When to initiate immunomodulatory therapy in sepsis.

Immunomodulatory therapy in sepsis has long failed to deliver consistent clinical benefit, in part because the heterogeneity of host responses and the dynamic nature of disease trajectories have been underestimated. Rather than equating the timing of initiation with a fixed interval after symptom onset, a more clinically meaningful definition is a chronology-informed clinical decision point at which standard sepsis care has been implemented, serial monitoring supports a dominant or clinically important discordant immunophenotype, and the organ dysfunction trajectory suggests that continued observation without reassessment or escalation may be unsafe. Using this operational definition as its framework, this review synthesizes the dynamic course of immune dysregulation in sepsis, the clinical utility and limitations of key biomarkers and functional assays, and the emerging evidence from enrichment-design trials that reassess the therapeutic windows of different strategies. Current evidence suggests that intravenous corticosteroids in adult septic shock remain the immunomodulatory approach closest to routine clinical practice, whereas anakinra, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), interleukin-7 (IL-7), and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade are more appropriately considered in biomarker-enriched settings with rigorous serial reassessment, ideally within research protocols or experienced centers. The central challenge for the future is not to identify a universal immune drug for all patients with sepsis, but to establish reproducible, bedside-applicable immune phenotyping and reassessment pathways that can determine who may benefit, from which intervention, and at what point in the disease course.