title: Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis.
abstract: BACKGROUND
  Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.
  
  
  OBJECTIVE
  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).
  
  
  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).
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Niigata, Japan. radical@med.niigata-u.ac.jp
authors.forename: Ryushi
authors.initials: R
authors.lastname: Tazawa
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Inoue
authors.forename: Toru
authors.initials: T
authors.lastname: Arai
authors.forename: Toshinori
authors.initials: T
authors.lastname: Takada
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nasuhara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hizawa
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hojo
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Ishii
authors.forename: Masanori
authors.initials: M
authors.lastname: Yokoba
authors.forename: Naohiko
authors.initials: N
authors.lastname: Tanaka
authors.forename: Etsuro
authors.initials: E
authors.lastname: Yamaguchi
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Eda
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tsuchihashi
authors.forename: Konosuke
authors.initials: K
authors.lastname: Morimoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Akira
authors.forename: Masaki
authors.initials: M
authors.lastname: Terada
authors.forename: Junji
authors.initials: J
authors.lastname: Otsuka
authors.forename: Masahito
authors.initials: M
authors.lastname: Ebina
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Kaneko
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.forename: Kohei
authors.initials: K
authors.lastname: Akazawa
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D007564:Japan; D008168:Lung / Q000000981:diagnostic imaging; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011649:Pulmonary Alveolar Proteinosis / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D011994:Recombinant Proteins; D014057:Tomography, X-Ray Computed / Q000379:methods; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor