Current status and future perspectives of fecal immunological markers in the differential diagnosis of Clostridioides difficile infection in children

The rising incidence of pediatric Clostridioides difficile infection (CDI) and its nonspecific clinical presentation pose a significant diagnostic challenge. Current methods (e.g., NAATs, toxin tests) fail to distinguish active infection from asymptomatic colonization reliably. This review assesses the potential of fecal immunological markers to improve the differential diagnosis of pediatric CDI. We synthesized current literature on the epidemiology and diagnostic challenges of pediatric CDI, the limitations of existing diagnostic strategies, and the evidence for fecal immunological markers—including inflammatory mediators, antimicrobial peptides, and immunoglobulins—in distinguishing CDI from non-CDI diarrhea. Fecal immunological markers, such as IL-8, IL-1β, calprotectin, and human defensin-5, reflect intestinal mucosal inflammation and the host response during CDI. Elevated IL-8 and IL-1β are associated with disease severity, while fecal calprotectin > 500 µg/g shows high specificity for CDI and predicts recurrence risk. Dynamic changes in sIgA correlate with mucosal immunity and relapse. CDI exhibits a distinct “hyper-inflammatory” profile dominated by IL-1β/IL-8, contrasting with the Th1/interferon-driven response typical of viral diarrhea. However, variability in assay methods, lack of pediatric reference thresholds, and insufficient validation in diverse cohorts limit current clinical applicability. Fecal immunological markers represent a promising shift toward a host-focused diagnostic approach for pediatric CDI. Future efforts should prioritize standardized assays, multi-marker panels, and well-designed prospective studies in children to validate their role in guiding diagnosis and personalized management.