Diagnostic Challenges in Pediatric Fever of Unknown Origin: Combined Role of Ferritin and Fever Duration

<b>Background:</b> Fever of unknown origin (FUO) in children remains a diagnostic challenge due to heterogeneous etiologies. This study investigated the etiological distribution, long-term outcomes of undefined cases, and laboratory predictors that differentiate infectious from non-infectious etiologies. <b>Methods</b>: We retrospectively evaluated 87 children (1 month-18 years) hospitalized with fever > 38.3 °C for ≥7 days with no detectable source (2018-2024). Patients were categorized into five groups: infectious, inflammatory, neoplastic, miscellaneous, and undefined. Comparisons between these groups were performed in terms of age, laboratory values, and duration of fever using the Kruskal-Wallis test and one-way ANOVA. Demographic, clinical, laboratory, and follow-up data were compared. ROC analysis and binary logistic regression identified predictors of non-infectious etiologies. <b>Results</b>: Infectious diseases (42.5%) and inflammatory disorders (19.5%) were the most common causes, while 17.2% of cases remained undefined. The median age was 60 months. Rash (31%) and fatigue (27.5%) were the most common complaints on admission. The undefined group showed complete spontaneous resolution during a median 63-month follow-up, with no recurrence or new diagnoses, except for one patient. Miscellaneous etiologies accounted for 14.9% of cases, and more than half of these were newly diagnosed primary immunodeficiencies. C-reactive protein and ferritin levels were significantly higher in the inflammatory disease group compared to the groups with unknown and infectious etiologies. In the binary logistic regression analysis, longer fever duration combined with elevated ferritin level was a combined predictor of non-infectious causes (AUC = 0.718). <b>Conclusions</b>: Infectious and inflammatory conditions predominate in pediatric FUO, yet a subset of cases resolve spontaneously and follow a benign course. The combination of fever duration and ferritin count may aid early differentiation of non-infectious etiologies, supporting more focused diagnostic approaches. Given the notable proportion of primary immune deficiencies, especially in populations with high consanguinity, early immunologic screening should be incorporated into FUO evaluation protocols.