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N Engl J Med. 2019 Sep 5;381(10):923-932. doi: 10.1056/NEJMoa1816216.

Inhaled GM-CSF for Pulmonary Alveolar Proteinosis.

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From Niigata University Medical and Dental Hospital, Niigata (R.T., T.U., K.A., T.S., A.H., Takahiro Tanaka, T. Takada, N.K., K.N.), the Department of Respirology, Graduate School of Medicine, Chiba University, Chiba (M.A., K. Tatsumi), Kurashiki Municipal Hospital, Kurashiki (R.E., S. Kondoh), the Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki (K.M., Takeshi Tanaka), the Division of Respiratory Medicine and Allergology, Department of Medicine, Aichi Medical University School of Medicine, Aichi (E.Y., A.T.), the Department of Respiratory Medicine, Kyorin University School of Medicine (M.O., H.I.), and the Center Hospital of the National Center for Global Health and Medicine (S.I., H.S., A.M.), Tokyo, Kobe City Medical Center General Hospital, Kobe (A.N., K. Tomii), the Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo (M.S., S. Konno), the Department of Respiratory Medicine and Department of Occupational Health, Tohoku University Graduate School of Medicine, Sendai (S.O., N.T.), the Departments of Advanced Medicine for Respiratory Failure (T. Handa) and Respiratory Medicine (T. Handa, T. Hirai), Graduate School of Medicine, Kyoto University, Kyoto, and the National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka (Y.I., T.A.) - all in Japan.



Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear.


We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25.


The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group.


In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).

[Indexed for MEDLINE]

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