Elevated Levels of Pleiotropic Interleukin-6 (IL-6) and Interleukin-10 (IL-10) are Critically Involved With the Severity and Mortality of COVID-19: An Updated Longitudinal Meta-Analysis and Systematic Review on 147 Studies

Abstract

Objectives: Disruption in the natural immune reaction due to SARS-CoV-2 infection can initiate a potent cytokine storm among COVID-19 patients. An elevated level of IL-6 and IL-10 during a hyperinflammatory state plays a vital role in increasing the risk of severity and mortality. In this study, we aimed to evaluate the potential of circulating IL-6 and IL-10 levels as biomarkers for detecting the severity and mortality of COVID-19.

Methods: This study was conducted according to the Cochrane Handbook and PRISMA guidelines. Authorized databases were searched to extract suitable studies using specific search terms. RevMan 5.4 was applied for performing the meta-analysis. Mean differences in IL-6 and IL-10 levels were calculated among COVID-19 patients via a random-effects model. NOS scoring, publication bias and sensitivity analyses were checked to ensure study quality.

Results: A total of 147 studies were selected, with 31 909 COVID-19 patients under investigation. In the severity analysis, the mean concentration of IL-6 was significantly higher in the severe COVID-19 cases than in the non-severe cases (MD: 19.98; P < .001; 95% CI: 17.56, 22.40). Similar result was observed for IL-10 mean concentration in severe COVID-19 cases (MD: 1.35; P < .001; 95% CI: 0.90, 1.80). In terms of mortality analysis, circulating IL-6 showed sharp elevation in the deceased patients (MD: 42.11; P < .001; 95% CI: 36.86, 47.36). IL-10 mean concentration was higher in the dead patients than in the survived patients (MD: 4.79; P < .001; 95% CI: 2.83, 6.75). Publication bias was not found except for comparing IL-6 levels with disease severity. Sensitivity analysis also reported no significant deviation from the pooled outcomes.

Conclusions: Elevated levels of circulating IL-6 and IL-10 signifies worsening of COVID-19. To monitor the progression of SARS-CoV-2 infection, IL-6 and IL-10 should be considered as potential biomarkers for severity and mortality detection in COVID-19.

Systematic review registration: INPLASY registration number: INPLASY202240046.

Keywords: COVID-19; cytokine storm; interleukin-10; interleukin-6; meta-analysis.

Figure 1.

Study flow chart representing the selection process of eligible studies.

Figure 2.

Forest plots showing IL-6 and IL-10 levels in COVID-19 patients based on disease severity index: (a) IL-6 levels in severe and non-severe COVID-19 cases and (b) IL-10 levels in severe and non-severe COVID-19 cases.

Figure 3.

Forest plots showing IL-6 and IL-10 levels in COVID-19 patients based on mortality index: (a) IL-6 levels in dead and survivors COVID-19 cases and (b) IL-10 levels in dead and survivors COVID-19 cases.

Figure 4.

Funnel plots for publication bias analysis in different meta-analysis models: (a) IL-6 and severity of COVID-19, (b) IL-10 and severity of COVID-19, (c) IL-6 and mortality of COVID-19, and (d) IL-10 and mortality of COVID-19.