Increased interleukin-6 levels associated with malaria infection and disease severity: a systematic review and meta-analysis

Interleukin-6 (IL-6) is generated by immune cells during infection with malaria parasites and they are associated with the immunopathogenesis of malaria. The present systematic review and metaanalysis aimed to compare the differences in IL-6 levels between several groups of patients with malaria and healthy control groups. The systematic review was registered at PROSPERO with a registration number: CRD42021290753. Systematic literature searches were conducted in PubMed, Web of Science, and Scopus until November 7, 2021 to obtain studies that documented IL-6 levels in patients with malaria. The quality of the included studies was assessed using critical appraisal tools from the Joanna Briggs Institute. Differences in the mean IL-6 levels among patients with: (1) severe and non-severe malaria, (2) uncomplicated malaria and controls, (3) uncomplicated and asymptomatic malaria, (4) asymptomatic malaria and healthy controls, and (5) those that died or survived were estimated using a random-effects model. Forty-three of 1,969 studies were included in the systematic review. Results of the meta-analysis showed that patients with severe malaria had higher mean IL-6 levels than those with non-severe malaria [P=0.04, weight mean difference (VVMD) = 96.63 pg/mL, 95% confidence interval (CI). 0.88 -19.38 pg/mL, I-2 =99.9%, 13 studies]. Patients with uncomplicated malaria had higher mean IL-6 levels than the controls (P < 0.001, WMD = 42.86 pg/mL, 95% CI = 30.17 - 55.56 pg/mL, I-2 =100%, 17 studies). No differences in the mean levels of IL-6 were found between patients with uncomplicated malaria and those with asymptomatic malaria (P = 0.063, WMD = 42.07 pg/mL, 95% CI = -2.23 pg/mL to- 86.37 pg/mL, I-2 =99.1%, 8 studies), or between patients with asymptomatic malaria and healthy controls (P = 0.45, WMD =1.67 pg/mL, 95% CI = - 2.73 pg/mL to - 6.07 pg/mL, I-2 = 98.1%, 2 studies). A higher mean level of IL-6 was observed in patients who died compared with the levels of those who survived (P = 0.007, WM D = 1,399.19 pg/mL, 95% CI = 384.16 - 2,414.2 pg/mL, I-2 =93.1%, 4 studies). Our meta-analysis of the pooled evidence can be used to guide future studies in which IL-6 levels are measured during malaria outbreaks to monitor malaria severity. Heterogeneity of the effect estimate among the included studies was the main limitation of this analysis. In conclusion, significantly increased levels of IL-6 were observed in patients with severe malaria compared with those in patients with non-severe malaria, which indicates that IL-6 is a candidate marker for severe malaria. Future studies should investigate the sensitivity and specificity of increased IL-6 levels to determine the effectiveness of assessments of IL-6 levels monitoring of malaria infection and severity.

Automated summary

This systematic review and meta-analysis compared IL-6 levels between different groups of malaria patients and healthy controls. The results showed significantly higher levels of IL-6 in patients with severe malaria compared to those with non-severe malaria, as well as in patients with uncomplicated malaria compared to the control group. However, no significant differences in IL-6 levels were found between patients with uncomplicated malaria and asymptomatic malaria, or between patients with asymptomatic malaria and healthy controls. Higher IL-6 levels were observed in patients who died compared to those who survived. These findings are important for monitoring and studying the severity of malaria.