ABSTRACT
Clinical and epidemiological studies have identified male sex as an important risk factor for COVID-19 clinical outcomes and mortality. This raises the question as to how this risk factor can be addressed in the prognosis, clinical management, and the treatment of patients with Coronavirus disease 2019 (COVID-19). Currently, there are no guidelines or protocols to help alter the course of sex-specific COVID-19 prognosis, especially in severe disease presentations. This is partly due to the lack of research studies characterizing the differences in male vs. female host response to the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and a lack of a well-rounded understanding of the molecular mechanisms involved. Here, we discuss three distinct but interconnected molecular-level differences in males and females that likely play an essential role in the COVID-19 prognosis. We review interactions of SARS-CoV-2 with host cell angiotensin-converting enzyme 2 (ACE2) in the viral entry between males vs. females and discuss the differential regulation of the renin-angiotensin system (RAS) between the two sexes. Next, we present immune response disparities and how immune function and endocrine regulation may render males increasingly vulnerable to severe COVID-19. We describe the interconnected roles of these three regulatory systems in males and females in response to SARS-CoV-2 infection. Finally, we highlight the clinical implications of these mechanisms to patients with COVID-19 and propose putative targeted therapies that can help reduce COVID-19 severity in those critically ill.
ABSTRACT
To successfully mitigate the extraordinary devastation caused by the Coronavirus disease 2019 (COVID-19) pandemic, it is crucial to identify important risk factors for this disease. One such neglected health determinant is the sex of the patient. This is an essential clinical characteristic, as it can factor into a patient's clinical management and preventative measures. Some clinical studies have shown disparities in the proportion between males and females that have more severe clinical outcomes or, subsequently, die from this disease. However, this association has not been unequivocally established. Thus, the purpose of this investigation was to examine the association between male sex and COVID-19 severity. We systematically reviewed the literature, identified studies that matched predetermined selection criteria, and performed a meta-analysis to evaluate the proportion of males among four disease severity categories. Appropriate assessment strategies were implemented to assess and minimize potential biases. The results of this meta-analysis indicated that males constituted a significantly higher proportion of those who had adverse clinical outcomes and died from COVID-19. As the coronavirus spread from the East to the West, male sex remained a consistent risk factor. Our results support the establishment of the male sex as an important risk factor for this disease. Early identification and appropriate medical care for males with lab-confirmed COVID-19 may substantially change the course of clinical prognosis, resulting in greater numbers of lives saved.