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

Randy M Stalter; Vidya Atluri; Fan Xia; Katherine K Thomas; Kristine F Lan; Alexander L Greninger; Rena C Patel

doi:10.2147/CLEP.S335494

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

Clin Epidemiol. 2022 Jan 25:14:115-125. doi: 10.2147/CLEP.S335494. eCollection 2022.

Authors

Randy M Stalter¹, Vidya Atluri², Fan Xia¹, Katherine K Thomas³, Kristine F Lan², Alexander L Greninger⁴, Rena C Patel²

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
² Department of Medicine, University of Washington, Seattle, WA, USA.
³ Department of Global Health, University of Washington, Seattle, WA, USA.
⁴ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

Abstract

Purpose: 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.

Grants and funding

K23 AI120855/AI/NIAID NIH HHS/United States