Abstract
ObjectivesSex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference. MethodsThis was a retrospective, observational cohort study among patients with severe COVID-19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death according to sex. Interaction was formally tested to compare the risk difference by sex in sub-populations. Mediation analysis with a binary endpoint IMV or death (yes/no) by day 28 of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted. ResultsAmong 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54–77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO2/FiO2 (254 mmHg vs. 191 mmHg; p 0.023). By 28 days from admission, 49.2% (95% CI 39.6–58.9%) of males vs. 31.7% (17.9–45.4%) of females underwent IMV or death (log-rank p < 0.0001) and this amounted to a difference in terms of HR of 0.40 (0.26–0.63, p 0.0001). The area under the curve in C-reactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex. DiscussionOur analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. Specifically, CRP showed a predominant role to mediate the difference in risk by sex.
Highlights
This was a retrospective, observational cohort study carried out at the University Hospital of Modena, Italy, among patients admitted to hospital between 21 February and 25 May 2020 for severe COVID-19 pneumonia
The inflammatory profile at hospital admission was better among women who showed lower levels of D-dimer, Creactive protein (CRP) and ferritin (Table 3)
This study explores the impact of sex on risk of unfavourable COVID-19 outcomes
Summary
Women seem to be protected from developing a severe disease [4,10,11], intensive care unit (ICU) admission and mortality [1,5,6,12]. A difference by sex expression/function of angiotensin converting enzyme 2 (ACE2), the host cell receptor of the virus, was found in both animal models and in humans (over-expressed in females). Male mice are more susceptible to severe acute respiratory syndromecoronavirus-1 (SARS-CoV-1) infection than age-matched females, but this protection is lost after ovariectomy [14], implying a pivotal role of sex hormones [15]. Asian men showed higher ACE2 expression than women [16]
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