The novel biomarker t6A accurately identified septic patients and animals in the early stage of the disease but failed to predict outcome

Background Diagnosis of sepsis at the ICU admission is burdened by uncertainty. There is a need for an accurate identification of patients with sepsis from those with non-infectious, e.g. post-surgical and random trauma. We tested diagnostic utility of a novel biomarker, nucleoside t ⁶ A ( N ⁶ -threonylcarbamoyladenosine) in animal sepsis models and in adult patients with sepsis compared to two different patient cohorts with elective coronary artery bypass graft surgery (CABG) and polytrauma. Methods We performed a multicenter retrospective comparative observational study in adult intensive care units (ICUs) at three university hospitals: 81 patients presenting to the ICU with sepsis; 81 patients after CABG (center 1), 64 patients with polytrauma (center 2; Injury Severity Score >15) and 49 patients with COVID-19 (center 3). All animal modeling was performed by a research institution (center 4). Results Circulating t ⁶ A measured by tandem mass spectrometry accurately identified patients with sepsis at the ICU admission when compared to CABG (AUC 95%) and polytrauma (AUC 97%) patients was superior to procalcitonin (PCT) with an AUC 88% ( p< 0.05) by ROC test. In identification of 49 COVID-19 patients at the ICU admission, t ⁶ A reached AUC of 88%. t ⁶ A was released to circulation approximately 6–8 h post-infection onset as demonstrated in the baboon E. coli septic shock and non-lethal abdominal sepsis mouse models. While PCT declined, t ⁶ A median concentration was constantly above the optimal ROC diagnostic threshold until day 10 post-admission. Both t ⁶ A (AUC 62%) and PCT (AUC 72%) poorly predicted sepsis outcome at-admission. There was no increase of t ⁶ A concentration in pig trauma. Compared to a normal human value, circulating t ⁶ A was of similar magnitude in the healthy baboon, pig, dog, rabbit, rat and mouse. Conclusion t ⁶ A was highly accurate in detecting sepsis at the ICU admission compared to surgical CABG and severe polytrauma patients. t ⁶ A rapid rise at the sepsis onset and its prolonged elevation makes t ⁶ A an apt marker for diagnosis of sepsis. Overall, t ⁶ A shows potential for a precise and early differentiation between septic and non-septic patients in the ICU.