Researchers Aditi Bhargava of the University of California, San Francisco, and Johannes Knapp of 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, leading to differences in COVID-19 disease severity. Their study, published in the journal Cells, reanalyzed data from early-stage COVID-19 patients to understand the factors that contribute to disease severity, focusing especially on how the immune system sometimes misfires and how differences between men and women affect disease outcomes.
In 2020, as the world grappled with the immense challenges posed by COVID-19, it became clear that the virus did not affect everyone in the same way. Among the many factors that influence how people get sick, gender differences stood out: Men often experience worse outcomes than women. Dr. Bhargava and Knapp’s study explores these differences by examining immune responses in patients who were hospitalized and a subset of them were admitted to intensive care units (ICUs) 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 an overactive immune response known as a cytokine storm in severe COVID-19 patients. The researchers found that men in the ICU showed more significant changes in their immune system and overall health than women, and a notable portion of the factors they analyzed showed clear differences between the sexes. One of the most striking findings was increased levels of certain immune cells, such as 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 notable when comparing men and women, highlighting the complex interactions between biological sex, immune response, and severity of disease outcomes.
Dr. Bhargava noted: “Our analysis shows how important biological sex is in shaping the immune response to COVID-19, especially in severe cases requiring intensive care. Understanding these differences is key to developing more effective treatments and/or care tailored to men and women.”
Additionally, the study found that obesity was the most significant risk factor leading to COVID-19-related deaths, even more so than other pre-existing conditions such as immunosuppression, chronic heart or lung disease. Obese patients had the worst outcomes, which researchers believe may be due to a more intense inflammatory response in these individuals. Despite the early use of treatments such as hydroxychloroquine, remdesivir, and tocilizumab, these therapies did not effectively reduce levels of IL-6, a key protein involved in the severe immune reaction known as cytokine storm in COVID-19 patients.
The researchers also compared the immune profiles of COVID-19 patients in the ICU and patients hospitalized outside the ICU and found that those in the ICU had significantly lower amounts 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 such as IL-6 and vascular endothelial growth factor A, pointing to a much more dysregulated immune and microvascular system in severely ill patients. However, the study also found that some treatments, particularly corticosteroids, did not significantly change these immune responses in the severely ill, suggesting that different treatment approaches might be needed.
The work of Dr. Bhargava and Knapp is a call to action for the scientific community to pay more attention to gender differences in clinical research, especially in diseases like COVID-19, where the immune system plays a crucial role in patient outcomes. As Dr. Bhargava commented, “By recognizing and understanding these differences, we can better tailor treatments and potentially improve outcomes for everyone, regardless of biological sex.” Gender differences could not be studied because data previously collected by the Yale IMPACT study did not specify gender. Gender and biological sex are not the same and should not be confused.
This study is a significant advance in our understanding of COVID-19 and highlights the importance of integrated analysis to understand and treat complex diseases.
Journal reference
Bhargava, A., & Knapp, J.D. (2023). “Immune failure and gender differences: similarities in early COVID-19 studies that missed opportunities to make a real impact.” Cells, 12(22), 2591. https://doi.org/10.3390/cells12222591
Another reference
Lucas, C.; Wong, P.; Klein, J.; Castro, TBR; Silva, J.; Sundaram, M.; Ellingson, MK; Mao, T.; Oh, JE; Israelow, B.; et al. Longitudinal analyses reveal immune failure in severe COVID-19. Nature 2020, 584463–469.
Takahashi, T.; Ellingson, MK; Wong, P.; Israelow, B.; Lucas, C.; Klein, J.; Silva, J.; Mao, T.; Oh, JE; Tokuyama, M.; et al. Sex differences in immune responses underlying COVID-19 disease outcomes. Nature 2020, 588315–320
Bhargava, A.; Arnold, AP; Bangasser, DA; Denton, KM; Gupta, A.; Hilliard Krause, LM; Mayer, EA; McCarthy, M.; Miller, WL; Raznahan, A.; et al. Consideration of sex as a biological variable in basic and clinical studies: a scientific statement from the Endocrine Society. Endocrinologist Rev.2021, 42219–258.
About the author
Dr. Bhargava Dr. Bhargava is a molecular neuroendocrinologist with expertise in studying sex differences in the (patho)physiology of stress at the molecular/cellular and physiological levels. She is Professor Emeritus at the Center for Reproductive Sciences, Department of Obstetrics and Gynecology at the University of California, San Francisco. She founded Aseesa Inc with a vision to unravel data from complex biological systems to generate integrated and accurate insights that are critical to success. Aseesa provides the scientific community with enterprise-grade analytics tools in an interface that rivals the best consumer-oriented applications and requires no programming knowledge. Dr. Bhargava has published over 70 peer-reviewed articles and four book chapters to her credit.
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