Proteomic biomarkers differentiate bacterial infections in febrile infants: A multicentre prospective study

To identify and validate plasma host-response protein biomarkers that improve discrimination of bacterial infection in febrile infants ≤90 days of age, and to assess whether novel biomarkers add value beyond established markers.

Sub-study of the prospective multicentre Febrile Infant Diagnostic Assessment and Outcome (FIDO) cohort. Novel biomarkers were identified through plasma proteomic profiling (Olink®) and combined with biomarkers and signatures from the literature for verification using Luminex and ELISA platforms. Diagnostic performance of novel biomarkers, established markers (CRP, PCT), and multi-protein signatures was evaluated.

Proteomic profiling of 110 samples identified 174 proteins differentially expressed between bacterial and viral infections, revealing distinct pathogen-specific immune signatures. Verification in the full cohort (n = 445) demonstrated PCT had the highest individual accuracy for invasive bacterial infection (IBI) (AUC 0.89). Combining PCT with novel biomarkers, particularly lipocalin-2 (LCN2), improved discrimination (AUC 0.96). Diagnostic performance for the combined IBI/urinary tract infection (UTI) outcome was consistently lower (AUC <0.8).

Febrile infants demonstrate biologically coherent host-response signatures that can be leveraged diagnostically. A PCT-LCN2 combination showed excellent accuracy for identifying IBI and may support future biomarker-guided diagnostic strategies, while reliable discrimination of UTI remains challenging.