We report a higher case fatality in males among COVID-19 notified cases including hospitalized cases which cannot be explained by differences in age-distribution or the prevalence of comorbidities. COVID-19 related mortality increased with increasing age, and was higher in males in every age group. Relative to the expected mortality in the general population, as reflected by the SMR, the risk of dying was also higher in male cases, suggesting that mortality differences have a COVID-19 specific component. However, when stratified by age, this COVID-19 specific effect could only be confirmed for cases aged 80 years or older. Strikingly, for the age-group 70–74 years, the standardized mortality ratio was higher in females, probably mainly due to the low mortality relative to males in the general population. In perspective of general population numbers, COVID-19 mortality strongly increased with age for both males and females and was higher in males among all age-groups. Differences in COVID-19 population mortality rates were greatest for the age-group 55–59 years but were lower in the oldest age-groups. Compared to the overall mortality rate in the population, mortality due to infectious diseases and mortality due to pneumonia, male-female ratio was higher for COVID-19 mortality. This again indicates that the observed male-female difference in mortality is a COVID-19 specific effect which cannot be attributed to sex-differences observed in mortality from infectious disease in general.
Hospitalization was found to be more frequent in males. In addition, the National Intensive Care Evaluation foundation (NICE) reported the vast majority of COVID-19 related ICU-patients to be males (71.8% vs. 28.2%, n = 2876). As well, in accordance with our findings, these ICU reports on COVID-19 indicate a higher risk of mortality among males admitted to the ICU (32.6%) than among females (23.7%) with an odds ratio of 1.66 [95% CI 1.27–1.89](22).
Although many countries report sex-disaggregated data on COVID-19 mortality, only few countries describe these differences in perspective of their population numbers and population-level mortality rates, and in relation to other factors including age and comorbidity (18,23). Worldwide, the CFR among confirmed COVID-19 cases is 1.4 times higher in men (12). Gebhard et al. reported male-female CFR-ratios in several European countries and China between 1.7 and 1.8. In our study we found a 1.3 times higher risk of mortality among male cases during the first 3 months of the outbreak in the Netherlands. However, with the inclusion of healthcare workers this ratio increases to 1.8, illustrating the influence of testing policy and gender-role factors on these nationwide data.
Population mortality rate ratios are less affected by testing policies than the CFR because deaths are related to known population size denominators, which are independent of case notification. However, the number of COVID-19 deaths in the numerator is still underestimated due to incomplete testing and incomplete reporting among notified cases. Furthermore, mortality rates do not purely reflect mortality risk but also include the risk of infection. Age-specific population mortality rates in the Netherlands show a similar pattern as in other countries, where an exponential increase with age with higher mortality rates in males has been reported (24,25). Standardized mortality ratios have not yet been reported by other countries. However, several studies have described sex-discrepancies in population mortality to be higher for COVID-19 than for all-cause mortality, confirming a COVID-19 specific effect on mortality (24,25).
There are various biological mechanisms described that could contribute to COVID-19 specific sex differences. Immune response differs between males and females in several areas due to, among others, X-chromosomal dependent and hormonal driven mechanisms (14,26–28). The influence of sex-hormones has also been pointed out as a contributing factor in sex discrepancies observed in mortality by SARS-CoV-1 and MERS (29). More specific for COVID-19, a study comparing differences in SARS-CoV-2 IgG antibodies found that in severe COVID-19 cases relatively higher IgG antibody levels were observed in females indicating a better antibody response against SARS-CoV2 in females (30). Another interesting finding is the dysfunction in the TRL7 gene located on the X-chromosome in young severely affected male COVID-19 patients, resulting in immunological defects in two types of interferons, crucial in viral immune response (31). Besides immunological processes, the involvement of the ACE-II receptor in cell penetration of SARS-COV-2 has been described as a factor likely contributing to sex discrepancies in COVID-19 severity because of sex differences in expression due to the location of this enzyme on the X-chromosome (14,32,33).
Although we excluded healthcare workers, gender related factors are likely to influence mortality. Health-seeking behavior generally tends to be higher in females, which may lead to earlier initiation of treatment, potentially resulting in a milder disease course (34). However, the restricted testing policies during the first wave made this less likely to be of significant impact. A systematic review on behavioral changes during and after the 2009 influenza pandemic showed that women were more likely to follow recommended measures such as hygiene regulations(35). These gender related factors remain difficult to quantify and cannot be fully distinguished from biological factors.
In addition, mortality differences seem to decrease with increasing age. Though not as evident in our data, this was reported by several other studies (14,18,23,25). Public health England described a two-fold higher chance of dying from COVID-19 in males compared to females of working population age (aged between 20 and 65 years), while this risk of death was only 1.5 times higher in older adults (aged above 65) (19). A study describing excess mortality during March 2020 in Lombardy, Italy (a region severely affected by the COVID-19 pandemic) reported excess mortality – based on national mortality data during the COVID-19 outbreak – to be higher in males. This difference decreased in older age-groups (18). Though our data also shows a decrease in mortality differences with older age, confidence intervals are wide in the younger age-groups due to low mortality. Furthermore, male-female differences are noticeably smaller around the age of 70, with even a higher SMR in females.
The data used for the analysis described here was based on surveillance of mandatory notifications, which provided a large dataset, but with suboptimal accuracy, especially during the peak of the pandemic in the regions most affected. Deaths in COVID-19 patients were registered without uniform criteria on whether death was directly caused by COVID-19. A major limitation is the underreporting of mortality in residential institutions. Due to testing policies in nursing homes, initially often only two-three symptomatic patients were tested per nursing home unit. Given that the majority of nursing home residents are women, this testing policy has likely led to underestimation of COVID-19 population mortality rate in elderly women. However, the effect of sex on mortality among notified cases is likely underestimated by the underreporting of cases in nursing homes. As already mentioned, testing strategies during the first months of the pandemic undeniably caused selection bias. Excluding healthcare workers from the analysis reduced this selection bias, but excluded a larger part of the female population at risk compared with males because healthcare workers are more likely to be female. This excluded population is expected to have a low risk of mortality since it is relatively healthy and contains only 1795 people with an age above 60 years (7.7% of the total amount of notified cases above 60). When it comes to comorbidities, the multivariable logistic regression did not account for obesity, while this is more prevalent in men and has been indicated as a major risk factor for severe COVID-19 outcomes.
It is evident that sex plays a role in COVID-19 severity, likely influenced by a combination of sex- and gender-dependent factors. Though several hypotheses on contributing biological processes have been proposed, few studies describe sex differences in relation to age and comorbidities.
Our study confirms male sex is a predisposing factor for severe outcomes of COVID-19, independent of age and comorbidities, and that the underlying mechanisms are likely to be COVID-19 specific. More knowledge is required regarding the specific underlying mechanisms to prioritize and personalize treatment for COVID-19 based on sex. It is, however, evident that sex should be considered as an important factor in further studies concerning COVID-19.