Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis.
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).
Tazawa
Ryushi
R
Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Niigata, Japan. radical@med.niigata-u.ac.jp
Trapnell
Bruce C
BC
Inoue
Yoshikazu
Y
Arai
Toru
T
Takada
Toshinori
T
Nasuhara
Yasuyuki
Y
Hizawa
Nobuyuki
N
Kasahara
Yasunori
Y
Tatsumi
Koichiro
K
Hojo
Masayuki
M
Ishii
Haruyuki
H
Yokoba
Masanori
M
Tanaka
Naohiko
N
Yamaguchi
Etsuro
E
Eda
Ryosuke
R
Tsuchihashi
Yoshiko
Y
Morimoto
Konosuke
K
Akira
Masanori
M
Terada
Masaki
M
Otsuka
Junji
J
Ebina
Masahito
M
Kaneko
Chinatsu
C
Nukiwa
Toshihiro
T
Krischer
Jeffrey P
JP
Akazawa
Kohei
K
Nakata
Koh
K
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
D015415:Biomarkers; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor