Hyperlipidemia Reduces Sepsis Risk Differently Across Infection Sources: Evidence From a Retrospective Cohort Study

Sepsis risk varies by source of infection, reflecting differences in pathogen type and host inflammatory responses. Lipoproteins can bind and neutralize bacterial toxins, suggesting that hyperlipidemia may modify the host response to infection. The objective of this study was to examine whether the association between hyperlipidemia and sepsis admission differs by infection source, treating source of infection as an effect modifier.

We conducted a retrospective cohort study of adults discharged from two tertiary care emergency departments with ICD-10-CM diagnoses of urinary tract infection (UTI), pneumonia, or cellulitis in a 39-month period. The primary outcome was time from emergency department index visit to sepsis admission. Hyperlipidemia was the main exposure, and source of infection was evaluated as an effect modifier. Cox proportional hazards models including interaction terms between hyperlipidemia and infection source were used to estimate source-specific hazard ratios for hyperlipidemia. Models were adjusted for age, sex, race, ethnicity, comorbidities, demographic factors, and medications, including statins and antibiotics.

Among 10,179 patients with UTI, pneumonia or cellulitis, 269 (2.6%) experienced sepsis admission within 90 days of initial ED visit. Hyperlipidemia was consistently associated with a lower hazard of sepsis admission, and the effect varied by infection source. In source-stratified analyses, hyperlipidemia significantly reduced the hazard in pneumonia (HR 0.34; 95% CI 0.14–0.83; p = 0.017) and cellulitis (HR 0.30; 95% CI 0.12–0.76; p = 0.011), with a moderate protective effect in UTI (HR 0.61; 95% CI 0.40–0.92; p = 0.020). These findings indicate that infection source modified the association between hyperlipidemia and sepsis, with the strongest protective effects observed in pneumonia and cellulitis.

Hyperlipidemia is independently associated with a lower risk of sepsis admission, and this protective effect varies by source of infection. The strongest protection was observed in pneumonia and cellulitis, while UTI also showed a significant but more moderate effect. These results emphasize the importance of analyzing sepsis risk by infection source when evaluating host factors, and support a potential role of lipid-mediated neutralization of bacterial toxins in reducing infection specific sepsis risk.