title: Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis.
abstract: Alveolar proteinosis (AP) is characterized by excessive surfactant accumulation, and most cases are of unknown etiology. Standard therapy for AP is whole-lung lavage, which may not correct the underlying defect. Because the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for normal surfactant homeostasis, we evaluated the therapeutic activity of GM-CSF in patients with idiopathic AP. Fourteen patients received 5 microg/kg/d GM-CSF for 6 to 12 wk with serial monitoring of the alveolar-arterial oxygen gradient ([A-a]DO2), diffusing capacity of carbon monoxide, computed tomographic scans, and exercise testing. Patients not responding to 5 microg/kg/d GM-CSF underwent stepwise dose escalation, and responding patients were retreated at disease recurrence. Stored pretreatment sera were assayed for GM-CSF-neutralizing autoantibodies. According to prospective criteria, five of 14 patients responded to 5 microg/kg/d GM- CSF, and one of four patients responded after dose escalation (20 microg/kg/d). The overall response rate was 43% (mean improvement in [A-a]DO2 = 23.2 mm Hg). Responses lasted a median of 39 wk, and were reproducible with retreatment. GM-CSF was well-tolerated, with no late toxicity seen. The only treatment-related factor predictive of response was GM-CSF-induced eosinophilia (p = 0.01). Each of 12 patients tested had GM-CSF-neutralizing autoantibodies present in pretreatment serum. We conclude that GM- CSF has therapeutic activity in idiopathic AP, providing a potential alternative to whole-lung lavage.
authors.affiliation: Melbourne Tumour Biology Branch, Ludwig Institute for Cancer Research, Parkville, Australia. jseymour@petermac.unimelb.edu.au
authors.forename: J F
authors.initials: JF
authors.lastname: Seymour
authors.forename: J J
authors.initials: JJ
authors.lastname: Presneill
authors.forename: O D
authors.initials: OD
authors.lastname: Schoch
authors.forename: G H
authors.initials: GH
authors.lastname: Downie
authors.forename: P E
authors.initials: PE
authors.lastname: Moore
authors.forename: I R
authors.initials: IR
authors.lastname: Doyle
authors.forename: J M
authors.initials: JM
authors.lastname: Vincent
authors.forename: K
authors.initials: K
authors.lastname: Nakata
authors.forename: T
authors.initials: T
authors.lastname: Kitamura
authors.forename: D
authors.initials: D
authors.lastname: Langton
authors.forename: M C
authors.initials: MC
authors.lastname: Pain
authors.forename: A R
authors.initials: AR
authors.lastname: Dunn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005080:Exercise Test / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011649:Pulmonary Alveolar Proteinosis / Q000175:diagnosis / Q000188:drug therapy*; D011653:Pulmonary Diffusing Capacity / Q000187:drug effects; D011994:Recombinant Proteins; D012008:Recurrence; D019233:Retreatment; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor