Measuring signatures of host resistance, disease tolerance, and damage in human sepsis: a prospective cohort study

PURPOSE: To understand how protein biomarkers in blood and urine that are aligned with host resistance to infection, disease tolerance, and damage are associated with clinical outcomes and sepsis subtypes in community-onset sepsis. METHODS: Adults meeting Sepsis-3 criteria were prospectively enrolled within 6 h of emergency department arrival and assigned clinical subtypes (α, β, γ, δ), using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Using structured expert ranking with consensus adjudication, 16 plasma and urinary biomarkers obtained from remnant biospecimens were grouped into three mechanistic axes contributing to sepsis pathophysiology: host resistance to infection, disease tolerance, and damage to the host. Biomarkers for each concept were analyzed with principal component analysis as a signature, and multivariable logistic regression tested associations of each signature with 90-day mortality and sepsis subtype membership. RESULTS: Among 444 adults, the mean age was 60 years [SD: 16], the mean SOFA score was 4.3 [SD: 2.3], and 90-day mortality was 17%. After adjustment for age, sex, and race, greater damage to the host was associated with increased 90-day mortality (adjusted odds ratio (aOR) = 1.70; 95% CI 1.38-2.11; p < 0.001), while greater host resistance (aOR = 0.83; 95% CI 0.54-1.10; p = 0.4) and greater disease tolerance (aOR = 0.83; 95% CI 0.68-1.01; p = 0.06) were not. Differences across sepsis subtypes were most pronounced for disease tolerance and damage signatures, where the δ‑type patients exhibited higher damage and lower disease tolerance and the α‑type patients had lower damage and higher disease tolerance. CONCLUSION: Biomarker signatures aligned with host resistance to infection, disease tolerance, and damage to the host, informed by expert consensus, were associated with clinical outcomes and sepsis subtype membership.