Hu Huating, Pan Hudan, Li Runze, He Kancheng, Zhang Han, Liu Liang
State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, China.
Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao, China.
Front Pharmacol. 2022 Feb 14;13:802228. doi: 10.3389/fphar.2022.802228. eCollection 2022.
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. 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. 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. 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.
2019冠状病毒病（COVID-2019）由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起，已成为全球大流行并夺走了数百万人的生命。越来越多的证据表明，细胞因子风暴与COVID-19的严重程度和死亡密切相关。在此，我们旨在探索与COVID-19严重程度和死亡相关的关键因素，特别是男性患者和西方国家患者。为了阐明炎性细胞因子是否在COVID-19严重程度和死亡中起作用，我们系统检索了PubMed、Embase、Cochrane图书馆和Web of Science，以识别关键词为“COVID-19”和“细胞因子”的相关研究。数据由Review Manager 5.3软件以95%置信区间（CI）的均值进行测量。使用适当的清单对每项研究的偏倚风险进行评估。我们从数据库中初步筛选了13468项研究。最终，我们的研究纳入了77篇文章，共13468名患者。在严重程度或死亡组中，白细胞介素-6（IL-6）、IL-10、白细胞介素-2受体（IL-2R）、肿瘤坏死因子（TNF）-α、IL-1β、IL-4、IL-8和IL-17等细胞因子的血清水平较高。值得注意的是，我们还发现男性和女性之间IL-6、IL-10、IL-2R和TNF-α的循环水平存在显著差异。男性的IL-6、IL-10、IL-2R和TNF-α血清水平远高于女性，这意味着男性死亡率和严重程度的增加部分归因于这些细胞因子的较高水平。此外，我们发现，在重症和非存活组中，欧洲患者的IL-6水平高于亚洲患者。这些大规模数据表明，IL-6、IL-10、IL-2R、IL-1β、IL-4、IL-8和IL-17的循环水平是COVID-19严重程度和高死亡率的潜在危险因素。同时，这些细胞因子的上调可能是性别和地区易感性的驱动因素。
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