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.