key: cord-0846593-tqpf95kk authors: Nimgaonkar, I.; Valeri, L.; Susser, E. S.; Hussain, S.; Sunderram, J.; Aviv, A. title: The Age Pattern of the Male- to- Female Ratio in Mortality from COVID-19 Mirrors that of Cardiovascular Disease but not Cancer in the General Population date: 2020-07-11 journal: nan DOI: 10.1101/2020.07.10.20149013 sha: 68606ac0deef7a096b5c4a36925848a9328919f1 doc_id: 846593 cord_uid: tqpf95kk Background: Males are at a higher risk of dying from COVID-19. Older age and cardiovascular disease are also associated with COVID-19 mortality. We compared the male-to-female (sex) ratios in mortality by age for COVID-19 with cardiovascular mortality and cancer mortality in the general population. Methods: We obtained data from official government sources in the US and five European countries: Italy, Spain, France, Germany, and the Netherlands. We analyzed COVID-19 deaths by sex and age in these countries and similarly analyzed their deaths from cardiovascular disease (coronary heart disease or stroke) and cancer, the two leading age-related causes of death in middle-to-high income countries. Findings: In both the US and European countries, the sex ratio of deaths from COVID-19 exceeded one throughout adult life. The sex ratio increased up to a peak in midlife, and then declined markedly in later life. This pattern was also observed for the sex ratio of deaths from cardiovascular disease, but not cancer, in the general populations of the US and European countries. Interpretation: The sex ratios of deaths from COVID-19 and from cardiovascular disease exhibit similar patterns across the adult life course. The underlying mechanisms are poorly understood, but could stem partially from sex-related biological differences that underlie the similar pattern for cardiovascular disease. These include, we propose, comparatively longer telomeres in females, ovarian hormones, and X chromosome mosaicism. Evidence before this study Mortality from COVID-19 is higher in males and older persons. We searched PubMed.gov in June 2020, with no date restrictions, for articles published in English using the search terms "COVID-19", "deaths", "mortality", "sex", "male", "female", "age", "disaggregated", "ratio", and "stratified". We identified studies in several countries that stratified COVID-19 mortality data by age or by sex, but no study examined male-to-female (sex) ratios by age at a multinational level. To our knowledge, this is the first study to aggregate data on COVID-19 deaths at a multinational level, and analyze how the sex ratio in deaths varies by age, taking into account the population at risk in each sex/age stratum. We found a distinctive pattern in sex ratio of deaths by age, illuminating the nature of the sex effect on death from COVID-19. Moreover, we found a similar pattern in sex ratio of deaths by age for cardiovascular disease, which is strongly associated with increased risk of dying from COVID-19. We did not find a similar age pattern for the sex ratio in deaths by cancer. The sex ratio in deaths from COVID-19 peaks in middle age and decreases at older ages, a pattern mirrored in deaths from cardiovascular disease. This intriguing similarity warrants research about whether sex-based differences in mortality from COVID-19 and from cardiovascular disease in general are partly due to common biological causes. More males than females die from COVID-19, the disease caused by the SARS-CoV-2 virus 1 . This was first observed in China, where 64% of COVID-19 deaths occurred in males 1 . As the epidemic spread worldwide, other countries similarly observed a higher percentage of deaths from COVID-19 occurring in males 1 . The higher number of deaths among males is consistent with mortality patterns observed in several major viral epidemics/pandemics of the 20 th and 21 st centuries, including the Western African Ebola virus epidemic (2013-2016) 2 and the H1N1 Spanish Flu pandemic of 1918 3 . Adult men also have an overall higher mortality rate than adult women from seasonal influenza based on an analysis of data in the US between 1997-2007, with some variation depending on age group and underlying conditions 4 . In contrast, COVID mortality by age differs from other viral pandemics. More than 80% of COVID-19 deaths in the US and European countries have occurred in individuals older than 65 years 5 , with very few deaths in young children 6 . Seasonal influenza causes relatively more pediatric deaths, especially in infants under the age of six months 7 , in addition to a disproportionate number of deaths in individuals over the age of 65 years 8 . Several major viral pandemics of the 20 th and 21 st centuries have also shown different age-based mortality patterns from COVID-19. For instance, in the Spanish Flu of 1918 a large proportion of deaths were in young adults 9 , and in the 2009 H1N1 influenza pandemic a large proportion occurred in children and non-elderly adults 10 . Therefore, COVID-19 mortality trends are consistent with sex-based, but not with age-based patterns seen in many other viral pandemics. In searching for explanations for the distinctive pattern of deaths in COVID-19, we first examined variation by age group in the male-to-female (sex) ratio of mortality in data from the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 11, 2020. . https://doi.org/10.1101/2020.07.10.20149013 doi: medRxiv preprint US and five European countries. Given that cardiovascular disease (CVD) has been strongly associated with increased risk of mortality in COVID-19 11 , we next examined variation in the sex ratio of CVD mortality by age group in the same countries. As CVD and cancer are the two major age-related disease categories that largely determine survival of adults in middle-and-high income societies, we further examined variation by age in the sex ratio of cancer mortality. Here we report our findings and offer potential explanations regarding their meaning. We focused our analysis on the US, Italy, Spain, France, Germany, and the Netherlands because of (a) availability of their sex-and age-disaggregated mortality data from COVID-19, (b) data stratification into age group bins of 10 years or less, and (c) a high number of cumulative deaths from COVID-19 (sources are shown in Supplementary Table 1) . COVID-19 mortality data were retrieved from national databases including the US Centers for Disease Control, the Italian National Institute of Health, the French Institute for Demographic Studies, the Spanish Ministry of Health, the German Federal Ministry of Health, and the Dutch Ministry for Health, Welfare and Sport. The data were retrieved on June 18 th , 2020 and reflect the cumulative COVID-19 deaths in each country from the beginning of the pandemic up to dates between May 29 th -June 17 th 2020 (see Supplementary Table 1 and Supplementary Table 2 for details). In the US, data were included for age groups 25 years and older, and stratified into 10-year bins. For the European Countries, data were included for age groups 30 years and above and stratified into 10-year bins, and deaths were combined across the five countries by age group and sex. Age groups with less than 200 total deaths were excluded from the analysis. The population at risk in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 11, 2020. . https://doi.org/10.1101/2020.07.10.20149013 doi: medRxiv preprint each age group was retrieved from populationpyramid.net, a website that aggregates data from the United Nations Department of Economic and Social Affairs, Population Division. For the analysis of mortality from CVD and cancer, data were extracted from the World Health Organization Mortality Database (https://www.who.int/healthinfo/mortality_data/en/), which collects national data on deaths from civil registries. The Database contains number of deaths by country, year, sex, age group and cause of death, and population size by country, year, sex and age group. The causes of death are categorized by International Classification of Disease (ICD)-10 codes. CVD deaths principally included deaths from coronary heart disease (ICD-10 codes I20-I25) or stroke (I60-I69) 12 . Cancer death data included deaths from all neoplasms (C00-C97, D00-D48) (Supplementary Table 3 Table 4 and Supplementary Table 5 ). Population adjustment was done using population data from the same years as the mortality data. These population data were also extracted from the World Health Organization Mortality Database. Plots and data visualizations were created using the ggplot2 package in R (https://ggplot2.tidyverse.org). Stratified by age, and adjusted for population at risk in each age group ( Supplementary Figure 1, Supplementary Table 2 ), the sex ratios for COVID-19 deaths among adults in the US and five European countries (Italy, Spain, France, Germany, and the Netherlands) showed similar overall patterns, initially rising to a peak in midlife and then falling (Figure 1) . Specifically, the sex ratio of mortality peaked between the ages of 35-44 years in the US and 60-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 11, 2020. . 69 years in the European countries, and then progressively declined at older ages without dropping below one. We next examined the sex ratio of CVD mortality by age in these countries (Figure 2 ). The sex ratio for CVD mortality initially rose to a peak in midlife and then declined, in both the US and Europe. For ages younger than 70 years, the sex ratio for CVD mortality in Europe was higher than in the US. As cancer is the other leading cause of adult mortality in the US and Europe 13 , we also examined the sex ratio for cancer mortality by age ( Figure 3 ). The sex ratio for cancer mortality increased after midlife with no evidence of decline thereafter. When the sex ratios of mortality by age for COVID-19, CVD and cancer were overlaid, the COVID-19 profile mirrored that of CVD, although, the ratio for CVD was much higher in Europe than the US for ages younger than 70 years (Figure 4 ). The profile of the sex mortality ratio by age for cancer, however, clearly differed from the ratios for COVID-19 and for CVD. Our key findings are as follows: (i) for all age groups, the death rate from COVID-19 was higher in males than females; (ii) the sex ratio rose to a peak in midlife and then narrowed with increasing age; and (iii) the sex mortality ratio for COVID-19 by age mirrored that for CVD but not cancer mortality. Since the COVID-19 data were not linked to population databases with individual-level health information, we could not specifically examine the potential contribution of CVD to the age pattern of the sex mortality ratio from COVID-19. We propose, nonetheless, based on data displayed in Figure 4 that the sex ratio for COVID-19 mortality, particularly for . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 11, 2020. . https://doi.org/10.1101/2020.07.10.20149013 doi: medRxiv preprint persons older than 60 years, might partially reflect the same underlying mechanisms that drive the age pattern of the sex mortality ratio for CVD in the general population. What then might be the mechanisms explaining the similar age patterning of the sex ratio for mortality in COVID-19 and in CVD? The underlying biological reasons are likely multifactorial and complex. We review several potential explanations: telomeres, ovarian hormones, and X chromosome mosaicism. Single nucleotide polymorphisms associated with leukocyte telomere length have been used as instrumental variables in Mendelian randomization studies to infer a causal role of short telomeres in CVD and long telomeres in major cancers 14 . Older persons with short leukocyte telomere length show a higher risk of dying from CVD 15 , and a recent paper proposed that short telomere length might be a common denominator that partially explains increased mortality from COVID-19 of older persons, males and individuals with CVD 16 . Telomeres are longer in females than males from birth onwards 17, 18 , a finding that might contribute to the skewed sex ratio in mortality from COVID-19 and CVD not only in older persons but also throughout the adult life course. Endogenous estrogens have been associated with a protective effect against CVD in premenopausal women 19 , while predisposing women to certain cancers 20 . Higher estrogen 21 and progesterone 22 levels in premenopausal women might also modulate immune responses and attenuate the severity of COVID-19. In this regard, data from the US show a decline in the sex . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 11, 2020. . https://doi.org/10.1101/2020.07.10.20149013 doi: medRxiv preprint ratio of COVID-19 mortality after ages 45-54 years, which coincides with the average age that women undergo menopause 23 . However, the data from the European countries suggest otherwise, with the drop in the sex ratio of COVID-19 mortality starting in the 70-79-year age group; well beyond the average age of menopause. Clinical trials are currently investigating whether estrogen or progesterone treatment can alleviate COVID-19 symptoms, which may provide clarity to the role of ovarian hormones in COVID-19 pathogenesis (ClinicalTrials.gov identifiers NCT04359329, NCT04365127). The two X chromosomes provide an advantage related to X-linked recessive diseases and other deleterious mutations on the X chromosome. Random inactivation in utero of one X chromosome in each somatic cell engenders mosaicism that provides females with somatic cell diversity and the potential for selection of cells with an X chromosome harboring advantageous variant genes 24 . X chromosome mosaicism might be particularly advantageous for surviving infectious disease, since the X chromosome encodes a number of genes engaged in immune function -therefore having two copies of these genes confers additional immunological diversity in women 25 . In addition, the X chromosome harbors ACE2, the gene encoding angiotensinconverting enzyme 2, the cellular receptor for SARS-CoV-2 26 . ACE2 variants might play a role in left ventricular hypertrophy that is often the outcome of hypertension 27 , a comorbidity that tracks with age 28 . Some of these variants might also influence CVD in general 29 , the severity of COVID-19 26 , or interact with other genes and environmental factors that influence mortality from both diseases. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 11, 2020. . https://doi.org/10.1101/2020.07.10.20149013 doi: medRxiv preprint Limitations to this study include: (a) potential differences in reporting COVID-19 deaths between the countries analyzed; (b) the lack of linked individual-level health and social databases; and (c) no information on the sex ratio of survival rates among people who acquired COVID-19. The latter would require, at a minimum, COVID-19 infection rates by age and sex in the general population (including asymptomatic infections) in order to determine whether there are sex-and age-based differences in survival from it. Additionally, the study does not account for some anomalies in the overall similar patterns for COVID-19 and CVD in the United States versus Europe. The peak sex ratio for COVID-19 occurs at an earlier age in the United States than Europe, and the sex ratio for CVD mortality is higher for Europe than the United States until the older age groups. Finally, we could not rule out that finding the lowest sex ratios in COVID-19 and CVD for the oldest age groups was partly due to selection by survival in that males who survive to an exceptionally old age are "escapers" who hardly represent the general population of older males, whereas females who survive to such an old age might be "delayers" who largely represent the general population of older females 30 . Our analyses show similar trends in the sex ratio by age of mortality from COVID-19 and from CVD. We propose that these findings might be due to some shared underlying biological mechanisms. Individual-level data are essential to examine potential shared mechanisms and to establish the potential contribution of CVD to the age patterning of the sex ratio of mortality in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 11, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 11, 2020. . https://doi.org/10.1101/2020.07.10.20149013 doi: medRxiv preprint COVID-19 sex-disaggregated data tracker Ebola Virus Disease among Male and Female Persons in West Africa The 1918 influenza epidemic's effects on sex differentials in mortality in the United States Age-and sex-related risk factors for influenza-associated mortality in the United States between 1997-2007 Department of Health & Human Services Coronavirus Disease 2019 in Children -United States Influenza-Associated Pediatric Deaths in the United States Archived Estimated Influenza Illnesses Influenza: the mother of all pandemics Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options Sex differences in coronary heart disease and stroke mortality: a global assessment of the effect of ageing between Deaths by Cause, Age, Sex, by Country and by Region Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies Telomeres and COVID-19 Reflections on telomere dynamics and ageing-related diseases in humans Leukocyte Telomere Length in Newborns: Implications for the Role of Telomeres in Human Disease The effects of oestrogens and their receptors on cardiometabolic health Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers Sex and Gender Differences in Health: What the COVID-19 Pandemic Can Teach Us Progesterone-based compounds affect immune responses and susceptibility to infections at diverse mucosal sites Age at natural menopause in Spain and the United States: results from the DAMES project Why females are mosaics, X-chromosome inactivation, and sex differences in disease The X chromosome in immune functions: when a chromosome makes the difference ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy Age related prevalence of severe left ventricular hypertrophy in essential hypertension: echocardiographic findings from the ETODH study The ACE2 gene: its potential as a functional candidate for cardiovascular disease