Pediatric fever of unknown origin: Diagnostic spectrum revealed by a multidisciplinary retrospective study

Determining the etiology of fever of unknown origin (FUO) often challenges pediatricians. This study aims to evaluate the clinical and laboratory findings, treatments, and etiologies of children diagnosed with FUO, in order to identify early diagnostic approaches for the underlying cause. A retrospective review was conducted on patients aged 0-18 years who were investigated for FUO between April 2021 and April 2024. A total of 90 patients were included. The median age was 53.5 months (2-213), 52.2% were female, 85.6% had no comorbidities, and 96.7% were fully vaccinated. The median total duration of fever was 11 days (8-72). The most common etiologies were infectious (46.7%) and rheumatological diseases (28.9%), and 20% had no identifiable etiology. When comparing patients with fever durations of 8-14 days to those lasting more than 14 days, the latter group had significantly higher leucocytes (10.5 vs 14.6 × 10³/µL, p = 0.032). Comparing infectious and inflammatory /autoimmune etiologies, the latter group had significantly higher median C-reactive protein (CRP), erythrocyte sedimentation rate, fibrinogen, ferritin, and interleukin-6 (IL-6) levels, as well as significantly lower median albumin levels (40.5 vs 117 mg/L, p = 0.003; 45 vs 60 mm/h, p = 0.012; 456 vs 540 mg/dL, p = 0.004;145 vs 510 µg/L, p = 0.002; 28 vs 108 pg/ml, p < 0.001; 41 vs 39 g/L, p = 0.014, respectively). In ROC analysis, the area under the curve for IL-6 in rheumatological etiologies was 0.843 (95% CI: 0.748-0.937; p < 0.001). Using an IL-6 cutoff value of 37 pg/ml yielded a sensitivity of 91.3%, a specificity of 65.9% and a negative predictive value of 93.1%. Complications were observed in 5.6% of patients; two patients died, while the others were discharged.

Our study shows that infections are the most common cause of FUO. The notably higher levels of neutrophils, ferritin, and IL-6 in rheumatological diseases suggest their potential utility in early differential diagnosis.

• Fever of unknown origin is a clinical and diagnostic dilemma for pediatricians.

• The higher leucocytes in prolonged fever and the notably higher levels of leucocytes, neutrophils, platelets, CRP, ESR, fibrinogen, ferritin, and IL-6 in rheumatological diseases suggest their potential utility in early differential diagnosis.