A study of sex-based differences in the risk of COVID-19 pneumonia finds that men were more likely to develop the complication than women (12.0% vs 7.0%) during the declared pandemic period and the early months of the endemic phase of the disease in Mexico.
Published in Scientific Reports, the study is based on national COVID-19 epidemiologic surveillance data on more than 1.6 million adult COVID-19 patients analyzed by Instituto Mexicano del Seguro Social–led researchers from February 2020 to August 2023. Of all patients, 53.7% were women, and the average age was 43.6 years.
"Pneumonia is a common and severe complication of COVID-19, often requiring hospitalization and intensive medical care," the researchers wrote, noting that men are at increased risk for severe COVID-19. "Accurate risk assessment for pneumonia development in COVID-19 cases is relevant for clinical decision-making and resource allocation and provides valuable insights into the changing dynamics of the disease."
Men at 3.3% higher risk
The risk of pneumonia was 9.3% (95% confidence interval [CI], 9.2% to 9.4%) overall, 7.0% (95% CI, 6.9% to 7.1%) for women, and 12.0% (95% CI, 11.9% to 12.1%) for men. This sex-based disparity was consistently seen throughout all phases of the pandemic, including the endemic phase.
After adjusting for age, primary viral genotype at symptom onset, and underlying medical conditions, men were at a 3.3% higher risk for pneumonia than were women (risk ratio [RR], 1.033; 95% CI, 1.032 to 1.034).
By predominant SARS-CoV-2 variant, the risk of pneumonia was highest with the wild-type virus (21.9%), followed by Delta B.1.617.2 (16.0%), B.1.1.519 (12.7%), and Omicron B.1.1.529 (2.5%), BQ1 (2.2%), and XBB.1.5 (2.0%). Among characteristics associated with more severe COVID-19, the presence of chronic kidney disease was associated with the highest increase in the risk of pneumonia (RR, 1.166).
Role of estrogen, X chromosome
Sex-based disparities in COVID-19 severity appear to be influenced by a complex interaction of genetic, hormonal, immunologic, and other factors, the researchers noted.
Estrogens, which are predominantly present in women, have been linked to an array of immunoprotective effects.
"Estrogens, which are predominantly present in women, have been linked to an array of immunoprotective effects," they wrote. "These hormones can stimulate both innate and adaptive immune responses, augmenting the production of antiviral interferons and cytokines."
"Conversely, men, who have lower estrogen levels but higher levels of testosterone, might experience a comparatively subdued immune response, potentially reducing the strength of their defense against the virus," they added.
Women's generally more vigorous immune responses, potentially also influenced by the presence of the X chromosome and different expression levels of angiotensin-converting enzyme 2 (ACE2), may help them eliminate pathogens more efficiently than men but can also raise their risk of the cytokine storm implicated in severe COVID-19, the researchers said.
The study results may help inform healthcare planning and the development of policies aimed at reducing the effects of COVID-19 on vulnerable groups: "Public health campaigns and educational resources should be designed to raise awareness of this heightened risk among men and individuals with comorbid conditions, encouraging them to seek healthcare promptly if they exhibit COVID-19 symptoms."
"Policies promoting high vaccination coverage and timely booster shots for all individuals, regardless of patients’ sex, remain essential," they concluded. "Lastly, the finding that chronic kidney disease is a significant risk factor for pneumonia in COVID-19 patients highlights the necessity for integrated healthcare management."
