Inhaled Granulocyte/Macrophage-Colony Stimulating Factor as Therapy for Pulmonary Alveolar Proteinosis
Inhaled Granulocyte/Macrophage-Colony Stimulating Factor as Therapy for Pulmonary Alveolar Proteinosis
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DOI：
10.1164/rccm.200906-0978oc
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发表时间：
2010-06-15
影响因子：
24.7
通讯作者：
Nakata, Koh
中科院分区：
文献类型：
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作者：
Tazawa, Ryushi;Trapnell, Bruce C.;Nakata, Koh
理由：吸入粒细胞/巨噬细胞集落刺激因子 (GM-CSF) 是治疗肺泡蛋白沉积症 (PAP) 的一种有前途的疗法，但尚未得到充分研究。目的：评估吸入 GM-CSF 对于持续性或进行性 PAP 患者的安全性和有效性。方法：我们在日本各地的 9 个肺中心进行了一项全国性、多中心、自我对照的 II 期试验。肺活检或细胞学结果诊断为 PAP、血清 GM-CSF 抗体水平升高且 Pa-O2 低于 75 mm Hg 的患者进入为期 12 周的观察期。观察期间改善的患者（即肺泡-动脉氧差 [A-aDO(2)] 降低 10 mm Hg）被排除。其余的进入连续的高剂量治疗期（第 1-8 天 250 μg，第 9-14 天无；x 6 个周期；12 周）；低剂量治疗（第 1-4 天 125 μg，第 5-14 天无治疗；x 6 个周期；12 周）和随访（52 周）。 测量和主要结果：50 名 PAP 患者参加了该研究。观察期间，9 例改善，2 例退出；所有这些都被排除在外。在完成高剂量和低剂量治疗的 35 名患者中，24 名患者病情有所改善，总体缓解率为 62%（24/39；意向治疗分析），A-aDO(2) 降低 12.3 mm Hg（95% 置信区间，8.4-16.2；n = 35，P < 0.001）。未发生严重不良事件，血清 GM-CSF 自身抗体水平未发生变化。 A-aDO(2) 和肺弥散能力之间存在治疗相关性，高分辨率 CT 显示磨玻璃样混浊有所改善。 35 例患者中的 29 例在 1 年内保持稳定，无需进一步治疗。结论：吸入 GM-CSF 治疗安全、有效，并为自身免疫性 PAP 提供持续的治疗效果。
Rationale: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.Objectives: 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-O2 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 mu g Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 mu g Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk).Measurements and Main 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.