Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by the accumulation of surfactant within alveolar macrophages and alveoli that impairs pulmonary gas transfer and is associated with a wide range of clinical manifestations ranging from asymptomatic respiratory insufficiency to respiratory failure and death.1-4 Pulmonary surfactant is a complex mixture of lipids and proteins vital to lung structure, function and host defense. Recent advances from basic science, clinical medicine and translational research have advanced our understanding of PAP, which is now recognized as a syndrome including heterogeneous disorders widely varying etiologies, pathogenesis, natural history, treatment approaches and prognosis.1,2,5-8 PAP belongs to a larger group of disorders of surfactant homeostasis that include (1) disorders of surfactant production and (2) disorders of surfactant clearance. Surfactant production disorders include several genetic diseases that are now known to cause pulmonary surfactant metabolic dysfunction (PSMD disorders). Diseases in this category include various mutations in genes that encode surfactant proteins (e.g., surfactant protein (SP)-B, SP-C),9 or proteins involved in surfactant lipid metabolism (e.g., ABCA3).10 While these disorders disrupt surfactant homeostasis to varying degrees, they are distinguished from PAP by their surfactant dysfunction, and widely differing clinical courses. PAP syndrome belongs to the second category, disorders of surfactant clearance, which can be grouped into primary and secondary clinical forms.1 Primary PAP is caused by disruption of signaling by the cytokine, granulocyte/macrophage- colony stimulating factor (GM-CSF),11 a role initially identified by research in GM-CSF deficient mice12,13 and recently confirmed in humans.14 Secondary PAP occurs as a consequence of the presence of one of several underlying diseases known to be associated with and thought to cause PAP. Research in animal models of PAP and humans with primary PAP revealed the critical role that GM-CSF plays in pulmonary surfactant homeostasis, and lung host defense. Based on a recent metaanalysis representing most or all cases of PAP reported in the medical literature through 19992 and a large contemporaneous study of PAP in Japan,4 ninety percent of cases are of the primary PAP clinical form and are strongly associated with neutralizing GM-CSF autoantibodies. This chapter will review the pathogenesis, classification, epidemiology, and clinical aspects of the PAP syndrome, focusing on primary PAP, and will emphasize progress since the previous edition of this textbook.