Cytokine levels in the severity of falciparum malaria: An umbrella review

This study aimed to synthesise evidence comparing the levels of cytokines in severe falciparum malaria with those in uncomplicated malaria from available systematic reviews and meta- analyses. Relevant individual meta-analyses were searched in PubMed, Ovid, and Google Scholar, following the selection criteria specified for this umbrella review. The AMSTAR-2 tool was applied to grade the quality of the meta-analyses identified. The random-effects model was applied to recalculate the effect sizes of each included meta-analysis. Heterogeneity between meta-analyses was investigated with I2 value. 95% predicting interval (PI) for the summary random-effects model was also made. In each meta-analysis identified, information on largest study's effect, the excess significance test, small study effects, and publication bias were addressed. This umbrella review included nine meta-analyses (n = 12,674) for nine unique cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, and TNF-α). Only one individual meta-analysis showed significantly higher levels of cytokine IL-1β (p: 0.009) amongst those with severe falciparum malaria compared to those with uncomplicated malaria. The 95% PIs did not show significance in any individual meta-analyses. Nine individual meta-analyses showed substantial heterogeneity, with I2 tests ranging from 81% to 99%. Two independent meta-analyses (the IL-4 and IL-12) showed evidence of 'excess significant bias'. The meta-analysis of IL-1β only showed "Class III evidence", indicating that this cytokine was "suggestive" in contributing to those with severity of malaria in comparison to those with uncomplicated malaria. The remaining eight cytokines showed "Class IV evidence," indicating "weak" evidence on the impact of malaria severity. In conclusion, the findings suggest that compared to uncomplicated malaria, pro-inflammatory cytokine IL-1β contributes to the development of severe falciparum malaria. Due to the limited level of evidence, further well-designed larger studies with multiple cytokines are needed to investigate cytokine levels as reliable biomarkers in malaria severity.