Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities

Abstract

The high mortality rate of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is a critical concern of the Coronavirus Disease 2019 (COVID-19) pandemic. Strikingly, men account for the majority of COVID-19 deaths, with current figures ranging from 59–75% of total mortality. However, despite clear implications in relation to COVID-19 mortality, most research has not considered sex as a critical factor in data analysis. Here, we highlight fundamental biological differences that exist between males and females, and how these may make significant contributions to the male-biased COVID-19 mortality. We present preclinical evidence identifying the influence of biological sex on the expression and regulation of angiotensin-converting enzyme 2 (ACE2), which is the main receptor used by SARS-CoV-2 to enter cells. However, we note that there is a lack of reports showing that sexual dimorphism of ACE2 expression exists and is of functional relevance in humans. In contrast, there is strong evidence, especially in the context of viral infections, that sexual dimorphism plays a central role in the genetic and hormonal regulation of immune responses, both of the innate as well as the adaptive immune system. We review evidence supporting that ineffective anti-SARS-CoV-2 responses, coupled with a predisposition for inappropriate hyperinflammatory responses, could provide a biological explanation for the male bias in COVID-19 mortality. A prominent finding in COVID-19 is the increased risk of death with pre-existing cardiovascular comorbidities such as hypertension, obesity and age. We contextualise how important features of sexual dimorphism and inflammation in COVID-19 may exhibit a reciprocal relationship with comorbidities, and explain their increased mortality risk. Ultimately, we demonstrate that biological sex is a fundamental variable of critical relevance to our mechanistic understanding of SARS-CoV-2 infection and the pursuit of effective COVID-19 preventative and therapeutic strategies.

Hypertension, a Moving Target in COVID-19

“…Of interest, in addition to trajectories over the life course for BP, 81 aging might thus also differentially affect the immunoinflammation status in patients with hypertension. In this regard, as recently indicated, 82 a sexual dimorphism affecting both the innate and adaptive immune system could contribute to the higher mortality risk of male patients 4 in COVID-19, particularly in the context of hypertension with inherent dysregulated immunoinflammation.…”

A Novel Soluble ACE2 Variant with Prolonged Duration of Action Neutralizes SARS-CoV-2 Infection in Human Kidney Organoids

“…The kidney organoids we used were of female origin, and ideally, one should examine this model originating from both sexes to consider that ACE2 is on the X chromosome and that in clinical studies, men appear more susceptible for severe COVID-19. 35 Studies in adult organoids, moreover, would also be important to better replicate the mature human kidney. Therefore, it would be important to test ACE2 treatment and SARS-CoV-2 in three-dimensional kidney spheroids/organoids of adult origin harboring mature phenotypes.…”

COVID-19: Molecular and Cellular Response

“…It is suggested that the different mortality rates in COVID-19 patients is due to the difference in the response to infection ( Bienvenu et al., 2020 ). Analysis of viral RNA in COVID-19 patients indicated that the males show delayed viral clearance ( Xu K. et al., 2020 ; Zheng S. et al., 2020 ).…”