Evaluating the risk of elevated IL-6 levels in pediatric patients: a stratified approach and evidence of interaction effects.

BACKGROUND: Distinguishing between an appropriate and a pathologically dysregulated elevation of interleukin-6 (IL-6) is challenging. This study aimed to explore how physiological function abnormalities could help identify subpopulations in whom IL-6 levels were associated with disease severity. METHODS: This retrospective study included pediatric patients with serum IL-6 test results. After selecting laboratory parameters that effectively identify a subpopulation in which IL-6 levels can predict adverse clinical outcomes, the chosen parameters were categorized into function groups. Using IL-6 levels and the number of impaired functions as stratifying parameters, the risk of adverse outcomes for each stratum was calculated. To assess the interaction effect between functional impairment and IL-6 elevation on adverse outcomes, the relative excess risk due to interaction (RERI) was calculated. RESULTS: A total of 56,170 pediatric patients were included. Fourteen laboratory parameters in pediatric patients could be used as stratifying parameters, where abnormal values suggest that IL-6 levels could be used as a prognostic marker [area under the receiver operating characteristic curves (AUCs) >0.7]. These parameters were categorized into five functional groups: immunological [white blood cell (WBC), neutrophils, monocytes], hepatic [aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bile acids], renal (creatinine, uric acid), coagulation [platelets, activated partial thromboplastin time (APTT), thrombin time], and myocardial enzymes [myoglobin, creatine kinase (CK), CK-MB]. For the rate of adverse outcomes, the rate difference (RD) between the IL-6 >85th and ≤85th percentile groups ranged from 0.7% [95% confidence interval (CI): 0.2%, 1.2%] in the stratum with 1 impaired function to 16.9% (95% CI: 12.5%, 21.3%) in the stratum with ≥4 impaired functions. Similar trends were observed for the rate of pediatric intensive care unit (PICU) admission and the length of hospital stays. For adverse outcomes, the RERI between the increased number of impaired functions and IL-6 levels increased from 1.06 (1 impaired function + IL-6 >85th percentile; 95% CI: 0.73, 1.38) to 42.79 (4 impaired functions + IL-6 >85th percentile; 95% CI: 34.49, 51.09). Consistent results were observed in the validation cohort and in disease-specific subpopulations. CONCLUSIONS: The risk associated with elevated IL-6 levels increases as the number of impaired functions grows, with an intensified interaction effect between IL-6 elevation and functional impairment on clinical outcomes, offering a simple method for clinical risk stratification.