Molecular Mechanisms Lead to Sex-Specific COVID-19 Prognosis and Targeted Therapies.

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.

Biopsychosocial and Spiritual Implications of Patients With COVID-19 Dying in Isolation.

Critically ill patients with the Coronavirus disease 2019 (COVID-19) are dying in isolation without the comfort of their family or other social support in unprecedented numbers. Recently, healthcare teams at COVID-19 epicenters have been inundated with critically ill patients. Patients isolated for COVID-19 have had no contact with their family or loved ones and may have likely experienced death without closure. This situation highlights concerns about patients' psychological and spiritual well-being with COVID-19 and their families, as they permanently part ways. While palliative care has advanced to adequately address these patients' needs, the COVID-19 pandemic presents several barriers that force healthcare teams to deprioritize these essential aspects of patient care. The severe acute respiratory syndrome (SARS) outbreak in 2003 gave us a glimpse of these challenges as these patients were also isolated in hospitals. Here, we discuss the importance of the biopsychosocial spiritual model in end-of-life care and its implications on patients dying with COVID-19. Furthermore, we outline an integrative approach to address the unique and holistic needs of critically ill patients dying with COVID-19. These include intentional and increased coordination with trained palliative care staff, early and frequent goals of care including discussion of end-of-life plans, broader use of technology to improve connectedness, and shared decision making with patients' families.

Early COVID-19 Interventions Failed to Replicate 1918 St. Louis vs. Philadelphia Outcomes in the United States.

The Coronavirus disease 2019 (COVID-19) pandemic has elicited an abrupt pause in the United States in multiple sectors of commerce and social activity. As the US faces this health crisis, the magnitude and rigor of their initial public health response was unprecedented. As a response, the entire nation shutdown at the state-level for the duration of a ~1-3 months. These public health interventions, however, were not arbitrarily decided, but rather, implemented as a result of evidence-based practices. These practices were a result of lessons learned during the 1918 influenza pandemic and the city-level non-pharmaceutical interventions (NPIs) taken across the US. During the 1918 pandemic, two model cities, St. Louis, MO, and Philadelphia, PA, carried out two different approaches to address the spreading disease, which resulted in two distinctly different outcomes. Our group has evaluated the state-level public health response adopted by states across the US, with a focus on New York, California, Florida, and Texas, and compared the effectiveness of reducing the spread of COVID-19. Our assessments show that while the states mentioned above benefited from the implementations of early preventative measures, they inadequately replicated the desired outcomes observed in St. Louis during the 1918 crisis. Our study indicates that there are other factors, including health disparities that may influence the effectiveness of public health interventions applied. Identifying more specific health determinants may help implement targeted interventions aimed at preventing the spread of COVID-19 and improving health equity.

Systematic Review and Meta-Analysis of Sex-Specific COVID-19 Clinical Outcomes.

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.