Treatment of Pulmonary Alveolar Proteinosis

Abstract

Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by the disruption of pulmonary surfactant homeostasis that results in hypoxemic respiratory insufficiency (Trapnell et al. 2003). The syndrome occurs in a heterogeneous group of distinct diseases usefully divided into disorders of surfactant production and disorders of surfactant clearance. The former comprises disorders caused by mutations in genes required for normal surfactant production (e.g., SFTPB, SFTPC, ABCA3, NKX2.1). Disorders of surfactant clearance can be further divided into primary and secondary PAP. Primary PAP is caused by disruption of GM-CSF signaling, either due to neutralizing granulocyte-/macrophage-colony-stimulating factor (GM-CSF) autoantibodies as occurs in the disease autoimmune PAP or due to mutations in the genes encoding the GM-CSF receptor alpha or beta genes (CSF2RA or CSF2RB). Secondary PAP is caused by another disease or condition that reduces either alveolar macrophage numbers or surfactant clearance (and other) functions. These include hematologic diseases (most commonly myelodysplasia), immune deficiency/chronic inflammatory diseases, toxic inhalation disorders (e.g., respirable silica, aluminum, titanium), and drug-induced phospholipidoses (e.g., cationic amphiphilic drugs such as amiodarone, fluoxetine, gentamicin) (Trapnell and Luisetti 2015). Whole lung lavage is widely held to be therapeutically effective in patients with autoimmune PAP and hereditary PAP, and is also effective in some diseases associated with Secondary PAP but is not effective in patients surfactant production disorders. Off-label use of GM-CSF has been studied in autoimmune PAP and appears to be effective, however, further studies are needed to establish safety and to identify an optimal dose. These and other therapeutic approaches are reviewed in this chapter.