Background and Objectives: Sepsis represents a global health challenge and requires advanced diagnostic and prognostic approaches due to its elevated rate of morbidity and fatality. Our study aimed to assess the value of a novel set of six biomarkers combined with severity scores in predicting 28 day mortality among patients presenting with sepsis in the Emergency Department (ED). Materials and Methods: This single-center, observational, prospective cohort included sixty-seven consecutive patients with septic shock and sepsis enrolled from November 2020 to December 2022, categorized into survival and non-survival groups based on outcomes. The following were assessed: procalcitonin (PCT), soluble Triggering Receptor Expressed on Myeloid Cells-1 (sTREM-1), the soluble form of the urokinase plasminogen activator receptor (suPAR), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and azurocidin 1 (AZU1), alongside clinical scores such as the Quick Sequential Organ Failure Assessment (qSOFA), Systemic Inflammatory Response Syndrome (SIRS), the Sequential Organ Failure Assessment (SOFA), the Acute Physiology and Chronic Health Evaluation II (APACHE II), the Simplified Acute Physiology Score II and III (SAPS II/III), the National Early Warning Score (NEWS), Mortality in Emergency Department Sepsis (MEDS), the Charlson Comorbidity Index (CCI), and the Glasgow Coma Scale (GCS). The ability of each biomarker and clinical score and their combinations to predict 28 day mortality were evaluated. Results: The overall mortality was 49.25%. Mechanical ventilation was associated with a higher mortality rate. The levels of IL-6 were significantly higher in the non-survival group and had higher AUC values compared to the other biomarkers. The GCS, SOFA, APACHEII, and SAPS II/III showed superior predictive ability. Combining IL-6 with suPAR, AZU1, and clinical scores SOFA, APACHE II, and SAPS II enhanced prediction accuracy compared with individual biomarkers. Conclusion: In our study, IL-6 and SAPS II/III were the most accurate predictors of 28 day mortality for sepsis patients in the ED.
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