Since the outbreak of the COVID-19 viral infection in the city of Wuhan, China in December 2019 there has been a growing recognition that men seem to be at greater risk of becoming severely ill with the disease and have a higher mortality rate.^(1–6)

In an analysis of 402 patients in Wuhan the mortality in men was 7.6% and 2.9% in females, with mortality in severely ill male patients greater than severely ill female patients ⁽²⁾. Overall, in China, as of February two-thirds of deaths were male⁽¹⁾. On-going analysis of the outbreak by Global Health 5050 demonstrate that in those countries where the data is broken down in the number of males and females affected that men predominate in both cases and deaths⁽⁶⁾.

In the UK, there is a lack of sex-disaggregated data. (The Men's Health Forum has called for this as a matter of urgency.) However, a report by the Intensive Care National Audit & Research Centre (INARC) on the 20th March 2020 covering the first 196 patients admitted to intensive care units (ICU) in England, Wales and Northern Ireland also shows this male excess. Of the 196 admitted 16 patients have died, 17 have been discharged alive and the remaining were still in ICU. These 196 patients comprised 57 (29.1%) females and 139 (70.9%) males, with a median age of 64 years⁽³¹⁾.

Age and co-existing problems

Age is an important factor in the risk of the disease, with patients over the age of 70 having a significantly higher risk of severe illness and death. In an analysis of Chinese deaths the fatalities in patients with confirmed disease younger than 30 years of age, 30 to 49, 50 to 69, 70 and older were 0, 1.0%, 4.2% and 20.0%⁽²⁾. This age effect is being seen in Italy, where the relatively higher number of deaths as compared to China is being put down to its older population. In London, where the general age profile is younger, with fewer over the age of 65 years, this may well keep mortality rates lower, but once it spreads out across the country greater numbers of fatalities may occur⁽⁷⁾.

It is easier to explain the impact of age on severity of the illness, due to the higher number of co-existing health problems and increasing frailty in the older population, but why men are more at risk is still being seen as an unanswered question⁽⁸⁾. There are some lessons from previous outbreaks of coronavirus and some more emerging findings from the current pandemic that may help answer the question. This blog will focus just on the underlying biology rather than behavioural issues that might also be important factors to consider.

Previous Coronaviruses

The current Coronavirus pandemic has been preceded by 8 other outbreaks of Coronavirus, most resulting in a mild disease, however there have been two previous outbreaks that led to more severe disease - the 2003 Severe Acute Respiratory Syndrome (SARS-CoV) and the 2012 Middle East Respiratory Syndrome (MERS). There are great similarities of COVID-19 to SARS-CoV, sharing over 85% of its genome, with comparable signs and symptoms leading to COVID-19 now being referred to as SARS-CoV2^(9,10).

There were sex-differences found in the 2003 SARS epidemic, with men having a higher case fatality rate of 21.9% as compared to 13.2% for females, with twice as many male deaths in the 0-44 age range⁽¹¹⁾. That analysis found that with age the relative risk decreased between the sexes, with little difference in those over 75 years old. In 2012, globally there were 71.6% male cases of MERS as compared to 28.4% of female cases, with a male to female ratio of 2.52, with 73.6% of all deaths male⁽¹²⁾.

Hormones

There is a growing understanding as to the reasons why men are more susceptible to both develop and to die from infectious diseases.

Women have a stronger immune response through their sex hormones, with oestrogens (specifically 17-β estradiol (E2)) and prolactin, acting to directly affect the function of the immune cells, whereas testosterone is immunosuppressive, there are also factors directly related to the X chromosomes, which has genes related to immunity that may also play a part^(13–15).

In a study of the effect of SARS-CoV on mice it was found that males were more susceptible to the disease, especially in their middle years, with less differences noted in young or old mice. When the female mice were deprived of their oestrogen, either through surgery or chemically, their mortality matched the male mice(16), which may help explain the diminished sex effect in the young or old (post-menopause) human victims of the disease.

Route of infection

Once infected the main route into the cells of the body is via a receptor that is found on cell walls, called angiotensin-converting enzyme 2 (ACE2). This was also the case for SARS-CoV⁽¹⁷⁾, but it seems that it is easier for SARS-CoV2 to use this route, which may result in greater transmission and more cases⁽¹⁸⁾. This receptor is found to be more highly expressed in males than females⁽²⁾ and is present in the lungs along with the renal tubular cells, Leydig cells and cells in seminiferous ducts in testis. ACE2 is more actively expressed in the lung cells of current and past smokers making them more susceptible to the virus(19,20). With more men having a history of smoking this again increases their risk of the disease⁽²¹⁾.

Possible effects on fertility

It has been suggested that the coronavirus can increase the risk of testicular damage, including orchitis, infertility and testicular tumour, with the possibility that it can be transmitted in seminal fluid^(22–24). This is speculation at the present time and may only have relevance at the population level when assessing fertility levels⁽³²⁾. It is, however, important to note that in an albeit small study orchitis was found to be a complication of the 2003 SARS-CoV epidemic⁽²⁵⁾. It may be necessary for some patients who have experienced testicular involvement with the disease for their reproductive function to be assessed⁽²⁵⁾.

Men and chronic disease

Pre-existing chronic disease may also be a factor for those who have the most severe disease, with hypertension, diabetes mellitus, heart disease, and chronic lung conditions being present in 37.2% of patients in a study of 43 patients in Wuhan in January 2020⁽¹⁾. Pre-existing cardiovascular disease has been suggested as the biggest risk followed by respiratory disease⁽⁴⁾. For all these chronic diseases there are a higher proportion of affected men, with a greater number affected at an earlier age⁽²⁶⁾. Smoking^(20,27) and alcohol⁽²⁸⁾ are also associated with worse conditions, with again men having higher levels of consumption^(21,29).

Call to action

The biological sex and socio-cultural gender differences in the risks men and women face during epidemics has been recognised for a long time and with action called for by the WHO as early as 2007⁽³⁰⁾. There have also been calls for greater attention paid to the risks men face as a result of SARS-CoV2 (COVID-19)^(3,6). It is also important to recognise that real and pressing issues also face women as a consequence of the SARS-CoV2 epidemic that also need to be taken into consideration and acted upon.

It should be a necessity for all data to be disaggregated by sex to allow for transparency of the sex-differences. It is also imperative that governments around the world consider how gender impacts on health differentially and that this is reflected in policy and practice.

Alan White PhD RN 
Emeritus Professor of Men’s Health, Leeds Beckett University
Patron, The Men’s Health Forum

WARNING: At this time, the majority of the scientific papers that have emerged about the outbreak are still referred to as ‘preprint’. They have been helpfully shared publicly but it means they have not yet gone through formal peer review process and may yet be amended or not accepted for publication.
1. Jin J-M, Bai P, He W, Liu S, Wu F, Liu X-F, et al. Higher severity and mortality in male patients with COVID-19 independent of age and susceptibility. medRxiv [preprint]. 2020; DOI: https://doi.org/10.1101/2020.02.23.20026864 
2. Wu Y, Guo W, Liu H, Qi B, Liang K, Xu B, et al. Clinical outcomes of 402 patients with COVID-2019 from a single center in Wuhan, China. medRxiv [preprint]. 2020; DOI: https://doi.org/10.1101/2020.03.07.20032672
3. Wenham C, Smith J, Morgan R. COVID-19: the gendered impacts of the outbreak. Lancet. 2020;395(10227):846–8.
4. Caramelo F, Ferreira N, Oliveiros B. Estimation of risk factors for COVID-19 mortality - preliminary results. medRxiv [preprint]. 2020; DOI: https://doi.org/10.1101/2020.02.24.20027268
5. Kadel S, Kovats S. Sex hormones regulate innate immune cells and promote sex differences in respiratory virus infection. Front Immunol. 2018; 9:1653 DOI: 10.3389/fimmu.2018.01653.
6. Global Health 5050. Sex, gender and COVID-19 [Internet]. [cited 2020 Mar 27]. Available from: https://globalhealth5050.org/covid19/
7. Dowd JB, Rotondi V, Adriano L, Brazel DM, Block P, Ding X, et al. Demographic science aids in understanding the spread and fatality rates of COVID-19. medRxiv [preprint]. 2020; DOI: https://doi.org/10.1101/2020.03.15.20036293
8. Purdie A, Hawkes S, Buse K, Onarheim K, Aftab W, Low N, et al. Sex, gender and COVID-19: Disaggregated data and health disparities [Internet]. Blog: BMJ Global Health. 2020 [cited 2020 Mar 24]. Available from: https://blogs.bmj.com/bmjgh/2020/03/24/sex-gender-and-covid-19-disaggreg...
9. Xu J, Zhao S, Teng T, Abdalla AE, Zhu W, Xie L, et al. Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses. 2020;12(2). pii: E244. DOI: 10.3390/v12020244
10. Cai X. An Insight of comparison between COVID-19 (2019-nCoV disease) and SARS in pathology and pathogenesis. OSF Preprints. 2020; DOI: 10.31219/osf.io/hw34x
11. Karlberg J, Chong DSY, Lai WYY. Do Men Have a Higher Case Fatality Rate of Severe Acute Respiratory Syndrome than Women Do? Am J Epidemiol. 2004;159(3):229–31.
12. Ahmadzadeh J, Mobaraki K, Mousavi SJ, Aghazadeh-Attari J, Mirza-Aghazadeh-Attari M, Mohebbi I. The risk factors associated with MERS-CoV patient fatality: A global survey. Diagn Microbiol Infect Dis. 2020;96(3):114876. DOI: https://doi.org/10.1016/j.diagmicrobio.2019.114876
13. Rubtsov A V, Rubtsova K, Kappler JW, Marrack P. Genetic and hormonal factors in female-biased autoimmunity. Autoimmun Rev . 2010 May;9(7):494–8.
14. Ortona E, Pierdominici M, Maselli A, Verona C, Aloisi F, Shoenfeld Y. Sex-based differences in autoimmune diseases. Ann Ist Super Sanità. 2016;52(2):205–12.
15. Taneja V. Sex hormones determine immune response. Front Immunol. 2018;9:1–5.
16. Channappanavar R, Fett C, Mack M, Eyck PP Ten, Perlman S, City I, et al. Sex-based differences in susceptibility to SARS-CoV infection. J Epidemiol. 2017;198(10):4046–53.
17. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875–9.
18. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260–3.
19. Cai G, Cui X, Zhu X, Zhou J. A Hint on the COVID-19 Risk: Population Disparities in Gene Expression of Three Receptors of SARS-CoV. OSF Preprints. 2020; DOI: 10.31219/osf.io/hw34x
20. Cai H. Sex difference and smoking predisposition in patients with COVID-19. Lancet Respir Med. 2020;2600(20):20020107. DOI: http://dx.doi.org/10.1016/S2213-2600(20)30117-X
21. WHO. Who global report on trends in prevalence of tobacco smoking 2000-2025, second edition. Geneva: World Health Organisation; 2018.
22. Zhang J, Wu Y, Wang R, Lu K, Tu M, Guo H, et al. Bioinformatic analysis reveals that the reproductive system is potentially at risk from SARS-CoV-2. Preprints [Internet]. 2020; 2020020307 DOI: 10.20944/preprints202002.0307.v1
23. Shen Q, Xiao X, Aierken A, Liao M, Hua J. The ACE2 Expression in Sertoli cells and Germ cells may cause male reproductive disorder after SARS CoV 2 Infection. medRxiv [preprint]. 2020; DOI: 10.31219/osf.io/fs5hd
24. Fan C, Li K, Ding Y, Lu WL, Wang J. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection. medRxiv [preprint]. 2020;2020.02.12.20022418.
25. Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, et al. Orchitis: A Complication of Severe Acute Respiratory Syndrome (SARS)1. Biol Reprod. 2006;74(2):410–6.
26. WHO. World Health Statistics 2019: Monitoring Health for the SDGs, sustainable development goals. Geneva: World Health Organisation; 2019.
27. Wang J, Luo Q, Chen R, Chen T, Li J. Susceptibility Analysis of COVID-19 in Smokers Based on ACE2. 2020; 2020030078 DOI: 10.20944/preprints202003.0078.v1
28. Sarkar D, Jung MK, Wang HJ. Alcohol and the immune system. Alcohol Res Curr Rev. 2015;37(2):153–5.
29. WHO. Global status report on alcohol and health 2018. Vol. 65, Global status report on alcohol. Geneva: World Health Organisation; 2018.
​30. WHO. Addressing sex and gender in epidemic-prone infectious diseases. Geneva, Switzerland: World Health Organisation; 2007.
31. “These data derive from the Case Mix Programme Database. The Case Mix Programme is the national clinical audit of patient outcomes from adult critical care coordinated by the Intensive Care National Audit & Research Centre (ICNARC). For more information on the representativeness and quality of these data, please contact ICNARC.” https://www.icnarc.org/DataServices/Attachments/Download/a9875849-f16c-e...
32. https://www.newsweek.com/chinese-scientists-coronavirus-male-fertility-1...​