Identifying thresholds of C-reactive protein, procalcitonin and interleukin-6 among children ≤ 36 months old with fever without source at risk of serious bacterial infections: a systematic review and meta-analysis

Natalia Sutiman¹Jiaying Lin²Rehena Sultana³Sarah Hui Wen Yao²Sharon Si Min Goh²Suzanne-Kae Rocknathan⁴Sashikumar Ganapathy¹Shu-Ling Chong^1*

• ¹Department of Emergency Medicine, KK Women's and Children's Hospital, Singapore, Singapore
• ²Department of Paediatric Medicine, KK Women's and Children's Hospital, Singapore, Singapore
• ³Centre of Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore
• ⁴Duke-NUS Medical School, Duke-NUS Medical School, Singapore, Singapore

ABSTRACT (292 words) INTRODUCTION: Management of children ≤36 months presenting with fever without source remains a challenge because the underlying aetiologies may range from self-limiting viral infections to serious bacterial infections (SBIs) including bacteraemia, urinary tract infection (UTI), pneumonia, bacterial meningitis, osteomyelitis or septic arthritis. This systematic review was conducted to determine the thresholds at which C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) can predict SBIs in this population. METHODS: We systematically searched electronic databases including MEDLINE, Cochrane, CINAHL and Web of Science for studies evaluating the diagnostic accuracies of CRP, PCT and IL-6 in detecting SBIs in children ≤36 months presenting with fever without source, from November 2013 to November 2023. Area under summary receiver operating curve (SROC) was calculated by the Rutter and Gatsonis method. I2 was used to quantify study heterogeneity. All tests were two-sided and p-value <0.05 was statistically significant. This review is registered with PROSPERO, CRD42023439093. RESULTS: Datasets from 37 studies were included. CRP cut-off of 10-20 mg/L had the highest pooled sensitivity of 0.75 (95% CI: 0.54-0.89) while CRP cut-off of >40 mg/L had the highest pooled specificity 0.92 (95% CI: 0.87-0.95). PCT cut-off of <0.5 ng/ml had the highest pooled sensitivity of 0.7812 (95% CI: 0.59-0.90) but the lowest pooled specificity of 0.69 (95% CI: 0.54-0.81). Based on ROC analysis, CRP cut-off between 10-20 mg/L and PCT cut-off of <0.5 ng/ml showed the best diagnostic performance with pooled AUC of 0.84 (95% CI: 0.79-0.90) and 0.816 (95% CI: 0.727-0.928), respectively. Only 1 study for IL-6 reported that threshold of 20 pg/dL had sensitivity and specificity of 79.1% and 91.6% respectively. CONCLUSION: PCT cut-off of 0.5 ng/ml and CRP cut-off of 10-20 mg/L have the best performance in identifying SBIs in children ≤36 months with fever without source.