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Pulmonary alveolar proteinosis

Abstract

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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Fig. 1: Alveolar surfactant homeostasis and its disruption in PAP.
Fig. 2: Algorithm for the differential diagnosis of PAP.
Fig. 3: Radiological findings in PAP.
Fig. 4: Currently available and emerging therapies to treat patients with PAP.

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Acknowledgements

The authors acknowledge support from the US National Heart Lung and Blood Institute (NHLBI) (R01 HL085453 to B.C.T.); the US National Center for Advancing Translational Sciences (NCATS)/NHLBI (U54 HL127672 to B.C.T.); the Japanese Agency for Medical Research and Development (JP17ek0109079h0003 to K.N.) and the Australian National Health and Medical Research Council (to J.H.).

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Nature Reviews Disease Primers thanks M. Hetzel and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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Introduction (I.C.); Epidemiology (K.N.); Mechanisms/pathophysiology (B.C.T. and J.H.); Diagnosis, screening and prevention (F.B. and C.Mc.); Management (C.Mo. and M.G.); Quality of life (T.W.); Outlook (V.C.); Overview of Primer (B.C.T.).

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Correspondence to Bruce C. Trapnell.

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Trapnell, B.C., Nakata, K., Bonella, F. et al. Pulmonary alveolar proteinosis. Nat Rev Dis Primers 5, 16 (2019). https://doi.org/10.1038/s41572-019-0066-3

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