, Zhao Z, et al. TNF-α neutralization improves experimental hepatopulmonary syndrome in rats.
Liver Int 2012; 32: 1018–1026.
37 Li TH, Lee PC, Lee KC, et al. Down-regulation of common NFκB–iNOS pathway by chronic thalidomide
treatment improves hepatopulmonary syndrome and muscle wasting in rats with biliary cirrhosis. Sci Rep 2016;
6: 39405.
38 Raevens S, Geerts A, Paridaens A, et al. Placental growth factor inhibition targets pulmonary angiogenesis and
represents a therapy for hepatopulmonary syndrome in mice. Hepatology 2018; 68: 634–651.
39 Schraufnagel DE, Malik R, Goel V, et al. Lung capillary changes in hepatic cirrhosis in rats. Am J Physiol 1997;
272: L139–L147.
40 Yang Y, Yu H, Yang C, et al. Krüppel-like factor 6 mediates pulmonary angiogenesis in rat experimental
hepatopulmonary syndrome and is aggravated by bone morphogenetic protein 9. Biol Open 2019; 8: bio040121.
41 Kawut SM, Krowka MJ, Forde KA, et al. Impact of hepatopulmonary syndrome in liver transplantation
candidates and the role of angiogenesis. Eur Respir J 2021; 60: 2102304.
42 Roberts KE, Fallon MB, Krowka MJ, et al. Genetic risk factors for portopulmonary hypertension in patients with
advanced liver disease. Am J Respir Crit Care Med 2009; 179: 835–842.
43 Tu L, Desroches-Castan A, Mallet C, et al. Selective BMP-9 inhibition partially protects against experimental
pulmonary hypertension. Circ Res 2019; 124: 846–855.
44 Bidart M, Ricard N, Levet S, et al. BMP9 is produced by hepatocytes and circulates mainly in an active mature
form complexed to its prodomain. Cell Mol Life Sci 2012; 69: 313–324.
45 Tillet E, Bailly S. Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Front Genet
2014; 5: 456.
46 Aldred MA, Morrell NW, Guignabert C. New mutations and pathogenesis of pulmonary hypertension: progress
and puzzles in disease pathogenesis. Circ Res 2022; 130: 1365–1381.
47 Balachandar S, Graves TJ, Shimonty A, et al. Identification and validation of a novel pathogenic variant in GDF2
(BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. Am
J Med Genet A 2022; 188: 959–964.
48 Owen NE, Alexander GJ, Sen S, et al. Reduced circulating BMP10 and BMP9 and elevated endoglin are
associated with disease severity, decompensation and pulmonary vascular syndromes in patients with
cirrhosis. EBioMedicine 2020; 56: 102794.
49 Duncan BW, Desai S. Pulmonary arteriovenous malformations after cavopulmonary anastomosis. Ann Thorac
Surg 2003; 76: 1759–1766.
50 Schenk P, Fuhrmann V, Madl C, et al. Hepatopulmonary syndrome: prevalence and predictive value of various
cut offs for arterial oxygenation and their clinical consequences. Gut 2002; 51: 853–859.
51 Schenk P, Schöniger-Hekele M, Fuhrmann V, et al. Prognostic significance of the hepatopulmonary syndrome in
patients with cirrhosis. Gastroenterology 2003; 125: 1042–1052.
52 Younis I, Sarwar S, Butt Z, et al. Clinical characteristics, predictors, and survival among patients with
hepatopulmonary syndrome. Ann Hepatol 2015; 14: 354–360.
53 Fallon MB, Krowka MJ, Brown RS, et al. Impact of hepatopulmonary syndrome on quality of life and survival in
liver transplant candidates. Gastroenterology 2008; 135: 1168–1175.
54 Abrams GA, Jaffe CC, Hoffer PB, et al. Diagnostic utility of contrast echocardiography and lung perfusion scan
in patients with hepatopulmonary syndrome. Gastroenterology 1995; 109: 1283–1288.
55 Swanson KL, Wiesner RH, Krowka MJ. Natural history of hepatopulmonary syndrome: impact of liver
transplantation. Hepatology 2005; 41: 1122–1129.
56 Baiges A, Turon F, Simón-Talero M, et al. Congenital extrahepatic portosystemic shunts (Abernethy
malformation): an international observational study. Hepatology 2020; 71: 658–669.
57 Han SK, Kim MY, Kang SH, et al. Hepatopulmonary syndrome is related to the development of acute-on-chronic
liver failure and poor prognosis in cirrhotic patients. Hepatol Int 2021; 15: 1207–1214.
58 Lejealle C, Paradis V, Bruno O, et al. Evidence for an association between intrahepatic vascular changes and the
development of hepatopulmonary syndrome. Chest 2019; 155: 123–136.
59 Gómez FP, Martínez-Pallí G, Barberà JA, et al. Gas exchange mechanism of orthodeoxia in hepatopulmonary
syndrome. Hepatology 2004; 40: 660–666.
60 Forde KA, Fallon MB, Krowka MJ, et al. Pulse oximetry is insensitive for detection of hepatopulmonary
syndrome in patients evaluated for liver transplantation. Hepatology 2019; 69: 270–281.
https://doi.org/10.1183/2312508X.10006023 235
61 Abrams GA, Nanda NC, Dubovsky EV, et al. Use of macroaggregated albumin lung perfusion scan to diagnose
hepatopulmonary syndrome: a new approach. Gastroenterology 1998; 114: 305–310.
62 Fussner LA, Iyer VN, Cartin-Ceba R, et al. Intrapulmonary vascular dilatations are common in portopulmonary
hypertension and may be associated with decreased survival. Liver Transpl 2015; 21: 1355–1364.
64 Olsson KM, Meyer K, Berliner D, et al. Development of hepatopulmonary syndrome during combination therapy
for portopulmonary hypertension. Eur Respir J 2019; 53: 1801880.
65 Gupta S, Faughnan ME, Lilly L, et al. Norfloxacin therapy for hepatopulmonary syndrome: a pilot randomized
controlled trial. Clin Gastroenterol Hepatol 2010; 8: 1095–1098.
66 Gupta LB, Kumar A, Jaiswal AK, et al. Pentoxifylline therapy for hepatopulmonary syndrome: a pilot study. Arch
Intern Med 2008; 168: 1820–1823.
67 Tanikella R, Philips GM, Faulk DK, et al. Pilot study of pentoxifylline in hepatopulmonary syndrome. Liver
Transpl 2008; 14: 1199–1203.
68 Kawut SM, Ellenberg SS, Krowka MJ, et al. Sorafenib in hepatopulmonary syndrome: a randomized,
double-blind, placebo-controlled trial. Liver Transpl 2019; 25: 1155–1164.
69 Lambert V, Ladarre D, Fortas F, et al. Cardiovascular disorders in patients with congenital portosystemic
shunts: 23 years of experience in a tertiary referral centre. Arch Cardiovasc Dis 2021; 114: 221–231.
70 Al-Harbi A, Abdullah K, Al-Abdulkareem A, et al. Prevalence, severity, and prognostic effect of hepatopulmonary
syndrome in liver transplant candidates. Ann Transplant 2016; 21: 180–184.
71 Pascasio JM, Grilo I, López-Pardo FJ, et al. Prevalence and severity of hepatopulmonary syndrome and its
influence on survival in cirrhotic patients evaluated for liver transplantation. Am J Transplant 2014; 14: 1391–1399.
72 Goldberg DS, Krok K, Batra S, et al. Impact of the hepatopulmonary syndrome MELD exception policy on
outcomes of patients after liver transplantation: an analysis of the UNOS database. Gastroenterology 2014; 146:
1256–1265.e1.
73 Raevens S, Rogiers X, Geerts A, et al. Outcome of liver transplantation for hepatopulmonary syndrome: a
Eurotransplant experience. Eur Respir J 2019; 53: 1801096.
74 Arguedas MR, Abrams GA, Krowka MJ, et al. Prospective evaluation of outcomes and predictors of mortality in
patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 2003; 37: 192–197.
75 Taillé C, Cadranel J, Bellocq A, et al. Liver transplantation for hepatopulmonary syndrome: a ten-year
experience in Paris, France. Transplantation 2003; 75: 1482–1489.
76 Aragon Pinto C, Iyer VN, Albitar HAH, et al. Outcomes of liver transplantation in patients with hepatopulmonary
syndrome in the pre and post-MELD eras: a systematic review. Respir Med Res 2021; 80: 100852.
77 Aragon Pinto C, Iyer V, Almodallal YA, et al. ICU and hospital outcomes in patients with hepatopulmonary
syndrome undergoing liver transplantation. Lung 2022; 200: 5–10.
78 Wu WK, Grogan WM, Ziogas IA, et al. Extracorporeal membrane oxygenation in patients with hepatopulmonary
syndrome undergoing liver transplantation: a systematic review of the literature. Transplant Rev 2022; 36: 100693.
79 Casey S, Schelleman A, Angus P. Recurrence of hepatopulmonary syndrome post-orthotopic liver
transplantation in a patient with noncirrhotic portal hypertension. Hepatology 2013; 58: 2205–2206.
Disclosures: L. Savale reports receiving the following, outside the submitted work: grants or contracts from
Acceleron, Janssen, GSK and MSD; consulting fees from Gossamer Bio, Janssen, MSD and AOP Orphan; and
honoraria for lectures at conferences from Janssen, Ferrer and MSD. L. Savale reports advisory board ( pulmonary
hypertension) roles for Acceleron, Janssen and MSD, outside the submitted work. M. Humbert reports receiving
the following, outside the submitted work: grants or contracts from Acceleron, AOP Orphan, Janssen, Merck and
Shou Ti; consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck,
MorphogenIX, Shou Ti and United Therapeutics; and payment or honoraria for lectures, presentations, speakers’
bureaus, manuscript writing or educational events from Janssen and Merck. M. Humbert reports participation on
data safety monitoring boards or advisory boards for Acceleron, Altavant, Janssen, Merck and United Therapeutics,
outside the submitted work. The remaining authors have nothing to disclose.
236 https://doi.org/10.1183/2312508X.10006023
Chapter 17
Systemic inflammatory diseases with lung

involvement
Eirini Vasarmidi, Eleni Bibaki and Katerina Antoniou
Dept of Respiratory Medicine and Laboratory of Molecular and Cellular Pneumonology, School of Medicine,
University of Crete, Heraklion, Crete, Greece.
Corresponding author: Katerina Antoniou (kantoniou@uoc.gr)
Cite as: Vasarmidi E, Bibaki E, Antoniou K. Systemic inflammatory diseases with lung involvement. In: Wagner TOF,
@ERSpublications
The respiratory system is often involved in rare systemic inflammatory diseases, such as Behçet disease and
Takayasu vasculitis, with varying manifestations and incidence, leading to impaired quality of life, morbidity
and mortality in these patients https://bit.ly/ERSM100
ISSN: 2312-5098.
The respiratory system is frequently involved in the course of systemic inflammatory diseases with
varying incidence and severity. Almost every part of the respiratory system can be affected, represented
mainly by the airways, lung parenchyma, pleura, respiratory muscles and pulmonary vessels.
Respiratory manifestations can also affect the course of the disease in a determinant or irreversible
manner. Early detection of respiratory-related symptoms combined with the appropriate use of
diagnostic tools and detailed physical examination can lead to early recognition of respiratory
involvement in the context of systematic inflammatory disease. The rarity and complicated nature of
such diseases make the multidisciplinary team crucial every time an important therapeutic decision has
to be made.
Introduction
Systemic inflammatory diseases can affect a variety of different components of the thorax
including the lungs, pleura, respiratory muscles, pericardium, lymph nodes, vessels and heart.
The diagnosis of respiratory involvement is made using several diagnostic tools. Imaging, and
particularly CT of the chest, has a crucial role in the assessment of lung abnormalities, as it
establishes the presence and pattern of lung disease, as well as disease extent [1]. CT findings
suggestive of ILD lead to a diagnostic work-up for the existence of an underlying systemic
disease in clinical practice [2].
There is little evidence for the use of PFTs as a screening method, while BAL is used mainly to
exclude some causes of respiratory pathology, such as infection, malignancy and diffuse
alveolar haemorrhage (DAH) [3, 4]. Most commonly, BAL shows increased cellularity because
of the activation of polymorphonuclear cells in autoimmune diseases [5]. Biopsy is only used
when the diagnosis is uncertain and other findings are nonspecific.
https://doi.org/10.1183/2312508X.10018722 237
This chapter summarises the range of respiratory manifestations in systemic inflammatory

disorders, which can be characterised from mild to life-threatening (table 1). Pulmonary
involvement is a well-established component that affects quality of life, morbidity and mortality.
It is worth highlighting that the complexity of systemic inflammatory disorders and the variety
of pulmonary manifestations explain the importance of a multidisciplinary approach.
Connective tissue diseases

Rheumatoid arthritis (RA) is the most common systemic inflammatory disease and its diagnosis
requires the presence of synovitis in combination with joint involvement, the presence of
rheumatoid factor or anti-citrullinated protein antibodies (ACPAs), and increased inflammatory
markers [6]. Although RA mainly causes symmetric polyarthritis, extra-articular manifestations
are also common [7]. With regard to the lung, RA can affect any compartment, and this can be
observed before, during or after the occurrence of articular disease (figure 1) [8].
The lung may play a crucial role from the beginning of RA pathogenesis, as smoking and
mucosal abnormalities are implicated in disease development. Multicompartment lung
involvement is associated with a range of symptoms from asymptomatic pulmonary nodules to
severe RA-ILD. Nodules are found in one out of every five patients, and are usually multiple;
they cavitate less commonly [9]. Bronchiectasis is observed in up to one-third of patients with
RA [9, 10]. Small-airways involvement (bronchiolitis) is found in almost two-thirds of patients
[11]. Upper-airway involvement is also observed, including cricoarytenoid arthritis, while
laryngeal nodules and vocal cord paralysis have been noticed very rarely [12]. Pleural disease,
pleural effusions and, less commonly, pleural thickening and pneumothorax affect more than
half of RA patients [13]. Pleural effusions are typically unilateral exudates, and may be
misdiagnosed as parapneumonic effusions [13].
Genetic and environmental factors seem to contribute to protein citrullination and lung epithelial
injury, leading to lung fibrosis development in patients with RA [14]. Patient cohorts have
shown that smoking history, disease activity and ACPA positivity may be related to ILD [15].
Remarkable similarities between idiopathic pulmonary fibrosis (IPF) and RA-ILD genetic risk
factors have been described, including a common variant in the promoter of the mucin 5B
TABLE 1 An overview of lung involvement in systemic inflammatory disorders
Disorder Lung involvement

Most common Less common
Rheumatoid arthritis Airways, nodules, ILD, pleura PH

Systemic sclerosis ILD, PH Pleura
Myositis ILD, muscle weakness PH, airways, pleura
Sjögren syndrome Airways, ILD Pleura, PH
Systemic lupus erythematosus Pleura, PH Diffuse alveolar haemorrhage,
airways, ILD
Mixed connective tissue disease ILD, PH Pleura, airways
Spondyloarthritis ILD, apical bullous disease Airways, pleura
Inflammatory bowel disease Airways ILD, pleura, pulmonary embolism,
nodules
Behçet disease Aneurysms, pulmonary embolism Airways, ILD, pleura
Takayasu arteritis Pulmonary embolism, aneurysms Pleura, nodules
238 https://doi.org/10.1183/2312508X.10018722
SYSTEMIC INFLAMMATORY DISEASES | E. VASARMIDI ET AL.
BD
and TAK
Spondyloarthritis
Inflammatory bowel diseases
Systemic lupus erythematosus/

Sjögren syndrome
Mixed connective tissue disease
Myositis
Systemic sclerosis
FIGURE 1 Relative prevalence of lung involvement within systemic inflammatory diseases based on the current
literature. The prevalence increases from top to bottom. BD: Behçet disease; TAK: Takayasu arteritis.
(MUC5B) gene (rs35705950) [16, 17]. In a recent UK cohort, a usual interstitial pneumonia
(UIP) pattern on HRCT was identified in more than half of cases (65%), and nonspecific
interstitial pneumonia (NSIP) in 24% [18]. In a separate cohort, approximately one-third of
RA-ILD patients showed a non-UIP pattern, and these patients demonstrated the most
favourable prognosis [19].
Therapies used to treat RA, particularly sulfasalazine and leflunomide, have been associated
with lung toxicity [20]. Currently, the potential relationship between the use of methotrexate
and fibrosis development has been questioned [21, 22].
The Spanish Societies of Rheumatology (SER) and Pneumology and Thoracic Surgery
(SEPAR) recently published recommendations on the treatment of RA-ILD, suggesting
abatacept or rituximab, while mycophenolate mofetil (MMF) and methotrexate may also be
beneficial [23]. The antifibrotic drug pirfenidone is currently under evaluation [24], while
nintedanib is approved for progressive disease [25, 26]. Janus kinase ( JAK) inhibitors seem
promising, although larger studies are needed to evaluate their benefit [27].
Systemic sclerosis
Systemic sclerosis or scleroderma (SSc) is characterised by three hallmark symptoms,
vasculopathy, inflammation and fibroblast dysfunction, leading to increased deposition of
extracellular matrix [28]. The clinical manifestations include skin thickening of the fingers,
fingertip lesions, telangiectasia, abnormal nailfold capillaries, ILD or PH, and Raynaud’s
phenomenon. Three subsets of SSc are detected: limited cutaneous SSc (lcSSc), diffuse
cutaneous SSc (dcSSc) and SSc without skin involvement [28].
https://doi.org/10.1183/2312508X.10018722 239
Lung involvement in SSc is the best studied of all the connective tissue diseases (CTDs)
[28, 29]. ILD is more prevalent in dcSSc (30–71%) compared with lcSSc (21–53%), possibly
associated with the presence of anti-topoisomerase antibodies (anti-Scl-70), which seem to
predict more severe disease and worse prognosis [30, 31]. Profibrotic markers associated with
genetic profiles have been also implicated in SSc-ILD susceptibility [32, 33].
An overall prevalence of SSc-ILD of 36.2% was described in the Scleroderma Patient-Centered

Intervention Network Cohort [34]. The most common pattern of SSc-ILD is NSIP, while UIP is
present in a minority of patients [31, 35]. A widely used staging system for the evaluation of
SSc-ILD severity distinguishes SSc-ILD into limited and extensive based on: 1) rapid
evaluation of the disease extent on HRCT (<20% or >20% extent), and 2) an FVC threshold of
70% [36]. Recently, a European consensus statement suggested HRCT as the primary diagnostic
tool for SSc-ILD, supported by PFTs for screening and diagnosis [37].
Oesophageal dilation and dysmotility in patients with SSc can promote reflux and cause
additional lung injury [38]. PH is also common, mainly in patients with lcSSc, either as an
isolated finding or in association with lung fibrosis [39, 40]. SSc-ILD, PH or a combination of
the two are considered the leading causes of mortality in SSc [40, 41], although SSc-ILD has
been associated with a better prognosis than IPF, most likely due in part to the predominant
NSIP histology [35].
The management of lung involvement in patients with SSc remains challenging [42].
Management of SSc-PH is based on current PH guidelines [43], although it can become
complicated, as pulmonary arterial hypertension can coexist with other forms of PH in SSc,
including PH related to left heart disease, ILD, chronic thromboembolism and pulmonary venous
occlusive disease [40]. For the treatment of SSc-ILD, the European Alliance of Associations for
Rheumatology (EULAR) guidelines recommend cyclophosphamide [44]. MMF and rituximab
are also considered effective treatments for SSc-ILD [45, 46]. In addition, tocilizumab, an
interleukin-6 inhibitor, seems beneficial based on the results of the focuSSced trial (A study of
the efficacy and safety of tocilizumab in participants with systemic sclerosis) [47], while the
antifibrotic drug nintedanib has been also approved [48, 49], and pirfenidone is currently under
evaluation [50, 51]. A recently published Delphi study, involving experts in pulmonology and
rheumatology, developed a management algorithm for screening and treatment criteria,
mentioning the role of antifibrotics and tocilizumab in patients with SSc-ILD [52].
Myositis
Myositis, also known as idiopathic inflammatory myopathies, comprises a heterogeneous group
of rare autoimmune diseases characterised by skeletal muscle inflammation, and extramuscular
signs such as arthritis, Raynaud’s phenomenon, mechanic’s hands and ILD [53]. The myositis
group includes polymyositis, dermatomyositis, clinically amyopathic dermatomyositis and
anti-synthetase syndrome [54].
Patients with anti-synthetase syndrome display manifestations of arthritis, Raynaud’s

phenomenon, mechanic’s hands and fever but can also present with isolated ILD [55, 56]. The
anti-synthetase antibodies (anti-Jo1, anti-PL7, anti-PL12, anti-KS, anti-OJ, anti-EJ, anti-SC,
anti-JS, anti-YRS and anti-Zo) targeting the aminoacyl-tRNA synthetase enzyme are the most
frequently found myositis-specific antibodies [57]. Anti PL-7 appears to be associated with ILD
preceding the diagnosis of myositis, whereas patients with anti-PL12 positivity have a higher
rate of isolated ILD [55].
240 https://doi.org/10.1183/2312508X.10018722
Anti-MDA5 (melanoma differentiation-associated protein 5) antibody ( previously known as

anti-CADM-140) is a myositis-specific antibody and its detection identifies a subgroup of
patients characterised by dermatomyositis skin rash, skin ulcers, calcinosis, mechanic’s hands,
ILD, arthritis and poor prognosis [58]. Lung involvement may be presented as rapidly
progressive ILD, with increased mortality [59].
Overall, ILD is the most frequent and severe extramuscular involvement of myositis, affecting
survival [60]. A prevalence varying between 20% and 86% has been reported, representing one
of the highest prevalences among CTDs [61, 62]. A recent study showed that patients with ILD
and amyopathic myositis had higher 1-year mortality compared with patients with evidence of
myopathy [63]. The most frequent pattern, radiologically and histologically, is an overlap of
NSIP and organising pneumonia (OP) [63].
With regard to muscle involvement, respiratory muscle weakness is a rare but potentially
life-threatening complication that can develop independently from skeletal muscle weakness.
The management is similar to that of peripheral muscle or extramuscular involvement and relies
on immunosuppressive treatment [64].
PH can be observed with a low prevalence as a consequence of ILD in most cases (group 3)
[39], although cases of myositis-associated pulmonary arterial hypertension (group 1) have been
reported [65].
Given the low prevalence and high heterogeneity of myositis, there is no guideline regarding
lung treatment. In rapidly progressive forms, an aggressive treatment is considered with
high-dose corticosteroids and cyclophosphamide, rituximab or a calcineurin inhibitor. In
patients with mild disease or chronic presentation, corticosteroids alone or in association with
MMF or azathioprine can be used [66]. In a recent meta-analysis, the 3-month survival in ILD
patients treated with cyclophosphamide was 72.4% in rapidly progressive cases [67]. The role of
rituximab in the management of severe or progressive myositis-ILD has been highlighted [68]
and recently supported by a randomised trial [69]. Intravenous Ig can be an option in patients
with refractory disease associated with muscular involvement or with contraindications to
immunosuppressive agents [70, 71].
Sjögren syndrome
Sjögren syndrome (SjS) is the second most common systemic autoimmune disease, following
RA. It is characterised by lymphocytic infiltration of the exocrine glands (mainly lacrimal and
salivary glands) but can involve also extraglandular, visceral manifestations [72]. It has a clear
female predominance, and occurs either as a primary disorder or in association with other CTDs
as secondary SjS. The prevalence of lung involvement is 10–20%, although up to half of
patients with SjS may have abnormal lung imaging [73, 74]. The main serum markers indicative
of SjS are anti-SSA and anti-SSB antibodies. High levels of these antibodies, and also
antinuclear antibodies and rheumatoid factor, as well as older age and smoking history, are
considered risk factors for pulmonary involvement [75].
Airway disorders due to mucosal dryness and impaired mucociliary clearance but also bronchiolitis
and bronchiectasis are frequently described in patients with SjS (>20%) [76]. ILD is considered to
develop later in the course of the disease, in up to half of patients in 15 years. However, in a
substantial proportion of patients, ILD may exist before other SjS manifestations [74, 77]. NSIP
seems to be the prominent pattern, while UIP, OP and lymphocytic interstitial pneumonia (LIP) are
less common [78, 79]. Clinicians should be careful, as lymphoma and amyloidosis can present with
https://doi.org/10.1183/2312508X.10018722 241
an LIP pattern on HRCT, and so tissue biopsy should be discussed on a case-by-case basis. Patients
with SjS display a high risk for both non-neoplastic and neoplastic monoclonal lymphoproliferative
disorders. The prevalence of lymphoma in SjS patients ranges from 5% to 18% [80].
Recent consensus guidelines have been published shedding light on the optimal way of treating
patients with SjS-ILD [73]. For patients presenting with mild disease, a regular follow-up is
recommended. In patients with symptomatic or moderate-to-severe lung function impairment
and HRCT findings, corticosteroids represent the first-line treatment, followed by azathioprine
or MMF. In refractory or rapidly progressive cases, high doses of steroids as well as rituximab
or cyclophosphamide should be considered [73]. In cases with an established UIP pattern, it is
doubtful whether immunosuppressive treatment ameliorates lung fibrosis.
Systemic lupus erythematosus and mixed CTD

Systemic lupus erythematosus (SLE) is an autoimmune disease that mostly involves young
women and affects a plethora of organs, including the respiratory system [81]. In particular,
SLE can cause pleural effusion, acute lupus pneumonitis, shrinking lung syndrome, ILD, DAH,
PH and pulmonary embolism [82]. Recently, new classification criteria were developed,
including one obligatory entry criterion ( positive antinuclear antibody), followed by additional
criteria grouped into seven clinical and three immunological domains [81]. Pleuropulmonary
manifestations are part of the clinical criteria as they are highly prevalent in SLE; pleural
disease is observed in ∼60% of patients, and airways can often be affected, even in
asymptomatic cases [82, 83]. Several cohorts have shown that the prevalence of respiratory
involvement throughout the course of the disease ranges from 20% to 90% [84].
Respiratory tract infection is very common in SLE patients, and thus clinicians should always
try to rule it out, particularly in the case of immunosuppression [85, 86]. The most
life-threatening lung manifestations include acute lupus pneumonitis and DAH, which are
observed in a minority of patients (2–4%) [87]. ILD is less common in SLE compared with
other autoimmune diseases [82, 88]. NSIP and OP represent the most commonly observed
patterns, while LIP and UIP have been also described [89, 90]. Pulmonary involvement has
been related to disease activity and increased levels of anti-double-stranded DNA antibodies,
while ILD has been associated with age, the presence of anti-Ro and anti-U1RNP
(U1 ribonuclear protein) antibodies, and scleroderma features [84, 89].
PH is a rare but severe complication of SLE, typically associated with scleroderma traits and
anti-U1RNP antibodies [91, 92]. Shrinking lung syndrome is another rare complication of SLE,
thought to be associated with diaphragmatic dysfunction, but actually no clear pathogenic
mechanism or therapeutic options have been claimed [93]. Anti-phospholipid syndrome has a
prevalence of 30% [94], and displays an increased risk of thrombotic events in SLE patients [95].
Mixed CTD (MCTD) is characterised by the detection of serum anti-RNP antibodies associated
with features of SSc, SLE and inflammatory myopathies [96]. The presence of anti-U1-snRNP
(U1 small nuclear RNP) autoantibodies is a mandatory diagnostic criterion [97]. Although
highly sensitive, this marker is characterised by low specificity and can also be found in SLE [98].
Two factors are considered highly indicative of MCTD: a positive anti-U1RNP IgG with
negative anti-U1RNP IgM, and elevated 70 kDa anti-U1RNP titres [99].
Lung involvement mainly includes ILD, occurring in about 36–50% of patients [100, 101]. PH
is another major clinical feature in MCTD, with a prevalence of 10–50% [98, 102]. Among
CTDs, MCTD was found to be the one most commonly associated with PH. In a national UK
242 https://doi.org/10.1183/2312508X.10018722
registry study of 484 patients, 8% of PH-CTD patients were diagnosed with MCTD compared
with 74% presenting with SSc [103], while in smaller cohorts up to 43% of PH-CTD patients
presented with MCTD [104]. In cases of SSc, oesophageal dysmotility causing recurrent
aspiration in the lungs should be considered.
With regard to treatment for SLE- and MCTD-associated parenchymal disorders, there is limited
evidence and no data from prospective controlled studies [105]. Therefore, treatment strategies
are mostly extrapolated from other autoimmune conditions with pulmonary involvement.
Treatment relies on corticosteroids, while cyclophosphamide, rituximab, plasmapheresis and i.v.
Ig have been used in critically ill patients [69, 106]. MMF or azathioprine has been proposed as
maintenance therapy [107].
Spondyloarthritis
The term spondyloarthritis (SpA) refers to a group of immune-mediated diseases that are
characterised by inflammation of the axial and peripheral skeleton and enthesitis, as well as
involvement of the skin, eyes and intestine. This group includes axial SpA, psoriatic arthritis,
arthritis associated with inflammatory bowel disease (IBD) and reactive arthritis [108]. These
diseases are also referred to as “seronegative spondyloarthropathy” because rheumatoid factor
and antinuclear antibodies are usually negative. Chronic inflammation may result in structural
damage to the joints and spine, causing fusion of the sacroiliac joint and spine in later stages,
called bamboo spine. The term “ankylosing spondylitis” is used when there is obvious
sacroiliitis on a radiograph [109].
The thoracic manifestations can be divided into those affecting the chest wall, airways, lung
parenchyma, heart and great vessels. Inflammation in the thoracic vertebrae and costovertebral
joints can lead to kyphosis, rigidity and immobility of the chest wall, while more than one-third of
patients develop chest wall pain [110, 111]. Thus, restrictive physiology can be associated with
structural damage to the thoracic cage but also with lung parenchyma, as upper-zone lung fibrosis
can progress to apical bullous disease [109]. In a systematic review of 303 patients, the prevalence
of lung abnormalities was 61%; NSIP was observed in 33% of patients (figure 2), upper lobe
fibrosis in 6.9%, emphysema in 18.1%, bronchiectasis in 10.8% and ground-glass opacities in
11.2% [112]. Pleural thickening, parenchymal bands and nodules could be also detected [112].
Apical bullous disease increases the likelihood of pneumothorax and makes it difficult to
differentiate infectious complications, particularly in patients under immunosuppression [113].
Aortitis and PH can be detected very rarely in patients with SpA [114, 115].
Lastly, recent studies suggest an association between sleep disturbances and spondylitis [116].
Several implicated mechanisms have been proposed, such as compression of the oropharyngeal
airway by cervical bridging syndesmophytes, central respiratory depression from compression of
the respiratory centres in the medulla from subluxation of the cervical spine, and lung
involvement [117].
Independently of lung involvement, treatment recommendations propose tumour necrosis factor-α

(TNFα) inhibitors as the first choice, while coadministration of methotrexate is not recommended
[118]. Antibodies against interleukin-17A are recommended in nonresponsive patients [118].
IBDs
IBDs represent chronic inflammatory diseases of the gastrointestinal tract, mainly ulcerative
colitis and Crohn disease, and are associated with increasing incidence worldwide [119]. The
https://doi.org/10.1183/2312508X.10018722 243
a) b)
c) d)
FIGURE 2 Spondyloarthritis-related ILD in a 63-year-old woman, 2 years after spondyloarthritis diagnosis.

a and b) Coronal reconstruction and c and d) axial HRCT images of the middle (c) and lower (d) lungs are
shown, which highlight peripheral reticulation and traction bronchiectasis.
prevailing theory about their pathogenesis supports a detrimental effect of both genetic and
environmental factors on the microbiome that results in aberrant intestinal immune activation.
Extraintestinal manifestations are not rare during the course of the disease, with possible
involvement of almost any organ, mainly the musculoskeletal system, eyes and mucous
membranes [120]. Gastrointestinal and respiratory systems share similarities based on
embryological origin, and structural and physiological aspects. Interestingly, several cohorts
have shown an increased prevalence of respiratory diseases in patients with IBD and vice versa
[121–123]. However, there are data suggesting that respiratory involvement remains
underreported, and if respiratory symptoms pre-date the diagnosis of IBD, airway involvement
might be misdiagnosed as asthma [124]. Nearly every compartment of the respiratory system
can be affected, in particular the airways, lung parenchyma, pleura and pulmonary vasculature,
whereas infections occur in the context of immunosuppression [125].
The spectrum of airways disease is wide and includes tracheobronchitis, asthma, bronchiectasis,
COPD, tracheal stenosis and bronchiolitis. Ulcerative colitis is more commonly associated with
airways disease, while >50% of patients present with bronchiectasis [125, 126]. IBD-ILD is less
common than airways disease, mostly presenting as OP and granulomatous disease, while
eosinophilic pneumonia, NSIP, acute interstitial pneumonia, desquamative interstitial pneumonia
and UIP are rarely observed [127, 128]. The pleura can be affected because of medication or
disease per se. Specific pleural manifestations include pleural effusions, pleuritis and
244 https://doi.org/10.1183/2312508X.10018722
pneumothorax. Pleural effusions are typically exudates in nature [129]. Disease-related medications,
including 6-mercaptopurine, azathioprine, mesalamine, TNFα inhibitors and sulfasalazine, may
cause interstitial and pleural disease [130, 131]. Thromboembolic events, pulmonary nodules,
sarcoidosis and α1-antitrypsin deficiency are seen less commonly in patients with IBD [132, 133].
Treatment strategies depend on the particular lung manifestation. When obstruction is due to
stenotic central airways, bronchoscopy will be helpful not only diagnostically but also
therapeutically [126]. In the case of IBD-ILD, data are scarce, and therefore treatment strategies
are based on autoimmune inflammatory disorders (non-IBD literature), mainly using
immunosuppressive agents.
Behçet disease
Behçet disease is a chronic, rare disorder, with vascular and perivascular inflammation being the
principal pathological process. It is a systemic variable vessel vasculitis, involving several
organs: the skin, central nervous system, joints, eyes, genitourinary and gastrointestinal tract,
cardiovascular system and lungs [134]. Recurrent relapses are observed, and men are more often
affected, following a more severe disease course compared with women [135]. A characteristic
clinical triad of manifestations has been described and is represented by genital and oral ulcers,
and uveitis.
The exact prevalence of thoracic manifestations is not clear, due to lack of representative
prospective studies in the field. A wide range of intrathoracic anatomical structures can be
involved during the course of the disease [136]. Regarding the vascular system, veins are more
frequently involved than arteries, mainly in the form of thrombophlebitis. The superior and
inferior vena cava can be affected by thrombophlebitis, while the incidence of pulmonary
embolism is considerably lower [137]. A characteristic manifestation of Behçet disease is the
development of aneurysms of pulmonary arteries and their branches (figure 3), events that
typically worsen the overall prognosis [138, 139]. Pulmonary thrombosis can cause
parenchymal infarctions [140], while pulmonary vasculitis can lead to focal haemorrhage [141].
Regarding lung parenchyma, its involvement per se is not rare, and it occasionally presents as
OP or eosinophilic pneumonia, fibrotic lesions, small-airways disease, emphysema or lower
respiratory tract infections [142]. Moreover, extensive mucosal ulcers can cause occlusion of the
central and proximal airways, while Behçet disease can rarely cause the diffuse and more
aggressive form of fibrosing mediastinitis [143]. Pleural involvement is represented by pleural
nodules and pleural effusions, which may display parapneumonic characteristics or occur in the
context of pulmonary infarctions [135].
Immunosuppression is the cornerstone of the therapeutic approach; glucocorticoids are used for
remission, while azathioprine is considered to prevent relapses. It is recommended that pulmonary
arterial aneurysms and occlusive vessel lesions are managed with cyclophosphamide and
high-dose glucocorticoids, with the contribution of vascular surgeons when appropriate [144].
Takayasu arteritis
Takayasu arteritis was first described in a Japanese patient with retinal vasculitis by the
ophthalmologist Mikito Takayasu [145]. It is a chronic large-vessel vasculitis characterised by
granulomatous inflammation and female predominance, occurring mostly before the fourth
decade of life [146]. It causes stenotic lesions and aneurysms of the aorta, its main branches and
pulmonary arteries. The disease usually follows a mild course; however, it can relapse acutely
causing devastating events such as strokes or visual loss [147].
https://doi.org/10.1183/2312508X.10018722 245
a) b)
FIGURE 3 Behçet disease presenting with an aneurysm in the thoracic aorta. a) Saccular aneurysm of the
descending aorta, 6.5×4.5×4.5 cm in size (arrow), causing severe pressure effects on the left main bronchus and
left branch of the pulmonary artery in a 40-year-old female patient. b) Stent placement in the descending
thoracic aorta of the same patient.
Symptoms related to pulmonary involvement may present insidiously and are nonspecific,
leading to misdiagnosis or delayed diagnosis. Pulmonary manifestations in Takayasu arteritis are
mainly the result of pulmonary artery involvement, which is the second most common site of
disease after the aorta [148]. Pulmonary artery walls undergo structural changes, granulation
tissue accumulation, rigidity, narrowing, fibrotic or calcified stenosis, thrombosis, aneurysms
and development of abnormal communication with systemic arteries [149]. Segmental and
subsegmental arteries are more frequently involved compared with the main pulmonary
arteries [150]. Approximately half of patients with Takayasu arteritis and pulmonary artery
involvement suffer from PH, which is mostly secondary to pulmonary artery stenosis or
occlusion [151, 152]. Less frequently, findings on chest CT include pleural effusions, cavities,
nodules, a mosaic pattern and areas of pulmonary haemorrhage [153, 154].
Oral corticosteroids are the fundamental therapy, while immunosuppressive agents, such as
methotrexate, azathioprine and anti-TNFα agents are currently suggested [155]. Regular
follow-up, limitation of vascular complications, and management of comorbidities and
cardiovascular risk factors are also part of the therapeutic plan. A multidisciplinary approach is
of crucial importance in all therapeutic decisions [156].
Progressive fibrotic phenotype

Regardless of the underlying diagnosis, whether CTD or vasculitis, a proportion of patients with
fibrotic ILD develop a progressive phenotype characterised by lung function decline and
increased mortality [157, 158]. A recent retrospective study including non-IPF ILD patients,
half of whom had autoimmune disease, demonstrated progression and 30% 5-year mortality,
which was higher in patients with a UIP pattern [159]. The term progressive pulmonary fibrosis
was proposed in the updated guidelines, and antifibrotic therapy was suggested based on recent
data [160]. The antifibrotic agent nintedanib is of benefit for patients with progressive
pulmonary fibrosis, as demonstrated by the INBUILD study (Efficacy and safety of nintedanib
in patients with progressive fibrosing interstitial lung disease) [25]. Furthermore, post-hoc analysis
showed nonsignificant differences in the efficacy of nintedanib across ILD subgroups [26].
Regarding the second antifibrotic agent, pirfenidone, the RELIEF trial (Exploring efficacy and
safety of oral pirfenidone for progressive, non-IPF lung fibrosis) included patients with
246 https://doi.org/10.1183/2312508X.10018722
progressive fibrosis, 29% of whom had CTD-ILD, and showed that pirfenidone reduced the rate
of FVC decline compared with placebo [50]. More data are needed to clarify the benefit of
antifibrotic drugs and to investigate whether and when they should be used in non-IPF ILDs.
Conclusion
In conclusion, a comprehensive and multidisciplinary approach is required for early
identification of lung involvement in systemic inflammatory disorders, which seems to have an
impact on mortality. Therefore, it is crucial to contextualise any respiratory symptoms in a given
patient with a systemic inflammatory disease. Treatment strategies should be adjusted following
a collaborative effort by specialised clinicians, mostly rheumatologists and pulmonologists.
Timely intervention for patients with a progressive fibrotic phenotype appears to be essential for
disease stabilisation. Further research will better clarify the strategies for the optimal
management of patients with lung involvement in systemic diseases.
References
1 Lynch DA, Sverzellati N, Travis WD, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner
Society White Paper. Lancet Respir Med 2018; 6: 138–153.
ALAT clinical practice guideline. Am J Respir Crit Care Med 2018; 198: e44–e68.
3 Bergantini L, d’Alessandro M, Cameli P, et al. Integrated approach to bronchoalveolar lavage cytology to
distinguish interstitial lung diseases. Eur J Intern Med 2021; 89: 76–80.
4 Chang SL, Tsai HC, Lin FC, et al. Clinical usefulness of bronchoalveolar lavage in patients with interstitial lung
diseases: a pilot study. J Thorac Dis 2020; 12: 3125–3134.
5 Meyer KC, Raghu G, Baughman RP, et al. An official American Thoracic Society clinical practice guideline: the
clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med
2012; 185: 1004–1014.
6 Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of
Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62:
2569–2581.
7 Turesson C. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors
over 46 years. Ann Rheum Dis 2003; 62: 722–727.
8 Mackintosh JA, Stainer A, de Sadeleer LJ, et al. Pulmonary involvement in rheumatoid arthritis. In: Wuyts WA,
Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases. Sheffield, European
9 Mori S, Cho I, Koga Y, et al. Comparison of pulmonary abnormalities on high-resolution computed
tomography in patients with early versus longstanding rheumatoid arthritis. J Rheumatol 2008; 35: 1513–1521.
10 Wilsher M, Voight L, Milne D, et al. Prevalence of airway and parenchymal abnormalities in newly diagnosed
rheumatoid arthritis. Respir Med 2012; 106: 1441–1446.
11 Lieberman-Maran L, Orzano IM, Passero MA, et al. Bronchiectasis in rheumatoid arthritis: report of four cases
and a review of the literature – implications for management with biologic response modifiers. Semin Arthritis
Rheum 2006; 35: 379–387.
12 Hamdan AL, Sarieddine D. Laryngeal manifestations of rheumatoid arthritis. Autoimmune Dis 2013; 2013: 103081.
13 Balbir-Gurman A, Yigla M, Nahir AM, et al. Rheumatoid pleural effusion. Semin Arthritis Rheum 2006; 35: 368–378.
14 Juge PA, Crestani B, Dieudé P. Recent advances in rheumatoid arthritis-associated interstitial lung disease.
Curr Opin Pulm Med 2020; 26: 477–486.
15 Ben Tekaya A, Mokaddem S, Athimini S, et al. Risk factors for rheumatoid arthritis-associated interstitial lung
disease: a retrospective study. Multidis Res Med 2022; 17: 877.
16 Juge PA, Lee JS, Ebstein E, et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung
17 Juge PA, Borie R, Kannengiesser C, et al. Shared genetic predisposition in rheumatoid arthritis–interstitial lung
disease and familial pulmonary fibrosis. Eur Respir J 2017; 49: 1602314.
18 Kelly CA, Saravanan V, Nisar M, et al. Rheumatoid arthritis-related interstitial lung disease: associations,
prognostic factors and physiological and radiological characteristics – a large multicentre UK study.
Rheumatology 2014; 53: 1676–1682.
19 Jacob J, Hirani N, van Moorsel CHM, et al. Predicting outcomes in rheumatoid arthritis related interstitial lung
disease. Eur Respir J 2019; 53: 1800869.
https://doi.org/10.1183/2312508X.10018722 247
20 Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in
rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum 2014; 43: 613–626.
21 Juge PA, Lee JS, Lau J, et al. Methotrexate and rheumatoid arthritis associated interstitial lung disease. Eur
Respir J 2021; 57: 2000337.
22 Kiely P, Busby AD, Nikiphorou E, et al. Is incident rheumatoid arthritis interstitial lung disease associated with
methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts. BMJ
Open 2019; 9: e028466.
23 Narváez J, Díaz del Campo Fontecha P, Brito García N, et al. SER-SEPAR recommendations for the
management of rheumatoid arthritis-related interstitial lung disease. Part 2: treatment. Reumatol Clín 2022;
18: 501–512.
24 Solomon JJ, Danoff SK, Woodhead FA, et al. Safety, tolerability, and efficacy of pirfenidone in patients with
rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled,
phase 2 study. Lancet Respir Med 2023; 11: 87–96.
25 Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J
Med 2019; 381: 1718–1727.
26 Wells AU, Flaherty KR, Brown KK, et al. Nintedanib in patients with progressive fibrosing interstitial lung
diseases – subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised,
double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med 2020; 8: 453–460.
27 Kalyoncu U, Bilgin E, Erden A, et al. Efficacy and safety of tofacitinib in rheumatoid arthritis-associated
interstitial lung disease: TReasure real-life data. Clin Exp Rheumatol 2022; 40: 2071–2077.
28 van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American
College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 2013;
65: 2737–2747.
29 Valentini G, Iudici M, Walker UA, et al. The European Scleroderma Trials and Research group (EUSTAR) task
force for the development of revised activity criteria for systemic sclerosis: derivation and validation of a
preliminarily revised EUSTAR activity index. Ann Rheum Dis 2017; 76: 270–276.
30 Hoffmann-Vold AM, Midtvedt Ø, Tennøe AH, et al. Cardiopulmonary disease development in anti-RNA
polymerase III-positive systemic sclerosis: comparative analyses from an unselected, prospective patient
cohort. J Rheumatol 2017; 44: 459–465.
31 Fischer A, Swigris JJ, Groshong SD, et al. Clinically significant interstitial lung disease in limited scleroderma:
histopathology, clinical features, and survival. Chest 2008; 134: 601–605.
32 Gorlova O, Martin JE, Rueda B, et al. Identification of novel genetic markers associated with clinical
phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet 2011; 7: e1002178.
33 Fonseca C, Lindahl GE, Ponticos M, et al. A polymorphism in the CTGF promoter region associated with
systemic sclerosis. N Engl J Med 2007; 357: 1210–1220.
34 Dougherty DH, Kwakkenbos L, Carrier ME, et al. The Scleroderma Patient-Centered Intervention Network
Cohort: baseline clinical features and comparison with other large scleroderma cohorts. Rheumatology 2018;
57: 1623–1631.
35 Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with
systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002; 165: 1581–1586.
36 Goh NSL, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging
system. Am J Respir Crit Care Med 2008; 177: 1248–1254.
37 Hoffmann-Vold AM, Maher TM, Philpot EE, et al. The identification and management of interstitial lung disease
in systemic sclerosis: evidence-based European consensus statements. Lancet Rheumatol 2020; 2: e71–e83.
38 Hoffmann-Vold AM, Allanore Y, Alves M, et al. Progressive interstitial lung disease in patients with systemic
sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis 2021; 80: 219–227.
39 Nikkho SM, Richter MJ, Shen E, et al. Clinical significance of pulmonary hypertension in interstitial lung
disease: a consensus statement from the Pulmonary Vascular Research Institute’s innovative drug
development initiative – Group 3 pulmonary hypertension. Pulm Circ 2022; 12: e12127.
40 Young A, Vummidi D, Visovatti S, et al. Prevalence, treatment, and outcomes of coexistent pulmonary
hypertension and interstitial lung disease in systemic sclerosis. Arthritis Rheumatol 2019; 71: 1339–1349.
41 Kolstad KD, Li S, Steen V, et al. Long-term outcomes in systemic sclerosis-associated pulmonary arterial
hypertension from the pulmonary hypertension assessment and recognition of outcomes in scleroderma
registry (PHAROS). Chest 2018; 154: 862–871.
42 Hoffmann-Vold AM, Distler O, Crestani B, et al. Recent advances in the management of systemic
sclerosis-associated interstitial lung disease. Curr Opin Pulm Med 2022; 28: 441–447.
44 Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of
systemic sclerosis. Ann Rheum Dis 2017; 76: 1327–1339.
248 https://doi.org/10.1183/2312508X.10018722
45 Volkmann ER, Tashkin DP, LeClair H, et al. Treatment with mycophenolate and cyclophosphamide leads to
clinically meaningful improvements in patient-reported outcomes in scleroderma lung disease: results of
Scleroderma Lung Study II. ACR Open Rheumatol 2020; 2: 362–370.
46 Sircar G, Goswami RP, Sircar D, et al. Intravenous cyclophosphamide vs rituximab for the treatment of early
diffuse scleroderma lung disease: open label, randomized, controlled trial. Rheumatology 2018; 57: 2106–2113.
47 Khanna D, Lin CJF, Furst DE, et al. Long-term safety and efficacy of tocilizumab in early systemic sclerosis–
interstitial lung disease: open-label extension of a phase 3 randomized controlled trial. Am J Respir Crit Care
Med 2022; 205: 674–684.
48 Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung
49 Highland KB, Distler O, Kuwana M, et al. Efficacy and safety of nintedanib in patients with systemic
sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS
51 Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and tolerability of pirfenidone
in patients with scleroderma-associated interstitial lung disease: the LOTUSS trial. J Rheumatol 2016; 43:
1672–1679.
52 Rahaghi FF, Hsu VM, Kaner RJ, et al. Expert consensus on the management of systemic sclerosis-associated
interstitial lung disease. Respir Res 2023; 24: 6.
53 Lundberg IE, Tjärnlund A, Bottai M, et al. 2017 European League Against Rheumatism/American College of
Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their
major subgroups. Arthritis Rheumatol 2017; 69: 2271–2282.
54 Lundberg IE, de Visser M, Werth VP. Classification of myositis. Nat Rev Rheumatol 2018; 14: 269–278.
55 Hamaguchi Y, Fujimoto M, Matsushita T, et al. Common and distinct clinical features in adult patients with
anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS One 2013; 8: e60442.
56 Liu Y, Liu X, Xie M, et al. Clinical characteristics of patients with anti-EJ antisynthetase syndrome associated
interstitial lung disease and literature review. Respir Med 2020; 165: 105920.
57 McHugh NJ, Tansley SL. Autoantibodies in myositis. Nat Rev Rheumatol 2018; 14: 290–302.
58 Allenbach Y, Uzunhan Y, Toquet S, et al. Different phenotypes in dermatomyositis associated with anti-MDA5
antibody: study of 121 cases. Neurology 2020; 95: e70–e78.
59 Moghadam-Kia S, Oddis CV, Sato S, et al. Antimelanoma differentiation-associated gene 5 antibody: expanding
the clinical spectrum in North American patients with dermatomyositis. J Rheumatol 2017; 44: 319–325.
60 Saketkoo LA, Ascherman DP, Cottin V, et al. Interstitial lung disease in idiopathic inflammatory myopathy. Curr
Rheumatol Rev 2010; 6: 108–119.
61 Mimori T, Nakashima R, Hosono Y. Interstitial lung disease in myositis: clinical subsets, biomarkers, and
treatment. Curr Rheumatol Rep 2012; 14: 264–274.
62 Sun KY, Fan Y, Wang YX, et al. Prevalence of interstitial lung disease in polymyositis and dermatomyositis: a
meta-analysis from 2000 to 2020. Semin Arthritis Rheum 2021; 51: 175–191.
63 Karampitsakos T, Tzilas V, Papaioannou O, et al. Clinical features and outcomes of patients with myositis
associated-interstitial lung disease. Front Med 2023; 9: 1096203.
64 Selva-O’Callaghan A, Labrador-Horrillo M, Muñoz-Gall X, et al. Polymyositis/dermatomyositis-associated lung
disease: analysis of a series of 81 patients. Lupus 2005; 14: 534–542.
65 Sanges S, Yelnik CM, Sitbon O, et al. Pulmonary arterial hypertension in idiopathic inflammatory myopathies:
data from the French pulmonary hypertension registry and review of the literature. Medicine 2016; 95: e4911.
66 Morisset J, Johnson C, Rich E, et al. Management of myositis-related interstitial lung disease. Chest 2016; 150:
1118–1128.
67 Barba T, Fort R, Cottin V, et al. Treatment of idiopathic inflammatory myositis associated interstitial lung
disease: a systematic review and meta-analysis. Autoimmun Rev 2019; 18: 113–122.
68 Andersson H, Sem M, Lund MB, et al. Long-term experience with rituximab in anti-synthetase
syndrome-related interstitial lung disease. Rheumatology 2015; 54: 1420–1428.
69 Maher TM, Tudor VA, Saunders P, et al. Rituximab versus intravenous cyclophosphamide in patients with
connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind,
double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med 2023; 11: 45–54.
70 Zhou AL, Maltez N, Ivory C. Use of subcutaneous immunoglobulin in inflammatory myositis. Rheumatol Adv
Pract 2021; 5: rkab070.
71 Ohad M, Shemer A, Lavie I, et al. Intravenous immunoglobulin for inflammatory myositis: experience in a
tertiary medical center. J Clin Rheumatol 2021; 27: e616–e621.
https://doi.org/10.1183/2312508X.10018722 249
72 Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against
Rheumatism classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology
involving three international patient cohorts. Ann Rheum Dis 2017; 76: 9–16.
73 Lee AS, Scofield RH, Hammitt KM, et al. Consensus guidelines for evaluation and management of pulmonary
disease in Sjögren’s. Chest 2021; 159: 683–698.
74 Sambataro G, Ferro F, Orlandi M, et al. Clinical, morphological features and prognostic factors associated with
interstitial lung disease in primary Sjögren’s syndrome: a systematic review from the Italian Society of
Rheumatology. Autoimmun Rev 2020; 19: 102447.
75 Flament T, Bigot A, Chaigne B, et al. Pulmonary manifestations of Sjögren’s syndrome. Eur Respir Rev 2016;
25: 110–123.
76 Lohrmann C, Uhl M, Warnatz K, et al. High-resolution CT imaging of the lung for patients with primary
Sjogren’s syndrome. Eur J Radiol 2004; 52: 137–143.
77 He C, Chen Z, Liu S, et al. Prevalence and risk factors of interstitial lung disease in patients with primary
Sjögren’s syndrome: a systematic review and meta-analysis. Int J Rheum Dis 2020; 23: 1009–1018.
78 Ramos-Casals M, Brito-Zerón P, Seror R, et al. Characterization of systemic disease in primary Sjögren’s
syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal
involvements. Rheumatology 2015; 54: 2230–2238.
79 Dong X, Zhou J, Guo X, et al. A retrospective analysis of distinguishing features of chest HRCT and clinical
manifestation in primary Sjögren’s syndrome-related interstitial lung disease in a Chinese population. Clin
Rheumatol 2018; 37: 2981–2988.
80 Vasaitis L, Nordmark G, Theander E, et al. Comparison of patients with and without pre-existing lymphoma at
diagnosis of primary Sjögren’s syndrome. Scand J Rheumatol 2019; 48: 207–212.
81 Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of
Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol 2019; 71: 1400–1412.
82 Shin JI, Lee KH, Park S, et al. Systemic lupus erythematosus and lung involvement: a comprehensive review.
J Clin Med 2022; 11: 6714.
83 Antoniou KM, Vasarmidi E, Trachalaki A, et al. Pulmonary involvement in systemic lupus erythematosus,
Sjögren syndrome and mixed connective tissue disease. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds.
Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society,
2019; pp. 106–123.
84 Alamoudi OSB, Attar SM. Pulmonary manifestations in systemic lupus erythematosus: association with disease
activity. Respirology 2015; 20: 474–480.
85 Noël V, Lortholary O, Casassus P, et al. Risk factors and prognostic influence of infection in a single cohort of
87 adults with systemic lupus erythematosus. Ann Rheum Dis 2001; 60: 1141–1144.
86 Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a
10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine 2003; 82:
299–308.
87 Keane MP, Lynch JP. Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax 2000; 55: 159–166.
88 Mageau A, Borie R, Crestani B, et al. Epidemiology of interstitial lung disease in systemic lupus erythematosus
in France: a nation-wide population-based study over 10 years. Respirology 2022; 27: 630–634.
89 Toyoda Y, Koyama K, Kawano H, et al. Clinical features of interstitial pneumonia associated with systemic
lupus erythematosus. Respir Investig 2019; 57: 435–443.
90 Enomoto N, Egashira R, Tabata K, et al. Analysis of systemic lupus erythematosus-related interstitial
pneumonia: a retrospective multicentre study. Sci Rep 2019; 9: 7355.
91 Zhao J, Wang Q, Liu Y, et al. Clinical characteristics and survival of pulmonary arterial hypertension associated
with three major connective tissue diseases: a cohort study in China. Int J Cardiol 2017; 236: 432–437.
92 Li M, Wang Q, Zhao J, et al. Chinese SLE Treatment and Research group (CSTAR) registry: II. Prevalence and
risk factors of pulmonary arterial hypertension in Chinese patients with systemic lupus erythematosus. Lupus
2014; 23: 1085–1091.
93 Smyth H, Flood R, Kane D, et al. Shrinking lung syndrome and systemic lupus erythematosus: a case series
and literature review. QJM 2018; 111: 839–843.
94 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752–763.
95 Somers E, Magder LS, Petri M. Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of
patients with systemic lupus erythematosus. J Rheumatol 2002; 29: 2531–2536.
96 Amigues JM, Cantagrel A, Abbal M, et al. Comparative study of 4 diagnosis criteria sets for mixed connective
tissue disease in patients with anti-RNP antibodies. J Rheumatol 1996; 23: 2055–2062.
97 Kasukawa R. Mixed connective tissue disease. Intern Med 1999; 38: 386–393.
98 Ciang NCO, Pereira N, Isenberg DA. Mixed connective tissue disease – enigma variations? Rheumatology 2017;
56: 326–333.
250 https://doi.org/10.1183/2312508X.10018722
99 Dima A, Jurcut C, Baicus C. The impact of anti-U1-RNP positivity: systemic lupus erythematosus versus mixed
connective tissue disease. Rheumatol Int 2018; 38: 1169–1178.
100 Bodolay E, Szekanecz Z, Dévényi K, et al. Evaluation of interstitial lung disease in mixed connective tissue
disease (MCTD). Rheumatology 2005; 44: 656–661.
101 Gunnarsson R, Aaløkken TM, Molberg Ø, et al. Prevalence and severity of interstitial lung disease in mixed
connective tissue disease: a nationwide, cross-sectional study. Ann Rheum Dis 2012; 71: 1966–1972.
102 Gunnarsson R, Andreassen AK, Molberg Ø, et al. Prevalence of pulmonary hypertension in an unselected,
mixed connective tissue disease cohort: results of a nationwide, Norwegian cross-sectional multicentre study
and review of current literature. Rheumatology 2013; 52: 1208–1213.
103 Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease-associated pulmonary arterial hypertension
in the modern treatment era. Am J Respir Crit Care Med 2009; 179: 151–157.
104 Shirai Y, Yasuoka H, Okano Y, et al. Clinical characteristics and survival of Japanese patients with connective
tissue disease and pulmonary arterial hypertension: a single-centre cohort. Rheumatology 2012; 51: 1846–1854.
105 Chaigne B, Scirè CA, Talarico R, et al. Mixed connective tissue disease: state of the art on clinical practice
guidelines. RMD Open 2019; 4: Suppl. 1, e000783.
106 Martínez-Martínez MU, van Oostdam DAH, Abud-Mendoza C. Diffuse alveolar hemorrhage in autoimmune
diseases. Curr Rheumatol Rep 2017; 19: 27.
107 Lim SW, Gillis D, Smith W, et al. Rituximab use in systemic lupus erythematosus pneumonitis and a review of
current reports. Intern Med J 2006; 36: 260–262.
108 Rudwaleit M, van der Heijde D, Landewé R, et al. The development of Assessment of SpondyloArthritis
International Society classification criteria for axial spondyloarthritis ( part II): validation and final selection.
Ann Rheum Dis 2009; 68: 777–783.
109 Danve A. Thoracic manifestations of ankylosing spondylitis, inflammatory bowel disease, and relapsing
polychondritis. Clin Chest Med 2019; 40: 599–608.
110 Brambila-Tapia AJL, Rocha-Muñoz AD, Gonzalez-Lopez L, et al. Pulmonary function in ankylosing spondylitis:
association with clinical variables. Rheumatol Int 2013; 33: 2351–2358.
111 Berdal G, Halvorsen S, van der Heijde D, et al. Restrictive pulmonary function is more prevalent in patients
with ankylosing spondylitis than in matched population controls and is associated with impaired spinal
mobility: a comparative study. Arthritis Res Ther 2012; 14: R19.
112 Maghraoui A E, Dehhaoui M. Prevalence and characteristics of lung involvement on high resolution computed
tomography in patients with ankylosing spondylitis: a systematic review. BMC Pulm Med 2012; 2012: 965956.
113 Ho HH, Lin MC, Yu KH, et al. Pulmonary tuberculosis and disease-related pulmonary apical fibrosis in
ankylosing spondylitis. J Rheumatol 2009; 36: 355–360.
114 Yang TY, Chen YH, Siao WZ, et al. Case report: a rare manifestation of pulmonary arterial hypertension in
ankylosing spondylitis. J Pers Med 2022; 13: 62.
115 Vendramin I, de Gaspari M, Lechiancole A, et al. Unexpected aortitis mimicking an ascending aorta intramural
hematoma in ankylosing spondylitis. Circ Cardiovasc Imaging 2021; 14: e011014.
116 Li Z, Fu T, Wang Y, et al. Sleep disturbances in ankylosing spondylitis: a systematic review and meta-analysis.
Psychol Health Med 2019; 24: 911–924.
117 Solak O, Fidan F, Dundar U, et al. The prevalence of obstructive sleep apnoea syndrome in ankylosing
spondylitis patients. Rheumatology 2009; 48: 433–435.
118 Ward MM, Deodhar A, Gensler LS, et al. 2019 Update of the American College of Rheumatology/Spondylitis
Association of America/Spondyloarthritis Research and Treatment Network recommendations for the
treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol 2019; 71:
1599–1613.
119 Gordon H, Biancone L, Fiorino G, et al. ECCO guidelines on inflammatory bowel disease and malignancies.
J Crohns Colitis 2022; in press [https://doi.org/10.1093/ecco-jcc/jjac187].
120 Harbord M, Annese V, Vavricka SR, et al. The first European evidence-based consensus on extra-intestinal
manifestations in inflammatory bowel disease. J Crohns Colitis 2016; 10: 239–254.
121 Labarca G, Drake L, Horta G, et al. Association between inflammatory bowel disease and chronic obstructive
pulmonary disease: a systematic review and meta-analysis. BMC Pulm Med 2019; 19: 186.
122 Wang J, Kou F, Han X, et al. Inflammatory bowel disease and risk of idiopathic pulmonary fibrosis: a protocol
for systematic review and meta-analysis. PLoS One 2022; 17: e0270297.
123 Pemmasani G, Loftus EV, Tremaine WJ. Prevalence of pulmonary diseases in association with inflammatory
bowel disease. Dig Dis Sci 2022; 67: 5187–5194.
124 Desai D, Patil S, Udwadia Z, et al. Pulmonary manifestations in inflammatory bowel disease: a prospective
study. Indian J Gastroenterol 2011; 30: 225–228.
125 Kröner PT, Lee A, Farraye FA. Respiratory tract manifestations of inflammatory bowel disease. Inflamm Bowel
Dis 2021; 27: 563–574.
https://doi.org/10.1183/2312508X.10018722 251
126 Suzuki T, Tsushima K, Sakairi Y, et al. Severe tracheobronchial stenosis and bronchiectasis complicating
ulcerative colitis. Respirol Case Rep 2014; 2: 48–50.
127 Eliadou E, Moleiro J, Ribaldone DG, et al. Interstitial and granulomatous lung disease in inflammatory bowel
disease patients. J Crohns Colitis 2020; 14: 480–489.
128 Pedersen N, Duricova D, Munkholm P. Pulmonary Crohn’s disease: a rare extra-intestinal manifestation treated
with infliximab. J Crohns Colitis 2009; 3: 207–211.
129 Lu S, Wang L, Zhang W, et al. Ulcerative colitis with acute pleurisy: a case report and review of the literature.
Medicine 2017; 96: e7630.
130 Panagi S, Palka W, Korelitz BI, et al. Diffuse alveolar hemorrhage after infliximab treatment of Crohn’s disease.
Inflamm Bowel Dis 2004; 10: 274–277.
131 Spagnolo P, Bonniaud P, Rossi G, et al. Drug-induced interstitial lung disease. Eur Respir J 2022; 60: 2102776.
132 Freeman HJ, Davis JE, Prest ME, et al. Granulomatous bronchiolitis with necrobiotic pulmonary nodules in
Crohn’s disease. Can J Gastroenterol 2004; 18: 687–690.
133 Andrade AR, Barros LL, Azevedo MFC, et al. Risk of thrombosis and mortality in inflammatory bowel disease.
Clin Transl Gastroenterol 2018; 9: e142.
134 International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD). The
International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and
specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28: 338–347.
135 Tharwat S, ElAdle SS, Moshrif AH, et al. Computed tomography pulmonary angiography (CTPA) in Behçet’s
disease patients: a remarkable gender gap and time to refine the treatment strategy. Clin Rheumatol 2022; 41:
195–201.
136 Tuzun H, Seyahi E, Guzelant G, et al. Surgical treatment of pulmonary complications in Behçet’s syndrome.
Semin Thorac Cardiovasc Surg 2018; 30: 369–378.
137 Tsukui D, Hirohata S, Kikuchi H, et al. Histopathology of pulmonary thromboembolism in a patient with
Behçet’s disease. Clin Exp Rheumatol 2021; 40: 1584–1587.
138 Chung JW, Kim HC, Choi YH, et al. Patterns of aortic involvement in Takayasu arteritis and its clinical
implications: evaluation with spiral computed tomography angiography. J Vasc Surg 2007; 45: 906–914.
139 Seyahi E, Melikoglu M, Akman C, et al. Pulmonary artery involvement and associated lung disease in Behçet
disease: a series of 47 patients. Medicine 2012; 91: 35–48.
140 Zhang Y, Li N, Li Q, et al. Analysis of the clinical characteristics of 176 patients with pathologically confirmed
cryptogenic organizing pneumonia. Ann Transl Med 2020; 8: 763.
141 Yıldırım R, Oğuzman S, Dinler M, et al. Scoping beyond pulmonary artery involvement; pulmonary involvement
in Behcet’s disease; a retrospective analysis of 28 patients. Clin Rheumatol 2023; 42: 849–853.
142 Ceylan N, Bayraktaroglu S, Erturk SM, et al. Pulmonary and vascular manifestations of Behcet disease:
imaging findings. AJR Am J Roentgenol 2010; 194: W158–W164.
143 Kanne JP, Mohammed TLH. Fibrosing mediastinitis associated with Behçet’s disease: CT findings. Clin Radiol
2007; 62: 1124–1126.
144 Hatemi G, Christensen R, Bang D, et al. 2018 update of the EULAR recommendations for the management of
Behçet’s syndrome. Ann Rheum Dis 2018; 77: 808–818.
145 Numano F, Kakatu T. Takayasu arteritis – five doctors in the history of Takayasu arteritis. Int J Cardiol 1996;
54: Suppl., S1–S10.
146 Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/EULAR classification criteria
for Takayasu arteritis. Ann Rheum Dis 2022; 81: 1654–1660.
147 Seyahi E. Takayasu arteritis: an update. Curr Opin Rheumatol 2017; 29: 51–56.
148 Kong X, Zhang J, Lin J, et al. Pulmonary findings on high-resolution computed tomography in Takayasu
arteritis. Rheumatology 2021; 60: 5659–5667.
149 Yang J, Peng M, Shi J, et al. Pulmonary artery involvement in Takayasu’s arteritis: diagnosis before pulmonary
hypertension. BMC Pulm Med 2019; 19: 225.
150 Mukoyama H, Shirakashi M, Tanaka N, et al. The clinical features of pulmonary artery involvement in Takayasu
arteritis and its relationship with ischemic heart diseases and infection. Arthritis Res Ther 2021; 23: 293.
151 Huang Z, Wang M, Hu F, et al. Long-term outcomes after percutaneous transluminal pulmonary angioplasty in
patients with Takayasu arteritis and pulmonary hypertension. Front Immunol 2022; 13: 828863.
152 Jiang X, Zhu YJ, Zhou YP, et al. Clinical features and survival in Takayasu’s arteritis-associated pulmonary
hypertension: a nationwide study. Eur Heart J 2021; 42: 4298–4305.
153 Néji H, Gaja A, Hantous-Zannad S, et al. Imagerie de l’atteinte artérielle pulmonaire au cours de la maladie de
Takayasu. [Imaging of pulmonary artery involvement in Takayasu disease.] J Mal Vasc 2014; 39: 264–269.
154 Yazici A, Kaymaz-Tahra S, Ozdemir Isik O, et al. The prevalence of non-vascular pulmonary manifestations in
Takayasu’s arteritis patients: a retrospective multi-centred Turkish cohort study. Scand J Rheumatol 2022; 51:
304–308.
252 https://doi.org/10.1183/2312508X.10018722
155 Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for
the management of giant cell arteritis and Takayasu arteritis. Arthritis Rheumatol 2021; 73: 1349–1365.
156 Saadoun D, Bura-Riviere A, Comarmond C, et al. French recommendations for the management of Takayasu’s
arteritis. Orphanet J Rare Dis 2021; 16: 311.
157 Wells AU, Brown KK, Flaherty KR, et al. What’s in a name? That which we call IPF, by any other name would
act the same. Eur Respir J 2018; 51: 1800692.
158 Hilberg O, Hoffmann-Vold AM, Smith V, et al. Epidemiology of interstitial lung diseases and their
progressive-fibrosing behaviour in six European countries. ERJ Open Res 2022; 8: 00597-2021.
159 Nasser M, Larrieu S, Si-Mohamed S, et al. Progressive fibrosing interstitial lung disease: a clinical cohort (the
PROGRESS study). Eur Respir J 2021; 57: 2002718.
160 Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive
pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care
Med 2022; 205: e18–e47.
https://doi.org/10.1183/2312508X.10018722 253
Chapter 18
ANCA-associated vasculitis and other pulmonary

haemorrhage syndromes
Samuel Falde and Ulrich Specks
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.
Corresponding author: Samuel Falde (falde.samuel@mayo.edu)
Cite as: Falde S, Specks U. ANCA-associated vasculitis and other pulmonary haemorrhage syndromes. In: Wagner TOF,
@ERSpublications
ANCA-associated vasculitis most commonly causes diffuse alveolar haemorrhage. Prompt diagnosis and
effective remission induction improve outcomes. Advances in management include not using plasma
exchange, fewer glucocorticoids and C5a receptor antagonists. https://bit.ly/ERSM100
ISSN: 2312-5098.
Diffuse alveolar haemorrhage (DAH) syndromes are diverse entities with immune and nonimmune
aetiologies. ANCA-associated vasculitis (AAV) including granulomatous with polyangiitis and
microscopic polyangiitis are the most common subtypes of immune-mediated capillaritis resulting in
DAH. DAH has a variable clinical presentation, ranging from subacute constitutional symptoms to
fulminant respiratory failure. Bronchoscopy is critical to confirm the diagnosis and exclude mimics of
DAH. History, clinical features, laboratory studies and radiographic findings can help to clarify the
aetiology of DAH. Alveolar haemorrhage represents a severe manifestation of AAV requiring prompt
induction of remission. Current evidence favours induction therapy with rituximab over cyclophosphamide,
in addition to glucocorticoids. Results from recent randomised controlled trials support more rapid
tapering of glucocorticoids once remission is induced, and there is no support for the use of plasma
exchange in AAV with the exception being patients positive for both ANCA and anti-glomerular
basement membrane antibodies.
Evaluation of alveolar haemorrhage syndromes

Alveolar haemorrhage syndromes are characterised histopathologically by the extravasation of
red blood cells into alveolar spaces [1–4]. Diffuse alveolar haemorrhage (DAH) carries a broad
differential diagnosis. DAH syndromes can be separated into those with immune or nonimmune
causes (table 1) [1, 4]. Overall, the ANCA-associated vasculitis (AAV) syndromes of
granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the most
common aetiologies of immune-mediated pulmonary capillaritis resulting in DAH.
Syndromes lacking capillaritis can be subdivided into cases with diffuse alveolar damage and
bland haemorrhage. Early case series reported pooled in-hospital mortality in up to half of
patients with DAH [5, 6]. Advances in diagnostics, supportive care and disease-related
treatments have improved in-hospital mortality to 10–25% [7–9]. In this chapter, we describe a
framework for efficient evaluation, diagnosis and management of patients presenting with DAH,
emphasising AAV and recent therapeutic advances [10–15].
254 https://doi.org/10.1183/2312508X.10027822
PULMONARY HAEMORRHAGE SYNDROMES | S. FALDE AND U. SPECKS
TABLE 1 Classification of diffuse alveolar haemorrhage based on immune- and nonimmune-mediated

mechanisms
Immune-mediated Nonimmune-mediated
ANCA-associated vasculitis Cardiac disease

Isolated pulmonary capillaritis Left ventricular dysfunction
Anti-GBM antibody syndrome Valvular disease
Systemic lupus erythematosus Infection
Anti-phospholipid antibody syndrome Medications
Henoch–Schönlein purpura/IgA vasculitis Crack cocaine inhalation
Cryoglobulinaemia vasculitis Vaping
Behçet syndrome Acute respiratory disease syndrome
Rheumatoid arthritis Coagulopathy
Drug-induced vasculitis Radiation exposure
Drug-induced lupus Occupational exposures
Inflammatory myopathies Idiopathic pulmonary haemosiderosis
Acute lung transplant rejection Bone marrow transplantation
Hypocomplementemic urticarial vasculitis Pulmonary infarction
Bone marrow transplantation Thrombocytopenia
Infective endocarditis Organising pneumonia
GBM: glomerular basement membrane; Ig: immunoglobulin.
Clinical presentation
The clinical presentation of DAH is variable, ranging from asymptomatic (up to 30% of
patients) and lacking haemoptysis (up to 50% of patients) to rapid progression to respiratory
failure [7, 16, 17]. The tempo of illness development combined with other clinical features
provides clues for potential aetiologies of DAH. Patients with AAV often report a prodrome
lasting days to weeks of constitutional symptoms including fever, malaise, anorexia and
arthralgia [5, 12, 13, 17, 18]. Consequently, it is important to carefully obtain the history of
present illness and a review of systems, and to closely examine current/historical medications
and explore past medical/social history. Physical examination primarily serves to evaluate
manifestations of systemic autoimmune disease, cardiac pathology, coagulopathy or infection.
Diagnostic evaluation
Following initial clinical evaluation, we recommend blood and urine testing as listed in table 2
as soon as a diagnosis of DAH is considered.
Radiographic presentations of DAH are nonspecific and evolve during the disease course;
HRCT is the imaging of choice when alveolar haemorrhage is suspected [20]. The most
common radiographic patterns in DAH include diffuse bilateral ground-glass or consolidative
opacities distributed in the mid- to lower lung zones, with subpleural sparing (figure 1) [20–22].
As DAH resolves, deposition of haemosiderin can result in a “crazy-paving” pattern with
thickening of interlobular septa [20]. Bilateral pulmonary nodules or masses (often with
cavitation) should increase suspicion for AAV in the right clinical context.
Bronchoscopy with BAL is necessary to unequivocally establish a diagnosis of DAH.

Increasingly haemorrhagic return on serial BAL aliquots is most suggestive of DAH, as this
supports active bleeding from the alveolar–capillary interface [23]. BAL without a bloody return
can occur in DAH if bleeding is subclinical or has ceased [16]. In the absence of a
https://doi.org/10.1183/2312508X.10027822 255
TABLE 2 Recommended testing for the evaluation of diffuse alveolar haemorrhage

General testing
Complete blood count with differential
Coagulation testing (international normalised ratio/prothrombin time/partial thromboplastin time)
Erythrocyte sedimentation rate
C-reactive protein
Basic metabolic panel (with serum creatinine)
BNP/NT-proBNP
Urinalysis with microscopy
Autoimmune evaluation
ANCA#
Anti-glomerular basement membrane antibodies
Anti-nuclear antigen antibodies
Anti-double-stranded DNA antibodies
Rheumatoid factor
Anti-cyclic citrullinated peptide antobodies
Creatinine kinase
Anti-phospholipid antibodies (including anti-cardiolipin antibodies, anti-β2-glycoprotein, and/or lupus
anticoagulant)
Complement testing (C3, C4, CH50)
Cryoglobulins
Case-specific testing
Urine drug screen
Anti-histone antibodies
Coeliac serology (anti-tissue transglutaminase and anti-endomysial IgA)
Faecal calprotectin
The recommended tests include general testing to gauge the degree of inflammatory activity and other organ
involvement and specific autoimmune studies to identify specific aetiologies. BNP: B-type natriuretic peptide;
NT-proBNP: N-terminal proBNP; Ig: immunoglobulin. #: ANCA testing should be performed according to current
guidelines [19].
progressively bloody BAL return, iron staining identifying >20% of macrophages as

haemosiderin laden suggests DAH [24, 25]. However, this threshold of 20% originally reported
from immunocompromised patients is not specific for DAH or capillaritis, as it can be met in
other conditions including diffuse alveolar damage and pulmonary oedema [26, 27]. BAL
specimens should undergo microbiological testing to identify infections as precipitants or
mimics of DAH. An immunocompromised host panel is indicated in immunosuppressed
patients. We recommend close observation after bronchoscopy with BAL with a low threshold
to increase levels of care when respiratory failure progresses, as early intensive care unit
admission can reduce mortality and the duration of mechanical ventilation [28, 29].
Surgical lung biopsy can identify capillaritis in ∼88% of patients, but is rarely necessary for
treatment decisions informed by results from less invasive diagnostic testing such as serology or
biopsies from other organs [3, 4, 30–32].
Supportive management
A minority of patients with DAH can be evaluated and treated as outpatients [8, 16, 24].
However, as the progression of DAH is unpredictable, we generally advise supportive care in a
unit equipped to closely monitor patient trends and intensify support as needed. Those requiring
either invasive or noninvasive ventilation should be managed in line with current
recommendations for acute respiratory distress syndrome strategies [33].
256 https://doi.org/10.1183/2312508X.10027822
FIGURE 1 Example of HRCT obtained in a patient with diffuse alveolar haemorrhage due to ANCA-associated
vasculitis, showing consolidation and ground-glass opacities with hilar and mid-lung predominance but sparing
of most subpleural regions.
Empirical treatment
After ensuring adequate respiratory support, medical decision making should focus on fast
initiation of effective therapy to control the underlying disease process. An immune-mediated
condition causing DAH necessitates immediate implementation of high-dose glucocorticoid
therapy. PICARD et al. [13] developed a weighted scale to differentiate immune- and
nonimmune-mediated aetiologies of DAH. Four variables were most predictive of
immune-mediated mechanisms (table 3). A weighted score of ⩾4 demonstrated areas under the
curve of 0.913 and 0.95 in the observation and validation cohorts, respectively, with a
sensitivity of 1.00 and specificity of 0.88 [12, 13]. Thus, it has become standard practice at the
Mayo Clinic and at most centres in the USA and Europe to empirically initiate glucocorticoids
with intravenous methylprednisone (500–1000 mg i.v. daily) for those with two or more of the
variables in table 3 until the results of further diagnostic studies are obtained.
Additional interventions
Laboratory evidence of coagulopathy should be corrected to minimise the predisposition to
haemorrhage. Most accepted targets include a platelet count of >50 000 cells·μL–1 and an
international normalised ratio of <1.5. Case reports and small case series have reported the use
of recombinant factor VIIa (rFVIIa) as salvage therapy for DAH not responding to the
interventions described above [34–38]. The proposed mechanism of rFVIIa is to promote
haemostasis through thrombin generation via activated platelets and can be administered either
i.v. or bronchoscopically [39]. Limitations of i.v. rFVIIa include a short half-life, risk of
thrombosis and overall poor reported efficacy [35, 38]. Conversely, small case series suggest
TABLE 3 Factors associated with immune cause of diffuse alveolar haemorrhage
Variable Points
Time since onset of first respiratory symptoms ⩾11 days +2

Fatigue and/or weight loss +2
Arthralgias/arthritis +3
Proteinuria +3
https://doi.org/10.1183/2312508X.10027822 257
relative safety and evidence of efficacy of intrapulmonary rFVIIa [40]. We avoid the use of i.v.
rFVIIa, and intrapulmonary rFVIIa can be considered in select patients with refractory DAH,
but prospective trials are needed.
ANCA-associated vasculitis
Overview
AAV comprises a group of necrotising vasculitides predominantly involving small vessels
characterised by ANCA and lack of immune complex tissue deposition, with the three subtypes
being GPA, MPA and eosinophilic GPA (EGPA) [41]. The overall prevalence of AAV is 300–421
cases per million of the population [42–45]. Infectious, age-related, genetic, epigenetic and
environmental factors have all been implicated in the pathogenesis of AAV [45, 46]. A loss of
immune tolerance to myeloperoxidase (MPO) or proteinase 3 (PR3) allows persistence of
ANCA targeting either PR3 or MPO, which activate neutrophils and monocytes in an
inflammatory environment leading to capillaritis [45, 47–50]. Recent evidence indicates that the
interaction of activated complement factor 5 (C5a) with its receptor on neutrophils mediates
disease activity and can be targeted by novel therapeutic agents [15, 51–53].
Necrotising granulomatous inflammation most often involving the ears, nose and upper/lower
respiratory tracts are disease-defining features of GPA, setting it apart from MPA [45, 54–56].
MPA and GPA share small-vessel vasculitis and capillaritis involving the lungs, kidneys, eyes,
skin and peripheral nervous system [17, 43, 45]. EGPA is characterised by eosinophilia and
asthma, and often presents with small-vessel vasculitis [45, 57–59]. Respiratory manifestations
other than DAH are beyond the scope of this chapter; they have been reviewed in detail elsewhere,
and their management has not changed significantly over the course of the last decade [60, 61].
DAH
Despite AAV representing the majority of immune-mediated DAH, the frequency of DAH
varies substantially among the AAV syndromes. In GPA, 10–25% of patients experience
alveolar haemorrhage compared with 10–40% of those with MPA; DAH is rare in EGPA
(<5%), the majority of whom are MPO positive [8, 57, 61–64]. In patients with AAV who
develop DAH, it is detected at diagnosis in up to 80% of patients [5, 18, 28]. Pre-existing
airway disease (bronchiectasis or centrilobular nodules) has been identified as a risk factor for
developing DAH in MPA in one study [65]. A multivariate analysis identified several predictors
for progressive respiratory failure in patients with DAH due to AAV [8]. These included an
initial oxygen saturation/fraction of inspired oxygen ratio of <450, C-reactive protein
>25 mg·dL−1 and a neutrophil count of >30% on the BAL cell differential [8].
Treatment
General concepts
Remission induction therapy is guided by disease severity and evidence of disease activity in
AAV. Severe disease is defined as vasculitis with life- or organ-threatening manifestations such
as alveolar haemorrhage. After confirmation of DAH and initiation of high-dose glucocorticoid
therapy, guidelines for remission induction therapy call for the addition of rituximab or
cyclophosphamide [66–68]. Remission induction therapy is intended to rapidly reduce
inflammation and prevent worsening accumulation of end-organ damage. Prompt and effective
induction of remission is essential because renal recovery at 6 months and rates of renal relapse
correlate strongly with survival [69]. The intensity of immunosuppression to achieve remission
must be weighed against the associated risk of infection, which represents the leading cause of
death at 1 year [70–73].
258 https://doi.org/10.1183/2312508X.10027822
Rituximab and cyclophosphamide

In 2010, the RAVE (Rituximab versus cyclophosphamide for ANCA-associated vasculitis) and
RITUXIVAS (Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis) trials
demonstrated that rituximab was noninferior when compared with previous standard therapy with
cyclophosphamide [74, 75]. Furthermore, RAVE illustrated that rituximab was superior to
cyclophosphamide in patients with relapsing disease with a post-hoc analysis also favouring its use
for patients with PR3-ANCA [66, 74, 76]. Data from randomised controlled trials informing
remission induction strategies in patients with DAH due to AAV remain limited. Although patients
requiring mechanical ventilation were excluded from RAVE, 25% of patients enrolled in the trial had
DAH at presentation, and their treatment responses mirrored those of the entire trial cohort [74]. A
single-centre retrospective cohort study focusing on DAH in AAV that included 37 patients requiring
mechanical ventilation found no difference in early outcomes in this subset between rituximab and
cyclophosphamide treatment, but favoured rituximab over cyclophosphamide in achievement of
complete remission by 6 months [8]. Furthermore, a recent retrospective cohort study evaluating 467
patients with renal involvement (251 with severe kidney disease (estimated glomerular filtration rate
(eGFR) <30 ml·min−1·1.73 m−2)) demonstrated no significant difference in the end-point of
remission (Birmingham Vasculitis Activity Score/GPA=0) at 6 months [77]. Based on the available
data, guidelines now favour rituximab over cyclophosphamide for most patients with severe AAV,
including those presenting with DAH [67, 68].
Plasma exchange
Plasma exchange (PLEX) as an adjuvant therapy for patients with severe AAV disease
manifestations including DAH or renal failure has long been controversial. The rationale for
PLEX is predicated on our current understanding of the role of ANCA in the pathogenesis of
AAV [45, 78]. Supported by early encouraging observational studies, a randomised trial in 2007
compared PLEX with pulse i.v. methylprednisolone therapy in addition to oral glucocorticoids
and cyclophosphamide in patients with severe renal involvement [79, 80]. This trial found
improved renal recovery in patients receiving PLEX; however, longer-term follow-up of this trial
cohort demonstrated no patient or renal survival benefit of PLEX [80, 81]. Other retrospective
studies did not find any benefit of PLEX in patients with AAV and DAH [8, 17, 18, 28]. The
PEXIVAS (Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis) trial
formally evaluated PLEX in 704 newly diagnosed or relapsed patients with severe AAV [11].
Most patients had renal involvement and 191 patients had DAH. Patients were enrolled to
independently evaluate treatment with PLEX versus no PLEX as well as standard versus
reduced-dose glucocorticoids. The primary composite end-point was progression to end-stage
kidney disease or death. There was no benefit of PLEX on the primary end-point in the cohort or
any of the prespecified subgroups including those with DAH [11]. A subsequent meta-analysis of
trials using PLEX in AAV including PEXIVAS data demonstrated no benefit related to mortality,
clinical remission or adverse events when comparing PLEX with control [82]. As a response to
this trial, the American Society of Apheresis (ASFA) has downgraded the level of evidence for
PLEX in AAV, and the American College of Rheumatology/Vasculitis Foundation (ACR/VF)
and Kidney Disease Improving Global Outcomes (KDIGO) guidelines do not recommend the use
of PLEX in DAH in AAV [67, 68, 83]. Nevertheless, the only current consensus indication for
PLEX in AAV is for patients who simultaneously have anti-glomerular basement membrane
(GMB) antibodies. This subset of patients requires prompt initiation of PLEX, as their clinical
response and renal recovery is more characteristic of anti-GBM disease than AAV [84–86].
Glucocorticoids
Glucocorticoids have remained the backbone of remission induction therapy for patients with
severe disease manifestations including DAH and rapidly progressive glomerulonephritis.
https://doi.org/10.1183/2312508X.10027822 259
Therapy with i.v. methylprednisolone pulses (1000 mg·day−1 for 1–3 days) are often started
empirically if AAV is suspected, before the diagnosis has been confirmed [13]. Subsequently,
oral prednisone (starting at 1 mg·kg−1·day−1) is tapered gradually over the following
4–6 months [14, 74, 76]. While glucocorticoids are most effective in controlling the acute
disease activity, serious infections have been identified as the major cause of 1-year mortality in
AAV [70, 72, 73, 87, 88]. Therefore, reduced dosing or accelerated tapering regimens have been
investigated in randomised trials over the last decade. PEXIVAS illustrated that a reduced-dose
glucocorticoid regimen was noninferior compared with a standard dose regimen both for the
composite outcome (death and end-stage kidney disease) and for sustained remission [11].
Furthermore, the incidence of serious infections was significantly lower in the reduced-dose
group (incidence rate ratio 0.69, 95% CI 0.52–0.92) [11]. Table 4 shows an adapted table
regarding prednisone dosing in the PEXIVAS trial; further details are provided in the trial
protocol [11]. Another trial comparing high-dose versus low-dose glucocorticoid regimens in
addition to rituximab for remission induction in 140 newly diagnosed patients with MPA
without DAH and without significant renal dysfunction found the low-dose regimen to have
noninferior efficacy but a reduced infection rate [89]. The ACR/VF 2021 guidelines now
recommend reduced glucocorticoid dosing [67].
Complement inhibitors
The approval of avacopan as an adjunct to remission induction therapy of severe AAV
represents an advance, allowing a substantial reduction in glucocorticoid exposure. Avacopan,
an oral inhibitor of the C5a receptor (CD88) in the alternative complement pathway, has
demonstrated promising efficacy and safety results in phase II clinical trials [52, 53]. The
ADVOCATE (Avacopan for the treatment of ANCA-associated vasculitis) trial, a
double-blinded, placebo-controlled, phase III study, compared avacopan 30 mg twice daily with
a standardised glucocorticoid in severe AAV [15]. Primary outcomes were noninferiority of
disease remission at 26 weeks and this was sustained at 52 weeks. Notably, all patients received
up to 3 g of i.v. methylprednisone, and those in the avacopan group could be tapered off oral
glucocorticoids by week 4. Avacopan demonstrated noninferiority at week 26 and superiority at
week 52 [15]. Furthermore, secondary outcomes including a change in eGFR/albuminuria from
TABLE 4 Reduced-dose glucocorticoid regimen for oral prednisone adapted from the PEXIVAS (Plasma
exchange and glucocorticoids in severe ANCA-associated vasculitis) protocol
Week Reduced-dose glucocorticoid, mg
1 60
2 30
3–4 25
5–6 20
7–8 15
9–10 12.5
11–12 10
13–14 7.5
15–16 5
17–18 5
19–20 5
21–22 5
23–52 5
Further details are provided in the trial protocol, including weight-based dosing. Reproduced and modified
from [11] with permission.
260 https://doi.org/10.1183/2312508X.10027822
baseline, indices of glucocorticoid toxicity and quality of life favoured avacopan over
prednisone [15]. Although patients requiring intubation for DAH were excluded, patients with
severe disease manifestations in the avacopan group exhibited effective induction of remission,
despite receiving substantially less glucocorticoid (mean of 1349 mg versus 3655 mg). These
data have generated significant interest in the renal protective effects of avacopan, as well as the
potential to reduce the cumulative glucocorticoid exposure. There is currently no consensus on
how fast to discontinue glucocorticoids when avacopan is used, or on the duration of therapy; at
the Mayo Clinic, we are currently using avacopan following the trial protocol until further data
are available [15]. The use in patients with DAH is currently limited by the lack of a liquid oral
or i.v. formulation for use in intubated patients.
Maintenance
Once remission has been induced successfully, patients should receive remission maintenance
therapy, usually for ⩾18 months. The need for further maintenance needs to be determined
based on patient-specific risk profiles. The risk for relapse is significantly higher in patients
with PR3-ANCA than in those with MPO-ANCA [81]. Patients who turned ANCA negative
during remission therapy are at low or no risk for relapse for as long as ANCA remain negative.
Randomised controlled trials have established rituximab as the preferred remission maintenance
agent over azathioprine (and, by proxy, methotrexate or mycophenolate mofetil) after remission
induction with cyclophosphamide or rituximab [90–92]. Repeat maintenance doses can be given
on a schedule every 4 or 6 months, or individually timed with intervals being determined by the
recurrence of B-cells and ANCA [93, 94].
Prophylaxis
Finally, both remission induction and remission maintenance therapy should always be
accompanied by careful monitoring for drug toxicities, appropriate vaccination, use of
prophylaxis against Pneumocystis jirovecii pneumonia and osteoporosis.
Other alveolar haemorrhage syndromes

In this section, we will briefly review the management of other immune-mediated DAH
syndromes. The management strategies for these are derived primarily from experience in
AAV. There have been no controlled trials or large retrospective studies in these rare
syndromes to further guide treatment, but the principles of remission induction therapies for
AAV have been found to be of merit in small series of patients with these conditions
[95, 96]. Furthermore, supportive care paradigms and empirical initiation of glucocorticoids
apply in these cases [13].
Anti-GBM disease
Anti-GBM disease is classified as a small-vessel vasculitis mediated by antibodies directed
towards type IV collagen in the basement membranes of glomeruli and alveoli [97]. Overall,
90% of patients present with glomerulonephritis, 50% with pulmonary renal syndrome and only
10% with isolated pulmonary involvement. High-dose glucocorticoids and PLEX should be
initiated as soon as possible; cyclophosphamide and rituximab have been used to prevent
antibody recurrence. Although renal survival is variable (dependent on renal function at
presentation), in-hospital mortality is low (<10%) and so is the relapse risk [84, 85, 97].
Primary anti-phospholipid antibody syndrome

DAH is a rare and poorly understood manifestation of primary anti-phospholipid antibody
syndrome. It is probably caused by capillaritis and is often accompanied by thrombotic changes
https://doi.org/10.1183/2312508X.10027822 261
on biopsy [98]. No prospective trials have been conducted, but retrospective series suggest that
rituximab or cyclophosphamide (sometimes in combination) are the most effective for induction
of remission [96, 98].
Isolated pauci-immune pulmonary capillaritis

Isolated pauci-immune pulmonary capillaritis (IPC) presents with alveolar haemorrhage in the
absence of systemic symptoms or circulating ANCA, although an autoimmune aetiology is
suspected [99]. The diagnosis requires biopsy confirmation of capillaritis after AAV and other
aetiologies have been excluded. Patients typically respond well to remission induction therapy
with glucocorticoids combined with rituximab, and the overall prognosis is fair [100, 101].
Idiopathic pulmonary haemosiderosis

Idiopathic pulmonary haemosiderosis (IPH) is typically a paediatric syndrome, representing a
diagnosis of exclusion in adults. Histologically, IPH can be differentiated from IPC by lacking
capillaritis and having an abundance of haemosiderin-laden macrophages. Recurrent episodes of
pulmonary haemorrhage may result in chronic anaemia. However, iron deficiency is not caused
by recurrent DAH but by malabsorption and should prompt evaluation for coeliac disease, even
without gastrointestinal symptoms. The association of IPH with coeliac disease is referred to as
Lane–Hamilton syndrome [102]. Serological evaluation to screen for coeliac disease and
endoscopic small-bowel biopsy should be pursued in patients with IPH and iron deficiency.
Gluten-free diets, glucocorticoids and other immunosuppressants have demonstrated modest
efficacy in these patients [103].
Haematopoietic stem-cell transplantation

Alveolar haemorrhage is rare after haematopoietic stem-cell transplantation (HSCT), occurring
in 2–14% of patients. Nevertheless, it is one of the most feared complications of HSCT,
carrying a mortality of 40–80% [104, 105]. This entity remains poorly understood, with both
immune and nonimmune aetiologies being proposed, although no clear immune mechanism has
been identified [34]. Risk factors for DAH in HSCT include a dose of myeloablative total-body
radiation, advanced age, delayed engraftment and graft failure [104, 105]. Typically, DAH
occurs within several days to 2 weeks of neutrophil engraftment. Glucocorticoids are widely
accepted as the initial therapy, although efficacy data are limited. Treatment with aminocaproic
acid (an antifibrinolytic agent) and intrapulmonary application of rFVIIa has been described in
refractory cases [35, 40, 106].
Conclusion
Alveolar haemorrhage syndromes represent diverse pathologies with variable clinical
presentations. A clinical framework to rapidly differentiate these syndromes based on history,
examination, laboratory studies, serology and imaging is provided. Bronchoscopy should be
performed in all but rare instances to confirm DAH. High-dose glucocorticoid therapy should be
initiated once an immune-mediated aetiology is suspected based on history and clinical findings.
AAV is the most common cause of immune-mediated capillaritis, and DAH is a severe disease
manifestation of AAV, for which rituximab is now preferred over cyclophosphamide for
induction of remission. There is no longer any evidence supporting PLEX for DAH caused by
AAV, except for patients who test positive for anti-GBM at the same time. Once remission has
been induced, more rapid glucocorticoid tapering regimens are now favoured, hoping to mitigate
the risk of serious infections. Avacopan, a C5a receptor inhibitor that was noninferior to
glucocorticoids for remission induction, holds promise to improve outcomes of severe AAV,
with substantially reduced glucocorticoid use and toxicity.
262 https://doi.org/10.1183/2312508X.10027822
References
1 Colby TV, Fukuoka J, Ewaskow SP, et al. Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol
2001; 5: 309–319.
2 Bosch X, López-Soto A, Mirapeix E, et al. Antineutrophil cytoplasmic autoantibody-associated alveolar
capillaritis in patients presenting with pulmonary hemorrhage. Arch Pathol Lab Med 1994; 118: 517–522.
3 Travis WD, Hoffman GS, Leavitt RY, et al. Surgical pathology of the lung in Wegener’s granulomatosis: review
of 87 open lung biopsies from 67 patients. Am J Surg Pathol 1991; 15: 315–333.
4 Travis WD, Colby TV, Lombard C, et al. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage
with lung biopsy confirmation. Am J Surg Pathol 1990; 14: 1112–1125.
5 Gallagher H, Kwan JTC, Jayne DRW. Pulmonary renal syndrome: a 4-year, single-center experience. Am J
Kidney Dis 2002; 39: 42–47.
6 Leatherman JW, Davies SF, Hoidal JR. Alveolar hemorrhage syndromes: diffuse microvascular lung
hemorrhage in immune and idiopathic disorders. Medicine (Baltimore) 1984; 63: 343–361.
7 de Prost N, Parrot A, Picard C, et al. Diffuse alveolar haemorrhage: factors associated with in-hospital and
long-term mortality. Eur Respir J 2010; 35: 1303–1311.
8 Cartin-Ceba R, Diaz-Caballero L, Al-Qadi MO, et al. Diffuse alveolar hemorrhage secondary to antineutrophil
cytoplasmic antibody-associated vasculitis: predictors of respiratory failure and clinical outcomes. Arthritis
Rheumatol 2016; 68: 1467–1476.
9 da Silva RC, Adhikari P. Granulomatosis with polyangiitis presenting with diffuse alveolar hemorrhage: a
systematic review. Cureus 2022; 14: e29909.
10 Casal Moura M, Irazabal MV, Eirin A, et al. Efficacy of rituximab and plasma exchange in antineutrophil
cytoplasmic antibody-associated vasculitis with severe kidney disease. J Am Soc Nephrol 2020; 31: 2688–2704.
11 Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis.
N Engl J Med 2020; 382: 622–631.
12 de Prost N, Parrot A, Cuquemelle E, et al. Immune diffuse alveolar hemorrhage: a retrospective assessment of
a diagnostic scale. Lung 2013; 191: 559–563.
13 Picard C, Cadranel J, Porcher R, et al. Alveolar haemorrhage in the immunocompetent host: a scale for early
diagnosis of an immune cause. Respiration 2010; 80: 313–320.
14 Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis.
N Engl J Med 2013; 369: 417–427.
15 Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J
Med 2021; 384: 599–609.
16 Lara AR, Schwarz MI. Diffuse alveolar hemorrhage. Chest 2010; 137: 1164–1171.
17 Tang S, Li X, Zhao KY, et al. Clinical characteristics and prognostic analysis of microscopic polyangiitis with
diffuse alveolar hemorrhage. J Rheumatol 2021; 48: 410–416.
18 Hruskova Z, Casian AL, Konopasek P, et al. Long-term outcome of severe alveolar haemorrhage in
ANCA-associated vasculitis: a retrospective cohort study. Scand J Rheumatol 2013; 42: 211–214.
19 Bossuyt X, Cohen Tervaert JW, Arimura Y, et al. Position paper: Revised 2017 international consensus on testing
of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nat Rev Rheumatol 2017; 13: 683–692.
20 Castañer E, Alguersuari A, Gallardo X, et al. When to suspect pulmonary vasculitis: radiologic and clinical
clues. RadioGraphics 2010; 30: 33–53.
21 Primack SL, Miller RR, Müller NL. Diffuse pulmonary hemorrhage: clinical, pathologic, and imaging features.
AJR Am J Roentgenol 1995; 164: 295–300.
22 Reisman S, Chung M, Bernheim A. A review of clinical and imaging features of diffuse pulmonary hemorrhage.
23 Robbins RA, Linder J, Stahl MG, et al. Diffuse alveolar hemorrhage in autologous bone marrow transplant
recipients. Am J Med 1989; 87: 511–518.
24 de Lassence A, Fleury-Feith J, Escudier E, et al. Alveolar hemorrhage. Diagnostic criteria and results in 194
immunocompromised hosts. Am J Respir Crit Care Med 1995; 151: 157–163.
25 Kahn FW, Jones JM, England DM. Diagnosis of pulmonary hemorrhage in the immunocompromised host. Am
Rev Respir Dis 1987; 136: 155–160.
26 Maldonado F, Parambil JG, Yi ES, et al. Haemosiderin-laden macrophages in the bronchoalveolar lavage fluid
of patients with diffuse alveolar damage. Eur Respir J 2009; 33: 1361–1366.
27 Grebski E, Hess T, Hold G, et al. Diagnostic value of hemosiderin-containing macrophages in bronchoalveolar
lavage. Chest 1992; 102: 1794–1799.
28 Mirouse A, Parrot A, Audigier V, et al. Severe diffuse alveolar hemorrhage related to autoimmune disease: a
multicenter study. Critical Care 2020; 24: 231.
29 Dumas G, Géri G, Montlahuc C, et al. Outcomes in critically ill patients with systemic rheumatic disease: a
multicenter study. Chest 2015; 148: 927–935.
https://doi.org/10.1183/2312508X.10027822 263
30 Cordier JF, Cottin V. Alveolar hemorrhage in vasculitis: primary and secondary. Semin Respir Crit Care Med
2011; 32: 310–321.
31 Mark EJ, Matsubara O, Tan-Liu NS, et al. The pulmonary biopsy in the early diagnosis of Wegener’s
( pathergic) granulomatosis: a study based on 35 open lung biopsies. Hum Pathol 1988; 19: 1065–1071.
32 Schnabel A, Holl-Ulrich K, Dalhoff K, et al. Efficacy of transbronchial biopsy in pulmonary vaculitides. Eur
Respir J 1997; 10: 2738–2743.
33 Fan E, Del Sorbo L, Goligher EC, et al. An official American Thoracic Society/European Society of Intensive
Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult
patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2017; 195: 1253–1263.
34 Pastores SM, Papadopoulos E, Voigt L, et al. Diffuse alveolar hemorrhage after allogeneic hematopoietic
stem-cell transplantation: treatment with recombinant factor VIIa. Chest 2003; 124: 2400–2403.
35 Elinoff JM, Bagci U, Moriyama B, et al. Recombinant human factor VIIa for alveolar hemorrhage following
allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2014; 20: 969–978.
36 Shenoy A, Savani BN, Barrett AJ. Recombinant factor VIIa to treat diffuse alveolar hemorrhage following
allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2007; 13: 622–623.
37 Betensley AD, Yankaskas JR. Factor VIIa for alveolar hemorrhage in microscopic polyangiitis. Am J Respir Crit
Care Med 2002; 166: 1291–1292.
38 Pathak V, Kuhn J, Gabriel D, et al. Use of activated factor VII in patients with diffuse alveolar hemorrhage: a
10 years institutional experience. Lung 2015; 193: 375–379.
39 Loecher AM, West K, Quinn TD, et al. Management of diffuse alveolar hemorrhage in the hematopoietic stem
cell transplantation population: a systematic review. Pharmacotherapy 2021; 41: 943–952.
40 Baker MS, Diab KJ, Carlos WG, et al. Intrapulmonary recombinant factor VII as an effective treatment for
diffuse alveolar hemorrhage: a case series. J Bronchology Interv Pulmonol 2016; 23: 255–258.
41 Jennette J, Falk R, Bacon P, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature
of Vasculitides. Arthritis Rheum 2013; 65: 1–11.
42 Mohammad AJ, Jacobsson LTH, Mahr AD, et al. Prevalence of Wegener’s granulomatosis, microscopic
polyangiitis, polyarteritis nodosa and Churg–Strauss syndrome within a defined population in southern
Sweden. Rheumatology (Oxford) 2007; 46: 1329–1337.
43 Watts RA, Mahr A, Mohammad AJ, et al. Classification, epidemiology and clinical subgrouping of antineutrophil
cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant 2015; 30: Suppl. 1, i14–i22.
44 Berti A, Cornec D, Crowson CS, et al. The epidemiology of ANCA associated vasculitis in Olmsted County,
Minnesota (USA): a 20-year population-based study. Arthritis Rheumatol 2017; 69: 2338–2350.
45 Kitching AR, Anders HJ, Basu N, et al. ANCA-associated vasculitis. Nat Rev Dis Primers 2020; 6: 71.
46 Kimoto Y, Horiuchi T. The complement system and ANCA associated vasculitis in the era of anti-complement
drugs. Front Immunol 2022; 13: 926044.
47 Falk RJ, Terrell RS, Charles LA, et al. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to
degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A 1990; 87: 4115–4119.
48 Savage CO, Pottinger BE, Gaskin G, et al. Autoantibodies developing to myeloperoxidase and proteinase 3 in
systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol 1992; 141:
335–342.
49 Huugen D, Xiao H, van Esch A, et al. Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis
by bacterial lipopolysaccharide: role of tumor necrosis factor-α. Am J Pathol 2005; 167: 47–58.
50 Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause
glomerulonephritis and vasculitis in mice. J Clin Invest 2002; 110: 955–963.
51 Xiao H, Schreiber A, Heeringa P, et al. Alternative complement pathway in the pathogenesis of disease
mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol 2007; 170: 52–64.
52 Merkel PA, Niles J, Jimenez R, et al. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in
patients with antineutrophil cytoplasmic antibody-associated vasculitis. ACR Open Rheumatol 2020; 2: 662–671.
53 Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized trial of C5a receptor inhibitor avacopan in
ANCA-associated vasculitis. J Am Soc Nephrol 2017; 28: 2756–2767.
54 Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med
1992; 116: 488–498.
55 Daum TE, Specks U, Colby TV, et al. Tracheobronchial involvement in Wegener’s granulomatosis. Am J Respir
Crit Care Med 1995; 151: 522–526.
56 Robson JC, Grayson PC, Ponte C, et al. 2022 American College of Rheumatology/European Alliance of Associations
for Rheumatology classification criteria for granulomatosis with polyangiitis. Ann Rheum Dis 2022; 81: 315–320.
57 Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss):
clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study
Group cohort. Arthritis Rheum 2013; 65: 270–281.
264 https://doi.org/10.1183/2312508X.10027822
58 Keogh KA, Specks U. Churg–Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies,
and leukotriene receptor antagonists. Am J Med 2003; 115: 284–290.
59 Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of
Associations for Rheumatology classification criteria for eosinophilic granulomatosis with polyangiitis. Ann
Rheum Dis 2022; 81: 309–314.
60 Nelson D, Specks U. Granulomatosis with polyangiitis (Wegener’s). Orphan Lung Dis 2011; 54: 1–14.
61 Thompson GE, Specks U. Update on the management of respiratory manifestations of the antineutrophil
cytoplasmic antibodies-associated vasculitides. Clin Chest Med 2019; 40: 573–582.
62 Niles JL, Böttinger EP, Saurina GR, et al. The syndrome of lung hemorrhage and nephritis is usually an
ANCA-associated condition. Arch Intern Med 1996; 156: 440–445.
63 Moura MC, Specks U. Lung involvement in ANCA-associated vasculitis. In: Rare Diseases of the Immune
System. Berlin, Springer Nature, 2020; pp. 163–176.
64 Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic
antibodies in Churg–Strauss syndrome. Arthritis Rheum 2005; 52: 2926–2935.
65 Kida T, Tanaka T, Yokota I, et al. Association between preexisting lung involvements and the risk of diffuse
alveolar hemorrhage in patients with microscopic polyangiitis: a multi-center retrospective cohort study.
Modern Rheumatol 2020; 30: 338–344.
66 Yates M, Watts RA, Bajema IM, et al. EULAR/ERA-EDTA recommendations for the management of
ANCA-associated vasculitis. Ann Rheum Dis 2016; 75: 1583–1594.
67 Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline
for the management of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Care Res 2021; 73:
1088–1105.
68 Rovin BH, Adler SG, Barratt J, et al. Executive summary of the KDIGO 2021 guideline for the management of
glomerular diseases. Kidney Int 2021; 100: 753–779.
69 de Joode AAE, Sanders JSF, Stegeman CA. Renal survival in proteinase 3 and myeloperoxidase
ANCA-associated systemic vasculitis. Clin J Am Soc Nephrol 2013; 8: 1709–1717.
70 Mohammad AJ, Segelmark M, Smith R, et al. Severe infection in antineutrophil cytoplasmic
antibody-associated vasculitis. J Rheumatol 2017; 44: 1468–1475.
71 Rathmann J, Jayne D, Segelmark M, et al. Incidence and predictors of severe infections in ANCA-associated
vasculitis: a population-based cohort study. Rheumatology (Oxford) 2021; 60: 2745–2754.
72 Garcia-Vives E, Segarra-Medrano A, Martinez-Valle F, et al. Prevalence and risk factors for major infections in
patients with antineutrophil cytoplasmic antibody-associated vasculitis: influence on the disease outcome.
J Rheumatol 2020; 47: 407–414.
73 Flossmann O, Berden A, de Groot K, et al. Long-term patient survival in ANCA-associated vasculitis. Ann
Rheum Dis 2011; 70: 488–494.
74 Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
N Engl J Med 2010; 363: 221–232.
75 Jones RB, Tervaert JWC, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal
vasculitis. N Engl J Med 2010; 363: 211–220.
76 Miloslavsky EM, Specks U, Merkel PA, et al. Clinical outcomes of remission induction therapy for severe
antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2013; 65: 2441–2449.
77 Geetha D, Specks U, Stone JH, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis with
renal involvement. J Am Soc Nephrol 2015; 26: 976–985.
78 Lionaki S, Falk RJ. Removing antibody and preserving glomeruli in ANCA small-vessel vasculitis. J Am Soc
Nephrol 2007; 18: 1987–1989.
79 Klemmer PJ, Chalermskulrat W, Reif MS, et al. Plasmapheresis therapy for diffuse alveolar hemorrhage in
patients with small-vessel vasculitis. Am J Kidney Dis 2003; 42: 1149–1153.
80 Jayne DRW, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage
methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007; 18: 2180–2188.
81 Walsh M, Casian A, Flossmann O, et al. Long-term follow-up of patients with severe ANCA-associated vasculitis
comparing plasma exchange to intravenous methylprednisolone treatment is unclear. Kidney Int 2013; 84: 397–402.
82 Yamada Y, Harada M, Hara Y, et al. Efficacy of plasma exchange for antineutrophil cytoplasmic
antibody-associated systemic vasculitis: a systematic review and meta-analysis. Arthritis Res Ther 2021; 23: 28.
83 Balogun RA, Sanchez AP, Klingel R, et al. Update to the ASFA guidelines on the use of therapeutic apheresis in
ANCA-associated vasculitis. J Clin Apher 2020; 35: 493–499.
84 Savage CO, Pusey CD, Bowman C, et al. Antiglomerular basement membrane antibody mediated disease in
the British Isles 1980-4. Br Med J 1986; 292: 301–304.
85 Briggs WA, Johnson JP, Teichman S, et al. Antiglomerular basement membrane antibody-mediated
glomerulonephritis and Goodpasture’s syndrome. Medicine (Baltimore) 1979; 58: 348–361.
https://doi.org/10.1183/2312508X.10027822 265
86 McAdoo SP, Tanna A, Hrušková Z, et al. Patients double-seropositive for ANCA and anti-GBM antibodies have
varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients. Kidney Int
2017; 92: 693–702.
87 Floyd L, Morris A, Joshi M, et al. Glucocorticoid therapy in ANCA vasculitis: using the glucocorticoid toxicity
index as an outcome measure. Kidney360 2021; 2: 1002–1010.
88 Walsh M, Merkel PA, Mahr A, et al. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil
cytoplasmic antibody-associated vasculitis: a meta-analysis. Arthritis Care Res 2010; 62: 1166–1173.
89 Furuta S, Nakagomi D, Kobayashi Y, et al. Effect of reduced-dose vs high-dose glucocorticoids added to
rituximab on remission induction in ANCA-associated vasculitis: a randomized clinical trial. JAMA 2021; 325:
2178–2187.
90 Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated
91 Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in
antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA 2010; 304:
2381–2388.
92 Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated
93 Charles P, Terrier B, Perrodeau É, et al. Comparison of individually tailored versus fixed-schedule rituximab
regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled,
phase III trial (MAINRITSAN2). Ann Rheum Dis 2018; 77: 1143–1149.
94 Pierre C, Perrodeau É, Samson M, et al. Long-term rituximab use to maintain remission of antineutrophil
cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2020; 173: 179–187.
95 McAdoo SP, Pusey CD. Antiglomerular basement membrane disease. Semin Respir Crit Care Med 2018; 39: 494–503.
96 Stoots SA, Lief L, Erkan D. Clinical insights into diffuse alveolar hemorrhage in antiphospholipid syndrome.
Curr Rheumatol Rep 2019; 21: 56.
97 Levy JB, Turner AN, Rees AJ, et al. Long-term outcome of anti-glomerular basement membrane antibody
disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001; 134: 1033–1042.
98 Waterer G, Latham B, Waring J, et al. Pulmonary capillaritis associated with the antiphospholipid antibody
syndrome and rapid response to plasmapheresis. Respirology 1991; 4: 405–408.
99 Jennings CA, King TE, Tuder R, et al. Diffuse alveolar hemorrhage with underlying isolated, pauciimmune
pulmonary capillaritis. Am J Respir Crit Care Med 1997; 155: 1101–1109.
100 Thompson G, Specks U, Cartin-Ceba R. Isolated pauciimmune pulmonary capillaritis successfully treated with
rituximab. Chest 2015; 147: e134–e136.
101 Thompson G, Klecka M, Roden A, et al. Biopsy-proven pulmonary capillaritis: a retrospective study of
aetiologies including an in-depth look at isolated pulmonary capillaritis. Respirology 2016; 21: 734–738.
102 Loachimescu OC, Sieber S, Kotch A. Idiopathic pulmonary haemosiderosis revisited. Eur Respir J 2004; 24:
162–169.
103 Chen XY, Sun JM, Huang XJ. Idiopathic pulmonary hemosiderosis in adults: review of cases reported in the
latest 15 years. Clin Respir J 2017; 11: 677–681.
104 Haider S, Durairajan N, Soubani AO. Noninfectious pulmonary complications of haematopoietic stem cell
transplantation. Eur Respir Rev 2020; 29: 190119.
105 Abdulai R, Cartin-Ceba R. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients:
10-year experience in a single center. Chest 2013; 144: 1019A.
106 Rathi NK, Tanner AR, Dinh A, et al. Low-, medium- and high-dose steroids with or without aminocaproic acid in
adult hematopoietic SCT patients with diffuse alveolar hemorrhage. Bone Marrow Transplant 2015; 50: 420–426.
Disclosures: S. Falde has nothing to disclose. U. Specks reports receiving the following outside the submitted
work: research grants from Genentech, Bristol Myer Squibb, AstraZeneca and GSK; and consulting fees from
ChemoCentryx, AstraZeneca and Boehringer Ingelheim.
266 https://doi.org/10.1183/2312508X.10027822
Chapter 19
Eosinophilic granulomatosis with polyangiitis

Yann Nguyen and Loïc Guillevin
Referral Center for Rare Systemic and Autoimmune Diseases, Dept of Internal Medicine, Hôpital Cochin, APHP,
Université Paris Descartes, Paris, France.
Corresponding author: Loïc Guillevin (loic.guillevin@orange.fr)
Cite as: Nguyen Y, Guillevin L. Eosinophilic granulomatosis with polyangiitis. In: Wagner TOF, Humbert M,
@ERSpublications
Eosinophilic granulomatosis with polyangiitis is a vasculitis occurring in patients with asthma. New
treatments targeting interleukin-5 and other cytokines could revolutionise treatment while reducing use of
corticosteroids and their side-effects. https://bit.ly/ERSM100
ISSN: 2312-5098.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis that primarily
affects small- and medium-sized blood vessels. It is characterized by the presence of asthma and
increased levels of eosinophils in the blood. While the presence of ANCA is not always observed,
EGPA is classified as an ANCA-associated vasculitis, primarily affecting small-sized blood vessels.
Although some clinical phenotypes and pathogenic mechanisms of this rare disease have been
described, there are still gaps in our understanding of the condition. Recent advancements in EGPA
management involve the use of various novel immunomodulatory drugs and biotherapies, which have
been or are currently being assessed for their effectiveness. This chapter addresses the epidemiology,
pathophysiology, clinical manifestations, outcomes and available therapeutic options for EGPA,
including potential future treatments.
Introduction
Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotising vasculitis of
small- and medium-sized vessels. EGPA is classified as an ANCA-associated vasculitis (AAV),
even though ANCA are not always detected. Its main characteristics are asthma, blood
eosinophilia and extrapulmonary manifestations [1–3]. In this chapter, we will discuss the
clinical aspects, outcomes and treatments for EGPA.
Epidemiology
Incidence and prevalence
EGPA prevalence worldwide ranges from 7.3 to 17.8 cases per million of the population [4, 5],
with an annual incidence of 0.9–2.4 cases per million [6, 7]. The mean age at diagnosis is
∼50 years [8].
Triggering factors
The quasi-constant asthma prodrome has led to allergens being suspected EGPA triggers, but
the pre-existing allergy rate is similar to that observed in the general population [9]. Many
https://doi.org/10.1183/2312508X.10004223 267
environmental factors are suspected but not confirmed EGPA triggers, such as inhaled antigens
(e.g. diesel fumes, grain dust, cereal dust, dust), desensitisation and immunisation [10, 11].
Leukotriene-receptor antagonists (e.g. montelukast and zafirlukast) and, more recently, anti-IgE
antibodies (e.g. omalizumab) have been considered potential triggers; however, their true
implication remains undetermined.
Clinical manifestations
General symptoms
Constitutional symptoms commonly precede overt systemic manifestations (table 1). In one
series, 50% of patients lost weight, 39% had fever or myalgias, and 30% had arthralgias [8].
Pulmonary symptoms
Asthma affects 91–100% of patients with EGPA, usually preceding systemic vasculitis (mean
asthma duration 9.3±10.8 years [8]). Indeed, asthma is one of the classification criteria of the
American College of Rheumatology (ACR) (table 2) [2]. Asthma onset often starts at ∼30–
40 years of age, but childhood onset is not unknown. Among patients treated for asthma, EGPA
incidence was 34.6 (range 21.4–53) cases per million person-years in one study [19]. Their
asthma was usually severe and glucocorticoid dependent.
Alveolar haemorrhage is uncommon in EGPA (4%) but can nonetheless be severe with massive
haemoptysis. Lung infiltrates are common (38.6%) and often regress after initiating
glucocorticoids [20].
Ear, nose and throat symptoms

Maxillary sinusitis, nasal polyposis and allergic rhinitis are common chronic ear, nose and
throat (ENT) symptoms. Polyposis and rhinitis, despite being considered EGPA symptoms,
usually precede overt vasculitis. In our opinion, they reflect an underlying predisposition to the
vasculitis, which renders these patients more likely to develop such symptoms.
Neurological symptoms
Peripheral neuropathies, mainly mononeuritis multiplex, are frequent, occurring in 46–75% of
EGPA patients [8], affecting the common peroneal nerve and/or internal popliteal nerve, and
then the radial, cubital and/or median, and cranial nerves [8]. Sequelae may indicate a poorer
functional outcome. The central nervous system is only rarely involved (5.2% in our series [8]),
with cerebral vasculitis.
Gastrointestinal symptoms
Gastrointestinal involvement is a poor-prognosis item [21, 22]. Abdominal pain (30–60%),
diarrhoea, nausea, vomiting and/or intestinal haemorrhage are often nonspecific. Bowel
perforation is associated with high mortality rates [23], and surgery may be necessary [15].
Cardiac symptoms
Heart involvement is strongly associated with death [21] and is the primary cause of EGPA
patient mortality. It manifests as pericarditis (15.1%), arterial hypertension, valvopathy,
eosinophilic myocarditis and/or congestive heart failure (16.4%) [8]. Indeed, 31% of the deaths
in our series were attributed to cardiac involvement [8]. In patients in remission, cardiac
involvement may persist, but most patients are asymptomatic [24].
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https://doi.org/10.1183/2312508X.10004223
TABLE 1 Clinical characteristics of patients with eosinophilic granulomatosis with polyangiitis, reported in the main published series
Characteristic First author [ref.]

CHUMBLEY LANHAM GUILLEVIN GASKIN GUILLEVIN SOLANS COMARMOND DUREL BETTIOL
[12] [13] [11] [14] [15] [16] COMARMOND [8] [17] [18]
Patient demographics
Patients, n 30 16 43 21 96 32 383 101 203
Male/female ratio, n 21/9 12/4 24/19 14/7 45/51 9/23 199/184 43/58 87/116
Mean age (range), years 47 (15–69) 38 43.2 (7–66) 46.5 (23–69) 48.2 (17–74) 42 (17–85) 50.3 (35–66) 49.2 59.1 (38–57)
Clinical features
General symptoms 72 70 69 28
Arthritis, arthralgias 20 51 28 43 41 29.8 68.3
Myalgias 68 54 38.9 82.2
Allergic rhinitis and/or ENT involvement 70 70 21 47 48 96 71
Asthma 100 100 100 100 100 100 91.1 53.4 92
Pulmonary infiltrates 27 72 77 43 38 53 38.6 53.5
Pleural effusion 29 19 8.9 3
Skin involvement 67 50 51 69 39.7 46.5
Purpura 48 28 31 41 22.5 24.7 7
EGPA | Y. NGUYEN AND L. GUILLEVIN

Nodules 27 30 21 19 6 9.7 8.9
Mononeuritis multiplex 63 66 67 70 78 44 46 54.5 23
GI involvement 17 59 37 58 33 38 23.2 25 4
CV involvement 16 47 49 15 30 28 27.4 20.8 5
Renal involvement 20 49 16 80 16 13 21.7 26 2.5
Values are expressed as percentages, unless otherwise stated. ENT: ear, nose and throat; GI: gastrointestinal; CV: cardiovascular.
269
TABLE 2 1990 American College of Rheumatology classification criteria for eosinophilic granulomatosis
with polyangiitis
Criterion Definition
Asthma History of wheezing or diffuse high-pitched rales on expiration

Eosinophilia Eosinophilia >10% of white blood cell differential count
Mononeuropathy or Development of mononeuropathy, multiple mononeuropathies or
polyneuropathy polyneuropathy (i.e. glove/stocking distribution) attributable to vasculitis
Pulmonary infiltrates, Migratory or transitory pulmonary infiltrates on radiographs (not including
nonfixed fixed infiltrates) attributable to systemic vasculitis
Paranasal sinus abnormality History of acute or chronic paranasal sinus pain or tenderness or radiographic
opacification of the paranasal sinuses
Extravascular eosinophils Biopsy including artery, arteriole or venule, showing accumulations of
eosinophils in extravascular areas
Cutaneous symptoms
EGPA skin manifestations affect 40–70% of patients, the most frequent being vascular purpura
(40–70%) of the lower limbs (table 1). S.c. nodules occur in 10–30% of EGPA patients.
Segmentary oedema, livedo reticularis, and urticarial or gangrenous necrotic lesions are other
possible cutaneous manifestations of EGPA [25].
When skin biopsies are performed, leukocytoclastic vasculitis with fibrinoid necrosis,
neutrophils of eosinophil inflammatory infiltrate and/or granulomatous infiltrate are often
observed [25].
Renal symptoms
Renal involvement affects 16–22% of EGPA patients [8]. When renal biopsies were obtained,
histological findings included focal or diffuse crescentic glomerulonephritis, and less frequently
eosinophilic infiltrates, granuloma(s) or renal vasculitis [26]. Glomerulonephritis in EGPA
patients is usually associated with anti-myeloperoxidase (MPO) ANCA positivity.
Ophthalmological symptoms
Ophthalmological ischaemic vasculitis, uveitis and episcleritis are rare EGPA manifestations that
have been reported [27].
Complementary investigations
The mean±SD eosinophil count at diagnosis for our series was 7569±6428 cells·mm−3 [8], but
counts of >50 000 cells·mm−3 have been reported [28]. Isolated eosinophilia cannot be
considered sufficient to diagnose a relapse. An inflammatory syndrome is documented in ∼80%
of EGPA patients [8].
About one-third of EGPA patients are ANCA positive; most of these ANCA generate
perinuclear immunofluorescence labelling, and enzyme-linked immunosorbent assays have
determined that ∼70% of them are directed against MPO. Rheumatoid factor can be
detected [29].
For patients with alveolar haemorrhage, red blood cells are seen in BAL fluid, and the Golde
score, based on the haemosiderin content of alveolar macrophages, is elevated.
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a) b)
c) d)
FIGURE 1 Chest radiograph and CT in a patient with eosinophilic granulomatosis with polyangiitis. a) Chest
radiograph showing consolidation in the right upper lobe. b–d) CT images showing bilateral ground-glass
opacities.
Histological findings have good sensitivity for confirmation of an EGPA diagnosis [13, 15].
The most common biopsy sites are skin, nerve and/or muscle. Three types of lesions can be
seen, although they are rarely found simultaneously: 1) necrotising vasculitis of small- to
medium-sized vessels, 2) extravascular granuloma(s), and 3) eosinophil infiltration of arterial
walls and adjacent tissues [30].
In a study by COTTIN et al. [31] of 157 EGPA patients, 58% had chest radiographic
abnormalities, but chest CT scans were more precise to detect abnormalities such as
micronodules <3 mm (24%), consolidation (28%), bronchial wall thickening (32%) and/or
ground-glass opacities (39%) (figure 1).
Echocardiography or cardiac MRI detected abnormalities in 38% of patients who were

asymptomatic or without ECG abnormalities [24]. Cardiac MRI is one of the diagnostic
investigation tools for cardiomyopathy, However, the meaning of T1-weighted cardiac MRI
abnormalities among asymptomatic patients needs to be investigated further [32, 33].
Diagnosis
Diagnostic criteria
In 1984, LANHAM et al. [13] used the following criteria to redefine EGPA: asthma, blood
eosinophilia >1500 cells·mm−3 and at least two organs with manifestations suggestive of vasculitis.
https://doi.org/10.1183/2312508X.10004223 271
The ACR published EGPA classification criteria in 1990 (table 2) [2]. A patient with
documented vasculitis must satisfy four of the criteria to be classified as having EGPA.
In 2012, the Chapel Hill Consensus Conference Nomenclature [3] defined EGPA as an “an
eosinophil-rich and necrotising granulomatous inflammation, frequently involving the
respiratory tract, and necrotising vasculitis predominantly affecting small-to-medium-sized
vessels, and associated with asthma and eosinophilia”.
The 2022 ACR/European League Against Rheumatism (EULAR) classification criteria for
EGPA introduced a weighted-symptom method for patient classification, but its usefulness
compared with previous classifications needs to be further validated [34, 35].
We believe that EGPA can be diagnosed with a high level of confidence when a patient has
asthma, eosinophilia and extrapulmonary manifestations, together with histological proof of
vasculitis and/or anti-MPO-positive ANCA. Without these results, the combination of clinical
symptoms is accepted as a probable diagnosis, albeit with some degree of uncertainty. Some
authors now apply the criteria of the MIRRA trial (A study to investigate mepolizumab in the
treatment of eosinophilic granulomatosis with polyangiitis) for EGPA diagnosis: asthma plus
eosinophilia (>1.0×109 cells·L−1 and/or >10% leukocytes); and at least two of the following:
histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration or
eosinophil-rich granulomatous, inflammation neuropathy, mono- or polymotor deficit or
nerve-conduction abnormality, pulmonary infiltrates, nonfixed sinonasal abnormality,
cardiomyopathy (established by echocardiography or MRI), glomerulonephritis (haematuria, red
cell casts, proteinuria), alveolar haemorrhage, palpable purpura, or anti-MPO or anti-proteinase
3 (PR3) ANCA positivity [36]. We also question the value of anti-PR3 antibodies, which would
rather be diagnostic for granulomatosis with polyangiitis (GPA), which can also be associated
with eosinophilia, and sometimes occurs coincidentally in asthmatic patients.
Diagnostic criteria for relapse or flare

Relapses are defined by the recurrence of active disease following a period of remission [37, 38].
However, when patients are already undergoing treatments, the diagnosis of a relapse is often
difficult. In our opinion, to diagnose an EGPA relapse, the patient must have systemic
manifestations.
Differential diagnoses
Before vasculitic manifestations appear, it can be difficult to distinguish EGPA from
eosinophilic asthma or allergic bronchopulmonary aspergillosis.
Chronic eosinophilic pneumonia is a rare disease with nonspecific respiratory symptoms and
eosinophilia that responds well to oral glucocorticoids [39–41]. Vasculitic and extrapulmonary
signs are absent.
Hypereosinophilic syndrome (HES) is a more difficult entity to exclude from the differential
diagnosis, because it too may also be associated with cardiopathy, nerve involvement and/or
pulmonary manifestations. HES has no vasculitic symptoms [42]. HES has two readily
differentiated variants: lymphocytic, predominantly affecting skin and soft tissues, attributed to
abnormal CD3– CD4+ T-cell subsets synthesising interleukin (IL)-5 [43]; and myeloid, characterised
by specifically elevated tryptase and vitamin B12 levels, signs enabling HES exclusion. The search
for mutations in the tyrosine kinase FIP1-like-1–platelet-derived growth factor receptor-α fusion
(FIP1L1–PDGFRA) and Janus kinase 2 (JAK2) genes can confirm a myeloid HES diagnosis [44].
272 https://doi.org/10.1183/2312508X.10004223
The EGPA Consensus Task Force experts have recommended the following complementary
investigations to exclude differential diagnoses: 1) serological testing for anti-IgE and -IgG
antibodies specific for toxocariasis, HIV and Aspergillus spp.; 2) a search for Aspergillus spp.
in sputum or BAL fluid; 3) determination of tryptase and vitamin B12 levels; 4) a search for
dysplastic eosinophil blasts in peripheral blood smears; and 5) a thoracic CT scan [45].
Prognoses and outcomes

EGPA prognoses have been transformed by glucocorticoids and immunosuppressants, with the
5-year survival rate rising from 10% in the 1950s to ∼90% today [8]. Notably, the presence or
absence of identified prognostic factors, as defined by the five-factor score (FFS) [22], can
impact these patient prognoses. Summation of the assigned points yielded the FFS; scores of 0,
1 or 2 were associated, respectively, with 5-year mortality rates of 12%, 26% or 46%.
More recently, a new analysis of 1108 vasculitis patients, including 230 with EGPA, generated
a revised FFS [21]. This analysis retains age >65 years, severe gastrointestinal involvement,
serum creatinine >150 μmol·L−1 and myocardial involvement (+1 point for each), with –1 point
awarded for ENT manifestations. A revised FFS of 0, 1 or 2, respectively, is associated with
5-year mortality rates of 9%, 21% or 40%.
Use of the revised FFS can contribute to identifying EGPA patients at high risk of death who
require treatment combining glucocorticoids and immunosuppressants. All current therapeutic
recommendations support making treatment choices based on the revised FFS [37].
Heart-related events (i.e. cardiac insufficiency, arrhythmia and/or myocardial infarction) were
responsible for 31% of the deaths in our series, followed by 11% for malignancies, 11% for
infections, 9% for respiratory failure (severe asthma or end-stage COPD) and 9% for active
vasculitis [8]. Notably, 78.6% (95% CI 64.3–84.3) of patients survived and were relapse free at
5 years; asthma flares, sinusitis and/or elevated eosinophilia levels were observed in 18%, thus
justifying the use of long-term glucocorticoids for 85% of patients [8].
Based on a series of 157 patients, the major problem of persistent asthma symptoms, despite
treatment, remains, with their severity unchanged months or even years after EGPA diagnosis
[31]. At diagnosis, 3 years and the most recent visit, respectively, 38%, 30% and 46% had
persistent airflow obstruction, and 57%, 48% and 56% had severe asthma despite inhaled and
often oral glucocorticoids [31].
Phenotypes according to ANCA status

ANCA positivity or negativity imposes significantly different EGPA clinical findings and
prognoses. Two phenotypes have been defined [46, 47]. Based on 93 serial patients, significantly
higher rates of vasculitis-associated manifestations (renal involvement (51.4% versus 12.1%;
p<0.001), pulmonary haemorrhages (20% versus 0%; p=0.001), and purpura and/or mononeuritis
multiplex) were associated with ANCA positivity, while more frequent eosinophilic lung infiltrates
(60.3% versus 34.2%) and/or cardiac involvement (22.4% versus 5.7%; p=0.042) were associated
with ANCA negativity [46]. After analysis of another series of 112 EGPA patients, ANCA
positivity was again found to be associated with higher rates of renal involvement (35% versus
4%), peripheral neuropathy (84% versus 65%) and biopsy-proven vasculitis [47]. Prognoses for our
patient series differed according to ANCA phenotype, with positivity being associated with more
frequent relapses (35.2% versus 22.5%; p=0.01) but fewer deaths (5.6% versus 12.5%; p<0.5) [8].
https://doi.org/10.1183/2312508X.10004223 273
A recent genome-wide association study on EGPA patients was also able to identify, both
genetically and clinically, two subentities, based on ANCA positivity with distinct genetic
profiles [48].
Treatment
Therapeutic strategies
Glucocorticoids and immunosuppressants still represent major options in the therapeutic
armamentarium for EGPA, together with the newer targeted biotherapies. EGPA treatment
combines two phases: the remission-induction and remission-maintenance phases. EULAR
recommendations for the management of AAV including EGPA have recently been updated
[38]. EGPA treatment is complex because asthma and/or ENT manifestations can persist even
after vasculitis remission has been obtained.
The FFS was devised to assess disease prognosis, but its application to adapt the therapeutic
regimen is now widely used by international guidelines, including the 2022 EULAR
recommendations [49].
For patients with an initial FFS of 0 (i.e. without poor-prognosis factors), remissions can
effectively and safely be induced and maintained with first-line glucocorticoids alone (figure 2).
Seventy-two patients with newly diagnosed EGPA and FFS=0 were recruited for the
prospective, randomised CHUSPAN trial (Treatment of polyarteritis nodosa and microscopic
polyangiitis without poor-prognosis factors). Notably, 93% entered remission on glucocorticoids
alone and their 5-year survival rate was 97%, but 35% relapsed [50].
For good-prognosis patients, the efficacy of immunosuppressant adjunction remains controversial.

The results of the prospective, randomised CHUSPAN2 trial (Association of corticosteroid/
EGPA
FFS=0 FFS ≥1
Pulse i.v. or high-dose daily

Remission GCs alone oral GCs (1 mg·kg–1·day–1)
induction If refractory or relapse, with gradual tapering
consider MEPO or other +
CYC
immunosuppressant
(or consider RTX)
(or MEPO?)
Continue GC taper
Maintenance Continue GC taper Switch CYC to
therapy ±MEPO AZA, MTX or MEPO
FIGURE 2 Proposed algorithm for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). FFS:
five-factor score; GC: glucocorticoid; MEPO: mepolizumab; CYC: cyclophosphamide; RTX: rituximab; AZA:
azathioprine; MTX: methotrexate.
274 https://doi.org/10.1183/2312508X.10004223
azathioprine in microscopic polyangiitis/polyarteritis nodosa or eosinophilic granulomatosis with

polyangiitis) showed that azathioprine adjunction to glucocorticoids did not improve the remission
rate or lower the relapse rate [51] and did not contribute notably to steroid sparing.
EGPA patients with poor-prognosis factors (i.e. FFS ⩾1) should be treated with a regimen
combining an immunosuppressant with glucocorticoids [45].
Regimens to induce remission

The first phase aims to induce clinical remission as rapidly as possible (i.e. no overt clinical
manifestations of vasculitis). The initial dose should be prednisone (∼1 mg·kg−1·day−1) for
2–3 weeks, followed by gradual tapering. Initial life-threatening symptoms require rapidly acting
intravenous methylprednisolone pulses. The glucocorticoid dose should be decreased gradually
to the lowest effective dose until withdrawal, if possible. However, the steroid-dependent asthma
of EGPA patients often necessitates long-term prednisone.
Cyclophosphamide has been investigated for the most severe forms of EGPA. Forty-eight
EGPA patients with FFS ⩾1 were enrolled in a prospective study to assess the efficacies of 12
versus six cyclophosphamide pulses; both arms also received glucocorticoids, but no
maintenance therapy was prescribed thereafter [52]. The two regimens achieved comparable
outcomes, with complete remission obtained in 78.5% of all patients. However, the high
relapses rates (28.6% versus 66.7% for the 12- versus six-pulse groups) indicate the need for
maintenance therapy. I.v. pulses or continuous oral cyclophosphamide (2 mg·kg−1·day−1) are
deemed equally effective. However, oral intake leads to higher cumulative cyclophosphamide
doses and more severe leukopenia and adverse events.
The standard of care has since become six cyclophosphamide pulses for induction followed by
maintenance therapy [45].
The CORTAGE trial (Treatment of necrotizing vasculitides for patients older than 65 years) of
108 patients with AAV (including 14 with EGPA) evaluated fixed, lower-dose, i.v.
cyclophosphamide pulses (500 mg·m−2 every 2–3 weeks until remission) versus the standard
regimen with limited glucocorticoid exposure and showed similar remission rates but fewer
serious adverse events with the “lower-dose” regimen.
New drugs for treatment of AAV

Rituximab
Rituximab is a chimeric monoclonal antibody that targets CD20+ B-lymphocytes. The ability of
rituximab to safely and effectively induce and maintain GPA and microscopic polyangiitis
(MPA) remissions has been thoroughly demonstrated [53, 54], but its treatment of EGPA has
only been described in case reports and case series [55–57]. Most ANCA-positive patients seem
to benefit from effective and safe remission induction with rituximab. The French Vasculitis
Study Group designed the prospective, randomised REOVAS trial (Rituximab in eosinophilic
granulomatosis with polyangiitis) to evaluate the remission-induction efficacy of rituximab in
patients stratified according to their initial FFS. The trial results showed that the ability of
rituximab to induce vasculitis remission was not superior to that of the conventional therapeutic
strategy [58]. However, its use could be considered over cyclophosphamide in some situations,
such as child-bearing potential or previous exposure to cyclophosphamide with a high
cumulative dosage [38].
https://doi.org/10.1183/2312508X.10004223 275
Mepolizumab and other anti-IL-5 agents

MOOSIG et al. [59] published the first results showing mepolizumab efficacy for remission
induction in 2011. Since then, no prospective series of patients have been reported and the only
prospective study evaluating mepolizumab for remission induction was organised by the French
Vasculitis Study Group, which is still recruiting patients (ClinicalTrials.gov identifier
NCT05030155). Despite the lack of evidence, the ACR has recommended mepolizumab as
first-line therapy for EGPA [37], which is highly debatable, because convincing data
demonstrating that mepolizumab is as effective on extrapulmonary manifestations of EGPA as it
is on pulmonary symptoms are lacking. In the latest EULAR guidelines, the use of
mepolizumab is recommended for induction of remission in patients with relapsing or refractory
EGPA without active organ-threatening disease [38].
Maintenance therapy
The remission-maintenance regimen should be started 2 weeks after the last cyclophosphamide
pulse or several days after completing the oral cyclophosphamide intake.
Azathioprine maintenance starts at 2 mg·kg−1·day−1; the dose can subsequently be adapted

according to the clinical response and toxicity. Mycophenolate mofetil it is not prescribed very
often because it has been shown to be a less effective remission-maintenance option for GPA
and MPA [60]. Methotrexate, as an alternative to azathioprine, seems to be an acceptable option [61].
Although the optimal maintenance therapy duration has not yet been determined, it must be
given for at least 18–24 months after remission to treat the vasculitis symptoms. To date, no
consensus criteria have been formulated for completely stopping treatment, but before the
anti-IL-5 era, long-term low doses of glucocorticoids were often needed to control asthma or
ENT symptoms.
Mepolizumab
The 1-year, phase III, clinical MIRRA trial enrolled 136 patients with relapsing or refractory
EGPA [36]. Its results indicated that addition of mepolizumab to standard care can prevent
EGPA relapses [38]. The glucocorticoid-sparing capacity of mepolizumab was also noteworthy:
during weeks 48–52, 66% of patients in the placebo group took glucocorticoids at a dose of
>7.5 mg daily, compared with 41% of the mepolizumab recipients; moreover, only 3% of
placebo-treated patients were completely off steroids compared with 18% of those given
mepolizumab. Mepolizumab at a monthly dose of 300 mg, and probably other anti-IL-5 drugs,
effectively prevents relapses and now assumes a larger place in the maintenance treatment of
EGPA. Lower doses of mepolizumab (100 mg·month–1) or benralizumab (30 mg every
2 months) have been shown to effectively control asthma and reduce the use of corticosteroids.
Other treatment options

Based on case reports and case series, i.v. immunoglobulins could be a second-line therapeutic
option to treat EGPA flares, after other therapeutics have failed [62, 63].
For selected ANCA-positive patients, with rapidly progressive glomerulonephritis or severe

pulmonary–renal syndrome and alveolar haemorrhage, plasma exchanges could be a therapeutic
alternative [64], although their long-term benefits remain unknown [65].
The ability of interferon-α to prevent major relapses seems limited, and it is best not prescribed
[66, 67].
276 https://doi.org/10.1183/2312508X.10004223
Omalizumab, a monoclonal antibody targeting IgE, can be given to treat allergic asthma and
allergic rhinitis, but its effectiveness against EGPA remains contradictory [68–71].
Prevention of adverse events

The improved EGPA prognosis is also the consequence of types of other therapeutic support,
such as using calcium and vitamin D supplementation and bisphosphonates for the prevention
of glucocorticoid-related complications.
Cotrimoxazole or pentamidine aerosol against Pneumocystis jirovecii pneumonia should be

prescribed in patients treated with immunosuppressants (cyclophosphamide, rituximab). The
enhanced risk of potentially fatal infections while on immunosuppressants strongly favours
immunising patients with inactivated vaccines against influenza and Streptococcus pneumoniae.
According to a prospective open study, seasonal influenza vaccine was safe and effective, with
80.3% of patients obtaining seroprotection [72].
In addition, patients treated with immunosuppressants, especially rituximab, are at high risk of
severe forms of coronavirus disease 2019 (COVID-19), and their vaccine response could be
compromised [73, 74]. Hence, prevention strategies and early treatments are strongly recommended.
References
1 Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951; 27:
277–301.
2 Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of
Churg–Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33: 1094–1100.
3 Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised international Chapel Hill consensus conference
nomenclature of vasculitides. Arthritis Rheum 2013; 65: 1–11.
4 Mahr A, Guillevin L, Poissonnet M, et al. Prevalences of polyarteritis nodosa, microscopic polyangiitis,
Wegener’s granulomatosis, and Churg–Strauss syndrome in a French urban multiethnic population in 2000: a
capture–recapture estimate. Arthritis Rheum 2004; 51: 92–99.
5 Sada KE, Amano K, Uehara R, et al. A nationwide survey on the epidemiology and clinical features of
eosinophilic granulomatosis with polyangiitis (Churg–Strauss) in Japan. Mod Rheumatol 2014; 24: 640–644.
6 Watts RA, Lane SE, Scott DG, et al. Epidemiology of vasculitis in Europe. Ann Rheum Dis 2001; 60: 1156–1157.
7 Gonzalez-Gay MA, Garcia-Porrua C, Guerrero J, et al. The epidemiology of the primary systemic vasculitides in
northwest Spain: implications of the Chapel Hill Consensus Conference definitions. Arthritis Rheum 2003; 49:
388–393.
8 Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss):
clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group
cohort. Arthritis Rheum 2013; 65: 270–281.
9 Bottero P, Bonini M, Vecchio F, et al. The common allergens in the Churg–Strauss syndrome. Allergy 2007; 62:
1288–1294.
10 Mouthon L, Khaled M, Cohen P, et al. Systemic small sized vessel vasculitis after massive antigen inhalation.
Ann Rheum Dis 2001; 60: 903–904.
11 Guillevin L, Guittard T, Blétry O, et al. Systemic necrotizing angiitis with asthma: causes and precipitating
factors in 43 cases. Lung 1987; 165: 165–172.
12 Chumbley LC, Harrison EG, DeReme RA. Allergic granulomatosis and angiitis (Churg–Strauss syndrome). Report
and analysis of 30 cases. Mayo Clin Proc 1977; 52: 477–484.
13 Lanham JG, Elkon KB, Pusey CD, et al. Systemic vasculitis with asthma and eosinophilia: a clinical approach to
the Churg–Strauss syndrome. Medicine (Baltimore) 1984; 63: 65–81.
14 Gaskin G, Clutterbuck EJ, Pusey CD, et al. Renal disease in the Churg–Strauss syndrome: diagnosis,
management and outcome. Contrib Nephrol 1991; 95: 58–65.
15 Guillevin L, Cohen P, Gayraud M, et al. Churg–Strauss syndrome. Clinical study and long-term follow-up of 96
patients. Medicine (Baltimore) 1999; 78: 26–37.
16 Solans R, Bosch JA, Pérez-Bocanegra C, et al. Churg–Strauss syndrome: outcome and long-term follow-up of 32
patients. Rheumatology (Oxford) 2001; 40:763–771.
https://doi.org/10.1183/2312508X.10004223 277
17 Durel CA, Berthiller J, Caboni S, et al. Long-term followup of a multicenter cohort of 101 patients with
eosinophilic granulomatosis with polyangiitis (Churg–Strauss). Arthritis Care Res (Hoboken) 2016; 68: 374–387.
18 Bettiol A, Urban ML, Dagna L, et al. Mepolizumab for eosinophilic granulomatosis with polyangiitis: a European
multicenter observational study. Arthritis Rheumatol 2022; 74: 295–306.
19 Harrold LR, Andrade SE, Go AS, et al. Incidence of Churg–Strauss syndrome in asthma drug users: a
population-based perspective. J Rheumatol 2005; 32: 1076–1080.
20 Choi YH, Im JG, Han BK, et al. Thoracic manifestation of Churg–Strauss syndrome: radiologic and clinical
findings. Chest 2000; 117: 117–124.
21 Guillevin L, Pagnoux C, Seror R, et al. The Five-Factor Score revisited: assessment of prognoses of systemic
necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore) 2011;
90: 19–27.
22 Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg–Strauss syndrome. A
prospective study in 342 patients. Medicine (Baltimore) 1996; 75: 17–28.
23 Guillevin L, Lhote F, Gallais V, et al. Gastrointestinal tract involvement in polyarteritis nodosa and Churg–
Strauss syndrome. Ann Med Interne (Paris) 1995; 146: 260–267.
24 Dennert RM, van Paassen P, Schalla S, et al. Cardiac involvement in Churg–Strauss syndrome. Arthritis Rheum
2010; 62: 627–634.
25 Frumholtz L, Laurent-Roussel S, Aumaître O, et al. Clinical and pathological significance of cutaneous
manifestations in ANCA-associated vasculitides. Autoimmun Rev 2017; 16: 1138–1146.
26 Sinico RA, di Toma L, Maggiore U, et al. Renal involvement in Churg–Strauss syndrome. Am J Kidney Dis 2006;
47: 770–779.
27 Takanashi T, Uchida S, Arita M, et al. Orbital inflammatory pseudotumor and ischemic vasculitis in Churg–
Strauss syndrome: report of two cases and review of the literature. Ophthalmology 2001; 108: 1129–1133.
28 Dietz A, Hübner C, Andrassy K. Makrolid-Antibiotika induzierte Vaskulitis (Churg–Strauss-Syndrom). [Macrolide
antibiotic-induced vasculitis (Churg–Strauss syndrome).] Laryngorhinootologie 1998; 77: 111–114.
29 Yokoyama A, Kohno N, Fujino S, et al. IgG and IgM rheumatoid factor levels parallel interleukin-6 during the
vasculitic phase in a patient with Churg–Strauss syndrome. Intern Med 1995; 34: 646–648.
30 Churg A. Recent advances in the diagnosis of Churg–Strauss syndrome. Mod Pathol 2001; 14: 1284–1293.
31 Cottin V, Bel E, Bottero P, et al. Respiratory manifestations of eosinophilic granulomatosis with polyangiitis
(Churg–Strauss). Eur Respir J 2016; 48: 1429–1441.
32 Dunogué B, Terrier B, Cohen P, et al. Impact of cardiac magnetic resonance imaging on eosinophilic
granulomatosis with polyangiitis outcomes: a long-term retrospective study on 42 patients. Autoimmun Rev
2015; 14: 774–780.
33 Pugnet G, Gouya H, Puéchal X, et al. Cardiac involvement in granulomatosis with polyangiitis: a magnetic
resonance imaging study of 31 consecutive patients. Rheumatology (Oxford) 2017; 56: 947–956.
34 Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of
Associations for Rheumatology classification criteria for eosinophilic granulomatosis with polyangiitis. Ann
Rheum Dis 2022; 81: 309–314.
35 Dejaco C, Guillevin L. New classification criteria for small-vessel vasculitis: is antineutrophil cytoplasmic
antibody inclusion their major advance? Arthritis Rheumatol 2022; 74: 383–385.
36 Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with
polyangiitis. N Engl J Med 2017; 376: 1921–1932.
37 Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline
for the management of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 2021; 73:
1366–1383.
38 Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR recommendations for the management of
ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2023; in press [https://doi.org/10.1136/
ard-2022-223764].
39 Carrington CB, Addington WW, Goff AM, et al. Chronic eosinophilic pneumonia. N Engl J Med 1969; 280: 787–798.
40 Marchand E, Reynaud-Gaubert M, Lauque D, et al. Idiopathic chronic eosinophilic pneumonia. A clinical and
follow-up study of 62 cases. Medicine (Baltimore) 1998; 77: 299–312.
41 Allen J, Wert M. Eosinophilic pneumonias. J Allergy Clin Immunol Pract 2018; 6: 1455–1461.
42 Kahn JE, Grandpeix-Guyodo C, Ackermann F, et al. Syndromes hyperéosinophiliques: actualités
physiopathologiques et thérapeutiques. [Hypereosinophilic syndromes: physiopathological and therapeutic
news]. Rev Med Interne 2010; 31: 268–276.
43 Roufosse F, Cogan E, Goldman M. Lymphocytic variant hypereosinophilic syndromes. Immunol Allergy Clin North
Am 2007; 27: 389–413.
44 Ogbogu PU, Bochner BS, Butterfield JH, et al. Hypereosinophilic syndromes: a multicenter, retrospective
analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009; 124: 1319–1325.e3.
278 https://doi.org/10.1183/2312508X.10004223
45 Groh M, Pagnoux C, Baldini C, et al. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA)
Consensus Task Force recommendations for evaluation and management. Eur J Intern Med 2015; 26: 545–553.
46 Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic
antibodies in Churg–Strauss syndrome. Arthritis Rheum 2005; 52: 2926–2935.
47 Sablé-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg–Strauss
syndrome. Ann Intern Med 2005; 143: 632–638.
48 Smith KGC. Genetic studies in ANCA-associated vasculitis point to a new, practical disease classification based
on autoantibody specificity. Rheumatology 2017; 56: Suppl. 3, iii3–iii4.
49 Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and
medium vessel vasculitis. Ann Rheum Dis 2009; 68: 310–317.
50 Ribi C, Cohen P, Pagnoux C, et al. Treatment of Churg–Strauss syndrome without poor-prognosis factors: a
multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum 2008; 58: 586–594.
51 Puéchal X, Pagnoux C, Baron G, et al. Adding azathioprine to remission-induction glucocorticoids for
eosinophilic granulomatosis with polyangiitis (Churg–Strauss), microscopic polyangiitis, or polyarteritis nodosa
without poor prognosis factors: a randomized, controlled trial. Arthritis Rheum 2017; 69: 2175–2186.
52 Cohen P, Pagnoux C, Mahr A, et al. Churg–Strauss syndrome with poor-prognosis factors: a prospective
multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients.
Arthritis Rheum 2007; 57: 686–693.
53 Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl
J Med 2010; 363: 221–232.
54 Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated
55 Pepper RJ, Fabre MA, Pavesio C, et al. Rituximab is effective in the treatment of refractory Churg–Strauss
syndrome and is associated with diminished T-cell interleukin-5 production. Rheumatology (Oxford) 2008; 47:
1104–1105.
56 Thiel J, Hässler F, Salzer U, et al. Rituximab in the treatment of refractory or relapsing eosinophilic
granulomatosis with polyangiitis (Churg–Strauss syndrome). Arthritis Res Ther 2013; 15: R133.
57 Mohammad AJ, Hot A, Arndt F, et al. Rituximab for the treatment of eosinophilic granulomatosis with
polyangiitis (Churg–Strauss). Ann Rheum Dis 2016; 75: 396–401.
58 Terrier B, Pugnet G, de Moreuil C, et al. Rituximab versus conventional therapeutic strategy for remission
induction in eosinophilic granulomatosis with polyangiitis: a double-blind, randomized, controlled trial. Arthritis
Rheumatol 2021; 73: Suppl. 9, Abstract L21.
59 Moosig F, Gross W, Hermann K, et al. Targeting interleukin-5 in refractory and relapsing Churg–Strauss
syndrome. Ann Intern Med 2011; 155: 341–343.
60 Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in
antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA 2010; 304:
2381–2388.
61 Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated
62 Danieli M, Cappelli M, Malcangi G, et al. Long term effectiveness of intravenous immunoglobulin in Churg–
Strauss syndrome. Ann Rheum Dis 2004; 63: 1649–1654.
63 Tsurikisawa N, Taniguchi M, Saito H, et al. Treatment of Churg–Strauss syndrome with high-dose intravenous
immunoglobulin. Ann Allergy Asthma Immunol 2004; 92: 80–87.
64 Klemmer PJ, Chalermskulrat W, Reif MS, et al. Plasmapheresis therapy for diffuse alveolar hemorrhage in
patients with small-vessel vasculitis. Am J Kidney Dis 2003; 42: 1149–1153.
65 Walsh M, Casian A, Flossmann O, et al. Long-term follow-up of patients with severe ANCA-associated vasculitis
comparing plasma exchange to intravenous methylprednisolone treatment is unclear. Kidney Int 2013; 84: 397–402.
66 Metzler C, Csernok E, Gross WL, et al. Interferon-alpha for maintenance of remission in Churg–Strauss
syndrome: a long-term observational study. Clin Exp Rheumatol 2010; 28: Suppl. 57, 24–30.
67 Metzler C, Schnabel A, Gross WL, et al. A phase II study of interferon-alpha for the treatment of refractory
Churg–Strauss syndrome. Clin Exp Rheumatol 2008; 26: Suppl. 49, S35–S40.
68 Puéchal X, Rivereau P, Vinchon F. Churg–Strauss syndrome associated with omalizumab. Eur J Intern Med 2008;
19: 364–366.
69 Bargagli E, Rottoli P. Omalizumab treatment associated with Churg–Strauss vasculitis. Int Arch Allergy Immunol
2008; 145: 268.
70 Detoraki A, di Capua L, Varricchi G, et al. Omalizumab in patients with eosinophilic granulomatosis with
polyangiitis: a 36-month follow-up study. J Asthma 2016; 53: 201–206.
71 Wechsler ME, Wong DA, Miller MK, et al. Churg–Strauss syndrome in patients treated with omalizumab. Chest
2009; 136: 507–518.
https://doi.org/10.1183/2312508X.10004223 279
72 Kostianovsky A, Charles P, Alves JF, et al. Immunogenicity and safety of seasonal and 2009 pandemic A/H1N1
influenza vaccines for patients with autoimmune diseases: a prospective, monocentre trial on 199 patients. Clin
Exp Rheumatol 2012; 30: Suppl. 70, S83–S89.
73 Avouac J, Drumez E, Hachulla E, et al. COVID-19 outcomes in patients with inflammatory rheumatic and
musculoskeletal diseases treated with rituximab: a cohort study. Lancet Rheumatol 2021; 3: e419–e426.
74 Hadjadj J, Planas D, Ouedrani A, et al. Immunogenicity of BNT162b2 vaccine against the Alpha and Delta variants
in immunocompromised patients with systemic inflammatory diseases. Ann Rheum Dis 2022; 81: 720–728.
Acknowledgement: The authors thank Ms Janet Jacobson for editorial assistance.
280 https://doi.org/10.1183/2312508X.10004223
Chapter 20
Idiopathic eosinophilic pneumonias

1,2
Vincent Cottin
1
Dept of Pulmonary Medicine, and National Reference Center for Rare Pulmonary Diseases, Louis Pradel Hospital,
Lyon, France. 2Claude Bernard Lyon 1 University, Lyon, France.
Corresponding author: Vincent Cottin (vincent.cottin@chu-lyon.fr)
Cite as: Cottin V. Idiopathic eosinophilic pneumonias. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare
[https://doi.org/10.1183/2312508X.10019022].
@ERSpublications
Diagnosis of idiopathic eosinophilic pneumonia is based on BAL in the appropriate clinicoradiological
setting, ruling out infection and drugs. Idiopathic acute eosinophilic pneumonia is often misdiagnosed as
infectious pneumonia. https://bit.ly/ERSM100
ISSN: 2312-5098.
Eosinophilic pneumonia may manifest with a slowly progressive onset in chronic idiopathic
eosinophilic pneumonia, or as the frequently severe acute eosinophilic pneumonia. The diagnosis is
supported by blood eosinophilia >1×109 cells·L−1 ( preferably >1.5×109 cells·L−1) when present, but
this may be absent, for example in the early phase of idiopathic acute eosinophilic pneumonia or in
patients already taking corticosteroids. BAL fluid showing high eosinophilia (>25%, and preferably
>40% of the differential cell count) is considered diagnostic in a compatible setting, negating the need
for video-assisted thoracic surgical lung biopsy. Possible causes of eosinophilic pneumonia must be
investigated thoroughly, including medications, illicit drugs and infections, especially parasitic.
Corticosteroids are the cornerstone of symptomatic treatment, with a generally dramatic response, but
relapses are common when tapering or stopping treatment in idiopathic chronic eosinophilic pneumonia
(ICEP). Evidence is accumulating for the efficacy of anti-interleukin-5 and anti-interleukin-5 receptor
monoclonal antibodies as steroid-sparing agents in relapsing ICEP.
Introduction
The definition of eosinophilic pneumonias is a prominent infiltration by eosinophils of the lung
parenchyma, a process that can be triggered by a limited number of determined causes, mainly
infections and exposure to drugs and toxins, or that may be idiopathic. Other eosinophilic lung
diseases mainly involve the airways [1, 2].
Polymorphonuclear eosinophils
Eosinophil leukocytes are especially important in the defence against parasitic infestation and
also have a broad role in homeostatic function, physiology and pathophysiology [3]. They are
now considered multifunctional cells implicated in the initial stage of innate and adaptive
immunity [3–5].
Progress has been made in our understanding of the molecular and intracellular pathways
regulating eosinophil differentiation, priming, activation, degranulation and mediator secretion [6].
https://doi.org/10.1183/2312508X.10019022 281
Eosinophils contain two types of intracytoplasmic granules [4–6]. The degranulation process by
activated eosinophils leads to the release of cationic proteins into the extracellular space, with
the potential for direct cytotoxicity to the heart, brain and bronchial epithelium in particular. In
addition, eosinophils release a number of preformed mediators including proinflammatory
cytokines, lipid- and arachidonic acid-derived mediators, enzymes, reactive oxygen species and
matrix metalloproteases [5].
Corticosteroids shorten eosinophil survival and facilitate eosinophil apoptosis. However, they
lack specificity for eosinophils and have numerous adverse effects. Conversely, drugs targeting
the interleukin (IL)-5/IL-5 receptor (IL-5R) pathway selectively impact the eosinophil cell
lineage and have dramatically changed the therapeutic landscape of eosinophilic disorders.
Other drugs are in development for eosinophilic disorders, especially targeting eosinotaxins,
CD2-binding protein and eosinophil surface-expressed inhibitory receptors such as sialic
acid-binding Ig-like lectin 8 (SIGLEC-8) [3, 5, 7].
Idiopathic chronic eosinophilic pneumonia

The eosinophilic pneumonias may manifest as chronic eosinophilic pneumonia, acute
eosinophilic pneumonia (AEP) or Löffler syndrome (generally of parasitic aetiology). They can
occur as a consequence of a determined cause or as an idiopathic condition.
Clinical features
Chronic eosinophilic pneumonia was first described in detail by CARRINGTON et al. [8] in 1969.
Idiopathic chronic eosinophilic pneumonia (ICEP) predominates in women with a female/male
ratio of 2/1 [9, 10], a peak of incidence in the fourth decade [9] and a mean age of 45 years at
diagnosis [10]. The majority of patients with ICEP are nonsmokers [9, 10].
About half of patients have a history of atopy [9, 10] and up to two-thirds have a history of
asthma [9–13]. Asthma may develop concomitantly with the diagnosis of ICEP (15% of
patients) or develop after ICEP (∼15% of patients) [12]. Asthma in patients with ICEP often
gets worse and requires long-term oral corticosteroid treatment [12].
ICEP is characterised by the progressive onset of cough, dyspnoea and chest pain [9, 10], with
a mean interval of 4 months between the onset of symptoms and diagnosis [10]. Mechanical
ventilation may be required on exceptional occasions. Haemoptysis is rare but can occur in up
to 10% of cases [9, 10]. Chronic rhinitis or sinusitis symptoms are present in ∼20% of
patients [10]. On lung auscultation, wheezes are found in one-third of patients [9] and crackles
in 38% [10]. Systemic symptoms and signs are often prominent, and include fever, weight loss
(>10 kg in ∼10% of patients), fatigue, malaise, asthenia, weakness, anorexia and night sweats.
However, no systemic organ involvement is found.
Imaging
Although the imaging features of ICEP are characteristic, they can overlap those of cryptogenic
organising pneumonia. Peripheral opacities on a chest radiograph are present in almost all cases
[8–10, 14, 15] and consist of alveolar opacities with ill-defined margins, with a density varying
from ground-glass opacities to consolidation. Alveolar consolidations are migratory in about
one-quarter of patients [10]. The classic pattern of “photographic negative or reversal of the
shadows usually seen in pulmonary oedema”, which is highly evocative of ICEP, is also seen in
only one-quarter of patients [9]; however, peripheral and upper-zone predominance of
abnormalities is usually present.
282 https://doi.org/10.1183/2312508X.10019022
IDIOPATHIC EOSINOPHILIC PNEUMONIAS | V. COTTIN
On HRCT, the opacities are bilateral in virtually all cases [10]. A predominance of ground-
glass attenuation and consolidation in the periphery and upper lobes of both lungs [9, 10] is
highly suggestive of ICEP (figure 1) [10, 15, 16]. Septal-line thickening is common [16].
Centrilobular nodules (<20% of cases) [15] and consolidation with segmental or lobar atelectasis
can also be seen.
Consolidation rapidly decreases in both extent and density following corticosteroid treatment,
potentially evolving to ground-glass attenuation, and then to streaky or band-like opacities
parallel to the chest wall. Cavitary lesions are extremely rare in ICEP and should result in
reconsideration of the diagnosis. The reverse halo sign, which is suggestive of organising
pneumonia, is rare in ICEP. Pleural effusions (common in idiopathic AEP (IAEP)) are rare and
usually mild or moderate in ICEP. Mediastinal lymph node enlargement may be seen in 15–20%
of cases [10].
Laboratory studies
Peripheral blood eosinophilia is a diagnostic criterion of ICEP. However, blood eosinophilia
may be absent if the patient has already received oral or intravenous corticosteroids, even for a
few hours. The mean blood eosinophilia was 5.5×109 cells·L−1 in a large series [10].
Eosinophils represent 26–32% of the total blood leukocyte count [9, 10].
C-reactive protein is elevated [9, 10], and the total blood IgE level is increased in about half of
cases and is >1000 kU·L−1 in 15% [10]. Antinuclear antibodies may occasionally be present [10],
but probably not more frequently than in the general population. The urinary eosinophil-derived
neurotoxin level indicating active eosinophil degranulation is markedly increased [17].
BAL
BAL eosinophilia is constant in untreated ICEP. BAL performed before any treatment is
therefore key to the diagnosis of ICEP, obviating the need for lung biopsy (table 1). The mean
eosinophil percentage in the BAL differential cell count was 58% at diagnosis in a large series
[10]. The percentage of neutrophils, mast cells and lymphocytes in BAL fluid (BALF) may be
increased [10] but is less than the percentage of eosinophils. Importantly, BAL contributes to
ruling out potential causes of eosinophilic pneumonia including infections and lymphoma, and
therefore must include both analysis of the differential cell count and microbiology. BAL
lymphocytes include CD4+ memory T-cells (CD45RO+, CD45RA– and CD62L–), and may
present clonal rearrangement of the T-cell receptor repertoire [18].
a) b)
FIGURE 1 CT scan of a patient with idiopathic chronic eosinophilic pneumonia showing bilateral peripheral
alveolar opacities with airspace consolidation and ground-glass opacities. a) Upper lobes, b) mid-trachea level.
https://doi.org/10.1183/2312508X.10019022 283
TABLE 1 Diagnostic criteria for idiopathic chronic eosinophilic pneumonia

Diffuse pulmonary alveolar consolidation with air bronchograms and/or ground-glass opacities on chest
imaging, especially with peripheral predominance
Eosinophilia on BAL differential cell count ⩾40% (or peripheral blood eosinophils ⩾1.0×109 cells·L−1)
Respiratory symptoms present for ⩾2–4 weeks
Absence of other known causes of eosinophilic lung disease (especially exposure to a drug susceptible to
inducing pulmonary eosinophilia)
Pathology
Lung biopsies are no longer used to diagnose ICEP, but a pattern of eosinophilic pneumonia
can be identified on video-assisted thoracoscopic surgical biopsy or transbronchial cryobiopsy
[19, 20], which is performed in difficult cases. The alveolar spaces are diffusely filled with
eosinophils representing the predominant inflammatory cell, together with a proteinaceous and
fibrinous exudate, respecting the global architecture of the lung [8, 9, 21]. Macrophages are also
present, with scattered multinucleated giant cells occasionally containing eosinophilic granules
or Charcot–Leyden crystals [8]. Some eosinophilic microabscesses may be observed, but they
are not as prominent. Degranulated eosinophils can be identified by electron microscopic or
immunohistochemical studies [22]. Some overlap can occur between organising pneumonia
and ICEP.
Differential diagnosis
Extrapulmonary manifestations, when present, lead to reconsideration of the diagnosis of ICEP.
Arthralgias, repolarisation (ST–T) abnormalities on the ECG, pericarditis, altered liver
biological tests or immune complex vasculitis in the skin have occasionally been reported in
ICEP [8, 10]. However, genuine systemic manifestations such as mononeuritis multiplex, skin
nodules and eosinophilic enteritis would now be considered eosinophilic granulomatosis with
polyangiitis (EGPA) and not ICEP. Furthermore, eosinophilic pneumonia may be a presenting
feature of EGPA.
PFTs
An obstructive ventilatory defect is present in about half of patients [9, 10], and a restrictive
ventilatory defect in the other half [10]. DLCO is decreased in half of patients. Hypoxaemia,
which is present in two-thirds of patients [10], may be due to right-to-left shunting in
consolidated areas of the lung [9].
With treatment, PFTs rapidly return to normal in most patients [9]. However, a persistent
ventilatory obstructive defect (not responsive to inhaled corticosteroids and bronchodilators)
may develop over a period of years in up to one-third of patients, especially those with
concurrent asthma and obstructive defects at diagnosis [23]. In one study, the persistence of a
ventilatory obstructive defect was associated with a markedly increased BAL eosinophilia at
initial evaluation [24].
Treatment
Spontaneous resolution of ICEP may occur [9, 10]; however, most patients receive
corticosteroids [9]. The response to corticosteroids is dramatic, with improvement of symptoms
within 1 or 2 weeks, and even within 48 h in ∼80% of cases [10], and rapid clearance of
pulmonary opacities on imaging [10]. Death resulting directly from ICEP is exceedingly rare.
Cases considered refractory to corticosteroids should lead the clinician to reconsider the
diagnosis of ICEP.
284 https://doi.org/10.1183/2312508X.10019022
The initial treatment is 0.5 mg·kg−1·day−1 of prednisone, followed by slow tapering over
6–12 months based on clinical evaluation and the blood eosinophil cell count. In an open-label,
randomised study, no significant difference was found in the cumulative rate of relapse between
patients with chronic eosinophilic pneumonia randomised to receive oral prednisolone for either
3 or 6 months [25]. Treatment may therefore be slowly tapered down to 5–10 mg·day−1 over
3 months based on clinical evaluation and blood eosinophil cell count.
Most patients, however, require treatment for >6–12 months because of relapse while decreasing
the daily dose of prednisone or after stopping corticosteroids [9, 10]. Relapses respond very
well to resumed corticosteroid treatment at a dose of ∼20 mg·day−1 of prednisone [10, 25].
Patients should therefore be informed of the possibility of relapse while the corticosteroids are
progressively tapered and then stopped. Such an approach reduces the patient’s overall exposure
to long-term corticosteroids and their anxiety.
Outcome and perspectives

Most patients need very prolonged corticosteroid treatment to prevent relapses. In a series with a
mean follow-up of 6.2 years, only 31% of patients were weaned at the last control visit [10].
In a series of 133 cases, relapse occurred in 56% of patients during a follow-up period of
>6 years [23].
In people with asthma, relapses of ICEP must be distinguished from asthma symptoms [10, 12].
Inhaled corticosteroids might contribute to prevent relapses and to reduce the daily dose of oral
corticosteroids but are not effective enough when given as monotherapy [26].
Long-term use of corticosteroids may lead to a variety of adverse events including osteoporosis
and weight gain. Alternate-day prescription of oral corticosteroids might reduce the adverse
events of treatment. Omalizumab, a recombinant humanised monoclonal antibody against IgE,
was proposed as a steroid-sparing agent but is not used routinely due to uncertain efficacy and
reports of omalizumab-related EGPA [27, 28].
The anti-IL-5 monoclonal antibody mepolizumab and the IL-5R antagonist benralizumab have
been used successfully in patients with ICEP, who are generally also suffering from severe
eosinophilic asthma. In a retrospective series of 29 patients treated with off-label mepolizumab
or benralizumab for ⩾3 months for relapsing and/or steroid-dependent ICEP despite long-acting
β-agonists and inhaled steroids, these medications prevented the relapse of eosinophilic
pneumonia and severe asthma exacerbations, while allowing safe tapering of the doses of oral
corticosteroids. However, given the exquisite sensitivity of ICEP to corticosteroids, such
off-label use of anti-IL-5/IL-5R medications should be carefully discussed on a case-by-case
basis in an expert centre, and restricted to cases with frequent relapses of ICEP and/or
intolerance or contraindications to oral corticosteroids. Cases considered refractory to
corticosteroids should lead to reconsideration of the diagnosis of ICEP.
IAEP and smoking-related AEP

Because fever and bilateral opacities on chest radiograph are present in nearly all patients, and
because blood eosinophilia is often lacking at presentation, IAEP is often misdiagnosed as
infectious pneumonia [29]. In contrast to ICEP, IAEP has an acute onset and a severe
presentation with hypoxaemia but does not relapse after clinical recovery [13, 29–36]. Known
causes of acute eosinophilic lung disease, particularly drug exposure, infection or vaporised
cannabis oil, must be excluded for the diagnosis of IAEP to be made (table 2) [37, 38].
https://doi.org/10.1183/2312508X.10019022 285
TABLE 2 Diagnostic criteria for idiopathic acute eosinophilic pneumonia

Acute onset of febrile respiratory manifestations (⩽1 month’s duration before consultation)
Bilateral diffuse opacities on chest radiography
Hypoxaemia, with PaO2 on room air <60 mmHg, and/or PaO2/FIO2 ⩽300 mmHg, and/or oxygen saturation on
room air <90%
Lung eosinophilia, with >25% eosinophils on BAL differential cell count (or eosinophilic pneumonia at lung biopsy)
Absence of infection or other known causes of eosinophilic lung disease (especially exposure to a drug
susceptible to inducing pulmonary eosinophilia)
PaO2: arterial oxygen tension; FIO2: inspiratory oxygen fraction.
Epidemiology
Most patients with IAEP are 20–40 years of age [29, 39, 40], without a prior asthma history [13].
There is a very strong predominance in males [34], largely related to the exposure history. The
majority of patients will have had recent exposure to dust or cigarette smoke in the days before
the onset of the disease, and often will have started smoking, restarted smoking or increased the
number of cigarettes smoked daily, or changed their smoking habits (e.g. smoking larger
quantities, smoking flavoured cigars), especially <1 month before the onset of “idiopathic” AEP
[34, 41]. The disease is therefore triggered by inhaled nonspecific causative agents in susceptible
individuals, rather than being truly “idiopathic”, but some cases can occur in the absence of any
inhaled exogenous trigger. AEP often relapses in patients who resume cigarette smoking after
having quit [34, 41]. In nonsmokers, the onset of IAEP may follow various other respiratory
exposures, including cave exploration, plant repotting, wood pile moving, smokehouse cleaning,
motocross racing in dusty conditions, indoor renovation work, gasoline tank cleaning, explosion
of a tear gas bomb, exposure to World Trade Center dust [29, 39, 42], use of electronic cigarettes
[43–45] and inhalation of vaporised cannabis oil [46].
Clinical features
IAEP develops acutely or subacutely over <1 month in previously healthy individuals, with
cough, dyspnoea, fever and chest pain at presentation [30, 39]. More than half of patients
present with acute respiratory failure [34]. Abdominal complaints and myalgias can also
occur [29]. Clinical signs include crackles or, less often, wheezes, as well as tachypnoea and
tachycardia. The initial diagnosis suspected is often that of severe community-acquired
pneumonia with acute respiratory distress syndrome.
Imaging
Imaging of patients with IAEP demonstrates the presence of bilateral alveolar and/or interstitial
opacities on chest radiography, in common with ICEP [29, 32, 33, 39]. However, bilateral
pleural effusion and Kerley B lines, which are absent in ICEP, are commonly present in IAEP
(figure 2) [29]. The chest radiograph returns to normal within 3 weeks [29, 39], with pleural
effusions being the last abnormality to disappear [29].
Typical HRCT abnormalities include ground-glass attenuation and airspace consolidation, with
poorly defined nodules (figure 2). Interlobular septal thickening and bilateral pleural effusion,
which are seen in a majority of patients, are highly suggestive of the diagnosis [14, 29, 32, 39, 47],
and should prompt BAL for both microbiology and differential cell count.
Laboratory studies
In IAEP, peripheral blood eosinophilia is usually lacking at presentation, in contrast to ICEP,
and the white blood cell count shows increased numbers of neutrophils. However, the
286 https://doi.org/10.1183/2312508X.10019022
FIGURE 2 CT scan of a patient with idiopathic acute eosinophilic pneumonia showing interlobular septal
opacities and moderate, bilateral, pleural effusion, associated with bilateral peripheral alveolar opacities with
airspace consolidation and ground-glass opacities.
eosinophil count often rises within a few days during the course of the disease [13, 29, 39],
which is highly suggestive of IAEP. When present at presentation, peripheral eosinophilia may
be associated with a milder disease status compared with those with a normal eosinophil count
[35, 48, 49]. Eosinophilia is also present in the pleural fluid differential cell count [29] and in
sputum (⩾3%) [13]. The IgE level may be elevated, while IgG levels may be reduced.
BAL
Analysis of BALF is key to the diagnosis of IAEP, particularly in patients without blood
eosinophilia at presentation. A finding of >25% eosinophils in BALF removes the need for lung
biopsy, at least in immunocompetent patients. The average percentage of eosinophils in the
BAL differential count varies among series (ranging from 37% [29] to 65% [50]). Lymphocyte
and neutrophil counts in BALF can be moderately increased. The eosinophil count in BALF
may remain elevated for several weeks after recovery; however, BAL is more likely to
TABLE 3 Distinctive features of idiopathic chronic eosinophilic pneumonia (ICEP) and idiopathic acute
eosinophilic pneumonia (IAEP)
Feature ICEP IAEP
Onset >2–4 weeks <1 month

History of asthma Yes No
Smoking history 10% Two-thirds, often with recent initiation
Respiratory failure No Usual
Initial blood eosinophilia Yes, on admission No (delayed)
BAL eosinophilia >25% (generally >40%) >25%
Chest imaging Homogeneous peripheral airspace Bilateral patchy areas of ground-glass
consolidation attenuation, airspace consolidation,
Predominance in upper lobes and lung interlobular septal thickening and
periphery bilateral pleural effusion
Relapse Yes, possibly multiple No
https://doi.org/10.1183/2312508X.10019022 287
contribute effectively to the diagnosis of AEP if performed within days after presentation and
before treatment is initiated. Bronchoscopy may show inflamed mucosa of the trachea [51].
Importantly, bacterial cultures of BALF are sterile and relevant stains are negative, ruling out an
infectious cause of AEP.
PFTs
Hypoxaemia may be severe in patients with IAEP, a majority of whom fit the definition of
acute respiratory distress syndrome of varying severity [52]. Nevertheless, shock is exceptional
TABLE 4 Main aetiologies of eosinophilic pneumonia other than idiopathic chronic eosinophilic pneumonia and
idiopathic or smoking-related eosinophilic pneumonia
Aetiology Comments First author [ref.]
EGPA Abnormalities predominate in the airspaces KIM [56], PRICE [57], SZCZEKLIK [58]
corresponding to eosinophilic pneumonia, or
in the airways corresponding to bronchiolar
and bronchial involvement
Hypereosinophilic Lung involvement is uncommon in the VALENT [59], DULOHERY [60], SIMON
syndrome reactive/lymphocytic variant, and is present [61], ROUFOSSE [62], CHUSID [63],
at chest CT in ∼40% of patients with the FAUCI [64]
clonal/neoplastic variant
ABPA Fleeting infiltrates due to eosinophilic MITCHELL [65], REFAIT [66],
pneumonia or mucus plugging with ensuing WARD [67]
segmental or lobar atelectasis are frequent
during the initial stage of the disease
Parasitic infestation The most common cause of eosinophilic COTTIN [1], SIMON [61],
pneumonia worldwide CORDIER [68], VIJAYAN [69],
Causative agents include Ascaris lumbricoides, FIORENTINI [70], VIJAYAN [71],
Toxocara canis, Wuchereria bancrofti, Brugia MING [72]
malayi and Strongyloides stercoralis; however,
typical eosinophilic pneumonia is rare
in this setting
Medication Antibiotics SPAGNOLO [73]
Nonsteroidal anti-inflammatory drugs
Other medication
Illicit drugs Cocaine, heroin, crack, BRANDER [74], SAUVAGET [75],
marijuana/cannabis NADEEM [76]
Noncigarette smoking Vaping, waterpipe smoking CHAABAN [77], PUEBLA NEIRA [78],
products and marijuana MULL [79]
Radiation therapy Up to 10 months after radiotherapy for breast COTTIN [80]
cancer in women, and rarely lung cancer
Pulmonary opacities may be unilateral
(irradiated lung) or bilateral, and
occasionally migrate
Bronchocentric Masses, alveolar opacities or consolidation, LIEBOW [81], KATZENSTEIN [82],
granulomatosis and possible reticulonodular opacities, WARD [83]
predominating in the upper lung zones and
generally unilateral
Hypereosinophilic Eosinophilic pneumonia is generally not CORDIER [84]
obliterative present, with the exception of
bronchiolitis hypereosinophilic obliterative bronchiolitis
occurring in the setting of EGPA, ABPA or
drug-induced eosinophilic lung disease
EGPA: eosinophilic granulomatosis with polyangiitis; ABPA: allergic bronchopulmonary aspergillosis.
288 https://doi.org/10.1183/2312508X.10019022
in IAEP and extrapulmonary organ failure does not occur. Hypoxaemia is related to right-to-left
shunting in areas with consolidation [29]. Hypoxaemia is therefore often refractory to breathing
100% oxygen [31, 39]. Although mechanical ventilation was necessary in a majority of patients
in earlier series [29, 39], more recent series have shown that the severity of IAEP is more varied
than originally reported [34].
When performed in less severe cases, PFTs show a mild restrictive ventilatory defect with a
normal ratio of forced expiratory volume in 1 s/FVC and reduced DLCO. After recovery, PFTs
are generally normal, with possible ventilatory restriction in some [29].
Lung biopsy
Lung biopsy or transbronchial lung biopsies are not necessary if the diagnosis of AEP is
suspected and BAL demonstrates alveolar eosinophilia. In older series, lung biopsy has shown
acute and organising diffuse alveolar damage together with interstitial alveolar and bronchiolar
infiltration by eosinophils, intra-alveolar eosinophils and interstitial oedema [29, 30, 46, 53, 54].
Treatment and prognosis

The exclusion of potential causes of AEP, especially infectious and drug-related causes, is key
to the management of patients with AEP. Recovery of IAEP can occur without corticosteroid
treatment [39, 50]. However, most patients diagnosed with IAEP receive a course of
corticosteroids, which is associated with rapid improvement [29], and most patients are rapidly
weaned from the ventilator. Clinical improvement generally begins within 3 days [34]. The
chest radiograph is normalised within 1 week in 85% of patients, but mild pulmonary infiltrates
and pleural effusion may still be present at CT at 2 weeks [34].
Corticosteroid treatment may be initiated with a daily dose of 30 mg of prednisone (or 60 mg of

i.v. methylprednisolone every 6 h in patients with respiratory failure), and tapered over 2 weeks
[34]. An even shorter treatment strategy (median 4 days) has been proposed for patients with
peripheral blood eosinophilia at presentation (who tend to have mild disease), with rapid
tapering of corticosteroids once clinical improvement has been obtained [55]. Given the short
duration of corticosteroid treatment and the lack of relapse, there is no indication for drugs
targeting the IL-5/IL-5R pathway in IAEP.
No relapse occurs after stopping treatment, in contrast to ICEP (table 3), except if cigarette
smoking is resumed after a period of abstinence. A relapse should lead the clinician to look for
a) b)
FIGURE 3 CT scan of a patient with allergic bronchopulmonary aspergillosis showing a) mucoid impaction, and
b) the tree-in-bud pattern and branching opacities in the left upper lobe.
https://doi.org/10.1183/2312508X.10019022 289
tobacco smoking, causative environmental exposures or another cause of AEP, especially

infectious or drug related. No significant clinical or imaging sequelae persist in the longer term.
Mortality is rare despite the frequent initial presentation with acute respiratory failure.
Other conditions
Eosinophilic pneumonias associated with other conditions are listed in table 4. Figure 3 shows
an example of allergic bronchopulmonary aspergillosis.
References
1 Cottin V. Eosinophilic lung diseases. In: Mason RJ, Ernst JD, King TE Jr, et al., eds. Murray and Nadel’s Textbook
of Respiratory Medicine. 7th Edn. Philadelphia, Elsevier, 2022; pp. 1322–1342.
2 Cottin V. Eosinophilic pneumonia. In: Cottin V, Cordier JF, Richeldi L, et al., eds. Orphan Lung Diseases:
A Clinical Guide to Rare Lung Disease. 2nd edn. London, Springer-Verlag, 2023 (in press).
3 Weller PF, Spencer LA. Functions of tissue-resident eosinophils. Nat Rev Immunol 2017; 17: 746–760.
4 Hogan SP, Rosenberg HF, Moqbel R, et al. Eosinophils: biological properties and role in health and disease. Clin
Exp Allergy 2008; 38: 709–750.
5 Wechsler ME, Munitz A, Ackerman SJ, et al. Eosinophils in health and disease: a state-of-the-art review. Mayo
Clin Proc 2021; 96: 2694–2707.
6 Blanchard C, Rothenberg ME. Biology of the eosinophil. Adv Immunol 2009; 101: 81–121.
7 O’Sullivan JA, Chang AT, Youngblood BA, et al. Eosinophil and mast cell Siglecs: from biology to drug target.
J Leukoc Biol 2020; 108: 73–81.
8 Carrington CB, Addington WW, Goff AM, et al. Chronic eosinophilic pneumonia. N Engl J Med 1969; 280: 787–798.
9 Jederlinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia. A report of 19 cases and a review of the
literature. Medicine (Baltimore) 1988; 67: 154–162.
10 Marchand E, Reynaud-Gaubert M, Lauque D, et al. Idiopathic chronic eosinophilic pneumonia. A clinical and
follow-up study of 62 cases. Medicine (Baltimore) 1998; 77: 299–312.
11 Liebow AA, Carrington CB. The eosinophilic pneumonias. Medicine (Baltimore) 1969; 48: 251–285.
12 Marchand E, Etienne-Mastroianni B, Chanez P, et al. Idiopathic chronic eosinophilic pneumonia and asthma:
how do they influence each other? Eur Respir J 2003; 22: 8–13.
13 Hayakawa H, Sato A, Toyoshima M, et al. A clinical study of idiopathic eosinophilic pneumonia. Chest 1994; 105:
1462–1466.
14 Johkoh T, Muller NL, Akira M, et al. Eosinophilic lung diseases: diagnostic accuracy of thin-section CT in 111
patients. Radiology 2000; 216: 773–780.
15 Furuiye M, Yoshimura N, Kobayashi A, et al. Churg–Strauss syndrome versus chronic eosinophilic pneumonia on
high-resolution computed tomographic findings. J Comput Assist Tomogr 2010; 34: 19–22.
16 Arakawa H, Kurihara Y, Niimi H, et al. Bronchiolitis obliterans with organizing pneumonia versus chronic
eosinophilic pneumonia: high-resolution CT findings in 81 patients. AJR Am J Roentgenol 2001; 176: 1053–1058.
17 Cottin V, Deviller P, Tardy F, et al. Urinary eosinophil-derived neurotoxin/protein X: a simple method for
assessing eosinophil degranulation in vivo. J Allergy Clin Immunol 1998; 101: 116–123.
18 Freymond N, Kahn JE, Legrand F, et al. Clonal expansion of T cells in patients with eosinophilic lung disease.
Allergy 2011; 66: 1506–1508.
19 Casoni GL, Tomassetti S, Cavazza A, et al. Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial
lung diseases. PLoS One 2014; 9: e86716.
20 Ussavarungsi K, Kern RM, Roden AC, et al. Transbronchial cryobiopsy in diffuse parenchymal lung disease:
retrospective analysis of 74 cases. Chest 2017; 151: 400–408.
21 McCarthy DS, Pepys J. Cryptogenic pulmonary eosinophilias. Clin Allergy 1973; 3: 339–351.
22 Olopade CO, Crotty TB, Douglas WW, et al. Chronic eosinophilic pneumonia and idiopathic bronchiolitis
obliterans organizing pneumonia: comparison of eosinophil number and degranulation by immunofluorescence
staining for eosinophil-derived major basic protein. Mayo Clin Proc 1995; 70: 137–142.
23 Suzuki Y, Oyama Y, Hozumi H, et al. Persistent impairment on spirometry in chronic eosinophilic pneumonia:
a longitudinal observation study (Shizuoka-CEP study). Ann Allergy Asthma Immunol 2017; 119: 422–428.e2.
24 Durieu J, Wallaert B, Tonnel AB. Long term follow-up of pulmonary function in chronic eosinophilic
pneumonia. Eur Respir J 1997; 10: 286–291.
25 Oyama Y, Fujisawa T, Hashimoto D, et al. Efficacy of short-term prednisolone treatment in patients with chronic
eosinophilic pneumonia. Eur Respir J 2015; 45: 1624–1631.
26 Minakuchi M, Niimi A, Matsumoto H, et al. Chronic eosinophilic pneumonia: treatment with inhaled
corticosteroids. Respiration 2003; 70: 362–366.
290 https://doi.org/10.1183/2312508X.10019022
27 Wechsler ME, Wong DA, Miller MK, et al. Churg–Strauss syndrome in patients treated with omalizumab. Chest
2009; 136: 507–518.
28 Cazzola M, Mura M, Segreti A, et al. Eosinophilic pneumonia in an asthmatic patient treated with omalizumab
therapy: forme-fruste of Churg–Strauss syndrome? Allergy 2009; 64: 1389–1390.
29 Pope-Harman AL, Davis WB, Allen ED, et al. Acute eosinophilic pneumonia. A summary of 15 cases and a
review of the literature. Medicine (Baltimore) 1996; 75: 334–342.
30 Tazelaar HD, Linz LJ, Colby TV, et al. Acute eosinophilic pneumonia: histopathologic findings in nine patients.
31 Allen JA. Acute eosinophilic pneumonia. Semin Respir Crit Care Med 2006; 27: 142–147.
32 Cheon JE, Lee KS, Jung GS, et al. Acute eosinophilic pneumonia: radiographic and CT findings in six patients.
33 King MA, Pope-Harman AL, Allen JN, et al. Acute eosinophilic pneumonia: radiologic and clinical features.
Radiology 1997; 203: 715–719.
34 Rhee CK, Min KH, Yim NY, et al. Clinical characteristics and corticosteroid treatment of acute eosinophilic
pneumonia. Eur Respir J 2013; 41: 402–409.
35 Sine CR, Hiles PD, Scoville SL, et al. Acute eosinophilic pneumonia in the deployed military setting. Respir Med
2018; 137: 123–128.
36 Ajani S, Kennedy CC. Idiopathic acute eosinophilic pneumonia: a retrospective case series and review of the
literature. Respir Med Case Rep 2013; 10: 43–47.
37 de Giacomi F, Vassallo R, Yi ES, et al. Acute eosinophilic pneumonia. causes, diagnosis, and management. Am J
38 de Giacomi F, Decker PA, Vassallo R, et al. Acute eosinophilic pneumonia: correlation of clinical characteristics
with underlying cause. Chest 2017; 152: 379–385.
39 Philit F, Etienne-Mastroianni B, Parrot A, et al. Idiopathic acute eosinophilic pneumonia: a study of 22 patients.
40 Ota K, Sasabuchi Y, Matsui H, et al. Age distribution and seasonality in acute eosinophilic pneumonia: analysis
using a national inpatient database. BMC Pulm Med 2019; 19: 38.
41 Uchiyama H, Suda T, Nakamura Y, et al. Alterations in smoking habits are associated with acute eosinophilic
pneumonia. Chest 2008; 133: 1174–1180.
42 Rom WN, Weiden M, Garcia R, et al. Acute eosinophilic pneumonia in a New York City firefighter exposed to
World Trade Center dust. Am J Respir Crit Care Med 2002; 166: 797–800.
43 Arter ZL, Wiggins A, Hudspath C, et al. Acute eosinophilic pneumonia following electronic cigarette use. Respir
Med Case Rep 2019; 27: 100825.
44 Thota D, Latham E. Case report of electronic cigarettes possibly associated with eosinophilic pneumonitis in a
previously healthy active-duty sailor. J Emerg Med 2014; 47: 15–17.
45 Henry TS, Kligerman SJ, Raptis CA, et al. Imaging findings of vaping-associated lung injury. AJR Am J
Roentgenol 2020; 214: 498–505.
46 Lee MH, Cool CD, Maloney JP. Histopathological correlation of acute on chronic eosinophilic pneumonitis
caused by vaporized cannabis oil inhalation. Chest 2021; 159: e137–e139.
47 Daimon T, Johkoh T, Sumikawa H, et al. Acute eosinophilic pneumonia: thin-section CT findings in 29 patients.
Eur J Radiol 2008; 65: 462–467.
48 Jhun BW, Kim SJ, Kim K, et al. Clinical implications of initial peripheral eosinophilia in acute eosinophilic
pneumonia. Respirology 2014; 19: 1059–1065.
49 Choi JY, Lim JU, Jeong HJ, et al. Association between peripheral blood/bronchoalveolar lavage eosinophilia
and significant oxygen requirements in patients with acute eosinophilic pneumonia. BMC Pulm Med 2020; 20: 22.
50 Miyazaki E, Nureki S, Ono E, et al. Circulating thymus- and activation-regulated chemokine/CCL17 is a useful
biomarker for discriminating acute eosinophilic pneumonia from other causes of acute lung injury. Chest 2007;
131: 1726–1734.
51 Park SY, Kim JH, Chung MJ, et al. Acute eosinophilic pneumonia and tracheitis associated with smoking. Am J
52 Thompson BT, Moss M. A new definition for the acute respiratory distress syndrome. Semin Respir Crit Care Med
2013; 34: 441–447.
53 Mochimaru H, Kawamoto M, Fukuda Y, et al. Clinicopathological differences between acute and chronic
eosinophilic pneumonia. Respirology 2005; 10: 76–85.
54 Kawayama T, Fujiki R, Morimitsu Y, et al. Fatal idiopathic acute eosinophilic pneumonia with acute lung injury.
Respirology 2002; 7: 373–375.
55 Jhun BW, Kim SJ, Kim K, et al. Outcomes of rapid corticosteroid tapering in acute eosinophilic pneumonia
patients with initial eosinophilia. Respirology 2015; 20: 1241–1247.
56 Kim YK, Lee KS, Chung MP, et al. Pulmonary involvement in Churg–Strauss syndrome: an analysis of CT,
clinical, and pathologic findings. Eur Radiol 2007; 17: 3157–3165.
https://doi.org/10.1183/2312508X.10019022 291
57 Price M, Gilman MD, Carter BW, et al. Imaging of eosinophilic lung diseases. Radiol Clin North Am 2016; 54:
1151–1164.
58 Szczeklik W, Sokolowska B, Mastalerz L, et al. Pulmonary findings in Churg–Strauss syndrome in chest X-rays
and high resolution computed tomography at the time of initial diagnosis. Clin Rheumatol 2010; 29: 1127–1134.
59 Valent P, Klion AD, Horny HP, et al. Contemporary consensus proposal on criteria and classification of
eosinophilic disorders and related syndromes. J Allergy Clin Immunol 2012; 130: 607–612.
60 Dulohery MM, Patel RR, Schneider F, et al. Lung involvement in hypereosinophilic syndromes. Respir Med 2011;
105: 114–121.
61 Simon HU, Plotz SG, Dummer R, et al. Abnormal clones of T cells producing interleukin-5 in idiopathic
eosinophilia. N Engl J Med 1999; 341: 1112–1120.
62 Roufosse F, Schandene L, Sibille C, et al. Clonal Th2 lymphocytes in patients with the idiopathic
hypereosinophilic syndrome. Br J Haematol 2000; 109: 540–548.
63 Chusid MJ, Dale DC, West BC, et al. The hypereosinophilic syndrome: analysis of fourteen cases with review of
the literature. Medicine (Baltimore) 1975; 54: 1–27.
64 Fauci AS, Harley JB, Roberts WC, et al. The idiopathic hypereosinophilic syndrome : clinical, pathophysiologic
and therapeutic considerations. Ann Intern Med 1982; 97: 78–92.
65 Mitchell TA, Hamilos DL, Lynch DA, et al. Distribution and severity of bronchiectasis in allergic
bronchopulmonary aspergillosis (ABPA). J Asthma 2000; 37: 65–72.
66 Refait J, Macey J, Bui S, et al. CT evaluation of hyperattenuating mucus to diagnose allergic bronchopulmonary
aspergillosis in the special condition of cystic fibrosis. J Cyst Fibros 2019; 18: e31–e36.
67 Ward S, Heyneman L, Lee MJ, et al. Accuracy of CT in the diagnosis of allergic bronchopulmonary aspergillosis
in asthmatic patients. AJR Am J Roentgenol 1999; 173: 937–942.
68 Cordier JF, Cottin V. Eosinophilic pneumonias. In: Schwarz MI, King TE Jr, eds. Interstitial Lung Disease. 5th
edn. Shelton, People’s Medical Publishing House, 2011; pp. 833–893.
69 Vijayan VK. How to diagnose and manage common parasitic pneumonias. Curr Opin Pulm Med 2007; 13: 218–224.
70 Fiorentini LF, Bergo P, Meirelles GSP, et al. Pictorial review of thoracic parasitic diseases: a radiologic guide.
Chest 2020; 157: 1100–1113.
71 Vijayan VK. Tropical pulmonary eosinophilia: pathogenesis, diagnosis and management. Curr Opin Pulm Med
2007; 13: 428–433.
72 Ming DK, Armstrong M, Lowe P, et al. Clinical and diagnostic features of 413 patients treated for imported
strongyloidiasis at the Hospital for Tropical Diseases, London. Am J Trop Med Hyg 2019; 101: 428–431.
73 Spagnolo P, Bonniaud P, Rossi G, et al. Drug-induced interstitial lung disease. Eur Respir J 2022; 60: 2102776.
74 Brander PE, Tukiainen P. Acute eosinophilic pneumonia in a heroin smoker. Eur Respir J 1993; 6: 750–752.
75 Sauvaget E, Dellamonica J, Arlaud K, et al. Idiopathic acute eosinophilic pneumonia requiring ECMO in a
teenager smoking tobacco and cannabis. Pediatr Pulmonol 2010; 45: 1246–1249.
76 Nadeem S, Nasir N, Israel RH. Loffler’s syndrome secondary to crack cocaine. Chest 1994; 105: 1599–1600.
77 Chaaban T. Acute eosinophilic pneumonia associated with non-cigarette smoking products: a systematic
review. Adv Respir Med 2020; 88: 142–146.
78 Puebla Neira D, Tambra S, Bhasin V, et al. Discordant bilateral bronchoalveolar lavage findings in a patient with
acute eosinophilic pneumonia associated with counterfeit tetrahydrocannabinol oil vaping. Respir Med Case
Rep 2020; 29: 101015.
79 Mull ES, Erdem G, Nicol K, et al. Eosinophilic pneumonia and lymphadenopathy associated with vaping and
tetrahydrocannabinol use. Pediatrics 2020; 145; e20193007.
80 Cottin V, Frognier R, Monnot H, et al. Chronic eosinophilic pneumonia after radiation therapy for breast cancer.
Eur Respir J 2004; 23: 9–13.
81 Liebow AA. The J. Burns Amberson lecture – pulmonary angiitis and granulomatosis. Am Rev Respir Dis 1973;
108: 1–18.
82 Katzenstein AL, Askin FB. Katzenstein and Askin’s Surgical Pathology of Non-Neoplastic Lung Disease. 3rd edn.
Philadelphia, WB Saunders, 1997.
83 Ward S, Heyneman LE, Flint JD, et al. Bronchocentric granulomatosis: computed tomographic findings in five
patients. Clin Radiol 2000; 55: 296–300.
84 Cordier JF, Cottin V, Khouatra C, et al. Hypereosinophilic obliterative bronchiolitis: a distinct, unrecognised
syndrome. Eur Respir J 2013; 41: 1126–1134.
Disclosures: V. Cottin reports the following, outside the submitted work: consulting fees from AstraZeneca; and
from AstraZeneca and GSK.
292 https://doi.org/10.1183/2312508X.10019022
Chapter 21
Sarcoidosis
1 2
Francesco Bonella , W. Ennis James and Paolo Spagnolo3
1
Pneumology Dept, Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik University Hospital, University of
Duisburg-Essen, Essen, Germany. 2Division of Pulmonary and Critical Care Medicine, Susan Pearlstine Sarcoidosis
Center of Excellence, Medical University of South Carolina, Charleston, SC, USA. 3Respiratory Disease Unit, Dept of
Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy.
Corresponding author: Francesco Bonella (francesco.bonella@rlk.uk-essen.de)
Cite as: Bonella F, James WE, Spagnolo P. Sarcoidosis. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare
[https://doi.org/10.1183/2312508X.10019122].
@ERSpublications
Understanding the complexity of sarcoidosis presentations, high-risk organ manifestations and complications
of advanced disease is a basic requirement for adopting the most appropriate treatment strategy and
improving patient outcomes https://bit.ly/ERSM100
ISSN: 2312-5098.
Sarcoidosis has highly variable clinical presentations and outcomes, which make the diagnosis and
management challenging. The lung is the most frequently involved organ, but radiological appearance,
functional impairment and respiratory symptoms are not specific. Multiple tools are available to assist
clinicians in excluding alternative causes of respiratory symptoms and assessing disease activity that may
respond to treatment. Cardiac, neurological and renal involvements are life-threatening manifestations of
sarcoidosis requiring a close follow-up and prompt changes in the treatment strategy if patients continue
to deteriorate. New imaging and molecular biomarkers are in development to better characterise the extent
of sarcoidosis in different organs and possibly guide treatment decisions. The most recent guideline on
sarcoidosis treatment recommends steroids as the first-line therapy in several organ manifestations,
although evidence is limited. Further immunosuppressive treatment should be considered to spare steroids
or in those patients with contraindications. Despite several negative clinical trials in the last decade,
promising compounds mainly targeting immunological mechanisms underlying sarcoidosis pathogenesis
are currently being tested in phase II and III trials, the results of which are expected in the next few years.
Introduction
Sarcoidosis is a systemic disease characterised by the formation of granulomas in several organs,
leading to a variety of clinical manifestations. In some countries, sarcoidosis is no longer classified
as a rare disease, but epidemiology varies according to geographical region: the prevalence ranges
from 2.2 in Taiwan to 160 in Sweden per 100 000 of the population [1]. The pathogenesis is
complex and not fully understood, whereas the interaction between genes and environment, the
activation of specific lymphocytes subpopulations and the release of pro-inflammatory cytokines
have been investigated intensively in the last decades. Innate immunity probably represents the
“missing link” to the initiation, maintenance and resolution of noncaseating granulomas [2].
In this chapter, we illustrate the most common and life-threatening clinical manifestations of
sarcoidosis and provide an overview of new diagnostic tools and drugs in development.
https://doi.org/10.1183/2312508X.10019122 293
Lung sarcoidosis
Lung involvement is observed in 90% of sarcoidosis patients. The clinical findings and outcomes
of pulmonary sarcoidosis are highly variable. Most patients will have spontaneous remission, but
up to 30% of patients will have chronic disease and ∼20% will develop fibrotic pulmonary
sarcoidosis [3–7]. Compared with the population at large, sarcoidosis patients have higher mortality
rates (2.8 and 4.3 per million of the population aged >12 and >20 years, respectively), and
mortality most often results from complications of fibrotic pulmonary sarcoidosis [8–12]. Recent
evidence suggests higher mortality rates in African Americans compared with Caucasians [13].
Up to 60% of pulmonary sarcoidosis patients, especially those with stage I disease, are
asymptomatic and may be diagnosed incidentally. When symptomatic, 30–50% of patients may
present with a nonproductive cough, dyspnoea and chest pain. Generalised symptoms such as
fevers, night sweats and weight loss can be present [14–16]. Fatigue is the most reported
symptom in sarcoidosis patients and is a better predictor of quality of life. Physical examination
findings are often normal, and respiratory abnormalities such as crackles are present in <20% of
patients. Wheezing, usually resulting from proximal airway narrowing or endobronchial disease,
is rare [17–19]. Digital clubbing and peripheral cyanosis are observed in those with end-stage
lung disease [18, 20–22].
The prevalence of radiographic abnormalities can range from 67% to 93% and most commonly
includes bilateral hilar adenopathy [4, 23]. Parenchymal abnormalities, typically in the upper
and mid-lung zones, are present bilaterally in 35–50% of patients [4, 24]. Unilateral adenopathy
or parenchymal abnormalities are atypical, and pleural effusions and spontaneous pneumothorax
are rare [25, 26].
The Scadding stages for pulmonary sarcoidosis, first published in 1961, have a poor correlation
with symptoms, PFTs and disease severity (table 1, figure 1) [28–31].
Conversely, CT imaging has a stronger correlation with PFT trends than plain radiographs and
can better delineate parenchymal abnormalities and adenopathy [32–35]. Mediastinal and/or
hilar adenopathy are typically symmetrical and homogeneous, and may be calcified in ∼50% of
patients [36, 37]. Typical parenchymal abnormalities include bilateral/symmetric nodular
opacities and micronodules in a perilymphatic distribution in the upper and mid-lung zones
(figure 2). The “galaxy sign” (confluent nodules in a mass surrounded by numerous smaller
nodules) is more commonly observed in sarcoidosis (23%) than in pulmonary tuberculosis (2%)
[38]. Patchy ground-glass opacities may also be seen [5].
In terms of lung function impairment, most sarcoidosis patients have normal PFTs [39, 40].
Abnormal PFTs are observed in up to 20% of patients with hilar adenopathy only, compared
TABLE 1 Pulmonary sarcoidosis: radiographic stages and clinical outcomes
Radiographic stage Radiographic description Frequency, % Resolution, %
I BHL 25–65 60–90

II BHL and pulmonary infiltrates 20–40 40–70
III Pulmonary infiltrates without BHL 10–15 10–20
IV Pulmonary fibrosis 5 0
A normal chest radiography, sometimes referred to as stage 0, can be observed in 5–15% of patients. BHL:
bilateral hilar adenopathy. Reproduced and modified from [27] with permission.
294 https://doi.org/10.1183/2312508X.10019122
SARCOIDOSIS | F. BONELLA ET AL.
a) b)
c) d)
FIGURE 1 Chest radiograph appearance of Scadding stages: a) stage I, b) stage II, c) stage III, d) stage IV.
a) b)
FIGURE 2 HRCT patterns of pulmonary sarcoidosis: a) “galaxy sign” (arrows) in a 48-year-old man, b) nodular
pulmonary sarcoidosis. Reproduced and modified from [27] with permission.
https://doi.org/10.1183/2312508X.10019122 295
with 40–80% of patients with parenchymal lung disease on chest imaging. A reduction in DLCO
is the most common abnormality observed overall [39, 41, 42]. Airflow obstruction is more
commonly observed in patients with advanced fibrocystic disease or proximal airway
involvement, while restriction and a reduced DLCO are more common in those with predominant
fibrosis [3, 6, 43–45].
Principles of diagnosis
Three criteria are required for a diagnosis of pulmonary sarcoidosis: 1) a compatible clinical
presentation, 2) histological evidence of granulomatous inflammation, and 3) exclusion of other
causes (figure 3) [46]. Certain characteristic presentations of sarcoidosis, including Löfgren
syndrome, lupus pernio, Heerfordt syndrome and asymptomatic bilateral hilar adenopathy, may
not need to undergo biopsy. For those patients with asymptomatic hilar adenopathy not
undergoing biopsy, a close clinical follow-up is recommended [46, 48]. All patients with
systemic symptoms such as weight loss, fevers or night sweats and imaging findings concerning
for pulmonary sarcoidosis should undergo biopsy if possible. Endobronchial ultrasound-guided
(EBUS) lymph-node sampling of mediastinal/hilar nodes has a diagnostic yield of 87% (95% CI
94–91%) and is recommended over mediastinoscopy [46, 49]. Other bronchoscopic biopsy
methods can be considered if EBUS is not available, such as endobronchial or transbronchial
lung biopsy [18, 49–54]. BAL fluid analysis, which typically shows a lymphocyte count >15%,
especially if accompanied by a CD4/CD8 ratio >3.5, can significantly strengthen suspicion of
the disease and may be helpful to exclude alternative diagnoses [46].
Clinical and radiological

presentation
Highly suggestive of sarcoidosis Consistent with sarcoidosis

• Asymptomatic bilateral hilar
adenopathy
• Heerfordt syndrome
• Löfgren syndrome
• Lupus pernio Biopsy
Probable sarcoidosis Non-necrotising Not consistent

Negative and
granulomatous with
inadequate
inflammation sarcoidosis
Alternative
Re-evaluate/consider Consider repeating
granulomatous
alternative diagnosis biopsy
disease excluded
Probable sarcoidosis
FIGURE 3 Diagnostic algorithm for sarcoidosis derived from the most recent diagnostic guidelines. Reproduced
and modified from [47] with permission.
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The recently proposed sarcoidosis diagnostic score (SDS), based on the World Association of
Sarcoidosis and Other Granulomatous disorders (WASOG) clinical manifestations, is a
promising scoring system to help in making a diagnosis of sarcoidosis [55].
Management and treatment

The most recent guideline recommends treatment in patients with life-threatening
manifestations, when functional impairment is present, or when symptoms significantly affect
quality of life [56]. Treatment is not needed in most sarcoidosis patients, such as asymptomatic
patients with radiographic stage I disease and those with stable disease [57–59]. Conversely,
advising treatment when lung function impairment or increased risk for mortality or permanent
disability is present can avoid long-term side-effects and drug-related complications [56]. In
some patients, the indication for treatment is determined by extrapulmonary involvement.
In pulmonary sarcoidosis, prednisone is generally the first-line treatment, with 20 mg representing

the recommended daily dose by the European Respiratory Society (ERS) treatment guideline
[19, 56], although the optimal dose should be tailored for individual patients balancing the clinical
and/or functional benefit and the risk of toxicity. In cardiac sarcoidosis (CS), higher prednisolone
doses are required (0.5 mg·kg−1) [56]. Tapering schedules should similarly be individualised, with
<10 mg daily representing the ideal maintenance dose. In patients experiencing disease
progression despite steroid therapy or in those who are unable to tolerate it, methotrexate is the
preferred second-line agent for several organ manifestations, according to both ERS guidelines
and Delphi consensus recommendations [56, 60]. A third-line agent such as infliximab should be
considered in patients whose disease is refractory to second-line agents or in those who cannot
tolerate them [60]. For more detailed recommendations on treatment, including second- and
third-line treatment options, we suggest the recently published guidelines [56].
The management of sarcoidosis can be demanding, and clinicians should be aware that
extrapulmonary manifestations and complications can develop over time. Accurate screening
and adequate follow-up are therefore mandatory (table 2). For complications such as fibrotic
pulmonary sarcoidosis, which is associated with a higher mortality risk, a complex management
is required, including timely referral to lung transplantation. Data on the use of antifibrotics in
fibrotic pulmonary sarcoidosis are limited [56].
A recent survey revealed that sarcoidosis patients want quality of life and functionality to be the
core outcomes of their treatment and care [61]. Once treatment has been started, the occurrence
of drug toxicity should be carefully monitored and the treatment response regularly assessed.
Life-threatening manifestations of sarcoidosis

Cardiac sarcoidosis
CS is clinically evident in ∼5% of patients with systemic disease, although post-mortem and
advanced imaging studies suggest significantly higher prevalence rates [62–64]. Cardiac
involvement can be benign and discovered incidentally, or may manifest as arrhythmias or
unexplained heart failure [62]. In addition, cardiac symptoms may precede systemic
manifestations of the disease, thus representing a diagnostic dilemma; such cases may account
for as many as 25% of all CS cases [65].
Clinical manifestations of CS depend on the location and extent of myocardial damage, with
conduction system disease (i.e. atrioventricular block) representing the most common presentation,
followed by supraventricular and ventricular tachyarrhythmias. Supraventricular arrhythmias
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TABLE 2 Assessment for extrathoracic disease at baseline according to the most recent guidelines
Organ/tissue of disease No symptoms/signs of Clinical suspicion of

extrathoracic disease extrathoracic disease
Haematological abnormalities Complete blood cell count

Ocular sarcoidosis Eye examination
Renal sarcoidosis Serum creatinine testing
Hepatic sarcoidosis Serum alkaline phosphatase
Serum transaminase (optional)
Cardiac sarcoidosis ECG MRI
TTE and 24 h ECG (Holter) to be Cardiac PET (if MRI is unavailable)
considered on a case-by-case basis
Calcium metabolism Serum calcium testing
PH TTE
Right-heart catheterisation (when TTE is
suggestive of PH, or on a case-by-case
basis if the suspicion of PH remains
strong after a negative TTE)
Vitamin D metabolism 25- and 1,25-dihydroxyvitamin D levels
in patients being evaluated for
possible vitamin D replacement
TTE: transthoracic echocardiography; PET: positron emission tomography. Reproduced and modified from [47]
with permission.
(i.e. paroxysmal atrial tachycardia, atrial flutter and atrial fibrillation), cardiomyopathy and heart
failure are also common [66]. The most common symptoms are palpitations, reduced exercise
tolerance, and presyncope, syncope and dyspnoea disproportionate to the extent of pulmonary
disease. Sudden death is the first manifestation of the disease in ∼15% of CS cases [67].
Because of the potential life-threatening nature of CS, all patients newly diagnosed with
sarcoidosis should be screened for cardiac involvement using clinical history, physical
examination and a 12-lead ECG [46]. Diagnosis of CS requires the integration of clinical data
and advanced cardiac imaging, with cardiac MRI with gadolinium-based contrast representing
the preferred imaging technique. The most typical, although not pathognomonic, morphological
abnormality detected by cardiac MRI is the presence of multifocal regions of late gadolinium
enhancement, which generally represent scar tissue. Most importantly, cardiac MRI has a high
negative predictive value for excluding CS when no areas of late gadolinium enhancement are
detected. If cardiac MRI cannot be performed (because of the presence of an incompatible
device or contraindications for gadolinium), 18F-fluorodeoxyglucose positron emission
tomography (18F-FDG-PET) with a dedicated PET camera is the alternative initial diagnostic
test. However, FDG uptake is not specific for sarcoidosis, as it can be seen in other myocardial
inflammatory diseases. Cardiac MRI and 18F-FDG-PET provide complementary information,
with the former informing about the presence and extent of scar tissue and the latter about the
presence, extent and severity of myocardial inflammation. Histological evidence of myocardial
granulomatous inflammation, particularly in cases of isolated CS or in the absence of
histological confirmation of noncaseating granulomas from other sources, provides the most
reliable means for diagnosing CS; however, endomyocardial biopsy has a low sensitivity, due to
the patchy distribution of the disease, and may expose patients to risks [68]. Overall, no single
tool can reliably detect early CS, and the best diagnostic strategy remains clinical suspicion of
cardiac involvement. For patients with extracardiac sarcoidosis but without CS at baseline, most
experts recommend yearly clinical re-evaluation with ECG to detect potential signs of CS.
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The treatment of CS consists of both immunosuppressive therapies, aimed at reducing

inflammation and thus preventing the development of fibrosis or cardiac dysfunction, and
appropriate management of arrhythmias and heart failure. Treatment is almost invariably
required, as spontaneous remission is rare [69]. Similar to extracardiac sarcoidosis,
corticosteroids are the most commonly used drugs, although there is no consensus on dosing or
duration of therapy [70]. Most experts initiate prednisone (or equivalent) at a daily dose of
40–60 mg with a taper regimen similar to that for pulmonary sarcoidosis [69]. Corticosteroid
treatment is generally continued for 1–2 years, but relapses are common after tapering or
discontinuation of therapy. If corticosteroids fail to induce remission or are not tolerated,
methotrexate is the preferred second-line agent [56], although it can be added at the same time
as prednisone is initiated. Anti-tumour necrosis factor (TNF) agents (i.e. infliximab) are
reserved for patients with refractory or progressive disease or who are intolerant to other agents
[56]. Infliximab is generally contraindicated in the case of severe heart failure (New York Heart
Association class III–IV). Rituximab may represent an alternative to infliximab [71].
The standard indications for a permanent pacemaker (i.e. complete atrioventricular block or
other high-grade conduction system disease) or for an implantable cardioverter defibrillator
(i.e. patients at highest risk of ventricular arrhythmias and sudden cardiac death) also apply to CS.
Heart transplantation should be considered in patients with refractory ventricular arrhythmias or
end-stage heart failure [72].
Neurosarcoidosis
Neurosarcoidosis (NS) occurs in 5–10% of all sarcoidosis patients, although one study
identified clinically occult disease in up to 34% of cases [73]. At presentation, only about
one-third of NS patients have systemic disease, whereas in 10–20% of cases, NS remains
isolated [74]. NS is an early manifestation, with ∼75% of patients developing NS within 2 years
of the diagnosis of sarcoidosis [75]. Any part of the nervous system can be involved, but the
cranial nerves (mainly optic, facial and vestibulocochlear nerves), meninges ( pachy- or
leptomeningitis), spinal cord (myelopathy) and peripheral nerves are most affected [76, 77]. NS
can cause optic neuritis secondary to chiasmal involvement or compressive optic neuropathy by
infiltrating or mass-like lesions. Hypothalamus/pituitary axis involvement may lead to endocrine
dysfunction that can manifest as hypopituitarism, hyperprolactinaemia and diabetes insipidus
[78]. Brain parenchymal disease may present as mass-like lesions causing seizures and focal
deficits. Encephalopathy, vasculopathy and neuropsychiatric manifestations are rarer
complications. Small-fibre neuropathy is a common manifestation of sarcoidosis and is believed
to underlie a variety of symptoms [79]. The diagnosis of NS should be suspected when
neurological symptoms develop in patients with an established diagnosis of sarcoidosis.
Conversely, NS that manifests in isolation is a diagnostic challenge. Based on diagnostic
certainty, NS is categorised as definite, probable and possible [80]. When performed,
cerebrospinal fluid analysis reveals pleocytosis with lymphocyte predominance, elevated protein
levels and hypoglycorrhachia, but these abnormalities are neither sensitive nor specific for NS.
If NS is suspected, gadolinium-enhanced MRI is the imaging procedure of choice. Gadolinium
enhancement is not a specific finding but is a marker of active disease.
Corticosteroids are the first-line therapy [81], although treatment recommendations derive from
expert opinion or small uncontrolled case series. The dose and duration of therapy depend on
disease severity and the response to treatment. For instance, manifestations such as altered
mental status, visual loss or rapidly progressive disease may require intravenous
methylprednisolone at a dose of 1 g·day–1 for 3–5 days [81, 82]. Due to the high risk of disease
recurrence, a slow prednisone taper is recommended. Methotrexate is the most common
https://doi.org/10.1183/2312508X.10019122 299
second-line (and corticosteroid-sparing) agent, but some experts suggest early combination of
corticosteroids and methotrexate in order to prevent symptom recurrence as corticosteroids are
gradually tapered [81]. Potential alternatives to methotrexate include azathioprine, cyclosporine,
cyclophosphamide and mycophenolate mofetil [77].
Similar to pulmonary and extrapulmonary sarcoidosis, NS refractory to other immunosuppressive

treatments may respond to infliximab [83]. Small-fibre neuropathy generally responds poorly to
standard therapy, with i.v. immunoglobulin and biological agents representing more efficacious
therapeutic options [84].
Renal sarcoidosis
Renal involvement is a rare but potentially serious complication of sarcoidosis that is commonly
undetected. In a French cohort of 1237 patients with pulmonary sarcoidosis, kidney disease was
present in 12% of cases [85]. The classical pathology of renal sarcoidosis is granulomatous
interstitial nephritis [86], which generally presents with elevated creatinine. When present,
sarcoid-related interstitial nephritis is an early manifestation of sarcoidosis, whereas it rarely
develops in patients with long-standing disease [87]. In the absence of a known diagnosis of
extrarenal disease, the diagnosis of sarcoidosis interstitial nephritis requires a renal biopsy,
although the presence of noncaseating granulomatous inflammation is suggestive but not
pathognomonic of sarcoidosis [88]. Disordered calcium metabolism, the most common
manifestation of renal sarcoidosis, is characterised by the uncontrolled synthesis of calcitriol (the
active metabolite of vitamin D) by activated macrophages. Calcitriol increases the
gastrointestinal absorption of ingested calcium and stimulates bone resorption [89], resulting in
increased hypercalciuria (in ∼40% of cases) and/or hypercalcaemia (in 2–20% of cases), which,
in turn, can cause nephrocalcinosis and nephrolithiasis [90]. Notably, similar abnormalities in
calcium metabolism can occur in other chronic granulomatous diseases. Glomerulonephritis is a
rarer presentation of the disease. Other causes of hypercalcaemia should be ruled out, for
example by measuring serum levels of calcitriol and parathyroid hormone.
In the case of hypercalcaemia, hypercalciuria or deterioration of renal function, corticosteroids

represent the first-line therapy. Corticosteroids rapidly normalise hypercalcaemia and
hypercalciuria. Calcium-rich foods, exposure to sunlight, and vitamin D and calcium
supplements should be avoided. Second-line (methotrexate, azathioprine) and third-line
(anti-TNF) agents are generally reserved for refractory disease or for patients intolerant to
corticosteroids.
New diagnostic and disease assessment tools

Imaging techniques play a pivotal role in the diagnosis and management of sarcoidosis. Besides
the well-established role of HRCT, evaluation of extrapulmonary localisation of sarcoidosis
requires additional imaging techniques such as PET and MRI. There have been impressive
advances in the nuclear imaging techniques field, and multimodal imaging is increasingly used
in the clinical routine for screening and follow-up of sarcoidosis.
Recent advances in CT and reconstruction software technology have led to a significant

reduction of the ionising radiation dose associated with this imaging modality and to the
introduction of low-dose CT, with radiation doses ranging from 1 to 2 mSv, and ultra-low-dose
CT, with a radiation dose of <1 mSv [91]. Although data in sarcoidosis are limited, low-dose CT
should be considered, especially in young patients and in those requiring repeated CT [91].
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18
F-FDG-PET is used to detect high glucose metabolism in malignancies and to identify
infectious or inflammatory foci [92, 93]. In sarcoidosis, inflammatory cells such as activated
macrophages and lymphocytes at the site of inflammation are responsible for the accumulation
of 18F-FDG [94–96].
In combination with CT, PET is more accurate for evaluating organ morphology and detecting
extrapulmonary involvement [54, 57]. The value of PET for screening for the presence of CS
has been illustrated in the previous section.
Interobserver agreement for PET is higher than for the widely used 67Ga scintigraphy, and is
less time-consuming [97]. Due to radiation exposure, costs and its limited availability, PET/CT
still cannot be recommended for routine work-up in sarcoidosis.
Performing a PET scan for the assessment of inflammatory activity is of added value in patients
with persistent disabling symptoms in the absence of signs of serological inflammatory activity,
or with lung functional or chest radiographic deterioration [98]. In advanced pulmonary
sarcoidosis, separating residual inflammation, which is potentially reversible, from fibrotic tissue
can be useful to drive therapeutic decisions (figure 4) [100].
18
F-FDG-PET maximal standard uptake value (SUVmax) has been investigated as an imaging
biomarker in several studies with promising results [101–103]. 18F-FDG-PET SUVmax was
found to predict a decline in DLCO after treatment stopped [102] and to correlate with clinical
improvement after initiating or modifying immunosuppressive therapy and to predict the
response, particularly in pulmonary disease [101–104].
Whether total lung glycolysis or volumetric 18F-FDG-PET analysis is superior to SUVmax as an

imaging biomarker for evaluation of sarcoidosis activity remains open [99].
Novel radiopharmaceutical PET tracers represent a rapidly evolving research field in nuclear
medicine, particularly for CS and NS [105]. The use of alternative, more specific tracers such as
68
Ga-DOTA-NaI-octreotide and 3′-deoxy-3′-18F-fluorothymidine may provide additional benefits
compared with 18F-FDG for the assessment of specific organ involvement in sarcoidosis [99, 106,
107], but more evidence is needed to confirm the added value of such tracers.
a) b)
FIGURE 4 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/CT findings in sarcoidosis with

signs of pulmonary fibrosis. a) Axial CT of the chest showing perihilar parenchymal consolidations,
reticulonodular opacities and architectural distortion of the parenchyma. b) The corresponding 18F-FDG-PET/CT
fusion image showing increased tracer uptake in the areas of consolidation as well as in the reticulonodular
opacities. Reproduced and modified from [99] with permission.
https://doi.org/10.1183/2312508X.10019122 301
In conclusion, further prospective, multicentre and large studies are mandatory to identify the
standard response criteria for PET and to validate PET-driven therapy in sarcoidosis.
Besides its established diagnostic and prognostic role in CS [46], MRI has been also
investigated for assessing pulmonary sarcoidosis. A good correlation between MRI and HRCT
for parenchymal opacifications and a weaker one for smaller nodules has been shown [108].
Proton MRI methods and contrast enhancement using hyperpolarised helium (3He) and xenon
(129Xe) offer the possibility of imaging ILD and structural changes at greater resolution and
assessing pulmonary perfusion [109–111]. These new techniques have mostly been investigated
in ILD, but a possible application in sarcoidosis is expected [91].
Although artificial intelligence-based imaging in ILD is currently undergoing accelerated

development, quantitative CT and deep learning have not been applied in pulmonary sarcoidosis
so far, and only sparse data are available in CS. Given the unmet needs and unresolved
questions about phenotyping and severity assessment in sarcoidosis, a wider exploration of these
technologies in the future is warranted [112].
Novel therapeutic agents in sarcoidosis

Although immunosuppressive drugs are currently used in clinical practice and recommended by
the current guidelines [56], sarcoidosis remains an orphan disease. Several new compounds are
currently under investigation or plan to be tested soon within clinical trials (table 3).
CMK389 is a fully human IgG1 monoclonal antibody directed against interleukin (IL)-18, a
macrophage-derived pro-inflammatory cytokine whose role in human granuloma formation has
been poorly investigated. Elevated serum levels have been reported in sarcoidosis patients [113],
and preclinical studies with CMK389 suggest that it selectively binds to and inhibits IL-18
activity [114].
GM-CSF has several pro-inflammatory effects and is increased in BAL fluid of patients with
active pulmonary sarcoidosis [115]. Namilumab is a fully human IgG1 monoclonal antibody
binding to GM-CSF with high affinity and neutralising its function [116]. The phase II trial
RESOLVE-Lung (ClinicalTrials.gov identifier NCT05314517) targets patients with
symptomatic chronic pulmonary sarcoidosis refractory to steroids, and another trial of patients
with active CS (RESOLVE-Heart, ClinicalTrials.gov identifier NCT05351554) is planned [117].
ATYR1923 is a potential first-in-class selective modulator of neuropilin 2 (NRP2) that works by

downregulating innate and adaptive immune responses [118]. Efzofitimod was tested in a
placebo-controlled, multicentre, phase IIa trial (ClinicalTrials.gov identifier NCT03824392),
where patients were assigned to three different doses of i.v.-administered ATYR1923
(1.0–5.0 mg·kg−1) [117]. Thirty-seven patients with pulmonary sarcoidosis were recruited and
underwent a protocol-guided oral glucocorticoid tapering regimen. Clinically meaningful
improvements were achieved across several patient-reported outcomes, several of which reached
statistical significance in the 5 mg·kg−1 dose arm [117].
Janus kinase ( JAK) inhibitors can selectively interfere in the JAK-signal transducer activator
transcription (STAT) pathway, which is induced by inflammatory cytokines, especially
interferon-γ [119, 120]. Tofacitinib, a JAK1/3 inhibitor approved for the treatment of
rheumatoid arthritis refractory to conventional therapy, was tested at 5 mg twice daily in several
patients with cutaneous, pulmonary and multiorgan sarcoidosis [121–124]. There was some
302 https://doi.org/10.1183/2312508X.10019122
https://doi.org/10.1183/2312508X.10019122
TABLE 3 Ongoing trials in sarcoidosis with novel molecules
Treatment Condition Study design Status Primary outcome ClinicalTrials.gov

identifier
CMK389 (anti-IL-18 Ab) Pulmonary sarcoidosis Phase II, RCT, multicentre Recruiting Change in FVC NCT04064242
Namilumab (anti-GM-CSF Ab) Pulmonary sarcoidosis Phase II, RCT, multicentre Recruiting Change in FVC at 26 weeks NCT05314517
Efzofitimod (ATYR1923, Pulmonary sarcoidosis Phase III, RCT, multiple Awaiting start Steroid tapering at 48 weeks, NCT05415137
selective NRP2 modulator) ascending dose safety and tolerability
Abatacept (CTLA-4–Ig fusion Pulmonary sarcoidosis Phase II, multicentre, open Awaiting results Infectious complications DRKS00011660#
protein) label, single arm
Canakinumab (ACZ885, Pulmonary sarcoidosis Phase II, RCT, multiple dose Awaiting results Change in pulmonary function NCT02888080
anti-IL-1β Ab) between baseline and
week 24
Tofacitinib (JAK1/3 inhibitor) Cutaneous sarcoidosis Phase I, nonrandomised, Awaiting results Change in CSAMI score NCT03910543
single group, open label
Anakinra (IL-1 receptor Cardiac sarcoidosis Phase II, RCT, double Recruiting Change in inflammation NCT04017936
antagonist) blinded marker
Namilumab (anti-GM-CSF Ab) Cardiac sarcoidosis Phase II, RCT, multicentre Awaiting start Safety and tolerability NCT05351554
Sarilumab (IL-6R Ab) Multiorgan, Phase II, RCT, withdrawal Recruiting Flare-free survival NCT04008069

glucocorticoid-dependent study
sarcoidosis
IL: interleukin; Ab: antibody; NRP2: neuropilin 2; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; JAK1/3: Janus kinase 1/3; RCT: randomised controlled trial; CSAMI:
Cutaneous Sarcoidosis Activity and Morphology Instrument; Ig: immunoglobulin. #: German Clinical Trial Registry identifier.
303
evidence of a response for extracutaneous manifestations and a corticoid-sparing effect [125].

An open-label trial for pulmonary and cutaneous sarcoidosis with tofacitinib is ongoing
(ClinicalTrials.gov identifier NCT03910543). The selective JAK1/2 inhibitors ruxolitinib and
baricitinib have shown promising results in patients with steroid-resistant sarcoidosis [126–128].
Altered regulatory T-cell functions with reduced expression of cytotoxic T-lymphocyte-

associated protein 4 (CTLA-4 or CD152) and prolonged inflammation have been demonstrated
in several autoimmune diseases and in sarcoidosis [129]. Abatacept is a CTLA-4–Ig fusion
protein that functions like an antibody [130]. In 2005, abatacept was approved for the treatment
of rheumatoid arthritis, and evidence for its use in lung fibrosis associated with rheumatoid
arthritis is increasing [131]. The results of a small open-label clinical trial of abatacept in
pulmonary sarcoidosis are expected soon [132].
Several studies have suggested a role for IL-1β, produced by macrophages after inflammasome
activation, in sarcoidosis and increased IL-1β levels in progressive pulmonary sarcoidosis [133]
Canakinumab, a fully human anti-IL-1β monoclonal antibody, was tested in a randomised
controlled trial for patients with pulmonary sarcoidosis (ClinicalTrials.gov identifier NCT02888080).
The trial recruited 40 patients and the final results are pending.
Anakinra inhibits IL-1α and IL-1β by antagonising the IL-1 receptor and is already approved for
the treatment of moderate-to-severe rheumatoid arthritis. It is currently being tested in a phase II,
double-blinded, randomised trial in patients with CS (ClinicalTrials.gov identifier NCT04017936).
IL-6 is produced mainly by macrophages, and its receptor (IL-6R) is present on the surface of
macrophages, B-cells and T-cells. IL-6 is upregulated in the lungs and BAL fluid of patients
with sarcoidosis and is believed to play a role in the initiation and maintenance of alveolitis by
activating T-cells [134]. Data on anti-human IL-6R monoclonal antibody use in sarcoidosis
patients are limited [135], but a small phase II trial with sarilumab is ongoing (ClinicalTrials.
gov identifier NCT04008069).
Conclusion
Sarcoidosis can have life-threatening manifestations, but most patients will recover spontaneously
and should not be treated with immunosuppressive drugs. None of the medications currently used
for sarcoidosis treatment has been rigorously studied in large RCTs [56], and the lack of
standardised clinical end-points represents a challenging issue for designing new trials in
sarcoidosis [125]. Several RCTs evaluating novel therapeutic targets and steroid-alternative
treatment regimens are ongoing in sarcoidosis with promising early-phase results.
References
1 Arkema EV, Cozier YC. Sarcoidosis epidemiology: recent estimates of incidence, prevalence and risk factors.
2 Chen ES. Innate immunity in sarcoidosis pathobiology. Curr Opin Pulm Med 2016; 22: 469–475.
3 Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of
sarcoidosis. Am J Respir Crit Care Med 2001; 164: 1885–1889.
4 Judson M, Boan A, Lackland D. The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a
large white and black cohort in the United States. Sarcoidosis Vasc Diff Lung Dis 2012; 29: 119–127.
5 Duan J, Xu Y, Zhu H, et al. Relationship between CT activity score with lung function and the serum angiotensin
converting enzyme in pulmonary sarcoidosis on chest HRCT. Medicine (Baltimore) 2018; 97: e12205.
6 Nunes H, Uzunhan Y, Gille T, et al. Imaging of sarcoidosis of the airways and lung parenchyma and correlation
with lung function. Eur Respir J 2012; 40: 750–765.
304 https://doi.org/10.1183/2312508X.10019122
7 Bonham CA, Strek ME, Patterson KC. From granuloma to fibrosis: sarcoidosis associated pulmonary fibrosis.
8 Swigris JJ, Olson AL, Huie TJ, et al. Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J
9 Mirsaeidi M, Machado RF, Schraufnagel D, et al. Racial difference in sarcoidosis mortality in the United States.
Chest 2015; 147: 438–449.
10 Baughman RP, Lower EE. Who dies from sarcoidosis and why? Am J Respir Crit Care Med 2011; 183: 1446–1447.
11 Rossides M, Kullberg S, Askling J, et al. Sarcoidosis mortality in Sweden: a population-based cohort study. Eur
Respir J 2018; 51: 1701815.
12 Jamilloux Y, Maucort-Boulch D, Kerever S, et al. Sarcoidosis-related mortality in France: a
multiple-cause-of-death analysis. Eur Respir J 2016; 48: 1700–1709.
13 Wells AU. Sarcoidosis: a benign disease or a culture of neglect? Respir Med 2018; 144S: S1–S2.
14 Wirnsberger RM, de Vries J, Wouters EF, et al. Clinical presentation of sarcoidosis in The Netherlands: an
epidemiological study. Neth J Med 1998; 53: 53–60.
15 Drent M, Marcellis R, Lenssen A, et al. Association between physical functions and quality of life in sarcoidosis.
Sarcoidosis Vasc Diffuse Lung Dis 2014; 31: 117–128.
16 Voortman M, Hendriks CMR, Elfferich MDP, et al. The burden of sarcoidosis symptoms from a patient
perspective. Lung 2019; 197: 155–161.
17 Udwadia ZF, Pilling JR, Jenkins PF, et al. Bronchoscopic and bronchographic findings in 12 patients with
sarcoidosis and severe or progressive airways obstruction. Thorax 1990; 45: 272–275.
18 Shorr A, Torrington K, Hnatiuk O. Endobronchial biopsy for sarcoidosis: a prospective study. Chest 2001; 120:
109–114.
19 McKinzie BP, Bullington WM, Mazur JE, et al. Efficacy of short-course, low-dose corticosteroid therapy for
acute pulmonary sarcoidosis exacerbations. Am J Med Sci 2010; 339: 1–4.
20 Marcias S, Ledda MA, Perra R, et al. Aspecific bronchial hyperreactivity in pulmonary sarcoidosis. Sarcoidosis
1994; 11: 118–122.
21 Bechtel JJ, Starr T, Dantzker DR, et al. Airway hyperreactivity in patients with sarcoidosis. Am Rev Respir Dis
1981; 124: 759–761.
22 Lynch JP, Kazerooni EA, Gay SE. Pulmonary sarcoidosis. Clin Chest Med 1997; 18: 755–785.
23 Kirks DR, McCormick VD, Greenspan RH. Pulmonary sarcoidosis. Roentgenologic analysis of 150 patients. Am J
Roentgenol Radium Ther Nucl Med 1973; 117: 777–786.
24 Hillerdal G, Nöu E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am
Rev Respir Dis 1984; 130: 29–32.
25 Liu Y, Dai HP, Xu LL, et al. Recurrent pneumothorax as a presenting manifestation of active sarcoidosis: a case
report and literature review. Chin Med J (Engl) 2010; 123: 1615–1616.
26 Huggins JT, Doelken P, Sahn SA, et al. Pleural effusions in a series of 181 outpatients with sarcoidosis. Chest
2006; 129: 1599–1604.
27 James WE, Bonella F. Pulmonary sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
28 Scadding JG. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’
observation. Br Med J 1961; 2: 1165–1172.
29 DeRemee RA. The roentgenographic staging of sarcoidosis. Historic and contemporary perspectives. Chest
1983; 83: 128–133.
30 Baughman RP, Judson MA, Teirstein A, et al. Presenting characteristics as predictors of duration of treatment
in sarcoidosis. QJM 2006; 99: 307–315.
31 Judson MA, Preston S, Hu K, et al. Quantifying the relationship between symptoms at presentation and the
prognosis of sarcoidosis. Respir Med 2019; 152: 14–19.
32 Sider L, Horton ES. Hilar and mediastinal adenopathy in sarcoidosis as detected by computed tomography.
J Thorac Imaging 1990; 5: 77–80.
33 Zappala CJ, Desai SR, Copley SJ, et al. Accuracy of individual variables in the monitoring of long-term change
in pulmonary sarcoidosis as judged by serial high-resolution CT scan data. Chest 2014; 145: 101–107.
34 Hennebicque AS, Nunes H, Brillet PY, et al. CT findings in severe thoracic sarcoidosis. Eur Radiol 2005; 15:
23–30.
35 Bergin CJ, Bell DY, Coblentz CL, et al. Sarcoidosis: correlation of pulmonary parenchymal pattern at CT with
results of pulmonary function tests. Radiology 1989; 171: 619–624.
36 Gawne-Cain ML, Hansell DM. The pattern and distribution of calcified mediastinal lymph nodes in sarcoidosis
and tuberculosis: a CT study. Clin Radiol 1996; 51: 263–267.
37 Calandriello L, Walsh SLF. Imaging for Sarcoidosis. Semin Respir Crit Care Med 2017; 38: 417–436.
38 Koide T, Saraya T, Tsukahara Y, et al. Clinical significance of the “galaxy sign” in patients with pulmonary
sarcoidosis in a Japanese single-center cohort. Sarcoidosis Vasc Diffuse Lung Dis 2016; 33: 247–252.
https://doi.org/10.1183/2312508X.10019122 305
39 Danila E, Jurgauskiene L, Malickaite R. BAL fluid cells and pulmonary function in different radiographic stages
of newly diagnosed sarcoidosis. Adv Med Sci 2008; 53: 228–233.
40 Sharp M, Psoter KJ, Balasubramanian A, et al. Heterogeneity of lung function phenotypes in sarcoidosis: role
of race and sex differences. Ann Am Thorac Soc 2023; 20: 30–37.
41 Chambellan A, Turbie P, Nunes H, et al. Endoluminal stenosis of proximal bronchi in sarcoidosis:
bronchoscopy, function, and evolution. Chest 2005; 127: 472–481.
42 Calaras D, Munteanu O, Scaletchi V, et al. Ventilatory disturbances in patients with intrathoracic sarcoidosis –
a study from a functional and histological perspective. Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 58–67.
43 Levinson RS, Metzger LF, Stanley NN, et al. Airway function in sarcoidosis. Am J Med 1977; 62: 51–59.
44 Harrison BD, Shaylor JM, Stokes TC, et al. Airflow limitation in sarcoidosis – a study of pulmonary function in
107 patients with newly diagnosed disease. Respir Med 1991; 85: 59–64.
45 Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected
pulmonary sarcoidosis – results of a cooperative study in former West Germany and Switzerland. Sarcoidosis
Vasc Diffuse Lung Dis 1998; 15: 178–182.
46 Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An Official American Thoracic
47 Trisolini R, Spagnolo P, Baughman RP. Sarcoidosis: principles of diagnosis. In: Bonella F, Culver DA, Israël-Biet
D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 57–74.
48 Reich JM, Brouns MC, O’Connor EA, et al. Mediastinoscopy in patients with presumptive stage I sarcoidosis: a
risk/benefit, cost/benefit analysis. Chest 1998; 113: 147–153.
49 Varela-Lema L, Fernandez-Villar A, Ruano-Ravina A. Effectiveness and safety of endobronchial ultrasound–
transbronchial needle aspiration: a systematic review. Eur Respir J 2009; 33: 1156–1164.
50 Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration vs
conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest 2014; 146: 547–556.
51 Goyal A, Gupta D, Agarwal R, et al. Value of different bronchoscopic sampling techniques in diagnosis of
sarcoidosis: a prospective study of 151 patients. J Bronchologu Interv Pulmonol 2014; 21: 220–226.
52 Agarwal R, Aggarwal A, Gupta D. Efficacy and safety of conventional transbronchial needle aspiration in
sarcoidosis: a systematic review and meta-analysis. Respir Care 2013; 58: 683–693.
53 Torrington KG, Shorr AF, Parker JW. Endobronchial disease and racial differences in pulmonary sarcoidosis.
Chest 1997; 111: 619–622.
54 Wessendorf TE, Bonella F, Costabel U. Diagnosis of sarcoidosis. Clin Rev Allergy Immunol 2015; 49: 54–62.
55 Jeny F, Vucinic V, Zhou Y, et al. Validation of the Sarcoidosis Diagnostic Score (SDS) in a multicontinental
study. Ann Am Thorac Soc 2022; 20: 371–380.
56 Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur
Respir J 2021; 58: 2004079.
57 Broos CE, Poell LHC, Looman CWN, et al. No evidence found for an association between prednisone dose and
FVC change in newly-treated pulmonary sarcoidosis. Respir Med 2018; 138S: S31–S37.
58 Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in newly
diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Chest 1999; 116:
424–431.
59 Hunninghake GW, Gilbert S, Pueringer R, et al. Outcome of the treatment for sarcoidosis. Am J Respir Crit Care
Med 1994; 149: 893–898.
60 Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommendations for a treatment algorithm
in pulmonary sarcoidosis. Eur Respir Rev 2020; 29: 190146.
61 Baughman RP, Barriuso R, Beyer K, et al. Sarcoidosis: patient treatment priorities. ERJ Open Res 2018; 4:
00141-2018.
62 Uemura A, Morimoto S, Hiramitsu S, et al. Histologic diagnostic rate of cardiac sarcoidosis: evaluation of
endomyocardial biopsies. Am Heart J 1999; 138: 299–302.
63 Kouranos V, Tzelepis GE, Rapti A, et al. Complementary role of CMR to conventional screening in the diagnosis
and prognosis of cardiac sarcoidosis. JACC Cardiovasc Imaging 2017; 10: 1437–1447.
64 Youssef G, Leung E, Mylonas I, et al. The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: a
systematic review and metaanalysis including the Ontario experience. J Nuclear Med 2012; 53: 241–248.
65 Kandolin R, Lehtonen J, Graner M, et al. Diagnosing isolated cardiac sarcoidosis. J Intern Med 2011; 270: 461–468.
66 Kouranos V, Sharma R. Cardiac sarcoidosis: state-of-the-art review. Heart 2021; 107: 1591–1599.
67 Ekstrom K, Lehtonen J, Nordenswan HK, et al. Sudden death in cardiac sarcoidosis: an analysis of nationwide
clinical and cause-of-death registries. Eur Heart J 2019; 40: 3121–3128.
68 Trivieri MG, Spagnolo P, Birnie D, et al. Challenges in cardiac and pulmonary sarcoidosis: JACC state-of-the-art
review. J Am Coll Cardiol 2020; 76: 1878–1901.
69 Sadek MM, Yung D, Birnie DH, et al. Corticosteroid therapy for cardiac sarcoidosis: a systematic review. Can J
Cardiol 2013; 29: 1034–1041.
306 https://doi.org/10.1183/2312508X.10019122
70 Hamzeh NY, Wamboldt FS, Weinberger HD. Management of cardiac sarcoidosis in the United States: a Delphi
study. Chest 2012; 141: 154–162.
71 Krause ML, Cooper LT, Chareonthaitawee P, et al. Successful use of rituximab in refractory cardiac sarcoidosis.
Rheumatology (Oxford) 2016; 55: 189–191.
72 Jackson KC, Youmans QR, Wu T, et al. Heart transplantation outcomes in cardiac sarcoidosis. J Heart Lung
Transplant 2022; 41: 113–122.
73 Joubert B, Chapelon-Abric C, Biard L, et al. Association of prognostic factors and immunosuppressive
treatment with long-term outcomes in neurosarcoidosis. JAMA Neurol 2017; 74: 1336–1344.
74 Fritz D, van de Beek D, Brouwer MC. Clinical features, treatment and outcome in neurosarcoidosis: systematic
review and meta-analysis. BMC Neurol 2016; 16: 220.
75 Krumholz A, Stern BJ. Neurologic manifestations of sarcoidosis. Handb Clin Neurol 2014; 119: 305–333.
76 Carlson ML, White JR Jr, Espahbodi M, et al. Cranial base manifestations of neurosarcoidosis: a review of 305
patients. Otol Neurotol 2015; 36: 156–166.
77 Bradshaw MJ, Pawate S, Koth LL, et al. Neurosarcoidosis: pathophysiology, diagnosis, and treatment. Neurol
Neuroimmunol Neuroinflamm 2021; 8: e1084.
78 Anthony J, Esper GJ, Ioachimescu A. Hypothalamic–pituitary sarcoidosis with vision loss and hypopituitarism:
case series and literature review. Pituitary 2016; 19: 19–29.
79 Drent M, Costabel U, Crouser ED, et al. Misconceptions regarding symptoms of sarcoidosis. Lancet Respir Med
2021; 9: 816–818.
80 Stern BJ, Royal W 3rd, Gelfand JM, et al. Definition and consensus diagnostic criteria for neurosarcoidosis:
from the Neurosarcoidosis Consortium Consensus Group. JAMA Neurol 2018; 75: 1546–1553.
81 Ungprasert P, Matteson EL. Neurosarcoidosis. Rheum Dis Clin North Am 2017; 43: 593–606.
82 Nozaki K, Judson MA. Neurosarcoidosis: clinical manifestations, diagnosis and treatment. Presse Med 2012; 41:
e331–e348.
83 Gelfand JM, Bradshaw MJ, Stern BJ, et al. Infliximab for the treatment of CNS sarcoidosis: a multi-institutional
series. Neurology 2017; 89: 2092–2100.
84 Tavee JO, Karwa K, Ahmed Z, et al. Sarcoidosis-associated small fiber neuropathy in a large cohort: clinical
aspects and response to IVIG and anti-TNFα treatment. Respir Med 2017; 126: 135–138.
85 Lhote R, Annesi-Maesano I, Nunes H, et al. Clinical phenotypes of extrapulmonary sarcoidosis: an analysis of a
French, multi-ethnic, multicentre cohort. Eur Respir J 2021; 57: 2001160.
86 Longcope WT, Freiman DG. A study of sarcoidosis: based on a combined investigation of 160 cases including
30 autopsies from The Johns Hopkins Hospital and Massachusetts General Hospital. Medicine (Baltimore)
1952; 31: 1–132.
87 Mahevas M, Lescure FX, Boffa JJ, et al. Renal sarcoidosis: clinical, laboratory, and histologic presentation and
outcome in 47 patients. Medicine (Baltimore) 2009; 88: 98–106.
88 Javaud N, Belenfant X, Stirnemann J, et al. Renal granulomatoses: a retrospective study of 40 cases and
review of the literature. Medicine (Baltimore) 2007; 86: 170–180.
89 Tebben PJ, Singh RJ, Kumar R. Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment.
Endocr Rev 2016; 37: 521–547.
90 Grunewald J, Grutters JC, Arkema EV, et al. Sarcoidosis. Nat Rev Dis Primers 2019; 5: 45.
91 Calandriello L, d’Abronzo R, Pasciuto G, et al. Novelties in imaging of thoracic sarcoidosis. J Clin Med 2021;
10: 2222.
92 Boellaard R, Delgado-Bolton R, Oyen WJ, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging:
version 2.0. Eur J Nucl Med Mol Imaging 2015; 42: 328–354.
93 Arnon-Sheleg E, Israel O, Keidar Z. PET/CT imaging in soft tissue infection and inflammation – an update.
Semin Nucl Med 2020; 50: 35–49.
94 Kouijzer IJE, Mulders-Manders CM, Bleeker-Rovers CP, et al. Fever of unknown origin: the value of FDG-PET/CT.
Semin Nucl Med 2018; 48: 100–107.
95 Keijsers RG, Verzijlbergen FJ, Oyen WJ, et al. 18F-FDG PET, genotype-corrected ACE and sIL-2R in newly
diagnosed sarcoidosis. Eur J Nucl Med Mol Imaging 2009; 36: 1131–1137.
96 Teirstein AS, Machac J, Almeida O, et al. Results of 188 whole-body fluorodeoxyglucose positron emission
tomography scans in 137 patients with sarcoidosis. Chest 2007; 132: 1949–1953.
97 Keijsers RG, Grutters JC, Thomeer M, et al. Imaging the inflammatory activity of sarcoidosis: sensitivity and
inter observer agreement of 67Ga imaging and 18F-FDG PET. Q J Nucl Med Mol Imaging 2011; 55: 66–71.
98 Mostard RL, van Kroonenburgh MJ, Drent M. The role of the PET scan in the management of sarcoidosis. Curr
Opin Pulm Med 2013; 19: 538–544.
99 Mostard RLM, Yadav R. Sarcoidosis: conventional and nuclear imaging techniques. In: Bonella F, Culver DA,
Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 75–90.
100 Sobic-Saranovic D, Grozdic I, Videnovic-Ivanov J, et al. The utility of 18F-FDG PET/CT for diagnosis and
adjustment of therapy in patients with active chronic sarcoidosis. J Nuclear Med 2012; 53: 1543–1549.
https://doi.org/10.1183/2312508X.10019122 307
101 Mostard RL, van Kuijk SM, Verschakelen JA, et al. A predictive tool for an effective use of 18F-FDG PET in
assessing activity of sarcoidosis. BMC Pulm Med 2012; 12: 57.
102 Keijsers RG, Verzijlbergen EJ, van den Bosch JM, et al. 18F-FDG PET as a predictor of pulmonary function in
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28: 123–129.
103 Chen H, Jin R, Wang Y, et al. The utility of 18F-FDG PET/CT for monitoring response and predicting prognosis
after glucocorticoids therapy for sarcoidosis. Biomed Res Int 2018; 2018: 1823710.
104 Vorselaars AD, Crommelin HA, Deneer VH, et al. Effectiveness of infliximab in refractory FDG PET-positive
sarcoidosis. Eur Respir J 2015; 46: 175–185.
105 Saric P, Young KA, Rodriguez-Porcel M, et al. PET imaging in cardiac sarcoidosis: a narrative review with focus
on novel PET tracers. Pharmaceuticals (Basel) 2021; 14: 1286.
106 Gormsen LC, Haraldsen A, Kramer S, et al. A dual tracer 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT pilot
study for detection of cardiac sarcoidosis. EJNMMI Res 2016; 6: 52.
107 Martineau P, Pelletier-Galarneau M, Juneau D, et al. FLT-PET for the assessment of systemic sarcoidosis
including cardiac and CNS involvement: a prospective study with comparison to FDG-PET. EJNMMI Res 2020;
10: 154.
108 Chung JH, Cox CW, Forssen AV, et al. The dark lymph node sign on magnetic resonance imaging: a novel
finding in patients with sarcoidosis. J Thorac Imaging 2014; 29: 125–129.
109 Chung JH, Little BP, Forssen AV, et al. Proton MRI in the evaluation of pulmonary sarcoidosis: comparison to
chest CT. Eur J Radiol 2013; 82: 2378–2385.
110 Kaushik SS, Robertson SH, Freeman MS, et al. Single-breath clinical imaging of hyperpolarized 129Xe in the
airspaces, barrier, and red blood cells using an interleaved 3D radial 1-point Dixon acquisition. Magn Reson
Med 2016; 75: 1434–1443.
111 Weatherley ND, Eaden JA, Stewart NJ, et al. Experimental and quantitative imaging techniques in interstitial
lung disease. Thorax 2019; 74: 611–619.
112 Wells AU, Walsh SLF. Quantitative computed tomography and machine learning: recent data in fibrotic
interstitial lung disease and potential role in pulmonary sarcoidosis. Curr Opin Pulm Med 2022; 28: 492–497.
113 Shigehara K, Shijubo N, Ohmichi M, et al. Increased levels of interleukin-18 in patients with pulmonary
sarcoidosis. Am J Respir Crit Care Med 2000; 162: 1979–1982.
114 Alehashemi S, Goldbach-Mansky R. Human autoinflammatory diseases mediated by NLRP3-, pyrin-, NLRP1-,
and NLRC4-inflammasome dysregulation updates on diagnosis, treatment, and the respective roles of IL-1 and
IL-18. Front Immunol 2020; 11: 1840.
115 Itoh A, Yamaguchi E, Furuya K, et al. Correlation of GM-CSF mRNA in bronchoalveolar fluid with indices of
clinical activity in sarcoidosis. Thorax 1993; 48: 1230–1234.
116 Tanaka S, Harada S, Hiramatsu N, et al. Randomized, double-blind, placebo-controlled, phase I study of the
safety and pharmacokinetics of namilumab in healthy Japanese and Caucasian men. Int J Clin Pharmacol Ther
2018; 56: 507–517.
117 Culver DA, Aryal S, Barney J, et al. Efzofitimod for the treatment of pulmonary sarcoidosis. Chest
2022; 163: 881–890.
118 Favier B, Alam A, Barron P, et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human
endothelial cell survival and migration. Blood 2006; 108: 1243–1250.
119 Prasse A, Georges CG, Biller H, et al. Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+
and CD8+ T cells. Clin Exp Immunol 2000; 122: 241–248.
120 Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int
Immunopharmacol 2020; 80: 106210.
121 Kerkemeyer KL, Meah N, Sinclair RD. Tofacitinib for cutaneous and pulmonary sarcoidosis: a case series. J Am
Acad Dermatol 2021; 84: 581–583.
122 Friedman MA, Le B, Stevens J, et al. Tofacitinib as a steroid-sparing therapy in pulmonary sarcoidosis, an
open-label prospective proof-of-concept study. Lung 2021; 199: 147–153.
123 Damsky W, Thakral D, McGeary MK, et al. Janus kinase inhibition induces disease remission in cutaneous
sarcoidosis and granuloma annulare. J Am Acad Dermatol 2020; 82: 612–621.
124 Damsky W, Young BD, Sloan B, et al. Treatment of multiorgan sarcoidosis with tofacitinib. ACR Open
Rheumatol 2020; 2: 106–109.
125 Obi ON, Saketkoo LA, Russell AM, et al. Sarcoidosis: updates on therapeutic drug trials and novel treatment
approaches. Front Med (Lausanne) 2022; 9: 991783.
126 Levraut M, Martis N, Viau P, et al. Refractory sarcoidosis-like systemic granulomatosis responding to
ruxolitinib. Ann Rheum Dis 2019; 78: 1606–1607.
127 Rotenberg C, Besnard V, Brillet PY, et al. Dramatic response of refractory sarcoidosis under ruxolitinib in a
patient with associated JAK2-mutated polycythemia. Eur Respir J 2018; 52: 1801482.
128 Scheinberg M, Maluf F, Wagner J. Steroid-resistant sarcoidosis treated with baricitinib. Ann Rheum Dis 2020;
79: 1259–1260.
308 https://doi.org/10.1183/2312508X.10019122
129 Broos CE, van Nimwegen M, in ’t Veen JC, et al. Decreased cytotoxic T-lymphocyte antigen 4 expression on
regulatory T cells and Th17 cells in sarcoidosis: double trouble? Am J Respir Crit Care Med 2015; 192: 763–765.
130 Dumont FJ. Technology evaluation: abatacept, Bristol-Myers Squibb. Curr Opin Mol Ther 2004; 6: 318–330.
131 Mena-Vazquez N, Rojas-Gimenez M, Fuego-Varela C, et al. Safety and effectiveness of abatacept in a
prospective cohort of patients with rheumatoid arthritis-associated interstitial lung disease. Biomedicines
2022; 10: 1480.
132 Frye BC, Rump IC, Uhlmann A, et al. Safety and efficacy of abatacept in patients with treatment-resistant
SARCoidosis (ABASARC) – protocol for a multi-center, single-arm phase IIa trial. Contemp Clin Trials Commun
2020: 19: 100575.
133 Huppertz C, Jager B, Wieczorek G, et al. The NLRP3 inflammasome pathway is activated in sarcoidosis and
involved in granuloma formation. Eur Respir J 2020; 55: 1900119.
134 Sahashi K, Ina Y, Takada K, et al. Significance of interleukin 6 in patients with sarcoidosis. Chest 1994; 106:
156–160.
135 Sharp M, Donnelly SC, Moller DR. Tocilizumab in sarcoidosis patients failing steroid sparing therapies and
anti-TNF agents. Respir Med X 2019; 1: 100004.
Disclosures: F. Bonella reports the following, outside the submitted work: consulting fees from Boehringer
Ingelheim, Sanofi, Roche and CSL Behring; payment or honoraria for lectures, presentations, speakers’ bureaus,
manuscript writing or educational events from Boehringer Ingelheim and Sanofi; support for attending meetings
and/or travel from Boehringer Ingelheim and AstraZeneca; participation on a Data Safety Monitoring Board or
Advisory Board for Boehringer Ingelheim and Sanofi; and leadership or fiduciary role in other board, society,
committee or advocacy groups, paid or unpaid for a German patients association. W.E. James has nothing to
disclose. P. Spagnolo reports the following, outside the submitted work: consulting fees from CLS Behring;
from Novartis and Chiesi; leadership or fiduciary role in other board, society, committee or advocacy groups, paid
or unpaid. P. Spagnolo is an Associate Editor of Chest, and Chair of the Sarcoidosis and other granulomatous
ILD/DPLD Group of the ERS.
https://doi.org/10.1183/2312508X.10019122 309
Chapter 22
Granulomatous and lymphocytic interstitial lung

disease in common variable immunodeficiency
1,2,3
Heba M. Bintalib , Siobhan O. Burns4,5 and John R. Hurst 1
1
UCL Respiratory, University College London, London, UK. 2Dept of Respiratory Care, King Saud bin Abdulaziz
University for Health Sciences, Jeddah, Saudi Arabia. 3King Abdullah International Medical Research Centre,
Jeddah, Saudi Arabia. 4Institute of Immunity and Transplantation, UCL, London, UK. 5Dept of Immunology, Royal
Free London NHS Foundation Trust, London, UK.
Corresponding author: Heba M. Bintalib (Heba.bintalib.20@ucl.ac.uk)
Cite as: Bintalib HM, Burns SO, Hurst JR. Granulomatous and lymphocytic interstitial lung disease in common
variable immunodeficiency. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory
System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 310–319 [https://doi.org/10.1183/
2312508X.10019222].
@ERSpublications
Granulomatous and lymphocytic ILD is a rare lung manifestation affecting 10–20% of people living with
common variable immunodeficiency disorder. It is difficult to diagnose and manage. Further research
cooperation will improve patient care and treatment. https://bit.ly/ERSM100
ISSN: 2312-5098.
Granulomatous and lymphocytic ILD (GLILD) is a rare noninfectious complication affecting patients
with common variable immunodeficiency disorder (CVID). Although the pathophysiology is not fully
understood, it is likely to involve autoimmune dysregulation. GLILD usually occurs together with other
noninfectious complications, raising morbidity and mortality. The symptoms are cough and dyspnoea,
but some patients remain asymptomatic. The clinical picture includes nodules, interlobular septal
thickening, ground-glass opacities and splenomegaly on imaging. Lung function varies among patients
but is typically restrictive with decreased gas transfer. Excluding malignancy and infection is necessary
as these may cause similar clinical presentations. Lung biopsy can be performed to confirm the
diagnosis. GLILD usually appears as mixed histological patterns, including lymphoid interstitial
pneumonitis, follicular bronchiolitis, lymphoid hyperplasia, organising pneumonia and non-necrotising
granuloma. Optimising immunoglobulin replacement therapy is essential before initiating treatment.
Glucocorticoids remain the recommended first-line therapy; however, relapse usually occurs on
dose tapering, and second-line immunosuppressants are recommended.
Introduction
Lung complications are a leading cause of poor quality of life and decreased life expectancy
in people living with common variable immunodeficiency disorder (CVID). CVID affects 1 in
25 000–50 000 of the population, and is the most common symptomatic antibody deficiency [1].
CVID is characterised by decreased levels of serum IgG, IgA and/or IgM with a poor response
to vaccines [2]. The common immune defect among these patients is B-cell dysfunction.
Defects in T-cell function have been reported in one-third of patients [3]. However, the cause of
these defects remains unclear. Patients can be phenotyped into two groups: 1) those with
recurrent infections only, and 2) those with additional noninfectious complications. Optimising
immunoglobulin replacement therapy has significantly reduced the infection rate; however, it
310 https://doi.org/10.1183/2312508X.10019222
GRANULOMATOUS AND LYMPHOCYTIC ILD | H.M. BINTALIB ET AL.
does not affect the development of autoimmune and inflammatory conditions [4, 5]. The more
challenging complications in CVID patients are therefore noninfectious complications [1, 6].
These include splenomegaly, autoimmunity, lymphoproliferative disorders, malignancy, and
granulomatous infiltrations of the lungs, lymph nodes and other organs [7].
The pulmonary manifestation in CVID may also be divided into two groups. Recurrent upper-
and lower-airway infections are usually caused by encapsulated bacteria such as Haemophilus
influenzae and Streptococcus pneumoniae. These frequent infections may lead to the
development of bronchiectasis [8, 9]. In contrast, systemic immune dysregulation is thought to be
related to the development of ILD in CVID (CVID-related ILD (CVIDrILD), also known as
granulomatous and lymphocytic ILD (GLILD)). CVIDrILD is a rare lung manifestation that
occurs in 8–20% of CVID patients in conjunction with other noninfectious complications,
raising morbidity and mortality in these patients [10, 11]. The purpose of this chapter is to review
and describe the existing evidence on the diagnosis and management of CVIDrILD/GLILD.
Term and definition

The term GLILD was initially coined in 2004 by BATES et al. [10] when they used it to describe
CVID patients with histological patterns of granulomata and lymphocytic infiltrates. Later, the
term was used to describe patients with different pathological processes and even in the absence
of granuloma, which makes the terminology confusing [12]. A consensus definition by the
British Lung Foundation and UK Primary Immunodeficiency Network (BLF/UKPIN) on what
constitutes GLILD concluded that GLILD is “a distinct clinico-radio-pathological ILD occurring
in patients with CVID, associated with a lymphocytic infiltrate and/or granuloma in the lung,
and in whom other conditions have been considered and where possible excluded” [13]. The
definition notes that GLILD is probably the lung manifestation of systemic immune
dysregulation. Although GLILD was initially reported in CVID, studies later also identified it in
immunodeficiency associated with specific genetic mutations. It has been reported in patients
with CTLA-4 (cytotoxic T-lymphocyte associated protein 4) haploinsufficiency, LRBA
(lipopolysaccharide-responsive and beige-like anchor protein) deficiency, XIAP (X-linked
inhibitor of apoptosis protein) deficiency, RAG (recombination activating gene) mutations,
22q11.2 deletion syndrome and Good syndrome [14–21]. This may suggest the need for further
consensus on what comprises GLILD. The term GLILD will be used in this chapter as
synonymous with CVIDrILD.
Diagnosis of GLILD
Diagnosis of GLILD is a challenge due to the heterogeneity of the disease and its unknown
natural history. The lung manifestations share clinical, radiological and histological
characteristics with other conditions. According to BLF/UKPIN, while CT abnormalities can
raise suspicion of GLILD, the presence of histopathological abnormalities on lung biopsy is still
required to definitively confirm the diagnosis [13]. Other cases might best be considered as
having “probable GLILD”. Thus, GLILD is a diagnosis of exclusion that persists after
excluding other possible differential diagnoses such as malignancy and lymphoma. The
diagnosis of GLILD relies on clinical, radiological and histopathological features.
Clinical features
The most common symptoms are chronic cough and dyspnoea, especially with exertion.
However, patients can be asymptomatic. This indicates the need for screening of patients with
CVID to help detect GLILD and allow early intervention. The extrapulmonary involvement of
granulomatous or inflammatory disease affects other organs such as the gastrointestinal tract,
https://doi.org/10.1183/2312508X.10019222 311
spleen, liver and lymph nodes [22], and patients with these complications and immune
cytopenias are at higher risk of GLILD. There is no relationship between sex, age or ethnicity
and GLILD development [23]. In addition, smoking and obesity are not reported to be risk
factors for developing GLILD [24].
PFTs
PFTs provide essential information for monitoring and evaluating the treatment response in
GLILD. PFT results vary among patients from a normal pattern, despite the abnormal changes
in CT, to severe restriction with decreased gas transfer [10, 25, 26]. Reduction in gas transfer
could be an early sign of GLILD. It is therefore recommended to obtain spirometry and gas
transfer data at the time of CVID diagnosis as a baseline, with annual follow-up monitoring [2].
Radiology
Diagnostic imaging is an essential tool in detecting lung diseases. In addition to changes in
symptoms and lung function, imaging may also assess the response to treatment. Chest
radiography is not sufficiently sensitive, whereas HRCT is considered to be the gold standard for
assessing lung changes in GLILD. CT findings include ill-defined large nodules (>5 mm) and
micronodules (<5 mm), which predominantly affect the peribronchovascular and lower lobes
with varying density. An air bronchogram and the halo sign (ground-glass opacity surrounding a
pulmonary nodule), bronchial wall thickening, interlobular septal thickening, consolidation, hilar
and/or mediastinal lymphadenopathy, and splenomegaly are also reported in GLILD (figure 1)
[26–29]. In order to standardise HRCT scores, MEERBURG et al. [30] evaluated two radiological
scores developed for CVID in patients with GLILD. The Hartmann score appeared more
valuable for longitudinal monitoring in that it considered more detail than the Baumann score.
The use of fluorodeoxyglucose positron emission tomography/CT may be a useful assessment

and monitoring tool in evaluating disease activity and treatment response in patients with
GLILD [31]. FRAZ et al. [32] reported that active pulmonary inflammation and progressive
disease can be reflected by the increase in the mean standardised uptake value when comparing
patients with progressive GLILD with stable patients.
FIGURE 1 CT image showing bilateral nodules with a ground-glass halo from a patient with granulomatous and
lymphocytic ILD.
312 https://doi.org/10.1183/2312508X.10019222
Given the benefit of HRCT, patients with lung complications related to CVID often undergo
several radiological follow-up scans throughout their lives. Radiosensitivity in a small number
of patients with CVID has been reported, and repeated radiation exposure may have contributed
to the increase in malignancy [33, 34]. Thus, risk–benefit assessment should be taken into
consideration before considering HRCT, such as lower-dose protocols or considering an
alternative approach such as MRI. MRI was reported to be reliable and noninferior to HRCT in
detecting bronchial and parenchymal abnormalities in GLILD. However, HRCT had higher
sensitivity to identifying peripheral airway abnormalities [35, 36].
Histopathology of GLILD
Abnormalities in lung imaging alone do not confirm the diagnosis of GLILD, as these changes are
indistinguishable from other pathologies. For this reason, biopsy of lung tissue has been suggested
[13]. The type of biopsy needed depends on evaluating risk, and the size and location of the lesion.
Bronchoscopy with BAL is usually performed first to exclude bacterial, fungal and viral infections,
and malignancy, with or without transbronchial biopsy, although the yield for the latter is low. The
need for surgical lung biopsy is raised when tissue is insufficient or there is a need for a definitive
histopathological diagnosis. Video-assisted thorascopic surgery is more widely performed than open
lung biopsy due to fewer complications [37]. Recently, transbronchial lung cryobiopsy was
described in two case reports as a less invasive approach to the diagnosis of GLILD [38, 39].
Histological findings of GLILD are usually described by mixed patterns, including lymphoid
interstitial pneumonitis, follicular bronchiolitis, lymphoid hyperplasia, organising pneumonia
and non-necrotising granuloma (figure 2) [12, 40]. GLILD shares some histological and
radiological features with sarcoidosis and lymphoma leading to misleading or delayed diagnoses
[13, 41]. Sarcoidosis is typically associated with hyper- but not hypogammablobulinaemia.
Excluding primary immunodeficiency and precise clinical and radiological assessment are
important to distinguish between these conditions.
The lung pathology in GLILD is heterogeneous and poorly understood. GLILD can be seen in
patients with CVID in the absence of bronchiectasis or pneumonia; this supports the assumption that
GLILD is likely to be related to immunological dysregulation [42]. Lymphoproliferation in some
a) b)
FIGURE 2 Histology of granulomatous and lymphocytic ILD (GLILD) showing a polymorphous infiltrate of
lymphocytes, plasma cells and macrophages. a) High- and b) low-power photomicrographs of a video-assisted
thorascopic surgery lung biopsy from a patient with common variable immunodeficiency disorder and GLILD.
Reproduced from [40] with permission.
https://doi.org/10.1183/2312508X.10019222 313
patients has been related to human herpesvirus 8 [43]. However, there is no evidence supporting the
relationship between cytomegalovirus or Epstein–Barr virus or bacterial infection and inflammatory
complications in these patients [44, 45]. A low serum IgA level, low switched memory B-cells and
marginal zone B-cells, expansion of CD21low B-cells, and lower CD3+, CD4+ and CD8+ T-cell
counts have all been identified as predictors of GLILD in patients with CVID [24, 26, 46].
Several studies have investigated the features of peripheral blood lymphocytes or BAL fluid in
patients with GLILD. In a comparison of BAL fluid, FRIEDMANN et al. [47] found that those with
GLILD have a higher percentage of B-cells, mostly consisting of CD21low B-cells, low regulatory
T-cells and high T-follicular helper-like memory composed mostly of T-helper 1 cells than patients
with sarcoidosis. MAGLIONE et al. [48] described the B-cell hyperplasia that develops tertiary
lymphoid structures and is driven by B-cell-activating factor (BAFF) as the key pathogenic feature
of GLILD. They reported a higher level of BAFF and serum IgM in CVID patients with
progressive ILD. In contrast, FRAZ et al. [49] recently reported that BAFF was not significantly
higher in their GLILD group and found that the levels of its soluble receptor form (soluble B-cell
maturation antigen) were significantly higher compared with patients with other noninfectious
complications or infections only. They also found increased levels of T-cell activation, pulmonary
epithelial cell injury and extracellular matrix remodelling markers. Their results were also consistent
with those of VAN STIGT et al. [50], who reported a high level of the soluble form of the
interleukin-2 receptor (sCD25) in 10 patients with GLILD compared with CVID patients with
infection only, and in patients with progressive disease compared with those with stable disease.
Prediction models
GLILD usually occurs in conjunction with other autoimmune complications, including
splenomegaly, adenopathy, thrombocytopenia, autoimmune haemolytic anaemia (AIHA),
polyarthritis, hepatitis and inflammatory bowel disease [10, 24, 26, 28, 46]. Splenomegaly,
along with AIHA and thrombocytopenia, were identified as possible risk factors for the
development of GLILD. Three studies developed predictive models for GLILD based on
clinical, laboratory and/or radiological findings. HARTONO et al. [24] reported that a history of
AIHA and/or immune thrombocytopenia, splenomegaly, IgA levels <13 mg·dL−1 and CD21low
B-lymphocytes >5% of total CD21+ B-cells are predictive of GLILD in CVID with a receiver
operating characteristic (ROC) curve of 0.86. CINETTO et al. [26] suggested similar models but
added low gas transfer as a functional measure, which increased the area under the ROC curve
to 0.98. The most recent model by CABANERO-NAVALON et al. [51] found that lymphadenopathies,
splenomegaly, a reduced number of CD8+ cells and a high Baumann’s GLILD composite score
predicted the presence of GLILD with a ROC curve of 0.985.
Treatment of GLILD
The underlying mechanisms of GLILD are poorly understood, contributing to challenges
managing this disease. Heterogeneity among studies regarding the optimal treatment for GLILD
still exists due to a lack of evidence-based guidelines on how and when to treat patients.
Immunoglobulin replacement therapy should be optimised in all individuals with GLILD in

order to maintain normal serum IgG levels [13, 52]. Antimicrobial prophylaxis can help to
reduce infections but does not appear to stop progression of the disease [52].
Additional treatment is required in cases of disease progression. A consensus about when to

commence treatment by BLF/UKPIN was based on changes in symptoms and lung function [13].
They recommended starting treatment in symptomatic patients with normal or abnormal but
314 https://doi.org/10.1183/2312508X.10019222
declining lung function, and in asymptomatic patients with normal but declining lung function
(figure 3). Thus, deterioration in symptoms, progression on HRCT or decreasing lung function
are the main indications to initiate treatment [13]. The selection of a therapy is influenced by a
variety of factors such as efficacy, cost and availability of the drug, patients’ opinions, and
risk/benefit assessment.
Glucocorticoids such as prednisone with a maximum dose of 0.1–1.0 mg·kg−1·day−1 are generally
suggested as the first-line treatment [13]. However, there is variability in the clinical response to
these. LAMERS et al. [53], in a systematic review on the efficacy of treatments of GLILD,
emphasised that 57% of patients treated with glucocorticoids failed to induce remission. In contrast,
VAN STIGT et al. [54], in their systematic review evaluating the treatment efficacy on granulomatous
disease in CVID patients, reported that steroid monotherapy induced remission in 67% of patients
with pulmonary granulomatous disease. In addition to different inclusion criteria, the main
difference between the studies was how they defined remission. LAMERS et al. [53] considered
remission as relapse-free improvement, while VAN STIGT et al. [54] reported remission when there
Confirmed diagnosis
of GLILD
Optimise IgRT
Symptoms
Persistent cough,
Asymptomatic
exertional dyspnoea
Lung function
Normal but declining Abnormal and declining Normal and stable
Treatment No treatment
First-line treatment: Monitor with repeat

prednisone 0.5–1 mg·kg–1 lung function every
to 60 mg max 6 months
Treatment decision
Improved symptoms
and/or lung function
and/or CT
No Yes
Second-line treatment: Tapered and/or

MMF, azathioprine or consider maintenance
rituximab therapy
FIGURE 3 Simplified algorithm depicting granulomatous and lymphocytic ILD (GLILD) treatment strategies. IgRT:
immunoglobulin replacement therapy; MMF: mycophenolate mofetil.
https://doi.org/10.1183/2312508X.10019222 315
was an improvement in symptoms, imaging and/or lung function. Additional treatment can be
considered as maintenance therapy to avoid the side-effects of long-term oral corticosteroids.
BINTALIB et al. [55] recently reported that the use of mycophenolate mofetil (MMF) as a second-line
treatment was linked to long-term efficacy and allowed corticosteroid weaning in patients with
GLILD, and that watchful waiting was associated with progressive lung function decline.
Second-line immunosuppressive agents such as azathioprine, MMF, rituximab, methotrexate,

cyclosporine and infliximab have been suggested when treatment fails to induce remission, or
when steroids cause problematic side-effects [13]. Of note, these agents have also been used in
some as a first-line treatment, which reflects the heterogeneity among studies.
Rituximab is a monoclonal antibody that binds to CD20 molecules and depletes B-cells. The
efficacy of rituximab as a monotherapy has been reported in case studies [56–58]. Rituximab in
combination with mycophenolate or azathioprine was reported to be effective in treating patients
with GLILD [48, 59]. VERBSKY et al. [59] reported a longitudinal retrospective analysis of 39
patients with GLILD who were treated with a combination of rituximab with either azathioprine
or MMF with the histological findings of B-cells and T-cells in the lung. They found an
improvement in HRCT and spirometry but not gas exchange in 75% of patients, and reported
relapse in only nine patients.
In patients with LRBA and CTLA-4 deficiency, abatacept has efficacy for lung disease, as well
as other complications [14, 15]. The efficacy of using this in patients with GLILD was reported
by VON SPEE-MAYER et al. [60] in a pilot study. They reported complete remission in five out of
10 GLILD patients with significant radiological and lung function improvement. No relapse was
reported, although this could be due to the short follow-up period.
Haemopoietic stem-cell therapy (HSCT) is a therapeutic intervention used in patients with

severe CVID, generally when a specific genetic mutation has been identified. Outcomes in
surviving patients are reassuring, but the mortality rate related to the procedure is still high
[2, 61]. Evidence for the use of HSCT to treat GLILD has been limited, and survival rates vary
from 48% to 70% [53]. This could be related to many factors including the severity of the
disease, other organ involvement and infection.
Controversy about the optimal treatment of GLILD prevails in the literature. The main
limitations of studies that focus on treatment are the small sample size and retrospective design.
Thus, there is a need for randomised controlled trials to standardise management. The results of
the STILPAD (Study of Interstitial Lung Disease in Primary Antibody Deficiency) large
multicentre observational trial are awaited and will shed further light on the efficacy of available
treatment options. A prioritisation exercise in GLILD addressed and prioritised unanswered
research questions [62]. The top questions were about optimal treatment to induce and maintain
remission, when to initiate treatment and what diagnostic approach could help detect GLILD in
CVID [62]. This indicates the urgent need for further research to understand the underlying
pathophysiology of GLILD to allow appropriate treatment.
Conclusion
GLILD is associated with reduced survival in patients with CVID. As a result, early detection
and ongoing follow-up are essential. HRCT and PFTs are the preferred monitoring approaches.
The decision to initiate treatment relies on close monitoring. Finally, controversy regarding
optimal treatment still exists, and randomised controlled trials are required.
316 https://doi.org/10.1183/2312508X.10019222
References
1 Resnick ES, Moshier EL, Godbold JH, et al. Morbidity and mortality in common variable immune deficiency
over 4 decades. Blood 2012; 119: 1650–1657.
2 Bonilla FA, Barlan I, Chapel H, et al. International consensus document (ICON): common variable
immunodeficiency disorders. J Allergy Clin Immunol Pract 2016; 4: 38–59.
3 Saikia B, Gupta S. Common variable immunodeficiency. Indian J Pediatr 2016; 83: 338–344.
4 Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: a review of
evidence. J Allergy Clin Immunol 2017; 139: S1–S46.
5 Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of
pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2002; 109: 1001–1004.
6 Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical
phenotypes. Blood 2008; 112: 277–286.
7 Maglione PJ, Overbey JR, Cunningham-Rundles C. Progression of common variable immunodeficiency
interstitial lung disease accompanies distinct pulmonary and laboratory findings. J Allergy Clin Immunol Pract
2015; 3: 941–950.
8 Oksenhendler E, Gerard L, Fieschi C, et al. Infections in 252 patients with common variable immunodeficiency.
Clin Infect Dis 2008; 46: 1547–1554.
9 Sperlich JM, Grimbacher B, Soetedjo V, et al. Predictive factors for and complications of bronchiectasis in
common variable immunodeficiency disorders. J Clin Immunol 2022; 42: 572–581.
10 Bates CA, Ellison MC, Lynch DA, et al. Granulomatous–lymphocytic lung disease shortens survival in common
variable immunodeficiency. J Allergy Clin Immunol 2004; 114: 415–421.
11 Odnoletkova I, Kindle G, Quinti I, et al. The burden of common variable immunodeficiency disorders: a retrospective
analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet J Rare Dis 2018; 13: 201.
12 Dhalla F, Lochlainn DJM, Chapel H, et al. Histology of interstitial lung disease in common variable immune
deficiency. Front Immunol 2020; 11: 605187.
13 Hurst JR, Verma N, Lowe D, et al. British Lung Foundation/United Kingdom Primary Immunodeficiency Network
consensus statement on the definition, diagnosis, and management of granulomatous–lymphocytic interstitial
lung disease in common variable immunodeficiency disorders. J Allergy Clin Immunol Pract 2017; 5: 938–945.
14 Lo B, Zhang K, Lu W, et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation
responsive to abatacept therapy. Science 2015; 349: 436–440.
15 Schwab C, Gabrysch A, Olbrich P, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte
antigen 4-insufficient subjects. J Allergy Clin Immunol 2018; 142: 1932–1946.
16 Lopez-Herrera G, Tampella G, Pan-Hammarstrom Q, et al. Deleterious mutations in LRBA are associated with a
syndrome of immune deficiency and autoimmunity. Am J Hum Genet 2012; 90: 986–1001.
17 Steele CL, Dore M, Ammann S, et al. X-linked inhibitor of apoptosis complicated by granulomatous lymphocytic
interstitial lung disease (GLILD) and granulomatous hepatitis. J Clin Immunol 2016; 36: 733–738.
18 Buchbinder D, Baker R, Lee YN, et al. Identification of patients with RAG mutations previously diagnosed with
common variable immunodeficiency disorders. J Clin Immunol 2015; 35: 119–124.
19 Mather MW, Hayhurst H, Bacon CM, et al. Mutation of TNFRSF13B in a child with 22q11 deletion syndrome
associated with granulomatous lymphoproliferation. J Allergy Clin Immunol 2015; 135: 559–561.
20 Sood AK, Funkhouser W, Handly B, et al. Granulomatous–lymphocytic interstitial lung disease in 22q11.2
deletion syndrome: a case report and literature review. Curr Allergy Asthma Rep 2018; 18: 14.
21 Jensen ML, Bendstrup E, Hilberg O. Granulomatous–lymphocytic interstitial lung disease and recurrent
sinopulmonary infections in a patient with Good’s syndrome. BMJ Case Rep 2015; 30: 30.
22 Cinetto F, Scarpa R, Rattazzi M, et al. The broad spectrum of lung diseases in primary antibody deficiencies.
Eur Respir Rev 2018; 27: 180019.
23 Boursiquot JN, Gerard L, Malphettes M, et al. Granulomatous disease in CVID: retrospective analysis of clinical
characteristics and treatment efficacy in a cohort of 59 patients. J Clin Immunol 2013; 33: 84–95.
24 Hartono S, Motosue MS, Khan S, et al. Predictors of granulomatous lymphocytic interstitial lung disease in
common variable immunodeficiency. Ann Allergy Asthma Immunol 2017; 118: 614–620.
25 Lopez AL, Paolini MV, Fernandez Romero DS. Lung disease in patients with common variable
immunodeficiency. Allergol Immunopathol (Madr) 2020; 48: 720–728.
26 Cinetto F, Scarpa R, Carrabba M, et al. Granulomatous lymphocytic interstitial lung disease (GLILD) in common
variable immunodeficiency (CVID): a multicenter retrospective study of patients from Italian PID referral
centers. Front Immunol 2021; 12: 627423.
27 Bouvry D, Mouthon L, Brillet PY, et al. Granulomatosis-associated common variable immunodeficiency disorder:
a case–control study versus sarcoidosis. Eur Respir J 2013; 41: 115–122.
28 Mannina A, Chung JH, Swigris JJ, et al. Clinical predictors of a diagnosis of common variable immunodeficiency-
related granulomatous–lymphocytic interstitial lung disease. Ann Am Thorac Soc 2016; 13: 1042–1049.
https://doi.org/10.1183/2312508X.10019222 317
29 Tanaka N, Kim JS, Bates CA, et al. Lung diseases in patients with common variable immunodeficiency: chest
radiographic, and computed tomographic findings. J Comput Assist Tomogr 2006; 30: 828–838.
30 Meerburg JJ, Hartmann IJC, Goldacker S, et al. Analysis of granulomatous lymphocytic interstitial lung disease
using two scoring systems for computed tomography scans – a retrospective cohort study. Front Immunol 2020;
11: 589148.
31 Jolles S, Carne E, Brouns M, et al. FDG PET-CT imaging of therapeutic response in granulomatous lymphocytic
interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clin Exp Immunol 2017; 187:
138–145.
32 Fraz MSA, Moe N, Revheim ME, et al. Granulomatous–lymphocytic interstitial lung disease in common variable
immunodeficiency – features of CT and 18F-FDG positron emission tomography/CT in clinically progressive
disease. Front Immunol 2020; 11: 617985.
33 Aghamohammadi A, Moin M, Kouhi A, et al. Chromosomal radiosensitivity in patients with common variable
immunodeficiency. Immunobiology 2008; 213: 447–454.
34 Mahmoodi M, Abolhassani H, Mozdarani H, et al. In vitro chromosomal radiosensitivity in patients with
common variable immunodeficiency. Cent Eur J Immunol 2018; 43: 155–161.
35 Arslan S, Poyraz N, Ucar R, et al. Magnetic resonance imaging may be a valuable radiation-free technique for
lung pathologies in patients with primary immunodeficiency. J Clin Immunol 2016; 36: 66–72.
36 Milito C, Pulvirenti F, Serra G, et al. Lung magnetic resonance imaging with diffusion weighted imaging
provides regional structural as well as functional information without radiation exposure in primary antibody
deficiencies. J Clin Immunol 2015; 35: 491–500.
37 Sigurdsson MI, Isaksson HJ, Gudmundsson G, et al. Diagnostic surgical lung biopsies for suspected interstitial
lung diseases: a retrospective study. Ann Thorac Surg 2009; 88: 227–232.
38 Doan J, Rao N, Kurman JS, et al. Granulomatous and lymphocytic interstitial lung disease diagnosed by
transbronchial lung cryobiopsy. Cryobiology 2020; 97: 231–234.
39 Sasaki J, Tominaga M, Sudou M, et al. Granulomatous lymphocytic interstitial lung disease in multiple
myeloma. Intern Med 2023; 62: 439–444.
40 Verma N, Grimbacher B, Hurst JR. Lung disease in primary antibody deficiency. Lancet Respir Med 2015; 3: 651–660.
41 Verbsky JW, Routes JM. Sarcoidosis and common variable immunodeficiency: similarities and differences.
Semin Respir Crit Care Med 2014; 35: 330–335.
42 Maglione PJ, Overbey JR, Radigan L, et al. Pulmonary radiologic findings in common variable
immunodeficiency: clinical and immunological correlations. Ann Allergy Asthma Immunol 2014; 113: 452–459.
43 Wheat WH, Cool CD, Morimoto Y, et al. Possible role of human herpesvirus 8 in the lymphoproliferative
disorders in common variable immunodeficiency. J Exp Med 2005; 202: 479–484.
44 Maglione PJ, Ko HM, Beasley MB, et al. Tertiary lymphoid neogenesis is a component of pulmonary
lymphoid hyperplasia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2014; 133:
535–542.
45 Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders
(CVIDs) and the management of patients with these conditions. Br J Haematol 2009; 145: 709–727.
46 Lopes JP, Ho HE, Cunningham-Rundles C. Interstitial lung disease in common variable immunodeficiency. Front
Immunol 2021; 12: 605945.
47 Friedmann D, Unger S, Keller B, et al. Bronchoalveolar lavage fluid reflects a TH1-CD21low B-cell interaction in
CVID-related interstitial lung disease. Front Immunol 2020; 11: 616832.
48 Maglione PJ, Gyimesi G, Cols M, et al. BAFF-driven B cell hyperplasia underlies lung disease in common
variable immunodeficiency. JCI Insight 2019; 4: e122728.
49 Fraz MSA, Michelsen AE, Moe N, et al. Raised serum markers of T cell activation and exhaustion in
granulomatous–lymphocytic interstitial lung disease in common variable immunodeficiency. J Clin Immunol
2022; 42: 1553–1563.
50 van Stigt AC, Dalm VASH, Nagtzaam NMA, et al. Soluble interleukin-2 receptor is a promising serum biomarker
for granulomatous disease in common variable immune deficiency. J Clin Immunol 2021; 41: 694–697.
51 Cabanero-Navalon MD, Garcia-Bustos V, Forero-Naranjo LF, et al. Integrating clinics, laboratory, and imaging for
the diagnosis of common variable immunodeficiency-related granulomatous–lymphocytic interstitial lung
disease. Front Immunol 2022; 13: 813491.
52 Hasegawa M, Sakai F, Okabayashi A, et al. Intravenous immunoglobulin monotherapy for granulomatous
lymphocytic interstitial lung disease in common variable immunodeficiency. Intern Med 2017; 56: 2899–2902.
53 Lamers OA, Smits BM, Leavis HL, et al. Treatment strategies for GLILD in common variable immunodeficiency: a
systematic review. Front Immunol 2021; 12: 1205.
54 van Stigt AC, Dik WA, Kamphuis LS, et al. What works when treating granulomatous disease in genetically
undefined CVID? A systematic review. Front Immunol 2020; 11: 606389.
318 https://doi.org/10.1183/2312508X.10019222
55 Bintalib HM, Lowe DM, Mancuso G, et al. Corticosteroid-induced remission and mycophenolate maintenance
therapy in granulomatous lymphocytic interstitial lung disease: long-term, longitudinal change in lung function
in a single-centre cohort. ERJ Open Res 2022; 8: 00024-2022.
56 Cereser L, de Carli R, Girometti R, et al. Efficacy of rituximab as a single-agent therapy for the treatment of
granulomatous and lymphocytic interstitial lung disease in patients with common variable immunodeficiency.
J Allergy Clin Immunol Pract 2019; 7: 1055–1057.e2.
57 Ng J, Wright K, Alvarez M, et al. Rituximab monotherapy for common variable immune deficiency-associated
granulomatous–lymphocytic interstitial lung disease. Chest 2019; 155: e117–e121.
58 Tessarin G, Bondioni MP, Rossi S, et al. Rituximab as a single agent for granulomatous lymphocytic interstitial
lung disease in common variable immune deficiency. J Investig Allergol Clin Immunol 2019; 29: 470–471.
59 Verbsky JW, Hintermeyer MK, Simpson PM, et al. Rituximab and antimetabolite treatment of granulomatous
and lymphocytic interstitial lung disease in common variable immunodeficiency. J Allergy Clin Immunol 2021;
147: 704–712.e17.
60 von Spee-Mayer C, Echternach C, Agarwal P, et al. Abatacept use is associated with steroid dose reduction and
improvement in fatigue and CD4-dysregulation in CVID patients with interstitial lung disease. J Allergy Clin
Immunol Pract 2021; 9: 760–770.e10.
61 Wehr C, Gennery AR, Lindemans C, et al. Multicenter experience in hematopoietic stem cell transplantation for
serious complications of common variable immunodeficiency. J Allergy Clin Immunol 2015; 135: 988–997.e6.
62 Hurst JR, Abbas SH, Bintalib HM, et al. Granulomatous–lymphocytic interstitial lung disease: an international
research prioritisation. ERJ Open Res 2021; 7: 00467-2021.
Disclosures: H.M. Bintalib has nothing to disclose. S.O. Burns reports the following: grant support from CSL
Behring and personal fees or travel expenses from Immunodeficiency Canada/IAACI, CSL Behring, GlaxoSmithKline,
Baxalta US Inc. and Biotest. J.R. Hurst reports the following: support to attend meetings, personal payment and
payment to his employer from companies that make medicines to treat respiratory disease and immunoglobulin
products.
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Chapter 23
Thoracic endometriosis and catamenial

pneumothorax
Antonio Bobbio1,2, Vincent de Pauw1,2, Imane Lefqih1,2, Antoine Sion1,2 and
Marco Alifano1,2
1
Service de Chirurgie Thoracique, Hôpitaux Universitaires Paris Centre, Paris, France. 2Faculté de Médecine,
Université Paris-Descartes, Paris, France.
Corresponding author: Antonio Bobbio (antonio.bobbio@aphp.fr)
Cite as: Bobbio A, de Pauw V, Lefqih I, et al. Thoracic endometriosis and catamenial pneumothorax. In: Wagner TOF,
@ERSpublications
Endometriosis is a scourge. Endometriosis implants in the thorax give rise to a wide variety of respiratory
signs and symptoms, which are a challenge for the respiratory physician caring for a gynaecological patient,
unless history-taking is focused. https://bit.ly/ERSM100
ISSN: 2312-5098.
Although thoracic endometriosis is a rare disease, it is not uncommon in women of child-bearing age
presenting with spontaneous pneumothorax. Other less frequent endometriosis-related conditions are
pleural effusion including haemothorax, pulmonary and tracheobronchial implants, diaphragmatic
hernia and chronic thoracic pain; when they arise during menses, these manifestations are referred to as
catamenial. The principal pathway of endometriosis migration from the abdomen and into the thorax is
through the right diaphragm, giving rise to a predominance of signs and symptoms on the right thoracic
side; through the same route, the air could pass into the pleura. Imaging varies with the hormonal
cycle, and the patient’s gynaecological history is crucial for diagnosis. Formal diagnosis of
endometriosis is almost always obtained at surgery by exploration of the extended pleura and excision
of all visible lesions. A combined surgical and medical approach is necessary to control the disease.
Introduction
Endometriosis is defined as a disease characterised by the presence of endometrium-like
epithelium and/or stroma outside the endometrium and myometrium, usually with an associated
inflammatory process [1]. It occurs most often in the pelvis, but endometriosis of virtually all
compartments of the body has been reported. A classification of extragenital endometriosis
formulated by MARKHAM et al. [2] in 1989 distinguishes between implants in digestive, urinary,
thoracic and other sites. Although rarely involved, the thoracic cavity is the most frequent
extra-abdominopelvic site of endometriosis [3].
The term thoracic endometriosis syndrome (TES) refers to a large spectrum of clinical and/or
radiological manifestations associated with the growth of endometrial tissue in the visceral or
parietal pleura, lung parenchyma, airways or diaphragm [4–8]. When these manifestations occur
during the period of menses, they are termed “catamenial”, but they can also occur outside this
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THORACIC ENDOMETRIOSIS AND CATAMENIAL PNEUMOTHORAX | A. BOBBIO ET AL.
period, and the adjective “endometriosis-related” is more comprehensive [9]. The most common
clinical picture of TES is spontaneous pneumothorax, which has been defined historically as
catamenial because of its frequent occurrence during menses, although it has been shown that it
can occur also outside this period. Other entities of TES are pleural effusion including
haemothorax, haemoptysis, endometriosis lung nodules, diaphragmatic hernia and catamenial
chest pain, which is a common but also under-recognised clinical manifestation of thoracic
endometriosis [7]. These manifestations can occur in isolation, concomitantly or in a sequential
temporal relationship. Initially, they are likely to be observed during menses, but subsequently,
as a result of irreversible anatomical modification and hormone escape, they can also be
observed outside the period of menses [1–4].
In this chapter, we review our recent understanding of thoracic endometriosis. Data on the
epidemiology of TES are analysed with the aim of extrapolating its incidence and trying to shed
light on its misdiagnosis. The pathways of migration and implantation of endometrial tissue into
the thorax are reviewed, as they are a fundamental step in recognising the respiratory symptoms
and signs of this gynaecological disease. Ultimately, the principal clinical entities of TES are
presented, with special attention paid to endometriosis-related pneumothorax. Haemothorax will
be considered as part of the larger entity, including all kinds of endometriosis-related pleural
effusion. Endometriosis-related diaphragmatic hernia and catamenial chest pain will be
considered as autonomous entities.
Epidemiology of thoracic endometriosis and endometriosis-related pneumothorax

Although peritoneal endometriosis is a common disease estimated to affect 5–15% of women of
child-bearing age, endometrial tissue in the thorax is considered a much rarer event in the
course of the disease [10]. In both cases, however, its prevalence is difficult to estimate because
the disease may occur with a few mild or no symptoms, while a formal pathological diagnosis
often necessitates invasive procedures, which are generally reserved for severe cases. In Western
countries, an overall diagnostic delay as long as 10 years has been reported [11].
In spite of such limitations, data on the incidence of thoracic endometriosis in women of

child-bearing age could be extrapolated from existing data on the incidence of catamenial
pneumothorax, which is thought to represent ~70% of cases of TES [3]. Data on the incidence
of catamenial pneumothorax can be found in studies that explore the epidemiology of
pneumothorax in large-scale administrative databases, as well as in surgical studies of women
operated on for spontaneous pneumothorax [7, 9, 12, 13].
In a Japanese national database registry of acute-care hospitalisations between 2010 and

2016, 874 cases of catamenial pneumothorax were found among 11 559 women aged
between 13 and 53 years. When considering the whole population, this corresponded to 3.1%
of cases. Obviously, the methodology of these studies is retrospective, and administrative
coding leads to loss of information (i.e. endometriosis-related noncatamenial pneumothorax).
However, surgical studies tend to concentrate on the most severe cases in surgical centres
with expertise in the disease. In a French surgical series, the rate of endometriosis-related
pneumothorax in women of child-bearing age was ~40% of all operated cases with
spontaneous pneumothorax. Interestingly, in such surgical studies, it is possible to identify
the rate of endometriosis-related pneumothorax occurring outside the period of menses. In a
similar series from a Japanese surgical team, endometriosis-related pneumothorax was noted
in 20% of all women of child-bearing age [8]. In conclusion, and taking into account the
high prevalence of endometriosis in women during the fertile period of their life, the
https://doi.org/10.1183/2312508X.10019322 321
diagnosis of thoracic endometriosis is rare. However, in women of child-bearing age operated

on for recurrent spontaneous pneumothorax, thoracic endometriosis is a frequent pathological
finding [13, 14].
Aetiopathogenesis of thoracic endometriosis and catamenial pneumothorax

Endometriosis is considered a systemic disease with hallmarks of development and diffusion,
sharing common characteristics with carcinogenesis [15]. Molecular studies on glandular tissue
from deep endometriosis have shown the presence of “driver” gene mutations (KRAS, PIK3CA
and ARID1A) typically associated with cancers, which enable cells to migrate, adhere to and
invade other tissues [16]. Endometrial tissue under cyclic hormonal impulses modifies the
micro-environment and induces a chronic state of local inflammation, and immune
dysregulation. In this scenario, macrophages play a pivotal role by secretion of proinflammatory
cytokines such as tumour necrosis factor-α and interleukin-6 and -8 [17]. During the
oestrogenic phases of the cycle, the secretion of growth factors will enable constitution of a new
vascular and nervous network, whereas during the progesterone period, the glands desquamate
and the micro-environment is characterised by scarring and fibrosis. Modification of the
microbiota and its interaction with the immune system, as well as with hormonal regulation, are
examples of the multiple factors involved in endometriosis [18].
From an anatomical point of view, the migration of endometrial tissue to the pleural cavity
seems to involve the passage of endometrial cells from the peritoneum to the pleural cavity
through the diaphragm. This is referred to as the “transdiaphragmatic” migration theory. This
pathophysiological cascade first involves “retrograde” menstruation of refluxed menstrual debris
containing viable endometrial tissue and stem cells through the fallopian tubes and into the
peritoneal cavity, as described by SAMPSON [19]. From the pelvis, endometrial tissue could
migrate into the peritoneal cavity following the physiological movements of peritoneal fluids
and reach the right subdiaphragmatic space through the right colic gutter [20]. At this point, the
hepatic falciform ligament, which attaches the liver to the front body wall, constitutes a barrier
and leads to accumulation of endometrial tissue in the right subphrenic region [21].
Transdiaphragmatic passage of endometrial tissue can further occur through congenital or
acquired diaphragmatic defects [2, 7, 20]. Although small, congenital diaphragmatic holes are
not uncommon, as observed in Meigs syndrome, the tendinous portion of the diaphragm could
be the site of local destruction as a consequence of proliferation/involution of endometrial
implants (figure 1) [21]. The “transdiaphragmatic” migration pathway of endometriosis explains
the high frequency of clinical manifestations of TES on the right thoracic side [21]. Another
pathway of endometriosis dissemination into the thorax is referred to as “embolic” because it
involves the migration of endometrial cells through lymphatic or vascular vessels. This
dissemination often results from trauma or the manipulation of uterine tissue, which gives rise
to tissue micro-embolisation. In contrast to the transdiaphragmatic pathway, in this latter case,
intrapulmonary or tracheobronchial localisations of thoracic endometriosis are often observed,
with no predominance on either thoracic side [1, 7, 17].
Catamenial pneumothorax and endometriosis-related pneumothorax

Definition and classification
Catamenial pneumothorax is defined on the basis of clinical rules as a recurrent pneumothorax
occurring between the day before menstruation and 72 h after its onset [1, 4]. Catamenial
pneumothorax is a spontaneous pneumothorax secondary to thoracic endometriosis, but it
should be noted that endometriosis-related pneumothorax can also occur outside the period of
menses and that thoracic endometriosis may be absent at thoracoscopic exploration of operated
322 https://doi.org/10.1183/2312508X.10019322
FIGURE 1 Perioperative view of liver herniation through the right diaphragm. Note on the side of the hernia the
presence of two round small holes in the tendinous portion of the diaphragm.
patients with catamenial pneumothorax. A classification based on clinical and pathological

findings has been proposed with the aim of clarifying the various clinical and pathological
presentations of spontaneous pneumothorax in women of child-bearing age (table 1) [7].
Pathogenesis
Endometriosis-related pneumothorax is due to anatomical modification in the lung, diaphragm
and/or pleura related to the presence and/or progression of endometriosis. In surgical series, the
most frequent site of endometriosis implants is the diaphragm, in the form of nodules, cysts
and/or holes (figure 2); such lesions are found at thoracoscopic exploration in up to 40% of
cases [5]. Two principal pathways lead to the accumulation of air in the pleural cavity
secondary to endometriosis. One is named “transdiaphragmatic” and has the unique feature that
the air accumulated in the pleura comes from the abdomen. During the menstrual period, the
cervical mucous plug is absent, and communication between the peritoneal cavity and the
outside through the uterine cavity and fallopian tubes could lead to the passage of air into the
peritoneal cavity. Once in the peritoneal cavity, the air is attracted to the subdiaphragmatic
region by negative intrapleural pressure and finally could pass into the pleural cavity through
pre-existing holes and perforations of the diaphragm [21]. This pathogenic cascade leads to the
observation of several cases in which, on chest radiography, a pneumoperitoneum is
TABLE 1 Classification of spontaneous pneumothorax in women of child-bearing age

Catamenial pneumothorax with endometriosis
Catamenial pneumothorax without endometriosis
Noncatamenial pneumothorax with endometriosis
Noncatamenial pneumothorax without endometriosis
https://doi.org/10.1183/2312508X.10019322 323
FIGURE 2 Perioperative view of endometriosis cysts on the tendinous portion of the left diaphragm.
synchronous with pneumothorax [22]. The other main mechanism to explain how endometriosis
induces pneumothorax is that of alveolar leakage secondary to the destruction of ectopic
endometrial tissue in the visceral pleura during menstruation [4].
Clinical features
Pain, cough and dyspnoea are the classical triad indicative of pneumothorax and are also present
in patients with endometriosis-related pneumothorax. In the case of women of reproductive age,
questioning regarding the timing of symptoms in relation to menses is crucial. A comprehensive
gynaecological history should also be used to rule out abdominal and pelvic signs and/or
symptoms of endometriosis, and to check for infertility and dysmenorrhoea as the most frequent
complications of the disease [23]. The patient should be asked about recurrent catamenial
thoracic pain with the characteristic of periscapular or neck-irradiated pain (“diaphragmatic
pain”). The presence of catamenial scapular pain associated with symptoms of pelvic
endometriosis in patients with catamenial pneumothorax is specific to thoracic endometriosis in
97.7% of cases [5]. A unique feature of catamenial pneumothorax is its high predominance on
the right side, as reported in up to 90% of cases in historical series [4–7]. This particularity, as
described earlier, is due to the anatomical pathway of distribution of endometriosis in the
abdomen, with accumulation in right subdiaphragmatic region [21]. Spontaneous pneumothorax
in adults is known to occur at a higher mean age in women than in men, but endometriosis-
related pneumothorax occurs at an even higher age than in women with idiopathic pneumothorax
[12]. Since the first epidemiological studies of spontaneous pneumothorax in women, it has been
found that body mass index and smoking status interact differently compared with in men as risk
factors in the occurrence or recurrence of pneumothorax [12, 24, 25].
Imaging and diagnostic procedures

Although rare, pneumothorax related to endometriosis can present specific alterations on the
chest radiograph, such as an associated pneumoperitoneum (figure 3) or the sign of
diaphragmatic herniation of abdominal viscera (figure 4) [26, 27]. A CT scan performed during
the acute phase of pneumothorax to detect pulmonary blebs or bullae sometimes reveals
anomalies in the diaphragm in the form of nodules or diaphragmatic defects and even herniation
of visceral hernia in the thoracic cavity. The use of an iodinated contrast product helps to
characterise these anomalies. When a work-up is planned for detection of thoracic
endometriosis, diaphragmatic MRI is the gold standard in ruling out thoracic endometriosis
implants. It should always take into account that the appearance of the implants depends on the
324 https://doi.org/10.1183/2312508X.10019322
FIGURE 3 CT scan showing pneumothorax and pneumoperitoneum.
period of the cycle, with the unique features of possible disappearance or growth following the
hormonal cycle. Demonstration of any diaphragmatic, pleural or pulmonary lesions is almost
always obtained by video-assisted thoracoscopy. To be complete, the exploration must include the
parietal pleura, visceral pleura and lung, and particular attention should be paid to the diaphragm.
Diaphragmatic abnormalities are the most common lesions and are generally found in the
tendinous centre of the muscle [4, 7, 21]. Brown or purple lesions (depending on the menstrual
cycle and the duration of bleeding) from a few millimetres up to 1 cm in size are generally
associated with perforations that most often are millimetric in size. Larger diaphragmatic defects
with perforations are possible and can give rise to lacerations of the diaphragm, with intrathoracic
FIGURE 4 CT scan showing right pneumothorax and liver herniation through the diaphragm visible as the
“bouchon de champagne” (champagne cork) sign.
https://doi.org/10.1183/2312508X.10019322 325
herniation of the abdominal organs (figure 4) [26–28]. Apart from lesions of the diaphragm, it is
advisable to look carefully for other lesions associated with endometriosis (nodules of the visceral
or parietal pleura) or not (apical bullous dystrophy), in order to avoid misdiagnosis.
Treatment
Rest, pleural exsufflation and/or drainage are used to control the patient’s clinical condition.
Surgery by video-assisted techniques is considered to allow pathological confirmation of the
disease and to prevent recurrence. As for the treatment of abdominal and pelvic endometriosis, the
goal of surgery is the excision of all visible implants [28, 29]. Endometrial implants left in place
may trigger new symptoms, as well as subsequent spread into the pleural cavity. In the case of
diaphragmatic nodules or perforations, partial diaphragmatic resection is necessary, and repair of
the defect is generally performed by direct suture [30]. Endometriosis-related pneumothorax is
characterised by a high rate of recurrence, and pleural symphysis by talc insufflation has been
shown to be the optimal treatment for permanent obliteration of the pleural cavity [30, 31]. In any
case of endometriosis-related pneumothorax, gynaecological advice is mandatory. Thoracic
endometriosis should be considered as an advanced stage of the disease because lesions have
spread and caused tissue destruction (lung, pleura and/or diaphragm). Ideally, the goal of medical
treatment is regression and healing of all residual microscopic endometriosis implants. Inhibition
of ovarian function for a period of 6 months after surgery in endometriosis-related pneumothorax
is generally prescribed with the objective of reducing the risk of recurrence. Gonadotropin-
releasing hormone analogues or continuous oral progesterone have been evaluated but could be
not tolerated and/or strongly interfered with the quality of life of these young women. The
combined oral contraceptive pill is a possible alternative, but in any case a tailored approach and
an open discussion establishing short- and long-term objectives must be planned [28, 30].
TES other than pneumothorax

In a review of the historical literature on all cases of TES published before 1994, JOSEPH and
SAHN [4] described three main clinical entities other than pneumothorax, namely, catamenial
haemothorax, catamenial haemoptysis and endometriotic lung nodules. They found one case of
pneumomediastinum and one case of isolated chest pain. More recently, a single-centre surgical
study of 31 cases of TES other than pneumothorax provided new insights into the clinical
presentation of TES [9]. Hereafter, we present endometriosis-related pleural effusion including
haemothorax, endometriosis-related diaphragmatic hernia and chest pain as new entities of TES.
Catamenial haemothorax and endometriosis-related pleural effusion

Catamenial haemothorax is historically considered to be the second most common clinical
presentation of TES (14% of all published cases of TES in 1994) [4]. It also represents the first
case of TES reported in the literature by NICHOLSON [31] in 1951 and was discussed in a second
report in 1953 by BARNES [32]. In the report of JOSEPH and SAHN [4], catamenial haemothorax was
classified on the basis of chest radiography as large (two cases), moderate (three cases) or small (10
cases) [4]. In a more recent surgical series, there were five cases of pleural effusion among 31 cases
of TES other than pneumothorax [9]. Three of these cases were defined as large haemorrhagic
pleural effusion requiring urgent surgery, but the other two were reported as chronic
serosanguineous pleural effusion. Interestingly, in two out of three patients, massive haemothorax
occurred early after ovarian stimulation (figure 5). Endometriosis-related pleural effusion may also
be associated with peritoneal ascites, simulating Meigs syndrome [33]. The clinical presentation
encompasses various heterogeneous clinical syndromes, and the thoracoscopic findings may also be
heterogeneous: diffuse and thick pleural endometriosis, but also the absence of macroscopic visible
implants, with a formal diagnosis obtained only on microscopic examination of the pleura [4, 9].
326 https://doi.org/10.1183/2312508X.10019322
FIGURE 5 CT scan showing compressive right endometriosis-related haemothorax occurring during ovarian
stimulation.
As for pneumothorax, a strong predominance of the syndrome is on the right thoracic side,
which, as discussed earlier, is a consequence of transdiaphragmatic migration of endometriosis
from the right subphrenic region. Although chest drainage is useful for initial management and
possibly in an emergency context, definitive treatment requires multidisciplinary surgical and
hormonal management. According to the intraoperative findings, the excision of all
macroscopically visible lesions is a goal, unless, as in some cases, the extent of the lesions is so
great that total excision proves impossible. As many as possible should be removed by extended
pleurectomy [8]. In such cases, hormonal treatment is crucial.
Endometriosis-related diaphragmatic hernia

Holes and perforations in the diaphragm are stigmata of diaphragmatic endometriosis, even in
the absence of macroscopic nodules and/or cysts. They are the result of cyclic proliferation/
desquamation of endometriosis implants leading to focal destruction, especially of the tendinous
part of the diaphragm, which is thin and poorly vascularised. These holes may explain passage
of abdominal air into the pleura in some cases of endometriosis-related pneumothorax. It should
be noted that during menses, which is when catamenial pneumothorax occurs, the implants of
endometriosis are absent and often only holes are found at thoracoscopy. Over time, the
alternation of proliferation and scarring can give rise to a larger defect and ultimately laceration
of the diaphragm, with herniation of abdominal organs in the thorax.
Apparently, the first case of diaphragmatic hernia secondary to thoracic endometriosis was
reported in 2007 [27] and, in 2015, a series of seven more cases was reported in a literature
review [34]. More recently, a single-centre series of six cases was published [9]. In all of the
published cases except one, the hernia was located on the right thoracic side. Obviously, the
liver was the organ most often herniated in the thorax. The hernia may be discovered
concomitantly with endometriosis-related pneumothorax, but in many cases it is associated with
and is preceded only by chronic thoracic pain [9].
https://doi.org/10.1183/2312508X.10019322 327
Chest radiography may suggest the presence of a hernia, but a CT scan and diaphragmatic MRI
are more precise in determining the extent and presence of associated lesions (figure 6). Surgery
is performed in the case of symptoms and, once the organs have been reintegrated into the
abdomen, the diaphragm can be repaired by direct suturing or, for a more extensive lesion, by
prosthesis positioning. As in the other clinical manifestations of TES, the pathological diagnosis
of endometriosis can be difficult, and it is recommended to look for endometrial tissue implants
on the margins of the diaphragmatic defect, which must therefore be excised [27].
Endometriosis-related thoracic pain

Pain is the cardinal symptom of endometriosis, and different mechanisms are responsible for its
onset and for it becoming chronic: nerve growth factor and vascular endothelial growth factor
are highly expressed in the glands and stroma of ectopic tissue, and neurogenesis with
cholinergic or adrenergic but also sensory fibres occurs around implants [35].
Catamenial chest pain is often diagnosed at the onset of pneumothorax, but may also be
isolated. Gynaecological studies have described the correlations between implants of
diaphragmatic endometriosis diagnosed by laparoscopy and catamenial chest pain isolated from
any other chest symptom [36, 37]. More recently, a series of patients with recurrent catamenial
chest pain without other symptoms of TES has been published [9]. Of the 19 patients, 11 were
operated on: diaphragmatic implant excision was performed in eight out of 11 cases, but in
three cases endometriosis could not be proven. In patients who had implants removed, an
improvement in the visual analogue scale pain score was noted [9].
Pain is typically located in the right scapula or next to the shoulder and sometimes radiates to
the neck or arm [37], in correspondence with the afferent dermatome of the phrenic nerve. In a
few cases, epigastric or right upper-quadrant pain is present. In most patients, it is limited to the
FIGURE 6 MRI showing herniation of the liver through the diaphragm: the “bouchon de champagne”
(champagne cork) sign.
328 https://doi.org/10.1183/2312508X.10019322
catamenial period, while in others it begins several days before menstruation [9, 36]. Persistent
pain with exacerbation during menses has also been reported [36]. First-line treatment, in the
case of pain related to endometriosis, is based on the prescription of nonsteroidal
anti-inflammatory drugs and on progesterone-based contraceptives. The second line of treatment
involves the use of gonadotropin-releasing hormone agonists, but their side-effects related to
pseudomenopause (bone demineralisation, vasomotor symptoms) generally limit their length of
use to <6 months. Surgical treatment should be reserved for women who cannot tolerate drug
treatment or if such treatment fails. The principle of surgical treatment is based on partial
diaphragmatic excision in order to remove all visible implants. Surgical treatment is often
followed by hormonal treatment [9, 36].
Conclusion
Endometriosis-related pneumothorax is the most common clinical presentation of TES and
accounts for a significant proportion of cases of spontaneous pneumothorax in women of
child-bearing age. Thoracic endometriosis can give rise to a large spectrum of other thoracic
clinical and/or radiological manifestations, which can be observed during menses but also outside
this period. Surgery and hormonal treatment are needed in complicated cases, unless a tailored
approach taking into account various objectives in terms of private and social quality of life should
be considered. No doubt because the pathophysiology of the disease includes genetic alterations,
immune dysregulation and chronic inflammation, a complete cure is currently not achievable,
suggesting that more research is needed to further improve our understanding of this disease.
References
1 Tomassetti C, Johnson NP, Petrozza J, et al. An international terminology for endometriosis. J Minim Invasive
Gynecol 2021; 28: 1849–1859.
2 Markham SM, Carpenter SE, Rock JA. Extrapelvic endometriosis. Obstet Gynecol Clin North Am 1989; 16: 193–219.
3 Alifano M, Trisolini R, Cancellieri A, et al. Thoracic endometriosis: current knowledge. Ann Thorac Surg 2006; 81:
761–769.
4 Joseph J, Sahn SA. Thoracic endometriosis syndrome: new observations from an analysis of 110 cases. Am J
Med 1996; 100: 164–170.
5 Alifano M, Roth T, Camilleri Broet S, et al. Catamenial pneumothorax. A prospective study. Chest 2003; 124:
1004–1008.
6 Ciriaco P, Muriana P, Lembo R, et al. Treatment of thoracic endometriosis syndrome: a meta-analysis and
review. Ann Thorac Surg 2022; 113: 324–336.
7 Legras A, Mansuet-Lupo A, Rousset-Jablonski C, et al. Pneumothorax in women of child-bearing age: an update
classification based on clinical and pathologic findings. Chest 2014; 145: 354–360.
8 Fukuoka M, Kurihara M, Haga T, et al. Clinical characteristics of catamenial and non-catamenial thoracic
endometriosis-related pneumothorax. Respirology 2015; 20: 1272–1276.
9 Bobbio A, Canny E, Mansuet Lupo A, et al. Manifestations of thoracic endometriosis syndrome other than
pneumothorax: clinical and pathological findings. Ann Thorac Surg 2017; 104: 1865–1871.
10 Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997; 24: 235–258.
11 Hudelist G, Fritzer N, Thomas A, et al. Diagnostic delay for endometriosis in Austria and Germany: causes and
possible consequences. Hum Reprod 2012; 27: 3412–3416.
12 Bobbio A, Dechartres A, Bouam S, et al. Epidemiology of spontaneous pneumothorax: gender-related
differences. Thorax 2015; 70: 653–658.
13 Hiyama N, Sasabuchi Y, Jo T, et al. The three peaks in age distribution of females with pneumothorax: a
nationwide database study in Japan. Eur J Cardiothorac Surg 2018; 54: 572–578.
14 Alifano M, Legras A, Rousset-Jablonski C, et al. Pneumothorax recurrence after surgery in women:
clinicopathologic characteristics and management. Ann Thorac Surg 2011; 92: 322–326.
15 Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020; 382: 1244–1256.
16 Anglesio MS, Papadopoulos N, Ayhan A, et al. Cancer-associated mutations in endometriosis without cancer.
N Engl J Med 2017; 376: 1835–1848.
17 Symons LK, Miller JE, Kay VR, et al. The immunopathophysiology of endometriosis. Trends Mol Med 2018; 24:
748–762.
https://doi.org/10.1183/2312508X.10019322 329
18 Jiang I, Yong PJ, Allaire C, et al. Intricate connections between the microbiota and endometriosis. Int J Mol Sci
2021; 22: 5644.
19 Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the
peritoneal cavity. Am J Obstet Gynecol 1927; 14: 422–469.
20 Foster DC, Stern JL, Buscema J, et al. Pleural and pulmonary endometriosis. Obstet Gynecol 1981; 58: 552–556.
21 Vercellini P, Abbiati A, Viganò P, et al. Asymmetry in distribution of diaphragmatic endometriotic lesions:
evidence in favour of the menstrual reflux theory. Hum Reprod 2007; 22: 2359–2367.
22 Glauser FL, Barlett RH. Pneumoperitoneum in association with pneumothorax. Chest 1974; 66: 536–540.
23 Olive DL, Schwartz LB. Endometriosis. N Engl J Med 1993; 328: 1759–1769.
24 Nakamura H, Konishiike J, Sugamura A, et al. Epidemiology of spontaneous pneumothorax in women. Chest
1986; 89: 378–382.
25 Sadikot RT, Greene T, Meadows K, et al. Recurrence of primary spontaneous pneumothorax. Thorax 1997; 52:
805–809.
26 Rousset P, Rousset-Jablonski C, Alifano M, et al. Thoracic endometriosis syndrome: CT and MRI features. Clin
Radiol 2014; 69: 323–330.
27 Bobbio A, Carbognani P, Ampollini L, et al. Diaphragmatic laceration, partial liver herniation and catamenial
pneumothorax. Asian Cardiovasc Thorac Ann 2007; 15: 249–251.
28 Yu PSY, Sihoe ADL. Beware the “raised right hemidiaphragm” in a female patient with previous pneumothorax
surgery: liver herniation through a massive endometrosis-related diaphragmatic fenestration. J Thorac Dis 2015;
7: 112–116.
29 Alifano M, Jablonski C, Kadiri H, et al. Catamenial and noncatamenial, endometriosis-related or nonendometriosis-
related pneumothorax referred for surgery. Am J Respir Crit Care Med 2007; 176: 1048–1053.
30 Triponez F, Alifano M, Bobbio A, et al. Endometriosis-related spontaneous diaphragmatic rupture. Interact
Cardiovasc Thorac Surg 2010; 11: 485–487.
31 Nicholson H. Endometriosis of the pleura. Thorax 1951; 6: 75–81.
32 Barnes J. Endometriosis of the pleura and ovaries. J Obstet Gynaecol Br Emp 1953; 60: 823–824.
33 Brews A. Endometriosis including endometriosis of the diaphragm and Meig’s syndrome. Proc R Soc Med 1954;
47: 461–463.
34 Arakawa S, Matsudaira H, Noda Y, et al. Catamenial pneumothorax with partial liver herniation due to
diaphragmatic laceration: a case report and literature review. J Cardiothorac Surg 2021; 16: 23.
35 Tokushige N, Markham R, Russell P, et al. High density of small nerve fibres in the functional layer of the
endometrium in women with endometriosis. Hum Reprod 2006; 21: 782–787.
36 Nezhat C, Seidman DS, Nezhat F, et al. Laparoscopic surgical management of diaphragmatic endometriosis.
Fertil Steril 1998; 69: 1048–1055.
37 Redwine DB. Diaphragmatic endometriosis: diagnosis, surgical management, and long-term results of
treatment. Fertil Steril 2002; 77: 288–296.
330 https://doi.org/10.1183/2312508X.10019322
Chapter 24
Chronic lung allograft dysfunction after lung

transplantation
Berta Saez Gimenez1,2, Merel Hellemons 3,4
, Stijn E. Verleden5, Jens Gottlieb 6,7
and Geert M. Verleden 8

1
Dept of Pneumology, Lung Transplant Unit, Hospital Universitari Vall d’Hebrón, Barcelona, Spain. 2Dept of Cell
Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain. 3Dept of Respiratory
Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. 4Erasmus MC Transplantation Institute,
Erasmus University Medical Center, Rotterdam, The Netherlands. 5Division of Thoracic surgery, Antwerp Surgical
Training, Anatomy and Research Centre (ASTARC), University of Antwerp, Wilrijk, Belgium. 6Respiratory Medicine,
Hannover Medical School, Hannover, Germany. 7German Center for Lung Research (DZL), Hannover, Germany.
8
Dept of Respiratory Diseases, Lung Transplantation Unit, University Hospital Gasthuisberg, Leuven, Belgium.
Corresponding author: Geert M. Verleden (geert.verleden@uzleuven.be)
Cite as: Gimenez BS, Hellemons M, Verleden SE, et al. Chronic lung allograft dysfunction after lung transplantation.
In: Wagner TOF, Humbert M, Wijsenbeek M, et al. eds. Rare Diseases of the Respiratory System (ERS Monograph).
@ERSpublications
Chronic lung allograft dysfunction affects up to 50% of patients within 5 years of lung transplantation.
Phenotyping is important for prognosis. There is currently no treatment that is able to reverse the decline in
pulmonary function. https://bit.ly/ERSM100
ISSN: 2312-5098.
Chronic lung allograft dysfunction (CLAD) remains one of the most important complications after lung
transplantation, affecting 50% of patients by 5 years post-transplant. It is a major cause of morbidity
and the leading cause of mortality beyond 5 years after the transplantation procedure. CLAD is
characterised by a persistent and mostly progressive fall in forced expiratory volume in 1 s (FEV1) of
>20% compared with the postoperative best FEV1 and is believed to be the consequence of chronic
rejection. In recent years, it has become clear that different phenotypes of CLAD can be identified,
based on the pulmonary function evolution and findings on chest imaging. In the present chapter, we
will focus on the current definition of CLAD and its phenotypes, risk factors for its development,
outcome and possible treatment options.
History of chronic lung allograft dysfunction

The first papers regarding chronic rejection after lung transplantation (LTx) were published
between 1984 and 1987 [1–3] and described heart–LTx recipients with obstructive airway
disease and obliterative bronchiolitis (OB) on anatomopathological examination. They suggested
that OB was a manifestation of chronic rejection. Although newly described after LTx, it was
already identified in pulmonary graft-versus-host disease after haematopoietic stem-cell
transplantation, autoimmune disorders, inhalation of toxins and viral infections [4].
In 1993, the term “bronchiolitis obliterans syndrome” (BOS) was introduced to label chronic
rejection, understood as a homogeneous condition where an obstructive ventilatory defect occurred
https://doi.org/10.1183/2312508X.10019422 331
secondary to a progressive airway disease [5]. Definition of this clinical syndrome was based on
spirometry [5, 6]; however, in a later update, it was acknowledged that many other conditions could
explain an obstructive pulmonary function after LTx and needed to be ruled out [7].
Early descriptions of chronic rejection also included cases with restrictive pulmonary function
decline and pleural thickening [8], which raised the concept of different phenotypes [9] and
introduced the term “chronic lung allograft dysfunction” (CLAD) [6]. This further led to the
introduction of the term “restrictive allograft syndrome” (RAS) in 2011 [10]. Based on these
phenotypes, VERLEDEN et al. [11] proposed a new classification of CLAD, which was used as an
umbrella term for all possible causes of lung function decline after LTx. In 2019, a consensus
document was published to differentiate chronic rejection from other situations of persistent
graft dysfunction and to standardise CLAD nomenclature, diagnosis and phenotyping as we
know it today [12].
Current definition/diagnosis of CLAD

CLAD is still diagnosed when a decline in forced expiratory volume in 1 s (FEV1) of ⩾20%
from baseline FEV1 is present. After a first fall in FEV1 ⩾20%, possible CLAD may be
diagnosed. If, despite treatment of alternative/underlying causes, a second PFT remains impaired
for ⩾3 weeks after the first ⩾20% decline, this indicates probable CLAD. After investigation
and adequate treatment for other/intercurrent causes of lung function decline, a diagnosis of
definite CLAD can be made when the FEV1 decrease persists for ⩾3 months (figure 1) [12].
CLAD is then staged depending on the decline in FEV1 (table 1). Clearly, other causes of FEV1
5.0
4.5
4.0 Baseline FEV1

Lung function, L
Lung allograft
3.5 dysfunction
3.0
2.5 Possible CLAD

Probable CLAD
2.0
Definite CLAD
1.5
0.1 0.2 0.3 0.4 0.5 0.6 1.1 1.2 1.3 1.5 1.6 1.8 2.3 2.8
Years after LTx
FVC FEV1 <10% decline FEV1 <20% decline FEV1
Lung allograft dysfunction

Possible CLAD: <3 weeks
Probable CLAD: >3 weeks–3 months
Definite CLAD: >3 months
FIGURE 1 Case illustration of the diagnosis of chronic lung allograft dysfunction (CLAD) after lung
transplantation (LTx), based on a progressive and persistent decline in forced expiratory volume in 1 s (FEV1).
Years are shown as decimal fractions.
332 https://doi.org/10.1183/2312508X.10019422
CHRONIC LUNG ALLOGRAFT DYSFUNCTION | B.S. GIMENEZ ET AL.
TABLE 1 Staging of chronic lung allograft dysfunction (CLAD) as defined in the International Society for Heart
and Lung Transplantation 2019 consensus document
CLAD stage FEV1 (% of baseline)
1 >65–80%
2 >50–65%
3 >35–50%
4 ⩽35%
Once CLAD is diagnosed, staging is performed according to the decline in forced expiratory volume in 1 s
(FEV1), compared with baseline. Baseline FEV1 is defined as the mean of the two best postoperative FEV1
values with ⩾3 weeks in between. The date of onset of CLAD is defined as the date at which the first value of
FEV1 ⩽80% of baseline was recorded. The same principle holds for each stage. Reproduced and modified from
[12] with permission.
decline need to be ruled out (e.g. suture stenosis, persistent pleural fluid, myopathy). A
concurrent acute rejection or infection does not prevent a CLAD diagnosis as long as adequate
treatment for these underlying conditions does not improve FEV1 to >80% of baseline [12], in
which case CLAD is no longer sustained.
Epidemiology and phenotypes of CLAD

According to the International Society for Heart and Lung Transplantation registry report,
between 4500 and 5000 LTx are performed worldwide for COPD, ILD, cystic fibrosis and
non-cystic fibrosis bronchiectasis, PH and redo transplantations as the main indications [13].
CLAD is one of the major post-transplantation problems, affecting up to 50% of transplanted
patients by 5 years after their LTx [13]. However, in individual centres, this percentage may be
as low as 18–33% [14, 15].
After CLAD is diagnosed, phenotyping should be performed, which is based on spirometry,

static lung volumes and lung imaging [12]. This is not always easy to do and interobserver
agreement is only moderate, especially in single LTx [16].
BOS
BOS is defined as CLAD with an obstructive ventilatory defect (FEV1/FVC <0.7) without
persistent opacities or pleural thickening on imaging. Lung volumes may indicate hyperinflation
as a sign of air trapping, which can be demonstrated on an expiratory CT scan. Other CT
features include bronchial wall thickening with bronchiectasis and distal airway obstruction [17].
BOS is the most common phenotype of CLAD, with different series reporting a prevalence of
between 60% and 75% [16–23].
RAS
The RAS phenotype is characterised by a restrictive ventilatory defect, defined as an additional
⩾10% decline in total lung capacity compared with baseline, together with persistent
(>3 months) parenchymal opacities (most frequently ground glass or consolidation) on HRCT or
chest radiograph, after exclusion of other causes [23–25]. With this definition, prevalence ranges
from 9% to 35% of patients with CLAD [10, 20, 24, 26]. Total lung capacity monitoring has
two limitations: 1) it is not routinely performed in LTx centres that have introduced lung volume
measurements by CT scan [27], and 2) it is difficult to interpret in single LTx. This might
explain why studies on single LTx report a lower prevalence of RAS (∼12–19%) [16, 21, 26]. A
stable or increased FEV1/FVC ratio or FVC trajectory (FVCCLAD/FVCBEST <0.8) [23, 28, 29]
have been used as surrogate markers for restriction but did not enter the consensus definition.
https://doi.org/10.1183/2312508X.10019422 333
Mixed phenotype
A mixed phenotype describes CLAD patients with a combination of obstructive and restrictive
ventilatory defects together with persistent opacities. This phenotype may occur at first
diagnosis of CLAD but also includes patients who transition from BOS or RAS to mixed
phenotype, with the first group being most frequently observed. In the Leuven cohort, 24
patients evolved from BOS to mixed phenotype, while only one went from RAS to mixed
phenotype [22]. The reported prevalence ranges between 3% and 9% [17, 18, 22, 23], and
around 11% of BOS patients might evolve to a mixed phenotype [22].
Undefined and unclassified phenotypes

These phenotypes represent all other CLAD patients who do not clearly fit in the previous
phenotypes (table 2). These phenotypes require close follow-up to reassess the diagnosis,
together with high suspicion of other causes mimicking CLAD, as suggested in a recent study
[28]. Up to 28% of single LTx recipients [16, 21] remained unclassified compared with only
15% of bilateral LTx [20], explained mainly by the involvement of the native lung in
physiological parameters. Table 2 summarises all possible phenotypes according to their
pulmonary physiology with or without persistent opacities.
Inherent diagnostic problems in phenotyping

Many conditions can cause a decline in FEV1 after LTx. Although the criteria for a CLAD
diagnosis can be met in these cases and alternative conditions do not preclude a diagnosis of
CLAD if adequately treated, the underlying pathophysiology is not always chronic rejection
[12]. Nonetheless, it was demonstrated that in patients with an alternative underlying condition
for FEV1 decline, prognosis was comparable to classical CLAD [30].
Some situations urge a recalculation of the baseline FEV1 (e.g. after lobectomy or in the case of
persistent pleural effusion or persistent suture stenosis). Other diseases involving the allograft
itself (e.g. pulmonary drug toxicity or infections) cannot easily be differentiated from CLAD
but do not necessarily prevent the diagnosis being made, as long as these conditions, upon
adequate treatment, do not lead to restoration of FEV1 >80% of baseline.
TABLE 2 Possible phenotypes according to pulmonary function evolution with or without persistent restrictive
allograft syndrome (RAS)-like opacities
Phenotype Combinations of PFTs and HRCT to phenotype CLAD

Obstruction: Restriction: HRCT
FEV1/FVC <0.7 TLC decline ⩾10% baseline opacities #
BOS Yes No No
RAS No Yes Yes
Mixed Yes Yes Yes
Undefined Yes No Yes
Undefined Yes Yes No
Unclassified No No No
Unclassified No Yes No
Unclassified No No Yes
CLAD: chronic lung allograft dysfunction; FEV1: forced expiratory volume in 1 s; TLC: total lung capacity; BOS:
bronchiolitis obliterans syndrome. #: HRCT opacities are defined following the International Society for Heart
and Lung Transplantation consensus report as parenchymal opacities and/or increasing pleural thickening
consistent with diagnosis of pulmonary and/or pleural fibrosis and likely to cause a restrictive physiology [13].
334 https://doi.org/10.1183/2312508X.10019422
Other clinically important confounders mimicking CLAD are significant weight gain,
osteoporotic spine fractures and lung ageing [28, 31]. In addition, the definition of obstructive
ventilatory defect may differ compared with a nontransplanted population. In this respect, a
patient with, for instance, an FEV1 decline of ⩾20%, without persistent pulmonary opacities but
a declining FEV1/FVC ratio (e.g. from 0.85 at baseline to 0.72 at diagnosis of CLAD) can still
be considered as BOS, although the FEV1/FVC ratio is by definition not obstructive [28].
Likewise, pulmonary function in patients after unilateral LTx and in patients who received small
or size-reduced donor lungs behaves differently, as their pulmonary function is not normal from
the beginning, and should be interpreted as such. The role of imaging in CLAD is therefore of
utmost importance, as it has been clearly illustrated that patients with unclassified or undefined
CLAD based on pulmonary function evaluation but with persistent opacities behave similarly to
RAS patients [20, 32].
Pathophysiology of CLAD
OB is a universal finding in BOS [33–35], RAS [36, 37] and mixed [22] phenotypes of CLAD.
The histopathological presentation of OB can vary from strictly inflammatory to concentric
subepithelial fibrosis, and is believed to be the main reason for the pulmonary function decline
in CLAD patients. OB is considered to be the result of repeated exposure of the respiratory
epithelium to microinjuries (e.g. air pollution, gastro-oesophageal reflux, micro-organisms,
repeated acute rejection). This may result in chronic inflammation, leading to impaired wound
healing with epithelial-to-mesenchymal transition and recruitment of (myo)fibroblasts and
circulating fibrocytes. Ultimately, this results in complete luminal obliteration of the smaller
airways, while the adjacent alveolar tissue remains largely unaffected [38]. In fact, 40–70% of
the airways from the ninth generation of branching were completely obliterated in end-stage
BOS lungs [39]. The largest study so far found OB in 73% of BOS patients, whereas earlier
BOS stages were less likely to show OB [34]. In patients without CLAD, OB lesions were
notably absent [35]. SAGGAR et al. [40] found OB in all patients with clinical BOS.
In patients with RAS, OB is also a common histopathological finding in >50% of specimens

[36, 37]. Airways were also found to be destroyed by ongoing fibrosis, leading to a significant
loss in the number of functional airways in RAS compared with BOS and controls [41]. In
contrast to BOS, there is also important pathology in the (sub)pleural and alveolar compartment
in RAS, with alveolar fibroelastosis (AFE), especially in the upper lobes. The stepwise
development of AFE is speculated to involve an initial injury leading to a filling of the alveoli
with fibrin-rich exudates, where subsequently recruited macrophages fail to clear the fibrin. This
leads to a strong inflammatory response with recruitment of B- and T-cells and eventually also
(myo)fibroblasts culminating in interstitial fibrosis [42].
For patients with the mixed phenotype, the pathology is believed to be a combination of
previously described processes where initially the airways are obliterated (i.e. BOS usually
develops first) and where a potential second hit leads to the development of AFE with
progression to alveolar fibrosis. This is also reflected in the observation that 80% of explant
specimens show OB in combination with AFE and organising pneumonia [37].
Risk factors for CLAD development

As the lung is in direct contact with the outside environment, a number of inhaled risk factors
(e.g. bacterial, viral and fungal colonisation/infection, such as Pseudomonas aeruginosa,
respiratory syncytial virus and Aspergillus fumigatus) may increase the development of
subsequent CLAD [43–45]. In addition, gastro-oesophageal reflux and chronic exposure to air
https://doi.org/10.1183/2312508X.10019422 335
pollution have also been suggested as risk factors [46, 47]. Innate risk factors such as primary
graft dysfunction, acute cellular rejection, lymphocytic bronchiolitis and antibody-mediated
rejection (AMR) may further increase the risk for CLAD. Primary graft dysfunction is the
clinical correlate of acute ischaemic injury in the first 72 h following LTx, and higher grades of
primary graft dysfunction increase the risk for CLAD during the later follow-up of the patient
[48]. Acute cellular rejection is pathologically defined as perivascular lymphocytic
inflammation. While a subclinical minimal acute rejection (grade A1) does not seem to increase
the risk for CLAD [49], a higher degree (⩾grade A2) increases the risk of CLAD 3-fold [50].
Lymphocytic bronchiolitis, the airway component of acute cellular rejection, is also accepted as
a risk factor for subsequent CLAD [51]. The importance of AMR has emerged only recently,
and a strong association between an episode of AMR and subsequent CLAD (more specifically
RAS) has been identified [52]. AMR is clinically characterised by the presence of circulating
donor-specific human leukocyte antigen (HLA) antibodies, together with typical lung histology,
with or without the presence of C4d-positive cells on biopsy [53]. Nonadherence to
immunosuppressive drugs is also an accepted and highly relevant risk factor [54]. So far,
besides AMR, risk factors do not seem to differ for later development of BOS, RAS or mixed
phenotype. Table 3 summarises the risk factors for CLAD development.
Biomarkers for CLAD

Finding an appropriate biomarker could significantly assist in early diagnosis and risk
stratification of CLAD. Given the aforementioned proposed differences in the pathophysiology
of CLAD phenotypes, it seems important to take CLAD phenotypes into account in biomarker
research. Multiple sources/compartments such as circulating blood, BAL and tissue but also
specific radiological examinations are being explored, such as parametric response mapping.
The latter technique uses voxel-to-voxel comparison of inspiratory and expiratory CT to assess
features of small-airways disease or parenchymal disease, and has proved to reliably separate
CLAD phenotypes and also bears important prognostic information [55, 56]. In most centres,
repetitive BAL and transbronchial biopsies are performed in the routine care of LTx patients,
and can be used for biomarker research. Elevated levels of inflammatory cells (i.e. eosinophils [57],
natural killer cells [58] and alarmin proteins [59], and proteins from the interleukin-6 [60, 61]
and chemokine receptor CXCR3 [62] axis) have been shown to contain either diagnostic or
prognostic information, although none of these has been implemented in routine clinical care.
Specific patterns on histopathological assessment of transbronchial lung biopsies, such as acute
fibrinoid organising pneumonia [63] or the presence of eosinophils [64], are found more often
in patients with RAS and portend a worse outcome. There is also much interest in identifying
specific molecular patterns where signatures of wound healing, fibrosis or inflammation have
been associated with CLAD development [65, 66]. Lastly, analysis of circulating markers seems
TABLE 3 Selected studies analysing the risk factors for chronic lung allograft dysfunction development
Risk factor First author [ref.]
Colonisation/infection with micro-organisms MITCHELL [43], DE ZWART [44], LE PAVEC [45]

Gastro-oesophageal reflux URSO [47]
Air pollution RUTTENS [46]
Primary graft dysfunction DAUD [48]
Acute cellular rejection DAVIS [50]
Lymphocytic bronchiolitis GLANVILLE [51]
Antibody-mediated rejection ROUX [52], LEVINE [53]
Nonadherence to immunosuppressive drugs BERTRAM [54]
336 https://doi.org/10.1183/2312508X.10019422
the easiest to do, and much progress has been made towards its clinical implementation.
Donor-specific antibodies are routinely assessed post-LTx, and patients with persistent
donor-specific antibodies, especially those against HLA-DQ [67], show a worse CLAD-free
(especially RAS) and overall survival [68]. Donor-derived cell-free DNA, which consists of
short fragments of DNA that are produced during necrosis, apoptosis or active secretion of cells,
is a promising biomarker. There is a large body of evidence showing that elevated rates of
donor-derived cell-free DNA are found during episodes of acute rejection or respiratory viral
infection [69–71], and therefore might serve as a general marker of injury and hence contain
prognostic information [72].
Outcome of CLAD
Survival after CLAD is worse in RAS than in BOS [10, 20, 24]. LEVY et al. [20] described
shorter allograft survival (time from CLAD to death or re-transplantation) in RAS and mixed
phenotype (2-year allograft survival of 20–25%) compared with BOS (65%). Other studies have
described similar data, with 2-year survival rates in RAS of 20–45% [10, 24, 29, 30, 73, 74]. In
a cohort of RAS and mixed-phenotype patients from five European centres, graft survival of
89%, 79% and 61% at 6, 9 and 12 months, respectively, after diagnosis was reported [75]. For
patients in the undefined and unclassified groups, CT opacities seem to be the best tool to
assess prognosis, as patients with RAS-like opacities demonstrated a worse survival [20]. Data
from single LTx report similar outcomes with a 20% 2-year survival in RAS and mixed-
phenotype patients compared with 45% in BOS [16].
CLAD is associated with reduced health-related quality of life [76–78] and increased costs.
Indeed, among 129 LTx patients who developed CLAD, healthcare costs were substantially
higher in the year following diagnosis compared with the year before [79].
Treatment of CLAD
Although highly challenging, prevention of CLAD is preferred over treatment of established
CLAD. In a randomised, double-blinded, placebo-controlled trial of oral azithromycin, given in
addition to conventional immunosuppression, azithromycin was shown to considerably delay
CLAD onset (hazard ratio 0.25) and improve long-term survival [80]. Some centres start
azithromycin upon novel pulmonary function decline, but it is increasingly part of a standard
immunomodulatory treatment regimen starting immediately or early (within 3 months) after
transplantation, aiming to decrease the incidence of CLAD.
Once CLAD is established, there are limited treatment options, which mostly result in a
temporary stabilisation of the FEV1 decline. There is no consensus on the best treatment
algorithm for CLAD, and different treatment options are highlighted in table 4. A switch in
immunosuppressive drugs (e.g. from cyclosporine to tacrolimus, or from azathioprine to
mycophenolate) led to a decrease in the decline of FEV1 in uncontrolled studies [81]. Other
options to modify CLAD progression involve lymphocyte depletion/modulation, such as total
lymphoid irradiation [82] and extracorporeal photopheresis (ECP). ECP involves incubating
isolated recipient leukocytes with 8-methoxypsoralen and exposing them to ultraviolet A light,
leading to lymphocyte apoptosis. ECP at regular intervals may lead to immunomodulation and
is well tolerated, but like the other treatment options, there is a lack of randomised clinical trials
and it is not available or reimbursed in all countries [83]. Other lymphocyte-depleting options
include antithymocyte globulin and alemtuzumab (which targets T-, B- and natural killer
lymphocytes). All of these treatment modalities led to a slower FEV1 decline in approximately
one-third of the patients [84, 85]. Lymphocyte depletion/modulation strategies are based mostly on
retrospective single-centre studies, and no randomised controlled studies are available so far [81].
https://doi.org/10.1183/2312508X.10019422 337
TABLE 4 Treatment options for chronic lung allograft dysfunction

Lymphocyte depletion/modulation
Total lymphoid irradiation
Extracorporeal photopheresis
Antithymocyte globulin
Alemtuzumab
Immunomodulatory treatments
Azithromycin
Montelukast
Antifibrotic treatment (RAS phenotype)
Nintedanib
Pirfenidone
Palliative/supportive care
Re-transplantation (very selected cases)
RAS: restrictive allograft syndrome.
In patients with established CLAD, azithromycin was shown to slow its progression in a
randomised trial and to improve pulmonary function after 12 weeks [86]. Consequently, an
azithromycin trial of 8 weeks is usually advised before a diagnosis of CLAD can be established
[12]. Some beneficial effects with add-on montelukast have also been observed in patients with
early stages of BOS [87], and attenuation in the rate of FEV1 decline was seen in a
nonrandomised case–control study [88].
As CLAD is characterised by fibrotic changes (airway fibrosis in BOS and interstitial fibrosis in
RAS), antifibrotic agents are of potential interest in its treatment [89]. However, a recent
multicentre trial with pirfenidone versus placebo could not demonstrate any benefit in BOS
[90]. A small case series and a case report in RAS have demonstrated promising results, with
stabilisation of the FEV1 decline [91, 92]. The results of a multicentre trial with antifibrotic
agents in RAS are currently pending [93].
If all treatment options fail, re-transplantation may be considered in strictly selected patients
with advanced CLAD. Nevertheless, a minority of patients qualify for re-transplantation, and
outcomes are often inferior to primary transplantation, especially after early CLAD and in the
case of RAS [94].
With the majority of CLAD patients developing respiratory failure, general therapeutic
principles of end-stage lung diseases may be applied if indicated, including bronchodilation,
long-term oxygen therapy, noninvasive ventilation and palliative care [81].
Conclusion and future prospects

CLAD remains a devastating condition after LTx, with a relatively poor prognosis when
diagnosed. Although phenotyping has led to improved insights regarding diagnosis and
prognosis, the real pathophysiology is still enigmatic. There is an unmet need for earlier
biomarkers in blood, BAL, lung tissue biopsies or exhaled breath that can predict or diagnose the
development of CLAD in the early stages. Besides better preventative treatment, which might
decrease the prevalence of CLAD, improved therapy is also needed once CLAD is diagnosed.
With the introduction of the new consensus guidelines on the diagnosis of CLAD [12], it is
hoped that multicentre ( preferably placebo-controlled) studies will further explore new treatment
options. The results of some ongoing studies with new treatments such as inhaled liposomal
338 https://doi.org/10.1183/2312508X.10019422
cyclosporine or Janus kinase ( JAK) inhibitors and antifibrotics are awaited, and it is hoped that
such therapy may indeed improve the quality of life and the life expectancy of patients suffering
from CLAD [95].
References
1 Burke CM, Theodore J, Dawkins KD, et al. Post-transplant obliterative bronchiolitis and other late lung sequelae
in human heart–lung transplantation. Chest 1984; 86: 824–829.
2 Glanville AR, Baldwin JC, Burke CM, et al. Obliterative bronchiolitis after heart–lung transplantation: apparent
arrest by augmented immunosuppression. Ann Intern Med 1987; 107: 300–304.
3 Yousem SA, Burke CM, Billingham ME. Pathologic pulmonary alterations in long-term human heart–lung
transplantation. Hum Pathol 1985; 16: 911–923.
4 Barker AF, Bergeron A, Rom WN, et al. Obliterative bronchiolitis. N Engl J Med 2014; 370: 1820–1828.
5 Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for
clinical staging of chronic dysfunction in lung allografts. J Heart Lung Transplant 1993; 12: 713–716.
6 Glanville AR. Bronchoscopic monitoring after lung transplantation. Semin Respir Crit Care Med 2010; 31: 208–221.
7 Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic
criteria. J Heart Lung Transplant 2002; 21: 297–310.
8 Pakhale SS, Hadjiliadis D, Howell DN, et al. Upper lobe fibrosis: a novel manifestation of chronic allograft
dysfunction in lung transplantation. J Heart Lung Transplant 2005; 24: 1260–1268.
9 Woodrow JP, Shlobin OA, Barnett SD, et al. Comparison of bronchiolitis obliterans syndrome to other forms of
chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant 2010; 29: 1159–1164.
10 Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung
allograft dysfunction. J Heart Lung Transplant 2011; 30: 735–742.
11 Verleden GM, Raghu G, Meyer KC, et al. A new classification system for chronic lung allograft dysfunction.
12 Verleden GM, Glanville AR, Lease ED, et al. Chronic lung allograft dysfunction: definition, diagnostic criteria, and
approaches to treatment – a consensus report from the Pulmonary Council of the ISHLT. J Heart Lung
Transplant 2019; 38: 493–503.
13 Chambers DC, Perch M, Zuckermann A, et al. The International Thoracic Organ Transplant Registry of the
International Society for Heart and Lung Transplantation: thirty-eighth adult lung transplantation report –
2021; focus on recipient characteristics. J Heart Lung Transplant 2021; 40: 1060–1072.
14 Ius F, Aburahma K, Boethig D, et al. Long-term outcomes after intraoperative extracorporeal membrane
oxygenation during lung transplantation. J Heart Lung Transplant 2020; 39: 915–925.
15 Gan CT, Hoek R, van der Bij W, et al. Long-term outcome and bridging success of patients evaluated and
bridged to lung transplantation on the ICU. J Heart Lung Transplant 2022; 41: 589–598.
16 Berra G, Huszti E, Levy L, et al. Phenotyping CLAD after single lung transplant: limits and prognostic
assessment of the 2019 ISHLT classification system. J Heart Lung Transplant 2022; 41: 599–607.
17 Hota P, Dass C, Kumaran M, et al. High-resolution CT findings of obstructive and restrictive phenotypes of
chronic lung allograft dysfunction: more than just bronchiolitis obliterans syndrome. AJR Am J Roentgenol 2018;
211: W13–W21.
18 Verleden SE, Vos R, Vanaudenaerde BM, et al. Chronic lung allograft dysfunction phenotypes and treatment.
J Thorac Dis 2017; 9: 2650–2659.
19 Nykanen A, Raivio P, Perakyla L, et al. Incidence and impact of chronic lung allograft dysfunction after lung
transplantation – single-center 14-year experience. Scand Cardiovasc J 2020; 54: 192–199.
20 Levy L, Huszti E, Renaud-Picard B, et al. Risk assessment of chronic lung allograft dysfunction phenotypes:
validation and proposed refinement of the 2019 International Society for Heart and Lung Transplantation
classification system. J Heart Lung Transplant 2020; 39: 761–770.
21 Leuschner G, Lauseker M, Howanietz AS, et al. Longitudinal lung function measurements in single lung
transplant recipients with chronic lung allograft dysfunction. J Heart Lung Transplant 2020; 39: 1270–1278.
22 Verleden SE, von der Thusen J, van Herck A, et al. Identification and characterization of chronic lung allograft
dysfunction patients with mixed phenotype: a single-center study. Clin Transplant 2020; 34: e13781.
23 Glanville AR, Verleden GM, Todd JL, et al. Chronic lung allograft dysfunction: definition and update of
restrictive allograft syndrome – a consensus report from the Pulmonary Council of the ISHLT. J Heart Lung
Transplant 2019; 38: 483–492.
24 Verleden SE, Ruttens D, Vandermeulen E, et al. Predictors of survival in restrictive chronic lung allograft
dysfunction after lung transplantation. J Heart Lung Transplant 2016; 35: 1078–1084.
25 Dettmer S, Grunwald V, Fuehner T, et al. CT patterns of organizing pneumonia in patients treated with VEGF/
mTOR inhibitors for metastatic renal cell cancer: an observational study. Acta Radiol Open 2017; 6:
2058460117694216.
https://doi.org/10.1183/2312508X.10019422 339
26 DerHovanessian A, Todd JL, Zhang A, et al. Validation and refinement of chronic lung allograft dysfunction
phenotypes in bilateral and single lung recipients. Ann Am Thorac Soc 2016; 13: 627–635.
27 Philippot Q, Debray MP, Bun R, et al. Use of CT-SCAN score and volume measures to early identify restrictive
allograft syndrome in single lung transplant recipients. J Heart Lung Transplant 2020; 39: 125–133.
28 Verleden GM, Godinas L, Vos R, et al. Chronic lung allograft dysfunction and restrictive allograft syndrome: are
phenotypes robust and helpful? Curr Opin Organ Transplant 2022; 27: 211–216.
29 Todd JL, Jain R, Pavlisko EN, et al. Impact of forced vital capacity loss on survival after the onset of chronic
lung allograft dysfunction. Am J Respir Crit Care Med 2014; 189: 159–166.
30 van Herck A, Verleden SE, Sacreas A, et al. Validation of a post-transplant chronic lung allograft dysfunction
classification system. J Heart Lung Transplant 2019; 38: 166–173.
31 Verleden GM, Vos R, Godinas L, et al. Natural decline in pulmonary function following bilateral lung
transplantation: a single-centre study. Eur Respir J 2022; 60: 2200633.
32 Fuchs E, Levy L, Huszti E, et al. Significance of phenotype change after chronic lung allograft dysfunction onset.
Transpl Int 2021; 34: 2620–2632.
33 Verleden SE, Vos R, Verleden GM. Chronic lung allograft dysfunction: light at the end of the tunnel? Curr Opin
Organ Transplant 2019; 24: 318–323.
34 Martinu T, Howell DN, Davis RD, et al. Pathologic correlates of bronchiolitis obliterans syndrome in pulmonary
retransplant recipients. Chest 2006; 129: 1016–1023.
35 Vanstapel A, Verleden SE, Verbeken EK, et al. Beyond bronchiolitis obliterans: in-depth histopathologic
characterization of bronchiolitis obliterans syndrome after lung transplantation. J Clin Med 2021; 11: 111.
36 Ofek E, Sato M, Saito T, et al. Restrictive allograft syndrome post lung transplantation is characterized by
pleuroparenchymal fibroelastosis. Mod Pathol 2013; 26: 350–356.
37 von der Thüsen JH, Vandermeulen E, Vos R, et al. The histomorphological spectrum of restrictive chronic lung
allograft dysfunction and implications for prognosis. Mod Pathol 2018; 31: 780–790.
38 Verleden SE, von der Thüsen J, Roux A, et al. When tissue is the issue: a histological review of chronic lung
allograft dysfunction. Am J Transplant 2020; 20: 2644–2651.
39 Verleden SE, Vasilescu DM, Willems S, et al. The site and nature of airway obstruction after lung
40 Saggar R, Ross DJ, Saggar R, et al. Pulmonary hypertension associated with lung transplantation obliterative
bronchiolitis and vascular remodeling of the allograft. Am J Transplant 2008; 8: 1921–1930.
41 Verleden SE, Vasilescu DM, McDonough JE, et al. Linking clinical phenotypes of chronic lung allograft
dysfunction to changes in lung structure. Eur Respir J 2015; 46: 1430–1439.
42 Jonigk D, Rath B, Borchert P, et al. Comparative analysis of morphological and molecular motifs in
bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation: fibrotic lung
remodelling and alloimmunity. J Path Clin Res 2017; 3: 17–28.
43 Mitchell AB, Glanville AR. The impact of resistant bacterial pathogens including Pseudomonas aeruginosa and
Burkholderia on lung transplant outcomes. Semin Respir Crit Care Med 2021; 42: 436–448.
44 de Zwart A, Riezebos-Brilman A, Lunter G, et al. Respiratory syncytial virus, human metapneumovirus, and
parainfluenza virus infections in lung transplant recipients: a systematic review of outcomes and treatment
strategies. Clin Infect Dis 2021; 22: ciab969.
45 Le Pavec J, Pradère P, Gigandon A, et al. Risk of lung allograft dysfunction associated with Aspergillus infection.
Transplant Direct 2021; 7: e675.
46 Ruttens D, Verleden SE, Bijnens EM, et al. An association of particulate air pollution and traffic exposure with
mortality after lung transplantation in Europe. Eur Respir J 2017; 49: 1600484.
47 Urso A, Leiva-Juárez MM, Briganti DF, et al. Aspiration of conjugated bile acids predicts adverse lung
transplant outcomes and correlates with airway lipid and cytokine dysregulation. J Heart Lung Transplant
2021; 40: 998–1008.
48 Daud SA, Yusen RD, Meyers BF, et al. Impact of immediate primary lung allograft dysfunction on bronchiolitis
obliterans syndrome. Am J Respir Crit Care Med 2007; 175: 507–513.
49 Levy L, Huszti E, Tikkanen J, et al. The impact of first untreated subclinical minimal acute rejection on risk for
chronic lung allograft dysfunction or death after lung transplantation. Am J Transplant 2020; 20: 241–249.
50 Davis WA, Finlen Copeland CA, Todd JL, et al. Spirometrically significant acute rejection increases the risk for
BOS and death after lung transplantation: SSAR increases risk for BOS and death. Am J Transplant 2012; 12:
745–752.
51 Glanville AR, Aboyoun CL, Havryk A, et al. Severity of lymphocytic bronchiolitis predicts long-term outcome
after lung transplantation. Am J Respir Crit Care Med 2008; 177: 1033–1040.
52 Roux A, Bendib Le Lan I, Holifanjaniaina S, et al. Antibody-mediated rejection in lung transplantation: clinical
outcomes and donor-specific antibody characteristics. Am J Transplant 2016; 16: 1216–1228.
53 Levine DJ, Glanville AR, Aboyoun C, et al. Antibody-mediated rejection of the lung: a consensus report of the
International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2016; 35: 397–406.
340 https://doi.org/10.1183/2312508X.10019422
54 Bertram A, Fuge J, Suhling H, et al. Adherence is associated with a favorable outcome after lung
transplantation. PLoS One 2019; 14: e0226167.
55 Belloli EA, Gu T, Wang Y, et al. Radiographic graft surveillance in lung transplantation: prognostic role of
parametric response mapping. Am J Respir Crit Care Med 2021; 204: 967–976.
56 Belloli EA, Degtiar I, Wang X, et al. Parametric response mapping as an imaging biomarker in lung transplant
recipients. Am J Respir Crit Care Med 2017; 195: 942–952.
57 Verleden SE, Ruttens D, Vandermeulen E, et al. Elevated bronchoalveolar lavage eosinophilia correlates with
poor outcome after lung transplantation. Transplantation 2014; 97: 83–89.
58 Greenland JR, Jewell NP, Gottschall M, et al. Bronchoalveolar lavage cell immunophenotyping facilitates
diagnosis of lung allograft rejection: BAL immunophenotypes in acute lung rejection. Am J Transplant 2014; 14:
831–840.
59 Saito T, Liu M, Binnie M, et al. Distinct expression patterns of alveolar “alarmins” in subtypes of
chronic lung allograft dysfunction: alarmin in chronic lung allograft dysfunction. Am J Transplant 2014; 14:
1425–1432.
60 Wheeler DS, Misumi K, Walker NM, et al. Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.
Am J Transplant 2021; 21: 2360–2371.
61 Verleden SE, Ruttens D, Vos R, et al. Differential cytokine, chemokine and growth factor expression in
phenotypes of chronic lung allograft dysfunction. Transplantation 2015; 99: 86–93.
62 Shino MY, Weigt SS, Li N, et al. The prognostic importance of CXCR3 chemokine during organizing pneumonia
on the risk of chronic lung allograft dysfunction after lung transplantation. PLoS One 2017; 12: e0180281.
63 Vanstapel A, Verleden SE, Weynand BM, et al. Late-onset “acute fibrinous and organising pneumonia” impairs
long-term lung allograft function and survival. Eur Respir J 2020; 56: 1902292.
64 Darley DR, Ma J, Huszti E, et al. Eosinophils in transbronchial biopsies: a predictor of chronic lung allograft
dysfunction and reduced survival after lung transplantation – a retrospective single-center cohort study. Transpl
Int 2021; 34: 62–75.
65 Parkes MD, Halloran K, Hirji A, et al. Transcripts associated with chronic lung allograft dysfunction in
transbronchial biopsies of lung transplants. Am J Transplant 2022; 22: 1054–1072.
66 Halloran K, Parkes MD, Timofte I, et al. Molecular T-cell-mediated rejection in transbronchial and mucosal lung
transplant biopsies is associated with future risk of graft loss. J Heart Lung Transplant 2020; 39: 1327–1337.
67 Tikkanen JM, Singer LG, Kim SJ, et al. De novo DQ donor-specific antibodies are associated with chronic lung
allograft dysfunction after lung transplantation. Am J Respir Crit Care Med 2016; 194: 596–606.
68 Verleden SE, Vanaudenaerde BM, Emonds MP, et al. Donor-specific and -nonspecific HLA antibodies and
outcome post lung transplantation. Eur Respir J 2017; 50: 1701248.
69 Bazemore K, Rohly M, Permpalung N, et al. Donor derived cell free DNA% is elevated with pathogens that are
risk factors for acute and chronic lung allograft injury. J Heart Lung Transplant 2021; 40: 1454–1462.
70 Jang MK, Tunc I, Berry GJ, et al. Donor-derived cell-free DNA accurately detects acute rejection in lung
transplant patients, a multicenter cohort study. J Heart Lung Transplant 2021; 40: 822–830.
71 Keller M, Bush E, Diamond JM, et al. Use of donor-derived-cell-free DNA as a marker of early allograft injury in
primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD). J Heart Lung
Transplant 2021; 40: 488–493.
72 Agbor-Enoh S, Wang Y, Tunc I, et al. Donor-derived cell-free DNA predicts allograft failure and mortality after
lung transplantation. EBioMedicine 2019; 40: 541–553.
73 Finlen Copeland CA, Snyder LD, Zaas DW, et al. Survival after bronchiolitis obliterans syndrome among bilateral
lung transplant recipients. Am J Respir Crit Care Med 2010; 182: 784–789.
74 Verleden SE, Ruttens D, Vandermeulen E, et al. Restrictive chronic lung allograft dysfunction: where are we
now? J Heart Lung Transplant 2015; 34: 625–630.
75 Gottlieb J, Verleden GM, Perchl M, et al. Disease progression in patients with the restrictive and mixed
phenotype of chronic lung allograft dysfunction – a retrospective analysis in five European centers to assess
the feasibility of a therapeutic trial. PLoS One 2021; 16: e0260881.
76 van den BJ, Geertsma A, van der BW, et al. Bronchiolitis obliterans syndrome after lung transplantation and
health-related quality of life. Am J Respir Crit Care Med 2000; 161: 1937–1941.
77 Künsebeck HW, Kugler C, Fischer S, et al. Quality of life and bronchiolitis obliterans syndrome in patients after
lung transplantation. Prog Transplant 2007; 17: 136–141.
78 Smeritschnig B, Jaksch P, Kocher A, et al. Quality of life after lung transplantation: a cross-sectional study.
79 Sheshadri A, Sacks NC, Healey B, et al. The healthcare resource utilization and costs of chronic lung allograft
dysfunction following lung transplantation in patients with commercial insurance in the United States. J Med
Econ 2022; 25: 650–659.
80 Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronic
rejection after lung transplantation. Eur Respir J 2011; 37: 164–172.
https://doi.org/10.1183/2312508X.10019422 341
81 Benden C, Haughton M, Leonard S, et al. Therapy options for chronic lung allograft dysfunction–bronchiolitis
obliterans syndrome following first-line immunosuppressive strategies: a systematic review. J Heart Lung
Transplant 2017; 36: 921–933.
82 Lebeer M, Kaes J, Lambrech M, et al. Total lymphoid irradiation in progressive bronchiolitis obliterans
syndrome after lung transplantation: a single-center experience and review of literature. Transplant Int 2020; 33:
216–228.
83 Greer M, Liu B, Magnusson JM, et al. Assessing treatment outcomes in CLAD: the Hannover-extracorporeal
photopheresis model. J Heart Lung Transplant 2022; 42: 209–217.
84 January SE, Fester KA, Bain KB, et al. Rabbit antithymocyte globulin for the treatment of chronic lung allograft
dysfunction. Clin Transplant 2019; 33: e13708.
85 Moniodis A, Townsend K, Rabin A, et al. Comparison of extracorporeal photopheresis and alemtuzumab for the
treatment of chronic lung allograft dysfunction. J Heart Lung Transplant 2018; 37: 340–348.
86 Corris PA, Ryan VA, Small T, et al. A randomised controlled trial of azithromycin therapy in bronchiolitis
obliterans syndrome (BOS) post lung transplantation. Thorax 2015; 70: 442–450.
87 Ruttens D, Verleden SE, Demeyer H, et al. Montelukast for bronchiolitis obliterans syndrome after lung
transplantation: a randomized controlled trial. PLoS One 2018; 13: e0193564.
88 Vos R, Eynde RV, Ruttens D, et al. Montelukast in chronic lung allograft dysfunction after lung transplantation.
89 Bos S, de Sadeleer LJ, Vanstapel A, et al. Antifibrotic drugs in lung transplantation and chronic lung allograft
dysfunction: a review. Eur Respir Rev 2021; 30: 210050.
90 Perch M, Besa V, Corris PA, et al. A European multi-center, randomized, double-blind trial of pirfenidone in
bronchiolitis-obliterans-syndrome grade 1–3 in lung transplant recipients (European Trial of Pirfenidone in BOS
(EPOS)). J Heart Lung Transplant 2020; 39: Suppl., S12.
91 Vos R, Verleden SE, Ruttens D, et al. Pirfenidone: a potential new therapy for restrictive allograft syndrome? Am
J Transplant 2013; 13: 3035–3040.
92 Suhling H, Bollmann B, Gottlieb J. Nintedanib in restrictive chronic lung allograft dysfunction after lung
transplantation. J Heart Lung Transplant 2016; 35: 939–940.
93 Venado A, Dewey K, Montas G, et al. Safety and tolerability of pirfenidone for restrictive chronic lung allograft
dysfunction (PIRCLAD): interim results. Chest 2020; 158: A2389–A2390.
94 Verleden SE, Todd JL, Sato M, et al. Impact of CLAD phenotype on survival after lung retransplantation: a
multicenter study. Am J Transplant 2015; 15: 2223–2230.
95 Glanville AR, Benden C, Bergeron A, et al. Bronchiolitis obliterans syndrome after lung or haematopoietic stem
cell transplantation: current management and future directions. ERJ Open Res 2022; 8: 00185-2022.
Disclosures: B.S. Giminez declares income from Janssen Pharmaceuticals (consultant and speakers’ bureau), CareDx
(speakers’ bureau) and Chiesi Spain (consultant, speakers’ bureau and travel grant). M. Hellemons declares income
from Boehringer Ingelheim (speaker) and Pfizer (consultant). S.E. Verleden has acted as a consultant for Sanofi,
Boehringer Ingelheim and Therakos. J. Gottlieb declares an institutional research grant from Zambon and income
from Theravance (advisory) and Novartis (speaker). G.M. Verleden declares advisory board participation for
Zambon, Theravance and Chiesi.
342 https://doi.org/10.1183/2312508X.10019422
Chapter 25
Malformations and idiopathic disorders

of the trachea
Valentina Luzzi1, Francesca Conway2, Diletta Cozzi3, Luca Ciani1,

Leonardo Giuntoli1, Marco Trigiani1 and Sara Tomassetti 1,4
1
Interventional Pulmonology Unit, Careggi University Hospital, Florence, Italy. 2Royal Brompton Hospital, Chelsea
and Westminster Hospital, National Heart and Lung Institute, Imperial College, London, UK. 3Dept of Radiology,
Careggi University Hospital, Florence, Italy. 4Dept of Experimental and Clinical Medicine, University of Florence,
Florence, Italy.
Corresponding author: Valentina Luzzi (valentinaluzzi@hotmail.com)
Cite as: Luzzi V, Conway F, Cozzi D, et al. Malformations and idiopathic disorders of the trachea. In: Wagner TOF,
@ERSpublications
Tracheopathies represent a heterogeneous group of diseases that can be congenital, acquired or idiopathic.
CT of the thorax and bronchoscopy are key diagnostic steps that allow evaluation of disease severity and
planning of treatment. https://bit.ly/ERSM100
ISSN: 2312-5098.
Disorders of the trachea represent a group of conditions that can occur at any age and are classified as
congenital, acquired or idiopathic. Congenital disorders are due to abnormal airway development during
embryogenesis and are often associated with syndromic and genetic alterations. Within this category are
congenital tracheomalacia, tracheal agenesis, congenital subglottic stenosis, laryngotracheo-oesophageal
cleft, tracheo-oesophageal fistula, and stenosis due to vascular compression or to complete tracheal
rings. Acquired disorders may be secondary to injury resulting from a systemic inflammatory state,
prolonged intubation or previous tracheostomy. Conditions in which no specific cause is identified are
idiopathic. These include tracheobronchopathia osteochondroplastica, idiopathic tracheal stenosis,
tracheomalacia, tracheobronchomegaly (Mounier-Kuhn syndrome), and systemic disorders with tracheal
involvement such as sarcoidosis and amyloidosis. The symptomatology in most cases is nonspecific.
Therefore, a thorough clinical assessment is crucial to making an accurate diagnosis. Patients should be
assessed for vocal cord motility, stenosis at each level, malacia, scar tissue, granulomas and dysphagia.
The presence of other comorbidities, including obstructive sleep apnoea and gastro-oesophageal reflux
disease or abnormal congenital abnormalities, and any history of previous intubation, should be elicited.
Investigations include CT scans of the thorax and neck and bronchoscopy.
Introduction
Disorders of the trachea represent a heterogeneous group of diseases that can be congenital,
acquired or idiopathic. They can occur at any age with variable phenotypes depending on the
type of underlying aetiology. CT of the thorax and bronchoscopy are key diagnostic steps that
allow evaluation of disease severity and treatment planning. Treatment approaches include
bronchoscopy and/or surgery. Here, we review the pathogenic and embryogenic mechanisms
and the clinical features of tracheal malformations and idiopathic disorders of the trachea.
https://doi.org/10.1183/2312508X.10019522 343
Embryogenesis
Development of the respiratory tract begins at day 22 of the fetal stage and is completed at
∼8 years of age. It is divided into five stages: embryonic, pseudoglandular, canalicular, saccular and
alveolar. The embryonic stage occurs from week 3 to week 6. The respiratory diverticulum derives
from the foregut endoderm, posterior to the pharynx. After week 4, the caudal end of the trachea
bifurcates into the left and right primary bronchial buds. During the pseudoglandular stage, from
week 5 to week 17, the bronchial tree is formed, together with formation of the arterial system,
cartilaginous tissue and smooth muscle. From week 16 to week 25, the respiratory tree divides into
the conducting and respiratory units. This is the canalicular stage. The saccular stage is responsible
for expansion of the gas-exchange surface area of the lungs and is completed at birth. Finally,
during the alveolar stage, there are alveolar divisions, and this continues until 3 years of age.
Many molecular signals are involved in the development of the lung, including bone
morphogenetic protein, epidermal growth factor, Hedgehog, fibroblast growth factor (FGF),
transforming growth factor-β, the Wingless-related integration site families, retinoic acid and Nkx2.
In particular, FGF10 has a large role during epithelial proliferation and elongation of the lung bud.
This transcription factor, located at the mesenchymal level, binds to its FGF2 receptor and activates
multiple signalling pathways involving protein kinases (mitogen-activated protein kinase kinase/
extracellular signal-regulated kinase) capable of stimulating numerous cell functions [1].
Inactivation, dysfunction and alterations of the normal function of the molecular signals are
responsible for abnormal growth of the respiratory system, which can cause damage and even death
of children. Morphogenetic error can occur at different stages of embryonic development.
Malformations of the respiratory tract represent 5–18% of congenital abnormalities. In some

cases, they present during the in utero period, with fetal hydrops and polyhydramnios, but more
frequently the symptoms occur in the early months of life. Sometimes the diagnosis is delayed
and made later in life due to the development of complications, or it may be identified as an
incidental finding [2].
Congenital disorders of the trachea

Tracheomalacia
Tracheomalacia (TM) is characterised by excessive tracheal collapse, resulting in reduction of
the tracheal lumen due to affected cartilage integrity or impaired laxity of the posterior wall. TM
may be localised or generalised, and is known as tracheobronchomalacia when the main bronchi
are involved.
Malacia is defined as a >50% reduction in the cross-sectional luminal area during expiration
during quiet respiration. The gold-standard diagnostic test is flexible bronchoscopy in a
spontaneously breathing child. In clinical practice, during bronchoscopy the anatomical changes
are arbitrarily described as mild (50–75% reduction in cross-sectional diameter), moderate
(75–90% reduction) or severe (>90% reduction) (figure 1).
TM can be congenital or acquired. Secondary forms are caused by extrinsic compression of the
trachea in the presence of heart disease, vascular rings or thoracic masses. The congenital form
is caused by an intrinsic alteration of airway cartilage and is more likely to occur in premature
infants and as part of various rare syndromes. It also coexists with other disorders, including
gastro-oesophageal reflux disease (GORD), tracheo-oesophageal fistula (TOF) and cardiac
abnormalities. Symptoms may be persistent or intermittent, and are varied and often
nonspecific; they range from stridor, monophonic expiratory wheeze and cough to, in severe
cases, airway obstruction with cyanosis, apnoea, and cardiac arrest or sudden infant death.
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TRACHEAL DISORDERS AND MALFORMATIONS | V. LUZZI ET AL.
FIGURE 1 Flexible airway endoscopy in tracheomalacia. U-shaped rings are visible with a wider posterior
membrane, demonstrating posterior intrusion.
TM typically presents with expiratory stridor at birth that worsens in the following weeks.
Symptoms may be more pronounced during crying or feeding, or with supine positioning when
the velocity of airflow is increased and when airway collapsibility gets worse due to an increase
in intrathoracic pressure [3–5].
Chest radiography is not diagnostic. PFTs performed in a cooperating child may be normal.
Airway endoscopy conducted during spontaneous breathing and under mild sedation is the
gold-standard investigation for diagnosis.
In recent years, dynamic contrast multidetection CT, which is a quick and noninvasive
technique, has proven to be a highly sensitive and accurate diagnostic tool, providing more
detail on the lung parenchyma and structures adjacent to the trachea. Clearly, given the
radiological exposure, this investigation should be reserved for cases where it is necessary to
exclude any extrinsic compression, or carried out concurrently when parenchymal imaging is
required. The need for sedation and intubation in younger children can alter the airway and the
tracheal dynamics. Dynamic MRI has the advantage of providing high-resolution imaging
without radiation, but publications about dynamic MRI are limited.
There is often no need for any type of treatment for TM, as symptoms can resolve
spontaneously with the physiological increase in the size of the airways and consolidation of the
cartilage at around 12–24 months of life [6]. Experts recommend treating comorbidities such as
GORD and eosinophilic oesophagitis, and stress the importance of passive smoke prevention,
immunisations, exercise and all aspects of good respiratory healthcare.
Continuous positive airway pressure is an effective therapeutic option, which, through

continuous intraluminal pressure, opposes the collapse of the airways during exhalation, thus
keeping the airways open. Surgical and endoscopic options are reserved for severe TM cases
and include tracheostomy, aortopexy, tracheal resection, tracheopexy (anterior or posterior),
internal stenting and external airway splinting.
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Tracheal agenesis
Tracheal agenesis is a rare embryological anomaly occurring in 1 in 50 000–100 00 live births
and almost always leads to death. Half of cases are associated with premature delivery and
approximately the other half are associated with polyhydramnios [7].
Three types of agenesis were distinguished by FLOYD et al. [8]. Type I involves agenesis of the
proximal trachea and the presence of a distal TOF. Type II is characterised by the complete
absence of the trachea and the presence of normal bifurcating bronchi, and most cases are
associated with congenital defects. In type III, the two main bronchi arise independently from
the oesophagus. Prenatal diagnosis can only be made via ultrasonography, and if the defect is
limited to the proximal trachea, survival of the patient relies on the use of an ex utero
intrapartum treatment procedure, with tracheotomy and eventual tracheal reconstruction.
When clinical signs such as polyhydramnios, absence of an audible cry at birth, failure to
intubate beyond the vocal folds and respiratory distress are present in a neonate, it is
recommended that tracheal agenesis is considered in the differential diagnoses.
The presence of a TOF or a broncho-oesophageal fistula in a neonate affected by tracheal agenesis

can change the prognosis because it allows oesophageal intubation and mechanical ventilation [9].
Laryngotracheo-oesophageal cleft
Laryngotracheo-oesophageal cleft (LTOC) is a rare disorder that arises due to a defect in fusion
of the midline of the tracheo-oesophageal wall occurring during embryonic development and
involves the upper airways and the digestive tract simultaneously [10]. It can be associated with
TOF, anal atresia, labioschisis, Meckel’s diverticulum, tracheal and bronchial stenosis, and
cardiovascular defects. Males are more affected than females. Although the defect is rare, it can
lead to considerable morbidity and mortality. The Benjamin–Inglis classification identifies four
categories: type 1 is an interarytenoid defect up to the vocal cords, type 2 is a defect involving
the cricoid cartilage posteriorly, type 3 is a defect involving the cricoid cartilage posteriorly and
deepening at the level of the cervical trachea, and type 4 involves extension of the defect to the
thoracic trachea [11].
Generally, typical symptoms include choking episodes, coughing, cyanosis, episodes of

aspiration and respiratory stridor. Chest radiographs may show changes suggestive of aspiration
or pneumonia. Inspiratory stridor is caused by the redundant mucosa of the supraglottic
structures, which reduce the patency of the airway lumen in the inspiratory phase. The
concomitant presence of expiratory stridor indicates coexisting TM. LTOC can be accompanied
by a TOF. The presentation can be nonspecific, and some symptoms are often mistaken for
sucking, swallowing or changes to the breathing pattern, especially in newborns. The diagnosis
can be difficult to make and is sometimes delayed.
The gold standard for diagnosis is endoscopic evaluation with a rigid endoscope under general
anaesthesia (figure 2). There are different approaches to treatment based on the type of LTOC
and disease severity. In the absence of clinical and radiological features of pulmonary
aspiration, surgical intervention is not required.
A type 1 laryngeal cleft generally does not need to be repaired because the majority of patients
are asymptomatic. Types 2, 3 and 4 require surgical repair. Endoscopic repair is indicated for
type 1 if the patient is symptomatic, and also for type 2 and even for some patients with type 3
LTOC. The approach of choice for types 3 and 4 is open transtracheal through the neck or via a
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FIGURE 2 Rigid bronchoscopy in type 4 laryngotracheo-oesophageal cleft. The upper aperture is the trachea and
the lower one is the oesophagus.
combined approach with a mid-sternotomy [12]. All types of cleft requiring intervention can be
repaired by this approach. A two-layer repair is essential, dissecting the tracheal and
oesophageal mucosal layer, and closing both mucosa separately [13].
TOF
A TOF is a pathological communication between the posterior wall of the trachea and the
anterior wall of the oesophagus. It may be congenital or acquired. The cause and embryological
origins of this condition remain unclear. When combined with oesophageal atresia (OA), up to
50% of cases are associated with other congenital abnormalities or genetic syndromes [14].
The most commonly used classification system is the Gross classification [15]. According to
this system, the OA types are: type A (isolated OA), type B (OA with proximal TOF), type C
(OA with distal TOF), type D (OA with proximal and distal fistulas) and type E (H-type fistula).
In congenital cases, 85% of the fistulas are located distally and are associated with OA (type C
according to the Gross classification [16]).
Prenatal diagnostics by ultrasonography may not always be straightforward because the findings
are nonspecific, subjective and sometimes transient, but recent data show that the accuracy of
successful prenatal detection can be greatly improved in specialist centres [17].
Because the symptoms are nonspecific, establishing the diagnosis can be difficult. Overall, 90%
of cases are diagnosed during the first year of life, but the nonspecific symptomatology makes
diagnosis difficult and rare cases may manifest in adulthood with recurrent pneumonia.
Patients with OA and a distal fistula may have excessive salivation, coughing, choking,
regurgitation, cyanosis during oral feeding, respiratory distress, abdominal distension,
pneumonia and growth delay [18–21]. Patients with an isolated fistula without atresia (H-type
https://doi.org/10.1183/2312508X.10019522 347
fistula) may have symptoms of respiratory distress of varying degrees, suffocation and cyanosis
during feeding, recurrent infections of the lower respiratory tract, abdominal distension and
growth delay. Once the diagnosis is suspected, the main investigation to confirm the diagnosis
is direct visualisation by bronchoscopy and oesophagoscopy (figure 3). An oesophagram may
also be useful, especially in the prone position [22].
TOF treatment can be achieved by open surgery or with an endoscopic procedure. Open surgery
is based on a transthoracic or transcervical approach and is considered the traditional treatment
option [23].
Vascular compression of the airways

As the airways are in close proximity to the heart and intrathoracic vessels, abnormalities of the
latter can occasionally lead to airway compression and obstruction [24]. In some cases, the
endoscopic presentation is so characteristic that it allows a precise diagnosis before radiological
imaging. Airway compression can be generated by complete or incomplete vascular rings. The
most common scenarios for compressions are: 1) a right aortic arch or double aortic arch,
commonly involving the orifice of the right main bronchus and occasionally the orifice of the
right upper lobe bronchus; 2) a pulmonary sling, most frequently involving the distal trachea;
3) innominate artery compression (the innominate artery is a normal vessel but in rare cases can
originate from a more distal part of the aorta causing compression of the distal third of the
trachea); or 4) abnormalities of the subclavian arteries, when the subclavian artery originates
from the aortic arch.
FIGURE 3 Endoscopic view of a tracheo-oesophageal fistula relapse at the 6 o’clock position.
348 https://doi.org/10.1183/2312508X.10019522
Congenital tracheo-bronchial stenosis due to complete tracheal rings

This condition is the result of a defect of development of the airway walls during
bronchogenesis (weeks 5–16 of gestation). One or more of the cartilaginous rings supporting
the tracheal wall are not formed by the typical posterior membranaceus pars and create a
complete ring. The degree of stenosis worsens with growth and the complete ring appears
progressively smaller. Clinical presentation may be variable and symptoms are more pronounced
in older children. The most typical is shortness of breath. Not all paediatric patients with this
defect require tracheal reconstruction surgery [25].
Other congenital disorders are a tracheal cartilage sleeve where the trachea consists of a single
cartilage sheet extending into the cricoid and progressing distally to the bronchi. There is an
absence of the tracheal rings, leading to stenosis or tracheal collapse. Punctate condrodysplasia,
a rare disorder with calcifications of the trachea, is often associated with other disorders.
Idiopathic disorders of the trachea

Subglottic stenosis
Subglottic stenosis can be defined as narrowing of the upper airway between the vocal folds and
the lower margin of the cricoid cartilage. It can be congenital, acquired or idiopathic [26].
Acquired lesions can occur in paediatric and adult populations. These are often iatrogenic and
secondary to different conditions such as intubation trauma and high position of the
endotracheal tube ( pressure-induced ischaemic necrosis), complications of tracheostomy tubes
(granulation tissue, suprastomal granuloma, A-frame deformity), inflammatory or infectious
conditions and their sequelae, blunt or penetrating trauma, inhalational injury, and malignant
and benign neoplasms.
The congenital form is caused by abnormal development of the upper respiratory tract, or it can
be associated with a genetic disorder. It represents a common cause of stridor in newborns due
to altered embryological development with an abnormal recanalisation of the laryngeal lumen.
The most common form is the membranous type, which is characterised by thickening of soft
tissues in the subglottic area resulting in a symmetrical bilateral narrowing of the subglottic
space. The cartilaginous stenosis is due to a malformation of the cricoid cartilage that causes a
circumferential stenosis, from a normal but small shape to a clearly abnormal shape.
Idiopathic subglottic stenosis is very rare and is a chronic, recurrent and fibroinflammatory
condition characterised by circumferential stenosis in the subglottic region and upper trachea in
the absence of any obvious preceding iatrogenic injury or other event [27]. The idiopathic
condition is much more common in healthy, middle-aged, white females, and symptoms can be
misinterpreted as asthma. They range from recurrent croup and exertional stridor to complete
airflow obstruction. The pathophysiology is unclear but the likely cause is a trigger, followed by
a phenomenon of dysregulated wound healing. This results in mechanical injury, localised
ischaemia, abnormal wound repair and fibrosis. This hypothesis is supported by histopathology,
which shows dense fibrosis of the keloidal type with interspersed fibroblasts. Moreover, the
overlying epithelium shows metaplasia and the cartilaginous rings are mostly normal.
As well as the increased incidence of the disease among young women, it appears that there
may be other factors relevant to the development of subglottic stenosis. One such proposed
mechanism is that oestrogen may be a contributory factor. Another hypothesis is that there is
acidic or enzymatic mucosal trauma secondary to laryngopharyngeal reflux [28–30], and that
this may contribute to the disease process.
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The signs and symptoms clearly depend on the degree of stenosis. Children may have a
wide range of problems from severe respiratory distress at birth to inspiratory or biphasic
stridor within the first months of life. In adults, symptoms may only occur when the stenosis is
more marked, because the lumen of the airway is bigger than in children and thus they are
better able to compensate. Typical symptoms are difficulty breathing after everyday activities
such as climbing stairs or walking, wheezing, persistent cough, difficulty expectorating
mucus, frequent colds, pneumonia or other respiratory infections, persistent asthma, apnoea and
sleep apnoea.
The diagnosis of subglottic stenosis can be made using CT and MRI, and these are useful to
locate the exact location and length of the stenotic segment [31]. Endoscopic evaluation with
flexible and/or rigid bronchoscopy remains the gold standard for direct visualisation to assess
the dynamics of vocal cord function and the upper airway plus the oesophagus (figure 4).
After diagnosing tracheal stenosis, it is important to grade it appropriately, and the calibre of the
luminal stenosis must be quantified. The original Cotton–Myer grading scale initially introduced
for grading subglottic stenosis is used to grade tracheal stenosis and is based on the percentage
of airway lumen narrowing [32]: grade I is 0–50%, grade II is 51–70%, grade III is 71–99%
and grade IV is no detectable lumen or atresia.
Typically, tracheal stenosis is divided into long-segment (LSTS) or short-segment (SSTS) lesions.
SSTS typically spans fewer than five tracheal rings, while LSTS is usually defined as a lesion that
spans 50–75% of the trachea, but these definitions can vary based on patient age and size.
In general, symptomatic patients meet indications for surgical reconstruction. When considering
tracheal stenosis repair, knowing the Cotton–Myer grade and determining whether it is an SSTS
or LSTS are critical.
FIGURE 4 Airway endoscopy of a subglottic stenosis demonstrating narrowing of the upper part of the trachea
below the vocal cords.
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Observation and conservative management are recommended for patients who are poor surgical
candidates (e.g. with other significant comorbidities making the surgery high risk), patients who
are ventilator dependent due to pulmonary disease, those with asymptomatic disease and
paediatric patients who are still growing.
Endoscopic surgical repair is recommended in symptomatic mild-to-moderate disease, when a

thin scar band or web is present, when the stenotic segment affects fewer than one or two
tracheal rings, or when open surgical repair needs adjunctive procedures. Open repair is
mandatory when there is SSTS and LSTS, when endoscopic repair fails, when there are
complete tracheal rings and if concomitant cardiopulmonary abnormalities require repair.
Surgical approaches can be endoscopy, open neck surgery or a tracheotomy.
Endoscopic techniques by rigid bronchoscopy include dilation by balloon or rigid dilation. They
also include radical incision using a carbon dioxide laser or cryoprobe and scar excision using a
cold knife, without dilation. Stent placement is often necessary. Adjunctive therapies also
include topical mitomycin and glucocorticoid injection to improve the patency of the airway in
the long term. In an infant born with subglottic stenosis, traditional management is to do a
tracheostomy and assess the child’s airway every 3 months to decide on the need for
reconstructive surgery. The second option is to perform an anterior or posterior cricoid split
under general anaesthesia to enlarge the cricoid lumen. The optimal treatment for acquired
subglottic stenosis is laryngotracheal reconstruction [33].
In adults, tracheal resection and end-to-end anastomosis is the gold standard for the treatment of
tracheal stenosis.
GHORBANI et al. [34] presented a scoring system helpful for decision making for therapeutic
procedures. They evaluated and graded the diameter of the stricture, the type of stenosis and the
clinical symptoms (each given a score of 1–4) and combined these in a scoring system where
the patient was graded from 2 to 12. A score of ⩾8.5 suggests that the patient requires surgical
treatment, whereas those scoring lower do not.
Tracheobronchopathia osteochondroplastica
Tracheobronchopathia osteochondroplastica (TO) is a rare, benign and indolent disease of the
large airways and is characterised by the growth of submucosal cartilage and by multiple
chondro-osseous submucosal nodules. The incidence is 0.1–4.2 per 100 000 of the population
with a male/female ratio of 3/2. Most patients are asymptomatic or present with nonspecific
respiratory symptoms in the first stage of disease. Later, symptoms develop slowly due to
further airway involvement and tracheal obstruction.
The pathogenesis of TO is poorly understood, but it has been postulated that it may be associated
with chronic infection, metabolic disorders, and chemical or mechanic stimulation of submucosal
cartilage. There is no evidence that smoking or genetics plays a role in its development.
CT is a very useful tool for diagnosis (figure 5). The typical features are a geographical
distribution of TO nodules, typically sparing the posterior tracheal wall. Its radiological pattern
can mimic that of tuberculosis, neoplastic diseases, endobronchial sarcoid and amyloidosis.
Diagnosis is made by bronchoscopy and pathological examination of bronchoscopy specimens.

Typical endoscopic findings are multiple firm and glossy nodules protruding into the lumen of
the trachea and proximal main bronchi with associated stenosis or irregularity. The biopsy usually
shows segments of cartilaginous/osseous tissue in the submucosa with normal mucosal tissue.
https://doi.org/10.1183/2312508X.10019522 351
a) b)
FIGURE 5 a) Coronal and b) axial CT images of tracheobronchopathia osteochondroplastica characterised by

irregular thickening and nodularity of tracheal cartilage, sparing the posterior (membranous) tracheal wall.
Patients are managed symptomatically, and bronchoscopic or surgical procedures are reserved
for patients with severe airway stenosis and obstruction [35, 36].
Tracheobronchomegaly (Mounier-Kuhn syndrome)

Tracheobronchomegaly is a very rare condition of unknown origin. It is probably secondary to
atrophy of the elastic fibres of the trachea and bronchi, resulting in thinning of the smooth
muscle that would normally lead to airway dilation. Factors such as barotrauma during intensive
neonatal ventilation with oxygen therapy or exposure to certain irritants (tobacco and air
pollution) are proposed to be a contributor to the development of the disease. No genes
involved in the disease have been yet identified, but an association with Ehlers–Danlos
syndrome and cutis laxa in children has been described [37, 38]. Three types are described:
type 1 with slight symmetrical dilation of the trachea and/or the main bronchi, type 2 where the
dilation and diverticula are distinct, and type 3 where the diverticular and sacculiform structures
extend to the distal bronchi. Symptoms are nonspecific, ranging from asymptomatic to severe
respiratory failure. Patients may experience recurrent bronchopulmonary infections and/or a
cough that is typically productive and sometimes accompanied by haemoptysis. It is often
associated with sinonasal polyposis and polymalformative genetic syndrome. The diagnosis of
tracheobronchomegaly is based on well-coded measurements of the trachea and the main bronchi
made from the patient’s CT scan [39]. Treatment aims to treat bronchopulmonary infections or,
better still, prevent them. Other possible treatments for more severe forms include long-term
continuous positive airway pressure, airway stenting, surgical tracheoplasty and laser treatment.
Tracheopathies associated with infiltrative lung disease

Amyloidosis is a heterogeneous disease that results from the deposition of toxic, insoluble,
β-sheet fibrillar protein, which aggregates in different tissues. Amyloidosis can be acquired or
hereditary, and localised or systemic. Amyloidosis can be classified according to systemic,
hereditary, central nervous system, ocular and localised aetiology. However, the most common
types are AL, AA, ATTR (amyloid transport protein transthyretin) and dialysis-related
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amyloidosis (β2M type). In AL amyloidosis, “A” represents amyloid, followed by an

abbreviation for the associated fibrillar protein, “L”, standing for light-chain fragment or
immunoglobulin light chain. In AA amyloidosis, the second “A” stands for the serum amyloid
A protein [40].
About 50% of amyloidosis cases are localised to the respiratory system and three forms can be
distinguished: tracheobronchial amyloidosis, nodular parenchymal amyloidosis, and diffuse
parenchymal or alveolar septal amyloidosis. Tracheobronchial amyloidosis is characterised by
amyloid deposits in tracheal and bronchial tissue and is very rare. Symptoms are related to fixed
upper airway obstruction caused by tracheal stenosis. Diagnosis is made with histopathology
performed on bronchoscopy samples, with biopsies staining positive for Congo red stain. CT
imaging is noninvasive and is recommended for the initial diagnostic assessment, as well as
episodically over time to monitor the course and progression of the disease [41–45].
Tracheobronchial amyloidosis requires a systemic approach to treatment. Of note, in some cases
of tracheobronchial amyloidosis where disease is localised and nonprogressive, systemic
treatment may be avoided and debridement or radiation may be an option [46].
The rarity of the disease means that the creation of a network among specialised centres with
dedicated registries is valuable. There are a variety of groups all over the world dedicated to the
support of patients with amyloidosis and current and former caregivers. Their goals are to set up
and help maintain peer group amyloidosis support group meetings and, by raising funds through
donations, help the groups to be self-sustaining and ongoing as long as necessary. Moreover,
the support group helps patients to connect with highly specialised centres.
Sarcoidosis is a multisystemic granulomatous disease of unknown cause that is characterised by

the formation of noncaseous epithelioid cell granulomas [47, 48]. Sarcoidosis involves the
respiratory system in 90% of cases, usually the hilar and mediastinal nodes and less frequently
the central airways. Airway involvement may lead to airflow limitation with typical symptoms
of shortness of breath and cough. PFTs, radiological imaging and bronchoscopy are important
for making the diagnosis (figure 6).
In the tracheal disease, typical manifestations are mucosal erythema, oedema, granularity and
cobble-stoning, plaques, nodules, and bronchial stenosis and airway distortion.
a) b)
FIGURE 6 a) Parenchymal window and b) mediastinal window CT images of tracheal involvement in sarcoidosis
with uneven wall thickening.
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Granulomatosis with polyangiitis, bronchitis, mediastinal granuloma and fibrosis,

histoplasmosis, blastomycosis, coccidioidomycosis, mycobacterioses, syphilis, actinomycosis,
malignant neoplasms, cartilaginous tumours, amyloidosis, papillomatoses, nonspecific mucosal
granulomas, inflammatory bowel disorders and radiation-induced mucositis should be
considered in the differential diagnosis [49–52]. In this broad scenario, a clinicopathological
correlation is essential to exclude nonsarcoid granulomatous disease, and the histopathological
examination is crucial.
The treatment of tracheal disease should be considered only if patients have obstructive
symptoms. In these limited cases, endoscopic eradication with laser therapy or cryoablation
therapy can be done. Otherwise, treatment will be guided by symptoms, extent of disease and
disease activity, and it is a systemic therapy [50].
Conclusion
Disorders of the trachea remain a diagnostic and therapeutic challenge for physicians because
the diseases that affect the trachea are varied and have different pathogeneses, aetiologies
and presentations. They may occur at any age, and the nonspecific symptomatology makes
diagnosis difficult.
In the diagnostic framework, the first step should be the medical history and a clinical
examination to elicit relevant symptoms, signs and comorbidities, and to exclude a possible
secondary nature of the disease. Radiological evaluation with a CT scan may confirm the
diagnosis, and finally an endoscopic examination is in almost all cases mandatory, and can also
help with obtaining material for histological evaluation.
Treatment depends on the severity of the disease, and it is important not to ignore the importance
of reducing predisposing risk factors and optimising comorbidities. Interventional approaches
may include bronchoscopic or surgical approaches, and the chosen modality will depend on
disease severity, patient comorbidities, and the success or failure of previous methods.
References
1 Rehman S, Bacha D. Embryology, Pulmonary. Treasure Island, StatPearls Publishing, 2022.
2 Kluth D, Steding G, Seidl W. The embryology of foregut malformations. J Pediatr Surg 1987; 22: 389–393.
3 Wallis C, Alexopoulou E, Antón-Pacheco JL, et al. ERS statement on tracheomalacia and bronchomalacia in
children. Eur Respir J 2019; 54: 1900382.
4 Yalcin E, Dogru D, Ozcelik U, et al. Tracheomalacia and bronchomalacia in 34 children: clinical and radiologic
profiles and associations with other diseases. Clin Pediatr 2005; 44: 777–781.
5 Carden KA, Boiselle PM, Waltz DA, et al. Tracheomalacia and tracheobronchomalacia in children and adults: an
in-depth review. Chest 2005; 127: 984–1005.
6 Fraga JC, Jennings RW, Kim PC. Pediatric tracheomalacia. Semin Pediatr Surg 2016; 25: 156–164.
7 Chou AK, Huang SC, Chen SJ, et al. Unilateral lung agenesis – detrimental roles of surrounding vessels. Pediatr
Pulmonol 2007; 42: 242–248.
8 Floyd J, Campbell DC Jr, Dominy DE. Agenesis of the trachea. Am Rev Respir Dis 1962; 86: 557–560.
9 de José María B, Drudis R, Monclús E, et al. Management of tracheal agenesis. Paediatr Anaesth 2000; 10:
441–444.
10 Smith N. Oesophageal atresia and tracheo-oesophageal fistula. Early Hum Dev 2014; 90: 947–950.
11 Benjamin B, Inglis A. Minor congenital laryngeal clefts: diagnosis and classification. Ann Otol Rhinol Laryngol
1989; 98: 417–420.
12 Varela P, Torre M, Schweiger C, et al. Congenital tracheal malformations. Pediatr Surg Int 2018; 34: 701–713.
13 Leboulanger N, Garabedian EN. Laryngo-tracheo-oesophageal clefts. Orphanet J Rare Dis 2011; 6: 81.
14 van Lennep M, Singendonk MMJ, Dall’Oglio L, et al. Oesophageal atresia. Nat Rev Dis Primers 2019; 5: 26.
15 Gross RE. The Surgery of Infancy and Childhood. Philadelphia, WB Saunders, 1953.
354 https://doi.org/10.1183/2312508X.10019522
16 Yang S, Yang R, Ma X. Detail correction for Gross classification of esophageal atresia based on 434 cases in
China. Chin Med J 2022; 135: 485–487.
17 Bradshaw CJ, Thakkar H, Knutzen L, et al. Accuracy of prenatal detection of tracheoesophageal fistula and
esophageal atresia. J Pediatric Surf 2016; 51: 1268–1272.
18 Al-Salem AH, Mohaidly MA, Al-Buainain HM, et al. Congenital H-type tracheoesophageal fistula: a national
multicenter study. Pediatr Surg Int 2016; 32: 487–491.
19 Meier JD, Sulman CG, Almond PS, et al. Endoscopic management of recurrent congenital tracheoesophageal
fistula: a review of techniques and results. Int J Pediatr Otorhinolaryngol 2007; 71: 691–697.
20 Beasley SW, Myers NA. The diagnosis of congenital tracheoesophageal fistula. J Pediatr Surg 1988; 23: 415–417.
21 Andrassy RJ, Ko P, Hanson BA, et al. Congenital tracheoesophageal fistula without esophageal atresia. A
22 year experience. Am J Surg 1980; 140: 731–733.
22 Laffan EE, Daneman A, Ein SH, et al. Tracheoesophageal fistula without esophageal atresia: are pull-back tube
esophagograms needed for diagnosis? Pediatr Radiol 2006; 36: 1141–1147.
23 Goyal A, Potter F, Losty PD. Transillumination of H-type tracheoesophageal fistula using flexible miniature
bronchoscopy: an innovative technique for operative localization. J Pediatr Surg 2005; 40: e33–e34.
24 Morel V, Corbineau H, Lecoz A, et al. Two cases of ‘asthma’ revealing a diverticulum of Kommerell. Respiration
2002; 69: 456–460.
25 Javia L, Harris MA, Fuller S. Rings, slings, and other tracheal disorders in the neonate. Semin Fetal Neonatal
Med 2016; 21: 277–284.
26 Carpenter DJ, Hamdi OA, Ariel M, et al. Laryngotracheal stenosis: mechanistic review. Head Neck 2022; 44:
1948–1960.
27 Jagpal N, Shabbir N. Subglottic Stenosis. Treasure Island, StatPearls Publishing, 2022.
28 Feinstein AJ, Goel A, Raghavan G, et al. Endoscopic management of subglottic stenosis. JAMA Otolaryngol Head
Neck Surg 2017; 143: 500–505.
29 Dumoulin E, Stather DR, Gelfand G, et al. Idiopathic subglottic stenosis: a familial predisposition. Ann Thorac
Surg 2013; 95: 1084–1086.
30 Jindal JR, Milbrath MM, Shaker R, et al. Gastroesophageal reflux disease as a likely cause of “idiopathic”
subglottic stenosis. Ann Otol Rhinol Laryngol 1994; 103: 186–191.
31 Gnagi SH, Howard BE, Anderson C, et al. Idiopathic subglottic and tracheal stenosis: a survey of the patient
experience. Ann Otol Rhinol Laryngol 2015; 124: 734–739.
32 Myer CM, O’Connor DM, Cotton RT. Proposed grading system for subglottic stenosis based on endotracheal
tube sizes. Ann Otol Rhinol Laryngol 1994; 103: 319–323.
33 Jagpal N, Shabbir N. Subglottic Stenosis. Treasure Island, StatPearls Publishing, 2023.
34 Ghorbani A, Dezfouli AA, Jahanshahi N. A proposed grading system for post-intubation tracheal stenosis.
Tanaffos 2012; 11: 10–14.
35 Johnston RF, Green RA. Tracheobronchiomegaly. Report of five cases and demonstration of familial occurrence.
Am Rev Respir Dis 1965; 91: 35–50.
36 Woodring JH, Barrett PA, Rehm SR, et al. Acquired tracheomegaly in adults as a complication of diffuse
pulmonary fibrosis. AJR Am J Roentgenol 1989; 152: 743–747.
37 Schoor J A, Joos G, Pauwels R. Tracheobronchomegaly – the Mounier-Kuhn syndrome: report of two cases and
review of the literature. Eur Respir J 1991; 4: 1303–1306.
38 Sane AC, Effmann EL, Brown SD. Tracheobronchiomegaly. The Mounier-Kuhn syndrome in a patient with the
Kenny–Caffey syndrome. Chest 1992; 102: 618–619.
39 Blake MA, Clarke PD, Fenlon HM. Thoracic case of the day. Mounier-Kuhn syndrome (tracheobronchomegaly).
AJR Am J Roentgenol 1999; 173: 822.
40 Bustamante JG, Zaidi SRH. Amyloidosis. Treasure Island, StatPearls Publishing, 2023.
41 Sideras K, Gertz MA. Amyloidosis. Adv Clin Chem 2009; 47: 1–44.
42 Lachmann HJ, Hawkins PN. Amyloidosis and the lung. Chron Respir Dis 2006; 3: 203–214.
43 Utz JP, Swensen SJ, Gertz MA. Pulmonary amyloidosis. The Mayo Clinic experience from 1980 to 1993. Ann
Intern Med 1996; 124: 407–413.
44 O’Regan A, Fenlon HM, Beamis JF Jr, et al. Tracheobronchial amyloidosis. The Boston University experience
from 1984 to 1999. Medicine 2000; 79: 69–79.
45 Crain MA, Lakhani DA, Balar AB. Tracheobronchial amyloidosis: a case report and review of literature. Radiol
Case Rep 2021; 16: 2399–2403.
46 Milani P, Basset M, Russo F, et al. The lung in amyloidosis. Eur Respir Rev 2017; 26; 170046.
47 Polychronopoulos VS, Prakash UBS. Airway involvement in sarcoidosis. Chest 2009; 136: 1371–1380.
48 Baughman RP, Lower EE, Tami T. Upper airway. 4: Sarcoidosis of the upper respiratory tract (SURT). Thorax
2010; 65: 181–186.
49 Brandstetter RD, Messina MS, Sprince NL, et al. Tracheal stenosis due to sarcoidosis. Chest 1981; 80: 656.
https://doi.org/10.1183/2312508X.10019522 355
50 Fouty BW, Pomeranz M, Thigpen TP, et al. Dilatation of bronchial stenoses due to sarcoidosis using a flexible
fiberoptic bronchoscope. Chest 1994; 106: 677–680.
51 Hennebicque AS, Nunes H, Brillet PY, et al. CT findings in severe thoracic sarcoidosis. Eur Radiol 2005; 15: 23–30.
52 Ryu JH, Maldonado F, Tomassetti S. Idiopathic tracheopathies. In: Cordier J-F, ed. Orphan Lung Diseases (ERS
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Chapter 26
Rare diseases of respiratory drive

Katie Rose1, Tamarin Foy1, Christopher Grime1 and Ian P. Sinha1,2
1
Alder Hey Children’s NHS Foundation Trust, Liverpool, UK. 2Division of Child Health, University of Liverpool,
Liverpool, UK.
Corresponding author: Katie Rose (katierose100@gmail.com)
Cite as: Rose K, Foy T, Grime C, et al. Rare diseases of respiratory drive. In: Wagner TOF, Humbert M, Wijsenbeek M,
et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023;
pp. 357–366 [https://doi.org/10.1183/2312508X.10019622].
@ERSpublications
Disorders affecting respiratory drive are a heterogeneous but rare group of conditions causing altered
breathing patterns, which, if left untreated, may have serious and sometimes fatal consequences
https://bit.ly/ERSM100
ISSN: 2312-5098.
Disorders affecting respiratory drive are an important group of conditions that relate to defects in the
neural circuits that control breathing. These disorders are a heterogeneous group of problems with
underlying genetic or structural abnormalities leading to altered breathing patterns, which, if undetected,
can be life threatening and cause serious sequelae. Investigation and management of these disorders
need to be individualised according to the underlying pathology. Management strategies often require
forms of invasive or noninvasive ventilatory support, which come with arduous care burdens for the
patient and their family. Good ventilatory support is required to enable adverse effects from
hypoxaemia and hypercapnia to be minimised, particularly in the early years when adverse
neurodevelopmental outcomes are a recognised consequence. This chapter seeks to provide an overview
of some of these rare conditions, highlighting their pathophysiology and management.
Introduction
Diseases of respiratory drive is a broad term encompassing a heterogeneous range of rare
conditions. These disorders relate to defects in the neural circuitry that controls breathing caused
by genetic mutations such as homeodomain transcription factor paired-like homeobox 2B
(PHOX2B) mutations or by structural lesions that may have direct effects on respiratory centres
or critical points in the brainstem and spinal cord. Other syndromes such as Rett syndrome and
Prader–Willi syndrome (PWS) may present similar challenges with underlying mechanisms that
are not fully understood.
Disorders of respiratory drive result in periods of hypoxia and hypercapnia with both acute and
long-term consequences. Presentations can range from fatal apnoea in the neonatal period to
long-term neurodevelopmental impairment [1], as well as effects on the pulmonary vasculature
and heart.
In this chapter, we seek to provide an overview of some of these conditions, highlighting their
pathophysiology and management.
https://doi.org/10.1183/2312508X.10019622 357
Central control of breathing

Central control of breathing is a complex interplay between respiratory centres and the central
and peripheral chemoreceptors. Located in the brainstem we have the dorsal respiratory group
within the nucleus of the solitary tract, the ventral respiratory column located in the
venterolateral medulla and the pontine respiratory group in the dorsolateral pons [2]. Central and
peripheral chemoreceptors are located throughout the body and detect changes in levels of
hydrogen ions, carbon dioxide (CO2) and oxygen (O2). The retrotrapezoid nucleus, located near
the medulla oblongata, is a region containing neurons that are activated by hypercapnia and
increase the effort of breathing when stimulated with glutamate or bicuculline via innervation of
caudal portions of the ventral respiratory column. PHOX2B has been identified in all neurons
within the retrotrapezoid nucleus and helps to explain why mutations within the PHOX2B gene
cause a failure to respond to changes in CO2 tension (PCO2) [3].
During sleep, chemoreceptor responses are likely to be reduced, with less rapid responses to
hypoxia and hypercarbia, particularly during rapid eye movement sleep. Sleep gives rise to a
new, higher set point of PCO2 in the respiratory centre leading to a small increase in PCO2 during
the night [4]. This, alongside reduced airway tone and subsequent increased airway resistance,
leads to reduced ventilation.
During wakefulness, behavioural influences and neurocompensatory responses prevent apnoeas,

even in the presence of marked reductions in PCO2. During sleep, these mechanisms do not
exist, and a reduction in PCO2 past a critical point, the “apnoea threshold”, leads to the cessation
of breathing [5]. This gives rise to central apnoeas and is particularly important in conditions
where chemoreceptor responses to hypoxia or hypercapnia may be impaired. For this reason,
sleep is the most useful state to assess the respiratory drive.
Basic tests such as overnight pulse oximetry recordings are often used as a screening tool to
detect hypoxic episodes during sleep; however, using oximetry alone will not adequately detect
hypoventilation. Polysomnography provides accurate sleep staging via electroencephalogram
monitoring, pulse oximetry, capnography, nasal airflow, and chest and abdominal respiratory
movement, as well as leg and eye movements. If there is a strong suspicion of sleep-disordered
breathing, full polysomnography is the gold standard first-line investigation.
Genetic disorders
Congenital central hypoventilation syndrome
First described as “Ondine’s curse” in 1970, characterising a newborn with “alveolar
hypoventilation due to an abnormality in the autonomic control of ventilation”, congenital
central hypoventilation syndrome (CCHS) is a rare condition with an incidence of 1 in 148 000–
200 000 and approximately 1300 genetically confirmed cases worldwide [6–8]. It encompasses
a clinical picture of alveolar hypoventilation due to abnormal or absent responses to hypercapnia
and hypoxia. The term CCHS was first used in 1978 in a case series published to describe
long-term phrenic nerve pacing as the primary management for the disorder [9].
Presentation
CCHS can present at any age but is generally divided into those with the more common
neonatal onset presenting in the first month of life, often with apnoeas, and those with later
onset in childhood, adolescence or even adulthood. Presentations can range from brief, resolved
and unexplained events (BRUE) to severe sleep apnoea, difficulties after routine anaesthesia or
episodes of desaturation associated with intercurrent illness. Genetic screening following
diagnosis of a family member is becoming more commonplace.
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DISEASES OF RESPIRATORY DRIVE | K. ROSE ET AL.
Diagnosis
While reduced ventilatory responses to hypercapnia and hypoxaemia can be seen in
wakefulness, diagnosis of CCHS involves assessing sleep for hypoventilation with a reduction
in respiratory rate or central apnoea. Episodes tend to be more severe during non-rapid eye
movement sleep stages. Alveolar hypoventilation can be defined arbitrarily as PCO2 >6.7 kPa
(50 mmHg) for >50% of total sleep time [10]. Figure 1 demonstrates central apnoeas despite a
raised CO2 level during polysomnography.
If hypoventilation is confirmed and other causes excluded, PHOX2B testing should be

considered [7]. In those with BRUE or central apnoea, it is recommended that prolonged
monitoring of PCO2 is undertaken to identify hypoventilation prior to considering PHOX2B
testing. Infants born to parents with CCHS, as well as parents of confirmed CCHS cases, should
automatically be considered for genetic testing after appropriate counselling [7].
Genetics
Heterozygous mutations in the PHOX2B gene on chromosome 4 (4p13) were first identified and
implicated in CCHS in 2003 [11]. Early work on murine models demonstrated a role for the
PHOX2B gene in encoding a transcription factor essential in the embryonic development of
both the central and peripheral autonomic nervous systems. This led to the investigation of
PHOX2B as a candidate gene for CCHS and explains associations between PHOX2B mutations
and other manifestations of autonomic dysfunction such as Hirschsprung disease and neural
crest tumours [6, 11]. Transmission of CCHS is autosomal dominant with variable expression
and penetrance [12].
PHOX2B mutations can be found in most patients (∼90%) with CCHS [8]. The most common
mutations are polyalanine repeat mutations in exon 3. The affected allele will often have 24–33
repeats compared with the normal 20 repeats in those unaffected by CCHS. Other mutations in
PHOX2B are possible but found less commonly. Recently, mutations in two further genes,
myosin IH (MYO1H) and ladybird homeobox 1 (LXB1), have been found to be implicated in
those with a clinical picture of hypoventilation or a phenotype similar to CCHS but with normal
PHOX2B genetics [13, 14].
ECG
Chest movement
Abdominal movement
Nasal flow
O2 saturation
Heart rate
Transcutaneous CO2
FIGURE 1 Central apnoeas present on polysomnography, despite raised transcutaneous carbon dioxide (CO2)
levels. O2: oxygen.
https://doi.org/10.1183/2312508X.10019622 359
Management
The primary aim of management in CCHS is to provide adequate ventilation and oxygenation,
with avoidance of sequelae related to chronic hypoxia and hypercapnia. The mainstays of
management involve invasive positive-pressure ventilation via tracheostomy, noninvasive
ventilation via a face mask or diaphragmatic pacing. Management of CCHS requires
multidisciplinary support with often arduous monitoring requirements, and frequently involves
many healthcare professionals [7].
Pressure-controlled ventilation with a back-up rate and set minimum inspiratory time is required in
most patients. This can be given invasively via tracheostomy or noninvasively as mask ventilation.
Ventilators should have adequate disconnection and low- and high-pressure/volume alarms. All
patients requiring ventilation should have home oximetry monitoring with alarms and should
undergo periodic studies with monitoring of PCO2 to assess the adequacy of ventilation [7].
Invasive ventilation via tracheostomy provides a secure airway and is recommended in infants
and young children with CCHS. This modality facilitates the best gas exchange and therefore
promotes optimal neurocognitive development in the early years. A 2010 policy statement from
the American Thoracic Society recommended invasive ventilation as the mainstay of ventilatory
management in all infants and children with CCHS, with noninvasive support being considered
only after 6–8 years of age in stable patients requiring overnight support only [15]. A more
recent paper from an Italian cohort describes the need for invasive ventilation in only 59% of
those with CCHS, with a trend towards noninvasive management in more recent years [16].
Noninvasive ventilation via a face mask is beneficial to those requiring overnight support only.
The risks and benefits of invasive and noninvasive ventilation are summarised in table 1 [7, 15].
Many of those who receive invasive ventilation during childhood are able to transition to mask
ventilation when they have adequate ventilation during wakefulness. They are closely monitored
prior to decannulation, often undergoing sleep studies while using mask ventilation with the
tracheostomy capped off prior to consideration of decannulation and transition [7].
Phrenic nerve pacing works by placing electrodes under each phrenic nerve causing stimulation
via electrical pulses, initiating contraction of the diaphragm and a subsequent inspiratory breath.
TABLE 1 Risks and benefits of invasive and noninvasive ventilation for management of congenital central
hypoventilation syndrome
Invasive Noninvasive
Benefits Secure airway Avoids risks of tracheostomy

Ability to provide ventilation during both Short training periods facilitating faster discharge
wakefulness and sleep from hospital
Ability to provide support when unwell without Normal development of speech and
need for admission to the intensive care unit oromotor skills
Risks Prolonged training requirements necessitating Nonsecure airway
long hospital stays after tracheostomy Facial pressure sores and deformity with
insertion long-term use
Complications of tracheostomy (infection, Dislodgement of mask/aspiration risk with
decannulation, granuloma formation) vomiting necessitating need for close monitoring
Interference with speech development Limited interfaces in infants
and feeding May require admission to the intensive care
unit for increased support/invasive ventilation
when unwell
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Pacing can be used day or night but is often a means of allowing ventilation-free time during
the day. It is not frequently used in isolation, particularly in the younger age groups.
Contraindications to pacing include upper airway obstruction or obstructive apnoea, chronic
lung disease, airway abnormalities and obesity. Surgery is required to insert the pacing wires
usually via thoracotomy or thoracostomy, with the receiver being placed in either the lower
thorax or upper abdomen. Pacing is then controlled via a small external transmitter.
Complications include infection of the wires or receiver postsurgery, as well as pacer
malfunction or problems with the transmitter [7]. Those reliant on diaphragmatic pacing still
require continuous monitoring to detect malfunctions in the system [15].
Complications/other system involvements

As well as respiratory drive complications, PHOX2B mutations can affect development of the
whole autonomic nervous system. Patients with CCHS often have multisystem involvement with
extensive autonomic nervous system dysregulation [15].
Hirschsprung disease occurs in up to 20% of those with CCHS as a result of absent ganglion
cells in the distal colon. It may present in the early neonatal period with failure to pass
meconium, or later with constipation refractory to usual medical management or intestinal
obstruction. Diagnosis is by rectal suction biopsy to examine tissue for the presence or absence
of submucosal ganglion cells. Surgical resection of the affected gut is indicated in most patients
with Hirschsprung disease [7].
Neural crest tumours occur in 3–5% of those with CCHS. Their presentation depends on the
location and tumour type, with the neck, chest and abdomen being the most common sites [7].
Associated cardiovascular disorders in those with CCHS include arrhythmias due to autonomic
dysfunction and blood pressure abnormalities. All those with a diagnosis of CCHS should
receive annual ECG monitoring with a Holter monitor. Pacing may be required in some patients.
Ocular disorders including abnormal pupillary responses are common in those with CCHS, and
it is recommended that screening is offered at diagnosis and annually [7].
Neurological disorders including breath-holding attacks, seizures and syncope may occur in
those with CCHS. These may be related to autonomic dysfunction with hypotension,
arrhythmias, hypoglycaemia or hypoxaemia itself. Underlying causes should be sought and
managed aggressively. Neurodevelopmental problems are common in those with CCHS, and
development should be closely monitored in the first years of life. Recent studies have found
that improved early ventilatory management is associated with better neurodevelopmental
outcomes [17].
CCHS is a life-long condition requiring life-long specialist input from centres with experience
in the condition. Regular multidisciplinary reviews are important and involve many different
professionals. The field is evolving, particularly around PHOX2B genetics and implications
related to specific mutations, and more personalised management may become more common in
the future.
Many with CCHS are living with successful ventilatory support into adulthood, with the
potential for a normal life span. However, undiagnosed cardiac complications, complications
related to recurrent hypoxaemia and hypercarbia, or poor compliance with ventilatory support
can contribute to premature death [12].
https://doi.org/10.1183/2312508X.10019622 361
Rett syndrome
Rett syndrome is a rare early-onset neurodevelopmental disorder first described by Andreas Rett
in 1966 [18]. It affects 1 in 10 000–15 000 female live births and is characterised by apparently
normal development until ∼18 months of age, followed by developmental regression with loss
of motor and communication skills and the development of stereotypical hand movements,
ataxia and seizures. The genetic basis of Rett syndrome was hypothesised long before the
identification of mutations in the methyl-CpG-binding protein 2 (MECP2) gene in 1999 [19].
MECP2 encodes a protein that is abundant in the central nervous system but is present
throughout the body. It has been suggested that MECP2 is involved in the maturation and
maintenance of neurons [20].
Respiratory problems in Rett syndrome can be variable, with many patients having episodes of
hypoventilation or breath holding, alternating with periods of irregular respiratory effort and
hyperventilation. It has been hypothesised that responses to mild hypercapnia are impaired,
raising the possibility that hyperventilation occurs only when hypercapnia becomes severe,
leading to periods of characteristic hypo- and hyperventilation [21]. Respiratory problems can
manifest early in the disease process, often first becoming apparent in the regressive phase.
Breath holding is common in younger children with Rett syndrome, with one study reporting a
prevalence of 63% by the age of 5 years [22]. Periods of hyperventilation and forced deep
breathing develop late, often alongside abnormal cardiac responses suggestive of disturbances in
cardiorespiratory coupling. Abnormalities are seen in both sleep and wakefulness. The reported
phenotypes are complex and probably reflect multiple underlying mechanisms.
Management of respiratory problems in Rett syndrome is complex and depends on the

individual clinical picture. Cardiorespiratory monitoring during periods of sleep and
wakefulness can be used in symptomatic patients. There are no specific treatments for
breath-holding episodes or irregular breathing patterns, although new pharmacological therapies
have had some promising effects in mouse models [23]. Obstructive episodes may require some
form of ventilatory support, and O2 may be given to those with evidence of hypoxia on
cardiorespiratory testing. The complex interplay and abnormal chemoresponses in these
individuals mean that responses to interventions are often unpredictable, with close monitoring
recommended.
PWS
PWS is a multisystem genetic disorder caused by lack of expression of paternally derived genes
on chromosome 15q11–q13. Presentation with hypotonia and poor feeding in the neonatal
period is common, followed by the development of a characteristic hyperphagia and obesity.
Those with PWS are at risk of a variety of breathing problems, particularly during sleep, due to
a multifactorial aetiology. Studies have demonstrated abnormal ventilatory responses to hypoxia
and hypercarbia in those with PWS, with a lack of response in minute ventilation following
exposure to 15% CO2 or exposure to 100% O2 when compared with controls [24]. Central
apnoeas in infants and young children are common, with abnormal chemoreceptor responses
hypothesised to play a role, and even brief periods of hypoxia may have a depressive effect on
central control of breathing leading to further apnoeas and subsequent further periods of
hypoxia [25]. Hypotonia and immature brainstem activity are also likely to contribute to
hypoxia in these patients. Central apnoeas in PWS respond to treatment with O2 therapy by
reducing fluctuations in saturations when asleep and therefore stabilising what can become a
vicious cycle of hypoxia–apnoea–hypoxia [25].
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Central apnoeas are seen almost exclusively in children <2 years old with PWS, with older
children being at risk of developing obstructive sleep apnoea (OSA) related to hypotonia and
obesity [25]. However, recent studies have found that in children with PWS and OSA,
hypoventilation can be disproportionate to the level of upper airway obstruction, suggesting that
further mechanisms may be at play [26]. There is evidence that growth hormone use, which can
have many benefits in those with PWS, has a risk of sudden death, which is probably related to
increased upper airway obstruction and subsequent worsening of obstructive events [27].
All infants with a diagnosis of PWS should be screened for sleep-disordered breathing in order to
detect central apnoeas and resultant hypoxia, which, if left untreated, may have unwanted effects
on the developing brain [25]. In older children with OSA syndrome, consideration should be
given to undertaking full polysomnography to rule out associated hypoventilation and to guide
management [26]. In addition, all children in whom growth hormone therapy is being considered
should undergo polysomnography and, if abnormal, interventions such as adenotonsillectomy or a
trial of noninvasive support should be considered prior to commencing therapy. Upon initiation of
growth hormone therapy, further polysomnography screening should be undertaken during the
first 3 months of treatment, which appears to be the highest-risk phase [27].
Structural brain lesions

Chiari malformations describe structural abnormalities of the brainstem and cerebellum with
variable descent of the tonsils, cerebellum and brainstem through the foramen magnum into the
upper cervical canal [28]. These lesions can be associated with central and obstructive
sleep-disordered breathing.
Chiari I malformations are often found incidentally, and investigating with polysomnography is
indicated in many of these children, particularly if they have a suggestive history. Chiari II
malformations are often associated with myelomeningocele and are usually identified
antenatally. It has been suggested that those with Chiari II malformations should have screening
polysomnography, with repeat testing following any neurosurgical interventions. Conversely, in
ECG
Chest movement
Abdominal movement
Nasal flow
O2 saturation
Heart rate
Transcutaneous CO2
FIGURE 2 Central apnoeas demonstrated on polysomnography in a child with history of pauses in breathing
during sleep, which were subsequently found to be secondary to Chiari I malformation. O2: oxygen; CO2: carbon
dioxide.
https://doi.org/10.1183/2312508X.10019622 363
FIGURE 3 MRI scan from the child in figure 2 demonstrating Chiari malformation with descent of the cerebellar
tonsils to a depth of ∼27 mm below the level of the foramen magnum.
any infant or child with unexplained central apnoea detected at polysomnography, consideration
should be given to undertaking MRI to identify structural abnormalities. In many of these
children, intervention in the form of surgical decompression may lead to a dramatic
improvement in their breathing pattern [29].
MRI findings in children with structural lesions may not correlate with clinical findings on
polysomnography. Undertaking regular surveillance if there are concerns is therefore important in
this group of patients. While definitive surgical management may be necessary, treatment of central
apnoea with overnight O2 supplementation or ventilation support is often required in these patients.
Figure 2 demonstrates polysomnography data illustrating central apnoeas in a child who went on
to have an MRI scan, which diagnosed a Chiari malformation (figure 3).
Other structural abnormalities such as Dandy–Walker malformations may also affect respiratory
control centres in the brainstem, and there should be a low threshold for investigation with
polysomnography.
Obesity hypoventilation syndrome

Obesity hypoventilation syndrome (OHS) is a rare complication of obesity. It can be defined as
obesity (body mass index (BMI) >30 kg·m−2) plus hypercapnia (PCO2 >45 mmHg) during
wakefulness that is not explained by other known causes of hypoventilation. The mechanisms
that underlie the development of OHS are poorly understood, and many with obesity will never
develop hypoventilation. Chronic increases in the mechanical load on the chest alongside
chronic upper airway obstruction and sleep-disordered breathing, as well as leptin resistance, are
all likely to contribute [30].
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In order to diagnose OHS, polysomnography and arterial blood gas measurements are required.
US guidelines suggest screening the highest-risk patients, who are those with severe obesity
(BMI >40 kg·m−2) and features suggestive of OHS, with arterial PCO2 measurement. In those
with low or moderate risk of OHS (BMI 30–40 kg·m−2), a serum bicarbonate measurement is
suggested as a screening tool, as a result of <27 mmol·L−1 effectively excludes chronic
hypercapnia [31]. OHS is associated with high levels of morbidity and mortality, with directly
related consequences such as the development of PH and right heart dysfunction, as well as
other risks that accompany obesity such as development of hypertension, diabetes mellitus,
hyperlipidaemia and ischaemic heart disease [30].
Ultimately, weight loss can reverse OHS and the risks associated with it [32]. Weight-loss
strategies should be initiated alongside any other management. Ventilation support such as
continuous positive airway pressure (CPAP) to overcome upper airway obstruction is the first
line of treatment in these patients and has been shown to improve symptoms and biochemical
parameters, with a reduction in the development of secondary complications. If CPAP is
unsuccessful, bilevel support via a face mask should be considered, and in some cases invasive
support via tracheostomy may be required. Many patients require supplemental O2 alongside
positive-pressure support, although this may be weaned over time with good adherence to their
noninvasive support [30].
Conclusion
Disorders of respiratory drive are a rare but heterogeneous group of conditions that can have
significant short-term as well as life-long consequences on the individual. There is no “one size
fits all” with regard to managing these patients, reflecting the complex and sometimes poorly
understood interplays within the underlying pathophysiology. These patients should be
investigated and managed in centres with specialist experience in ventilation strategies to ensure
optimal outcomes.
References
1 Charnay AJ, Antisdel-Lomaglio JE, Zelko FA, et al. Congenital central hypoventilation syndrome: neurocognition
already reduced in preschool-aged children. Chest 2016; 149: 809–815.
2 Alheid G, McCrimmon D. The chemical neuroanatomy of breathing. Respir Physiol Neurobiol 2008; 164: 3–11.
3 Guyenet P, Bayliss D. Neural control of breathing and CO2 homeostasis. Neuron 2015; 87: 946–961.
4 Eckert D, Jordan A, Merchia P, et al. Central sleep apnea. Chest 2008; 131: 595–607.
5 Dempsey J. Crossing the apnoeic threshold: causes and consequences. Exp Physiol 2005; 90: 13–24.
6 Di Lascio S, Benfante R, Cardani S, et al. Research advances on therapeutic approaches to congenital central
hypoventilation syndrome (CCHS). Front Neurosci 2020; 14: 615666.
7 Trang H, Samuels M, Ceccherini I, et al. Guidelines for diagnosis and management of congenital central
hypoventilation syndrome. Orphanet J Rare Dis 2020; 15: 252.
8 Trang H, Dehan M, Beaufils F, et al. The French Congenital Central Hypoventilation Syndrome Registry: general
data, phenotype, and genotype. Chest 2005; 127: 72–79.
9 Hunt CE, Matalon SV, Thompson TR, et al. Central hypoventilation syndrome: experience with bilateral phrenic
nerve pacing in 3 neonates. Am Rev Respir Dis 1978; 118: 23–28.
10 Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM
Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force
of the American Academy of Sleep Medicine. J Clin Sleep Med 2012; 8: 597–619.
11 Amiel J, Laudier B, Attie-Bitach T, et al. Polyalanine expansion and frameshift mutations of the paired-like
homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 2003; 33: 459–461.
12 Weeze-Mayer D, Rand C, Khaytin I, et al. Congenital central hypoventilation syndrome. In: Adam MP, Everman
DB, Mirzaa GM, et al., eds. GeneReviews. Seattle, University of Washington, 2004.
13 Hernandez-Miranda LR, Ibrahim DM, Ruffault PL, et al. Mutation in LBX1/Lbx1 precludes transcription factor
cooperativity and causes congenital hypoventilation in humans and mice. Proc Natl Acad Sci USA 2018; 115:
13021–13026.
https://doi.org/10.1183/2312508X.10019622 365
14 Spielmann M, Hernandez-Miranda LR, Ceccherini I, et al. Mutations in MYO1H cause a recessive form of central
hypoventilation with autonomic dysfunction. J Med Genet 2017; 54: 754–761.
15 Weese-Mayer D, Berry-Kravis E, Ceccherini I, et al. An official ATS clinical policy statement: congenital central
hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med 2010; 181:
626–644.
16 Porcaro F, Paglietti M, Cherchi C, et al. How the management of children with congenital central
hypoventilation syndrome has changed over time: two decades of experience from an Italian center. Front
Pediatr 2021; 9: 648927.
17 Ogata T, Muramatsu K, Miyana K, et al. Neurodevelopmental outcome and respiratory management of
congenital central hypoventilation syndrome: a retrospective study. BMC Pediatr 2020; 20: 342.
18 Rett A. [On a unusual brain atrophy syndrome in hyperammonemia in childhood]. Wien Med Wochenschr 1966;
116: 723–726.
19 Amir RE, van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding
methyl-CpG-binding protein 2. Nat Genet 1999; 23: 185–188.
20 Kishi N, Macklis JD. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal
maturation rather than cell fate decisions. Mol Cell Neurosci 2004; 27: 306–321.
21 Zhang X, Su J, Cui N, et al. The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome.
Am J Physiol Cell Physiol 2011; 301: 729–738.
22 Mackay J, Downs J, Wong K, et al. Autonomic breathing abnormalities in Rett syndrome: caregiver perspectives
in an international database study. J Neurodev Disord 2017; 9: 15.
23 Katz D, Bird A, Coenraads M, et al. Rett syndrome: crossing the threshold into clinical translation. Trends
Neurosci 2016; 39: 100–113.
24 Gozal D, Arens R, Omlin KJ, et al. Absent peripheral chemosensitivity in Prader–Willi syndrome. J Appl Physiol
1994; 77: 2231–2236.
25 Cohen M, Hamilton J, Narang I. Clinically important age-related differences in sleep related disordered
breathing in infants and children with Prader–Willi syndrome. PLoS One 2014; 9: e101012.
26 Abel F, Tan H, Negro V, et al. Hypoventilation disproportionate to OSAS severity in children with Prader–Willi
syndrome. Arch Dis Child 2019; 104: 166–171.
27 Stafler P, Wallis C. Prader–Willi syndrome: who can have growth hormone? Arch Dis Child 2008; 93: 341–345.
28 Schijman E. History, anatomic forms, and pathogenesis of Chiari I malformations. Childs Nerv Syst 2004;
20: 323–328.
29 Khatwa U, Ramgopal S, Mylavarapu A, et al. MRI findings and sleep apnea in children with Chiari I
malformation. Paediatr Neurol 2013; 48: 299–307.
30 Mokhlesi B, Kryger MH, Grunstein RR. Assessment and management of patients with obesity hypoventilation
syndrome. Proc Am Thorac Soc 2008; 5: 218–225.
31 Mokhlesi B, Masa J, Brozek J, et al. Evaluation and management of obesity hypoventilation syndrome. An
official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2019; 200: e6–e24.
32 Kakazu MT, Soghier I, Afshar M, et al. Weight loss interventions as treatment of obesity hypoventilation
syndrome. A systematic review. Ann Am Thorac Soc 2020; 17: 492–502.
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Chapter 27
Pleural mesothelioma
Joachim G.J.V. Aerts1,2,4 and Jan P. van Meerbeeck2,3,4
1
Department of Pulmonology, Erasmus MC Rotterdam, Rotterdam, the Netherlands. 2European Reference Network
for Rare Diseases of the Respiratory System (ERN-LUNG), Frankfurt, Germany. 3Department of Thoracic Oncology,
Antwerp University Hospital, Edegem, Belgium. 4Both authors contributed equally.
Corresponding author: Joachim G.J.V. Aerts ( j.aerts@erasmusmc.nl)
Cite as: Aerts JGJV, van Meerbeeck JP. Pleural mesothelioma. In: Wagner TOF, Humbert M, Wijsenbeek M, et al.,
eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023;
pp. 367–380 [https://doi.org/10.1183/2312508X.10019722].
@ERSpublications
Recent insights into the pathophysiology of pleural mesothelioma have improved therapeutic options;
however, many needs are still present. This chapter discusses the new options and novel developments.
https://bit.ly/ERSM100
ISSN: 2312-5098.
Mesothelioma is a rare cancer with a poor prognosis despite aggressive treatments. In recent years, new
treatment options have become available. This chapter provides a comprehensive overview of advances
in the epidemiology, aetiology, carcinogenesis, clinical and radiological presentation, pathology,
genetics, prognosis, biomarkers and treatment of pleural mesothelioma.
Introduction
Mesothelioma is a rare cancer, accounting for a mere 0.17% of the total estimated cancer cases
in 2020. It originates from the unicellular mesothelial layer of either the pleura, the peritoneum
or the pericardium. The tumour has become a global health issue due to its poor prognosis and
its increasing incidence. There has been an improvement in knowledge in recent years, leading
to several recent systematic reviews and meta-analyses, as well as evidence-based guidelines
[1–3]. The interested reader is encouraged to get acquainted with these guidelines, as the present
chapter will start from this consolidated evidence and provide a comprehensive overview of
advances since, in the epidemiology, aetiology, carcinogenesis, clinical and radiological
presentation, pathology, genetics, prognosis, biomarkers and treatment of pleural mesothelioma.
Where no relevant new data are available, the authors will refer to the existing
recommendations. Based on the recent World Health Organization (WHO) classification, the
term malignant has to be omitted when speaking of mesothelioma (https://tumourclassification.
iarc.who.int/welcome).
Epidemiology and aetiology

The world age-standardised rate of mesothelioma in 2020 was 0.30 per 100 000 persons, with
North-Western Europe reporting the highest incidence rates (figure 1) [4], clustering mainly
around shipyards and asbestos cement industries in specific areas with higher past and probably
future incidence.
https://doi.org/10.1183/2312508X.10019722 367
Males Females
Luxembourg
UK
The Netherlands
Belgium
Malta
Switzerland
Croatia
Italy
Denmark
Slovenia
Finland
Cyprus
Norway
Germany
Sweden
France
Austria
Ireland
Iceland
Populations
Montenegro
Poland
Spain
Slovakia
Russian Federation
Bulgaria
World
Albania
Czechia
Greece
Ukraine
Portugal
Belarus
Hungary
Serbia
Bosnia and Herzegovina
Lithuania
Latvia
North Macedonia Incidence
Romania Mortality
Republic of Moldova
Estonia
7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0
Age-standardised rate per 100 000
FIGURE 1 Estimated (world) age-standardised incidence and mortality rates of mesothelioma in 2020 by gender
for all ages. Data from GLOBOCAN 2020 (https://gco.iarc.fr/today/home).
Mesothelioma is more common in men than women, with a male:female ratio of 3:1. The
disease is more common in older adults, with a median age at diagnosis of 72 years. Countries
with a higher human development index, gross domestic product per capita and asbestos
exposure have higher mesothelioma rates. With the exception of Bulgaria and Korea, the overall
trend of mesothelioma incidence is decreasing. The significant decline in mesothelioma
incidence during the past decade may relate to the restriction of asbestos use in some countries.
In contrast, the increasing trend in mesothelioma incidence observed in females might indicate
an increase in environmental exposure to mineral fibres. During the period 2011–2017, the
5-year relative survival rate of people diagnosed with mesothelioma was 12%, significantly
lower than the 5-year survival rate of 62.7% for all cancers. In addition, mesothelioma has a
remarkably long latency period, which could last for 30–40 years, generally from the first
exposure to asbestos and its onset.
The major risk factor for mesothelioma is asbestos exposure, which can be traced back to the
occupational environment. Asbestos is considered a group 1 full carcinogen by the International
Association for Research on Cancer (IARC) [5]. Another main source of mesothelioma is
environmental asbestos exposure, which includes household and neighbourhood exposure to
asbestos. Mesothelioma caused by environmental asbestos exposure occurs at the same rate in
men and women. The increasing incidence seen amongst women in Russia and Kazakhstan
suggests that the environment is being affected by the presence of chrysotile mines and the
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PLEURAL MESOTHELIOMA | J.G.J.V. AERTS AND J.P. VAN MEERBEECK
unrestricted use of asbestos. Extensive use of asbestos and the failure to dispose of large
quantities of the resulting waste safely, has created an environmental problem. New asbestos
bans will not affect the millions of tons of asbestos that have already contaminated the
environment [6].
Evidence has shown other risk factors that might be associated with mesothelioma. For instance,
heterozygous germline BAP1 pathogenic mutations and ionising radiation have been associated
with a higher incidence of mesothelioma [7–9].
Pathogenesis, presentation, natural history and diagnosis

Chronic inflammation is a hallmark of cancer and is a crucial first step in asbestos
carcinogenesis (figure 2). This process typically starts on the lower dorsal parietal pleura and
expands over the chest wall and adjacent lung before invading either, leading to dyspnoea and/
or chest pain (figure 3a). Dyspnoea is due to the compression of the lung by the presence of an
(often massive) pleural effusion and/or the cuirass-like thickening of the visceral pleura
hindering the lung expansion, and also due to the chest pain by the invasion of the intercostal
nerve endings. The pain is of the neurogenic type and irradiates to the epigastrium and flank,
simulating a gastric or urinary origin. Progressive invasion in the chest wall and intrathoracic
organs results in the variable occurrence of chest wall lumps (figure 3b and c), superior vena
cava or Horner syndrome, pericardial tamponade, cardiac rhythm or conduction disturbances,
diaphragm paralysis, dysphagia by oesophageal compression and contralateral pleural effusion.
Expansion to the abdomen and peritoneum comes with ascites, constipation or ileus. Distant
Necrotic
Mesothelial cell
cell death
Inflammatory
Asbestos HMGB1
microenvironment Mesothelioma
Fe3+
ROS or RNS
Macrophage
Cytokines Survival
and
Autophagy transformation
Loss of tumour suppressor
Frustrated genes (BAP1, CDKN2A,
ROS or RNS
phagocytosis NF2, TP53 and SETD2)
FIGURE 2 Asbestos-induced chronic inflammation and mesothelioma carcinogenesis. Trapped in the lung, asbestos
fibres generate reactive oxygen species (ROS) and reactive nitrogen species (RNS) via a combination of frustrated
phagocytosis of asbestos fibres and iron-catalysed Fenton reactions. ROS or RNS in turn lead to DNA damage, lipid
peroxidation, cell death via ferroptosis and release of pro-inflammatory cytokines. Cytokines released in response
to asbestos also induce epithelial-to-mesenchymal transition and initiate activator-protein 1, a mediator of
continuing inflammation and cell proliferation. Immune cells are also affected by the chronic inflammatory
process, which in turn leads to reduced tumour immunity. Together, these factors lead to a loss of tumour
suppressor activity, altered epigenetic status and cell proliferation, resulting in oncogenic transformation.
https://doi.org/10.1183/2312508X.10019722 369
a) b) c)
FIGURE 3 Clinical presentation of malignant pleural mesothelioma. a) Coronal section of the lung and pleura of
a patient with pleural mesothelioma showing the cuirass-like thickening of both pleural envelopes surrounding
and compressing the left lung, Note the invasion in the fissure (arrow). b) Hunch-like left chest wall lump in a
woman with progressive pleural mesothelioma. c) Positron emission tomography scan and low-dose CT scan of
the same patient, showing the hypermetabolic tumour expanding from the left lung in the thoracic wall.
metastases occur in the later stages of disease and are not so infrequent in the final months of
life, owing to the increased longevity afforded by treatment. The clinical presentation may be
similar to other respiratory diseases, which can make diagnosis challenging. Symptoms may
also include weight loss, fatigue and anorexia.
There is an unexplained right-sided predominance in the presentation. Chest radiography is

aspecific and often shows a massive pleural effusion with contralateral mediastinal
displacement. Spontaneous pneumothorax has been regularly described as a first-presenting
symptom. Contrast-enhanced CT scan of the chest and upper abdomen is the cornerstone exam,
preferably performed after evacuation of gross pleural fluid. The spectrum of lesions vary from
a discrete pleural thickening over focal areas of abnormal pleura (with or without a pleural
effusion) to widespread rind-like circumferential lung encasement with shrinking of the
hemithorax [10]. Findings suggestive of mesothelioma are the involvement of the fissural
pleura, the presence of bilateral symmetrical pleural plaques or a rounded atelectasis in the
lower lobe, the sequel of prior benign pleurisy. CT scans typically underestimate the magnitude
of involvement in the soft tissue structures of the chest wall and mediastinum.
The presence of free pleural fluid, the operator’s expertise and the availability of technical
equipment are decisive factors in the choice of the diagnostic procedure. In the presence of free
pleural fluid, thoracoscopic biopsy has a pooled sensitivity 92.6% [11], with video-assisted
thoracic surgery and medical thoracoscopy having a diagnostic equipoise. In a randomised trial,
the sensitivity of thoracoscopy was 94.1 versus 87.5% for CT-guided biopsy [12]. In the
absence of (free) pleural fluid or when a contrast-enhanced thoracic CT scan of a patient shows
a focal area of abnormal pleura (with or without a pleural effusion), image-guided cutting
needle biopsy is preferred, either CT-guided, with a yield of 83–86%, or ultrasound-guided,
with an overall yield of 70–94%.
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Diagnostic and molecular pathology

Histopathological examination of mesothelioma usually shows malignant cells that form a
diffuse or nodular pattern, which are composed of cuboidal or columnar cells with abundant
eosinophilic cytoplasm and elongated nuclei. The tumour cells may also form papillary
structures and invade the surrounding tissue. Mesothelioma is classified into three subtypes
based on the morphology of the tumour cells: epithelioid, sarcomatoid and biphasic. The
epithelioid subtype is the most common and has a better prognosis than the other subtypes.
Cytological evaluation of pleural fluid is insufficiently sensitive, as it misses the hallmark
characteristic of invasiveness of cancer through the basal membrane or in the pleural fat.
Whenever a definitive histological diagnosis is needed and a treatment is considered, biopsies
offer a better opportunity to reach a definitive diagnosis. Cytology can be sufficient to prove
relapse or the presence of a metastasis of an otherwise diagnosed mesothelioma, or in cases that
are beyond any therapeutic implication. The 5th Edition of the WHO classification is
recommended, because it provides a comparative basis for diagnosis, prognosis and therapeutic
management of the patient [13]. Besides conventional stains for light microscopy, an
appropriate immunohistochemistry panel is required with positive and negative stains to allow
diagnosis and differentiation in epithelioid and non-epithelioid subtypes. The loss of BAP-1
expression by immunohistochemistry and/or CDKN2A ( p16) homozygous deletion may allow
the discrimination from benign pleural lesions and metastatic carcinoma.
The genomic landscape of mesothelioma is quite heterogeneous. Both germline and somatic
mutations are described in literature, and tumour development is mostly driven by inactivation
of tumour suppressor genes (TSGs), rather than by oncogene activation 1 [14]. Mutations occur
in >19 genes, but alterations in BAP1, CDKN2A, CDKN2B, NF2, MTAP, TP53 and SETD2
have a prevalence in ⩾10% of patients, with BAP1, CDKN2A and NF2 being the most common
TSGs. As well as single nucleotide polymorphisms that inactivate TSGs, copy number
alterations also occur in ⩾15% of malignant pleural mesotheliomas [15]. Most common copy
number losses occur in chromosomes 3p (BAP1), 9p (CDKN2A) and 22q (NF2), but multiple
regions with copy number gains, harbouring interesting cancer-associated genes, have also been
observed. Taken by themselves, these genetic alterations do not form the potential to be
malignant pleural mesothelioma-specific biomarkers. However, by combining them, a
mesothelioma-specific mutational pattern may be found.
Prognosis and prognostic factors, biomarkers and (re-)staging

Untreated cases of mesothelioma have a grim prognosis with a median survival of 6–9 months
and few 5-year survivors. The clinical factors that are associated with a worse prognosis
for mesothelioma include older age, male gender, smoking history and poor performance
status. Patients who have a longer duration of symptoms, a larger tumour size and the presence of
chest pain are also associated with a worse prognosis. Disease extent and histological subtype are
independent tumoural prognostic factors. Several biomarkers have been reported for screening,
diagnostic, prognostic or predictive purposes, either from tumour tissue, blood, pleural fluid,
urine or exhaled breath. With the sole exception of serum mesothelin, which has obtained US
Food and Drug Administration (FDA) approval as a marker of treatment response, none of the
single circulating biomarkers has reached adequate accuracy to ensure its use in clinical use [16].
As mesothelioma is a heterogeneous tumour, a combination of different markers could contribute
to improve diagnostic accuracy. Currently, none of these biomarkers is recommended for
diagnosis, screening or treatment allocation. Although the decision process may be helped by
other prognostic factors and scoring systems, these cannot be applied on an individual basis
outside clinical trials, as they have not been validated for this purpose.
https://doi.org/10.1183/2312508X.10019722 371
TABLE 1 TNM definitions and stage groupings for pleural mesothelioma

T – Primary tumour
T1 Tumour involving the ipsilateral parietal or visceral pleura only
T2 Tumour involving ipsilateral pleura (parietal or visceral pleura) with invasion involving at least one of
the following:
Diaphragmatic muscle
Pulmonary parenchyma
T3 Tumour involving ipsilateral pleura (parietal of visceral pleura) with invasion involving at least one of
the following:
Endothoracic fascia
Mediastinal fat
Chest wall, with or without associated rib destruction (solitary, resectable)
Pericardium (non-transmural invasion)
T4 Tumour involving ipsilateral pleura (parietal or visceral pleura) with invasion involving at least one of
the following:
Chest wall, with or without associated rib destruction (diffuse or multifocal, unresectable)
Peritoneum (via direct transdiaphragmatic extension)
Contralateral pleura
Mediastinal organs (oesophagus, trachea, heart, great vessels)
Vertebra, neuroforamen, spinal cord or brachial plexus
Pericardium (transmural invasion with or without a pericardial effusion)
N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasised
N1 Metastases to ipsilateral intrathoracic lymph nodes (includes ipsilateral bronchopulmonary, hilar,
subcarinal, paratracheal, aortopulmonary, paraoesophageal, peridiaphragmatic, pericardial,
intercostal and internal mammary nodes)
N2 Metastases to contralateral intrathoracic lymph nodes
Metastases to ipsilateral or contralateral supraclavicular lymph nodes
M – Distant metastasis
M0 No distant metastasis
M1 Distant metastasis present
The current edition of the American Joint Committee on Cancer (AJCC)/Union for International
Cancer Control (UICC) classification remains difficult to apply to clinical staging with respect to
both T and N components, and thus may be imprecise in predicting prognosis and for allocating
treatment (table 1) [17]. The ongoing analysis of the prospective database by the International
Association for the Study of Lung Cancer (IASLC) staging subcommittee on mesothelioma will
hopefully improve on this weakness by assessing tumour volume and thickness measured at three
levels of the hemithorax. This will inform the 9th revision of the UICC’s TNM (tumour, node
and metastasis) staging system, which is scheduled to be in use in January 2024. The extent of the
staging procedures is determined by the initial assessment of the patient’s fitness for treatment.
Other factors include the histotype of the tumour and TNM staging.
A summary of noninvasive staging is presented in figure 4. If radical therapy is considered,

CT-scan-occult nodal and distant metastases should be excluded using positron emission
tomography, and the absence of extension in critical mediastinal structures should be confirmed
using MRI, ultrasound or endoscopic procedures.
In patients treated with chemotherapy, adoption of the modified RECIST (Response Evaluation
Criteria in Solid Tumours) 1.1 for mesothelioma is recommended, to harmonise the application
372 https://doi.org/10.1183/2312508X.10019722
Basic staging: Staging in those Further staging in

all patients fit for suitable for surgery those of borderline
treatment# and chemotherapy resectability prior
to radical surgery
Chest/abdominal
±brain (if clinical
signs)
(FDG)¶ MRI
PET-CT
Laparoscopy/
CT contralateral VATS
Chest radiography
thorax/abdomen
EBUS/EUS Mediastinoscopy
FIGURE 4 A staging algorithm for patients with malignant pleural mesothelioma. FDG: fluorodeoxyglucose; PET:
positron emission tomography; EBUS: endobronchial ultrasound; EUS: endoscopic ultrasound; VATS:
video-assisted thoracic surgery. #: including patients unfit for any tumour-directed treatment but deriving benefit
from palliative procedures (e.g. pleurodesis). ¶: after talcage, PET-CT is less accurate than functional MRI.
of tumour measurement and response assessment across clinical trials [18]. These criteria will
have to be adapted to become suitable for patients treated with immunotherapy, which has since
become the new standard of care (see Mesothelioma treatment section).
Mesothelioma treatment
Recent therapeutic developments create new potential for patients – specialised treatments in
specialised centres after thorough discussion in a multidisciplinary team with experience in
mesothelioma. As treatments can be associated with severe morbidity or even mortality,
treatment decisions should be shared and should take patient preferences into account. An
algorithm of management is presented in figure 5. For the purposes of this chapter, we hereafter
focus on established treatments only.
Systemic treatment: first-line treatment

The phase III Checkmate (CM)743 study opened up the possibility of a chemotherapy-free
regimen as first-line treatment for patients with mesothelioma [19]. In the study, 605
unresectable, treatment-naïve patients with either epithelioid or non-epithelioid mesothelioma of
good performance status were randomised to either standard chemotherapy with platinum
pemetrexed for up to six cycles or a combination treatment of nivolumab (3 mg·kg−1 every
2 weeks) and ipilimumab (1 mg·kg−1 every 6 weeks) for a maximum of 2 years. The primary
endpoint of overall survival (OS) was met with a hazard ratio (HR) of 0.74 (95% CI 0.61–0.89;
p=0.002) for the population as a whole. Interestingly, the OS was similar for patients of either
histology who were randomised to immunotherapy, whilst chemotherapy was less effective in
patients with non-epithelioid histology. In recently published 3-year OS data, it was shown that
23% of patients treated with immunotherapy were still alive, whilst this was only true of 15% of
patients on chemotherapy [20]. 14% of the patients who survived for 3 years were without
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374

Diagnosis Malignant pleural mesothelioma
Asbestos exposure?
Minimal biology tests and cardiorespiratory evaluation
Pretreatment Malignant pleural mesothelioma
+ basic staging for all patients fit for treatment:
work-up compensation according to
chest/abdomen CT scan (with iodine contrast)
state law
Patients suitable for multimodal treatment including surgery with MCR
Yes No
Staging and patient allocation Patient suitable for medical treatment?
Yes No
https://doi.org/10.1183/2312508X.10019722
First-line dual
Multimodal treatment
nivolumab-ipilimumab Best supportive care only,
including MCR
Treatment immunotherapy or including palliative
(in expert centres only,
platinum-pemetrexed radiotherapy if necessary
within a RCT if possible)
chemotherapy
FIGURE 5 Algorithm for the management of patients with malignant pleural mesothelioma. MCR: macroscopic complete resection; RCT: randomised controlled trial.
progression after immunotherapy; only 1% of chemotherapy-treated patients were without

progression. In the original analysis no difference was found in progression-free survival (PFS)
or response rate between chemotherapy and immunotherapy.
Combination immunotherapy of this kind is accompanied by significant toxicity, with 30% of

patients experiencing grade 3–4 toxicity and 23% discontinuing treatment due to toxicity. The
quantity of patients with grade 3–4 toxicity is equal to that found in chemotherapy; autoimmune
toxicity in immunotherapy has a different profile and haematological toxicity is greater during
chemotherapy.
Based on these results, nivolumab plus ipilimumab is now approved as first-line treatment for
mesothelioma of all histologies, without biomarker restriction by the European Medicines
Agency (EMA) or the FDA.
The comparator arm as the standard of care in this study by PETERS et al. [20] was platinum
pemetrexed. This treatment was based on two large, randomised trials showing a survival
benefit of an anti-folate combined with cisplatin compared to cisplatin monotherapy [21, 22].
Both studies used a different anti-folate – pemetrexed or raltitrexed – and showed a survival
benefit compared with monotherapy (mean OS 12.1 versus 9.3 months and 11.4 versus
8.8 months, respectively). Owing to these studies, this combination treatment has become the
standard of care for patients during the last 20 years. Later, the efficacy of cisplatin and
carboplatin was found to be equal, and this is now used an alternative treatment [23].
The choice between the “old” standard of platinum anti-folate or immunotherapy, or best
supportive care must be based on shared decision-making with the patient after thorough discussion
with a multidisciplinary team about the potential benefits and harms of the different treatment
options. We recently gathered real world data in a cohort of patients treated with immunotherapy
and noted a high proportion of grade 3–4 toxicity leading to significant morbidity and mortality
(unpublished data). Given this higher number of toxicity, as for other malignancies, we advocate
centralised treatment of patients with mesothelioma who start treatment with immunotherapy.
Although platinum pemetrexed was the standard of care in the CM743 study, in the French MAPS
(Mesothelioma Avastin Cisplatin Pemetrexed Study) study it was shown that the combination of
this chemotherapy regimen and an angiogenesis inhibitor (bevacizumab) had superiority in terms
of OS compared with chemotherapy alone (increase from 16.1 to 18.8 months, HR 0.77, 95% CI
0.62–0.95), with minimal increases in toxicity and no impact on quality of life [24]. However, this
combination treatment has not been submitted for regulatory approval.
Although pemetrexed is the standard of care in nonsmall-cell lung cancer maintenance, no

benefits have been established for this treatment in mesothelioma [25]. Gemcitabine after
induction treatment with platinum pemetrexed proved beneficial with regard to the PFS but not
OS. PFS increased from a median of 3.2 months (95% CI 2.8–4.1) to 6.2 months (95% CI 4.6–8.7,
HR 0.48 95% 0.33–0.71).
Second-line treatment
The introduction of immunotherapy without chemotherapy as first-line treatment opens up the
possibility of platinum pemetrexed as potential second-line treatment. To the best of our
knowledge, no data on the efficacy and toxicity of this treatment are available in this setting.
Retreatment with platinum pemetrexed after a certain interval seems a potential option in
patients who achieved an earlier benefit with this regimen [26]. Historically, gemcitabine and
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vinorelbine have been used as second-line treatments without real clear scientific data. The
PROMISE-meso trial investigated pembrolizumab (PD-1) monotherapy versus either of these
chemotherapy regimens, but found no difference in PFS or OS [27]. The CONFIRM study
showed a survival benefit when comparing the PD-1 checkpoint inhibitor nivolumab to best
supportive care [28].
The role of surgical treatment in mesothelioma

Surgical series in mesothelioma tend to overestimate the effect of resection and are subject to
several kinds of biases [29]. Surgery, with the aim of complete macroscopic resection, includes an
extrapleural pleuropneumonectomy or a lung parenchyma sparing (extended) pleurectomy/
decortication. The latter procedure is currently favoured in view of its lower morbidity and
mortality and similar outcome. The choice of whether to perform surgery and the type of operation
performed is based on shared decision-making with the patient after thorough discussion in a
specialised multidisciplinary board meeting. Surgery should always be part of a multimodality
treatment with the potential inclusion of chemotherapy, immunotherapy and/or radiotherapy. The
optimal timing of the different modalities is currently the subject of ongoing clinical trials [30].
Radiotherapy
Modern techniques offer the potential of delivering high dosages of radiotherapy with acceptable
side-effects to patients. As mentioned above, adjuvant radiotherapy can be part of the
multimodality treatment. Neo-adjuvant radiotherapy still has to be considered as experimental. As
this is an evolving field and only performed in specialised centres, no standard regimen for
radiotherapy can be provided here. Theoretically, proton therapy may be beneficial to reducing
side-effects even further, but data are on this are still scarce.
Apart from the high radical dosages, radiotherapy can also be used for palliation of symptoms.
Prophylactic irradiation of instrumentation tracks has been abandoned and is no longer the
standard of care [31].
As mesothelioma is so difficult to treat, the care team should also focus on end-of-life planning.
Patients experience specific support needs, which require collaboration between a
multidisciplinary team both in the hospital setting and in the home [32].
Future prospects
Rodent transgenic models of mesothelioma help develop understanding of the biology of this
highly lethal cancer [33]. The relatively fast development of mesothelioma when the appropriate
combination of lesions is introduced, with or without exposure to asbestos, make the mouse
models particularly useful for testing new treatment strategies in an immunocompetent setting.
In contrast, patient-derived xenograft models are particularly useful for assessing the effects of
inter- and intra-tumour heterogeneity and human-specific features of mesothelioma. New
insights obtained by studying these experimental systems will lead to more effective treatments
for this devastating disease.
Organoids, an in vitro “organ-like” three-dimensional structure derived from patient tumour

tissue that faithfully mimics the biology and complex architecture of cancer and largely
overcomes the limitations of other existing models, are the next-generation tumour model [34].
Although the development of mesothelioma organoids is still in its infancy, their potential for
understanding pathobiology, discovering new therapeutic targets and developing personalised
treatments is promising.
376 https://doi.org/10.1183/2312508X.10019722
Despite the efficacy of immunotherapy, major improvements have to be made to increase its
benefits to a larger proportion of patients for a longer duration. Multiple ongoing studies are
investigating novel combination treatments with different immunotherapy agents, the addition of
chemotherapy or cellular therapy. In a single-arm phase 2 study, the combination of pemetrexed
platin and the anti-PD-L1 checkpoint inhibitor durvalumab was promising [35]. This has now been
tested in a multicentre phase III study, which compares this regimen to chemotherapy alone [36].
Cellular therapy is an interesting concept in immunological ignorant tumours such as

mesothelioma in terms of enhancing immune activation.
Various different cell types targeting different antigens are under investigation. For example,
ADUSUMILLI et al. [37] successfully generated a chimeric antigen receptor T-cell that can be
delivered locally at the tumour site, with signs of efficacy in early clinical studies. We have
investigated the value of a dendritic cell-based vaccine in mesothelioma, where we load the
dendritic cell with a broad spectrum of tumour-associated antigens generated from cell lines
[38]. The therapy was proven safe and radiographical responses were established [38]. These
treatments can be combined with PD-1 [39].
Small molecules targeting molecular aberrations are also in clinical development. These
molecular aberrations were reviewed by YAP et al. [40]. Currently, several potential targeted
therapies are under development, both in clinical trials and in preclinical phases. These potential
drugs inhibit molecules in the pathways downstream from the most commonly mutated genes
(BAP1, CDKN2A and NF2) [14].
Prevention and screening

In view of the strong causal relation between the exposure to asbestos and the incidence rate of
mesothelioma, banning the use of asbestos is the most sensible measure authorities should take.
Countries ban asbestos for the purpose of eliminating the future burden of asbestos-related
diseases. However, it has been proposed that countries also ban asbestos as a consequence of
the mesothelioma burden. Asbestos is banned in 54 countries but 144 still have not prohibited
its import and/or use [41]. Among the latter are the USA, India, Indonesia, Nigeria and China,
accounting for more than half of the world’s population. The continued harm caused by
asbestos cannot be reduced without ceasing all asbestos mining and trade, increasing public
awareness, enforcing regulations and improving diagnosis and treatment [42].
The need for chemopreventive approaches is highlighted by the poor survival rates of patients
with mesothelioma and the long interval between first asbestos exposure and mesothelioma
diagnosis. Randomised chemoprevention studies in asbestos-exposed individuals using vitamins,
antioxidants and anti-inflammatory drugs have not shown positive results; unfortunately, cancers
were more common among participants receiving the antioxidant beta-carotene [43].
Targeted screening for mesothelioma can be performed in populations at high risk by: collecting
various biomarkers from body fluids and volatile compounds from exhaled breath; or by chest
imaging. Neither approach has yielded success so far, although several promising molecules are
currently being evaluated at the clinical utility stage of development. A prospective, multicentre,
cross-sectional study of 2132 subjects with asbestos exposure enrolled between 2010 and 2012,
used a low-dose CT scan [44]. Pathological diagnosis of lung cancer was confirmed in 45
(2.1%) cases and in pleural mesothelioma was found in seven (0.3%) cases. In previous studies,
two and zero cases of malignant pleural mesothelioma were identified in 516 and 1045
https://doi.org/10.1183/2312508X.10019722 377
asbestos-exposed workers, respectively [45, 46]. Despite little evidence of efficacy in

randomised trials, asbestos-exposed workers are currently offered routine periodic CT scans in
Germany and France. The results of these surveillance series are expected.
Living with mesothelioma

Pleural mesothelioma is a physically and morally devastating disease, occurring mostly in
middle-aged people with comorbid disease, around or after their retirement from a profession in
which they were unintentionally exposed to the carcinogen. Although several countries have set
up compensation programmes (e.g. recognition as an occupational disease and/or compensation
from asbestos victims’ funds), the literature suggests that mesothelioma cases are
undercompensated. Their high mortality, poor survival, lower educational background and
senior age mean victims are less likely to dispute lack acknowledgement alongside patient
advocacy groups.
Conclusion
Despite being called a rare disease, the condition’s impact on the total number of deaths in the
coming decades and the death rate of the disease due to therapy resistance mean mesothelioma
is actually impactful. Although progress is relatively slow, recent insights into the
pathophysiology and impact of different treatments on outcome have renewed hope of a better
outcome for patients. It is the responsibility of clinicians and researchers to collaborate in order
to speed up these developments and improve outcome.
References
1 Scherpereel A, Opitz I, Berghmans T, et al. ERS/ESTS/EACTS/ESTRO guidelines for the management of
malignant pleural mesothelioma. Eur Respir J 2020; 55: 1900953.
2 Kindler HL, Ismaila N, Armato SG, III, et al. Treatment of malignant pleural mesothelioma: American Society of
Clinical Oncology clinical practice guideline. J Clin Oncol 2018; 36: 1343–1373.
3 Woolhouse I, Bishop L, Darlison L, et al. British Thoracic Society Guideline for the investigation and
management of malignant pleural mesothelioma. Thorax 2018; 73: Suppl. 1, i1–i30.
4 Huang J, Chan SC, Pang WS, et al. Global incidence, risk factors, and temporal trends of mesothelioma:
a population-based study. J Thorac Oncol 2023; 18: 792–802.
5 International Agency for Research on Cancer. Monographs on the evaluation of carcinogenic risks to humans.
http://monographs.iarc.fr/ENG/Classification/index.php
6 van Zandwijk N, Rasko JE, George AM, et al. The silent malignant mesothelioma epidemic: a call to action.
Lancet Oncol 2022; 23: 1245–1248.
7 Carbone M, Pass HI, Ak G, et al. Medical and surgical care of mesothelioma patients and their relatives carrying
germline BAP1 mutations. J Thorac Oncol 2022; 17: 873–889.
8 Zhai Z, Ruan J, Zheng Y, et al. Assessment of global trends in the diagnosis of mesothelioma from 1990 to
2017. JAMA Netw Open 2021; 4: e2120360.
9 Visci G, Rizzello E, Zunarelli C, et al. Relationship between exposure to ionizing radiation and mesothelioma
risk: a systematic review of the scientific literature and metaanalysis. Cancer Med 2022; 11: 778–789.
10 Wang ZJ, Reddy GP, Gotway MB, et al. Malignant pleural mesothelioma: evaluation with CT, MR imaging, and
PET. Radiographics 2004; 24: 105–119.
11 Bibby AC, Dorn P, Psallidas I, et al. ERS/EACTS statement on the management of malignant pleural effusions.
Eur J Cardiothorac Surg 2019; 55: 116–132.
12 Mohamed EE, Talaat IM, Abd Alla AEDAA, et al. Diagnosis of exudative pleural effusion using ultrasound guided
versus medical thoracoscopic pleural biopsy. Egypt J Chest Dis Tuberc 2013; 62: 607–615.
13 Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization classification of lung tumors:
impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015; 10: 1243–1260.
14 Paajanen J, Bueno R, De Rienzo A. The rocky road from preclinical findings to successful targeted therapy in
pleural mesothelioma. Int J Mol Sci 2022; 23: 13422.
15 Hylebos M, Van Camp G, Vandeweyer G, et al. Large-scale copy number analysis reveals variations in genes not
previously associated with malignant pleural mesothelioma. Oncotarget 2017; 8: 113673–113686.
378 https://doi.org/10.1183/2312508X.10019722
16 Viscardi G, Di Natale D, Fasano M, et al. Circulating biomarkers in malignant pleural mesothelioma. Explor
Target Antitumor Ther 2020; 1: 434–451.
17 Nowak AK, Chansky K, Rice DC, et al. The IASLC mesothelioma staging project: proposals for revisions of the
T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma. J Thorac
Oncol 2016; 11: 2089–2099.
18 Armato SG III, Nowak AK. Revised modified response evaluation criteria in solid tumors for assessment of
response in malignant pleural mesothelioma (version 1.1). J Thorac Oncol 2018; 13: 1012–1021.
19 Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural
mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. The Lancet 2021; 397:
375–386.
20 Peters S, Scherpereel A, Cornelissen R, et al. LBA65 First-line nivolumab (NIVO) plus ipilimumab (IPI) vs
chemotherapy (chemo) in patients ( pts) with unresectable malignant pleural mesothelioma (MPM): 3-year
update from CheckMate 743. Ann Oncol 2021; 32: S1341–S1342.
21 Vogelzang NJ, Rusthoven J, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin
versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636–2644.
22 van Meerbeeck JP, Gaafar R, Manegold C, et al. Randomized phase III study of cisplatin with or without
raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation
for Research and Treatment of Cancer, Lung Cancer Group and the National Cancer Institute of Canada. J Clin
Oncol 2005; 23: 6881–6889.
23 Taylor P, Castagneto B, Dark G, et al. Single-agent pemetrexed for chemonaïve and pretreated patients with
malignant pleural mesothelioma: results of an International Expanded Access Program. J Thorac Oncol 2008; 3:
764–771.
24 Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the
Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
The Lancet 2016; 387: 1405–1414.
25 Dudek AZ, Wang X, Gu L, et al. Randomized study of maintenance pemetrexed versus observation for treatment
of malignant pleural mesothelioma: CALGB 30901. Clin Lung Cancer 2020; 21: 553–561.e1.
26 Petrelli F, Ardito R, Conti B, et al. A systematic review and meta-analysis of second-line therapies for treatment
of mesothelioma. Respir Med 2018; 141: 72–80.
27 Popat S, Curioni-Fontecedro A, Dafni U, et al. A multicentre randomised phase III trial comparing
pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma:
the European Thoracic Oncology Platform (ETOP 9–15) PROMISE-meso trial. Ann Oncol 2020; 31: 1734–1745.
28 Fennell DA, Ewings S, Ottensmeier C, et al. Nivolumab versus placebo in patients with relapsed malignant
mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 2021; 22: 1530–1540.
29 Raskin J, Van Schil PEY, Van Meerbeeck JP. Surgical series in mesothelioma: navigating between biases.
Translat Lung Cancer Res 2023; 12: 184–186.
30 Burt BM, Ripley RT, Groth SS. To slay a dragon: timing of chemotherapy in resectable pleural mesothelioma.
J Thorac Cardiovasc Surg 2019; 157: 767–768.
31 Clive AO, Taylor H, Dobson L, et al. Prophylactic radiotherapy for the prevention of procedure-tract metastases
after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre,
open-label, phase 3, randomised controlled trial. Lancet Oncol 2016; 17: 1094–1104.
32 Frissen AR, Burgers S, van der Zwan JM, et al. Experiences of healthcare professionals with support for
mesothelioma patients and their relatives: identified gaps and improvements for care. Eur J Cancer Care 2021;
30: e13509.
33 Testa JR, Berns A. Preclinical models of malignant mesothelioma. Front Oncol 2020; 10: 101.
34 Gao Y, Kruithof-de Julio M, Peng RW, et al. Organoids as a model for precision medicine in malignant pleural
mesothelioma: where are we today? Cancers (Basel) 2022; 14: 3758.
35 Nowak AK, Lesterhuis WJ, Kok PS, et al. Durvalumab with first-line chemotherapy in previously untreated
malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in. Lancet
Oncol 2020; 21: 1213–1223.
36 Forde PM, Anagnostou V, Sun Z, et al. Durvalumab with platinum-pemetrexed for unresectable pleural
mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial. Nat Med 2021; 27:
1910–1920.
37 Adusumilli PS, Zauderer MG, Rivière I, et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in
patients with malignant pleural disease, in combination with the antiPD1 agent pembrolizumab. Cancer Discov
2021; 11: 2748–2763.
38 Aerts JG, de Goeje PL, Cornelissen R, et al. Autologous dendritic cells pulsed with allogeneic tumor cell lysate
in mesothelioma: from mouse to human. Clin Cancer Res 2018; 24: 766–776.
39 van Gulijk M, Belderbos B, Dumoulin D, et al. Combination of PD1/PDL1 checkpoint inhibition and dendritic
cell therapy in mice models and in patients with mesothelioma. Int J Cancer 2023; 152: 1438–1443.
https://doi.org/10.1183/2312508X.10019722 379
40 Yap TA, Aerts JG, Popat S, et al. Novel insights into mesothelioma biology and implications for therapy. Nat Rev
Cancer 2017; 17: 475–488.
41 Chimed-Ochir O, Rath EM, Kubo T, et al. Must countries shoulder the burden of mesothelioma to ban asbestos?
A global assessment. BMJ Global Health 2022; 7: e010553.
42 Furuya S, Chimed-Ochir O, Takahashi K, et al. Global asbestos disaster. Int J Environ Res Public Health 2018;
15: 1000.
43 Merler E, Buiatti E, Vainio H. Surveillance and intervention studies on respiratory cancers in asbestos-exposed
workers. Scand J Work Environ Health 1997; 23: 83–92.
44 Kato K, Gemba K, Ashizawa K, et al. Low-dose chest computed tomography screening of subjects exposed to
asbestos. Eur J Radiol 2018; 101: 124–128.
45 Roberts HC, Patsios DA, Paul NS, et al. Screening for malignant pleural mesothelioma and lung cancer in
individuals with a history of asbestos exposure. J Thorac Oncol 2009; 4: 620–268.
46 Fasola G, Belvedere O, Aita M, et al. Lowdose computed tomography screening for lung cancer and pleural
mesothelioma in an asbestosexposed population: baseline results of a prospective, nonrandomized feasibility
trial – an Alpeadria Thoracic Oncology Multidisciplinary Group Study (ATOM 002). Oncologist 2007; 12: 1215–1224.
Disclosures: J.G.J.V Aerts reports receiving consultancy and speakers’ fees from MSD, AstraZeneca, Takeda, BMS,
Amphera, Eli-Lilly and BIOCAD. J.G.J.V Aerts owns stocks in Amphera. J.P. van Meerbeeck reports receiving
personal speakers’ fees from BMS and institutional fees from BMS and Amphera BV.
380 https://doi.org/10.1183/2312508X.10019722
ERS monograph
Rare Diseases of the Respiratory System

ERS monograph
Diagnosing rare diseases can be challenging, and treating
these conditions is complex
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Respiratory System
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address this, the
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European Respiratory Society (ERS) has published Rare
Diseases of the Respiratory System. Structured into thematic Edited by Thomas O.F. Wagner,
sections, the book covers: the identification of rare diseases
of the respiratory system and their differential diagnosis; Marc Humbert, Marlies Wijsenbeek,
rare diseases of the lung interstitium; rare diseases of the
airways or alveoli; and rare pulmonary vascular diseases. The
Guest Editors and authors belong to and/or support the vision
and mission of the European Reference Network for Rare
Diseases of the Respiratory System (ERN-LUNG), which offers
expert support to both patients and professionals. As such,
this comprehensive book will prove an excellent resource for
healthcare professionals, researchers and students interested
in rare diseases of the respiratory system.
ERS monograph 100
ISBN 978-1-84984-166-5
Print ISBN: 978-1-84984-166-5
Online ISBN: 978-1-84984-167-2
June 2023
€60.00
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Rare Diseases of The Respiratory System

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ERS monograph

Rare Diseases of the Respiratory System

This book is one in a series of ERS Monographs. Each individual issue

ERS Monographs are available online at books.ersjournals.com and print

Managing Editor: Rachel Gozzard

Published by European Respiratory Society ©2023

Guest Editors viii

List of abbreviations xiv

1. How to identify rare diseases of the respiratory system 1

2. Differential diagnosis of reciprocal mimics of neoplastic and 10

Rare diseases of the lung interstitium

4. Rare interstitial lung diseases of environmental origin 40

5. Amyloidosis and the lungs and airways 53

6. Diffuse cystic lung diseases including lymphangioleiomyomatosis 69

Rare disease of the airways or alveoli

8. Pulmonary alveolar proteinosis 103

9. Primary ciliary dyskinesia 118

10. Cystic fibrosis and other ion channel-related diseases 135

12. α1-Antitrypsin deficiency and other rare forms of emphysema 165

Pulmonary vascular diseases

14. Chronic thromboembolic pulmonary hypertension 192

15. Pulmonary hypertension in orphan lung diseases 204

16. Hepatopulmonary syndrome: a liver-induced oxygenation defect 224

Rare lung diseases in systemic inflammatory disorders

18. ANCA-associated vasculitis and other pulmonary haemorrhage 254

19. Eosinophilic granulomatosis with polyangiitis 267

20. Idiopathic eosinophilic pneumonias 281

21. Sarcoidosis 293

22. Granulomatous and lymphocytic interstitial lung disease in common 310

Other rare lung diseases

24. Chronic lung allograft dysfunction after lung transplantation 331

26. Rare diseases of respiratory drive 357

27. Pleural mesothelioma 367

Peter M.A. Calverley

Welcome to this, the 100th issue of the ERS Monograph. The

Although they are individually infrequent, taken together, one or more

This volume is timely, not just because it marks an important milestone

Disclosures: P.M.A. Calverley reports receiving grants, personal fees and

Thomas O.F. Wagner is a professor of internal medicine, and from

Thomas received his medical and research training at Bonn

Thomas’ main research activities include lung transplantation,

Thomas is the Coordinator of the European Reference Network for

Since his active role in a European pilot project in RD networking

Marc Humbert is Dean and Professor of Respiratory Medicine at

Marc is Past President of the European Respiratory Society (ERS).

Marc has received several distinctions, including the 2006 ERS

Since 2017, Marc has been the Vice-Coordinator of the European

In 2018, Clarivate Analytics listed Marc as one of the world’s most

Marlies Wijsenbeek is a pulmonary physician and Professor of

Marlies’ research interests include e-health, patient-centred outcome

Marlies is Chair of the Idiopathic Interstitial Pneumonia Group of

Michael Kreuter is Director of the Lung Center Mainz (Mainz,

Michael is board certified in internal medicine, pulmonology and

Michael’s clinical and scientific interest focuses on interstitial and

Helge Hebestreit is Professor and Vice Director of Paediatrics,

Helge’s main research interests include: health service research in

Corresponding author: T.O.F. Wagner (t.wagner@em.uni-frankfurt.de)

ANCA antineutrophil cytoplasmic autoantibodies