Clinical utility of biomarkers for outcomes prediction in adults with suspected sepsis presenting to the emergency department: a synthesis of current evidence

Background: Sepsis is characterised as life-threatening organ dysfunction due to a dysregulated host response to infection. It carries high mortality and is a major public health issue globally. Among adults presenting to the emergency department with features of suspected sepsis, rapid and accurate differentiation of those at high risk for prompt delivery of key therapies and escalation of care may improve outcomes. Objectives: To conduct a comprehensive evidence synthesis assessing the clinical utility of established and novel biomarkers - used individually or in combination - for predicting the risk of death or clinical deterioration in adults with clinically suspected sepsis presenting to the emergency department. Design and methods: Search strategies were designed to identify English-language studies published between 2013 and 2023 evaluating biomarker performance to predict mortality or clinical deterioration in adults with suspected sepsis. Eligible studies had to evaluate biomarker performance in patients with clinically suspected sepsis (as defined by study authors) at emergency department presentation. Outcomes of interest included all-cause mortality, critical care admission, septic shock and organ failure. A comprehensive search was conducted across multiple databases, including MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials (search date 5 July 2023). For each biomarker, used alone or in combination, risk ratios, hazard ratios, odds ratios and area under the receiver-operating characteristics curve values were extracted. Subgroup analyses were planned to compare patients in terms of age, presence of comorbidities, National Health Service or other health systems, and biomarker assessment timing. Methodological quality was evaluated using the Quality in Prognostic Factor Studies tool. Results: Of 1986 citations identified, 884 duplicates were removed, and 1102 were screened by title and abstract. Of the 430 full-text articles assessed, 377 were excluded as they did not meet the eligibility criteria, and 53 reports, related to 51 studies, were deemed suitable for inclusion. A total of 107 unique biomarkers or biomarker combinations were assessed across the included studies. However, due to limited data and clinical heterogeneity, only biomarkers commonly used in clinical practice (lactate, C-reactive protein and procalcitonin) were analysed through meta-analyses, and none effectively predicted adverse outcomes. Although novel biomarkers could not be pooled, several (Inflammatix Severity 2, mid-regional proadrenomedullin, neutrophil gelatinase-associated lipocalin, tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2, monocyte distribution width and neutrophil-to-lymphocyte ratio) showed potential for predicting mortality and admission to critical care. The predictive accuracy of these biomarkers improved when combined with other biomarkers and/or clinical scores. Limitations: There was considerable heterogeneity across included studies and insufficient data for meta-analysis of novel biomarkers. Conclusions: In emergency department patients with clinically suspected sepsis, lactate, C-reactive protein and procalcitonin did not effectively predict mortality or need for clinical care admission. However, some novel biomarkers showed promise for the prediction of these outcomes, particularly when combined with other biomarkers and/or commonly used clinical scores. Future research: Focusing on prospectively designed studies, there should be standardisation of biomarker thresholds, measurement timing and identification of participants to facilitate comparability across studies. Researchers should apply a clear and consistent definition of suspected sepsis. Adjusted and unadjusted analyses should be reported, accounting for critical variables. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR159912.