Condition

Pulmonary Alveolar Proteinosis (PAP)

Editors: Mark Metersky MD; Esther Jolanda van Zuuren MD; Terence K. Trow MD, FACP, FCCP

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Background Information

Description

  • rare pulmonary syndrome characterized by excessive accumulation of surfactant lipids and proteins in alveoli and terminal airways
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Also called

  • alveolar proteinosis
  • alveolar phospholipidosis
  • pulmonary alveolar lipoproteinosis
  • pulmonary alveolar phospholipoproteinosis

Types

  • types of PAP
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    • primary PAP - associated with primary disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling
      • autoimmune (idiopathic, acquired) PAP (about 90%) - GM-CSF autoantibodies
      • hereditary (familial) PAP (< 1%) - colony-stimulating factor 2 receptor alpha and beta (CSF2RA and CSF2RB) mutations
    • secondary PAP (7%-10%) - associated with underlying clinical condition secondarily affecting alveolar macrophages
    • congenital (< 2%) - associated with surfactant production disorders (genetic mutations result in abnormal surfactant protein or lipid production)

Epidemiology

Who is most affected

  • men (male to female ratio 2-2.7 to 1)
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  • median age at diagnosis 35-51 years
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  • for autoimmune PAP, smokers
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Incidence/Prevalence

  • rare - approximate reported incidence and prevalence varies based on type
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    • autoimmune PAP (accounts for 90% of PAP)
      • incidence - 0.2-0.49 per million persons/year
      • prevalence - 3.7-6.2 per million persons
    • secondary PAP (accounts for 7%-10% of PAP)
      • incidence - 0.05 per million persons/year
      • prevalence - 0.5 per million persons
    • congenital PAP - incidence and prevalence not reported, but accounts for < 2% of PAP

Likely risk factors

Etiology and Pathogenesis

Causes

  • primary PAP - acquired or hereditary defect in alveolar macrophage processing of surfactant proteins
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  • secondary PAP - underlying clinical conditions secondarily affecting alveolar macrophages
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  • congenital PAP - autosomal recessive transmission of mutations that result in surfactant production disorders
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Pathogenesis

  • in normal lung, balance of secretion and removal of pulmonary surfactant tightly regulated to maintain homeostasis
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    • functions of pulmonary surfactant
      • maintains lung function by creating air-liquid interface on alveolar surface that reduces surface tension and prevents alveolar collapse
      • contributes to host defense against infection
    • pulmonary surfactant comprised of 90% lipids, primarily phospholipids, and 10% proteins, including surfactant protein (SP)-A, SP-B, SP-C, and SP-D
    • secretion and removal of pulmonary surfactant
      • synthesized and secreted by alveolar type II epithelial cells
      • removed by
        • uptake, recycling, and catabolism in alveolar type II epithelial cells
        • uptake and catabolism in alveolar macrophages
      • catabolism of surfactant in alveolar macrophages requires presence of granulocyte-macrophage colony-stimulating factor (GM-CSF)
  • in PAP, defects in regulation of pulmonary surfactant lead to accumulation of surfactant in alveolar macrophages and alveoli; defects may include
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    • autoimmune or hereditary defects in alveolar macrophage processing of surfactant proteins, including
      • neutralizing antibodies against GM-CSF in autoimmune PAP
      • mutations in colony-stimulating factor 2 receptor alpha and beta (CSF2RA and CSF2RB) in hereditary PAP
    • underlying clinical conditions may secondarily affect alveolar macrophages as in secondary PAP
    • surfactant production disorders caused by autosomal recessive mutations, including SFTPB, SFTPC, ABCA3, and TTF1 (NKX2.1) in congenital PAP
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DynaMed provides easy-to-interpret Level of Evidence labels so users can quickly find and determine the quality of the best available evidence. Evidence may be labeled in one of three levels:

1Level 1 (likely reliable) Evidence
Representing research results addressing clinical outcomes and meeting an extensive set of quality criteria which minimizes bias.
There are two types of conclusions which can earn a Level 1 label: levels of evidence for conclusions derived from individual studies and levels of evidence for conclusions regarding a body of evidence.
2Level 2 (mid-level) Evidence
Representing research results addressing clinical outcomes, and using some method of scientific investigation, but not meeting the quality criteria to achieve Level 1 evidence labeling.
3Level 3 (lacking direct) Evidence
Representing reports that are not based on scientific analysis of clinical outcomes. Examples include case series, case reports, expert opinion, and conclusions extrapolated indirectly from scientific studies.

Grades of Recommendation

Guideline producers are now frequently using classification approaches for their evidence and recommendations, and these classifications are recognized and requested by guideline users. When summarizing guideline recommendations for DynaMed users, the DynaMed Editors are using the guideline-specific classifications and providing guideline classification approach when this is done.

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