Sex and Gender Differences in Testing, Hospital Admission, Clinical Presentation, and Drivers of Severe Outcomes From COVID-19
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Abstract
Background: Males experience increased severity of illness and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with females, but the mechanisms of male susceptibility are unclear. Methods: We performed a retrospective cohort analysis of SARS-CoV-2 testing and admission data at 5 hospitals in the Maryland/Washington DC area. Using age-stratified logistic regression models, we quantified the impact of male sex on the risk of the composite outcome of severe disease or death (World Health Organization score 5–8) and tested the impact of demographics, comorbidities, health behaviors, and laboratory inflammatory markers on the sex effect. Results: Among 213 175 SARS-CoV-2 tests, despite similar positivity rates, males in age strata between 18 and 74 years were more frequently hospitalized. For the 2626 hospitalized individuals, clinical inflammatory markers (interleukin-6, C-reactive protein, ferritin, absolute lymphocyte count, and neutrophil:lymphocyte ratio) were more favorable for females than males (P < .001). Among 18–49-year-olds, male sex carried a higher risk of severe outcomes, both early (odds ratio [OR], 3.01; 95% CI, 1.75 to 5.18) and at peak illness during hospitalization (OR, 2.58; 95% CI, 1.78 to 3.74). Despite multiple differences in demographics, presentation features, comorbidities, and health behaviors, these variables did not change the association of male sex with severe disease. Only clinical inflammatory marker values modified the sex effect, reducing the OR for severe outcomes in males aged 18–49 years to 1.81 (95% CI, 1.00 to 3.26) early and 1.39 (95% CI, 0.93 to 2.08) at peak illness. Conclusions: Higher inflammatory laboratory test values were associated with increased risk of severe coronavirus disease 2019 for males. A sex-specific inflammatory response to SARS-CoV-2 infection may underlie the sex differences in outcomes.
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Most studies of COVID-19 report a male dominance of around 60% men to 40% women.
“Most studies of COVID-19 report a male dominance of around 60% men to 40% women. 12,13”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [13]
The introduction (p. 1) says surveillance and meta-analyses of more than 3 million cases found a similar proportion of COVID-19 cases in males and females, contrary to a general 60%–40% male dominance. It reports male excess specifically for hospitalization, ICU admission, and mortality, not for cases overall. (LLM, conf=0.85)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredCOVID-19 occurs predominantly in men, which may be explained at least in part by a higher expression of ACE2 on male versus female cells.
“COVID-19 occurs predominantly in men, 11-13 which may be explained, at least in part, by a higher expression of ACE2 on male versus female cells.”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [13]
The citation is attached to the claim that COVID-19 occurs predominantly in men. The Introduction (p. 1) says surveillance and meta-analyses found a similar proportion of cases in males and females; it distinguishes this from the higher rates of hospitalization, ICU admission, and mortality in males. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredTwo large studies detected no sex difference in PCR positivity for SARS-CoV-2, although men had higher rates of hospitalization, ICU admission, and mortality.
“Two large studies of 3 000 000 and 200 000 patients, respectively, detected no sex difference in whether patients tested PCR positive for SARS-CoV-2, although men had higher rates of hospitalization, intensive care unit admission, and mortality. 13,119”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [13]
The Results (p. 1) report 213,175 tests, similar overall positivity, and more frequent hospitalization among males aged 18–74; the introduction (p. 1) also reports higher male ICU admission and mortality. But “no sex difference” in PCR positivity is too broad: SARS-CoV-2 Testing and Demographics (p. 3) says positivity was higher among males aged 18–74, while comparable positivity in the Discussion (p. 7) concerns asymptomatic testing. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMen have more neutrophils and monocytes, whereas women have more T cells, similar to autoimmune myocarditis.
“And men have more neutrophils and monocytes, whereas women have more T cells, 13,121-123 similar to autoimmune myocarditis. 124,125”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [13]
The Laboratory Measures section (p. 4) reports higher neutrophil-to-lymphocyte ratios and lower absolute lymphocyte counts in hospitalized males, but does not establish that men had more neutrophils or monocytes, or that women had more T cells. The introduction (p. 1) reports more durable T-cell responses in females, which is different from a higher T-cell count. The autoimmune-myocarditis comparison is attached to separate citations in the citing sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredProinflammatory cytokines and cardiac biomarkers are elevated in men with COVID-19 compared with women, including ferritin, CRP, IL-6, IL-8, and IL-18.
“Proinflammatory cytokines and cardiac biomarkers have been reported to be elevated in men with COVID-19 compared with women including ferritin, CRP (C-reactive protein), IL-6, IL-8, and IL-18. 13,121-123”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [13]
The Laboratory Measures section (p. 4) reports higher ferritin, IL-6, and CRP levels in hospitalized males than females. It does not report higher IL-8, IL-18, or cardiac biomarkers; the listed laboratory measures (p. 2) do not include them. (LLM, conf=0.89)
Experimental — accuracy not yet measured
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- Authors
- Scully, E. P., Schumock, G., Fu, M., Massaccesi, G., Muschelli, J., Betz, J., Klein, E. Y., West, N. E., Robinson, M., Garibaldi, B. T., Bandeen-Roche, K., Zeger, S., Klein, S. L., & Gupta, A.
- Affiliations
- Johns Hopkins University (US)
- Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Corresponding author
- Scully, Eileen P
- Klein, Sabra L
- Gupta, Amita
- ORCID
- Venue
- Open Forum Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-08-31
- Volume
- 8
- Issue
- 9
- Pages
- ofab448-ofab448
- ISSN
- 2328-8957 (ISSN-L)
- PMC
- PMC8465334
- OpenAlex
- W3197904967
- Cited by
- 73
- References
- 59
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 11 · 2023: 17 · 2022: 22 · 2021: 7
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Open Forum Infectious Diseases (publishedVersion, cc-by-nc-nd)
- medRxiv (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- ImmPort
- Funders
- National Institutes of Health
- National Cancer Institute
- COVID-19 Serology Center of Excellence (U54CA260492, R01AI154541)
- National Institute of Allergy and Infectious Diseases (UM1AI069645)
- Office for Research on Women’s Health
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Keywords
- COVID-19 pandemic, SARS-CoV-2, sex differences, male sex, mortality, inflammatory markers, C-reactive protein, interleukin-6, ferritin, neutrophil-to-lymphocyte ratio, hospitalization, clinical features, comorbidities, health behavior, young adults
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