Pulmonary alveolar proteinosis

Hereditary pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterised by abnormal accumulation of surfactant within the alveoli. The surfactant-derived lipoproteinaceous material fills the alveolar spaces and impairs gas exchange. Clinical manifestations range from asymptomatic disease to progressive respiratory insufficiency. Affected individuals may present with dyspnoea, cough, fatigue, failure to thrive, hypoxaemia or recurrent respiratory infections. Age at presentation varies according to the underlying genetic cause. Individuals with defects of the GM-CSF receptor pathway are often diagnosed during childhood. In some patients, PAP occurs as part of a multisystem disorder and may be associated with features such as liver abnormalities, hypogammaglobulinaemia or splenomegaly. Pulmonary fibrosis may occur in specific genetic forms, including MARS1-related disease.

Reported prevalence estimates for pulmonary alveolar proteinosis range from 3.7 to 40 per million inhabitants, with substantial variation between countries. However, these figures include both hereditary and non-hereditary forms of the disease and are therefore not specific to the genetic forms. More than 90% of cases are autoimmune, whereas hereditary GM-CSF receptor deficiency accounts for only a small proportion of cases.

Pulmonary alveolar proteinosis results from disrupted alveolar surfactant homeostasis, a balance that is normally maintained by alveolar macrophages. CSF2RA and CSF2RB encode the alpha- and beta-chains of the GM-CSF receptor. Biallelic pathogenic variants in these genes impair GM-CSF signalling, which is required for macrophage-mediated surfactant clearance, and represent the most common cause of hereditary pulmonary alveolar proteinosis. Pathogenic variants in MARS1, SLC7A7 and OAS1 may also cause pulmonary alveolar proteinosis, either as part of a multisystem disorder or through impaired number or function of alveolar macrophages.

Inheritance depends on the underlying genetic cause. CSF2RA, CSF2RB, MARS1 and SLC7A7 are associated with autosomal recessive disease, whereas OAS1-related disease is inherited in an autosomal dominant manner. Genetic counselling is recommended to discuss recurrence risks and family testing options.

Diagnosis is based on bronchoalveolar lavage and characteristic imaging findings. Bronchoalveolar lavage typically yields a milky, lipoproteinaceous effluent, and computed tomography shows ground-glass opacification with interlobular septal thickening, often described as a crazy-paving pattern.
Quantitative GM-CSF autoantibody testing is used to identify autoimmune pulmonary alveolar proteinosis. In individuals without detectable GM-CSF autoantibodies, additional investigations of the GM-CSF signalling pathway may indicate an underlying hereditary form and prompt molecular genetic testing.

• Establishing the diagnosis and informing management: Identification of the underlying pathogenic variant confirms the diagnosis at the molecular level and may support condition-specific monitoring and management.
• Family risk assessment and reproductive counselling: Identification of the causative variant enables predictive testing of at-risk relatives and provides information relevant to family planning.

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