Rare Diseases of the Respiratory System 9781849841665, 9781849841672

Table of contents :
Preface
Guest Editors
Thomas O.F. Wagner
Marc Humbert
Marlies Wijsenbeek
Michael Kreuter
Helge Hebestreit
Introduction
References
How to identify rare diseases of the respiratory system
Abstract
Introduction
Clinical clues
Measures of respiratory function at rest and during exercise
Laboratory values
Imaging
BAL
Histology
Next-generation sequencing
Artificial intelligence and clinical decision support systems
Case conferences
Conclusion
References
Differential diagnosis of reciprocal mimics of neoplastic and non-neoplastic pulmonary disorders: multidisciplinary approaches
Abstract
Introduction
Cancers mimicking orphan lung diseases at imaging
Cancer mimics of organising pneumonia
Lung adenocarcinoma/bronchioloalveolar carcinoma
Primary pulmonary lymphoma
Cancer mimics of ILDs
Lymphangitic carcinomatosis
Lymphomatoid granulomatosis
EHE and angiosarcoma
Cancer mimics of multiple cystic/cavitary lung disorders
Cancer mimics of PH
Lung “pseudo”-myofibroblastic tumours
Borderline neoplastic/non-neoplastic disorders
Respiratory tract papillomatosis
Amyloid and nonamyloid immunoglobulin deposition disorders
Pulmonary Langerhans cell histiocytosis
Lessons learned: rare tumours versus orphan lung diseases
Conclusion
References
Interstitial lung diseases: an overview
Abstract
Introduction
Classification and epidemiology of ILDs
Pathogenesis of ILDs
Genetics
Inflammation
Fibrosis
Diagnosis of ILDs
Disease course of ILDs, definition of PPF and prognosis
Management
Pharmacological management
Supportive and non-pharmacological management
Lung transplantation
The future of ILDs and concluding remarks
References
Rare interstitial lung diseases of environmental origin
Abstract
Introduction
Hypersensitivity pneumonitis
Definition
Epidemiology
Pathogenesis
Diagnosis and treatment
Prognosis
Pneumoconiosis
Definition
Epidemiology
Pathogenesis
Diagnosis and treatment
Prognosis and prevention
Specific environments and exposures associated with rare ILDs
Farming
Food manufacturing
Textile manufacturing
Nanoparticles
Indium lung
Effects of environmental exposure on other ILDs
References
Amyloidosis and the lungs and airways
Abstract
Introduction
Diagnosis of amyloidosis
Systemic AA amyloidosis
Systemic AL amyloidosis
Localised amyloidosis
Laryngeal amyloidosis
Tracheobronchial amyloidosis
Parenchymal pulmonary amyloidosis
Amyloidosis in Sjögren syndrome
Amyloid lymphadenopathy
Pleural amyloidosis
Conclusion
References
Diffuse cystic lung diseases including lymphangioleiomyomatosis
Abstract
Introduction
Radiological features
Clinical management
LAM
Pathogenesis
Clinical manifestation and diagnosis
Treatment: present and future
PLCH
Pathogenesis
Clinical manifestation and diagnosis
Treatment
BHD
Pathogenesis
Clinical manifestation and diagnosis
Conclusion
References
Bronchiolitis
Abstract
Introduction
Aetiology and histopathology
Cellular bronchiolitis
Acute bronchiolitis
Chronic bronchiolitis
Follicular bronchiolitis
Lymphocytic bronchiolitis
Eosinophilic bronchiolitis
Granulomatous bronchiolitis
Chronic aspiration bronchiolitis
Diffuse panbronchiolitis
Proliferative bronchiolitis
CB
Clinical aspects
Imaging
Diagnostic approach
Specific forms of bronchiolitis
Exposure-related bronchiolitis
Mineral dust-associated diseases
Diffuse bronchiolar disease as a result of chronic occult aspiration
Infectious bronchiolitis
Postinfectious bronchiolitis
Bronchiolar complications of CTDs
PAMS
Post-transplant bronchiolitis obliterans syndrome
Drugs associated with bronchiolitis
IBD
DPB
EB
Respiratory bronchiolitis
Rare genetic disorders
Idiopathic OB
References
Pulmonary alveolar proteinosis
Abstract
Introduction
Pathophysiology
Epidemiology
Clinical features
Clinical presentation
Pulmonary infections
Pulmonary fibrosis
Diagnostic approach
PFTs
Radiology
Bronchoscopy and biopsy
Laboratory investigations
Management
WLL
GM-CSF augmentation therapy
Therapies targeting autoantibodies to GM-CSF
Emerging therapies
LTx
Future directions and advances in PAP
References
Primary ciliary dyskinesia
Abstract
Introduction
Classical clinical presentation of PCD
Noncharacteristic phenotypes associated with PCD
Motile cilia
Genetics of PCD
Diagnostic workflow
Medical history
Family history
Individual medical history
Imaging diagnostics in PCD care
Further diagnostics of the airways
Diagnostic methods
Nasal nitrite oxide measurements
High-speed videomicroscopy
Electron microscopy
IF analysis
ALI culture
Genetic analysis
Predictive tools for PCD
Treatment of PCD
Lower airways
Inhalation
Antibiotic therapies
Surgical interventions
Upper airways
Secretolysis
Anti-inflammatory treatment
Antibiotic therapies
Tympanic drainage tubes and hearing aids
Surgical intervention
Fertility
References
Cystic fibrosis and other ion channel-related diseases
Abstract
Introduction
Pathophysiology of CF lung disease
Clinical presentation of CF lung disease
Clinical and molecular diagnostics
Breakthroughs in therapies targeting the underlying molecular defects in CF
The potential role of ion channels in other muco-obstructive lung diseases
The potential role of acquired CFTR dysfunction in other lung diseases
Conclusions and outlook
References
Bronchiectasis: from orphan disease to precision medicine
Abstract
Introduction
Epidemiology
Pathophysiology
Rare diseases that can cause bronchiectasis
Primary ciliary dyskinesia
CF
Nontuberculous mycobacteria
Tracheobronchomegaly
Allergic bronchopulmonary aspergillosis
Immunodeficiency
Inflammatory bowel disease-associated bronchiectasis
Investigation of bronchiectasis
Management of bronchiectasis: treatable traits
Treatable causes
Phenotypes and endotypes
Treatable traits-targeted management
Idiopathic disease in the future: precision medicine
Conclusion
References
α1-Antitrypsin deficiency and other rare forms of emphysema
Abstract
Introduction
Molecular background of AATD
Pathological mechanisms behind severe AATD-related lung emphysema
Molecular diagnostics of AATD
AATD-related lung diseases
AATD-related liver disease
Other disease manifestations of AATD
Other rare diseases conferring increased risk of pulmonary emphysema
Conclusion
References
Pulmonary arterial hypertension
Abstract
Introduction
Clinical classification
Pathology and pathobiology
Diagnostic considerations
Risk stratification
Treatment
Conclusion
References
Chronic thromboembolic pulmonary hypertension
Abstract
Introduction
Definitions
Epidemiology
Pathophysiology
Diagnosis
Surgical treatment
Medical treatment
Interventional treatment
Multimodal approach
Conclusion
References
Pulmonary hypertension in orphan lung diseases
Abstract
Introduction
PAH with features of venous/capillary (PVOD/PCH) involvement (group 1.5)
PAH associated with small patella syndrome (group 1.2)
PH in CPFE (group 3)
PH associated with LAM (group 3)
PH associated with sarcoidosis (group 5.2)
PH associated with PLCH (group 5.2)
PH associated with neurofibromatosis type 1 (group 5.2)
Conclusion
References
Hepatopulmonary syndrome: a liver-induced oxygenation defect
Abstract
Introduction
Histological features and pathophysiology of HPS
Histological features
Consequences for gas exchange
Pathophysiological mechanisms
Pulmonary vasodilation
Bacterial translocation, endotoxaemia and intravascular monocyte/macrophage recruitment
Increased pulmonary angiogenic function
Prevalence of HPS and impact on survival
Diagnostic approach and clinical investigations
Liver disease
Clinical characteristics
Abnormal arterial oxygenation
IPVDs
Other investigations
Management of HPS
Medical treatment
Liver transplantation
Management after liver transplantation
Conclusion
References
Systemic inflammatory diseases with lung involvement
Abstract
Introduction
Connective tissue diseases
Rheumatoid arthritis
Systemic sclerosis
Myositis
Sjögren syndrome
Systemic lupus erythematosus and mixed CTD
Spondyloarthritis
IBDs
BehÇet disease
Takayasu arteritis
Progressive fibrotic phenotype
Conclusion
References
ANCA-associated vasculitis and other pulmonary haemorrhage syndromes
Abstract
Evaluation of alveolar haemorrhage syndromes
Clinical presentation
Diagnostic evaluation
Supportive management
Empirical treatment
Additional interventions
ANCA-associated vasculitis
Overview
DAH
Treatment
General concepts
Rituximab and cyclophosphamide
Plasma exchange
Glucocorticoids
Complement inhibitors
Maintenance
Prophylaxis
Other alveolar haemorrhage syndromes
Anti-GBM disease
Primary anti-phospholipid antibody syndrome
Isolated pauci-immune pulmonary capillaritis
Idiopathic pulmonary haemosiderosis
Haematopoietic stem-cell transplantation
Conclusion
References
Eosinophilic granulomatosis with polyangiitis
Abstract
Introduction
Epidemiology
Incidence and prevalence
Triggering factors
Clinical manifestations
General symptoms
Pulmonary symptoms
Ear, nose and throat symptoms
Neurological symptoms
Gastrointestinal symptoms
Cardiac symptoms
Cutaneous symptoms
Renal symptoms
Ophthalmological symptoms
Complementary investigations
Diagnosis
Diagnostic criteria
Diagnostic criteria for relapse or flare
Differential diagnoses
Prognoses and outcomes
Phenotypes according to ANCA status
Treatment
Therapeutic strategies
Regimens to induce remission
New drugs for treatment of AAV
Rituximab
Mepolizumab and other anti-IL-5 agents
Maintenance therapy
Mepolizumab
Other treatment options
Prevention of adverse events
References
Idiopathic eosinophilic pneumonias
Abstract
Introduction
Polymorphonuclear eosinophils
Idiopathic chronic eosinophilic pneumonia
Clinical features
Imaging
Laboratory studies
BAL
Pathology
Differential diagnosis
PFTs
Treatment
Outcome and perspectives
IAEP and smoking-related AEP
Epidemiology
Clinical features
Imaging
Laboratory studies
BAL
PFTs
Lung biopsy
Treatment and prognosis
Other conditions
References
Sarcoidosis
Abstract
Introduction
Lung sarcoidosis
Principles of diagnosis
Management and treatment
Life-threatening manifestations of sarcoidosis
Cardiac sarcoidosis
Neurosarcoidosis
Renal sarcoidosis
New diagnostic and disease assessment tools
Novel therapeutic agents in sarcoidosis
Conclusion
References
Granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency
Abstract
Introduction
Term and definition
Diagnosis of GLILD
Clinical features
PFTs
Radiology
Histopathology of GLILD
Prediction models
Treatment of GLILD
Conclusion
References
Thoracic endometriosis and catamenial pneumothorax
Abstract
Introduction
Epidemiology of thoracic endometriosis and endometriosis-related pneumothorax
Aetiopathogenesis of thoracic endometriosis and catamenial pneumothorax
Catamenial pneumothorax and endometriosis-related pneumothorax
Definition and classification
Pathogenesis
Clinical features
Imaging and diagnostic procedures
Treatment
TES other than pneumothorax
Catamenial haemothorax and endometriosis-related pleural effusion
Endometriosis-related diaphragmatic hernia
Endometriosis-related thoracic pain
Conclusion
References
Chronic lung allograft dysfunction after lung transplantation
Abstract
History of chronic lung allograft dysfunction
Current definition/diagnosis of CLAD
Epidemiology and phenotypes of CLAD
BOS
RAS
Mixed phenotype
Undefined and unclassified phenotypes
Inherent diagnostic problems in phenotyping
Pathophysiology of CLAD
Risk factors for CLAD development
Biomarkers for CLAD
Outcome of CLAD
Treatment of CLAD
Conclusion and future prospects
References
Malformations and idiopathic disorders of the trachea
Abstract
Introduction
Embryogenesis
Congenital disorders of the trachea
Tracheomalacia
Tracheal agenesis
Laryngotracheo-oesophageal cleft
TOF
Vascular compression of the airways
Congenital tracheo-bronchial stenosis due to complete tracheal rings
Idiopathic disorders of the trachea
Subglottic stenosis
Tracheobronchopathia osteochondroplastica
Tracheobronchomegaly (Mounier-Kuhn syndrome)
Tracheopathies associated with infiltrative lung disease
Conclusion
References
Rare diseases of respiratory drive
Abstract
Introduction
Central control of breathing
Genetic disorders
Congenital central hypoventilation syndrome
Presentation
Diagnosis
Genetics
Management
Complications/other system involvements
Rett syndrome
PWS
Structural brain lesions
Obesity hypoventilation syndrome
Conclusion
References
Pleural mesothelioma
Abstract
Introduction
Epidemiology and aetiology
Pathogenesis, presentation, natural history and diagnosis
Diagnostic and molecular pathology
Prognosis and prognostic factors, biomarkers and (re-)staging
Mesothelioma treatment
Systemic treatment: first-line treatment
Second-line treatment
The role of surgical treatment in mesothelioma
Radiotherapy
Future prospects
Prevention and screening
Living with mesothelioma
Conclusion
References

Citation preview

Diagnosing rare diseases can be challenging, and treating Pantone PASTEL 9081 CMJN Pantone 200 CMJN (darker) Pantone 647 CMJN these conditions is complex because of Cyan their often quite 0 Cyan 0 Cyan 100 Magenta 0 Magenta 100 Magenta 56 6 Yellow 70 and treatment Yellow 0options. ToYellow specific needs address this, the Black 8 Black 14 Black 24 European Respiratory Society (ERS) has published Rare Diseases of the Respiratory System. Structured into thematic sections, the book covers: the identification of rare diseases of the respiratory system and their differential diagnosis; 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.

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

ERS monograph 100

ISBN 978-1-84984-166-5

Rare Diseases of the Respiratory System

ERS monograph

ERS monograph

Pantone 200 CMJN (darker) Cyan 0 Magenta 100 Yellow 70 Black 14

Rare Diseases of the Respiratory System Pantone 647 CMJN Cyan 100 Magenta 56 Yellow 0 Black 24

Pantone PASTEL 9081 CMJN Cyan 0 Magenta 0 Yellow 6 Black 8

Edited by Thomas O.F. Wagner, Marc Humbert, Marlies Wijsenbeek, Michael Kreuter and Helge Hebestreit

Rare Diseases of the Respiratory System Edited by Thomas O.F. Wagner, Marc Humbert, Marlies Wijsenbeek, Michael Kreuter and Helge Hebestreit 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: [email protected] 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 Print ISSN: 2312-508X Online ISSN: 2312-5098 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 List of abbreviations

xi

1. How to identify rare diseases of the respiratory system Helge Hebestreit, Florian Gahleitner, Simon Veldhoen and Matthias Griese

1

2. Differential diagnosis of reciprocal mimics of neoplastic and non-neoplastic pulmonary disorders: multidisciplinary approaches Nicolas Girard

10

Rare diseases of the lung interstitium 3. Interstitial lung diseases: an overview Theodoros Karampitsakos, Marlies Wijsenbeek, Jose D. Herazo-Maya,

xiv

23

Argyris Tzouvelekis and Michael Kreuter

4. Rare interstitial lung diseases of environmental origin Carlos Robalo Cordeiro, Tiago Alfaro and Sara Freitas

40

5. Amyloidosis and the lungs and airways Joshua A. Bomsztyk, Jennifer H. Pinney and Helen J. Lachmann

53

6. Diffuse cystic lung diseases including lymphangioleiomyomatosis Davide Elia, Antonella Caminati, Lisa Tescaro, Roberto Cassandro and Sergio Harari

69

Rare disease of the airways or alveoli 7. Bronchiolitis Venerino Poletti, Claudia Ravaglia, Alessandra Dubini, Sissel Kronborg-White,

85

Salvatore Cazzato and Sara Piciucchi

8. Pulmonary alveolar proteinosis Evelyn Lynn, Omaima Omar, Ali Ataya, Elisabeth Bendstrup, Alessandro N. Franciosi

103

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

Simon Y. Graeber and Marcus A. Mall

135

11. Bronchiectasis: from orphan disease to precision medicine Hayoung Choi and James D. Chalmers

150

12. α1-Antitrypsin deficiency and other rare forms of emphysema Joanna Chorostowska-Wynimko, Sabina Janciauskiene, Magdalena Pelc,

165



Pavel Strnad and David Parr

Pulmonary vascular diseases 13. Pulmonary arterial hypertension Sarah Cullivan and Sean Gaine

180

14. Chronic thromboembolic pulmonary hypertension Marion Delcroix, Laurent Godinas, Rozenn Quarck, Catharina Belge, Bart Meyns,

192

15. Pulmonary hypertension in orphan lung diseases David Montani, Mithum Kularatne, Etienne-Marie Jutant and Marc Humbert

204

16. Hepatopulmonary syndrome: a liver-induced oxygenation defect Laurent Savale, Fabien Robert, Ly Tu, Marie-Caroline Certain, Audrey Baron,

224





Geert Maleux and Tom Verbelen

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 Eirini Vasarmidi, Eleni Bibaki and Katerina Antoniou

237

18. ANCA-associated vasculitis and other pulmonary haemorrhage syndromes Samuel Falde and Ulrich Specks

254

19. Eosinophilic granulomatosis with polyangiitis Yann Nguyen and Loïc Guillevin

267

20. Idiopathic eosinophilic pneumonias

281

21. Sarcoidosis Francesco Bonella, W. Ennis James and Paolo Spagnolo

293

22. Granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency

310

Vincent Cottin



Heba M. Bintalib, Siobhan O. Burns and John R. Hurst

Other rare lung diseases 23. Thoracic endometriosis and catamenial pneumothorax Antonio Bobbio, Vincent de Pauw, Imane Lefqih, Antoine Sion and Marco Alifano 24. Chronic lung allograft dysfunction after lung transplantation Berta Saez Gimenez, Merel Hellemons, Stijn E. Verleden, Jens Gottlieb and

Geert M. Verleden

320 331

25. Malformations and idiopathic disorders of the trachea Valentina Luzzi, Francesca Conway, Diletta Cozzi, Luca Ciani, Leonardo Giuntoli,

343

26. Rare diseases of respiratory drive Katie Rose, Tamarin Foy, Christopher Grime and Ian P. Sinha

357

27. Pleural mesothelioma Joachim G.J.V. Aerts and Jan P. van Meerbeeck

367



Marco Trigiani and Sara Tomassetti

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.

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. 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 KremlinBicêtre, 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 ([email protected]) @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 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.

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

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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, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 40–52. 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

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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). Sheffield, European Respiratory Society, 2023; pp. 69–84. 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, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 135–149. 12 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. 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, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 192–203. 16 Montani D, Kularatne M, Jutant E-M, et al. Pulmonary hypertension in orphan lung diseases. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 204–223. 17 Savale L, Robert F, Tu L, et al. Hepatopulmonary syndrome: a liver-induced oxygenation defect. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 224–236.

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.

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List of abbreviations ANCA BAL CT DLCO FVC GM-CSF HRCT ILD MRI PAS PFT PH

antineutrophil cytoplasmic autoantibodies bronchoalveolar lavage computed tomography diffusing capacity of the lung for carbon monoxide forced vital capacity granulocyte–macrophage colony stimulating factor high-resolution CT interstitial lung disease magnetic resonance imaging periodic acid–Schiff pulmonary function test/ing 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. European Reference Network for Rare Diseases of the Respiratory System (ERN-LUNG), Frankfurt, Germany. 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.

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Corresponding author: Helge Hebestreit ([email protected]) Cite as: 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 [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 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.

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 wholegenome 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

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TABLE 1 Overview and categorisation of rare pulmonary diseases Category

Examples

Congenital malformations (gross structural abnormalities) Airway disorders ILDs (diffuse parenchymal) Lung native parenchymal disorders

Congenital pulmonary airway malformation, sequestration, bronchogenic cyst Cystic fibrosis, primary ciliary dyskinesia

Systemic disease-related disorders Exposure-related disorders Vascular disorders

Alveolar capillary dysplasia, surfactant deficiency disorders (SFTPC, ABCA3) Connective tissue-related ILDs, telomerase deficiencies, pulmonary alveolar proteinosis due to immunodeficiency Hypersensitivity disorder, drug-induced ILD 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

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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) 2

Flow L·s–1 0 2

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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.

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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.

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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 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

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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

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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. Sheffield, European Respiratory Society, 2022; pp. 296–303. 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

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IDENTIFYING RARE DISEASES | H. HEBESTREIT ET AL. 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.

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Chapter 2

Differential diagnosis of reciprocal mimics of neoplastic and non-neoplastic pulmonary disorders: multidisciplinary approaches Nicolas Girard1,2,3 1 3

Institut du Thorax Curie Montsouris, Institut Curie, Paris France. 2Paris Saclay University, UVSQ, Versailles, France. European Reference Network EURACAN, Centre Léon Bérard, Lyon, France. Corresponding author: Nicolas Girard ([email protected])

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 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.

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

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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

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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.

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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.

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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

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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.

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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”, “plasmacell/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 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 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.

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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.

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Acute or chronic clinical presentation with systematic symptoms (e.g. fever, chills, asthenia)

Pulmonary diffuse cysts

Clinical history: PNX, chylothorax, chyloascites, family clinical history (TSC) Physical examination: skin examination (ANF, shagreen patches, ash-leaf patches), abdominal masses Systemic involvement: TSC

Clinical history: PNX, smoking, tumours (blood malignancies, lung cancer) Physical examination: skin examination (erythematous, maculopapular or nodular lesions; seborrhoeic and crusted lesions on the scalp) Systemic involvement: diabetes insipidus

LAM

Clinical history: PNX, familiar tumours (renal tumours), tumours (in particular, chromophobe renal cell carcinomas or oncocytoma) Physical examination: skin examination, FF, TD

PLCH

Investigate for infections

Clinical history: blood disorders and malignancies Systemic involvement: Sjögren syndrome, amyloidosis

BHD syndrome

LIP/FB, amyloidosis, LCDD

Focus on cyst features: shape, size, quantity and distribution

Small, diffuse, round, regular

Irregular, bizarre cysts may be associated with nodules and cavities U/M lobes distribution with C/P angle sparing PLCH

Presence of TSC/AML/chylothorax/ lymphangioleiomyoma/ chylous ascites

BAL: CD1a+ cells >5%

Yes Yes LAM

Serum VEGF-D >800 pg·mL–1 No Consider lung biopsy

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FIGURE 4. Legend overleaf.

PLCH

Lung biopsy#

Round, diffuse cysts of different sizes May be associated with GGO, septal thicking, nodules

Cystic pattern not specific for other diseases described

BHD syndrome

LIP/FB, amyloidosis, LCDD

Trauma Metastatic neoplasm Infectious aetiologies

Major criteria: ≥5 FF or TD (histology) FLCN mutation Minor criteria: Characteristic CT scan Family history of BHD syndrome Renal cancer

Supportive tests and features: Sicca symptoms SSA, SSB SPEP, UPEP Presence of autoimmune/immune deficiency Myeloma

≥1 major or ≥2 minor criteria BHD syndrome

VATS biopsy¶

LIP/FB, amyloidosis, LCDD

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LAM

Elliptical/lentiform cysts Basilar subpleural distribution near vessels

ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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

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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) 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% 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

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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]. Clinical manifestation and diagnosis 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

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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.

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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.

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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.

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Chapter 7

Bronchiolitis Venerino Poletti 1,2,3, Claudia Ravaglia2, Alessandra Dubini4, Sissel Kronborg-White3, Salvatore Cazzato5 and Sara Piciucchi

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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 ([email protected]) 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 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.

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

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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

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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

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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 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

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BRONCHIOLITIS | V. POLETTI ET AL. 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 Diffuse panbronchiolitis 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)

Subacute course

Chronic course with insidious onset

Symptoms

Signs

Specific forms (prototypes) of bronchiolitis

Fever Purulent sputum Dyspnoea on effort (Pan)sinusitis Dry cough Dyspnoea on effort

Purulent sputum Inspiratory–expiratory ronchi Headache (sinusitis)

Infectious bronchiolitis Diffuse panbronchiolitis

End-inspiratory squeaks Wheezing

Mineral dust bronchiolitis Idiopathic constrictive bronchiolitis

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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 Directs signs Centrilobular nodules (ground-glass opacities) Tree-in-bud pattern Indirect signs Mosaic oligaemia with expiratory air trapping Mosaic oligaemia/centrilobular nodules Ancillary findings Bronchioloectasis/bronchiectasis

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Histopathological background

Cellular chronic bronchiolitis (mainly follicular and respiratory) Proliferative bronchiolitis (mainly when the process spills over into the centrilobular airspaces) Acute bronchiolitis (mainly infectious) Diffuse panbronchiolitis Cicatricial bronchiolitis Proliferative bronchiolitis (when the process is mainly limited to membranous bronchioles) 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

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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

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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

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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

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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 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

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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 proliferatoractivated 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 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

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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

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a)

DNAH5

GAS8

Merge

DIC

GAS8

Merge

DIC

RSPH9

Merge

DIC

RSPH9

Merge

DIC

SPEF2

Merge

DIC

SPEF2

Merge

DIC

Control DNAH5

DNAH5 mutant b)

Ac. tub.

Control Ac. tub.

RSPH9 mutant c)

Ac. tub.

Control Ac. tub.

HYDIN mutant FIGURE 2. Legend overleaf.

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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

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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

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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].

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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.

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Chapter 10

Cystic fibrosis and other ion channel-related diseases Simon Y. Graeber

1,2,3

and Marcus A. Mall

1,2,3

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 ([email protected]) Cite as: Graeber SY, Mall MA. Cystic fibrosis and other ion channel-related diseases. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 135–149 [https://doi.org/10.1183/2312508X.10018022]. @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 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.

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

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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

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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

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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

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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

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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

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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

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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

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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

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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 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

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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. Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med 2020; 8: 65–124. Hill DB, Button B, Rubinstein M, et al. Physiology and pathophysiology of human airway mucus. Physiol Rev 2022; 102: 1757–1836. 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. Mall MA, Hartl D. CFTR: cystic fibrosis and beyond. Eur Respir J 2014; 44: 1042–1054. Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest 2002; 109: 571–577. 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. 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. 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. 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. 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. 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. Boucher RC. Muco-obstructive lung diseases. N Engl J Med 2019; 380: 1941–1953. Mall MA. ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapies. Eur Respir J 2020; 56: 2000946. 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. 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. 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. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918–951. 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. 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. 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. 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. 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 J Respir Crit Care Med 2014; 189: 1082–1092. 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. 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. Sommerburg O, Schenk JP. Abdominelle Manifestationen bei Mukoviszidose: Klinische Übersicht [Abdominal manifestations in cystic fibrosis: clinical review]. Radiologe 2020; 60: 781–790. https://doi.org/10.1183/2312508X.10018022

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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

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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 Respir Crit Care Med 2018; 197: 1433–1442. 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 T p.Glu288Val

PI*MZ

25.4 (15–42) [5] 14.8 (12.1–18.4) [6]

138 (81.5–228.3) [5] 80.5 (66–100) [6]

16.6 (11.4–27.8) [5] 16.4 (11.2–28.7) [7]

90 (62–151) [5] 89 (61–156) [7]

c.1096G>A p.Glu366Lys

PI*SS

28 (20–48) [5] 15.6 (13.4–19.5) [6]

152.2 (108.7–260.9) [5] 84.9 (73–106) [6]

17.5 (7.9–28.3) [5] 17.5 (9.0–33.3) [7]

95 (43–154) [5] 95 (49–181) [7]

PI*SZ

16.5 (10–23) [5] 10.2 (9–12.1) [6]

89.7 (54.3–25) [5] 55.5 (49–66) [6]

11.4 (6.1–19.9) [5] 11.8 (7.7–19.9) [7]

62 (33–108) [5] 64 (42–108) [7]

PI*ZZ

5.3 (3.4–7) [5] 5.9 [6]

28.8 (18.5–38) [5] 32 [6]

⩽5.3 (⩽5.3–9.6) [5] 4.6 (2.8–10.5) [7]

⩽29 (⩽29–52) [5] 25 (15–57) [7]

c.863A>T p.Glu288Val homozygous c.863A>T p.Glu288Val, c.1096G>A p.Glu366Lys c.1096G>A p.Glu366Lys homozygous

PI*Q0BresciaQ0Brescia

Undetectable

Undetectable

Undetectable

Undetectable

PI*Q0CasablancaQ0Casablanca

A p.? c.841G>T p.Glu281* c.611_612del p.Thr204Serfs*11 c.985C>T p.Gln329* c.1182del p.Phe394Leufs*4 c.787del p.Val263Cysfs*3 c.787del p.Val263Cysfs*3 c.1052del p.Leu351Argfs*12 c.559A>T p.Lys187* c.1192_1195del p.Met398Leufs*15

RENOUX [9]

FERRAROTTI [8] RENOUX [9] FERRAROTTI [8] FERRAROTTI [8] FERRAROTTI [8] FERRAROTTI [8] FERRAROTTI [8] FERRAROTTI [8] FERRAROTTI [8] RENOUX [9] SILVA [10]

# : 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).

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TABLE 2 Continued

a1-ANTITRYPSIN DEFICIENCY | J. CHOROSTOWSKA-WYNIMKO ET AL.

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

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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 (3 mmHg·L−1·min−1 between rest and exercise Incremental exercise tests (step or ramp protocol) with repeated haemodynamic measurements can be used May expose left ventricular dysfunction in patients with PAWP 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

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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

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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.

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195

b) Intravascular leiomyomatosis

c) Multiple congenital stenosis

d) Takayasu disease

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.

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196

a) Intima sarcoma

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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 obstructions

PEA

Distal PA fibrotic obstructions

Microvasculopathy

BPA

CTEPH drug therapy

PEA/ BPA

2

1 3

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.

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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 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

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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.

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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

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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

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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 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

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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 1

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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.

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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 ([email protected])

Cite as: Savale L, Robert F, Tu L, et al. Hepatopulmonary syndrome: a liver-induced oxygenation defect. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 224–236 [https://doi.org/10.1183/2312508X.10006023]. @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 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.

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 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

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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

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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

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Objectives

Characteristics in HPS

Room air arterial blood gas analysis in an upright position

To detect abnormal arterial oxygenation To assess the severity of HPS

Contrast-enhanced echocardiography

To detect intrapulmonary vascular dilations

Technetium-labelled macroaggregated albumin scan PFTs

To detect intrapulmonary vascular dilations

A–aDO2 ⩾15 mmHg, or >20 mmHg in patients >64 years# PaO2 >80 mmHg indicates mild HPS, 60–80 mmHg indicates moderate HPS, 50–60 mmHg indicates severe HPS and 5 mmHg in sitting position Passage of microbubbles from the right cavities to the left cavities visualised after three cardiac cycles# Macroaggregated albumin particles in extrathoracic organs#

Thoracic CT

To detect associated pulmonary disease that could contribute to gas-exchange abnormalities To detect associated pulmonary disease that could contribute to gas-exchange abnormalities

Normal volumes and flows in isolated HPS Decreased DLCO: nonspecific for HPS Normal in most cases of isolated HPS Pulmonary vascular dilations in the 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

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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 (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

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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 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 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

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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

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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

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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

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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

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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 methotrexate, azathioprine and anti-TNFα agents are follow-up, limitation of vascular complications, and cardiovascular risk factors are also part of the therapeutic of crucial importance in all therapeutic decisions [156].

immunosuppressive agents, such as currently suggested [155]. Regular management of comorbidities and plan. A multidisciplinary approach is

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

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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 2 3 4 5

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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. 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. 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. 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. 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. 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. Turesson C. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 2003; 62: 722–727. 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 Respiratory Society, 2019; pp. 44–67. 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. 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. 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. Hamdan AL, Sarieddine D. Laryngeal manifestations of rheumatoid arthritis. Autoimmune Dis 2013; 2013: 103081. Balbir-Gurman A, Yigla M, Nahir AM, et al. Rheumatoid pleural effusion. Semin Arthritis Rheum 2006; 35: 368–378. Juge PA, Crestani B, Dieudé P. Recent advances in rheumatoid arthritis-associated interstitial lung disease. Curr Opin Pulm Med 2020; 26: 477–486. 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. Juge PA, Lee JS, Ebstein E, et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. N Engl J Med 2018; 379: 2209–2219. 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. 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. Jacob J, Hirani N, van Moorsel CHM, et al. Predicting outcomes in rheumatoid arthritis related interstitial lung disease. Eur Respir J 2019; 53: 1800869.

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Disclosures: None declared.

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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 ([email protected]) Cite as: Falde S, Specks U. ANCA-associated vasculitis and other pulmonary haemorrhage syndromes. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 254–266 [https://doi.org/10.1183/2312508X.10027822]. @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 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.

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

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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 Isolated pulmonary capillaritis Anti-GBM antibody syndrome Systemic lupus erythematosus Anti-phospholipid antibody syndrome Henoch–Schönlein purpura/IgA vasculitis Cryoglobulinaemia vasculitis Behçet syndrome Rheumatoid arthritis Drug-induced vasculitis Drug-induced lupus Inflammatory myopathies Acute lung transplant rejection Hypocomplementemic urticarial vasculitis Bone marrow transplantation Infective endocarditis

Cardiac disease Left ventricular dysfunction Valvular disease Infection Medications Crack cocaine inhalation Vaping Acute respiratory disease syndrome Coagulopathy Radiation exposure Occupational exposures Idiopathic pulmonary haemosiderosis Bone marrow transplantation Pulmonary infarction Thrombocytopenia 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

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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

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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 1.0×109 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

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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%; p1×109 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

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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

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On HRCT, the opacities are bilateral in virtually all cases [10]. A predominance of groundglass 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 (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.

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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

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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

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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 25% (generally >40%) Homogeneous peripheral airspace consolidation Predominance in upper lobes and lung periphery Yes, possibly multiple

25% Bilateral patchy areas of ground-glass attenuation, airspace consolidation, interlobular septal thickening and bilateral pleural effusion No

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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 EGPA

Hypereosinophilic syndrome

ABPA

Parasitic infestation

Medication

Illicit drugs Noncigarette smoking products Radiation therapy

Bronchocentric granulomatosis

Hypereosinophilic obliterative bronchiolitis

Comments

First author [ref.]

Abnormalities predominate in the airspaces corresponding to eosinophilic pneumonia, or in the airways corresponding to bronchiolar and bronchial involvement Lung involvement is uncommon in the reactive/lymphocytic variant, and is present at chest CT in ∼40% of patients with the clonal/neoplastic variant Fleeting infiltrates due to eosinophilic pneumonia or mucus plugging with ensuing segmental or lobar atelectasis are frequent during the initial stage of the disease The most common cause of eosinophilic pneumonia worldwide Causative agents include Ascaris lumbricoides, Toxocara canis, Wuchereria bancrofti, Brugia malayi and Strongyloides stercoralis; however, typical eosinophilic pneumonia is rare in this setting Antibiotics Nonsteroidal anti-inflammatory drugs Other medication Cocaine, heroin, crack, marijuana/cannabis Vaping, waterpipe smoking and marijuana Up to 10 months after radiotherapy for breast cancer in women, and rarely lung cancer Pulmonary opacities may be unilateral (irradiated lung) or bilateral, and occasionally migrate Masses, alveolar opacities or consolidation, and possible reticulonodular opacities, predominating in the upper lung zones and generally unilateral Eosinophilic pneumonia is generally not present, with the exception of hypereosinophilic obliterative bronchiolitis occurring in the setting of EGPA, ABPA or drug-induced eosinophilic lung disease

KIM [56], PRICE [57], SZCZEKLIK [58]

VALENT [59], DULOHERY [60], SIMON [61], ROUFOSSE [62], CHUSID [63], FAUCI [64] MITCHELL [65], REFAIT [66], WARD [67]

COTTIN [1], SIMON [61], CORDIER [68], VIJAYAN [69], FIORENTINI [70], VIJAYAN [71], MING [72]

SPAGNOLO [73]

BRANDER [74], SAUVAGET [75], NADEEM [76] CHAABAN [77], PUEBLA NEIRA [78], MULL [79] COTTIN [80]

LIEBOW [81], KATZENSTEIN [82], WARD [83]

CORDIER [84]

EGPA: eosinophilic granulomatosis with polyangiitis; ABPA: allergic bronchopulmonary aspergillosis.

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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.

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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

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IDIOPATHIC EOSINOPHILIC PNEUMONIAS | V. COTTIN 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. Am J Respir Crit Care Med 1997; 155: 296–302. 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. AJR Am J Roentgenol 1996; 167: 1195–1199. 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 Respir Crit Care Med 2018; 197: 728–736. 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. Am J Respir Crit Care Med 2002; 166: 1235–1239. 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 Respir Crit Care Med 2017; 195: 1671–1672. 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

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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 payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca and GSK.

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Chapter 21

Sarcoidosis Francesco Bonella

1

, W. Ennis James

2

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 ([email protected]) Cite as: Bonella F, James WE, Spagnolo P. Sarcoidosis. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 293–309 [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 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.

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

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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 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 • Asymptomatic bilateral hilar adenopathy • Heerfordt syndrome • Löfgren syndrome • Lupus pernio

Probable sarcoidosis

Consistent with sarcoidosis

Biopsy

Non-necrotising granulomatous inflammation

Not consistent with sarcoidosis

Negative and inadequate

Alternative granulomatous disease excluded

Re-evaluate/consider alternative diagnosis

Consider repeating biopsy

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 35–50% ⩽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 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 80% of baseline. TABLE 2 Possible phenotypes according to pulmonary function evolution with or without persistent restrictive allograft syndrome (RAS)-like opacities Phenotype

BOS RAS Mixed Undefined Undefined Unclassified Unclassified Unclassified

Combinations of PFTs and HRCT to phenotype CLAD Obstruction: FEV1/FVC 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

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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 Colonisation/infection with micro-organisms Gastro-oesophageal reflux Air pollution Primary graft dysfunction Acute cellular rejection Lymphocytic bronchiolitis Antibody-mediated rejection Nonadherence to immunosuppressive drugs

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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 mixedphenotype 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

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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

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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. 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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

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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. 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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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. J Heart Lung Transplant 2019; 38: 516–527. 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.

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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 ([email protected])

Cite as: Luzzi V, Conway F, Cozzi D, et al. Malformations and idiopathic disorders of the trachea. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 343–356 [https://doi.org/10.1183/2312508X.10019522]. @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 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.

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

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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. 344

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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. https://doi.org/10.1183/2312508X.10019522

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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 346

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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

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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.

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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. https://doi.org/10.1183/2312508X.10019522

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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

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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 352

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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.

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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

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TRACHEAL DISORDERS AND MALFORMATIONS | V. LUZZI ET AL. 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.

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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 Monograph). Sheffield, European Respiratory Society, 2011; pp. 187–200.

Disclosures: None declared.

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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 ([email protected]) 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 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.

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

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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. 358

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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.

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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 Benefits

Risks

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Secure airway Ability to provide ventilation during both wakefulness and sleep Ability to provide support when unwell without need for admission to the intensive care unit Prolonged training requirements necessitating long hospital stays after tracheostomy insertion Complications of tracheostomy (infection, decannulation, granuloma formation) Interference with speech development and feeding

Noninvasive Avoids risks of tracheostomy Short training periods facilitating faster discharge from hospital Normal development of speech and oromotor skills Nonsecure airway Facial pressure sores and deformity with long-term use Dislodgement of mask/aspiration risk with vomiting necessitating need for close monitoring Limited interfaces in infants 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

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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]. 362

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Central apnoeas are seen almost exclusively in children 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]. 364

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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 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

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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 Reproduced and modified from [17] with permission.

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

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Basic staging: all patients fit for treatment#

Staging in those suitable for surgery and chemotherapy

(FDG)¶ PET-CT

Chest radiography

Further staging in those of borderline resectability prior to radical surgery Chest/abdominal ±brain (if clinical signs) MRI Laparoscopy/ contralateral VATS

CT 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. Reproduced and modified from [1] with permission.

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 https://doi.org/10.1183/2312508X.10019722

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Pretreatment work-up

Malignant pleural mesothelioma

Minimal biology tests and cardiorespiratory evaluation + basic staging for all patients fit for treatment: chest/abdomen CT scan (with iodine contrast)

Asbestos exposure? Malignant pleural mesothelioma compensation according to state law

Patients suitable for multimodal treatment including surgery with MCR

Yes

Staging and patient allocation

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Patient suitable for medical treatment?

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Treatment

Multimodal treatment including MCR (in expert centres only, within a RCT if possible)

First-line dual nivolumab-ipilimumab immunotherapy or platinum-pemetrexed chemotherapy

No

Best supportive care only, including palliative radiotherapy if necessary

FIGURE 5 Algorithm for the management of patients with malignant pleural mesothelioma. MCR: macroscopic complete resection; RCT: randomised controlled trial. Reproduced and modified from [1] with permission.

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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 https://doi.org/10.1183/2312508X.10019722

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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

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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

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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

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PLEURAL MESOTHELIOMA | J.G.J.V. AERTS AND J.P. VAN MEERBEECK 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

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ERS MONOGRAPH | RARE DISEASES OF THE RESPIRATORY SYSTEM 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.

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Diagnosing rare diseases can be challenging, and treating Pantone PASTEL 9081 CMJN Pantone 200 CMJN (darker) Pantone 647 CMJN these conditions is complex because of Cyan their often quite 0 Cyan 0 Cyan 100 Magenta 0 Magenta 100 Magenta 56 6 Yellow 70 and treatment Yellow 0options. ToYellow specific needs address this, the Black 8 Black 14 Black 24 European Respiratory Society (ERS) has published Rare Diseases of the Respiratory System. Structured into thematic sections, the book covers: the identification of rare diseases of the respiratory system and their differential diagnosis; 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.

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

ERS monograph 100

ISBN 978-1-84984-166-5

Rare Diseases of the Respiratory System

ERS monograph

ERS monograph

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Rare Diseases of the Respiratory System Pantone 647 CMJN Cyan 100 Magenta 56 Yellow 0 Black 24

Pantone PASTEL 9081 CMJN Cyan 0 Magenta 0 Yellow 6 Black 8

Edited by Thomas O.F. Wagner, Marc Humbert, Marlies Wijsenbeek, Michael Kreuter and Helge Hebestreit