Autoimmune pulmonary alveolar proteinosis (ORPHA:747)
A rare primary interstitial lung disease characterized by the accumulation of lipids and proteins related to surfactant in the alveoli in association with the presence of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). The disease leads to a progressive impairment of gas exchange and respiratory insufficiency.
Epidemiology
The prevalence of autoimmune pulmonary alveolar proteinosis (aPAP) ranges from 1/38,000 in Japan to 1/150,000 in the United States, although the latter figure is likely an underestimate due to underdiagnosis.
Clinical description
Patients are usually 20 to 50 years of age at presentation (although earlier presentation is possible) and onset is mostly gradual. Some patients have very mild or even no clinical manifestations of the disease (one third of cases). The clinical course is variable with some patients spontaneously improving, others remaining stable and a subset progressing in severity. Symptoms may include fatigue, malaise, weight loss, progressive and exertional dyspnea, persistent cough (dry or productive), and chest discomfort. Pulmonary hypertension and hemoptysis are rarely reported. The lower and rear lung regions are most commonly affected. The main complication is chronic respiratory insufficiency with cor pulmonale, lung infections, and more rarely pulmonary fibrosis.
Etiology
GM-CSF is required to stimulate and maintain alveolar macrophage differentiation and function, particularly to catabolize and remove surfactant from the alveolar space. Dysfunction of GM-CSF signaling mediated by GM-CSF autoantibodies results in abnormal surfactant accumulation, leading to the clinical respiratory manifestations of the disease. Dust and fume inhalation also seem to be associated with the development of aPAP. A large proportion of patients have a history of smoking.
Diagnostic methods
The disease is generally suspected on the basis of the clinical signs and disease history. High resolution computed tomography with crazy-paving pattern is supportive. Bronchoalveolar lavage (BAL) is the primary diagnostic method on suspicion of the disorder. Positive periodic acid-Schiff (PAS) staining on BAL is required for diagnosis. In serum, elevated autoantibody concentrations against GM-CSF confirms diagnosis. Transbronchial lung biopsy shows alveoli filled with non-foamy surfactant. Surgical lung biopsy is rarely required to confirm diagnosis. Chest X-ray is useful as follow-up investigation.
Differential diagnosis
Differential diagnoses include alveolar filling syndromes, like diffuse alveolar hemorrhage and lung edema, as well as infectious diseases (pneumocystis jrovecii pneumonia) and lung cancer.
Management and treatment
Treatment depends on the severity of the clinical manifestations. Whole-lung lavage to remove lipoproteinaceous material from the lungs is the therapy of choice and generally has a good success rate. Inhaled and systemic GM-CSF has proven to be beneficial in up to two-thirds of patients. B-lymphocyte depletion through rituximab administration also seems to be a valid option for aPAP. In particular, the latter treatment is still experimental. Patients with a severe course and respiratory failure may be candidates for lung transplantation.
Prognosis
Prognosis has improved with introduction of whole lung lavage and is now considered excellent in most, but not all cases.

                            Last update: 
                            July 2021


                            - Expert reviewer(s): 
                            Pr Matthias GRIESE | ERN-LUNG*


                                * European Reference Network