Temporal Transitions of the Hyperinflammatory and Hypoinflammatory Phenotypes in Critical Illness.

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) and two randomized controlled trials in ARDS (ALVEOLI) and sepsis (CLOVERS). Critically ill patients having biomarkers available at multiple timepoints (Day 0-4) were included. We employed a validated classifier model incorporating plasma interleukin-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 2407, 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 to persistently Hyperinflammatory patients. Mediation analysis indicated that only a minor proportion of this improvement could be attributed to ameliorating organ failure.

Conclusion: The prevalence of the Hyperinflammatory phenotype, as assigned by a parsimonious biomarker classifier model, decreases over the first several days of critical illness, irrespective of ARDS diagnosis. The transition from Hyperinflammatory to Hypoinflammatory mediates a trajectory towards recovery beyond the resolution of organ failure.