Authors: Maria Tokuyama, PhD, Assistant Professor at UBC Microbiology & Immunology; Joshua Mao, University of California Berkeley, Summer Intern at the Tokuyama Lab, UBC Microbiology & Immunology | Editors: Negin Nia and Arrthy Thayaparan (Blog Coordinators)
Published: September 10th, 2021
Since March 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has drastically changed our lives and has killed over four million people worldwide. Although people of all ages and sex get COVID-19, a striking observation is that the number of female COVID-19 deaths were half of what was seen in males. Data analysis from New York City Health found that of all death cases 38.2% were female and 61.8% were male. So what are the factors that contribute to this sex difference in COVID-19 outcomes? Several research studies have shown that differences in immune response and metabolism during disease may partly explain the worse outcomes in males than females. Here, we will summarize the key takeaways from those studies.
The immune system is largely divided into two parts: the innate and adaptive immune system. The innate immune system is the body’s first line of defence against infection. It is able to recognize danger within minutes and rapidly fire inflammatory factors called cytokines and chemokines to recruit immune cells to sites of infection and set off alarms to engage the adaptive immune system. The adaptive immune response takes about five to seven days to fully kick-in, but once activated, it is very specific to the invading pathogen and provides long-term memory responses that can be quickly recalled to fight future infections by the same pathogen. The adaptive arm of the immune system is what is provided by vaccinations. During viral infection, both the innate and adaptive immune responses work together to fight the infection. Ultimately, the magnitude and quality of the immune response dictate disease outcomes.
Male patients show increased activation of the innate immune response.
In a study published by Yale in August 2020, researchers compared immune responses between female and male hospitalized COVID-19 patients, who were not taking anti-inflammatory drugs. They found that male patients had higher amounts of key inflammatory molecules, interleukin 8 (IL-8) and 18 (IL-18), in their blood compared to female patients, despite having similar amounts of SARS-CoV-2 RNA. In addition, male patients had a higher amount of a type of innate immune cells called non-classical monocytes. These findings are supported by another study that reported worsening health conditions in males due to SARS-CoV-2 infection was related to increased innate immune activation. Although the immune response is intended to fight the infection, over activation of the innate immune response can lead to tissue damage and may be one explanation for why males have worse outcomes than females in COVID-19.
Female patients have a stronger adaptive immune response.
The two major players of the adaptive immune responses are B cells and T cells. B cells make virus-specific antibodies that bind to the virus and prevent the virus from infecting cells. T cells recognize cells that are infected and destroy them to prevent further spread of the virus. T cells also help B cells make more antibodies and strengthen the immune response.
From the same Yale study, researchers found no difference in the amount of antibodies against SARS-CoV-2 between male and female COVID-19 hospitalized patients. However, female patients had a higher amount of fully activated T cells than males. This means that female patients are better able to control the infection through their T cells, and the weaker T cell response in males may be another reason for worse outcomes with COVID-19.
Kynurenic acid levels correlate with deteriorating disease in males.
The metabolism regulates the immune system through metabolites, which are small molecules that are produced through chemical reactions in the body. A study published in July 2021 found that a higher amount of a key metabolite called kynurenic acid (KA) produced from kynurenine was related to higher innate immune responses in both female and male COVID-19 patients, but this association was more pronounced in males. Male patients with worse COVID-19 had a higher ratio of kynurenic acid to kynurenine (KA:K), which also seemed to predict higher innate immune responses and lower amounts of activated T cells. A higher Body Mass Index and increased age were associated with worsening disease in male COVID-19 patients. Overall, the metabolic status of individuals seems to contribute to disease outcomes, where certain amounts of KA predicted over activation of the innate immune response and worse disease in males.
Different levels of sex hormones in COVID-19 patients.
Estradiol and estrone are major and minor female sex hormones, and testosterone is a major male sex hormone. Sex hormones can affect many aspects of the immune system and are important to consider. A preprint article, that has not yet been peer-reviewed, reported that both male and female COVID-19 patients have higher levels of estradiol and estrone compared to healthy individuals. However, only male COVID-19 patients had decreased testosterone levels. Whether lower testosterone levels in male patients results in worse disease is not known, but it will be an important factor to monitor moving forward.
A wide range of disease outcomes have been observed in COVID-19 including a major difference between males and females. These studies highlight key sex differences in SARS-CoV-2 infection that affect severity of COVID-19 including differences in the coordination between the innate and adaptive immune response, metabolism and potentially, sex hormones. These differences between sexes may be important factors that explain why fewer females have died from COVID-19 than males.
“Worldometer Coronavirus Death Toll.” Worldometer, 2020, https://www.worldometers.info/coronavirus/coronavirus-death-toll/. (Accessed 1 August 2021).
Takahashi, Takehiro et al. “Sex differences in immune responses that underlie COVID-19 disease outcomes.” Nature. 2020 Dec;588(7837):315-320.
Petrey, Aaron C, et al. “Summary of Cytokine release syndrome in COVID-19: Innate immune, vascular, and platelet pathogenic factors differ in severity of disease and sex.” J Leukoc Biol. 2021 Jan;109(1):55-56.
Cai, Yuping, et al. “Kynurenic acid may underlie sex-specific immune responses to COVID-19.” Sci Signal. 2021 Jul 6;14(690):eabf8483.
Schroeder, Maria, et al. “Sex hormone and metabolic dysregulation are associated with critical illness in male Covid-19 patients.” MedRxiv, 2020, https://www.medrxiv.org/content/10.1101/2020.05.07.20073817. (Accessed September 2021).