RATIONALE Lymphopenia in 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, and cytokine and chemokine release. We explored if decreased concentrations of lymphocyte-derived proteins in lymphopenic patients were associated with an increase in mortality. We sought to identify host response phenotypes in patients with lymphopenia by cluster analysis of plasma biomarkers. RESULTS 439 COVID-19 general ward patients were stratified by baseline lymphocyte counts: normal (>1.0x109/L, n=167), mild lymphopenia (>0.5 x109/L - ≤1.0 x109/L, n=194) and severe lymphopenia (≤0.5x109/L, n=78). Lymphopenia was associated with alterations in each host response domain. Lymphopenia was associated with increased mortality. Moreover, within lymphopenic patients (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 least p<0.01). A Cluster analysis revealed three host response phenotypes in lymphopenic patients: 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, high anti-inflammatory cytokines yet low proinflammatory cytokines. CONCLUSIONS Lymphopenia in COVID-19 signifies a heterogenous group with distinct host response features. Specific host responses contribute to lymphopenia-associated mortality in COVID-19, including reduced CCL5 levels. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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。

基本原理 COVID-19 中的淋巴细胞减少与死亡率增加有关。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 43 种血浆生物标志物，反映了四个病理生理学领域：内皮细胞和凝血激活、炎症和器官损伤以及细胞因子和趋化因子释放。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。结果 439 名普通病房患者按基线淋巴细胞计数进行分层：正常（>1.0x109/L，n=167）、轻度淋巴细胞减少（>0.5 x109/L - ≤1.0 x109/L，n=194）和重度淋巴细胞减少(≤0.5x109/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（至少 p<0.01） 。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%）、高细胞因子血症（36.4%）和炎症损伤性（40.4%），死亡率差异显着，分别为 9.5%、5.1% 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、较高的抗炎细胞因子和较低的促炎细胞因子的显着组合。结论 COVID-19 中的淋巴细胞减少表明具有不同宿主反应特征的异质群体。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。本文是开放获取的，并根据知识共享署名非商业性无衍生许可证 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/) 的条款进行分发。