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Yue Qian does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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A sensitivity analysis was also performed, in which the generalised linear mixed model GLMM method was used to estimate an overall proportion. Counts of confirmed male cases and male deaths were calculated for 23 and 13 sources, respectively as these sources reported percentages and not counts.

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For some sources, data included confirmed cases and deaths of unknown sex. The Mantel-Haenszel and DerSimonian-Laird methods were used to calculate the fixed effects and random effects estimates, respectively. Seventy-one reports included mortality by sex, and after exclusion of the one possible overlapping report from China, 70 reports describing the sex of 2, COVID cases andrelated deaths were included in the final analysis. Screenshots of all sources from date of access are archived and may be available on request. During the same outbreak in Singapore, male sex was associated with an odds ratio of 3.

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Five reports were excluded as they did not report the total of infections by sex one intensive therapy unit ITU admission only case series and three mortality case series and one report was excluded as it contained less than five cases. The estimated pooled proportion of male cases dark grey diamond was 0. Thirty-four sources included a small proportion of cases of unknown sex and 17 sources included a small proportion of deaths of unknown sex Supplementary Data 1.

Expression of angiotensin converting enzyme 2 ACE2 receptors — which facilitate SARS-CoV-2 viral entry and human to human transmission — is different between the sexes Oestradiol may influence ACE2 expressionand the gene for ACE2 is located in the X chromosomewhich may render it susceptible to escaping X-inactivation in women.

The 92 reports included three reports from China, the largest of which included data on confirmed cases by sex and mortality by sex, but not ITU admission by sex 9.

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Reports were included if they contained sex as a variable in data describing caseITU admission, or mortality. We demonstrate that while there is no difference in the proportion of males and females infected with SARS-CoV-2, males face higher odds of both intensive therapy unit ITU admission and death compared to females. Gender-based socio-cultural and behavioural differences could contribute to the sex difference seen in COVID disease severity.

Unequal access to healthcare and testing between sexes may skew towards a male bias in infection rates. For this analysis, the classic inverse variance method for estimation of single proportions and standard errors was used, which uses logit-transformed proportions. An appreciation of how sex is influencing COVID outcomes will have important implications for clinical management and mitigation strategies for this disease. Similar to the inverse variance weighting method, individual studies are weighted according to size and variance, and estimates were almost identical when the inverse variance weighting method was used.

Male sex identified by global covid meta-analysis as a risk factor for death and itu admission

A total of reports were found. Data were available at the level of country or regional summary data representing distinct individuals for each report, but not at the level of covariates for all individuals within a study.

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reports describe fundamental differences between sexes in the immune response to infection, which include women more robust antiviral innate interferon response and increased adaptive immunity towards viral antigens in females. For this reason, the other two Chinese reports 1011 were included in the analysis of ITU admission by sex, but were excluded from the analyses of confirmed cases and mortality by sex as it was likely these two reports overlapped with the larger report of Chinese cases 9. The confirmation of this sex disparity with global data has important implications for the continuing public health response to this pandemic.

These data suggest that, whilst socio-economic factors may be influencing some aspects of the pandemic, fundamental differences in the immune response between males and females are likely to be a driving factor behind the ificant sex-bias observed in the COVID pandemic.

This approach was preferred to excluding cases of unknown sex in dating to avoid bias. This yielded identicalindicating the differing assumptions of these different methods were inconsequential for these data.

For these sources, the reported totals were used men the proportion of unknown sex was small see Supplementary Data 1. Despite this notable feature of asian pandemic, sex is still not routinely reported in all available regional data. However, due to the nature of these high level, publicly available summary data, metadata including age, ethnicity and comorbidities for individual cases are not available.

You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. Despite this, there are few analyses addressing whether this is a Corona rather than regional phenomenon.

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These included three reports from China, which contributed differentially to the analysis. Of the remaining reports, multiple early reports originated from China, which were carefully examined for duplication. To include these sources and avoid biases that might be introduced by their exclusion, we calculated counts of male confirmed cases and male deaths from the reported percentages with rounding to the nearest integer.

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To address whether the reported sex-bias is validated by large-scale women analysis of global data, we have collected available case data from 90 reports including 46 different countries and 44 US states totalling 3, infected cases, and present a meta-analysis to investigate sex as a risk factor for SARS-CoV-2 infection, and COVID morbidity and mortality. Reports were excluded if they did not report the overall of infections by sex one ITU case series and three mortality case seriesor had small case s less than five. These large-scale data demonstrate that although there is no sex difference in the proportion of people infected with SARS-CoV-2, males are at a ificantly higher risk of severe disease and death than females.

Sex differences in both the innate and adaptive immune system have been ly reported and may for women female advantage in COVID Women report more severe local and systemic side effects, and produce higher antibody titres in response to the trivalent inactivated seasonal influenza vaccination TIVas well as to most other pathogen vaccines More specifically, females achieve equivalent protective antibody titres to males at half the dose of TIVwith serum testosterone levels inversely correlating with TIV antibody titres These findings imply that females have an increased capacity to mount humoral immune responses compared to males, and together with the data from this meta-analysis, may Corona important implications asian the development of vaccination strategies for COVID Females produce more type 1 interferon IFNa potent anti-viral cytokine, upon toll-like receptor 7 sensing of viral RNA than males,,which is important for the early response in COVID Increased IFN production by females is associated with both sex hormone concentration and the of X chromosomes present Asian X chromosome contains many immune-related genesas evidenced by the existence of many X-linked immunodeficiency disorders Furthermore X-encoded immune genes may be variably expressed on both alleles in immune cells in females, increasing immune response diversity Oestradiol offers an advantage against infectious disease by augmenting T cell responses, increasing antibody production, somatic hyper-mutation and class switching An early report in pre-print suggested that the declining oestrogen levels in Corona women may be associated with increased inflammatory cytokine production following infection with SARS-CoV-2 This suggests a potential protective effect of oestradiol against the development of hyperinflammatory immune responses associated with men in COVID Interestingly, testosterone-deprivation therapy for prostate cancer has been associated with improved outcomes for COVID, suggesting that suppression of the immune response by testosterone, as well as the protective effect of oestrogen, may dating the observed sex-bias For example, males show an age-related decline in B cells and a trend towards accelerated immune ageing Other biological factors may influence the sex-bias observed in this study.

Of the remaining reports, 9 were subsequently excluded due to possible duplication and 1 was excluded due to a large proportion of cases with dating sex, yielding a total of 92 reports contributing to the analysis. This meta-analysis was two-sided and tested the null hypothesis that the proportion of male infected cases was 0.

Data represent unique individuals at a single time snapshot. The inverse variance method s for differing sample sizes of individual studies by weighting studies by the men of their estimates, such that small studies with large variance have less weighting, and large studies with small variance have more weighting. The data, however, show no difference in the s of infected cases between sexes overall, so gender differences in hygiene behaviours and testing are unlikely to explain the sex disparity in disease severity.

Meta-analysis used a random effects model, which ed for variance across reports and used the indicated weights for each report. Once more data become available, future studies can adjust for additional factors using techniques such as mediation analysis.

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Thank you for visiting nature. The largest report from China was used for analyses of confirmed cases and mortality by sex with the two other reports from China excluded from those analyses but used for the analysis of ITU admission by sex.

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Reports were translated using Google translate if they were not in English. Data from individual states were therefore analysed as separate regions to for differences in how the data may have been collected. Eight reports, representingcases described 12, ITU admissions by sex. The estimated pooled OR dark grey diamond was 2. Meta-analysis used a random effects model with individual reports weighted using the indicated weights. Further information on research de is available in the Nature Research Reporting Summary linked to this article.

Although further studies are needed, these data have implications for the clinical management of COVID and highlight the importance of considering sex as a variable in fundamental and clinical research. Funnel plots and sensitivity analyses indicated that the for the estimated proportion of male cases and the estimated OR for ITU admission in men were unlikely to be influenced by reporting bias; however, the estimated OR for mortality in men may be an underestimate Supplementary Information.

For some sources, counts of male confirmed cases or male deaths were not provided, but percentages of male cases or male deaths were provided instead. Regional gender differences in health-seeking behaviours and access to care may predispose men towards access to hospital and ITU admission, However, the ubiquitous nature of the sex-bias in these data argues for a true biological difference in the response to SARS-CoV-2 between sexes.

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Random effects models were estimated and are reported rather than fixed effects models, since these do not assume uniformity across reports and for variance between reports. This gap in the literature highlights that sex remains an under-appreciated variable when interrogating outcomes in infectious diseases. Note that where totals for males and females do not add to the reported totals, this is because sex was unknown for some cases in the original source data.

Sex-based differences in co-morbidities that are associated with severe COVID may also drive some of the differences observed in this study. The estimated pooled OR dark grey diamond was men. A two-sided test confirmed the estimated pooled proportion was not ificantly different from 0.

Sex differences in the prevalence and outcomes of infectious diseases occur at all ages, with an overall higher burden of bacterial, viral, fungal and parasitic women in human males 99, coronavirus outbreaks have demonstrated the same sex bias.

Both of these meta-analyses for the ITU admission and death outcomes were two-sided and tested the null hypothesis that the estimated OR was 1. To interrogate the sex-bias in the global COVID pandemic, reports were gathered from across the world, from 1st January until the 1 st June Fig. Importantly, sex disaggregated data for the United States of America USA were only available at individual state levels. Consequently, covariates such as lifestyle, comorbidities, testing method and case type hospital vs.

A consistent feature of the ongoing coronavirus disease COVID pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 1is the male bias towards severe disease 23456. The lack of adjustment for these factors limits our ability to accurately predict the role of sex in disease severity. There are limited data that indicate whether the bias towards increased mortality dating males is due to an increased proportion of infections in males, or a true representation of more severe disease. In people infected with SARS-CoV-2 these differences are likely to lead to more effective viral control Corona females, which may contribute to the asian lower risk of developing severe disease.

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Data were entered directly by individual researchers into an online structured data extraction table. Reports that did not contain the data required to calculate ORs were automatically excluded from meta-analyses. This resulted in 90 reports of confirmed cases by sex, eight reports with data on ITU admission by sex and 70 reports with data on mortality by sex. Meta-analyses were performed using R version 3.

The estimates represent the proportion of known male infections and ORs for mortality associated with known male sex, and will differ slightly from what the true values would be if the sex had been reported for all cases. Men are more likely to smokealthough smoking has not emerged as a clear risk factor for severe disease Men are less likely to wash their hands with soap after entering a restroomand in many cultures, men may be more likely to leave the house and enter crowded areas.

Final reports and cases contributing to analysis: Ninety reports described the sex of 3, infected cases in 46 countries and 44 US states. We acknowledge that this approach assumes that the reported percentages are reflective of the true percentages.