Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis.

RATIONALE: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. OBJECTIVES: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. METHODS: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk). MEASUREMENTS AND MAIN RESULTS: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. CONCLUSIONS: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).