Pulmonary alveolar proteinosis

Professor:  Venerino Poletti 

Artikel link | DOI | PubMed | Journal: Nat Rev Dis PrimersI Dato: 2019 Marts

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Pulmonary Alveolar Proteinosis (PAP) is a rare disorder with a prevalence of 7 cases per milion individuals (more prevalent in smokers) .It is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages. This accumulation results in progressive dyspnea of insidious onset, hypoxaemic respiraytory failure, secondary infections (Nocardia, atyical mycobacteria,..) and in a minority of cases pulmonary fibrosis.

The CT scan hallmark of the syndrome is the socalled "crazy paving" pattern.

Diagnosis is confirmed by analysis of the bronchoalveolar lavage (BAL). PAP can be classified into different types on the basis of the pathogenetic machanism:primary PAP is characterized by the disruption of granulocytes-macrophage colony-stimulating factor GM-CSF) signalling  and can be autoimmune (caused by elevated levels of GM-CSF autoantibodies; the most frequent form) or hereditary (due to mutations in CSF2RA or CSF2RB encoding GM-CSF receptor subunits); secondary AP results from various underlying conditions; and congenital PAP is caused by mutations in genes involved in surfactant production.
Whole lung lavage  effectively removes excessive surfactant. However novel pathogenesis-based therapies are in development, targeting
GM-CSF signalling , immune modulation and cholesterol homeostasis. This is a concise and very well written review on this rare disorder.

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.