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

Abstract

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 meta-analysis 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 (WMD) = 96.63 pg/mL, 95% confidence interval (CI) = 0.88 − 19.38 pg/mL, I2 = 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, I2 = 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, I2 = 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, I2 = 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, WMD = 1,399.19 pg/mL, 95% CI = 384.16 − 2,414.2 pg/mL, I2 = 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.

The effect of genetically proxied IL-6 signalling on severe malaria: A Mendelian randomisation analysis

“…A recent meta-analysis confirmed that IL-6 is prognostic for severe outcomes, and differentiates uncomplicated from severe malaria. 2 However, our work suggests, in contrast to COVID-19 (and perhaps bacterial sepsis), those with genetically proxied reduced IL-6 signalling do not have altered risk of severe disease. 7,8 IL-6 levels are raised (and associate with) a huge number of conditions, and so it is plausible that IL-6 may represent a useful biomarker but one that is not causally related to severe malaria.…”

“…1 Increased IL-6 is known to be associated with mortality within severe malaria, and studies have suggested that it may be causal for worse outcomes. 2,3 However, animal models have so far failed to identify robust evidence that IL-6 manipulation (e.g. therapeutic blockade) improves outcomes in severe malaria, although data are inconclusive.…”

Elevation of serum interleukin-1β levels as a potential indicator for malarial infection and severe malaria: a meta-analysis

“…Egger’s test with statistical significance ( p < 0.05) might indicate that funnel plot asymmetry was due to a small-study effect [ 26 ]. A contour-enhanced funnel plot was used to explore the cause (s) of funnel plot symmetry [ 27 ]. To investigate potential sources of variation, research designs, study sites, Plasmodium spp., age groups and methodologies for IL-1β measurement were used as covariates.…”

Prevalence, probability, and characteristics of malaria and filariasis co-infections: A systematic review and meta-analysis

“…We used the JBI tools for case-control and cohort studies to determine the quality of those study designs. The quality of the included studies was rated using the percentile as described previously [16,17].…”