Our results were analyzed using population-based data in South Korea. The number of COVID-19 patients was greater in women than men. Baseline CCI score was greater in women than men. However, survival and clinical outcomes including AKI, the use of inotropes, conventional oxygen therapy, HFNC, MV, and cardiac events were greater in men than women. The mortality rate was the highest for the populations aged 50–64 or ≥65 years. Subgroup analyses for age, DM, or hypertension showed favorable results for patient survival or clinical outcomes in women compared to men. The proportions of patients with DM or hypertension as major comorbidities were higher among men than among women of the some age groups; however, there were no significant differences in patients aged ≥65 years at a high risk of mortality. In addition, CCI score was similar between two sexes in all age groups.
Previous studies have reported that male patients with COVID-19 had poorer outcomes compared to female patients [3-6]. The favorable outcomes in women would be hypothesized by several issues. First, high expressions of ACE-2 and transmembrane serine protease-2 (TMPRSS2) in men, compared to women, would be associated with poor outcome in COVID-19. The ACE-2 is expressed in various tissues including cardiovascular system, kidney, or lung and SARS-CoV-2 enters the cell through ACE-2. Liu et al. investigated an experimental study using gonadectomized mice with or without estrogen therapy and showed that the expression of renal ACE-2 was decreased by estrogen therapy [12]. Stelzig et al. showed that estrogen was associated with low expression in human bronchial epithelial cells [13]. TMPRSS2 is a critical protease associated with viral spread through cleavage of spike protein of SARS-CoV-2 [14]. Expression of TMPRSS2 would be associated with activity of androgen receptor, which may lead to high expression of TMPRSS2 in men. Therefore, difference in ACE-2 and TMPRSS2 between sexes may be associated with severity or prognosis of COVID-19 patients. However, there were few studies regarding differences in two enzymes by sex and the impact of clinical outcomes.
Second, sex differences in innate or humoral immunities after viral infection may be associated with severity in COVID-19. Although there were few clinical data for sex difference in immunity after COVID-19, previous data for response to other viral infection, vaccines, or autoimmunity suggested that immune responses to COVID-19 may be different between sexes. Women generally have greater antibody production response to viral infection, which is associated with estrogen effect or inherent difference in B cell response after infection [7,15]. In addition, there were evidences for sex differences in cytokine production or gene expression in innate cell subsets [7]. Previous studies showed that women are associated with more stimulation in toll-like receptor-7 and interferon production after viral infection compared to men [16,17]. These differences may lead to different response for removal of virus, which result in sex difference for severity or mortality in COVID-19 patients.
Third, comorbidities caused by sex or gender related factors may influence the difference. To date, there were few data regarding the different comorbidities according to sex, using disaggregated data of men or women COVID-19 patients. We compared the proportion of patients with DM or hypertension according to sex and age groups. Our study showed higher prevalence in men in DM for 50–64 age group and hypertension for <35, 35–49, or 50–64 age groups than women, but ≥65 age group with highest mortality had no difference in DM and hypertension. In addition, CCI score as merged indicator was not different between two sexes. Both analyses using aggregated data and subgroup analyses for DM, hypertension, or age groups showed mostly favorable results in women. These reveal that comorbidities are associated with clinical outcomes in COVID-19 patients in both sexes, but difference of underlying comorbidities may not lead to sex difference in clinical outcomes in COVID-19 patients.
In our study, clinical outcomes were poor in men, but incidence rate was higher in women than in men. According to Korean Statistical Information Service in May 2020, the numbers of men and women in South Korea were 25,856,030 and 25,985,341, respectively. The incidence rate in men and women was approximately 0.0115% and 0.0168%, respectively [18]. World Health Organization merged each disaggregated data and reported that the distribution of infection between women and men is relatively similar [19]. Global Health 50/50 research initiatives also presented that 55 among 92 countries identifiable with incidence by sex had male predominance [6]. In our study, it is not clear whether female dominance in COVID-19 infection is associated with biological effect or gender-related factors. Considering male predominance from biological data, gender related factors such as life style, socioeconomic status, or religious gathering may have greater influence on female predominance in South Korea. Besides biologic factors, gender related factors were also important to incidence or prognosis in COVID-19 [20]. Alcohol intake or number of cigarettes smoked was generally greater in men than in women, which may be another leading to sex differences the clinical outcomes [21].
Our study has several limitations. First, our study was performed using health insurance claims with procedural or diagnostic codes from HIRA. Therefore, our study did not include laboratory or clinical data. The dataset has the possibility of over or undercoding, which may lead to discrepancies between the relevant code and actual diseaset. Second, our study did not identify the causal relationship by sex. Our study analyzed insurance data alone and did not include data for biologic effects such as ACE2, TMPRSS2 levels, or data for immunologic status. In addition, gender related factors were not included. Therefore, we revealed that men had poor clinical outcomes compared to women, especially elderly. However, we could not identify the cause of sex difference in COVID-19. Third, we did not present sex difference in young population. In our study, the populations aged <35 years or 35–49 years had better outcomes compared to those aged 50–64 years or ≥65 years. We did not perform analyses beyond simple descriptive analysis results for the young population.
In conclusion, our population-based study showed that female patients with COVID-19 were associated with favorable outcomes, including survival. The impact of sex was more evident in population aged 50–64 or ≥65 years. Further studies, including laboratory investigations or evaluation of sex-related factors, are required to identify the causal relationship and impact of sex in the young population.
Perspectives and significance
Previous studies have reported the association between sex and clinical outcomes; however, the most relevant results were obtained as part of analyses evaluating other prognostic factors or analyses using aggregated data for sex. Our population-based study shows that female patients with COVID-19 were associated with favorable outcomes, including survival. The impact of sex was more evident in population aged 50–64 or ≥65 years at a high risk of mortality and two age groups had no difference in comorbidities. Both analyses using aggregated data and subgroup analyses for DM, hypertension, or age groups showed mostly favorable results in women. These reveal that comorbidities are associated with clinical outcomes in COVID-19 patients in both sexes, but difference of underlying comorbidities may not lead to sex difference in clinical outcomes in COVID-19 patients.