Covid-19 and Gender: Lower Rate but Same Mortality of Severe Disease in Women

An Observational Study

Federico Raimondi; Luca Novelli; Arianna Ghirardi; Filippo Maria Russo; Dario Pellegrini; Roberta Biza; Roberta Trapasso; Lisa Giuliani; Marisa Anelli; Mariangela Amoroso; Chiara Allegri; Gianluca Imeri; Claudia Sanfilippo; Sofia Comandini; England Hila; Leonardo Manesso; Lucia Gandini; Pietro Mandelli; Martina Monti; Mauro Gori; Michele Senni; Ferdinando Luca Lorini; Marco Rizzi; Tiziano Barbuil Laura Paris; Alessandro Rambaldi; Roberto Cosentini; Giulio Guagliumi; Simonetta Cesa; Michele Colledan; Maria Sessa; Arianna Masciulli; Antonello Gavazzi; Sabrina Buoro; Giuseppe Remuzzi; Piero Ruggenenti; Annapaola Callegaro; Andrea Gianatti; Claudio Farina; Antonio Bellasi; Sandro Sironi; Stefano Fagiuoli; Fabiano Di Marco


BMC Pulm Med. 2021;21(96) 

In This Article


The main results from this study, aimed at evaluating the role of gender in Covid-19 hospitalized patients, can be summarized as follows. First, women are less prevalent than men in our setting, representing about a third of hospitalized male population. Second, both 28-day mortality and severe disease occur less frequently in women. Third, different mortality in sex categories cannot be ascribed to age per se. Fourth, once severe disease has occurred, the risk of dying from Covid-19 is not affected by gender.

The importance of the evaluation of sex- and gender-specific effects of Covid-19 has been recently emphasized, with the aim to develop approaches able to address the acute and long-term effect of the disease.[19] Availability and access to health care facilities, especially in low income countries, could be different for women and men.[20] As largely expected, in our cohort, we do not find any significant difference between gender categories in terms of pre hospital antibiotic treatment, home or professional exposure to confirmed Covid-19 cases and interval between symptoms onset and hospital presentation, suggesting an equitable access to healthcare. Our study population mainly consists of male individuals (72.4% vs 27.6%), with a male/female ratio of 2.6:1. Available Covid-19 literature shows variable sex prevalence depending on clinical setting. Epidemiological reports based on notification of infectious disease describe similar prevalence between sex categories.[12,21,22] On the other hand, when considering hospitalized Covid-19 population, a ratio of about 1.5:1 is found.[9,10,23] Moreover, male prevalence increases in ICU setting, ranging from 1.5 to 2.0:1 up to 4:1 in a recent Italian study.[24–26] Taken together, our study and other epidemiological data confirm a more severe disease in males. Furthermore, as a clue of this result, we found an exclusive use of IL-6 inhibitors only in few males with particular compromised clinical condition and relentless deterioration in gas exchanges in spite of optimized conventional therapy (Table 3). Considering mortality, women are significantly more likely than men to survive the infection, in accordance with recent literature on Covid-19.[9] Of note, in order to standardize and valorise the analysis, we described mortality at 28-day since hospitalization, which is a shared and reasonable interval of time in acute settings.

In the case of Covid-19, an enzymatic system involved in this different sex predisposition could be represented by angiotensin converting enzyme 2 (ACE2), which allows penetration of SARS-CoV-2 into cells and is down-regulated by the virus.[13] ACE2 is counter regulatory to the activity of angiotensin II, leading to angiotensin-(1–7) formation, which exerts vasodilatory, anti-inflammatory, antifibrotic, and antigrowth effects. Animal model observations demonstrated a hormonal susceptibility of ACE2. In mice it has been shown that 17ß-estradiol increases the expression and activity of ACE2 while ovariectomy results in a decreased activity. Conversely hypertensive male mice have a higher myocardial ACE2 expression than females and its levels decreases after orchiectomy.[27,28] Moreover, sex hormones can affect the immune and inflammatory modulation during infection, with estrogens promoting both innate and adaptive immunity and testosterone having a suppressive effect on immune function.[29] Actually, in our cohort, biochemical profile at presentation (i.e. platelets counts, coagulation, liver and renal function, CRP and PCT) suggests a tendency to a lower inflammatory status and organs impairment in females (Table 4). Finally, preliminary data have advocated a crucial role of endothelium in Covid-19. A role of estrogen (i.e. 17β-estradiol or E2) on vascular function and the endothelium have been suggested.[30] The mechanisms proposed include the generation of NO and prostacyclin, promotion of endothelial repair and regeneration, anti-inflammatory and antioxidant effects.[31] Our female population confirmed to be less fragile in this field, having few lifestyle risk factors (i.e. smoking history), and a lower rate of vasculopathy and myocardial infarction (Table 1). Thus, the lower severity of Covid-19 in women can be due to the influence of gender-related factors at least on: (1) the mechanism of cell entry of the virus; (2) the immune and inflammatory modulation during infection; (3) the endothelium and vascular function. Moreover, gastrointestinal symptoms at presentation, which were inconsistently correlated to outcome in previous reports, are more common in females (Table 2).[32–35] This result could reflect the higher expression of ACE2 in colon transverse in females. As a matter of fact, a recent systematic survey showed that ACE2 presents remarkable differences in male–female expression levels possibly due to differences in escape from X inactivation.[36]

Interestingly, in our multivariable analysis, sex does not result an independent predictor of death. Similar results were found during SARS in 2003, where a significantly higher mortality rate in males have been described, even if sex was not an independent predictor of mortality.[37] Specifically, when we add the severity of respiratory failure at presentation in the multivariable model (i.e. PaO2/FiO2 ratio < 200 mmHg at presentation and CPAP/NIV need in the first 24 h), it prevails on sex influence. The multivariable model is confirmed by survival analysis which demonstrates that male and female patients who required CPAP or NIV in the first 24 h have similar outcome (Figure 2).

Our study has several limitations. First, it must be acknowledged that this is a retrospective study based on electronic medical records collected during a medical emergency, thus the accuracy of data may be reasonably questioned. We cannot exclude that missing data could have affected the significance of some variables. However, the effect of gender on mortality risk did not change (OR male vs. female = 1.39, 95% CI 0.76–2.45, p = 0.288) if we imputed missing values using multiple imputation by chained equation (MICE) with 20 imputation sets. Of note, this is a large series of cases coming from the forefront of the outbreak, addressing gender differences and providing a substantial follow-up length on hard endpoints. Secondly, our cohort consists of a large proportion of male patients, and this could have brought to an imbalance between represented sex categories. Moreover, research on sex and gender exceeds stratification of patients by these variables, needing the evaluation of biological (e.g. hormonal state, immune function and comorbidities), and gender-related factors (e.g. lifestyle and socioeconomic status).[19] Prospective studies are required to better characterize patients by the evaluation of more specific sex- and gender-related parameters.