Measuring Signatures of Host Resistance, Disease Tolerance, and Damage in Human Sepsis: a Prospective Cohort Study

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. 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. 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