Orphan Lung Diseases (out of print)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.