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.

Figure 1

Study flow diagram.

Figure 2

Differences in IL-6 levels between patients with severe malaria and non-severe malaria. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.00 or less than 0.05, significant heterogeneity.

Figure 3

Differences in IL-6 levels between patients with severe malaria and non-severe malaria by continents. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.00 or less than 0.05, significant heterogeneity.

Figure 4

Differences in IL-6 levels between patients with severe malaria and non-severe malaria by complications. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.00 or less than 0.05, significant heterogeneity.

Figure 5

Differences in IL-6 levels between patients with severe malaria and non-severe malaria by age groups. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.00 or less than 0.05, significant heterogeneity.

Figure 6

Differences in IL-6 levels between patients with severe malaria and non-severe malaria by assays for IL-6. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 7

Differences in IL-6 levels between patients with uncomplicated malaria and controls. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 8

Differences in IL-6 levels between patients with uncomplicated malaria and controls by continents. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 9

Differences in IL-6 levels between patients with uncomplicated malaria and controls by Plasmodium spp. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 10

Differences in IL-6 levels between patients with uncomplicated malaria and controls by age groups. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 11

Differences in IL-6 levels between patients with uncomplicated malaria and controls by assays for IL-6. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 12

Differences in IL-6 levels between patients with uncomplicated malaria and controls by types of controls. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 13

Differences in IL-6 levels between patients with uncomplicated malaria and asymptomatic malaria. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 14

Differences in IL-6 levels between patients with asymptomatic malaria and controls. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 15

Differences in IL-6 levels between patients who died and those who survived. Abbreviation: WMD, weighted mean difference; CI, confidence interval; black diamond symbol, point estimate; solid line in the middle of the graph at 0, zero effect size; Dashed red line: pooled WMD between the two groups; I², level of heterogeneity; P = 0.000 or less than 0.05, significant heterogeneity.

Figure 16

Funnel plot demonstrating the distribution of the effect size (WMD) and standard error of the effect size (seES) among studies included in the meta-analysis of severe and non-severe malaria.

Figure 17

The contour-enhanced funnel plot demonstrated the effect estimates (WMD) were located in a significant area (P < 1%, 0.01), indicating that the cause of the funnel plot asymmetry was due to publication bias rather than other causes.

Figure 18

Funnel plot demonstrating the distribution of the effect size (WMD) and standard error of the effect size (seES) among studies included in the meta-analysis of uncomplicated malaria and controls.

Figure 19

The contour-enhanced funnel plot demonstrated the effect estimates (WMD) were located in a significant area (P < 1%, 0.01), indicating that the cause of the funnel plot asymmetry was due to publication bias rather than other causes.