Background: Lymphopenia in COVID-19 is associated with increased mortality and is generally considered an immunosuppressive feature.

Objectives: To investigate the association between lymphopenia, host response aberrations and mortality in patients with lymphopenic COVID-19.

Methods: We determined 43 plasma biomarkers reflective of endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We identified host response phenotypes in lymphopenic patients by clustering plasma biomarkers and explored phenotype-dependent differences in the corticosteroid response.

Results: 439 COVID-19 general ward patients were stratified by baseline lymphocyte counts: no (>1.0x109/L, n=167), mild (>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. 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 machine learning 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. The benefit of corticosteroids was phenotype-dependent (interaction term, p<0.05).

Conclusions: Lymphopenia in COVID-19 signifies a heterogenous group with distinct host response features associated with mortality.