Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator

Abstract

Objectives: Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference.

Methods: This was a retrospective, observational cohort study among patients with severe COVID-19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death according to sex. Interaction was formally tested to compare the risk difference by sex in sub-populations. Mediation analysis with a binary endpoint IMV or death (yes/no) by day 28 of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted.

Results: Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO₂/FiO₂ (254 mmHg vs. 191 mmHg; p 0.023). By 28 days from admission, 49.2% (95% CI 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank p < 0.0001) and this amounted to a difference in terms of HR of 0.40 (0.26-0.63, p 0.0001). The area under the curve in C-reactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex.

Discussion: Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. Specifically, CRP showed a predominant role to mediate the difference in risk by sex.

Keywords: COVID-19; COVID-19 pneumonia; Inflammation; Mediation; Prognosis; Sex differences.

Fig. 1

Direct acyclic graph (DAG) of the underlying causal structure of the data.

Fig. 2

(A) HR of invasive mechanical ventilation (IMV)^a/death associated with sex overall and in subsets from fitting a standard unadjusted Cox regression model. ^aDefinition: Indication for IMV were neurologic failure (i.e. altered consciousness with a Glasgow Coma Scale score <10), cardiovascular failure (i.e. vasopressor requirement or major ECG changes including arrhythmia or changes in repolarization phase) and respiratory failure defined by the presence of at least two of the following criteria: respiratory rate >30 bpm, respiratory distress with activation of accessory respiratory muscles, need for FiO₂ at 80% or more to maintain an SaO₂ level at 90%, or a PaO₂/FiO₂ <100 mm [23]. (B) HR of death associated with sex overall and in subsets from fitting a standard unadjusted Cox regression model.

figs1

figs2