Clinical Epidemiology (Jan 2022)

Elucidating Pathways Mediating the Relationship Between Male Sex and COVID-19 Severity

  • Stalter RM,
  • Atluri V,
  • Xia F,
  • Thomas KK,
  • Lan KF,
  • Greninger AL,
  • Patel RC

Journal volume & issue
Vol. Volume 14
pp. 115 – 125

Abstract

Read online

Randy M Stalter,1 Vidya Atluri,2 Fan Xia,1 Katherine K Thomas,3 Kristine F Lan,2 Alexander L Greninger,4 Rena C Patel2 1Department of Epidemiology, University of Washington, Seattle, WA, USA; 2Department of Medicine, University of Washington, Seattle, WA, USA; 3Department of Global Health, University of Washington, Seattle, WA, USA; 4Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USACorrespondence: Randy M StalterDepartment of Epidemiology, University of Washington, UW Box 359927 325 Ninth Avenue, Seattle, WA, 98104, USA, Tel +1-412-760-8134, Email [email protected]: To examine associations between male sex and SARS-CoV-2 test positivity, severe COVID-19 disease, and death in a single-site cohort, and assess whether male sex impacts risk for severe COVID-19 disease through socioeconomic status (SES), comorbidities, or inflammation.Materials and 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. Our exposure was sex assigned at birth. We used Poisson regression to assess associations between sex and 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 32,919 males and 34,733 females included, 1469 (4.5%) and 1372 (4.0%) tested positive for SARS-CoV-2, respectively. Males were 14% more likely to test positive (RR = 1.14; 95% CI: 1.06– 1.23), had 80% higher risk for severe COVID-19 disease (RR = 1.80; 95% CI: 1.39– 2.33) and had 58% higher risk for death (RR = 1.58; 95% CI: 1.10– 2.26) compared to females after adjusting for age and race/ethnicity. Mediation analyses indicated non-significant interventional indirect effects of male sex on severe COVID-19 disease through elevated inflammatory markers, SES and comorbidities, but the greatest effect was through the inflammation pathway.Conclusion: Males appear to be at higher risk at all steps of the continuum of COVID-19 illness. The strongest mediating signal, albeit non-significant, is with inflammatory pathways. Further elucidation of causal pathways linking sex and COVID-19 severity is needed in larger cohorts.Keywords: SARS-CoV-2, disease severity, mediation, sex-based differences

Keywords