COVID-19: Why do men get sicker than women?

Global clinical data show that COVID-19 affects men more severely than women. According to a first recent study on the issue, SARS-CoV-2-infected women may develop a more potent immune response.

Global clinical data show that Covid-19 affects men more severely than women. The difference in immune system responses may be the key. According to a recent study, the first on the subject, women infected with SARS-CoV-2 may develop a more potent immune response. This would explain, in men, the development of a damaging inflammatory state.

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Since the appearance of SARS-CoV-2, studies have shown that the virus does not behave indiscriminately. It poses a threat to certain categories of people, including the elderly, people suffering from certain diseases, and African Americans. Early reports from Wuhan showed that men were more severely affected, a trend that was later confirmed in various parts of the world.

A universal but varying degree of male-female difference

The degree of this disparity between men and women varies. For example, data from the USA’s Centers for Disease Control and Prevention (CDC) collected up to the beginning of June 2020, showed that in the US men account for 54% of COVID-19-related deaths. An analysis of data from more than 1,000 Chinese patients showed that men died 2.4 times more than women.

Dr. Akiko Iwasaki and colleagues from the Howard Hughes Medical Institute published a preprint article describing the analysis of the immune responses of 93 COVID-19 patients admitted at the Yale-New Haven Hospital, USA. They wanted to identify possible immunological differences between males and females that might play a role in the clinical manifestations of COVID-19. The analysis was performed on blood and nasopharyngeal samples from a group of men and women with moderate disease.

Dr. Iwasaki's team distinguished between the two defense mechanisms of the immune system. At the onset of a viral infection, the first system reacts quickly. Infected cells produce a cytokine response that attracts immune cells to fight the infection. The inflammatory process thus triggered can be dangerous if left unchecked. In the case of COVID-19, this "cytokine storm" can cause death. Then within a few days, the second immune defense system is activated: this finely calibrated response uses T and B cells that learn to recognize the enemy and eliminate it.

More T-cells vs. more cytokines

During this study, researchers made two discoveries: women had more T cells against the virus, while men had higher levels of cytokines (which promote inflammation). "This suggests that there is a blockage in men at the early stage of the immune response," concludes Dr. Iwasaki. "Men don't properly activate the second, more targeted defense system, so inflammation persists and increases."  

His team also assessed the severity of these patients' disease. The men whose condition remained stable had generated a strong T-cell response, much like the women. On the other hand, men who did not benefit from this strong lymphocyte response experienced clinical deterioration (hospitalization in intensive care and artificial ventilation).

These results suggest that women respond better to SARS-CoV-2 infection because of the behavior of their T cells. The authors point out that while the T-cell count in men decreases with age, in women it remains high until the age of 90. Male patients may, therefore, benefit from therapies aimed at increasing or making T cells more effective. But this study has several limitations, including the fact that it has not yet been peer-reviewed, and it involves a small number of patients.

1. Takahashi T, Wong P, Ellingson M, et al. Sex differences in immune responses to SARS-CoV-2 that underlie disease outcomes. Preprint. medRxiv. 2020;2020.06.20123414. Published 2020 Jun 9. doi:10.1101/2020.06.20123414
2. Rosen M. - Why Men May Fare Worse than Women Against SARS-CoV-2. Howard Hughes Medical Institute. Jun 24 2020