Biomarker-Enriched Host-Directed Trials in Sepsis: Integrating Immune, Endothelial, Coagulation, Redox, and Metabolic Domains

Sepsis is a life-threatening, biologically heterogeneous syndrome in which immune dysregulation, endothelial injury, coagulation activation, redox imbalance, and metabolic reprogramming contribute to microvascular and organ dysfunction. This structured narrative review integrates these five domains to inform biomarker-enriched trials of host-directed interventions, emphasizing the endothelium as an interface between inflammation, immunothrombosis, and impaired cellular bioenergetics. Candidate biomarkers of immune competence, endothelial injury, coagulation, and metabolism are examined alongside investigational immunomodulatory and restorative strategies. The proposed framework distinguishes three functional tiers: screening and biological enrichment; pharmacodynamic target engagement and safety assessment; and patient-centered outcomes. Candidate host-response profiles are hypothesis-generating, may overlap, and require prospective validation, with explicit provisions for mixed and indeterminate classifications. A complementary implementation model separates routine assessments from trial-specific assays and advanced mechanistic substudies, addressing sampling, reporting, missing measurements, and assay harmonization. Evidence remains heterogeneous and largely preclinical, observational, or early-phase; predictive thresholds, therapeutic windows, and patient-centered benefits remain unestablished for most candidate strategies. This framework supports prospective trial design rather than routine bedside treatment selection. Biomarker improvement must be evaluated alongside pathogen control, organ recovery, adverse events, and longer-term outcomes and should not be assumed to indicate clinical benefit.