Sepsis in multimorbidity: a domain-based framework for systemic vulnerability and precision care

Sepsis is a leading cause of morbidity and mortality, amplified by multimorbidity. This narrative review synthesizes epidemiological, pathophysiological, and immunological evidence to show how prevalent conditions-type 2 diabetes and obesity, heart failure and cerebrovascular disease, COPD, chronic kidney disease, cancer/HIV, and severe mental illness-reshape sepsis biology and outcomes. Convergent mechanisms include low-grade inflammation, impaired innate and adaptive immunity, endothelial injury with immunothrombosis/NETosis, barrier disruption with dysbiosis, and neuroendocrine maladaptation. These processes drive an early hyperinflammatory peak followed by immunoparalysis, increasing risks of secondary infection, multiorgan dysfunction, and death. Malnutrition modulates trajectories, and nosocomial sepsis contributes disproportionately to mortality. We propose an integrative framework in which comorbidities differentially load risk across five domains-immunity/inflammation, endothelium, barriers/microbiota, neuroaxis, and immunometabolism-clarifying bedside heterogeneity and therapeutic tolerance. Clinical implications include mechanism- and phenotype-aligned care: titrated fluids and vasoactives for limited cardiac or renal reserve; PK/PD optimization and timely antimicrobial de-escalation in obesity and chronic kidney disease; and immune/organ monitoring (e.g., monocyte HLA-DR, NGAL/KIM-1). System priorities include stronger prevention bundles for hospital-acquired sepsis and post-sepsis follow-up. Research needs include endotyping and trials testing mechanism-matched therapies, alongside PK/PD studies and cohorts tracking neurocognitive and cardiometabolic outcomes. Viewing sepsis through multimorbidity enables personalized care and reduced long-term burden.