key: cord-0996430-yi1lcabv authors: rajabinejad, m.; Asgarian-Omran, H. title: COVID-19 gender difference pattern in Iranian population, compared to the global pattern; a systematic review and meta-analysis date: 2021-05-25 journal: nan DOI: 10.1101/2021.05.23.21257692 sha: 8a137f0359c204eee8858d3d6a7a650e9705a845 doc_id: 996430 cord_uid: yi1lcabv The coronavirus disease 2019 (COVID-19) pandemic has highlighted Sex-related immune responses. In this review, gender differences in seroprevalence, severity, mortality, and recovery in the Iranian population were systematically compared to the COVID-19 global pattern. This compressive meta-analysis was conducted on studies published up to April 1, 2021, examining seroprevalence in the general population as well as disease outcomes in hospitalized patients. Data were analyzed based on gender to determine differences between men and women in COVID-19. The PubMed, Scopus, Google Scholar, WOS, medRxiv, and bioRxiv were searched. The odds ratio (OR) was calculated based on the random-effects model, with a corresponding 95% confidence interval (CI), according to the number of participants reported in papers. Subgroup analyses were performed according to the age, antibody isotype, and detection assay. Overall, 61 studies with 225799 males and 237017 females were eligible for meta-analysis. Seroprevalence was 1.13 times higher (95% CI: 1.03, 1.24), mortality was 1.45 times higher (95% CI: 1.19, 1.77), and severity was up to 1.37 times higher (95% CI: 1.13, 1.67) in males than those of females in the general population across the globe. Mortality was higher in Iranian patients up to 26% in men (95% CI: 1.20, 1.33), but no significant difference was observed between disease severity and serum prevalence between men and women. Besides, the rate of recovery was 29% (global pattern) and 21% (Iran pattern) lower in males than in females. The results of subgroup analyses for seroprevalence were not significant for the age, antibody isotype, and detection methods. The results of our meta-analyses showed that the patient mortality and recovery patterns are similar in Iran and other countries in the context of gender differences, and the disease is more fatal in men. It has been almost a year and a half since the first case of the coronavirus disease 2019 was reported in Wuhan, China. In January 2020 the World Health Organization (WHO) declared it as a Public Health Emergency of International Concern, and shortly thereafter in March 2020, it was officially declared as a pandemic (1). The cause of this pandemic is a virus, with an unclear origin, from the coronavirus strain called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (2). This virus has a single-stranded RNA genome encoding several open reading frames, including structural proteins spike (S), matrix (M), envelope (E), and nucleocapsid (N) (3). Despite the start of vaccination in most parts of the world, many countries, including Iran, are still severely affected by the high prevalence of the disease. The unknown pathogenic and immunological dimensions of SARS-CoV-2 have caused a very high amount of mortality. One of the most important key points of this pandemic is to understand the individual differences in disease severity and mortality. Although the COVID-19 pandemic has become a global infodemic, many aspects of the disease remain unknown, and even serious disagreements and contradictions have arisen among scientists on some issues. From the beginning, reports showed a higher mortality rate in men than women, highlighting the role of chromosome X in host immune response (4). It was initially reported that the reasons for this discrepancy are stronger adaptive and innate immune responses in women, and even better antiviral responses such as early production of interferons (5, 6); but over time, controversy arose over COVID-19 gender difference (7). Preliminary studies have suggested that estrogen, 17β-estradiol, may play a protective role by regulating ACE2 expression as the major cell entry receptor for SARS-CoV-2. However, the results of studies on the effects of estrogen on ACE2 expression are controversial and cannot be commented on with complete certainty (Table 1) . For this reason, researchers are now debating the effects of estrogen on regulation of ACE2 and how it affects the pathogenesis of SARS-CoV-2. Another factor that is somewhat questionable is the effect of interferon responses on virus inhibition and its role in the gender differences in show that only early interferon type 1 responses can control the virus pathogenesis (8). In addition, various studies have been performed on the effect of interferons on ACE2 expression, and these results are slightly different (Table 2 ). However, most of these studies have reported that type 1 and 2 interferons in both in vivo and in vitro environments may be associated with increased expression of ACE2, whereas how interferon can play a role in gender differences is still controversial. COVID-19 can be compared to an iceberg which more than half of it is underwater and invisible (9) . Therefore, if the goal is to evaluate the mortality, severity, or pathogenicity of coronavirus, the underwater part should also be clearly seen. Seroprevalence studies can give a good view of the coronavirus infection in the general population and estimate the frequency of challenged people (10). These types of studies identify and report the number of people who have a negative RT-PCR test but a positive serology test for anti-coronavirus IgM or IgG. Summarizing this group of information can provide a very good view of the number of asymptomatic patients in the population, and may eventually be used to refute or confirm the controversial theory of herd immunity (11). The most important step in treatment and vaccination is to fully understand all differences in the target population, and perhaps the first step in achieving personalized medicine is to know the gender characteristics in treatment and vaccination. The potential gender differences in COVID-19 pathogenicity can also affect the effectiveness and safety of ongoing vaccination. For these 1 1 RT-PCR negative for COVID-19, showed that there was a significant difference in the global seroprevalence rate. Analysis indicated that males (4395 out of 139285) were 13% more seropositive than females (5071 out of 163417) in the general population [OR 1.13 (95% CI: 1.03, 1.24), p-value =0.009, Fig. 2a ]. However, no significant difference was seen in the seroprevalence rate between males and females in Iran [OR 0.93 (95% CI: 0.79, 1.11 Sex-specific comparison in COVID-19 confirmed cases across the globe (76844 patients) indicated that there was a significant difference in mortality between males and females, which was 45% higher in men (4789 out of 41982) than women (2792 out of 34862 individuals) [OR 1.45 (95% CI: 1.19, 1.77), p-value <0.001, Fig. 5a ]. The results of the meta-analysis 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 May 25, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 mortality of Iranian patients were in line with the global pattern (4612 death in 24681 M and 2858 death in 18126 F) and 26% higher in men [OR 1.26 (95% CI: 1.20, 1.33) , p-value <0.001, Sex-based meta-analysis in COVID-19 confirmed cases (37351 patients) showed that the disease is 37% more severe in men (4604 out Fig. 5d ]. Studies' risk of biases is provided in Table 5 -6. The Newcastle-Ottawa Scale was used to assess the overall quality. For the included studies to evaluate seroprevalence, three criteria were evaluated, including the study population and participants' characteristics, detection assay, and outcomes. For the rest of the studies the type of study and study population, the comparability, 1 3 and the outcomes were evaluated. Most of the included studies had moderate to high quality of evidence. Besides, a total of twelve studies were evaluated as low quality. . 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 May 25, 2021. Since the introduction of serological diagnostic kits for SARS-CoV-2 and their availability to researchers around the world, various studies and papers have been published to investigate seroprevalence rates among various ethnic populations (13). These types of studies can be a very valuable screenshot to check the immune status as well as the previous exposure to the virus. However, many factors can affect seroprevalence in the general population, including sampling time, epidemic status in the studied country, use of personal protective equipment (PPE), type of targeted antigen, type of detection assay, antibody isotype, and its cut-off value. Although the WHO has defined a population-based serological study protocol (14), our searches showed that, to date, at least a small number of studies have met these standard protocols (13). For this reason, heterogeneity could be high in our reviewed published papers. In addition to the subgroup analyses which were performed in the present study, every effort was made to include studies that have the maximum similarity for meta-analyses. In order to reduce the impact of jobs, exposure, and the use of PPE on main outcomes, only studies conducted on the general population were reviewed. However, the information reported in the papers on how and to what extent possible exposure to the virus was very incomplete, and this was one of the major limitations we faced. The results of our pooled analysis showed that there was a significant difference in seroprevalence rate between males and females which males 13% more likely to be seropositive than females in the general population. Although the results of the meta-analysis were not significant for seroprevalence among the Iranian population, it did not seem to follow the global pattern and the prevalence of anti-COVID-19 Ab was higher in women (7%). Of course, this difference can be due to the variations in the number of articles included for the analysis. There 1 5 was no significant difference in subgroup analyses based on age, antibody isotype, and detection assays. The difference between male and female seroprevalence in the global pattern can be due to several reasons. First, males may be more exposed to COVID-19 than women and may use less PPE (15, 16) . Second, based on the previous knowledge about stronger immune responses in females, perhaps the reason for the lower seroprevalence in them is the stronger innate immune response including type 1 interferon at the onset of the disease (17) (18) (19) . Although, the results obtained from analyses in Iranian population showed that this pattern is not similar in all countries and regions. Besides, no significant difference was observed in seroprevalence analyses based on age, which is an effective factor in the rate of exposure. A recent systematic review study reported a positive association between seroprevalence and age among participants younger than 65 years and no significant difference between males and females (20), unlike our study. However, this study was performed on all populations, including healthcare workers and close contacts, and was not limited to the general population. Consistent with the results of two recent systematic reviews (21, 22), we have also found that males have more severe disease and a worse prognosis than females and their mortality rate is up to 45% higher than females. The results of the analysis on the Iranian population also showed a similar pattern, albeit with a milder slope (26%). The meta-analyses also showed that the age difference between the dead and rescued people in the Iranian population is only 0.73 years, while this number is 2.71 years for other countries. Our present study also examined the number of men and women who were recovered and discharged from the hospital, and the results showed that, as expected, males have up to 29% less recovery and discharge than females. The results in the Iranian population, in line with the global pattern, also showed a recovery of up to 21% more in women than men. There are several 1 6 reasons for this situation that have not been proven with certainty to date. Studies have shown that Angiotensin-converting enzyme 2 (ACE2), expressed on the PAR region of the X chromosome, is regulated by estrogen (23). Lambert et al. showed in their study on SARS-CoV-1 that females may express more circulating ACE2 which can protect them against acute respiratory distress syndrome (24). Besides, both humoral and cellular immunity is stronger in women (25), and it has been shown that early IFN responses and the production of neutralizing antibodies are highly effective in reducing disease severity (8, 26) . But as shown in Tables 1 and 2 , there are conflicting results about the effects of estrogen as the main female hormone on ACE2 expression. Also, despite the proven strong antiviral effects of interferons, especially interferon type 1, it is still not possible to comment with certainty on its role in gender differences. In summary, by aggregating the results of meta-analyses for seroprevalence, severity, mortality, and recovery, it is clear that there are gender differences in COVID-19. Also, comparing the mortality and recovery rate in global pattern with Iran showed similar results. However, there seem to be interesting differences in serum prevalence between different populations of the world. The reason for this difference is not completely understood, but what is clear and has been proven in many autoimmune diseases is that there are sex biases in immune responses. Therefore, it seemed that a new approach should be taken in the fight against COVID-19 and the population of men, especially older men, should be further studied and cared for. Besides, the results of this study and similar studies can be a warning to those who have started a dangerous game with herd immunity regardless of scientific support. Hoping for COVID-19-free days. . 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 May 25, 2021. ; https://doi.org/10.1101/2021.05.23.21257692 doi: medRxiv preprint 1 9 The authors thank the immunology department of Mazandaran University of Medical Sciences for their kind and prompt support. . . 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 May 25, 2021. ; https://doi.org/10.1101/2021.05.23.21257692 doi: medRxiv preprint 0 1 8 . T a k a h a s h i T , E l l i n g s o n M K , W o n g P , I s r a e l o w B , L u c a s C , K l e i n J , e t a l . S e x d i f f e r e n c e s i n i m m u n e r e s p o n s e s t h a t u n d e r l i e C O V I D -1 9 d i s e a s e o u t c o m e s . N a t u r e . 2 0 2 0 . 1 9 . . 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 May 25, 2021. ; https://doi.org/10.1101/2021.05.23.21257692 doi: medRxiv preprint 1 e s e f e m a l e m i c e r e v e r s e s o b e s i t y -h y p e r t e n s i o n t h r o u g h a n A C E 2 -d e p e n d e n t m e c h a n i s m . A m e r i c a n J o u r n a l o f P h y s i o l o g y -E n d o c r i n o l o g y a n d M e t a b o l i s m . 2 0 1 5 ; 3 0 8 ( 1 2 ) : . 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 May 25, 2021. . 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 May 25, 2021. . . . 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 May 25, 2021. ; https://doi.org/10.1101 /2021 : . 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) 1 0 6 . J a l i l i M , P a y a n d e m e h r P , S a g h a e i A , S a r i H N , S a f i k h a n i H , K o l i v a n d P . C h a r a c t e r i s t i c s a n d m o r t a l i t y o f h o s p i t a l i z e d p a t i e n t s w i t h C O V I D -1 9 i n I r a n : a N a t i o n a l R e t r o s p e c t i v e C o h o r t S t u d y . A n n a l s o f i n t e r n a l m e d i c i n e . 2 0 2 1 ; 1 7 4 ( 1 ) : 1 2 5 -7 . 1 0 7 . A l i z a d e h s a n i R , A l i z a d e h S a n i Z , B e h j a t i M , R o s h a n z a m i r Z , H u s s a i n S , A b e d i n i N , e t . 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 May 25, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 . 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. . 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 May 25, 2021. ; https://doi.org/10.1101/2021.05.23.21257692 doi: medRxiv preprint vs. . 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