Evidence of immune-metabolic imbalance prior to sepsis: a prospective study in the UK Biobank.

BACKGROUND

Sepsis is a severe systemic inflammatory response syndrome, and effective metabolic signatures for predicting its risk are currently lacking. This study seeks to evaluate the associations between inflammatory vulnerability (IVX), metabolic malnutrition (MMX), and metabolic vulnerability (MVX) and the risk of sepsis.

METHODS

We conducted a prospective cohort study using data from the United Kingdom Biobank. Cox proportional hazards models were utilized to examine the association between these composite indices and sepsis risk, while restricted cubic spline (RCS) analysis was applied to identify potential nonlinear trends. Subgroup analyses based on medical history, lifestyle factors, and demographic characteristics were performed in fully adjusted models. Sensitivity analyses employed 3-year left truncation and adjusted for CRP and glycated hemoglobin, as well as excluding participants with baseline comorbidities.

RESULTS

In fully adjusted models, a 1-SD increase in MVX corresponded to an 18% higher sepsis risk (HR: 1.18; 95% CI, 1.15-1.20; p < 0.01), whereas the highest quartile (Q4) showed a 43% increased risk versus Q1 (HR: 1.43; 95% CI, 1.35-1.52; p < 0.01). Positive associations were also observed for IVX (HR per SD: 1.15; 95% CI, 1.13-1.18; p < 0.01) and MMX (HR per SD: 1.10; 95% CI, 1.07-1.12; p < 0.01). Subgroup demonstrated that MVX was consistently linked to sepsis across various subgroups, with a stronger association than IVX or MMX. Notably, in participants with normal BMI, females, and those with severely decreased eGFR, the risk increased by 23% (HR: 1.23), 26% (HR: 1.26), and 28% (HR: 1.28) per SD increase in MVX, respectively (all p < 0.01). RCS analysis confirmed nonlinear dose-response relationships (nonlinear p = 0.018), with an inflection point of 38 for MVX; beyond this threshold, sepsis risk increased sharply. Sensitivity analyses supported the aforementioned results.

CONCLUSION

MVX, IVX, and MMX all demonstrated positive correlations with sepsis risk characterized by distinct nonlinear patterns. The composite index MVX, integrating inflammation and metabolic factors, was slightly more strongly associated with sepsis compared to IVX or MMX.