Diagnosing rare diseases can be challenging, and treating these conditions is complex because of their often quite specific needs and treatment options. To address this, the 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.
This site only provides online access to the book. To order a print copy, visit ersbookshop.com
- Page 1AbstractCorresponding author: Helge Hebestreit (hebestreit@uni-wuerzburg.de)
Diagnosing a rare disease of the respiratory system may be straightforward, for example with positive neonatal screening or typical radiographic findings. However, in many cases, only unspecific signs and symptoms are present. Among other clues, a suspicious family history, an atypical clinical course or a poor response to treatment may trigger first thoughts about an underlying rare condition. Integrating information from medical history, clinical signs, laboratory values, BAL findings, whole-exome or whole-genome sequencing, PFTs, imaging and/or histology is usually required to establish a diagnosis. Case conferences may prove essential in the process. This chapter highlights important elements, from medical history to diagnostic tools and data integration, for diagnosing a rare disease of the respiratory system.
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].
- Page 10AbstractCorresponding author: Nicolas Girard (nicolas.girard2@curie.fr)
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.
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].
- Page 23AbstractCorresponding author: Michael Kreuter (michael.kreuter@unimedizin-mainz.de; michael.kreuter@marienhaus.de)
ILDs represent a heterogeneous group of parenchymal lung diseases. Outcomes vary considerably and range from spontaneous reversibility to progressive pulmonary fibrosis. Timely identification and management are crucial for patients’ quality of life and survival. However, diagnosis is often challenging and thus referral to specialised centres is of paramount importance. This chapter aims to provide an introduction to epidemiology, classification, pathogenesis, clinical features, diagnosis and management of ILDs, as well as to novel developments in the field.
Cite as: Karampitsakos T, Wijsenbeek M, Herazo-Maya JD, et al. Interstitial lung diseases: an overview. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 23–39 [https://doi.org/10.1183/2312508X.10017322].
- Page 40AbstractCorresponding author: Carlos Robalo Cordeiro (carlos.crobalo@gmail.com)
The lung represents an immense interface with the external environment, inhaling close to 20 000 L of air every day containing a diversity of aggressive and polluting agents, not only in the general environment but also at the occupational and housing level. Therefore, a detailed respiratory clinical history is essential to identify current or previous inhalation risks. Rare ILDs of environmental origin require a personalised approach, involving a high degree of clinical suspicion, which must fundamentally include removal of the offending agent, monitoring of the clinical, radiological and functional evolution, and differentiated therapeutic options when necessary. This chapter discusses hypersentivity pneumonitis, pneumoconiosis and other ILDs caused by environmental exposures, and the effects of environmental exposures on other ILDs.
Cite as: 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 [https://doi.org/10.1183/2312508X.10017422].
- Page 53AbstractCorresponding author: Helen J. Lachmann (h.lachmann@ucl.ac.uk)
Amyloidosis can both complicate long-standing respiratory conditions and be deposited within the respiratory system itself. In acquired systemic amyloidosis, control of the underlying condition that is producing the circulating amyloid precursor protein is paramount. Systemic AA amyloidosis can result from unremitting chronic inflammation or infection such as in bronchiectasis. Control of the inflammation is paramount to amyloid regression. For systemic AL amyloidosis, treatment requires the use of chemotherapy or novel immunotherapies targeting the underlying plasma cell dyscrasia or lymphoproliferative disease that produce the abnormal amyloidogenic light chain. Localised amyloidosis can occur anywhere along the respiratory tract and can present with marked heterogeneity. In localised amyloidosis, management generally involves resection or ablation of symptomatic deposits. On occasion, localised pulmonary amyloidosis can be a manifestation of underlying Sjögren syndrome. Novel treatments are beginning to become available, including specific drug therapies to prevent translation of amyloidogenic proteins, stabilise amyloid precursor proteins and interfere with amyloid fibrillogenesis.
Cite as: Bomsztyk JA, Pinney JH, Lachmann HJ. Amyloidosis and the lungs and airways. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 53–68 [https://doi.org/10.1183/2312508X.10017522].
- Page 69AbstractCorresponding author: Sergio Harari (sergio@sergioharari.it)
Diffuse cystic lung diseases (DCLDs) are a heterogeneous group of pulmonary disorders characterised by cysts within the lung parenchyma. In some cases, a characteristic HRCT image indicates a diagnosis. There are a large number of cystic lung diseases, which have been divided into six groups according to their pathogenesis: neoplastic, congenital/genetic, lymphoproliferative, infectious, associated with ILD and other causes. In this chapter, the main characteristics of DCLDs are described, along with more detailed descriptions of ultra-rare cystic disorders such as lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and Birt–Hogg–Dubé syndrome.
Cite as: 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 [https://doi.org/10.1183/2312508X.10017622].
- Page 85AbstractCorresponding author: Venerino Poletti (venerino.poletti@gmail.com)
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.
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].
- Page 103AbstractCorresponding author: Cormac McCarthy (cormac.mccarthy@ucd.ie)
Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterised by progressive accumulation of pulmonary surfactant. This results in dyspnoea, secondary pulmonary and systemic infection, and in occasional cases respiratory failure. PAP syndrome occurs in distinct diseases, classified according to pathogenetic mechanism; these include primary PAP (due to disruption of GM-CSF signalling), secondary PAP (due to reduction in alveolar macrophage numbers/functions) and congenital PAP (due to disruption of surfactant production). The most common cause is autoimmune PAP, in which antibodies against GM-CSF disrupt alveolar macrophage function resulting in reduced surfactant clearance. The current standard therapy is whole-lung lavage, which must be performed in carefully selected patients. However, there is increasing evidence to support the use of inhaled GM-CSF and other novel therapies.
Cite as: Lynn E, Omar O, Ataya A, et al. Pulmonary alveolar proteinosis. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 103–117 [https://doi.org/10.1183/2312508X.10017822].
- Page 118AbstractCorresponding author: Heymut Omran (Heymut.Omran@ukmuenster.de)
Primary ciliary dyskinesia (PCD) is a rare genetically and clinically heterogeneous group of diseases with more than 50 associated genes. PCD is characterised by dysfunction of multiple motile cilia, resulting in aberrant mucociliary clearance. Hallmark symptoms are chronic airway infections due to mucostasis that may lead to irreversible lung damage. Approximately 50% of affected individuals display situs inversus totalis or, less commonly, situs ambiguous. Additional symptoms can occur such as hydrocephalus and infertility or subfertility. PCD diagnosis should be established as early as possible to prevent permanent lung damage. PCD diagnosis is complex and consists of a combination of multiple tests, as many PCD variants cannot be detected with a single method. There is currently no curative therapy for PCD. Thus, the focus is on symptomatic measures such as regular airway cleaning and treatment of recurrent respiratory infections. Most recommendations for patient management are modelled on therapeutic approaches for other respiratory diseases such as cystic fibrosis, COPD and idiopathic bronchiectasis.
Cite as: 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 [https://doi.org/10.1183/2312508X.10017922].
- Page 135AbstractCorresponding author: Marcus A. Mall (marcus.mall@charite.de)
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.
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].
- Page 150AbstractCorresponding author: James D. Chalmers (jchalmers@dundee.ac.uk)
Bronchiectasis is a chronic lung disease characterised radiologically by permanent bronchial dilation and clinically by the presence of cough, sputum and recurrent chest infection. Once bronchiectasis is diagnosed, an initial clinical investigation should be conducted to identify the treatable underlying causes, including allergic bronchopulmonary aspergillosis, immunodeficiency and nontuberculous mycobacterial lung disease. Uncommon genetic diseases, including primary ciliary dyskinesia and cystic fibrosis, are also important causes of bronchiectasis and may be identified even in adults with bronchiectasis. The identified treatable cause can be a therapeutic target in the management of bronchiectasis. For cases of bronchiectasis without a treatable cause, management includes improving airway clearance, controlling infection and preventing complications. These features can be highly individualised, and so a precision medicine approach incorporating phenotypes and endotypes is recommended. Such an approach can guide the administration of therapy that can effectively reduce symptom burden and prevent exacerbations.
Cite as: Choi H, Chalmers JD. Bronchiectasis: from orphan disease to precision medicine. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 150–164 [https://doi.org/10.1183/2312508X.10018122].
- Page 165AbstractCorresponding author: Joanna Chorostowska-Wynimko (j.chorostowska@igichp.edu.pl)
α1-Antitrypsin deficiency (AATD) is the major single-gene disorder linked to high-risk emphysema. AATD is inherited in an autosomal-recessive pattern with codominant expression of the alleles. It results from carrying biallelic pathogenic variants of the SERPINA1 gene encoding α1-antitrypsin (AAT). AAT is the key serum protease inhibitor, and its depletion in quantity and/or serum activity leads to protease–antiprotease imbalance, as well as disrupted regulation of inflammatory and antimicrobial responses. The sequelae of these effects are the degradation of lung tissue with eventual progression to emphysema and COPD. Other lung phenotypes include bronchial asthma and bronchiectasis. While augmentation therapy with human AAT protein is the only currently approved specific treatment for AATD-related emphysema, optimised treatment, both pharmacological and nonpharmacological, as well as recommended lifestyle changes, including a smoke-free environment, should be in line with the currently accepted clinical guidelines for lung disease. Some AAT protein variants (PI*Z) confer an increased risk of liver pathology, mainly liver cirrhosis resulting from hepatocytic accumulation of the abnormal AAT protein. Regular follow-up in a highly specialised AATD clinical centre is recommended. Other monogenic syndromes leading to a high risk of emphysema involvement are mainly linked to genes regulating connective tissue metabolism or telomerase functional activity.
Cite as: Chorostowska-Wynimko J, Janciauskiene S, Pelc M, et al. α1-Antitrypsin deficiency and other rare forms of emphysema. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 165–179 [https://doi.org/10.1183/2312508X.10018222].
- Page 180AbstractCorresponding author: Sarah Cullivan (sarahkcullivan@gmail.com)
Pulmonary arterial hypertension (PAH) is a progressive condition that is characterised by inflammation, remodelling and progressive luminal narrowing in the pulmonary vasculature. Diagnosis requires right heart catheterisation and demonstration of a mean pulmonary artery pressure >20 mmHg, pulmonary vascular resistance >2 Wood units and a pulmonary artery wedge pressure ≤15 mmHg. In the preceding decades, our understanding of the epidemiology, pathology and pathobiology of PAH has expanded. There is a greater appreciation of the importance of multidisciplinary care and individualised, goal-orientated treatment decisions. While current PAH therapies focus on three specific pathways, there are several promising emerging therapies on the horizon.
Cite as: Cullivan S, Gaine S. Pulmonary arterial hypertension. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 180–191 [https://doi.org/10.1183/2312508X.10018322].
- Page 192AbstractCorresponding author: Marion Delcroix (marion.delcroix@uzleuven.be)
Chronic thromboembolic PH (CTEPH) is a rare complication of acute pulmonary embolism (PE), in which the increased pulmonary vascular resistance results from persistent large-vessel fibrothrombotic obstruction combined with a secondary microvasculopathy. Symptoms such as exertional dyspnoea are nonspecific, and the diagnosis requires dedicated pulmonary perfusion imaging. Consequently, CTEPH is underdiagnosed and frequently misdiagnosed as acute PE. It should be suspected immediately when signs of PH and chronic pulmonary arterial obstructions are observed at echocardiography or at CT pulmonary angiography. The treatment is essentially surgical and consists of removing the intravascular material and the internal layer of the involved pulmonary arteries, called pulmonary endarterectomy. When patients are inoperable because of a disease that is too distal, a haemodynamic severity disproportionate to imaging abnormalities or severe comorbidities, medical therapy with PH drugs, targeting the microvasculopathy, and balloon pulmonary angioplasty, targeting (sub)segmental lesions, are recommended. The combination of these therapeutic approaches aiming to normalise pulmonary haemodynamics is currently recommended.
Cite as: 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 [https://doi.org/10.1183/2312508X.10018422].
- Page 204AbstractCorresponding author: David Montani (davidmontani@gmail.com)
PH may develop in the clinical course of certain orphan lung diseases and is typically associated with decreased survival. PH is usually related to the degree of pulmonary parenchymal involvement, but disproportionate involvement of the pulmonary vasculature can occur, particularly in diseases such as sarcoidosis, pulmonary Langerhans cell histiocytosis, neurofibromatosis type 1, combined pulmonary fibrosis and emphysema, and lymphangioleiomyomatosis. TBX4 syndrome is a genetic disorder typically affecting development of the lower extremities and lungs, but pulmonary vascular involvement can be observed and typically coexists with specific parenchymal findings. Pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) is a characteristic form of PH with preferential involvement of the pulmonary venous compartment. Its heritable form is associated with autosomal-recessive transmission due to mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene. PVOD/PCH is associated with a poor response to pulmonary arterial hypertension-specific therapy and results in a poor prognosis, necessitating early recognition and referral for lung transplantation.
Cite as: Montani D, Kularatne M, Jutant E, 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 [https://doi.org/10.1183/2312508X.10018522].
- Page 224AbstractCorresponding author: Laurent Savale (laurent.savale@aphp.fr)
A diagnosis of hepatopulmonary syndrome (HPS) is based on the clinical triad of liver disease and/or portal hypertension, intrapulmonary vascular dilation and abnormal arterial oxygenation. HPS is clearly identified as a significant comorbidity affecting both the functional status and prognosis of patients with chronic liver disease. Although substantial progress has been made in the description of the clinical characteristics and outcomes, no specific targeted therapy has been shown to have a long-term effect on the evolution of HPS. Liver transplantation, which remains the only option to reverse HPS, must be considered an essential option in the management of severe HPS (arterial oxygen tension <60 mmHg), regardless of the severity of the underlying liver disease. Progress in our understanding of the pathophysiological mechanisms involved in HPS and in the regulatory mechanisms between the liver and the lung circulation is needed to identify potential targeted therapies in the future.
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].
- Page 237AbstractCorresponding author: Katerina Antoniou (kantoniou@uoc.gr)
The respiratory system is frequently involved in the course of systemic inflammatory diseases with varying incidence and severity. Almost every part of the respiratory system can be affected, represented mainly by the airways, lung parenchyma, pleura, respiratory muscles and pulmonary vessels. Respiratory manifestations can also affect the course of the disease in a determinant or irreversible manner. Early detection of respiratory-related symptoms combined with the appropriate use of diagnostic tools and detailed physical examination can lead to early recognition of respiratory involvement in the context of systematic inflammatory disease. The rarity and complicated nature of such diseases make the multidisciplinary team crucial every time an important therapeutic decision has to be made.
Cite as: Vasarmidi E, Bibaki E, Antoniou K. Systemic inflammatory diseases with lung involvement. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 237–253 [https://doi.org/10.1183/2312508X.10018722].
- Page 254AbstractCorresponding author: Samuel Falde (falde.samuel@mayo.edu)
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.
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].
- Page 267AbstractCorresponding author: Loïc Guillevin (loic.guillevin@orange.fr)
Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis that primarily affects small- and medium-sized blood vessels. It is characterized by the presence of asthma and increased levels of eosinophils in the blood. While the presence of ANCA is not always observed, EGPA is classified as an ANCA-associated vasculitis, primarily affecting small-sized blood vessels. Although some clinical phenotypes and pathogenic mechanisms of this rare disease have been described, there are still gaps in our understanding of the condition. Recent advancements in EGPA management involve the use of various novel immunomodulatory drugs and biotherapies, which have been or are currently being assessed for their effectiveness. This chapter addresses the epidemiology, pathophysiology, clinical manifestations, outcomes and available therapeutic options for EGPA, including potential future treatments.
Cite as: Nguyen Y, Guillevin L. Eosinophilic granulomatosis with polyangiitis. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 267–280 [https://doi.org/10.1183/2312508X.10004223].
- Page 281AbstractCorresponding author: Vincent Cottin (vincent.cottin@chu-lyon.fr)
Eosinophilic pneumonia may manifest with a slowly progressive onset in chronic idiopathic eosinophilic pneumonia, or as the frequently severe acute eosinophilic pneumonia. The diagnosis is supported by blood eosinophilia >1×109 cells·L−1 (preferably >1.5×109 cells·L−1) when present, but this may be absent, for example in the early phase of idiopathic acute eosinophilic pneumonia or in patients already taking corticosteroids. BAL fluid showing high eosinophilia (>25%, and preferably >40% of the differential cell count) is considered diagnostic in a compatible setting, negating the need for video-assisted thoracic surgical lung biopsy. Possible causes of eosinophilic pneumonia must be investigated thoroughly, including medications, illicit drugs and infections, especially parasitic. Corticosteroids are the cornerstone of symptomatic treatment, with a generally dramatic response, but relapses are common when tapering or stopping treatment in idiopathic chronic eosinophilic pneumonia (ICEP). Evidence is accumulating for the efficacy of anti-interleukin-5 and anti-interleukin-5 receptor monoclonal antibodies as steroid-sparing agents in relapsing ICEP.
Cite as: Cottin V. Idiopathic eosinophilic pneumonias. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 281–292 [https://doi.org/10.1183/2312508X.10019022].
- Page 293AbstractCorresponding author: Francesco Bonella (francesco.bonella@rlk.uk-essen.de)
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.
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].
- Page 310AbstractCorresponding author: Heba M. Bintalib (Heba.bintalib.20@ucl.ac.uk)
Granulomatous and lymphocytic ILD (GLILD) is a rare noninfectious complication affecting patients with common variable immunodeficiency disorder (CVID). Although the pathophysiology is not fully understood, it is likely to involve autoimmune dysregulation. GLILD usually occurs together with other noninfectious complications, raising morbidity and mortality. The symptoms are cough and dyspnoea, but some patients remain asymptomatic. The clinical picture includes nodules, interlobular septal thickening, ground-glass opacities and splenomegaly on imaging. Lung function varies among patients but is typically restrictive with decreased gas transfer. Excluding malignancy and infection is necessary as these may cause similar clinical presentations. Lung biopsy can be performed to confirm the diagnosis. GLILD usually appears as mixed histological patterns, including lymphoid interstitial pneumonitis, follicular bronchiolitis, lymphoid hyperplasia, organising pneumonia and non-necrotising granuloma. Optimising immunoglobulin replacement therapy is essential before initiating treatment. Glucocorticoids remain the recommended first-line therapy; however, relapse usually occurs on dose tapering, and second-line immunosuppressants are recommended.
Cite as: Bintalib HM, Burns SO, Hurst JR. Granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 310–319 [https://doi.org/10.1183/2312508X.10019222].
- Page 320AbstractCorresponding author: Antonio Bobbio (antonio.bobbio@aphp.fr)
Although thoracic endometriosis is a rare disease, it is not uncommon in women of child-bearing age presenting with spontaneous pneumothorax. Other less frequent endometriosis-related conditions are pleural effusion including haemothorax, pulmonary and tracheobronchial implants, diaphragmatic hernia and chronic thoracic pain; when they arise during menses, these manifestations are referred to as catamenial. The principal pathway of endometriosis migration from the abdomen and into the thorax is through the right diaphragm, giving rise to a predominance of signs and symptoms on the right thoracic side; through the same route, the air could pass into the pleura. Imaging varies with the hormonal cycle, and the patient's gynaecological history is crucial for diagnosis. Formal diagnosis of endometriosis is almost always obtained at surgery by exploration of the extended pleura and excision of all visible lesions. A combined surgical and medical approach is necessary to control the disease.
Cite as: Bobbio A, de Pauw V, Lefqih I, et al. Thoracic endometriosis and catamenial pneumothorax. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 320–330 [https://doi.org/10.1183/2312508X.10019322].
- Page 331AbstractCorresponding author: Geert M. Verleden (geert.verleden@uzleuven.be)
Chronic lung allograft dysfunction (CLAD) remains one of the most important complications after lung transplantation, affecting 50% of patients by 5 years post-transplant. It is a major cause of morbidity and the leading cause of mortality beyond 5 years after the transplantation procedure. CLAD is characterised by a persistent and mostly progressive fall in forced expiratory volume in 1 s (FEV1) of >20% compared with the postoperative best FEV1 and is believed to be the consequence of chronic rejection. In recent years, it has become clear that different phenotypes of CLAD can be identified, based on the pulmonary function evolution and findings on chest imaging. In the present chapter, we will focus on the current definition of CLAD and its phenotypes, risk factors for its development, outcome and possible treatment options.
Cite as: Gimenez BS, Hellemons M, Verleden SE, et al. Chronic lung allograft dysfunction after lung transplantation. In: Wagner TOF, Humbert M, Wijsenbeek M, et al. eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 331–342 [https://doi.org/10.1183/2312508X.10019422].
- Page 343AbstractCorresponding author: Valentina Luzzi (valentinaluzzi@hotmail.com)
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.
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].
- Page 357AbstractCorresponding author: Katie Rose (katierose100@gmail.com)
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.
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].
- Page 367AbstractCorresponding author: Joachim G.J.V. Aerts (j.aerts@erasmusmc.nl)
Mesothelioma is a rare cancer with a poor prognosis despite aggressive treatments. In recent years, new treatment options have become available. This chapter provides a comprehensive overview of advances in the epidemiology, aetiology, carcinogenesis, clinical and radiological presentation, pathology, genetics, prognosis, biomarkers and treatment of pleural mesothelioma.
Cite as: Aerts JGJV, van Meerbeeck JP. Pleural mesothelioma. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 367–380 [https://doi.org/10.1183/2312508X.10019722].