Background. Rates of severe illness and mortality from SARS-CoV-2 are greater for males, but the mechanisms for this difference are unclear. Understanding the differences in outcomes between males and females across the age spectrum will guide both public health and biomedical interventions. Methods. Retrospective cohort analysis of SARS-CoV-2 testing and admission data in a health system. Patient-level data were assessed with descriptive statistics and logistic regression modeling was used to identify features associated with increased male risk of severe outcomes. Results. In 213,175 SARS-CoV-2 tests, despite similar positivity rates (8.2%F vs 8.9%M), males were more frequently hospitalized (28%F vs 33%M). Of 2,626 hospitalized individuals, females had less severe presenting respiratory parameters and males had more fever. Comorbidity burden was similar, but with differences in specific conditions. Medications relevant for SARS-CoV-2 were used at similar frequency except tocilizumab (M>F). Males had higher inflammatory lab values. In a logistic regression model, male sex was associated with a higher risk of severe outcomes at 24 hours (odds ratio (OR) 3.01, 95%CI 1.75, 5.18) and at peak status (OR 2.58, 95%CI 1.78,3.74) among 18-49 year-olds. Block-wise addition of potential explanatory variables demonstrated that only the inflammatory labs substantially modified the OR associated with male sex across all ages. Conclusion. Higher levels of clinical inflammatory labs are the only features that are associated with the heightened risk of severe outcomes and death for males in COVID-19.

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We read with interest the recently published clinical report by Baraka et al. (1). Although we were fascinated by their observation, we are disturbed by a potentially serious flaw in the deduction of their final conclusion. Without properly addressing certain physiologic variables (as discussed in the following paragraphs), the conclusion that "(less pulmonary shunt is) . . . attributed to an exaggerated HPV response in these patients" is simply inadequate.When a patient is placed in the lateral decubitus position, the three zones of pulmonary blood flow distribution, as dictated by gravity, are determined by pulmonary arterial pressure (2). In zone 3, with both transmural pulmonary arterial pressure and transmural pulmonary venous pressure higher than the alveolar pressure, the lung units receive the most pulmonary blood flow. On the other hand, in zone 1, where alveolar pressure is higher than both transmural pulmonary arterial pressure and transmural pulmonary venous pressure, the lung units receive the least blood flow (3). The dependent lung, with most of its units situated in zone 3, will receive more pulmonary blood flow than the nondependent lung, which has most of the units situated in zone 1. Decreasing the pulmonary arterial pressure will cause expansion of zone 1 and contraction of zone 3. Pulmonary arterial pressure must be controlled when evaluating hypoxic pulmonary vasoconstriction.The cardiac catheterization measurement of patient 1 revealed a right ventricular pressure of 3 5 D 1 mm Hg with a pulmonary artery pressure of 21/4 mm Hg. Similarly, in patient 2, the catheterization measurement revealed a right ventricular pressure of 50/20 mm Hg and pulmonary arterial pressure of 36/12 mm Hg. In both cases, there existed a 14-mm Hg systolic pressure gradient across the pulmonic valve. Without aortic blood flow through a patent ductus arteriosus, the pressure gradient across the pulmonary valve can only be higher. The existence of this gradient indicated that both patients have subclinical pulmonary valvular stenosis. In otherwise normal patients, the closure of patent ductus arteriosus will cause a decrease in pulmonary arterial pressure. In patients with pulmonary stenosis, the closure of a patent ductus arteriosus could cause an even more significant decrease in pulmonary arterial pressure. In the face of a changing pulmonary arterial pressure, it is unreasonable to assume that the amount of hypoxic pulmonary vasoconstriction can be quantitated with any degree of certainty.In conclusion, as a result of surgical closure of the patent ductus arteriosus, we would expect to see an increased proportion of pulmonary blood flow to the dependent lung. This redistribution of pulmonary blood flow will be even more pronounced in patients with concomitant pulmonary stenosis. The quantitation of hypoxic pulmonary vasoconstriction in this situation is not possible without quantitating the exact change in pulmonary arterial pressure.