Biomarker Signatures in Sepsis: Linking Host Response to Clinical Outcomes

Highlights

1. Biomarker signatures for host resistance, disease tolerance, and damage were analyzed in sepsis patients.

2. Greater host damage was significantly associated with increased 90-day mortality.

3. Sepsis subtypes showed distinct patterns in disease tolerance and damage signatures.

Background

Sepsis remains a leading cause of mortality worldwide, with complex pathophysiology involving host resistance to infection, disease tolerance, and host damage. Despite advances in understanding, biomarkers that reliably predict outcomes and subtype classifications are needed to guide personalized treatment strategies.

Study Design

The study prospectively enrolled 444 adults meeting Sepsis-3 criteria within 6 hours of emergency department arrival. Participants were assigned clinical subtypes (α, β, γ, δ) using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Sixteen plasma and urinary biomarkers were grouped into three mechanistic axes: host resistance, disease tolerance, and damage. Principal component analysis and multivariable logistic regression were used to assess associations with 90-day mortality and sepsis subtype membership.

Key Findings

The mean age of participants was 60 years, with a mean SOFA score of 4.3 and a 90-day mortality rate of 17%. Greater host damage was significantly associated with increased mortality (aOR = 1.70; 95% CI 1.38-2.11; p < 0.001), while host resistance and disease tolerance showed no significant association. Sepsis subtypes exhibited distinct biomarker profiles, with δ-type patients showing higher damage and lower disease tolerance, and α-type patients showing the opposite pattern.

Expert Commentary

This study provides valuable insights into the mechanistic underpinnings of sepsis, highlighting the role of host damage in mortality. The findings suggest that biomarker signatures could enhance subtype classification and prognostication, though further validation is needed. Limitations include the single-center design and reliance on remnant biospecimens.

Conclusion

Biomarker signatures aligned with host resistance, disease tolerance, and damage offer a novel approach to understanding sepsis pathophysiology and outcomes. These findings may inform future research and therapeutic strategies, addressing unmet needs in sepsis management.

Funding and ClinicalTrials.gov

The study was supported by institutional funding. ClinicalTrials.gov registration was not provided.

References

Chowdhury A, et al. Intensive Care Medicine. 2026.