Researchers Dr. Aditi Bhargava from the University of California, San Francisco, and Johannes Knapp from Aseesa Inc. have revealed important insights into how biological sex is an important variable in regulating the immune system’s reaction to SARS-CoV-2, causing differencences in COVID-19 disease severity. Their study, published in the journal Cells, reanalyzed data from early COVID-19 patients to understand the factors that contribute to how severe the disease becomes, particularly focusing on how the immune system sometimes misfires and how differences between men and women impact disease outcomes.

Back in 2020, as the world faced the immense challenges posed by COVID-19, it became evident that the virus didn’t affect everyone in the same way. Among the many factors influencing how sick people got, sex differences stood out, with men often experiencing worse outcomes than women. Dr. Bhargava and Knapp’s study explores these differences by examining immune responses in patients who were hospitalized with a subset admitted to intensive care units (ICU) due to COVID-19. Their findings could lead to better ways to treat and manage the disease.

The study, published in Cells, highlights the crucial role of a hyperactive immune response known as the cytokine storm in severely ill COVID-19 patients. The researchers found that men in the ICU showed more significant changes in their immune system and overall health than women, with a noticeable portion of the factors they analyzed showing clear differences between the sexes. One of the most striking findings was the higher levels of certain immune cells, like granzyme-B-producing GzB+CD8+ T cells, CD8Temra, and a subset of cytokines such as interferon-γ (IFN-γ), interleukin-2 (IL-2), and IL-1α in patients who did not survive. These immune cell numbers and cytokine levels were less prominent in those who recovered. This difference was especially noticeable when comparing men and women, highlighting the complex interactions between biological sex, immune response, and how severe the disease outcomes are.

Dr. Bhargava noted, “Our analysis shows just how important biological sex is in shaping the immune response to COVID-19, especially in severe cases that require intensive care. Understanding these differences is key to developing more effective treatments and/or care tailored to men and women.”

Moreover, the study found that obesity was the most significant risk factor leading to COVID-19-related deaths, even more than other pre-existing conditions such as immunosuppression, chronic heart or lung diseases. Obese patients had the worst outcomes, which the researchers believe may be due to a more intense inflammatory response in these individuals. Despite the early use of treatments like hydroxychloroquine, remdesivir, and tocilizumab, these therapies didn’t effectively reduce the levels of IL-6, a key protein involved in the severe immune reaction known as the cytokine storm in COVID-19 patients.

The researchers also compared the immune profiles of COVID-19 patients in ICU and hospitalized non-ICU patients and found that those in the ICU had significantly less numbers of several different subtypes of immune cells compared to those not in intensive care. This included a significant decrease in certain types of T cells and increases in proteins like IL-6 and vascular endothelial growth factor A, which points to a much more dysregulated immune and microvascular systems in critically ill patients. However, the study also found that some treatments, particularly corticosteroids, didn’t significantly change these immune responses in the critically ill, suggesting that different treatment approaches might be needed.

Dr. Bhargava and Knapp’s work is a call to action for the scientific community to pay more attention to sex differences in clinical research, especially in diseases like COVID-19, where the immune system plays a crucial role in how patients fare. As Dr. Bhargava commented, “By recognizing and understanding these differences, we can better tailor treatments and possibly improve outcomes for everyone, regardless of biological sex.” Gender differences could not be studied as the pre-collected data by the Yale IMPACT study did not specify gender. Gender and biological sex are not the same and should not be conflated.

This study is a significant step forward in our understanding of COVID-19 and highlights the importance of integrated analysis in understanding and treating complex diseases.

Journal Reference

Bhargava, A., & Knapp, J. D. (2023). “Immunological Misfiring and Sex Differences: Similarities in Early COVID-19 Studies Missed Opportunities of Making a Real IMPACT.” Cells, 12(22), 2591. https://doi.org/10.3390/cells12222591

Other Reference

Lucas, C.; Wong, P.; Klein, J.; Castro, T.B.R.; Silva, J.; Sundaram, M.; Ellingson, M.K.; Mao, T.; Oh, J.E.; Israelow, B.; et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 2020, 584, 463–469. 

Takahashi, T.; Ellingson, M.K.; Wong, P.; Israelow, B.; Lucas, C.; Klein, J.; Silva, J.; Mao, T.; Oh, J.E.; Tokuyama, M.; et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature 2020, 588, 315–320

Bhargava, A.; Arnold, A.P.; Bangasser, D.A.; Denton, K.M.; Gupta, A.; Hilliard Krause, L.M.; Mayer, E.A.; McCarthy, M.; Miller, W.L.; Raznahan, A.; et al. Considering Sex as a Biological Variable in Basic and Clinical Studies: An Endocrine Society Scientific Statement. Endocr. Rev.2021, 42, 219–258.

About the Author

Dr. Bhargava is a molecular neuroendocrinologist with expertise in studying sex differences in (patho)physiology of stress at molecular/cellular to physiological levels. She is Professor Emerita at the Center for Reproductive Sciences, Department of Obstetrics and Gynecology at the University of California San Francisco. She founded Aseesa Inc with the vision to unravel data from complex biological systems to generate integrated and precise information that is foundational. Aseesa provides the scientific community with enterprise-grade analysis tools in an interface that rivals the best consumer-oriented apps and doesn’t require any programming knowledge. Dr. Bhargava has published over 70 peer-reviewed papers and four book chapters to her credit.