Efficacy and Safety of Inhaled GM-CSF in Autoimmune Pulmonary Alveolar Proteinosis: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PURPOSE: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disorder characterized by autoantibodies against Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF). Whole-lung lavage is the conventional treatment, but it does not address the underlying pathophysiology. This systematic review and meta-analysis aims to further evaluate the effects of inhaled GM-CSF on gas exchange, oxygenation, and lung volume.

METHODS

We conducted a systematic review and meta-analysis following PRISMA guidelines. A literature search was performed across PubMed, Embase, and the Cochrane Library from inception to October 2025. Randomized Controlled Trials (RCTs) comparing inhaled GM-CSF to a control in adult patients with aPAP were included. The primary outcomes assessed pulmonary gas exchange, oxygenation, and lung volume, while exercise capacity and dyspnea levels were secondary outcomes. Statistical analyses were performed using Review Manager (RevMan) version 5.4.1 and R version 4.5.2, with heterogeneity assessed using I2 statistics.

RESULTS

Four phase III RCTs comprising 402 patients (224 inhaled GM-CSF, 178 control) with ≥ 25 weeks of follow-up were included. Inhaled GM-CSF significantly enhanced DLCO% predicted (MD 5.09; 95% CI 2.05 to 8.13; p = 0.001; I2 = 0%) and reduced PA-aO₂ (MD - 4.25; 95% CI - 6.62 to - 1.88; p = 0.0004; I2 = 0%), with corresponding increases in PaO₂. Dyspnea scores significantly improved (SMD - 0.49; 95% CI - 0.70 to - 0.29; I2 = 9%). No significant improvements were observed in lung volume or exercise capacity. Continuous and intermittent regimens demonstrated comparable efficacy and side effects across subgroups.

CONCLUSION

Inhaled GM-CSF improves gas exchange, oxygenation, and dyspnea in aPAP while maintaining a favorable safety profile, indicating its potential as a noninvasive, targeted therapy.