An Open-Label Trial of Granulocyte Macrophage Colony Stimulating Factor Therapy for Moderate Symptomatic Pulmonary Alveolar Proteinosis: Discussion

An Open-Label Trial of Granulocyte Macrophage Colony Stimulating Factor Therapy for Moderate Symptomatic Pulmonary Alveolar Proteinosis: DiscussionThe improvement in clinical parameters was not apparent until 8 to 12 weeks after initiation of therapy in our study. This was similar to the study by Seymour et al, in which improvement in P(A-a)O2 was not evident until 4 to 6 weeks, with maximal improvement achieved at approximately 6 to 10 weeks of therapy. These observed delays are consistent with published data that GM-CSF is required for immature precursor cells to be recruited to the lung and stimulated to differentiate into functional alveolar macrophages and, hence, help in surfactant clearance. In a trial of aerosolized GM-CSF in GM-CSF-deficient mice, improvement of the lung histology was first evident only after 4 to 5 weeks of therapy. avandia generic
One observation from our study is that several patients who were receiving GM-CSF treatment noted a response only after prolonged therapy (from 6 to 12 months). Four patients received therapy for 48 weeks, and two patients received therapy for 52 weeks. This is in contrast to the study by Seymour et al, in which only seven patients received treatment beyond 10 to 12 weeks and one patient for 26 weeks. Our study suggests that prolonged duration of therapy may be necessary in a subgroup of PAP patients to demonstrate clinical improvement. Whether there are any features that would identify a particular group of patients that would benefit from prolonged therapy is still unclear.
The total (peripheral) WBC count was unchanged with GM-CSF therapy both in responders and nonresponders to therapy. This observation was also noted by Seymour et al. We did not find any increase in the total circulating WBC count or eosinophilia with GM-CSF therapy. This is at variance with the study by Seymour et al and the case report by Barraclough and Gillies, which showed treatment-related eosinophilia was a predictor of response. All patients in our study had anti-GM-CSF antibodies, and it is possible that the antibodies blunt the hematopoietic response to exogenously administered GM-CSF. Two of the patients in the responder group in our study had increases in WBC count with GM-CSF therapy. This is similar to the observation by Seymour et al, in which three of their patients with PAP had modest neutrophilia with escalating doses of GM-CSF therapy, suggesting that the responsiveness of the WBC count to GM-CSF therapy in PAP patients was impaired but not absent.

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