Archive for the ‘Pulmonary Function’ Category

An Open-Label Trial of Granulocyte Macrophage Colony Stimulating Factor Therapy for Moderate Symptomatic Pulmonary Alveolar Proteinosis: ConclusionThe other factor that would argue in favor of a treatment effect for the observed clinical response is that many of these patients required frequent WLL for symptom relief before enrolling in our study, suggesting that they did not have many quiescent periods in their disease activity.
GM-CSF therapy was well tolerated, with minor side effects such as local skin reactions. The mean duration of follow-up was 39 months, and we did not see toxicity such as pulmonary fibrosis or bone marrow suppression with this therapy. The duration of follow-up may not be adequate to rule out longterm pulmonary or hematologic toxicity. Long-term follow-up of PAP patients treated with GM-CSF is ongoing.
All patients in our study had pretreatment anti-GM-CSF antibody, indicating an important diagnostic role for this antibody in the noninvasive diagnosis of PAP. In a study conducted at our institution, all adult patients (n = 40) with idiopathic PAP were found to have systemic and localized antibodies against GM-CSF, and the autoantibody response was specific for GM-CSF. The lowest serum end-titer for the PAP population was 1:400, and the highest titer was > 1:25,600. None of the healthy control subjects had end-titers > 1:10, and two of other pulmonary disease control subjects (beryllium lung disease) had end-titers at 1:100. The sensitivity of the serum anti-GM-CSF assay was 100%, and the specificity improved to 100% (using a cut-off end-titer of 1:400).

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Two plausible mechanisms for this observation in our patients are that both of these patients received escalating doses of GM-CSF for 26 weeks and 48 weeks, respectively, which may have overcome the inhibitory effect of the anti-GM-CSF antibody. The second mechanism could be that these two patients had a relatively lower anti-GM-CSF titer (1:3200 and 1:6400, respectively) compared to the other responders, which may have made them more susceptible to the stimulating effects of GM-CSF. birth control pills online
We have previously reported that the GM-CSF antibody titer is a predictor of response to GM-CSF therapy.” In 11 patients who completed the GM-CSF open-label clinical trial, it was demonstrated that the level of anti-GM-CSF titer is higher in patients with active disease and is lower in patients in remission. The anti-GM-CSF titer at baseline was lower and decreased further in responders to GM-CSF therapy. GM-CSF therapy did not induce or further increase the anti-GM-CSF titer. The data from this study indicate that the anti-GM-CSF titer correlates with PAP disease activity and also the response to therapy. There is also a case report of clinically successful treatment of PAP with GM-CSF that was associated with a profound reduction in GM-CSF-neutralizing autoantibodies (both serum and BAL) and improvement in alveolar macrophage morphology and function.
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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. there
Overall, the drug was well tolerated. Table 5 lists 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.
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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.
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An Open-Label Trial of Granulocyte Macrophage Colony Stimulating Factor Therapy for Moderate Symptomatic Pulmonary Alveolar Proteinosis: ResultsTwenty-seven patients with adult idiopathic PAP were screened, and 25 patients were enrolled in the trial. Figure 1 is 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 complete the study and were not evaluable. One patient withdrew due to arthralgia, one patient became pregnant and was withdrawn, one patient refused follow-up care, and one patient died of acute hypoxemic respiratory and multiorgan failure. so

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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 symptoms as assessed by a dyspnea questionnaire, pulmonary function tests, 6-min walk distance with oxygen saturation, and CXR abnormalities; (2) overall tolerability of therapy; (3) requirement for WLL and sustainability of a response as assessed by follow-up telephone interview; and (4) quality of life as measured by the SF-36 survey.
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. Scores were determined for degree of opacification, extent of opacification, and severity of opacification.

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An Open-Label Trial of Granulocyte Macrophage Colony Stimulating Factor Therapy for Moderate Symptomatic Pulmonary Alveolar Proteinosis: Dosage and Dose EscalationPatients 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 Mg/d, which was progressively increased to 5 |xg/kg/d for the second month of study, and to 9 |xg/kg/d for the third month. After the patient received therapy for 3 months, if the clinical response was still suboptimal and the patient was tolerating therapy, the patient underwent further dose escalation from 9 to 18 |xg/kg/d (12 Mg/kg/d at 3 months, 15 Mg/kg/d at 4 months, and 18 Mg/kg/d at 5 months). If the patient had an adequate response based on above-mentioned criteria, that dose was continued from 3 to 12 months. more

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