Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is accumulation of surfactant lipoproteinaceous material in the alveoli due to impaired surfactant clearance by alveolar macrophages.

Autoimmune PAP (about 90%): neutralising anti GM CSF autoantibodies, onset 30 to 50 years, smokers, prevalence about 7 per million.

Secondary PAP: haematological malignancy (myelodysplastic syndrome), immunodeficiency, inhalation (silica, aluminium, titanium), infection, chemotherapy.

Congenital PAP: mutations in CSF2RA/CSF2RB, SFTPB, SFTPC, ABCA3, NKX2 1 (neonatal respiratory failure).

Complications: secondary infections (Nocardia, mycobacteria, fungi), respiratory failure, fibrosis in a minority.

• Insidious exertional dyspnoea, dry or mildly productive cough, fatigue, low grade fever, weight loss; some asymptomatic.
• Crackles (usually few), clubbing in chronic disease, cyanosis.
• Milky effluent on lavage.

• HRCT: bilateral ground glass with superimposed septal thickening ("crazy paving"), geographic sparing.
• Bronchoalveolar lavage: milky fluid, foamy macrophages, PAS positive material, eosinophilic granular debris.
• Serum anti GM CSF antibody (highly specific, diagnostic in the right setting, avoiding biopsy); LDH, KL 6, surfactant protein D raised.
• Pulmonary function: reduced DLCO, restriction; arterial blood gas for hypoxaemia.
• Lung biopsy rarely needed. Investigate secondary causes: blood count, bone marrow, immune work up, genetic testing in children.

• Mild asymptomatic disease: observation.
• Whole lung lavage under general anaesthesia (double lumen tube, 10 to 20 L warmed saline in aliquots of 500 to 1000 mL per lung, chest percussion) is the standard for symptomatic hypoxaemic disease (PaO2 under 65 mmHg, shunt over 10 to 12%); one lung treated at a time, repeated as needed; improvement in 80 to 90%, lasting 12 to 15 months on average.
• Inhaled GM CSF (molgramostim 300 micrograms once daily for 7 days of 14 day cycles) improves gas exchange in autoimmune PAP; subcutaneous sargramostim 5 micrograms/kg/day also used.
• Rituximab and plasmapheresis in refractory autoimmune PAP (limited data).
• Secondary PAP: treat underlying condition (stem cell transplant for haematological disease), avoid exposure.
• Congenital PAP: lung transplantation and hematopoietic stem cell transplant for CSF2RB.
• Avoid glucocorticoids (increase infection risk). Treat infections, stop smoking, vaccination, oxygen.
• Monitor DLCO and CT every 3 to 6 months.