Sex-related differences in lung injury distribution and outcomes in COVID-19 acute respiratory failure: insights from the CT-COVID19 multicenter study group

Background: Sex-related differences have been consistently reported in the epidemiology of acute hypoxemic respiratory failure (AHRF) and COVID-19. However, whether computed tomography (CT)-derived measures of lung injury differ between sexes and contribute to outcome disparities remains unclear. Methods: In this large multicenter retrospective cohort study, we analyzed 850 spontaneously breathing patients with COVID-19-related AHRF who underwent early chest CT at hospital admission. Quantitative CT analysis provided measures of lung density, volume, mass, and superimposed pressure (SP), a CT-derived estimate of gravitational stress. Sex-stratified analyses compared morphological, physiological, and outcome variables. Multivariable logistic regression models identified independent predictors of mortality. Results: Among 850 patients (35% women), men exhibited larger lung volume (2.91 vs. 2.28 L, p < 0.001), greater lung mass (1.14 vs. 0.93 kg, p < 0.001), and higher SP (5.79 vs. 5.21 cmH₂O, p < 0.001) despite similar fractions of ground-glass opacities and consolidation. In the multivariable model, older age (OR 1.08, 95% CI 1.06-1.11; p < 0.001), lower PaO2/FiO2 (OR 0.99, 95% CI 0.98-0.99; p < 0.001), higher SOFA score (OR 2.67, 95% CI 1.43-4.98; p = 0.002 for SOFA ≥ 2), higher global SP (OR 1.18, 95% CI 1.05-1.34; p = 0.005), and male sex (OR 1.76, 95% CI 1.06-2.92; p = 0.028) were independently associated with an increased risk of mortality. In the mediation analysis, the effect of global SP on mortality does not appear to be mediated by male sex (coefficient 0.00). Conclusions: Male patients with COVID-19-related AHRF exhibited higher global SP than females, reflecting greater gravitational lung load and mechanical disadvantage. Both global SP and male sex were independently associated with mortality, with no evidence of mediation of male sex on mortality. These finding suggest that, beyond anatomical and mechanical differences, biological and hormonal factors likely contribute to the increased disease severity observed in men.