Increased Circulating Cytokines Have a Role in COVID-19 Severity and Death With a More Pronounced Effect in Males: A Systematic Review and Meta-Analysis

Abstract

Background: Coronavirus disease 2019 (COVID-2019), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide epidemic and claimed millions of lives. Accumulating evidence suggests that cytokines storms are closely associated to COVID-19 severity and death. Here, we aimed to explore the key factors related to COVID-19 severity and death, especially in terms of the male patients and those in western countries. Methods: To clarify whether inflammatory cytokines have role in COVID-19 severity and death, we systematically searched PubMed, Embase, Cochrane library and Web of Science to identify related studies with the keywords "COVID-19″ and "cytokines". The data were measured as the mean with 95% confidence interval (CI) by Review Manager 5.3 software. The risk of bias was assessed for each study using appropriate checklists. Results: We preliminarily screened 13,468 studies from the databases. A total of 77 articles with 13,468 patients were ultimately included in our study. The serum levels of cytokines such as interleukin-6 (IL-6), IL-10, interleukin-2 receptor (IL-2R), tumor necrosis factor (TNF)-α, IL-1β, IL-4, IL-8 and IL-17 were higher in the severity or death group. Notably, we also found that the circulating levels of IL-6, IL-10, IL-2R and TNF-α were significantly different between males and females. The serum levels of IL-6, IL-10, IL-2R and TNF-α were much higher in males than in females, which implies that the increased mortality and severity in males was partly due to the higher level of these cytokines. Moreover, we found that in the severe and non-survivor groups, European patients had elevated levels of IL-6 compared with Asian patients. Conclusion: These large-scale data demonstrated that the circulating levels of IL-6, IL-10, IL-2R, IL-1β, IL-4, IL-8 and IL-17 are potential risk factors for severity and high mortality in COVID-19. Simultaneously, the upregulation of these cytokines may be driving factors for the sex and region predisposition.

Keywords: COVID-19; cytokines; meta-analysis; mortality; sex bias.

FIGURE 1

Literature search and screening process.

FIGURE 2

Forest plot for the male and female groups. The serum levels of IL-6 levels in the groups of male and female (A). The serum levels of IL-2R levels in the groups of male and female (B). The serum levels of IL-10 levels in the groups of male and female (C). The serum levels of TNF-α levels in the groups of male and female (D).

FIGURE 3

The serum levels of IL-6 in the different continent of mild and severe.

FIGURE 4

The serum levels of IL-6 in the different continents of the alive and death.

FIGURE 5

Increased circulating cytokines affect the development of COVID-19. The SARS-CoV-2 S protein engages with the host ACE2 receptor and is subsequently cleaved at S1/S2 and S2’ sites by TMPRSS2 protease. In the severe patients, COVID-19 invades the alveoli and activates innate immune responses to primary cytokines, such as type I and III IFNs, IL-6 and TNF-α, which further evokes the secondary cytokines and leads to cytokines storm. In the mild patients, immune cells have the ability of eliminating viruses and inhibiting them from invading alveoli, which leads to down-regulate cytokines in serum. ¹The cytokines have significant differences between mild and severe groups. ²The cytokines between alive and death groups have significant differences. ³This cytokines have significant differences between male and female groups. ⁴This cytokines have significant differences between different regions.