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

Area of Science:

• Critical Care Medicine
• Immunology
• Epidemiology

Background:

• Sepsis is a major global health challenge, with outcomes significantly worsened by the presence of multiple chronic conditions (multimorbidity).
• Prevalent comorbidities like type 2 diabetes, obesity, heart failure, COPD, and chronic kidney disease profoundly impact sepsis pathophysiology and patient prognosis.

Purpose of the Study:

• To synthesize evidence on how common comorbidities reshape sepsis biology, immune responses, and clinical outcomes.
• To propose an integrative framework for understanding sepsis heterogeneity in multimorbid patients.
• To inform clinical care, system priorities, and future research directions.

Main Methods:

• Narrative review synthesizing epidemiological, pathophysiological, and immunological data.
• Analysis of convergent biological mechanisms linking comorbidities to sepsis.
• Framework development categorizing comorbidity impact across five key domains.

Main Results:

• Convergent mechanisms include chronic low-grade inflammation, immune dysfunction, endothelial injury, barrier disruption, and neuroendocrine changes.
• These alterations lead to a biphasic immune response (hyperinflammation followed by immunoparalysis), increasing risks of secondary infections and organ dysfunction.
• An integrative framework highlights how comorbidities differentially affect immunity, endothelium, barriers, neuroaxis, and immunometabolism.

Conclusions:

• Multimorbidity creates distinct sepsis phenotypes, necessitating personalized, mechanism-aligned clinical care.
• Optimizing fluid management, pharmacokinetics/pharmacodynamics, and antimicrobial strategies are crucial.
• Future research should focus on endotyping sepsis and testing mechanism-matched therapies to improve patient outcomes and reduce long-term burden.