Inhaled Granulocyte/Macrophage-Colony Stimulating Factor as Therapy for Pulmonary Alveolar Proteinosis

• Published in: American journal of respiratory and critical care medicine Vol. 181; no. 12; pp. 1345 - 1354
• Main Authors: TAZAWA, Ryushi, TRAPNELL, Bruce C, ISHII, Haruyuki, YOKOBA, Masanori, TANAKA, Naohiko, YAMAGUCHI, Etsuro, EDA, Ryosuke, TSUCHIHASHI, Yoshiko, MORIMOTO, Konosuke, AKIRA, Masanori, TERADA, Masaki, OTSUKA, Junji, INOUE, Yoshikazu, EBINA, Masahito, KANEKO, Chinatsu, NUKIWA, Toshihiro, KRISCHER, Jeffrey P, AKAZAWA, Kohei, NAKATA, Koh, ARAI, Toru, TAKADA, Toshinori, NASUHARA, Yasuyuki, HIZAWA, Nobuyuki, KASAHARA, Yasunori, TATSUMI, Koichiro, HOJO, Masayuki
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 15.06.2010
• Subjects: Administration, Inhalation; Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Biomarkers - blood; C. Critical Care; Cohort Studies; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay - methods; Female; Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage; Granulocyte-Macrophage Colony-Stimulating Factor - blood; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Humans; Intensive care medicine; Japan; Lung - diagnostic imaging; Male; Medical sciences; Middle Aged; Pneumology; Prospective Studies; Pulmonary Alveolar Proteinosis - blood; Pulmonary Alveolar Proteinosis - diagnostic imaging; Pulmonary Alveolar Proteinosis - drug therapy; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Recombinant Proteins; Tomography, X-Ray Computed - methods; Treatment Outcome; Lung disease; Intensive care; Treatment; Pulmonary alveolar proteinosis; Respiratory disease; Granulocyte macrophage colony stimulating factor; Resuscitation; Inhalation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200906-0978oc

Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. 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). 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. 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).