European Respiratory Society

Orphan Lung Diseases (out of print)

Edited by J-F. Cordier
Orphan Lung Diseases (out of print)

This book has been superseded by a newer edition. Orphan lung diseases differ from the more common pulmonary disorders, due to the fact that the respiratory physician will only see a few of them each year or even during their career. However, as a specialist, it is necessary to identify and confirm such a diagnosis in a patient. This Monograph comprehensively covers the most common and/or complex of these orphan lung diseases. This Monograph should be seen as a solid companion for the respiratory specialist each time they need to consider a diagnosis of one of these orphan diseases.

  • European Respiratory Society Monographs
  1. Page v
  2. Page vi
  3. Page vii
  4. Page 1
    Correspondence: U. Specks, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail:

    Granulomatosis with polyangiitis (Wegener’s) (GPA) is part of the family of small vessel vasculitides associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). The pathogenesis of the disease is currently not completely understood but probably involves the loss of self-tolerance, leading to the expression of characteristic autoantibodies (ANCA), which in turn may promote the development of systemic vasculitis. Respiratory manifestations of GPA are common and their severity varies widely, from asymptomatic lung nodules to nonspecific respiratory symptoms related to large airway involvement and to life-threatening alveolar haemorrhage. Pulmonary disease often requires both pharmacological and nonpharmacological therapies and the choice of agents depends on the extent of disease (limited versus severe) and stage of treatment (remission induction versus maintenance). The cornerstone of therapy has been immunosuppression with remission induction requiring the combination of glucocorticoids with cyclophosphamide (CYC). This paradigm has now been challenged, as rituximab (RTX) has been shown to be non-inferior to CYC for remission induction in newly diagnosed patients with GPA and microscopic polyangiitis, but superior to CYC for treatment of severe disease relapses. RTX has also emerged as the de facto standard of care for patients with refractory GPA.

  5. Page 15
    Correspondence: R. Lazor, Service de Pneumologie, Centre Hospitalier Universitaire Vaudois, BU44/07, Rue du Bugnon 44, 1011 Lausanne, Switzerland. Email:

    Alveolar haemorrhage (AH) is a rare and potentially life-threatening condition characterised by diffuse blood leakage from the pulmonary microcirculation into the alveolar spaces due to microvascular damage. It is not a single disease but a clinical syndrome that may have numerous causes. Autoimmune disorders account for fewer than half of cases, whereas the majority are due to nonimmune causes such as left heart disease, infections, drug toxicities, coagulopathies and malignancies. The clinical picture includes haemoptysis, diffuse alveolar opacities at imaging and anaemia. Bronchoalveolar lavage is the gold standard method for diagnosing AH. The lavage fluid appears macroscopically haemorrhagic and/or contains numerous haemosiderin-laden macrophages. The diagnostic work-up includes search for autoimmune disorders, review of drugs and exposures, assessment of coagulation and left heart function, and search for infectious agents. Renal biopsy is often indicated if AH is associated with renal involvement, whereas lung biopsy is only rarely useful. Therapy aims at correction of reversible factors and immunosuppressive therapy in autoimmune causes, with plasmapheresis in selected situations.

  6. Page 32
    Correspondence: O. Uzun, 19 Mayıs Universitesi, Tıp Fak, Göğüs Hst. ABD 55139, Kurupelit, Samsun, Turkey. Email:

    Behçet’s disease (BD) is an inflammatory disorder characterised by a triad of recurrent oral and genital ulcers with relapsing uveitis. There is a predilection of young male patients for pulmonary involvement in BD. Pulmonary artery aneurysm (PAA) and pulmonary artery thrombosis without aneurysm are the most frequent types of pulmonary involvement in BD. Thrombi within PAA is common. Death usually occurs due to massive haemoptysis in patients with PAA. Immunosuppresion is the main therapy for pulmonary vasculitis in BD.

    Takayasu’s arteritis (TA) is a chronic inflammatory disease of medium- and large-sized arteries that commonly affects the aorta, its main branches and to a lesser extent the pulmonary arteries. TA is most common in young females in their second and third decades of life, and affects them approximately 10 times more often than males. Granulomatous inflammation most commonly involves the aorta and its major branches, and symptoms result from the stenosis, occlusion and aneurysm of involved arteries. Pulmonary artery involvement is nearly always associated with the involvement of the aorta or its branches. Immunosuppresion, with or without surgery, constitute the main treatment options in TA.

  7. Page 46
    Correspondence: J.F. Cordier, Dept of Respiratory Diseases, Reference Center for Rare Pulmonary Disease, Louis Pradel Hospital, Claude Bernard University, Lyon (Bron) 69677, France. Email:

    Multiple cystic lung disease (MCLD) is defined by the presence of multiple, round, parenchymal lucencies of low-attenuating area that have a well-defined interface with a normal lung and a wall thickness <2 mm. The three major causes of MCLD are lymphangioleiomyomatosis (either sporadic or associated with tuberous sclerosis) Langerhans' cell histiocytosis and, recently, Birt–Hogg–Dubé syndrome, which is associated with mutations of the folliculin (FLCN) gene.

    These disorders are associated with extrapulmonary manifestations that may strongly contribute to diagnosis. Other causes of MCLD include lymphoid disorders of the lung, especially in Sjögren’s syndrome, with further recent descriptions of: nonamyloid immunoglobulin deposition disease; infections; malignancies, especially metastases of sarcomas; desquamative interstitial pneumonia; hypersensitivity pneumonitis; and a variety of other disorders.

    MCLD is a rare computed tomography imaging syndrome often associated with pneumothorax resulting mostly from rare orphan disorders.

  8. Page 84
    Correspondence: V. Poletti, Dipartimento Toracico, Ospedale GB Morgagni, Via Forlanini 34, 47100 Forlì, Italy. Email:

    Bronchiolitis may be defined as an inflammatory and fibrosing disorder, centred in and around the membranous and/or respiratory bronchioles, sparing a considerable portion of the other parenchymal structures and usually with a mild involvement of the larger airways. Damage to the bronchiolar epithelium is considered the first step of the process. Most cases of bronchiolitis are infectious in nature or related to the inhalation of toxins, dusts or gases. Other causes of bronchiolitis include drugs, collagen vascular disease, graft versus host disease, lung transplantation, chronic occult aspiration and inflammatory bowel disease. Although an aetiological classification is useful for reminding the physician when to suspect the presence of bronchiolitis, the more convenient classification scheme is based on histological characteristics. Histological patterns (cellular bronchiolitis, bronchiolitis with inflammatory or intraluminal polyps, constrictive or cicatricial bronchiolits, peribronchial fibrosis and bronchiolar metaplasia) generally show an improved correlation with the radiological manifestations, the natural history of disease and the response to therapy.

  9. Page 104
    Correspondence: B.W. Kinder, 2055 Hospital Drive, Suite 200, Batavia, OH 45103, USA. Email:

    The aetiology and classification of interstitial lung diseases have been a challenge for many years. Recent data suggests that a particular subset of patients previously classified as having an idiopathic interstitial pneumonia have extrathoracic symptoms and signs, laboratory features, and histopathological findings that are suggestive of an autoimmune aetiology of their interstitial lung diseases when carefully assessed. Although data are limited, it appears that patients with interstitial lung diseases and autoimmune features may have a better prognosis and be more responsive to treatment than patients with idiopathic pulmonary fibrosis. Barriers to appropriate case recognition and classification need to be addressed at local, national, and international levels.

  10. Page 118
    Correspondence: V. Cottin, Service de pneumologie, Hôpital Louis Pradel, University Claude Bernard Lyon I, UMR754, 69677 Lyon (Bron) Cedex, France. Email:

    Eosinophilic pneumonias may manifest as chronic or acute eosinophilic pneumonia or as Löffler syndrome. Known causes must be thoroughly investigated, especially exposure to drugs or toxic substances and fungi.

    Idiopathic chronic eosinophilic pneumonia presents with chronic onset of dyspnoea, cough, weight loss, fatigue, mild fever and patchy alveolar infiltrates, predominating in the upper lobes and in the peripheral areas of the lungs and possibly migratory. Blood and alveolar eosinophilia is the key to the diagnosis. Response to oral corticosteroids is dramatic, but with frequent relapses.

    Idiopathic acute eosinophilic pneumonia develops in <1 month in previously healthy young adults, with progressive dyspnoea, fever, chest pain and possible respiratory failure. It may be triggered by initiation of tobacco smoking. Chest imaging typically shows ground-glass attenuation and airspace consolidation, with bilateral pleural effusion and interlobular thickening. Blood eosinophilia is usually lacking at presentation, and the diagnosis is confirmed by alveolar eosinophilia. Corticosteroid treatment is usually given for 2–4 weeks, with no relapse.

  11. Page 140
    Correspondence: L. Guillevin, INSERM U1060, Dept of Internal Medicine, Hôpital Cochin, Université Paris Descartes, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France. Email:

    Churg–Strauss syndrome (CSS) is a rare small- and medium-sized vessel vasculitis, which is characterised by a constant association with asthma and eosinophilia and, in approximately 40% of patients, the presence of antimyeloperoxidase and antineutrophil cytoplasmic antibodies (ANCA). Vasculitis typically develops in a previously asthmatic and eosinophilic middle-aged patient, and most frequently involves the peripheral nerves and skin. However, other organs may be affected and must be screened for vasculitis, especially those associated with a poor prognosis, such as the heart, kidney and gastrointestinal tract, as assessed by the recently revised Five-Factor Score. Overall survival of CSS patients is good but relapses are not uncommon and require maintenance or steroid-sparing therapies. All patients require corticosteroids, often for prolonged periods, combined with immunosuppressants, e.g. induction (cyclophosphamide) and maintenance therapy (azathioprine), for those with poor prognoses. Recent insights, especially concerning clinical differences associated with ANCA status, showed that CSS patients might constitute a heterogeneous group, both clinically and pathogenically.

  12. Page 152
    Correspondence: H.J. Lachmann, National Amyloidosis Centre, Dept of Medicine, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. E-mail:

    Amyloid fibrils can both complicate long-standing respiratory conditions and be deposited within the respiratory system itself. The manifestations, significance and prognosis of amyloid deposits are dependent on their aetiology and anatomical distribution. Amyloidosis is extremely heterogeneous and can be benign or life threatening. Each patient therefore requires thorough evaluation to determine the extent and significance of amyloid deposition and to ensure the optimal treatment. In most cases of localised amyloidosis, disease management is essentially supportive and involves resection or ablation of symptomatic deposits. In contrast, systemic anti-inflammatory treatment and chemotherapy can be extremely effective in patients with the systemic AA and AL forms of the disease. Encouragingly, the development of specific drug therapies to stabilise amyloid precursor proteins, interfere with amyloid fibrillogenesis and accelerate the clearance of tissue amyloid deposits are all on the horizon.

  13. Page 171
    Correspondence: U. Costabel, Dept of Pneumology and Allergology, Ruhrlandklinik, Tueschener Weg 40, 45239 Essen, Germany. Email:

    Pulmonary alveolar proteinosis (PAP) is a rare and heterogeneous group of disorders characterised by abundant deposition of surfactant-like material in the alveoli. The autoimmune form, distinguished by the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, accounts for 90% of cases. Secondary PAP is GM-CSF autoantibody negative and is associated with infections, haematological disorders and inhalation exposure. There are several conditions mimicking PAP and the crazy paving pattern on computed tomography can be shared with infections, neoplasm, other interstitial lung diseases, inhalation disorders and pulmonary haemorrhage syndromes. A diagnostic strategy based on bronchoalveolar lavage and the detection of serum GM-CSF autoantibodies allows uncertain clinical and radiological pictures to be clarified.

    Whole lung lavage (WLL), the gold standard for treatment of PAP, can induce complete remission in ∼50% of cases. Administration of exogenous GM-CSF, preferably by inhalation, alone or in combination with WLL, seems to be a promising approach for patients with autoimmune PAP resistant to WLL alone. The treatment of secondary PAP should focus on the underlying disease: the role of WLL and GM-CSF in this disorder needs clarification.

  14. Page 187
    Correspondence: J.H. Ryu, Division of Pulmonary and Critical Care Medicine, Gonda 18 South, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. -mail:

    Tracheal diseases are most commonly infectious or neoplastic in nature. However, there are several tracheal disorders of obscure aetiology that pulmonologists need to be aware of, particularly since tracheal diseases can easily be overlooked in patients presenting with nonspecific respiratory complaints. These include tracheobronchopathia osteochondroplastica, idiopathic tracheal stenosis, tracheomalacia and tracheobronchomegaly (Mounier-Kuhn syndrome), as well as tracheal involvement in systemic disorders such as relapsing polychondritis, granulomatosis with polyangiitis (Wegener’s), sarcoidosis and amyloidosis.

    Diagnostic evaluation includes computed tomography scanning and bronchoscopy to identify the cause, character and distribution of abnormalities, the severity of airway compromise, and associated intrathoracic findings such as lymphadenopathy. Treatment of tracheal disease depends on the nature of the underlying lesion, its severity, and the presence or absence of associated systemic disease. Bronchoscopic interventions including laser therapy and stent placement can benefit patients with stenotic tracheal lesions as well as those with collapsible airways from malacia. In those patients with tracheal involvement in systemic disorders, the underlying disease needs to be treated.

  15. Page 201
    Correspondence: J.S.A. Lucas, Primary Ciliary Dyskinesia Centre, University Child Health, Infection Inflammation and Immunity (MP 803), NIHR Respiratory Biomedical Research Unit, Southampton University Hospitals NHS Trust, Tremona Road, Southampton, SO16 6YD, UK. Email:

    Primary ciliary dyskinesia (PCD) is an autosomal recessive disease with an incidence estimated between 1:2,000 and 1:40,000. Ciliated epithelia line the airways, nasal and sinus cavities, Eustachian tube and fallopian tubes. Congenital abnormalities of ciliary structure and function impair mucociliary clearance. As a consequence, patients present with chronic sinopulmonary infections, recurrent glue ear and female subfertility. Similarities in the ultrastructure of respiratory cilia, nodal cilia and sperm result in patients with PCD also presenting with male infertility, abnormalities of left-right asymmetry (most commonly situs inversus totalis) and congenital heart disease. Early diagnosis is essential to ensure specialist management of the respiratory and otological complications of PCD. Diagnostic tests focus on analysis of ciliary function and electron microscopy structure. Analysis is technically difficult and labour intensive. It requires expertise for interpretation, restricting diagnosis to specialist centres. Management is currently based on the consensus of experts, and there is a pressing need for randomised clinical trials to inform treatment.

  16. Page 218
    Correspondence: C.L. Shovlin, HHTIC London, Dept of Respiratory Medicine, Hammersmith Hospital, Du Cane Rd, London, W12 0NN, UK. Email:

    Pulmonary arteriovenous malformations (PAVMs) are vascular structures that provide a direct capillary-free communication between the pulmonary and systemic circulations. The majority of patients have no PAVM-related symptoms, but are at risk of major complications that can be prevented by appropriate interventions. More than 90% of PAVMs occur as part of hereditary haemorrhagic telangiectasia (HHT), the genetic condition most commonly recognised by nosebleeds, anaemia due to chronic haemorrhage, and/or the presence of arteriovenous malformations in pulmonary, hepatic or cerebral circulations. Patients with HHT are also at higher risk of pulmonary hypertension and pulmonary embolic disease, management of which can be compounded by other aspects of their HHT.

    This chapter primarily addresses PAVMs and pulmonary HHT in the clinical setting, in order to improve patient care. Clinical presentation patterns, diagnostic strategies and management options are presented in detail. Relevant pathophysiological mechanisms discussed include new topics for the PAVM literature, such as the alveolar transit of venous bubbles during diving and contrast echocardiography.

  17. Page 246
    Correspondence: R. Rodríguez-Roisin, Servei de Pneumologia (Institut del Tòrax), Hospital Clínic, Villarroel 170, CP-08036 Barcelona, Spain. Email:

    Hepatopulmonary syndrome (HPS) is characterised by a defect in arterial oxygenation induced by pulmonary vascular dilatation in the setting of liver disease. Patients of all ages can be affected. This clinical syndrome has three components: liver disease; pulmonary vascular dilatation; and a defect in oxygenation. A classification of the severity of HPS based on abnormalities in arterial oxygenation is vital because severity influences survival and is useful in determining the timing and risks of orthotopic liver transplantation, currently the only therapeutic approach for HPS. Gas exchange abnormalities primarily reflect a widespread non-uniform dilatation of the pulmonary vasculature at both the pre-capillary and capillary levels, to allow mixed venous blood to pass either quickly or even directly into the pulmonary veins, thus minimising overall arterial oxygen saturation. This structural derangement is vital for the development of ventilation–perfusion imbalance, the dominant mechanism of underlying arterial hypoxaemia; although uncommon, pulmonary and pleural arteriovenous communications may also be present. A better understanding of the pathophysiology underlying pulmonary gas exchange abnormalities is vital for the current management of HPS.

  18. Page 265
    Correspondence: M. Alifano, Service de Chirurgie Thoracique, Hôtel-Dieu, 1, Place du Parvis Notre-Dame, 75181 Paris, France. Email:

    Catamenial pneumothorax is defined as a recurrent pneumothorax occurring within the first 72 h from the onset of menstruation, and is often associated with thoracic endometriosis. However, cases of endometriosis-related non-catamenial pneumothorax and non-catamenial but endometriosis-related pneumothorax have been described and should be kept in mind during the differential diagnostic process. Although, until recently, considered rare conditions, it is now accepted that these types of pneumothorax account for approximately one-third of all pneumothorax in females referred for surgery. These pneumothoraxes represent the most frequent manifestations of the thoracic endometriosis syndrome, which includes three other well-recognised clinical entities, namely catamenial haemothorax, catamenial haemoptysis and endometriotic lung nodules, as well as some exceptional presentations. Aetiological mechanisms are not well understood, and different theories (coelomic metaplasia, lymphatic or haematogenous embolisation and retrograde menstruation with subsequent transabdominal–transdiaphragmatic migration of endometrial tissue) have been proposed. Controversies exist about optimal management, as experience is drawn from case reports and relatively small clinical series. Surgery, hormonal treatments and combined approaches have all been proposed, with variable results in terms of short- and long-term outcome.

  19. Page 282
    Correspondence: L. Richeldi, Center for Rare Lung Disease, University Hospital Policlinic of Modena, Via del Pozzo 71, 41124 Modena, Italy. Email:

    Cigarette smoking has a clear epidemiological association with lung diseases, characterised by chronic inflammation of both the bronchiolar and the interstitial lung compartments. There are several different smoking-related interstitial lung diseases, mainly desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease and pulmonary Langerhans’ cell histiocytosis. The epidemiology of such diseases is largely unknown, although the prevalence of cigarette smoking, particularly in low-income developing countries, indicates that smoking-induced interstitial lung disorders represent a high burden of disease worldwide. The role of chest high-resolution computed tomography has become increasingly important in differential diagnosis and follow-up. A new entity, the syndrome of combined pulmonary fibrosis and emphysema, emerged as another important smoking-related lung disorder with a poor prognosis, associated with the high prevalence of pulmonary hypertension. At the moment the role of anti-inflammatory and immunosuppressive treatment remains unclear, although in clinical practice most of these patients will receive at least one course of corticosteroid therapy. It is vital to stress the importance of identifying these patients and helping them quit smoking.

  20. Page 301
    Correspondence: C.M.S. Robalo Cordeiro, Dept of Pulmonology and Allergy, University Hospital of Coimbra, Rua Mota Pinto, Coimbra 3000, Portugal. Email:

    When treating a patient suffering from interstitial lung disease (ILD), the clinician must carry out a detailed occupational and environmental history based on a high degree of clinical suspicion.

    Organic dusts are an increasing cause of occupational exposure and respiratory disease. The mechanisms by which this exposure leads to disease are, however, poorly understood. The combination of case reports and large clinical trials may help to identify new noxious exposures. It is essential that there is clarification about the mechanisms.

    Despite the implemented preventive strategies, pneumoconiosis still accounts for a significant proportion of ILDs. New sources of exposure, newly identified agents and the present critical economic climate may contribute to the persistance of this disease, making closer surveillance and prevention a priority.

    Also, more knowledge regarding the toxicological effects of nanoparticles is fundamental, regarding the increased concern of potential harmful exposures in public and occupational settings. Finally, for an ILD to be considered idiopathic all the possible aetiologic factors, including environmental or occupational, have to be excluded.

  21. Page 317
    Correspondence: D. Montani, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie, Hôpital Antoine-Béclère, Assistance Publique – Hôpitaux de Paris, Université Paris-Sud 11, 157 rue de la Porte de Trivaux, 92140 Clamart, France. Email:

    Pulmonary hypertension (PH) may occur in patients presenting with orphan lung diseases, and is associated with a decreased survival. Development of PH is usually related to chronic respiratory failure, but its mechanisms may vary profoundly between diseases. Of note, some patients may develop disproportionate pulmonary vascular involvement, affecting possibly the venous compartment particularly in the case of sarcoidosis and histiocytosis.

    In sarcoidosis, PH is usually caused by the fibrotic destruction of the pulmonary vascular bed or by chronic hypoxaemia. PH may also be induced by distal vasculopathy or extrinsic compression of pulmonary arteries.

    In pulmonary Langerhans’ cell histiocytosis, PH is frequently reported in patients with advanced lung impairment, but is regularly unrelated to lung parenchymal injury, affecting the venous compartment. Severe PH is frequently reported in patients with combined pulmonary fibrosis and emphysema syndrome. PH was initially described in neurofibromatosis type 1 (NF1) patients with advaned parenchymal lung disease, but cases of NF1-associated PH were recently reported. Lymphangioleiomyomatosis patients may rarely develop a mild or moderate PH related to the severity of pulmonary involvement.

  22. Page 332
    Correspondence: J. Gottlieb, Dept of Respiratory Medicine, Hannover Medical School, OE6870, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Email:

    Lung transplantation is a suitable treatment to improve survival of patients with various end-stage pulmonary diseases. Lung transplantation is an orphan therapy with an annual incidence of approximately five procedures per million inhabitants in most Western countries. Orphan lung diseases account for ∼5% of all indications. Lymphangioleiomyomatosis (LAM), obliterative bronchiolitis and pulmonary manifestations of connective tissue diseases are the major indications among these.

    Some of these orphan diseases have systemic manifestations that may lead to special post-transplant problems and must be investigated carefully before transplantation. Typical post-operative complications in LAM include intraoperative intrathoracic bleeding, chylothorax, pneumothorax, and bleeding of angiomyolipomas. In Langerhans’ cell histiocytosis X, extrapulmonary manifestations in the bones and pituitary gland may progress after transplantation. Some orphan diseases typically recur in the allograft, but these recurrences may be asymptomatic. Long-term results of large volume centres demonstrate improving results after lung transplantation. Bronchiolitis obliterans syndrome and infections are the main causes of death. Survival of patients with orphan diseases is similar to patients receiving transplants for other diseases or even superior.

  23. Page 341
    Correspondence: N. Girard, Dept of Respiratory Medicine, Reference Center for Rare Pulmonary Disease, Louis Pradel Hospital, Claude Bernard University, Lyon (Bron) 69677, France. Email:

    Rare neoplastic and non-neoplastic disorders may develop in the lung, pleura and mediastinum. Some disorders may have a propensity to mimic lung carcinoma at some level of examination, as they may share clinical, radiological, pathological and even molecular features. The term “pseudo-tumour” has widely been used to designate such disorders, but now refers to a heterogeneous group of diseases characterised by circumscribed fibrous tissue and inflammatory cells. Among these inflammatory pseudo-tumours, neoplastic/non-neoplastic borderline disorders have been identified, such as inflammatory myofibroblastic tumour, which present with clonal proliferation and have emerged as a true neoplasm.

    The management of pulmonary pseudo-tumours and reciprocal mimics of neoplastic and non-neoplastic disorders involves a specific strategy that is similar to that developed for both orphan diseases and rare pulmonary malignancies. The main points are: the identification of suggestive clinical and radiological features; the cautious interpretation of small-size biopsies, which may not be representative enough of the tumour as a whole; the realisation of specific molecular analyses that may have diagnostic and predictive value for therapeutics; and, ultimately, a dedicated multidisciplinary expert consensus.

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