BACKGROUND Imatinib reduced 90-day mortality in hospitalised coronavirus disease 2019 (COVID-19) patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19 and what baseline biological profile moderates the effect of imatinib. METHODS We undertook a secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxaemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the aforementioned method. RESULTS 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin (Ang)-2/Ang-1 ratio, E-selectin, tumour necrosis factor (TNF)-α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers. Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (hazard ratio 0.30, 95% CI 0.10-0.92). CONCLUSIONS The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes.

中文翻译：

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免疫调节和内皮屏障保护介导口服伊马替尼与住院 COVID-19 患者死亡率之间的关联。


背景 在最近的一项临床试验中，伊马替尼降低了 2019 年冠状病毒病 (COVID-19) 住院患者的 90 天死亡率，但导致临床结果改善的生物学效应尚不清楚。我们的目的是确定伊马替尼在 COVID-19 患者中引起的生物学变化，以及什么基线生物学特征可以调节伊马替尼的作用。方法 我们对住院低氧 COVID-19 患者口服伊马替尼的随机、双盲、安慰剂对照试验进行了二次分析。通过结合线性混合效应模型和联合模型，研究了 25 种血浆宿主反应生物标志物血浆浓度变化对随机分组和 90 天死亡率之间关联的中介效应。通过 Cox 回归模型评估基线生物标志物浓度的调节。我们使用沃德方法聚类识别了亚表型，并使用上述方法评估了这些亚表型的调节。结果 385 名参与者中有 332 名拥有可用的血浆样本。伊马替尼增加表面活性蛋白D（SP-D）的浓度，并降低白细胞介素-6、降钙素原、血管生成素（Ang）-2/Ang-1比值、E-选择素、肿瘤坏死因子（TNF）-α、伊马替尼对 90 天死亡率的影响完全是由这些生物标志物的变化介导的。聚类分析揭示了三种宿主反应亚表型。伊马替尼的死亡率获益仅存在于以肺泡上皮损伤为特征的亚表型中，该损伤表现为全身炎症和内皮功能障碍背景下 SP-D 水平升高（风险比 0.30，95% CI 0.10-0.92）。 结论 伊马替尼对住院 COVID-19 患者死亡率的影响是通过调节先天免疫反应和逆转内皮功能障碍介导的，并可能受到生物亚表型的调节。