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Nat Rev Dis Primers. 2019 Mar 7;5(1):16. doi: 10.1038/s41572-019-0066-3.

Pulmonary alveolar proteinosis.

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Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Bioscience Medical Research Center, Niigata University, Niigata, Japan.
Interstitial and Rare Lung Disease Unit, Pneumology Department, Ruhrlandklinik University Hospital, University of Essen, Essen, Germany.
Pneumology Unit, IRCCS San Matteo Hospital Foundation, Pavia, Italy.
Pediatric Pneumology, University of Munich, German Center for Lung Research (DZL), Munich, Germany.
University of Melbourne, Parkville, Victoria, Australia.
Department of Medicine, University of California, Los Angeles, CA, USA.
Department of Critical Care and Anaesthesia, Royal Brompton Hospital, London, UK.
National Reference Center for Rare Pulmonary Diseases, University of Lyon, Lyon, France.
Department of Medicine, St. Vincent's University Hospital and University College Dublin, Dublin, Ireland.


Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages. PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis. PAP can be classified into different types on the basis of the pathogenetic mechanism: primary PAP is characterized by the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling and can be autoimmune (caused by elevated levels of GM-CSF autoantibodies) or hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits); secondary PAP results from various underlying conditions; and congenital PAP is caused by mutations in genes involved in surfactant production. In most patients, pathogenesis is driven by reduced GM-CSF-dependent cholesterol clearance in alveolar macrophages, which impairs alveolar surfactant clearance. PAP has a prevalence of at least 7 cases per million individuals in large population studies and affects men, women and children of all ages, ethnicities and geographical locations irrespective of socioeconomic status, although it is more-prevalent in smokers. Autoimmune PAP accounts for >90% of all cases. Management aims at improving symptoms and quality of life; whole-lung lavage effectively removes excessive surfactant. Novel pathogenesis-based therapies are in development, targeting GM-CSF signalling, immune modulation and cholesterol homeostasis.


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