98 - Pulmonary Alveolar Proteinosis Syndrome

Abstract

Pulmonary alveolar proteinosis (PAP) is a syndrome of alveolar surfactant accumulation resulting in progressive dyspnea of insidious onset, hypoxemic respiratory failure and, in some patients, secondary infections and/or pulmonary fibrosis. PAP-causing disease can be classified on the basis of the pathogenetic mechanism into primary PAP, which is characterized by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling either by GM-CSF autoantibodies (autoimmune PAP) or by mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor α and β chains (hereditary PAP), respectively; secondary PAP, which results from various underlying conditions that reduce alveolar macrophage numbers and/or functions; and disorders of surfactant production (historically called congenital PAP), which is caused by mutations in genes involved in surfactant production. The prevalence of PAP has been determined to be at least 7 per 1 million in large population studies and can occur in men, women, and children of all ages, ethnicities, and geographic locations, irrespective of socioeconomic status. Autoimmune PAP is more common in smokers. In most patients, pathogenesis is driven by reduced GM-CSF–dependent cholesterol clearance in alveolar macrophages, which impairs alveolar surfactant clearance. Autoimmune PAP accounts for more than 90% of all cases. Therapy depends on which PAP-causing disease is present; autoimmune PAP, hereditary PAP, and some forms of secondary PAP are currently treated by whole-lung lavage, which targets improving symptoms and quality of life but does not usually result in a durable clinical benefit. Genetic disorders of surfactant production can be treated by lung transplantation when respiratory failure becomes life-threatening. Novel pathogenesis-based therapies are in development for various PAP-causing diseases, including restoration of GM-CSF signaling, immune modulation, and cholesterol homeostasis.