Transcriptomic innate immunity subtypes. A transcriptomic innate immunity subtype associates with hyperinflammation and mortality in sepsis

RATIONALE: Effective clinical management of sepsis is hampered by extensive immunological heterogeneity, necessitating an individualized treatment approach. OBJECTIVES: To identify transcriptomic innate immunity subtypes in sepsis and explore their immunological correlates, prognostic value, and potential use as a therapeutic target. METHODS: Subtypes were derived from gene expression and plasma cytokine response data of 110 healthy volunteers undergoing experimental endotoxemia (1 ng/kg lipopolysaccharide [LPS] i.v.) twice, one week apart. Subtypes were subsequently validated in 522 patients with sepsis. MEASUREMENTS AND MAIN RESULTS: The first LPS challenge resulted in a marked rise in circulating cytokines and a distinct shift in monocyte gene expression, while the second challenge triggered a significantly blunted response (p<0.0001), demonstrating endotoxin tolerance. Three subtypes were derived: Innatehyper, Innateinter, and Innatehypo, with the first exhibiting the most profound response to the first LPS challenge and the most pronounced tolerance to the second. Patients with the Innatehyper subtype (n=88, 17%) had the highest SOFA scores and plasma concentrations of inflammatory, endothelial and coagulation markers. Furthermore, they exhibited the highest 30-day mortality (HR 2.04 [1.36 – 3.10] and 2.80 ]1.74 – 4.50]) compared with the Innateinter and Innatehypo subtypes, respectively (p<0.001). Prognostic separation by these novel subtypes was better than with previously published Mars1-4 endotype classification (28-fold lower log-rank p-value). Hydrocortisone was predicted to reverse the Innatehyper transcriptomic signature most strongly. CONCLUSIONS: Transcriptomic innate immunity subtypes derived during endotoxemia were consistently associated with clinical outcomes and inflammatory profiles of patients with sepsis, demonstrating better prognostic separation than previously described endotypes.