Pulmonary Alveolar Proteinosis

Updated: Dec 18, 2019
  • Author: Roger B Olade, MD, MPH; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Practice Essentials

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder of unknown etiology characterized by disorders of surfactant homeostasis (clearance and production), which are caused in part by mutations in genes necessary for normal surfactant production. [1, 2, 3]  The alveoli and terminal airways [1]  fill with floccular material that stains positive using the periodic acid-Schiff (PAS) method and is derived from surfactant phospholipids and protein components (see the images below). This process results in impaired gas exchange and may lead to respiratory failure. [1, 2, 3, 4]  PAP was first described in 1958. [5]  

Pulmonary alveolar proteinosis. A periodic acid-Sc Pulmonary alveolar proteinosis. A periodic acid-Schiff histochemical stain of transbronchial biopsy: Alveolar spaces contain considerable amounts of granular material.
Pulmonary alveolar proteinosis. Intra-alveolar mat Pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase-PAS, x200).

Two forms of PAP are recognized: hereditary and acquired. The hereditary form is autosomal-recessive and usually is diagnosed in infancy or early childhood, although adult onset has been reported. [6, 7]  The acquired form is subdivided into autoimmune and secondary forms. Approximately 90% of PAP cases comprise the autoimmune form, which is related to granulocyte-macrophage colony-stimulating factor (GM-CSF) deficiency, GM-CSF-receptor defects, abnormal macrophage function from endogenous or exogenous triggers, and genetic anomalies of surfactant production. [3]  Secondary forms include those associated with malignancies, immunodeficiency disorders, infectious diseases, drug reactions, and occupational exposure to silica, indium, and various toxic inhalation injuries. [8]  Associations with Niemann-Pick disease, [9]  myelodysplastic syndrome, [10, 11]  and hemophagocytic lymphohistiocytosis [12]  have been reported.

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

The clinic course of PAP is variable, ranging from spontaneous resolution (< 10%) to respiratory failure and death. As many as 30% of patients are asymptomatic, even with diffuse chest radiograph (CXR) abnormalities. The most common clinical symptoms are gradual onset with progressive dyspnea, cough, fever, and chest pain. Physical examination findings may include inspiratory crackles, digital clubbing, and cyanosis. The diagnosis is reached on the basis of clinical history, radiologic, and bronchoalveolar lavage and/or histopathologic findings. [1]

Management of pulmonary alveolar proteinosis (PAP) depends on the progression of the illness, coexisting infections, and degree of physiologic impairment. The standard of care for PAP is mechanical removal of the lipoproteinaceous material by whole-lung lavage (WLL). Inhaled GM-CSF was initially shown to be safe and effective in providing a sustained therapeutic effect in autoimmune PAP [13] ; more recently, it appears to have only a modest salutary laboratory effects on arterial oxygen tension without clinical benefits in mild-to-moderate autoimmune PAP. [14]  For refractory PAP, rituximab, plasmapheresis, and lung transplantation may be therapeutic considerations. [3]  In secondary PAP, appropriate treatment of the underlying cause is warranted. Lung transplantation is the treatment of choice in patients with congenital PAP and in adult patients with end-stage interstitial fibrosis and cor pulmonale.



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. [1, 2, 3]  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 have yielded animals with PAP-like disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases the effectiveness of alveolar macrophages in the catabolism of surfactant. Other studies have demonstrated the presence of neutralizing autoantibodies against GM-CSF in patients with PAP. In addition, 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. [15]



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]  



Autoimmune pulmonary alveolar proteinosis (PAP) acounts for 90% of cases, with an estimated prevalence of 1 case per 100,000 population. A specific, severe hereditary form of PAP is prevalent on Réunion Island, in the Indian Ocean, where the incidence is at least 1 in 10,000 newborns. [24, 23]  The male incidence four times higher than for females, and the presentation is typically in adults aged 20-50 years.



The overall prognosis for primary pulmonary alveolar proteinosis (PAP) is very good, with complete remission achieved in many patients. Whole-lung lavage most often results in a dramatic response. Some patients require repeated lavages; these patients usually progress to pulmonary fibrosis and have a poor outcome. Congenital PAP responds favorably to lung transplantation.

The major complications are lung infections with Nocardia asteroidesPneumocystis carinii, and/or Mycobacterium avium-intracellulare. [25]  Pulmonary fibrosis and/or cor pulmonale also can complicate PAP.

There has been some association between anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF) autoantibodies and some cases of cryptococcal meningitis in otherwise immunocompetent patients. [26]

Mortality as high as 30% within several years of disease onset has been reported, but the actual mortality rate may be less than 10%. A severe form of congenital PAP in children from la Réunion Island has an overall mortality rate of 59% and is characterized by an early onset, associated liver involvement, and frequent progression to lung fibrosis, despite treatment with whole-lung lavage treatment. [24]  

The natural history of secondary PAP depends on the underlying etiologic entity.