Pulmonary Alveolar Proteinosis

Updated: Dec 17, 2015
  • Author: Roger B Olade, MD, MPH; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Overview

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 the image below). PAP was first described in 1958. [1]

A periodic acid-Schiff histochemical stain of tran A periodic acid-Schiff histochemical stain of transbronchial biopsy: Alveolar spaces contain considerable amounts of granular material.

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, indium-tin oxide and insecticides. Incidence of PAP is increased in patients with hematologic malignancies and AIDS, suggesting a relationship with immune dysfunction. Associations with Niemann-Pick disease [2] and myelodysplastic syndrome [3] have been reported.

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

PAP is related to granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies and GM-CSF deficiency.

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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-B, 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 escalator. A  relationship has been demonstrated between PAP and impaired macrophage maturation or function, which accounts for the 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  increases 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. [4]

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Epidemiology

Frequency

United States

PAP has an estimated prevalence of 1 case per 100,000 population, but is probably underreported.

International

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

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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