What causes pulmonary alveolar proteinosis (PAP)?

Updated: Dec 18, 2019
  • Author: Roger B Olade, MD, MPH; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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The etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it has been associated with a number of other processes, implying a causal relationship. Causes may include the following:

  • Inhalation of silica dust (acute silicoproteinosis) [8]

  • Exposure to insecticides, aluminum dust, titanium dioxide, indium-tin oxide and other inorganic dusts [16, 17, 18]

  • Hematologic malignancies, mostly myeloid disorders

  • Lysinuric protein intolerance (rare)

  • Infection with human immunodeficiency virus (HIV) (acquired immunodeficiency syndrome [AIDS])

  • Leflunomide: Case report (disease-modifying antirheumatic arthritis therapy) [19]

Recessive CSF2RA mutations have been implicated in the hereditary form of PAP. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling may be absent or severely reduced, and the GM-CSF-receptor alpha chain may be absent or abnormal, paralleling the GM-CSF signaling defects. This is unlike secondary PAP, in which a deficiency of GM-CSF and increased autoantibodies are noted. Genetic analysis may reveal multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. [20, 21]  In 2011, a homozygous missense mutation in CSF2RB was reported to cause PAP in a 9-year-old girl. [22]  Onset of the hereditary form of PAP is generally in infancy or early childhood, but adult onset has been reported. [6, 7]

Biallelic missense mutations in MARS were identified in a specific severe form of pediatric PAP, prevalent on the island of Réunion in the Indian Ocean. [23]  

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