Evaluating factors mediating the relationship between male sex and COVID-19 severity

Background: Males have experienced higher rates of severe COVID-19 outcomes compared to females but the underlying causal mechanisms of this relationship are not well understood. We leveraged existing electronic medical records (EMR) to evaluate associations between sex and COVID-19 test positivity, disease severity, viral burden, and death, and assess factors that mediate the relationship between male sex and severe COVID-19 disease. Methods: We conducted a retrospective cohort study with data collected from University of Washington Medicine EMR from March 1 to September 29, 2020. All persons, regardless of age, were included if they had a conclusive diagnostic COVID-19 PCR test result. We defined severe COVID-19 disease as a score >5 on the WHO clinical progression scale. We used Poisson regression to assess sex differences in risk for COVID-19 test positivity, disease severity and COVID-19 related death, and linear regression to compare viral cycle threshold at the first positive test. We conducted mediation analyses to assess interventional indirect effects of male sex on severe COVID-19 risk through socioeconomic status (SES, based on area deprivation and insurance type), comorbidities, and inflammation status. Models controlled for age and race/ethnicity. Results: Of individuals with SARS-CoV-2 testing records, 32,919 males and 34,733 females had a conclusive PCR test during our observation period. Males were 13% more likely to test positive than females in multivariable analysis (RR=1.13;95% CI: 1.04-1.24;Table). Males had 85% higher risk for severe COVID-19 disease (RR=1.85;95% CI: 1.33-2.62) and 66% higher risk for COVID-19 related death (RR=1.66;95% CI: 0.95-2.98) than females following a positive test result. No difference was observed in cycle threshold at first positive test between males and females (p=0.69). Mediation analyses indicated a significant interventional indirect effect of male sex on severe COVID-19 disease through inflammation status (RR=1.07;95% CI: 1.01-1.13), and less so through SES or comorbidities. Conclusion: In our cohort, males had higher test positivity and greater risk of COVID-19 severity and death. This relationship between male sex and severe COVID-19 seems to act in part through inflammation status. Additional analyses in larger cohorts are needed to better understand the full range of socio-behavioral and biologic factors that mediate the relationship between sex and poor COVID-19 outcomes. (Figure Presented).