Definition and research guide
This page combines a MeSH definition, publication statistics and selected research abstracts. It is a starting point for reading the literature, not a medical textbook or a systematic evidence review.
Content available: 4 complete abstracts (708 words), 10 references. Full article text is not stored or reproduced here; follow the PMID, DOI or PMC links to read the original sources and their access terms.
Definition
A pulmonary alveoli-filling disease, characterized by dense phospholipoproteinaceous deposits in the alveoli, cough, and dyspnea. This disease is often related to, congenital or acquired, impaired processing of pulmonary surfactants by alveolar macrophages, a process dependent on granulocyte-macrophage colony-stimulating factor.
Definition: NLM Medical Subject Headings (MeSH) scope note (Public domain (U.S. National Library of Medicine); attribution requested). View the MeSH record.
Also known as: Alveolar Proteinoses, Pulmonary; Alveolar Proteinosis, Pulmonary; Proteinoses, Pulmonary Alveolar; Proteinosis, Pulmonary Alveolar; Pulmonary Alveolar Proteinoses.
Where it fits in the MeSH classification
- Broader topics
- Lung Diseases
Related concepts
- Pulmonary Alveoli-
- Dyspnea
- Pulmonary Surfactants
- Granulocyte-Macrophage Colony-Stimulating Factor
Research landscape
PubMed indexes 1,939 records tagged with the MeSH heading “Pulmonary Alveolar Proteinosis” (counts retrieved 2026-11-04). 312 of them (16.1%) were published from 2020 onward, and the busiest period so far is through 1999 with 821 records.
Reviews account for 246 records (12.7%) and meta-analyses for 7. Randomized controlled trials number 6 (0.3%) as a share of all records on the topic. Randomized trials make up only a small share of this literature, so much of what is known comes from laboratory, observational or descriptive work.
Show the data
| Period | Records |
|---|---|
| through 1999 | 821 |
| 2000-2009 | 345 |
| 2010-2019 | 461 |
| 2020 onward | 312 |
Publication-type chart data
| Type | Records | Share |
|---|---|---|
| Reviews | 246 | 12.7% |
| Meta-analyses | 7 | 0.4% |
| Randomized controlled trials | 6 | 0.3% |
Method: PubMed query "Pulmonary Alveolar Proteinosis"[MeSH Terms] with publication-type and date filters, retrieved 2026-11-04.
Reading the evidence in respiratory medicine
Research on airway and lung disease mixes lung-function tests, symptom diaries, imaging and hospital records, so what was measured and in whom matters as much as the result. Many conditions here, such as asthma and COPD, vary between people and over time, and exposure studies (smoking, pollution, workplace dust) show association rather than proof of cause. Nothing on this page is advice about treatment or inhalers; anyone with breathing difficulty should seek care from a qualified clinician. Check how the condition was defined, the severity of the people studied and whether outcomes were symptoms, lung function or hospital admissions.
Evidence from open-access studies
These open-access studies come from PubMed’s best-match results for this heading (papers whose main topic it is), ranked here by citation count, with one recent addition. Each abstract is reproduced in full under its recorded open licence so that you can read the authors’ own words. They illustrate the literature; they are not a systematic summary of it. Citation counts measure attention, not reliability or clinical benefit.
| Study / authors | Year | Source label / design | Europe PMC citations | Licence / source |
|---|---|---|---|---|
| Human autoantibodies underlying infectious diseases | 2022 | Research article Design not recorded in structured metadata | 96 | cc by PMID 35319722 · DOI · PMC8952682 |
| Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis | 2015 | Research article Design not recorded in structured metadata | 88 | cc by PMID 26077231 · DOI · PMC4477037 |
| Prevalence and healthcare burden of pulmonary alveolar proteinosis | 2018 | Research article Design not recorded in structured metadata | 80 | cc by PMID 30064481 · DOI · PMC6069872 |
| Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of STAT2 (TIMS2) | 2026 | Research article Design not recorded in structured metadata | 0 | cc by PMID 42461263 · DOI · PMC7619351 |
Human autoantibodies underlying infectious diseases [1]
Abstract reading summary — source excerpts
- Opening excerpt
- The vast interindividual clinical variability observed in any microbial infection-ranging from silent infection to lethal disease-is increasingly being explained by human genetic and immunological determinants.
- Closing excerpt
- Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (158 words)
The vast interindividual clinical variability observed in any microbial infection-ranging from silent infection to lethal disease-is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 35319722 · DOI · PMC8952682
Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis [2]
Abstract reading summary — source excerpts
- Opening excerpt
- Pulmonary alveolar proteinosis (PAP) is a severe autoimmune disease caused by autoantibodies that neutralize GM-CSF resulting in impaired function of alveolar macrophages.
- Closing excerpt
- Taken together, these findings provide a plausible explanation for the severe phenotype of PAP patients and for the safety of treatments based on single anti-GM-CSF monoclonal antibodies.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (150 words)
Pulmonary alveolar proteinosis (PAP) is a severe autoimmune disease caused by autoantibodies that neutralize GM-CSF resulting in impaired function of alveolar macrophages. In this study, we characterize 21 GM-CSF autoantibodies from PAP patients and find that somatic mutations critically determine their specificity for the self-antigen. Individual antibodies only partially neutralize GM-CSF activity using an in vitro bioassay, depending on the experimental conditions, while, when injected in mice together with human GM-CSF, they lead to the accumulation of a large pool of circulating GM-CSF that remains partially bioavailable. In contrast, a combination of three non-cross-competing antibodies completely neutralizes GM-CSF activity in vitro by sequestering the cytokine in high-molecular-weight complexes, and in vivo promotes the rapid degradation of GM-CSF-containing immune complexes in an Fc-dependent manner. Taken together, these findings provide a plausible explanation for the severe phenotype of PAP patients and for the safety of treatments based on single anti-GM-CSF monoclonal antibodies.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 26077231 · DOI · PMC4477037
Prevalence and healthcare burden of pulmonary alveolar proteinosis [3]
Abstract reading summary — source excerpts
- Opening excerpt
- Pulmonary alveolar proteinosis (PAP) is a rare syndrome of alveolar surfactant accumulation, resulting hypoxemic respiratory failure, and increased infection risk.
- Closing excerpt
- Considering the high diagnostic accuracy of serum GM-CSF autoantibody testing and predominance of autoimmune PAP, these results emphasize the importance of utilizing blood-based testing in PAP syndrome to identify the PAP-causing disease rather than invasive lung biopsies, resulting in earlier diagnosis, reduced morbidity and lower healthcare costs.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (241 words)
Pulmonary alveolar proteinosis (PAP) is a rare syndrome of alveolar surfactant accumulation, resulting hypoxemic respiratory failure, and increased infection risk. Despite advances in our understanding of disease pathogenesis and the availability of improved diagnostics, the epidemiology and healthcare burden of PAP remain poorly defined. To determine the prevalence, and healthcare utilization and costs associated with PAP, we interrogated a large health insurance claims database containing comprehensive data for approximately 15 million patients in the United States. We also evaluated data from a referral-based diagnostic testing program collected over a 15-year period. The prevalence of PAP was determined to be 6.87 ± 0.33 per million in the general population, similar in males and females, and increased with age, however considering difficulties and delays in diagnosing this is likely a minimum estimate of true prevalence. PAP patients had significantly more comorbidities, health care utilization and associated costs compared to control patients precisely matched for age and gender. Between 2004 and 2018, 249 patients confirmed to have PAP were evaluated to identify the PAP-causing disease; 91.5% had autoimmune PAP, 3% had hereditary PAP caused by GM-CSF receptor mutations, 4% had secondary PAP, and 1.5% had congenital PAP. Considering the high diagnostic accuracy of serum GM-CSF autoantibody testing and predominance of autoimmune PAP, these results emphasize the importance of utilizing blood-based testing in PAP syndrome to identify the PAP-causing disease rather than invasive lung biopsies, resulting in earlier diagnosis, reduced morbidity and lower healthcare costs.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 30064481 · DOI · PMC6069872
Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of STAT2 (TIMS2) [4]
Abstract reading summary — source excerpts
- Opening excerpt
- Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies.
- Closing excerpt
- Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (159 words)
Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 42461263 · DOI · PMC7619351
Key reviews and meta-analyses
The most cited review-type papers among PubMed’s best-match results for this heading, listed with bibliographic details only. Follow the links for the full text and access terms.
- Research article Pulmonary alveolar proteinosis [5]
- Research article Pulmonary alveolar proteinosis: progress in the first 44 years [6]
- Research article Pulmonary alveolar proteinosis [7]
- Research article Pulmonary alveolar proteinosis [8]
- Research article The molecular basis of pulmonary alveolar proteinosis [9]
- Research article Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis [10]
References
- Puel A, Bastard P, Bustamante J, Casanova JL. Human autoantibodies underlying infectious diseases. . 2022. PMID 35319722 · DOI · PMC8952682
- Piccoli L, Campo I, Fregni CS, Rodriguez BM, Minola A, Sallusto F, et al.. Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. . 2015. PMID 26077231 · DOI · PMC4477037
- McCarthy C, Avetisyan R, Carey BC, Chalk C, Trapnell BC. Prevalence and healthcare burden of pulmonary alveolar proteinosis. . 2018. PMID 30064481 · DOI · PMC6069872
- Gruber C, Ramba M, Debnath B, Cuollo L, Neehus AL, Lee A, et al.. Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of STAT2 (TIMS2). . 2026. PMID 42461263 · DOI · PMC7619351
- Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003. PMID 14695413 · DOI
- Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. 2002. PMID 12119235 · DOI
- Trapnell BC, Nakata K, Bonella F, Campo I, Griese M, Hamilton J, et al.. Pulmonary alveolar proteinosis. Nat Rev Dis Primers. 2019. PMID 30846703 · DOI
- Borie R, Danel C, Debray MP, Taille C, Dombret MC, Aubier M, et al.. Pulmonary alveolar proteinosis. Eur Respir Rev. 2011. PMID 21632797 · DOI · PMC9487789
- Carey B, Trapnell BC. The molecular basis of pulmonary alveolar proteinosis. Clin Immunol. 2010. PMID 20338813 · DOI · PMC2866141
- Shah PL, Hansell D, Lawson PR, Reid KB, Morgan C. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. 2000. PMID 10607805 · DOI · PMC1745595
About this article
- Sources
- NLM Medical Subject Headings (definition, synonyms); NCBI PubMed (counts, identifiers); Europe PMC (open-access abstracts and citation counts).
- Verification
- Every reference was resolved against PubMed on 2026-11-04; title, year and DOI matched.
- Review state
- automated source verified; no human expert review has been recorded yet.
- Version
- 1, last updated 2026-11-04.
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Evidence strength
EvidenceHelix's computed view of the study designs behind this topic: how common meta-analyses, randomized trials and reviews are, how recent the literature is, and a plain-language reading. It describes the design mix of the literature. It is not a quality appraisal of any study, and it is not medical advice.