Chest
Volume 130, Issue 1, July 2006, Pages 227-237
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Original Research
An Open-Label Trial of Granulocyte Macrophage Colony Stimulating Factor Therapy for Moderate Symptomatic Pulmonary Alveolar Proteinosis

https://doi.org/10.1378/chest.130.1.227Get rights and content

Pulmonary alveolar proteinosis (PAP) is a rare idiopathic autoimmune lung disease in adults characterized by the accumulation of lipoproteinaceous material within the alveoli of the lung. The natural history of this disease is poorly defined. Current therapy of bilateral whole-lung lavage (WLL) under general anesthesia is invasive and has its limitations. Data suggest that relative granulocyte macrophage colony stimulating factor (GM-CSF) deficiency may be involved in the pathogenesis of this disease. There have been several case series that have described clinical improvement with exogenous GM-CSF therapy in a subset of patients with PAP. We describe the results of a prospective, open-label clinical trial of daily subcutaneous GM-CSF therapy in a group of adult patients with idiopathic PAP. In this series of 25 patients, the largest reported to date, administration of GM-CSF improved oxygenation as assessed by a 10 mm Hg decrease in alveolar-arterial oxygen gradient, as well as improvement in other clinical and quality of life parameters in 12 of 25 patients (48%) with moderate symptomatic disease who completed the trial. In addition, the serum anti–GM-CSF antibody titer correlated with lung disease activity and was a predictor for responsiveness to therapy. These data indicate that subcutaneous GM-CSF therapy is a promising alternative to WLL for symptomatic patients with PAP.

Section snippets

Materials and Methods

The study was a prospective, open-label clinical trial of daily GM-CSF therapy in a group of patients with idiopathic PAP. The study was approved by the Institutional Review Board at the Cleveland Clinic Foundation, and informed consent was obtained from all patients prior to enrollment. A diagnosis of idiopathic PAP was confirmed by transbronchial lung biopsy (n = 8) or open-lung biopsy (n = 17) in all patients. All patients had pretreatment serum assayed for GM-CSF–neutralizing antibody as

Dosage and Dose Escalation

Patients were treated with recombinant human yeast-derived GM-CSF (Leukine; formerly Immunex Corporation and now Berlex; Seattle, WA) administered subcutaneously once daily for 3 months. Patients were trained to self-administer daily subcutaneous therapy. The starting dose was 250 μg/d, which was progressively increased to 5 μg/kg/d for the second month of study, and to 9 μg/kg/d for the third month. After the patient received therapy for 3 months, if the clinical response was still suboptimal

Monitoring During Therapy

The first dose was administered in the clinic, and patients were observed for 2 h. Injection sites were rotated between the anterior abdominal wall and upper thighs. Outpatient follow-up occurred at 2 weeks and months 1, 2, 3, 4, 5, and 6 after initiation of therapy. During follow-up, a CXR, complete pulmonary function studies, a 6-min walk test, a dyspnea questionnaire, and a Short Form-36 (SF-36) quality of life questionnaire were obtained. A CBC with differential was obtained on a weekly

Parameters for Study Discontinuation

The study was discontinued if patients had one of the following: (1) progression of the underlying PAP leading to deterioration of the respiratory status requiring hospitalization for WLL (assessed based on symptoms, physical examination, CXR, and oxygenation); (2) serious allergic or anaphylactic reaction with the first dose of GM-CSF or during subsequent therapy; (3) persistent significant laboratory abnormalities including, but not limited to, WBC count > 50,000/μL, absolute neutrophil count

Study Outcomes

The primary end point was an improvement in oxygenation as assessed by a ≥ 10 mm Hg decrease in the room air alveolar-arterial oxygen gradient (P[A-a]O2). For the patients who received GM-CSF therapy after hospital admission for bilateral lavage (history of two or more WLLs in the prior 4 months), the primary outcome variable was the need for subsequent therapeutic lavage or further hospital admission days (rather than oxygenation). Secondary end points were as follows: (1) improvement in

Radiographic Grading

Single frontal CXRs were graded as to the presence and extent of lung opacification using a visual scoring system similar to one described by Remy-Jardin et al.17 Scores were determined for degree of opacification, extent of opacification, and severity of opacification.

The CXRs (n = 21) were interpreted blindly by our radiologist (M.M.), without the knowledge of clinical, laboratory, or pulmonary function test results, or whether the radiographs were before or after treatment. The presence and

Statistical Analysis

The two groups were compared on the normally distributed variables using Student t test and on the nonnormally distributed variables using Wilcoxon rank-sum test. The responders and nonresponders were compared on the difference between follow-up and baseline variables of interest (Pao2, P(A-a)O2, diffusing capacity, total lung diffusion capacity/alveolar volume, total lung capacity, FVC, 6-min walk distance, WBC count, lactate dehydrogenase [LDH], and the duration and maximum dose of therapy).

Results

Twenty-seven patients with adult idiopathic PAP were screened, and 25 patients were enrolled in the trial. Figure 1is a flow chart showing the disposition of all screened patients. Circulating anti–GM-CSF antibodies were present in all patients, measured in pretreatment sera as previously described. Among the 25 patients enrolled in the trial, 18 were men and 7 were women. The demographics and baseline characteristics are shown in Table 1. Of the 25 patients enrolled, 4 patients did not

Long-term Follow-up

The patients were followed up for a mean (± SD) duration of 39 ± 17.3 months. Of the 12 responders, 8 patients (67%) did not require WLL or home oxygen, and 4 patients (33%) required WLL for a mean of two occasions (range, one to five occasions). Of the nine nonresponders, four patients (44%) did not require WLL or home oxygen, and five patients (56%) required WLL once. Of four others screened initially, three required WLL.

Toxicity

Overall, the drug was well tolerated. Table 5lists the adverse events noted in the study participants. The majority of the side effects were minor and included injection-site edema, erythema, and malaise. Shortness of breath was noted in 10 patients. It is unclear whether the shortness of breath was related to PAP or the GM-CSF therapy. There were no bone marrow or lung toxicities.

Discussion

The primary finding from this open-label study was that administration of GM-CSF improved oxygenation as assessed by a decrease in P(A-a)O2 as well as other clinical variables in 12 of 25 adult patients (48%) with idiopathic PAP with moderately symptomatic disease. Response to GM-CSF conferred a meaningful benefit clinically to the patients with PAP, with improvements in symptomatology (both dyspnea as well as overall quality of life), reduction in supplemental oxygen requirement, frequency of

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  • Cited by (0)

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

    Dr. Venkateshiah is presently at Creighton University, Omaha, NE.

    This study was supported by a research grant from Berlex, formerly Immunex Corporation, Seattle, WA.

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