Is There a Disparity in Covid-19 Incidence and Mortality by Sex? By Nana Kwame Ghansah

Coronavirus Covid-19 Disease Control Emerging Infectious Diseases Global Pandemic Men's health National Public Health Emergency SARS-CoV-2 women's health

One very noticeable thing about COVID-19 is the disparity in mortality between men and women. First noticed by the Chinese, it seems to be playing out in other countries too.
According to a meta-analysis by Mohammad Javad Nasiri from the University of Miami and his group, even though both sexes are infected at close rates, men have three times the risk from dying versus women. In Italy for instance, close to 75% of all those who have died from COVID-19 are men.
The CDC has yet to release detailed data on the gender make-up of COVID-19 fatalities in the US but as of Friday, April 3, 2020, men made up 59 percent of overall hospitalizations in New York City and 62 percent of more than 1,800 fatalities.
This phenomenon was also noticed with SARS and MERS. During the SARS outbreak in Hong Kong, nearly 22% of infected men died, compared to around 13% of women. With MERS around 32% of men died versus 26% of women.

Various reasons have been given for this disparity, some social, others biological. Men smoke and drink more, making them more susceptible to diseases of the lungs and heart. They also do not wash their hands as often and tend to seek medical care much later than women.
Biologically, the fact that women have two X chromosomes may also give them an edge. There is a system of receptors in the human body that allows for recognition of pathogens. These receptors are called Pattern Recognition Receptors (PRR). One class of these are the Toll-Like Receptors (TLR). Gender differences among these receptors may also place women at an advantage. Other important players may be the sex hormones – estrogen and testosterone – and we will discuss that a bit.

It is a known fact that the tissues of the immune system have receptors that these sex hormones can bind to and thus influence immune activity. It is also known that due to these hormonal differences, men and women have different reactions to different pathogens.
In general, it thought that testosterone is anti-inflammatory while estrogen is more pro-inflammatory in nature.
Very instrumental in the innate immune response are the T-Helper cells. It is thought that the hormones act differently on them giving different reactions in men versus women.
This might explain why women tend to suffer more from auto-immune diseases and may also develop sepsis easier in some instances than men. However, this is not true across the board and the effect of gender on disease really depends on the pathogen. (Erin E. McClelland did an amazing review of this in her 2011 paper – Arch. Immunol. Ther. Exp. (2011) 59:203–213. Also a review in “Frontiers of Immunology” from July 2018 and edited by V. Rider is helpful).

Thus women with acute HIV infections have 40 percent less viral genetic material in their blood than men. They are also less prone to get Hepatitis B and C. On the other hand, women do worse with Influenza A and have a higher prevalence of Herpes simplex.

Back in 2017, the team of Stanley Perlman at the University of Iowa (J Immunol May 15, 2017, 198 (10) 4046-4053), infected male and female mice of different age groups with the virus that causes SARS – SARS-CoV. Both groups did develop the disease but the male mice did significantly worse. They developed more elevated virus titers, enhanced vascular leakage, and alveolar edema. This got worsened with age – the older male mice, the higher the mortality. Then, they blocked the effects of the sex hormones by giving the male mice flutamide and the female ones tamoxifen. This increased the mortality in the female mice but did not alter outcomes in the male mice. It looked like estrogen was protecting the female mice from the effects of the virus. It should be noted that estrogen even reduced the viral load in the nasal passages of the female mice but had no effect on the males. In the paper, there is a detailed discussion about how estrogen may reduce the excessive inflammation seen with SARS.

This study, though in mice, reflects the observations made about the disparities in mortality of SARS, MERS, and COVID-19 between men and women.
Could estrogen be the reason why women seem to be doing better in COVID-19?
Notice that above age 75 or so, this disparity disappears and older men and women seen to have about an equal risk of dying from COVID-19. So the advantage seems to be with younger and middle-aged women. This was also seen with the mice.

To take it another step, let us look at the ACE-II receptor. Since the coronaviruses seem to bind to the ACE-II receptor, could there be a gender difference in these receptors, especially in the lungs? In experiments with knock-out (genetically-altered) mice, the team of Patrica Gallagher at Winston-Salem (Exp Physiol. 2008 May; 93(5): 658–664) showed that where estrogen altered the number of ACE-II receptors in the kidney and heart, it did not seem to affect those in the lung.

It is quite evident that more men are dying from COVID-19 than women and social as well as biological factors may be at play. One of these biological factors may be the hormone estrogen. It may possibly be protective in CIVID-19 among middle-aged women and this effect could be its influence on the innate immune system through its receptors.
Although men do produce a little estrogen and have estrogen receptors (RB Dickson 1981), the amount of hormone might not be enough and/or there might be no receptors in the tissues of the immune system to allow that protection.

Stay safe y’all!

Nana Dadzie Ghansah is an anesthesiologist who lives and works in Lexington, Kentucky

A physician providing primary medical care to patients across the lifespan