Association between interleukin-2 cytokine levels and Plasmodium infections: a systematic review and meta-analysis

Abstract

Background: Interleukin-2 (IL-2) is a central cytokine in T-cell mediated immunity, playing a dual role in both pro-inflammatory responses and immune regulation. While cytokines such as IL-6 and tumor necrosis factor-α (TNF-α) have been extensively studied in malaria pathogenesis, the role of IL-2 remains poorly understood and inconsistently reported across studies. This systematic review and meta-analysis aimed to synthesize available evidence on IL-2 levels in malaria patients and assess their association with disease severity. Methods: A systematic search was conducted across five databases (PubMed, MEDLINE, EMBASE, Scopus, and CENTRAL) without date restrictions. Studies were eligible if they reported IL-2 levels in human participants with malaria, compared to uninfected individuals, and/or across malaria severity. Risk of bias was assessed using Joanna Briggs Institute (JBI) tools. Standardized mean differences (SMD) were calculated using a random-effects model. Heterogeneity, subgroup analyses, meta-regression, and publication bias were evaluated using established statistical methods. Results: Out of 3,023 records screened, 30 studies met the inclusion criteria for the systematic review. Most studies reported no significant differences in IL-2 levels between individuals with malaria and uninfected controls. The meta-analysis confirmed this finding, showing no significant difference (P = 0.25, SMD = 4.56, 95% CI [-3.16; 12.29], I² = 98.6%, 1074 participants, random-effects model). Similarly, the majority of studies comparing IL-2 levels between severe and non-severe malaria cases found no significant differences. Meta-analysis results were consistent, showing no significant association (P = 0.57, SMD = 0.37, 95% CI [-0.91; 1.67], I² = 97.4%, 694 participants, random-effects model). Subgroup analyses suggested that geographic region significantly influenced IL-2 expression patterns. Conclusion: This systematic review and meta-analysis found no consistent evidence of altered IL-2 levels in individuals with Plasmodium infection compared to uninfected controls, nor between patients with severe and non-severe malaria. However, substantial heterogeneity across studies limits the interpretability of these findings. Future well-designed studies that account for geographic, methodological, and host-related factors are needed to determine whether IL-2—alone or in combination with other immunological markers—can serve as a reliable biomarker for malaria infection or disease severity.