Host-protein biomarkers for distinguishing bacterial from non-bacterial illness in hospitalised children: an exploratory case–control diagnostic study

Abstract Background Distinguishing bacterial from viral or inflammatory conditions in hospitalised children is clinically challenging due to overlapping clinical features and limitations of existing diagnostics. Culture-based tests are slow, and commonly used biomarkers such as C-reactive protein (CRP) lack sufficient accuracy, contributing to empirical antibiotic use and antimicrobial resistance. We aimed to evaluate the diagnostic performance of novel blood protein biomarkers for bacterial infection in children admitted with infection or inflammatory illness. Methods We performed a prospective observational diagnostic accuracy study of children ≤ 16 years admitted to the Royal Belfast Hospital for Sick Children (2020–2023) with bacterial infection, viral infection or inflammatory illness. Plasma samples were analysed for previously reported novel biomarkers and signatures (LCN2; TRAIL + IP-10 + CRP; E-selectin+IL18 + NCAM1+LCN2 + IFN-γ + LG3BP and E-selectin+IL18 + NCAM1+LCN2 + IFN-γ). The diagnostic accuracy of individual biomarkers and biomarker signatures was assessed using ROC curves. Results Fifty-two children were included (13 bacterial, 20 viral, 19 inflammatory). All evaluated biomarker signatures and LCN2 distinguished bacterial from viral infection (AUC 0.819–0.935), with the TRAIL + IP-10 + CRP signature achieving the highest accuracy (AUC 0.935). In bacterial–inflammatory comparisons, performance was lower (AUCs 0.607–0.745); the E-selectin + IL-18 + NCAM1+LCN2 + IFN-γ signature performed best (AUC 0.745) and outperformed CRP (AUC 0.595). A novel three-protein signature (E-selectin+LCN2 + IFN-γ) had a significantly higher AUC than CRP for distinguishing bacterial infections from non-bacterial (viral and inflammatory combined). Conclusions Several novel host protein biomarkers and signatures had a higher diagnostic accuracy than CRP for differentiating bacterial from non-bacterial illness (viral and inflammatory) in hospitalised children. These findings provide preliminary evidence for biomarker-guided diagnostics to improve accuracy and facilitate earlier antibiotic de-escalation. Importantly, the identification of the novel signature (E-selectin+LCN2 + IFN-γ) should be considered hypothesis-generating and requires external validation.