Novel blood protein biomarkers for distinguishing bacterial from non-bacterial infection in children: a case–control study

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.

We performed a prospective case–control 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.

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).

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 support the potential of biomarker-guided diagnostics to improve accuracy and facilitate earlier antibiotic de-escalation. Competing Interest Statement The authors have declared no competing interest. Clinical Trial NCT04347408 Funding Statement Funding: This study was supported by Queen's University Belfast internal funding (Martha Moffett and John Alexander Moore research funds, awarded to CM, TW and HG) and Northern Ireland's Public Health Agency (COM/5712/22, awarded to TW). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study ethics: Ethical approval was obtained from London-Chelsea Research Ethics Committee (REC reference - 20/HRA/1731) and the Belfast Health & Social Care Trust Research Governance (Reference 19147TW-SW). Informed consent was obtained for all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes