Sex Differences in COVID-19 Outcomes

Men infected with SARS-CoV-2 consistently experience more severe illness, higher intensive treatment unit admissions and greater mortality than women. This disparity reflects a convergence of biological, immunological and hormonal factors as well as social and behavioural determinants. Biologically, differences in innate and adaptive immune responses are evident, with females mounting stronger antiviral defences and more rapid viral clearance. Hormone-driven regulation of receptors such as ACE2 and proteases that facilitate viral entry further modulates susceptibility, while mitochondrial function and oxidative phosphorylation programmes in immune cells exhibit sex-specific patterns that influence disease progression. Pre-existing conditions, notably cardiovascular disease, interact with sex to shape outcomes, yet these interactions cannot fully account for the observed male disadvantage. Recognition of sex as a critical variable has informed risk stratification, guided therapeutic strategies and underscored the need for sex-sensitive analyses in vaccine and drug trials worldwide.

Research from Nature Portfolio

A comprehensive global meta-analysis of over three million COVID-19 cases revealed that male patients have nearly threefold higher odds of requiring intensive treatment and a significantly elevated risk of death compared with female patients. This pattern held across diverse regions, age groups and healthcare settings, underscoring sex as an independent risk factor. The findings have prompted calls to integrate sex-disaggregated data into clinical guidelines and mitigation strategies, ensuring that treatment thresholds and resource allocation account for the heightened vulnerability of men.

Sex Differences in COVID-19 Outcomes publication trend

The graph below shows the total number of articles in sex differences in covid-19 outcomes across all publications each year (not limited to Nature Index journals).

Technical terms

Oxidative phosphorylation (OXPHOS): The mitochondrial process by which cells produce adenosine triphosphate (ATP) through electron transport and proton gradients.

Intensive treatment unit (ITU): A specialised hospital ward providing advanced life support, organ support and close monitoring for critically ill patients.

Angiotensin converting enzyme 2 (ACE2): A cell-surface enzyme and receptor that mediates SARS-CoV-2 entry into host cells, influencing viral infectivity and disease severity.

References

1. The unique interplay of mitochondrial oxidative phosphorylation (OXPHOS) and immunity and its potential implication for the sex‐ and age‐related morbidity of severe COVID‐19 patients. MedComm (2023).
2. Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study. BMJ Medicine (2023).
3. Estrogen-modulating treatment among mid-life women and COVID-19 morbidity and mortality: a multiregister nationwide matched cohort study in Sweden. BMC Medicine (2024).
4. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nature Communications (2020).