Inhaled granulocyte-macrophage colony-stimulating factor for autoimmune pulmonary alveolar proteinosis: From...

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare, diffuse lung disease characterized by surfactant accumulation in the alveoli, leading to impaired gas exchange and progressive respiratory insufficiency. It is caused by neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), which disrupts the GM-CSF signaling required for alveolar macrophage maturation and surfactant clearance. Whole-lung lavage (WLL), the standard treatment for aPAP, improves oxygenation by removing accumulated surfactants, but is invasive and often must be repeated. An improved understanding of disease pathogenesis has shifted therapy toward restoring GM-CSF signaling, rather than simply removing alveolar material. Thus, inhaled recombinant human GM-CSF is a promising disease-directed therapeutic agent for aPAP. Direct delivery to the alveolar compartment is intended to restore GM-CSF signaling, while minimizing systemic exposure. Randomized controlled trials have demonstrated improvements in oxygenation, pulmonary function, and radiographic findings. Despite these advances, important questions remain unresolved because aPAP is rare and clinical studies have been limited, including the optimal dose, treatment duration, maintenance strategy, and the role of device-dependent drug delivery to the distal lung. This review summarizes the pathogenesis of aPAP, biological rationale for GM-CSF replacement, available formulations and aerosol delivery strategies, and clinical evidence supporting inhaled GM-CSF therapy. This review also discusses unresolved issues and future directions, including the potential contributions of quantitative models of aerosol deposition and pharmacokinetics to optimize treatment.