Abstract
Background: Melioidosis, caused by Burkholderia pseudomallei, remains a major cause of sepsis-related mortality in tropical regions. Despite effective antimicrobial therapy, deaths frequently result from dysregulated host inflammation rather than uncontrolled bacterial replication. Interleukin-6 (IL-6), a key mediator of systemic inflammation, has been proposed as a prognostic biomarker in sepsis, but its predictive value in melioidosis has not been systematically evaluated. Methods: A systematic review and meta-analysis were performed following PRISMA 2020 guidelines (PROSPERO CRD420251152797). MEDLINE, Embase, and Scopus were searched from inception to 15 March 2025. Eligible studies included patients with culture-confirmed melioidosis reporting circulating IL-6 concentrations stratified by survival outcome. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random effects models. Heterogeneity and robustness were examined through leave-one-out and sensitivity analyses. Publication bias assessment was not performed due to insufficient study numbers (n = 4). Results: Eight studies were included qualitative systematic review, and four studies comprising 411 patients were eligible for quantitative meta-analysis. Pooled analysis demonstrated significantly higher IL-6 levels among non-survivors compared with survivors (SMD = 0.80, 95% CI 0.02-1.57; I(2) = 86.3%). Leave-one-out diagnostics indicated no single study unduly influenced the pooled effect. Sensitivity analysis excluding the largest dataset reduced heterogeneity to 34.5% and yielded an SMD of 0.51 (95% CI -0.28-1.30), maintaining the same direction of association. Conclusions: Circulating IL-6 levels are elevated in fatal melioidosis and may serve as a promising prognostic biomarker for mortality. Although interstudy heterogeneity was substantial, the association remained consistent in direction across populations and analytical methods despite the limited number of eligible studies. These findings support further prospective validation of IL-6 in clinical risk stratification and host response-guided management of severe melioidosis, though larger multicenter studies are needed to confirm these preliminary findings.