Excerpt from Pulmonary Alveolar Proteinosis

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Background

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder of unknown etiology characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff (PAS) method and is derived from surfactant phospholipids and protein components (see Media File 1). PAP was first described in 1958.¹

Two forms are recognized, (1) primary (idiopathic) and (2) secondary (due to lung infections; hematologic malignancies; and inhalation of mineral dusts such as silica, titanium oxide, aluminum, and insecticides). Incidence of PAP is increased in patients with hematologic malignancies and AIDS, suggesting a relationship with immune dysfunction.

A similar disorder affects neonates deficient in surfactant-associated protein B (SP-B).

The discovery that PAP may be related to granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies or GM-CSF deficiency has been noted.

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Pathophysiology

The alveoli in pulmonary alveolar proteinosis (PAP) are filled with proteinaceous material, which has been analyzed extensively and determined to be normal surfactant composed of lipids and surfactant-associated proteins A, B, C, and D (SP-A, SP-C, SP-D). Evidence exists of a defect in the homeostatic mechanism of either the production of surfactant or the clearance by alveolar macrophages and the mucociliary elevator. A clear relationship has been demonstrated between PAP and impaired macrophage maturation or function, which might account for the high association with malignancies and unusual infections, eg, infection with Nocardia asteroides.

Studies of genetically altered mice ("knock-out mice") with targeted gene deletions for GM-CSF yielded animals with PAP-like disease. GM-CSF has been demonstrated to increase the effectiveness of alveolar macrophages in the catabolism of surfactant. Recent studies have demonstrated the presence of neutralizing autoantibodies against GM-CSF in patients with PAP. Also documented is that alveolar macrophages from some PAP patients have decreased levels of the transcription factor peroxisome proliferator-activated receptor–gamma (PPAR-gamma), which normalize after treatment with GM-CSF.²

Frequency

United States

PAP has an estimated prevalence of 1 case per 100,000 population.

International

Frequency is believed to be similar to that in the United States, but notification systems do not exist.

Mortality/Morbidity

• Mortality rates of as high as 30% within several years of disease onset have been reported previously, but the actual mortality rate may be less than 10%. Solitary pulmonary PAP is increasingly being seen and may resolve spontaneously over several months.
• The natural history of secondary PAP depends on the underlying etiologic entity.

Race

• Isolated studies have reported predominance in patients of Arabian origin, but no other definitive studies are available.

Sex

• Incidence for males is 4 times higher than for females.

Age

• Patients are typically aged 20-50 years at presentation.

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