Temporal analyses of immune responses in sepsis reveal asynchrony between clinical stage of illness and immune states

Deeper understanding of the temporal immune response architecture in sepsis may enable effective therapeutic interventions. Here, we investigated longitudinal immune response programs in critically ill patients with sepsis, as compared with elective cardiac surgery patients. Although transcriptomic profiles obtained at four clinical time points between admission and recovery or death showed substantial overlap, pseudotime analysis revealed a trajectory comprising three sepsis temporal immune states (STImS1–3). Weighted gene co-expression network analysis and immunophenotypic and cytokine profiles identified distinct programs associated with each STImS, and corresponding hub genes mapped to putative immunomodulatory targets, including interleukin 6 blockade, iron chelation, and anthracyclines. STImS1 was characterized by the strongest innate immune responses, elevated resistance programs, variable disease tolerance programs, and enrichment of low-resilience features, including mortality-associated signatures. In contrast, STImS3 was enriched for adaptive immune responses. Thus, clinical time and immune response trajectory are partially decoupled in sepsis, illustrating the need to align therapeutic intervention with the temporal immune state in sepsis.