Host-Response Biomarkers for Distinguishing Bacterial and Viral Infections: A Review of Diagnostic Performance and Antibiotic Stewardship Program

Abstract

Distinguishing bacterial from viral infection remains difficult when symptoms overlap, pathogen testing is incomplete, or microbial detection does not establish causation. Host-response biomarkers offer complementary information by measuring the patient's inflammatory and immune response rather than identifying the organism alone. This narrative review examines conventional inflammatory markers, multianalyte protein signatures and blood transcriptomic classifiers, with particular attention to acute respiratory illness and their implications for antibiotic stewardship. Evidence from diagnostic studies, randomized trials, economic evaluations and clinical guidelines was considered separately to distinguish biological discrimination from demonstrated clinical benefit. C-reactive protein and procalcitonin can support selected prescribing pathways, but neither provides a universal bacterial–viral classification rule. Multianalyte combinations incorporating TRAIL, IP-10 and C-reactive protein, and transcriptomic assays incorporating interferon-associated and bacterial-response genes, have shown promising discrimination in validation cohorts. However, performance varies with patient selection, reference standards, disease severity, immune status and the handling of indeterminate results. Procalcitonin-guided strategies have reduced antibiotic exposure in some trials, whereas the ProACT trial found no reduction, illustrating the importance of clinical context and implementation. Emerging protein-panel intervention studies remain insufficient to establish benefit across populations. Safe adoption requires timely results, explicit intended use, clinical override mechanisms, follow-up and evaluation of both antibiotic use and missed bacterial infection. Host-response testing should complement clinical assessment and pathogen-based diagnostics within validated stewardship pathways, rather than replace them.