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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>A total of 439 general ward patients with COVID-19 were stratified by baseline lymphocyte counts: normal (&amp;gt;1.0\u2009\u00d7\u2009109\/L; n\u2009=\u2009167), mild lymphopenia (&amp;gt;0.5 to \u22641.0\u2009\u00d7\u2009109\/L; n\u2009=\u2009194), and severe lymphopenia (\u22640.5\u2009\u00d7\u2009109\/L; n\u2009=\u200978). Lymphopenia was associated with alterations in each host response domain. Lymphopenia was associated with increased mortality. Moreover, in patients with lymphopenia (n\u2009=\u2009272), 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\u2009&amp;lt;\u20090.01 or stronger significance levels). A cluster analysis revealed three host response phenotypes in patients with lymphopenia: \u201chyporesponsive\u201d (23.2%), \u201chypercytokinemic\u201d (36.4%), and \u201cinflammatory-injurious\u201d (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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202305-0890oc","type":"journal-article","created":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T16:50:40Z","timestamp":1699635040000},"page":"402-416","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":9,"title":["Host Response Changes and Their Association with Mortality in COVID-19 Patients with Lymphopenia"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-2444","authenticated-orcid":false,"given":"Erik H. A.","family":"Michels","sequence":"first","affiliation":[{"name":"Center for Experimental and Molecular Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4560-8410","authenticated-orcid":false,"given":"Brent","family":"Appelman","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3596-5086","authenticated-orcid":false,"given":"Justin","family":"de Brabander","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9296-8518","authenticated-orcid":false,"given":"Rombout B. E.","family":"van Amstel","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine C. A.","family":"van Linge","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1629-8588","authenticated-orcid":false,"given":"Osoul","family":"Chouchane","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1764-0114","authenticated-orcid":false,"given":"Tom D. Y.","family":"Reijnders","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex R.","family":"Schuurman","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Titia A. 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