Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach

Pulmonary alveolar proteinosis (PAP) is a diffuse lung disease that results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages due to abnormal surfactant homoeostasis. Identification of the granulocyte–macrophage colony-stimulating factor (GM-CSF) as an indispensable mediator of macrophage maturation and surfactant catabolism was the key discovery leading to the current understanding of the pathogenesis of most forms of PAP. Impaired GM-CSF bioavailability due to anti-GM-CSF autoimmunity is the cause of approximately 90% of adult PAP cases. Abnormal macrophage function due to endogenous or exogenous triggers, GM-CSF receptor defects, and other genetic abnormalities of surfactant production account for the remainder of causes. The usual physiological consequence of PAP is impairment of gas exchange, which can lead to dyspnoea, hypoxaemia, or even respiratory failure and death. Pulmonary fibrosis occurs occasionally in patients with PAP. For patients with moderate to severe disease, whole lung lavage is still the first-line treatment of choice. Supplemental GM-CSF is also useful, but details about indications, choice of agent, and dosing remain unclear. Other therapies, including rituximab, plasmapheresis, and lung transplantation have been described but should be reserved for refractory cases.