Plasma H3.1 nucleosomes as biomarkers of infection, inflammation and organ failure

Background: Neutrophil extracellular traps (NETs) are a vital part of the innate immune response, while excessive NET formation can cause tissue damage. H3.1 nucleosomes, a component of NETs, have emerged as a potential biomarker. This study aimed to evaluate H3.1 nucleosomes in critical illness, assessing their relationship with sepsis, organ failure, inflammatory subphenotypes and outcomes. Methods: The MARS cohort was used, comprising of consecutive Intensive Care Unit patients, with plasma samples collected on days 0, 2 and 4. H3.1 nucleosome concentrations were measured using the Nu.Q® NETs Immunoassay. H3.1 nucleosome concentrations were compared across sepsis presence and organ failure, both at baseline and longitudinally. The relationship between H3.1 nucleosome concentrations and clinical outcomes was investigated. Results: 1713 critically ill patients were included, with a total of 3671 plasma samples. Baseline H3.1 nucleosome concentrations differed between sepsis confirmed by clinical adjudication (740 ng/mL), sepsis unconfirmed by clinical adjudication (416 ng/mL) and non-sepsis (463 ng/mL, P < 0.001). H3.1 concentrations were associated with SOFA score (r = 0.40) and were higher in patients with disseminated intravascular coagulation, acute kidney injury and hyperinflammatory sepsis. H3.1 concentration was highly predictive for the need of renal replacement therapy (hazard ratio 2.00 per log10 increase), correcting for mortality. Conclusions: Sepsis and organ failure were closely associated with plasma H3.1 nucleosome concentrations. While individual diagnostic performance for sepsis and organ failure remained low, H3.1 levels predicted the need for renal replacement therapy and disseminated intravascular coagulation, revealing unique insights into the innate immune response. Trial registration: ClinicalTrials.gov identifier NCT01905033; IRB number 10-056C, registered June 16, 2010.