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Rationale: Systemic molecular phenotypes of critical illness are prognostically informative, yet their temporal kinetics and implications of changing phenotypes remain incompletely understood. Objectives: To determine the temporal nature of the Hyperinflammatory and Hypoinflammatory phenotypes and assess the impact of transition between the phenotypes on mortality. Methods: We used data from one prospective observational cohort (MARS [Molecular Diagnosis and Risk Stratification of Sepsis]) and two randomized controlled trials in acute respiratory distress syndrome (ALVEOLI [Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury]) and sepsis (CLOVERS [Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis]). Critically ill patients with biomarkers available at multiple time points (Days 0-4) were included. We used a validated classifier model incorporating plasma IL-8, protein C, and serum bicarbonate to assign phenotypes on each day. We determined the association of longitudinal phenotype transition and 90-day all-cause mortality. Measurements and Main Results: Data from 2,407, 527, and 868 patients were included in MARS, ALVEOLI, and CLOVERS, respectively. In MARS, 36.0% were classified by the parsimonious model as Hyperinflammatory at Day 0, decreasing to 15.6% by Day 2 and 6.3% by Day 4. In ALVEOLI and CLOVERS, 26.4% and 24.8% of patients were Hyperinflammatory at Day 0, decreasing to 13.4% and 5.7% at Day 3, respectively. In all three cohorts, switching classification from Hyperinflammatory (Day 0) to Hypoinflammatory over time was associated with significantly improved mortality compared with persistently Hyperinflammatory patients. Mediation analysis indicated that only a minor proportion of this improvement could be attributed to ameliorating organ failure. Conclusions: The prevalence of the Hyperinflammatory phenotype, as assigned using a parsimonious biomarker classifier model, decreases over the first several days of critical illness, irrespective of acute respiratory distress syndrome diagnosis. The transition from Hyperinflammatory to Hypoinflammatory mediates a trajectory toward recovery beyond the resolution of organ failure.

Rationale: Lymphopenia in coronavirus disease (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, cytokine release, and chemokine release. 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. Measurements and Main Results: A total of 439 general ward patients with COVID-19 were stratified by baseline lymphocyte counts: normal (>1.0 × 10 9 /L; n  = 167), mild lymphopenia (>0.5 to ⩽1.0 × 10 9 /L; n  = 194), and severe lymphopenia (⩽0.5 × 10 9 /L; n  = 78). Lymphopenia was associated with alterations in each host response domain. Lymphopenia was associated with increased mortality. Moreover, in patients with lymphopenia ( 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 P  < 0.01 or stronger significance levels). A cluster analysis revealed three host response phenotypes in patients with lymphopenia: "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 with high antiinflammatory cytokine levels yet low proinflammatory cytokine levels. Conclusions: 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.