Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Department of Pulmonary and Critical Care, TidalHealth Peninsula Regional Medical Center, Salisbury, MD 21801, USA.
Mil Med. 2023 Jul 22;188(7-8):e2629-e2638. doi: 10.1093/milmed/usac362.
INTRODUCTION: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein produced in the lung, is essential for pulmonary host defense and alveolar integrity. Prior studies suggest potential benefits in several pulmonary conditions, including acute respiratory distress syndrome and viral infections. This trial evaluated the effect of the addition of inhaled sargramostim (yeast-derived, glycosylated recombinant human GM-CSF) to standard of care (SOC) on oxygenation and clinical outcomes in patients with COVID-19-associated acute hypoxemia. MATERIALS AND METHODS: A randomized, controlled, open-label trial of hospitalized adults with COVID-19-associated hypoxemia (oxygen saturation <93% on ≥2 L/min oxygen supplementation and/or PaO2/FiO2 <350) randomized 2:1 to inhaled sargramostim (125 mcg twice daily for 5 days) plus SOC versus SOC alone. Institutional SOC before and during the study was not limited. Primary outcomes were change in the alveolar-arterial oxygen gradient (P(A-a)O2) by day 6 and the percentage of patients intubated within 14 days. Safety evaluations included treatment-emergent adverse events. Efficacy analyses were based on the modified intent-to-treat population, the subset of the intent-to-treat population that received ≥1 dose of any study treatment (sargramostim and/or SOC). An analysis of covariance approach was used to analyze changes in oxygenation measures. The intubation rate was analyzed using the chi-squared test. All analyses are considered descriptive. The study was institutional review board approved. RESULTS: In total, 122 patients were treated (sargramostim, n = 78; SOC, n = 44). The sargramostim arm experienced greater improvement in P(A-a)O2 by day 6 compared to SOC alone (least squares [LS] mean change from baseline [SE]: -102.3 [19.4] versus -30.5 [26.9] mmHg; LS mean difference: -71.7 [SE 33.2, 95% CI -137.7 to -5.8]; P = .033; n = 96). By day 14, 11.5% (9/78) of sargramostim and 15.9% (7/44) of SOC arms required intubation (P = .49). The 28-day mortality was 11.5% (9/78) and 13.6% (6/44) in the sargramostim and SOC arms, respectively (hazard ratio 0.85; P = .76). Treatment-emergent adverse events occurred in 67.9% (53/78) and 70.5% (31/44) on the sargramostim and SOC arms, respectively. CONCLUSIONS: The addition of inhaled sargramostim to SOC improved P(A-a)O2, a measure of oxygenation, by day 6 in hospitalized patients with COVID-19-associated acute hypoxemia and was well tolerated. Inhaled sargramostim is delivered directly to the lung, minimizing systemic effects, and is simple to administer making it a feasible treatment option in patients in settings where other therapy routes may be difficult. Although proportionally lower rates of intubation and mortality were observed in sargramostim-treated patients, this study was insufficiently powered to demonstrate significant changes in these outcomes. However, the significant improvement in gas exchange with sargramostim shows this inhalational treatment enhances pulmonary efficiency in this severe respiratory illness. These data provide strong support for further evaluation of sargramostim in high-risk patients with COVID-19.
简介：粒细胞-巨噬细胞集落刺激因子（GM-CSF）是一种在肺部产生的蛋白质，对肺部宿主防御和肺泡完整性至关重要。先前的研究表明，GM-CSF 在几种肺部疾病中具有潜在益处，包括急性呼吸窘迫综合征和病毒感染。这项试验评估了在 COVID-19 相关低氧血症患者中添加吸入用 sargramostim（酵母衍生的，糖基化重组人 GM-CSF）到标准治疗（SOC）对氧合和临床结局的影响。
材料和方法：一项随机、对照、开放标签的住院 COVID-19 相关低氧血症（氧饱和度 <93%，接受 ≥2 L/min 氧补充和/或 PaO2/FiO2 <350）患者的试验，将患者以 2:1 的比例随机分为吸入用 sargramostim（125 mcg 每日两次，共 5 天）加 SOC 组与 SOC 组。研究期间 SOC 不受限制。主要终点是第 6 天肺泡-动脉氧梯度（P（A-a）O2）的变化和 14 天内插管的患者百分比。安全性评估包括治疗后出现的不良事件。疗效分析基于改良意向治疗人群，即接受任何研究治疗（sargramostim 和/或 SOC）至少 1 剂的意向治疗人群子集。采用协方差分析方法分析氧合指标的变化。采用卡方检验分析插管率。所有分析均被认为是描述性的。该研究得到了机构审查委员会的批准。
结果：共有 122 名患者接受了治疗（sargramostim 组，n=78；SOC 组，n=44）。与 SOC 组相比，sargramostim 组在第 6 天 P（A-a）O2 改善更大（最小二乘[LS]均值变化从基线[SE]：-102.3[19.4]与-30.5[26.9]mmHg；LS 均值差异：-71.7[SE 33.2，95%CI -137.7 至-5.8]；P=0.033；n=96）。到第 14 天，sargramostim 组和 SOC 组分别有 11.5%（9/78）和 15.9%（7/44）的患者需要插管（P=0.49）。sargramostim 组和 SOC 组的 28 天死亡率分别为 11.5%（9/78）和 13.6%（6/44）（风险比 0.85；P=0.76）。sargramostim 组和 SOC 组分别有 67.9%（53/78）和 70.5%（31/44）的患者发生治疗后不良事件。
结论：在 COVID-19 相关急性低氧血症住院患者中，添加吸入用 sargramostim 到 SOC 可在第 6 天改善氧合的 P（A-a）O2，且耐受性良好。吸入用 sargramostim 直接输送到肺部，最大限度地减少了全身效应，并且给药简单，使其成为其他治疗途径可能困难的患者的可行治疗选择。尽管 sargramostim 治疗患者的插管率和死亡率比例较低，但本研究的效力不足以证明这些结局有显著变化。然而，sargramostim 显著改善气体交换表明，这种吸入性治疗增强了这种严重呼吸系统疾病的肺效率。这些数据为进一步评估 sargramostim 在 COVID-19 高危患者中的应用提供了强有力的支持。
Orphanet J Rare Dis. 2023-11-11
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