Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis

Alveolar proteinosis (AP) is characterized by excessive surfactant accumula tion, and most cases are of unknown etiology. Standard therapy for AP is wh ole-lung lavage, which may not correct the underlying defect. Because the h ematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM- CSF) is required for normal surfactant homeostasis, we evaluated the therap eutic activity of CM-CSF in patients with idiopathic AP. Fourteen patients received 5 mug/kg/d CM-CSF for 6 to 12 wk with serial monitoring of the alv eolar-arterial oxygen gradient ([A-a]Do(2)), diffusing capacity of carbon m onoxide, computed tomographic scans, and exercise testing. Patients not res ponding to 5 mug/kg/d CM-CSF underwent stepwise dose escalation, and respon ding patients were retreated at disease recurrence. Stored pretreatment ser a were assayed for CM-CSF-neutralizing autoantibodies. According to prospec tive criteria, five of 14 patients responded to 5 mug/kg/d GM-CSF, and one of four patients responded after dose escalation (20 mug/kg/d). The overall response rate was 43% (mean improvement in [A-a]Do(2) = 23.2 mm Hg). Respo nses lasted a median of 39 wk, and were reproducible with retreatment. CM-C SF was well-tolerated, with no late toxicity seen. The only treatment-relat ed factor predictive of response was CM-CSF-induced eosinophilia (p = 0.01) . Each of 12 patients tested had GM-CSF-neutralizing autoantibodies present in pretreatment serum. We conclude that GM-CSF has therapeutic activity in idiopathic AP, providing a potential alternative to whole-lung lavage.