Host Response Changes and Their Association with Mortality in COVID-19 Patients with Lymphopenia
American Journal of Respiratory and Critical Care Medicine, 2023
Michels E., Appelman B., de Brabander J., van Amstel R., van Linge C., Chouchane O., Reijnders T., Schuurman A., Sulzer T., Klarenbeek A., Douma R., Bos L., Wiersinga W., Peters-Sengers H., van der Poll T., van Agtmael M., Algera A., Appelman B., van Baarle F., Beudel M., Bogaard H., Bonta M., Bos L., Botta M., de Brabander J., de Bree G., de Bruin S., Bugiani M., Bulle E., Buis D., Cloherty O., Dijkstra M., Dongelmans D., Dujardin R., Elbers P., Fleuren L., Geijtenbeek S., Girbes A., Goorhuis B., Grobusch M., Hagens L., Hamann J., Harris V., Hemke R., Heunks S., Hollmann M., Horn J., Hovius J., de Jong H., de Jong M., Koning R., Lemkes B., Lim E., van Mourik N., Nellen J., Nossent E., Olie S., Paulus F., Peters E., Pina-Fuentes D., van der Poll T., Preckel B., Raasveld J., Reijnders T., de Rotte M., Schinkel M., Schultz M., Schrauwen F., Schuurman A., Schuurmans J., Sigaloff K., Slim M., Smeele P., Smit M., Stijnis C., Stilma W., Teunissen C., Thoral P., Tsonas A., Tuinman P., van der Valk M., Veelo D., Volleman C., de Vries H., Vught L., van Vugt M., Wouters D., Zwinderman A., Brouwer M., Wiersinga W., Vlaar A., van de Beek D.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Infectious Diseases | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
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 (>1.0×109/L, n=167), mild lymphopenia (>0.5 x109/L – ≤1.0 x109/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, 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.