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/).

Original languageEnglish
JournalAmerican journal of respiratory and critical care medicine
Publication statusE-pub ahead of print - 10 Nov 2023

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