Rationale: Lymphopenia in coronavirus disease (COVID-19) is associated with increased mortality. Objectives: To explore the association between lymphopenia, host response aberrations, and mortality in patients with lymphopenic COVID-19. Methods: We determined 43 plasma biomarkers reflective of four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, cytokine release, and chemokine release. We explored if decreased concentrations of lymphocyte-derived proteins in patients with lymphopenia were associated with an increase in mortality. We sought to identify host response phenotypes in patients with lymphopenia by cluster analysis of plasma biomarkers. Measurements and Main Results: A total of 439 general ward patients with COVID-19 were stratified by baseline lymphocyte counts: normal (>1.0 × 109/L; n = 167), mild lymphopenia (>0.5 to ⩽1.0 × 109/L; n = 194), and severe lymphopenia (⩽0.5 × 109/L; n = 78). Lymphopenia was associated with alterations in each host response domain. Lymphopenia was associated with increased mortality. Moreover, in patients with lymphopenia (n = 272), decreased concentrations of several lymphocyte-derived proteins (e.g., CCL5, IL-4, IL-13, IL-17A) were associated with an increase in mortality (at P < 0.01 or stronger significance levels). A cluster analysis revealed three host response phenotypes in patients with lymphopenia: "hyporesponsive" (23.2%), "hypercytokinemic" (36.4%), and "inflammatory-injurious" (40.4%), with substantially differing mortality rates of 9.5%, 5.1%, and 26.4%, respectively. A 10-biomarker model accurately predicted these host response phenotypes in an external cohort with similar mortality distribution. The inflammatory-injurious phenotype showed a remarkable combination of relatively high inflammation and organ damage markers with high antiinflammatory cytokine levels yet low proinflammatory cytokine levels. Conclusions: Lymphopenia in COVID-19 signifies a heterogenous group of patients with distinct host response features. Specific host responses contribute to lymphopenia-associated mortality in COVID-19, including reduced CCL5 levels.

中文翻译：

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患有淋巴细胞减少症的 COVID-19 患者的宿主反应变化及其与死亡率的关系。


理由：冠状病毒病 (COVID-19) 中的淋巴细胞减少与死亡率增加相关。目的：探讨淋巴细胞减少症 COVID-19 患者的淋巴细胞减少症、宿主反应异常和死亡率之间的关联。方法：我们确定了反映四个病理生理学领域的 43 种血浆生物标志物：内皮细胞和凝血激活、炎症和器官损伤、细胞因子释放和趋化因子释放。我们探讨了淋巴细胞减少症患者淋巴细胞衍生蛋白浓度的降低是否与死亡率增加相关。我们试图通过血浆生物标志物的聚类分析来识别淋巴细胞减少症患者的宿主反应表型。测量和主要结果：共有 439 名普通病房的 COVID-19 患者根据基线淋巴细胞计数进行分层：正常（>1.0 × 109/L；n = 167），轻度淋巴细胞减少（>0.5 至 ⩽1.0 × 109/L；n = 167）。 n = 194），以及严重淋巴细胞减少症（⩽0.5 × 109/L；n = 78）。淋巴细胞减少症与每个宿主反应域的改变有关。淋巴细胞减少与死亡率增加相关。此外，在淋巴细胞减少症患者 (n = 272) 中，几种淋巴细胞衍生蛋白（例如 CCL5、IL-4、IL-13、IL-17A）浓度降低与死亡率增加相关（P < 0.01 或更强的显着性水平）。聚类分析揭示了淋巴细胞减少症患者的三种宿主反应表型：“低反应性”(23.2%)、“高细胞动力学”(36.4%) 和“炎症损伤性”(40.4%)，死亡率差异显着，分别为 9.5%、5.1%分别为 % 和 26.4%。 10 个生物标志物模型准确预测了具有相似死亡率分布的外部队列中的这些宿主反应表型。 炎症损伤表型显示出相对较高的炎症和器官损伤标志物与较高的​​抗炎细胞因子水平和较低的促炎细胞因子水平的显着组合。结论：COVID-19 中的淋巴细胞减少意味着一组具有不同宿主反应特征的异质患者。特定的宿主反应会导致 COVID-19 中与淋巴细胞减少相关的死亡率，包括 CCL5 水平降低。