Biomarkers for Early Severity Prediction in Clostridioides difficile Infection: Current Evidence, Clinical Utility, and Future Directions

infection (CDI) is a leading healthcare-associated infection worldwide, causing significant morbidity, mortality, healthcare burden, and costs. Clinical manifestations range from mild, self-limiting diarrhea to severe, life-threatening complications such as toxic megacolon and septic shock. Early identification of patients at high risk of severe disease is essential to guide clinical decision-making and optimize therapy. This narrative review summarizes recent epidemiological data, current trends, and known risk factors as clinical context for severity prediction and then examines the utility and limitations of biomarkers that may predict CDI severity, including inflammatory, hematological, fecal, renal, and immune-response biomarkers. While some markers are already used in guideline-based assessment or routine clinical practice (e.g., C-reactive protein, white blood cell count, serum creatinine), they have limited specificity. Other markers emerging from CDI research, including procalcitonin, interleukins, and presepsin, may provide complementary prognostic information. The key challenge is not simply to identify additional biomarkers but to determine which biomarkers are clinically useful, at which stage of CDI progression, and in which patients they add value beyond conventional severity criteria. Validated predictive models integrating combinations of these biomarkers with clinical and microbiological data are needed to support early risk stratification and therapeutic decision-making at the time of diagnosis.