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

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.

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.

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.

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.