Manoj Suva, M.Pharm.a, Viraj Suvarna, M.D., M.Sc.a, Swapneil Parikh, D.N.B. b, Firuza Parikh, M.D., Ph.D.c, Craig Niederberger, M.D.d
a Eris Lifesciences Limited, Commerce House-4, Prahlad Nagar, Ahmedabad 380015, Gujarat, India.
b Kasturba Hospital of Infectious Diseases, Sane Guruji Marg, Mumbai, 400034, Maharashtra, India.
cDepartment of Assisted Reproduction and Genetics, Jaslok-FertilTree International Fertility Centre, Jaslok Hospital and Research Centre, Mumbai, India.
dDepartment of Urology, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA.
The world is facing an unprecedented healthcare crisis caused by the global spread of Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). Since scientific evidence is gathering that the infection affects males more adversely than females, it is essential to explore the reasons for the same. While many papers have been published about clinical presentation and the outcomes of Corona Virus Disease 2019 (COVID-19), we wanted to explore if there is a difference in the disease outcomes based on the gender, and postulate the possible reasons behind such a difference.[1-3]
Evidence of Gender Disparity in Clinical Outcomes of COVID-19
Interesting differences between men and women regarding infection rates, disease severity and mortality rates for COVID-19 are surfacing.[4,5]
An early study from 21 hospitals in Wuhan, China in January 2020 reported that 75% (126/168) of the patients dying due to COVID-19 pneumonia were males. A retrospective study involving 548 COVID-19 patients also from Wuhan, China also showed higher mortality in males (22.2%) than females (10.4%). Male patients had severe inflammation with elevated levels of inflammatory markers such as TNF-α, IL-10, lactose dehydrogenase, hsCRP and ferritin, but lower lymphocyte counts compared to females. An analysis from China between Dec-2019 and Feb-2020 showed that men accounted for around 60% of infected individuals of COVID-19. As of February 11, the Chinese CDC reported 44,600 COVID-19 cases, and the fatality rate among men with COVID-19 was 65% higher than women with COVID-19. A report from Wuhan Children’s Hospital revealed that 61% of children and adolescents with COVID-19 were male. In Italy, there were 13,882 cases of COVID-19 resulting in 803 deaths between February 21 and March 12, and 58% of all cases and 72% of all deaths were males. Among hospitalized patients with confirmed COVID-19, males were 75% more likely to die than females. Another analysis from Italy based on 3,200 COVID-19 related deaths revealed higher death rates for males (70.5% cases) than females across all age groups. Eight out of the 9 deaths of patients younger than 40 years were male. A mortality analysis due to COVID-19 in five European countries revealed that among COVID-19 patients aged >65 years, males had two-fold higher deaths than females.
In India, a preliminary analysis found that higher proportion of males were affected than females in New Delhi and Maharashtra, and the case fatality rate was higher in males (4.8%) than females (4.0%). At the pan-India level, a study analyzing the preliminary data obtained from https://www.covid19india.org/ on 20th May 2020 reported a higher burden of COVID-19 in males (66%) than females (34%) and males accounted for 63.1% of all deaths due to COVID-19.
A large meta-analysis of 29 studies related to 206,128 COVID-19 patients concluded that males had a higher risk of admission to intensive care unit and a higher mortality risk as compared to females. An analysis of data derived from government sources of six European countries revealed that among COVID-19 patients above 20 years of age, males had a higher fatality rate than females. Fatality rate was reported with an overall median male-to-female ratio of 3.1:1 up to the age of 60 years and 2.2:1 after the age of 60 years.
Preliminary observation of sex-disaggregated mortality data from across various countries indicates that the overall case fatality ratio is higher in males than in females in all countries with available data.[15-17] As of June 17 2020, the largest male to female ratios (proportion of deaths) among countries with more than 20,000 reported COVID-19 cases were seen in The Netherlands (2.1:1), Dominican Republic (1.9:1), Romania, Spain, Belgium, Sweden, and England (all 1.8:1). The sex-disaggregated data (partial or complete) of mortality due to COVID-19 from major countries is summarized in Table 1.
Thus, an overview of all the relevant information from across the world suggests that males have a higher predilection for infection as well as higher mortality than female patients with COVID-19.
Why are susceptibility and death rates of COVID-19 higher in males than in females?
Various theories can be proposed for the perceived gender differences in susceptibility and mortality due to COVID-19 between males and females.
- Angiotensin Converting Enzyme 2 (ACE2): A disintegrin and metalloproteinase domain containing protein 17 gene (ADAM-17) is the key enzyme which regulates the tissue and plasma levels of ACE2. The ADAM-17 enzyme cleaves tissue ACE2 to form plasma ACE2. Further, higher plasma levels of ACE2 may reflect lower tissue ACE2 levels. It is believed that SARS-CoV-2 activates ADAM-17, thereby not only causing a super inflammatory response, but also reducing the cardioprotective ACE2 in tissues. Thus, lower level of tissue ACE2 can worsen the cardiovascular disease among susceptible patients and could result in unfavourable outcomes. An analysis of different types of cells obtained from normal human lung transplant donors revealed that the ACE2 distribution and expression was higher among males when compared with females. A recently published analysis of two independent cohorts of heart failure patients has reported that a higher plasma concentration of ACE2 (and thereby implying a lower tissue ACE2 concentration) was found in males than in females, irrespective of the use of ACE inhibitors or Angiotensin receptor blockers. ACE2 has a beneficial role of converting Angiotensin II to the Angiotensin 1-7 which has vasodilatory and anti-inflammatory effects. Interestingly, the development of CVD is related with gender specific differences with males more likely to develop coronary diseases than females, so the location of the ACE2 gene on the X chromosome is an interesting area to explore. It has also been observed that smoking increases the gene expression of ADAM-17, TMPRSS2, ACE and ACE2, which might represent a storm of excess viral receptors or cofactor availability and excess angiotensin II or AT1 receptor activity. This might be important as it has been observed that the tendency for smoking is generally higher in males than females.
Gender variation in immune response: Compared to males, females generally show a higher activity of innate and adaptive immune system.[23-26] These observations lead to the hypothesis that the X chromosome and sex hormones play an essential role in developing innate and adaptive  Further, females generally tend to develop a more robust immune response towards pathogens, and hence represent a clinical phenotype of being relatively protected against infection and malignancy, with relatively decreased self-tolerance and being more prone to developing autoimmune diseases. On the contrary, males tend to have better self-tolerance, but have a less robust response towards pathogens. In fact, a gender variation has been previously documented in various infectious and inflammatory diseases and cancers as well (Figure 1). Extending the same argument, it may be possible that by virtue of the more robust immune response, women may have an increased resistance to pneumonia caused by COVID-19.
Figure 1. Sex bias in developing infectious diseases, inflammatory diseases and cancers 
- Influence of the X chromosome on COVID-19 response: The X chromosome carries an abundance of immune function genes, as documented by the existence of many X-linked immunodeficiency disorders.[29,30] The X chromosome acts on multiple elements such as CD40L, CXCR3, FOXP3, TLR7 and TLR8 which can be over-expressed in females and influence the response to viral infections as well as vaccinations. The pair of X chromosomes each carry a copy of the protective TLR7 gene, and as a result, women tend to have higher immune responses and increased resistance to viral infections, and such a resistance might also include resistance to COVID-19 infection. TLR7 gene is also expressed in innate immune cells which recognize SARS-CoV-2 by promoting antibodies production and synthesis of pro-inflammatory cytokines (IL-1 and IL-6). In addition, the IL-6 production after viral infection is lower in females than in males. In many acute viral diseases with severe inflammatory reactions, TLR7 enables women to have a lower mortality rate.
- Influence of Sex Hormones on COVID-19 response: Oestradiol affects many aspects of innate immunity including the functional activity of innate immune cells that influence downstream adaptive immune responses. The lymphoid tissue cells contain an abundant quantity of oestrogen receptors (ER). The immune profile has been observed to vary based on circulating levels of oestradiol: while low levels of oestradiol correspond to a T-helper-1-type response and prominent cell-mediated immunity, higher oestradiol levels (such as in pregnancy) correspond to a T-helper-2-type response and prominent humoral immunity. Oestradiol is associated with increased antibody production, somatic hypermutation and class switching, abundance of neutrophils, and increased monocyte/macrophage cytokine production. With the help of T cells, neutralizing antibodies production occurs in the germinal centers of lymphoid organs that require the affinity-maturation of activated B cells. Activated B cells undergo antibody affinity-maturation which involves two key events: somatic hypermutation and immunoglobulin class-switch. The first event involves the generation of somatic hypermutations in Immunoglobulin (Ig) variable region (V region) genes which increases the affinity of antibodies for antigens. In the second event, Ig class-switch recombination directs antibody production towards the synthesis of IgG1, IgG2, IgA and IgE. These two processes require a B-cell-specific molecule activation-induced cytidine deaminase, whose activity can be up-regulated by oestradiol that in turn generates humoral immune response.[33,34] In human T cells, nearly 50% of the activated genes have an oestrogen response element in their promoter region. On the other hand, testosterone is thought to slightly diminish the immune response: a lack of testosterone has been associated with an increased level of inflammatory cytokines, antibody titres, CD4/CD8 ratios and natural killer cells, and a decrease in the levels of T-reg cells.[14,28,32] It is believed that the SARS-CoV2 utilises the enzymes ACE2 and TMPRSS2 for cell entry and S protein priming respectively. Since TMPRSS2 overexpression is documented in advanced and metastatic prostate cancers, it has been hypothesized that androgens upregulate TMPRSS2 not only in the prostate but also in the lungs, and by virtue of the higher presence of androgens in males, the SARS-CoV2 entry might be facilitated in males more easily than in females. Such differential effects might contribute to higher susceptibility and mortality in males.
- Higher proportion of comorbidities among males: The proportion of comorbidities such as hypertension, cardiovascular disease, chronic lung diseases and diabetes are often higher among males. Also, consumption of tobacco (e.g., smoking), alcohol abuse and occupational exposure are generally higher in males. These may contribute to this gender variation.[4,16]
- Behavioural and social/cultural differences in following guidelines and advice to mitigate transmission: Cultural, religious and secular factors may contribute to gender differences in the presentation of infections, particularly in conservative societies, where women could derive extra protection against developing infections due to traditional clothing. Some studies have suggested that women are more likely than men to follow hand-hygiene practices and seek preventive care. Facial hair among males may act as a fomite, thereby increasing the risk of infection among males. A study pointed out that females may have a more responsible approach and attitude towards the pandemic control measures compared to males, especially with regards to following safety measures (such as wearing of face mask, frequent hand washing, and staying at home). It remains to be seen to what extent these behavioural and social factors contribute to the gender differences in COVID-19 vulnerability.
The data on COVID-19 is still evolving. While the initial data suggest that males are more frequently and severely affected by COVID-19 pneumonia, it remains to be seen if this is indeed the case. In this review, we have explored the possible reasons for such a differential presentation and outcomes of COVID-19. Of the many hypotheses for why this difference exists, the one which holds the most scientific promise appears to be the differential effect of the male and female sex hormones on the immune system (the biological hypothesis). We have elucidated the differences in the biological and behavioural aspects between males and females which might contribute towards the differential levels of severity and presentation of COVID-19. The higher incidence of acquired comorbidities among males is also an important factor towards this difference. More emphasis should be given on controlling co-morbid conditions and medical and social practices for improving outcomes in COVID-19. The issues discussed in this review should be a pointer towards future research to establish the proper reasons for such gender-based disease vulnerability. The increased frequency and severity of COVID-19 among males should serve as a pointer for higher precaution among males for both patients and the caregivers. The societal impact of the sex differential in infections should impact public health policies. Males need to take this virus and disease seriously and eschew risk-taking behaviours and similarly women also need to be more cautious regardless of age in the context of COVID-19.
The information expressed in this article would be valuable for all of us involved in the battle against COVID-19, and would equip us to devise strategies involving modification of social habits, expectant management of comorbidities, and institution of medical therapies. This information would also guide health agencies and governments to design national and regional policies and interventions to limit the spread of the virus until herd immunity or vaccine-induced immunity is in place in order to end this pandemic.
MS, VS, SP, FP, and CN made substantial contributions to the conception of the work and to literature search, contributed significantly to writing the manuscript, revised it critically for important intellectual content, approved its final version, and agreed to its submission.
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