Enduring insights from sex differences in COVID-19: a retrospective post hoc analysis from a large Italian patient cohort

Background: In the early phase of the coronavirus disease 2019 (COVID-19) pandemic, before containment strategies and without vaccines or targeted therapies, clinical outcomes among hospitalized patients were heterogeneous. Preliminary reports suggested possible sex-related differences in susceptibility and disease severity. This study examined sex-based differences in clinical presentation, radiological involvement, laboratory findings, and in-hospital outcomes among patients admitted during the pre-lockdown phase of the outbreak in Italy. Methods: We conducted a retrospective observational study of 689 consecutive adults hospitalized at Parma University Hospital between 28 February and 22 March 2020, with chest CT findings consistent with COVID-19–related interstitial pneumonia, regardless of RT-PCR results. Demographics, comorbidities, symptoms, laboratory parameters, and outcomes were compared between males and females. Lung involvement was quantified using a CT visual score. Multivariable logistic regression identified predictors of in-hospital mortality. Results: Females accounted for 39% of the cohort and were significantly older and frailer than males, with a higher prevalence of Rockwood ≥7 (15 vs. 5%). Despite this, females demonstrated a lower CT visual score (25 vs. 30%), higher oxygenation parameters, and a less pronounced inflammatory and tissue-damage profile, including lower CRP, LDH, and CPK. Females had shorter hospital stays (5 vs. 6 days) and lower age-adjusted mortality. Multivariable analysis confirmed female sex as independently protective (OR 0.597), an effect largely mediated by reduced radiological lung involvement and attenuated inflammatory response. Conclusions: Females showed milder radiological and biochemical profiles and reduced mortality despite being older and frailer. These findings highlight intrinsic sex-related biological differences in host response. These early patterns remain relevant today, as sex-specific vulnerability may inform precision medicine and risk stratification.