{"doi":"10.2147/clep.s335494","title":"Elucidating Pathways Mediating the Relationship Between Male Sex and COVID-19 Severity","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.","journal":"Clinical Epidemiology","year":2022,"id":283107,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.5851,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":881120,"name":"Vidya Atluri","orcid":"0000-0002-4830-0569","position":1,"is_corresponding":false},{"id":559001,"name":"Fan Xia","orcid":"0000-0001-7705-4638","position":2,"is_corresponding":false},{"id":959961,"name":"Katherine K Thomas","orcid":null,"position":3,"is_corresponding":false},{"id":959962,"name":"Kristine F Lan","orcid":null,"position":4,"is_corresponding":false},{"id":959963,"name":"Alexander L Greninger","orcid":null,"position":5,"is_corresponding":false},{"id":404274,"name":"Rena C. Patel","orcid":"0000-0001-9893-5856","position":6,"is_corresponding":false},{"id":959960,"name":"Randy M Stalter","orcid":null,"position":0,"is_corresponding":true}],"reference_count":24,"raw_metadata":null,"created_at":"2026-07-19T00:29:23.777809Z","pmid":"35115840","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}