In this paper we analyze shares of men and women infected by SARS-Cov-2, normalized on the demographic structure of the population, to investigate differences in sex and gender infection incidence.
The first Italian patients were identified in Italy at the end of February 2020 and soon after the lockdown was declared. Observing the OR Male/Female of patient-cases stratified by age (Fig. 1), it is possible to follow the trend during epidemic from the beginning to May 20, 2020 and the differences between age classes. Overall, the OR shows a different evolution in time for each age class due to different factors: endogenous (biological sex and age physiology), and exogenous (sociality, habits, job and lifestyle). As previously detailed, we assume that infection data were determined by a random spread of the virus until March 11, 2020, with detectable consequences until two weeks after, and by a non-random virus circulation after that date. For this reason, we analyzed separately the two periods: until March 26, 2020 (hereafter named “pre-lockdown”) and the second one until May 20, 2020 (named “post lockdown”).
We first analyze the differences between pre- and post-lockdown periods, and subsequently, we discuss the gender issue during the pre-lockdown period.
Male/Female infection ratio in each age class during epidemic.
Age class 0-9: the OR was at first slightly in favor of more infected boys than girls, but then decreased towards 1.0 (boys and girls tended to be infected at the same level). This change was likely due to habits for boys of staying outside in larger groups more often than the girls and the propensity to practice team sports like football: during lockdown they had to reduce these physical contacts.
Age class 10-19: the value of OR remains essentially the same in pre- and post-lockdown. As for teenager peer groups are essential to social and general development and the social distancing imposed by lockdown did not change the infection ratio, we suppose that this was mostly due to biological factor (sex, hormones).
Age class 20-29: maybe the most interesting. Indeed, the OR remains constantly significantly in favor to more infected women than men during the whole reporting period, likely for biological reasons that were not affected by and thus independent from a different lifestyle during lockdown.
Age classes 30 to 49: data started with an OR~1.0 to then reach values significantly <1.0, towards a larger proportion of infected women.
Age class 50-59: the trend is similar to the previous one, though with starting value of OR significantly >1.0.
It is possible that this increase of the middle age infected women in post-lockdown was due to a larger portion of women that are healthcare-worker, compared to men (84% for European region) that were selectively infected in RSA. In Italy on April 28, 2020, 69% of infected healthcare-workers were women .
Age classes >60: a huge difference in OR men/women is present in the pre-lockdown period, with men infected even more than twice than women. The trend shows a rapid evolution towards lower values after lockdown, particularly for people in the age class 80-89, where, at the end, men and women appear equally likely infected and, particularly for people aged 90+ with a clearly higher proportion on infected women. We suppose that the rapid change toward a larger incidence in women was heavily due to a non-random diffusion of the virus in the elderly. At the end of March, the virus diffused in hospitals often through emergency room and in the RSA, in which older people are admitted (usually age 65 and over). This happened in a framework where women account for the majority of population (Fig. 1), male/female population sex-ratio decreases from 0.92 to 0.37 in 60-69 to 90+ age classes respectively, and in such older Italian population cohort about 56% are women over 65 years old (63% for age >80) (Supplementary Table S1). ISS official bulletins from April 23 to May 20, 2020 report that RSA host 40-60% of new diagnosed cases with a large majority of women.
Differential male/female risk of death.
Scientific literature and official web sites on COVID-19 report a higher fatality rate in men than women are across the whole age spectrum . Our statistical analysis confirms this difference in fatality rate and shows that this trend does not changes between pre- and post-lockdown period and even increases a bit (Fig. 3) although in some age classes women are more likely infected than men. To highlight this aspect we choose two representative dates of pre- and post-lockdown phases for disease incidence and death cases: March 26, 2020, the end of period with data reflecting the exponential phase of the infection spread, and May 20, 2020, for the post-lockdown phase. Figure 4 shows the cumulative counts of patient-cases and deaths in these two time points. It is to note that, although the incidence of infection increases in women from March 26 to May 20, 2020 (Supplementary Fig. S2), the fatality rate remains higher in men than women (Fig. 3) probably because the COVID-19 disease in men tends to be more severe than in women .
Analysis of infection incidence in exponential virus spreading.
As discussed above, SARS-CoV-2 virus spread freely, with an exponential growth of infection until March 11, 2020. After lockdown the virus was characterized by a forced non-random spreading due to social distancing, Thus the weeks between February and the end of March allow to analyze the virus spreading in the different age and sex classes of population, with minima confounding effects (dates March 12-19-23-26, 2020 in Fig. 2).
We should consider several aspects possibly involved in sex-specific response to SARS-CoV-2.
Female gender is known to have a stronger immune response to viral infections compared to male gender, due to more robust innate and adaptive immune responses . Immune system is under the sex hormones influence: as a general rule, estrogens promote both innate and adaptive immune responses, which result in a better and faster response to pathogens. Instead androgens have an immune suppressive effect which may explain the greater susceptibility to infectious diseases observed in men, but a minor incidence of asthma in boys than girls . X-chromosome inactivation in women causes an imbalance of genes involved in immune response, such as CD40L and TLR7, and ACE2 that exert a protective function in pathologies like hypertension, cardiovascular diseases and acute respiratory distress syndrome, which are concurrent conditions representing a major risk of worse prognosis in COVID-19 [7, 21]. ACE2 expression is higher in young people than in elderly individuals and higher in women than in men . Other factors may be involved in infection such as hormone-regulated expression of genes or environmental factors like smoking, drinking and personal care . Chronic activation of innate and adaptive immune functions increases with age and leads to a decline of the immune system response, causing a greater sensitivity to infections and chronic diseases .
On the basis of these few elements, we try to explain our results.
The 0-9 age class presents a larger proportion of infected male children. This result could be due to a better response of female gender immune system and higher level of ACE2 in female than male gender.
In the 10-19 age class, sex hormones change the OR bringing it closer to 1.0. Although estrogens give a better immune performance than androgens, it is possible that other unknown mechanisms occur, possibly linked to sex maturation. These mechanisms may be crucial since in the 20-29 age class, when the sexual identity is fully defined, the OR is significantly inverted, with clearly more infected women than men. This is a relevant result also because it is reported in foreign European and extra-European countries . It is to note that no environmental factors like social distancing due to lockdown change the OR in the 20-29 age class during the epidemic (May 20, 2020, last date reported in this work).
The population aged 30-49 shows a more balanced ratio of infected man and women, though still with a slightly larger women proportion.
The population aged 50-59, and mainly from 60 to 90+ shows a larger presence of infected men, up to more than two-fold than women,
In the older age, the presence of overexpressed X-linked genes might reveal its greater importance. Women are more protected by infection by their strong immune system, and they have higher level of ACE2 than men. In addition, women in midlife and over usually assume Vitamin D to help the menopausal transition and to prevent osteoporosis due to the lack of estrogens, while in older men vitamin D deficiency is not adequately evaluated. It is known that adequate vitamin D levels would contribute to reduce inflammation and acute respiratory tract infection. Many authors speculate that, among other factors, the different susceptibility to virus infection may be the consequence of lower vitamin D levels in men in their sixties, compared with age-matched women .