Background: The rapid outbreak of coronavirus disease 2019 (COVID-19) has turned into a public health emergency of international concern. Epidemiological research has shown that sex is associated with the severity of COVID-19, but the underlying mechanism of sex predisposition remains poorly understood. We aim to study the gendered differences in inflammation reaction, and the association with severity and mortality of COVID-19.

Methods: In this retrospective study, we enrolled 548 COVID-19 inpatients from Tongji Hospital from 26 January to 5 February 2020, and followed up to 3 March 2020. Epidemiological, demographic and clinical features, and inflammatory indexes were collected and compared between males and females. The Cox proportional hazard regression model was applied to identify the gendered effect on mortality of COVID-19 after adjusting for age, comorbidity, and smoking history. The multiple linear regression method was used to explore the influence of sex on inflammation reaction.

Results: Males had higher mortality than females did (22.2% vs 10.4%), with an hazard ratio of 1.923 (95% confidence interval, 1.181-3.130); elder age and comorbidity were significantly associated with decease of COVID-19 patients. Excess inflammation reaction was related to severity of COVID-19. Male patients had greater inflammation reaction, with higher levels of interleukin 10, tumor necrosis factor-α, lactose dehydrogenase, ferritin, and hyper-sensitive C-reactive protein, but a lower lymphocyte count than females adjusted by age and comorbidity.

Conclusions: Sex, age, and comorbidity are critical risk factors for mortality of COVID-19. Excess innate immunity and proinflammation activity, and deficiency in adaptive immunity response promote males, especially elder males, to develop a cytokine storm, causing potential acute respiratory distressed syndrome, multiple organ failure and decease.