The Confounder in Plain Sight: A Retrospective Analysis on the Impact of Comorbidity on C-Reactive Protein Utility for Differentiating Bacterial vs. Viral Infections

Background: The antimicrobial resistance crisis is driven by antibiotic overuse, often due to the difficulty in distinguishing bacterial from viral infections. While Point-of-care C-Reactive Protein (CRP) testing aids in this differentiation, its diagnostic accuracy is frequently compromised by chronic inflammatory comorbidities that elevate baseline CRP levels.Objective: This study evaluated the diagnostic utility of CRP in an Emergency Department (ED) cohort and validated a novel “Comorbidity Confounder Score” (CCS) to identify patient subgroups in whom CRP retains high diagnostic value.Methods: We conducted a retrospective cohort study of 92 patients presenting to a tertiary ED with acute flu-like symptoms between 2023 and 2025. Microbiological diagnoses were confirmed using culture and PCR. The diagnostic performance of CRP (Area Under the Curve - AUC) was assessed in the total cohort and stratified into “Low-Utility” (high comorbidity, CCS $\ge$ 2) and “High-Utility” (low comorbidity, CCS < 2) subgroups.Results: In the unselected total cohort, CRP demonstrated poor diagnostic utility (AUC = 0.61). However, stratification revealed significant divergence. In the “Low-Utility” group, CRP had no diagnostic value (AUC = 0.52). Conversely, in the “High-Utility” group, CRP performance improved markedly (AUC = 0.84).Conclusion: The diagnostic value of CRP in unselected ED patients is clinically insufficient due to confounding comorbidities. Applying the CCS algorithm effectively identifies specific patient populations for whom CRP testing remains a reliable diagnostic tool.