Chapter 398 Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP) is a rare cause of interstitial lung disease characterized by the intra-alveolar accumulation of pulmonary surfactant. Histopathologic examination shows distal air spaces to be filled with a granular, eosinophilic material that stains positively with periodic acid–Schiff reagent and is diastase resistant. Two clinically distinct forms of PAP have been described in children: a fulminant, usually fatal form manifesting shortly after birth (termed congenital PAP) and a gradually progressive type manifesting in older infants and children that is similar to the PAP observed in adults. PAP in older individuals has historically been classified as either primary or secondary to a number of recognized conditions, although this terminology is evolving as specific etiologies for PAP are identified. In the congenital form, alveolar proteinosis is a histologic feature that is found along with alveolar type II cell hyperplasia, interstitial thickening and inflammation, and alveolar macrophage accumulation in what are now being classified as disorders of surfactant metabolism or surfactant dysfunction (Chapter 399).
Etiology and Pathophysiology
Disordered signaling of granulocyte-macrophage colony-stimulating factor (GM-CSF) is the major underlying cause of primary PAP in children and adults. Most cases of primary or idiopathic PAP in older children and adults are mediated by autoantibodies directed against GM-CSF, which can be detected in serum and bronchoalveolar lavage (BAL) fluid. These autoantibodies block binding of GM-CSF to its receptor, thereby inhibiting alveolar macrophage function and surfactant clearance. Mutations in the gene encoding the α subunit of the GM-CSF receptor (CSF2RA) in children with primary alveolar proteinosis demonstrate a genetic basis for some forms of primary PAP in childhood. Deficiency in expression of the β subunit of the GM-CSF receptor has been observed in infants with alveolar proteinosis, although the underlying molecular mechanism for absence of receptor expression has not been elucidated. Alveolar proteinosis has also been reported in children, including young infants, with lysinuric protein intolerance (LPI), a rare autosomal recessive disorder caused by mutations in the cationic amino acid transporter SLC7A7 (Chapter 79.14). These children generally present with vomiting, hyperammonemia, and failure to thrive, although their pulmonary disease may prove fatal. The relationship between the basic defect and the development of PAP is unclear, although a case of recurrence of the disease after lung transplantation suggests that alveolar macrophage dysfunction is likely important in the pathogenesis of PAP associated with LPI. PAP has also been recognized in association with some subtypes of Niemann-Pick disease.
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