Rosen, Castleman, and Liebow described pulmonary alveolar proteinosis (PAP) more than 50 years ago.¹ Currently, there are three main forms of PAP: hereditary, secondary, and autoimmune, the last type by far the most frequent (Table 28.1).^2,3 Autoimmune PAP has previously been termed “idiopathic,” “acquired,” or the “adult type” of PAP.

All three types of PAP have in common impaired clearance of surfactant by alveolar macrophages, which normally catabolize surfactant via the granulocyte-monocyte colony-stimulating factor (GM-CSF) receptor.²

Various mutations have been associated with congenital PAP, the rarest form, including mutations in the CSF2RA and CSF2RB genes, encoding alpha and beta chains of the GM-CSF receptor, respectively, mutations in the SFTPB (surfactant protein B) gene, and the gene encoding for ABC transporter A3.^2,3 The majority of congenital pulmonary alveolar proteinoses are transmitted by autosomal recessive inheritance.²

Secondary PAP (5% to 10% of cases) is caused by, or associated with, a variety of neoplastic, inhalational, and infectious processes (Table 28.2). The etiology of PAP in these conditions is unclear, but presumed related to toxic effects on macrophages and usually not related to autoantibodies to GM-CSF receptor.² In the case of hematologic conditions, defective expression of GM-CSF receptor has been described.⁴ In the case of indium exposure and PAP, there may be an autoimmune mechanism involving autoantibodies to GM-CSF.^5,6,7

Patients with idiopathic PAP (up to 90% of cases) have high levels of autoantibodies against GM-CSF in blood and tissues, including the pulmonary alveolar fluid.⁸ These antibodies bind to epitopes on the GM-CSF molecule, blocking the interaction of GM-CSF with its receptor and critically impairing the process of surfactant clearance
in the lung.⁸ This impairment involves decreased ability of macrophages for adhesion, chemotaxis, microbicidal activity, phagocytosis, and phagolysosome fusion.³ These mechanisms have been studied in knockout mice defective in the GM-CSF or GM-CSF receptor genes. These genetically altered animals develop a disease similar to PAP, and surprisingly few infectious complications.⁹

The prevalence of autoimmune PAP is between 3.7 and 6.2 cases per million.^2,3,10 The corresponding incidence has been estimated at 0.36 new cases per 1 million persons each year.¹⁰

Infants with congenital PAP characteristically present with an acute onset of rapidly progressive respiratory distress immediately after birth.³