Specific diseases

There are no reliable epidemiological data for most rare respiratory diseases. Lung involvement in rare diseases may occur in various contexts: 1) rare disease limited to the lung (e.g. idiopathic alveolar proteinosis); 2) the lung involvement of a rare systemic disease (e.g. granulomatosis with polyangiitis (Wegener’s)); 3) a rare lung disease that may be either sporadic or inherited and possibly associated with multi-organ manifestations (e.g. lymphangioleiomyomatosis, sporadic or associated with tuberous sclerosis complex); and 4) an iatrogenic lung disease caused by treatment of a rare condition. 

Vasculitides of the lung 

Inflammation of the small blood vessels of the lung (pulmonary vasculitis) occurs as part of systemic disorders characterised by widespread inflammation of the vessels in several organs and associated with the presence of antineutrophil cytoplasmic autoantibodies (ANCAs):

  • Granulomatosis with polyangiitis particularly involves the upper respiratory tract, the lungs and the kidneys. Typical pulmonary features include radiographically visible multiple nodules, which are often cavitary, or consolidation (the filling of alveolar tissue with liquid). ANCAs are mainly cytoplasmic with anti-proteinase 3 specificity.
  • Microscopic polyangiitis often manifests in the lung by producing alveolar haemorrhage. ANCAs are mainly perinuclear with anti-myeloperoxidase specificity. Necrotising glomerulonephritis is usually associated (pulmonary–renal syndrome).
  • Eosinophilic granulomatosis with polyangiitis (Churg– Strauss syndrome) is particularly characterised by severe asthma and a raised blood eosinophil count, together with eosinophilic pneumonia and, often, myocardial involvement resulting in heart failure.

The cornerstones of treatment of these vasculitides are corticosteroids, immunosuppressive drugs, and the monoclonal antibody rituximab.

Inflammation of the larger blood vessels (large-vessel vasculitis) may also include pulmonary involvement:

  • Behçet’s disease, characterised by recurrent oral and genital ulcers with relapsing uveitis, may be associated with pulmonary artery aneurysms, the risk of rupture and pulmonary artery thrombosis.
  • Takayasu’s arteritis is a chronic inflammation of the aorta and its branches, and less commonly of the pulmonary arteries.

Alveolar haemorrhage syndromes  

The main manifestations of diffuse alveolar haemorrhage are haemoptysis (coughing up blood), diffuse alveolar opacities on imaging and rapidly increasing anaemia. Bronchoalveolar lavage retrieving bloody fluid is the key to diagnosis. Associated glomerulonephritis is present in small-vessel vasculitis with alveolar haemorrhage, and in the anti-basement membrane (Goodpasture’s) syndrome. Other causes of alveolar haemorrhage syndrome are numerous and include infectious diseases such as leptospirosis. 


Inflammation and fibrosis of the small airways result in airflow obstruction. Causes include inhalation of toxins, gases and dusts, lung transplantation, graft-versus-host disease and inflammatory intestinal disorders. Bronchiolitis may develop in patients with rheumatoid arthritis and in patients with inflammatory interstitial diseases. It may also be idiopathic. Airflow obstruction and characteristic high-resolution computed tomography (HRCT) features (centrilobular micronodules, ‘tree-in-bud’ pattern, mosaic pattern) are the main diagnostic signs.

Idiopathic eosinophilic pneumonias

Idiopathic chronic eosinophilic pneumonia manifests as dyspnoea, patchy/diffuse alveolar opacities on imaging and high blood eosinophil count. It may also be associated with asthma. The response to corticosteroids is dramatic but relapses are very common. Idiopathic chronic eosinophilic pneumonia may also be drug-induced or occur in association with diseases caused by parasitic (worm) infestation.

Acute eosinophilic pneumonia results in an adult respiratory distress-like syndrome with alveolar eosinophilia contrasting with the initial absence of blood eosinophilia. It improves with or without corticosteroids. Recent commencement of smoking frequently precedes its development.

Pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis is characterised by deposition of surfactant-like material in the alveoli, and is an autoimmune condition associated with autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). Alveolar opacities and ground-glass attenuation with a so-called ‘crazy paving’ pattern on HRCT are characteristic of the disorder. Bronchoalveolar lavage retrieving milky fluid allows diagnosis. Whole-lung lavage is the standard treatment, but inhaled exogenous GM-CSF has become an efficient therapy for this condition.

Idiopathic tracheopathies

The key tools for diagnosis of tracheal disorders are HRCT and endoscopy.

Tracheobronchopathia osteochondroplastica is characterised by osseous submucosal nodules projecting into the tracheal lumen. It manifests as chronic cough and usually has a benign clinical course.

Tracheobronchomegaly (Mounier–Kuhn syndrome) is associated with chronic cough and recurrent respiratory infections.

Both relapsing polychrondritis and granulomatosis with polyangiitis may involve the trachea and eventually result in severe stenosis (narrowing) of the trachea.

Primary ciliary dyskinesia

Primary ciliary dyskinesia is an autosomal recessive disease with abnormalities of the cilia of airway epithelial cells. It results in impaired mucociliary clearance, with ensuing chronic recurring sinopulmonary infections, further diffuse bronchiectasis and, eventually, chronic respiratory failure.

Thoracic endometriosis and catamenial pneumothorax

Endometriosis in women sometimes affects the respiratory system and may cause pneumothorax (air between the lung and chest wall) around the time of menstruation (catamenial pneumothorax). It has been suggested that as many as one-third of pneumothoraces in young women referred for surgery may be due to this condition.

Multiple cystic lung diseases

These conditions often give rise to pneumothorax, which is the most common presenting manifestation. Extensive lung cysts may result in airflow obstruction and chronic respiratory failure.

Sporadic lymphangioleiomyomatosis (LAM) is a disorder occurring in young women. It may be associated with tuberous sclerosis complex, a disorder of genetic origin (TSC1 and TSC2 genes) with frequent skin and neurological manifestations, in addition to pulmonary features. Associated angiomyolipoma(s) are common. Guidelines for the diagnosis and management of LAM have been published by an ERS Task Force.

Pulmonary Langerhans’ cell histiocytosis develops in smokers, with HRCT showing diffuse nodules which may cavitate, giving rise to cysts. Improvement has been reported with cladribin.

The Birt–Hogg–Dubé syndrome, which is related to mutations of the FLCN gene, is characterised by a family history of pneumothorax, cutaneous lesions, and a strongly increased risk of kidney cancer.

Other causes of multiple lung cysts include congenital cystic disorders, cavitating metastases of malignancies (especially sarcomas), pulmonary infection by Pneumocystis jiroveci or Staphylococcus, and lymphoid interstitial pneumonia.

See the entire Rare and orphan lung diseases Chapter