The Association between TNF-α, IL-6, and Vitamin D Levels and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis

Background: An increasing number of scientific journals have proposed a connection between tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and the severity of COVID-19. Vitamin D has been discussed as a potential therapy for COVID-19 due to its immunomodulatory effects. This meta-analysis aims to determine the relationship, if any, between TNF-alpha, IL-6, vitamin D, and COVID-19 severity and mortality. Methods: The design of the study is a systematic review and meta-analysis. A literature search is performed using PubMed, Cochrane, ProQuest, and Google Scholar. Results: TNF-alpha insignificantly increases the risk of COVID-19 severity (adjusted odds ratio (aOR) = 1.0304; 95% CI 0.8178-1.2983; p = 0.80) but significantly increases the risk of COVID-19 mortality (crude hazard ratio (HR) = 1.0640; 95% CI 1.0259-1.1036; p = 0.0009). IL-6 significantly increases the risk of COVID-19 severity (aOR = 1.0284; 95% CI 1.0130-1.0441; p = 0.0003) and mortality (aOR = 1.0076; 95% CI 1.0004-1.0148; p = 0.04; adjusted hazard ratio (aHR) = 1.0036; 95% CI 1.0010-1.0061; p = 0.006). There is a statistically insignificant difference of the mean vitamin D levels between patients with severe COVID-19 and non-severe COVID-19 (mean difference (MD) = -5.0232; 95% CI 11.6832-1.6368; p = 0.14). A vitamin D deficiency insignificantly increases the risk of mortality of COVID-19 patients (aOR = 1.3827; 95% CI 0.7103-2.6916; p = 0.34). Conclusion: IL-6 is an independent prognostic factor towards COVID-19 severity and mortality.