Autoimmune Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant-derived lipoproteinaceous material within alveoli, impairing gas exchange. Three forms exist: autoimmune (aPAP, ~90% of cases) due to anti-GM-CSF autoantibodies impairing alveolar macrophage function; congenital due to surfactant protein or GM-CSF receptor mutations; and secondary due to underlying conditions affecting macrophages (hematologic malignancies, dust inhalation).

Pathophysiology: GM-CSF (granulocyte-macrophage colony-stimulating factor) is critical for alveolar macrophage maturation and function, including surfactant catabolism. Anti-GM-CSF antibodies neutralize circulating GM-CSF, leading to dysfunctional macrophages that cannot clear surfactant, resulting in alveolar filling. Patients are also at increased risk for opportunistic infections (Nocardia, mycobacteria, fungi).

Clinical presentation includes progressive dyspnea, cough, fatigue, and weight loss. Diagnosis combines characteristic high-resolution CT findings (crazy paving pattern: ground-glass opacities with septal thickening), bronchoalveolar lavage showing milky fluid with PAS-positive material, elevated serum anti-GM-CSF antibodies, and elevated KL-6 and surfactant protein-D. Treatment options include: whole lung lavage (gold standard for symptomatic disease, performed under general anesthesia), inhaled GM-CSF (sargramostim), rituximab for refractory cases, and lung transplantation in advanced disease.