Clinical Report: Biomarkers of Host Resistance, Disease Tolerance, and Damage in Sepsis

Overview

This prospective cohort study evaluated 16 plasma and urinary biomarkers categorized into host resistance, disease tolerance, and damage signatures in patients with community-onset sepsis. The findings revealed that a sepsis clinical subtype with the highest 90-day mortality exhibited low disease tolerance and high tissue damage, suggesting new avenues for targeted therapies beyond traditional host resistance approaches.

Background

Sepsis is a heterogeneous and deadly syndrome with current treatments focusing on antimicrobial therapy and organ support. Traditional models emphasize host immune resistance to pathogens but often overlook disease tolerance mechanisms and tissue damage. Disease tolerance involves tissue-protective responses that preserve function without reducing pathogen burden, while damage results from pathogen or immune-mediated injury. Understanding these distinct biological domains may improve sepsis subtype classification and guide personalized treatment strategies.

Data Highlights

Key Findings

• Sixteen candidate biomarkers were assigned to host resistance, disease tolerance, and damage domains using expert consensus.
• The sepsis subtype with the highest 90-day mortality showed low disease tolerance and high tissue damage signatures.
• Host resistance biomarkers included inflammatory cytokines and endothelial activation markers.
• Disease tolerance biomarkers reflected tissue-protective stress responses, such as cell-cycle arrest proteins.
• Damage biomarkers indicated endothelial injury and release of damage-associated molecular patterns.
• These mechanistic signatures correlated with clinical sepsis subtypes derived from machine learning models.

Clinical Implications

Measuring biomarker signatures of host resistance, disease tolerance, and damage can improve sepsis subtype identification and risk stratification. Recognizing patients with low disease tolerance and high tissue damage may guide the development of adjunctive therapies targeting tissue protection and metabolic adaptation, complementing current antimicrobial and organ support strategies. This approach supports personalized sepsis management beyond immune modulation alone.

Conclusion

This study highlights the importance of integrating host resistance, disease tolerance, and damage biomarkers to better characterize sepsis heterogeneity and outcomes. Targeting disease tolerance mechanisms offers a promising avenue to reduce mortality in high-risk sepsis subtypes.

References

1. International Sepsis Forum/2024 -- Evaluating Biomarkers of Host Resistance, Disease Tolerance, and Tissue Damage in Human Sepsis