There is growing evidence that gender may be associated with COVID-19 infection, presentation, and prognosis.1-4 Most published evidence, however, has focused on individual aspects, such as specific symptoms or prognoses. We sought to provide a comprehensive analysis of gender and COVID-19 infection from admission to 30 days after discharge in a large, multinational cohort.
The registry HOPE-COVID-19 (Health Outcome Predictive Evaluation for COVID-19, NCT04334291) is an international investigator-initiated study.5 The study was approved by the ethics committee of the promoting center and was appraised and accepted by the institutional review board or local committee of each participating hospital. It was designed as an ambispective cohort study. Patients are eligible for enrollment when discharged (whether dead or alive) after an in-hospital admission with a positive COVID-19 test or if their attending physician considered them highly likely to have presented with SARS-CoV-2 infection. All decisions and clinical procedures were performed by the attending physician team independently of this study, following the local regular practice and protocols. The information presented here corresponds to the HOPE-COVID-19 Registry, with a cutoff date of April 18, 2020.
Enrolled patients were divided into two groups according to their gender, then propensity score matching (PSM) analysis was performed (1:1 nearest neighbor matching, caliper = 0.01, without replacement and maximizing execution performance). Our primary end point was all-cause mortality at 30 days. Other clinically relevant events were recorded as secondary end points: invasive mechanical ventilation, noninvasive mechanical ventilation, pronation, respiratory insufficiency, heart failure, renal failure, upper respiratory tract involvement, pneumonia, sepsis, systemic inflammatory response syndrome, clinically relevant bleeding, hemoptysis, and embolic events. Events were allocated based on HOPE-COVID-19 registry definitions, following local researchers’ criteria. Abnormal blood test values were classified according to the reference values of local laboratories (Appendix 2).
Statistical analysis methods are outlined in Appendix 1.
Of the 2,798 patients consecutively enrolled in the HOPE registry, 1,111 were women (39.7%) and 1,687 were men (60.3%). Of the 2,375 (84.9%) patients who had a nasopharyngeal swab positive for COVID-19, 962 were women and 1,413 were men. Among the 2,798 patients initially included in the analysis, 876 gender-balanced pairs were selected after PSM.
Baseline Characteristics and Clinical Presentation
The baseline characteristics and clinical presentation of the overall population included in the study are summarized in Appendix Table 1. In the raw population, men had a significantly higher prevalence of conventional cardiovascular risk factors, such as diabetes, dyslipidemia, and smoking history, as well as a history of lung and cardiovascular diseases. On presentation, the most common symptoms for all patients were fever, cough, and dyspnea. Fever was more common in men, whereas vomiting, diarrhea, and upper airway symptoms (eg, sore throat, hyposmia/anosmia, dysgeusia) were more common in women.
Most patients had increased values of acute phase reactants. C-reactive protein (CRP) was elevated in 90.2% and D-dimer in 64.2% of patients, both significantly more often in men. Lymphocytopenia was present in 75.4% of patients, more commonly among men. Bilateral pneumonia occurred in 69.2% of the population, more frequently in men.
After PSM analysis (Appendix Table 2), a higher prevalence of hyposmia/anosmia and gastrointestinal symptoms in women was confirmed, as well as a higher prevalence of fever in men. Laboratory tests in men still presented alterations consistent with a more severe COVID-19 infection (significantly higher CRP, troponin, transaminases, lymphocytopenia, thrombocytopenia, and ferritin). There was no significant difference in the time between onset of symptoms and hospital admission by gender (6.2 ± 7.1 days in women vs 5.9 ± 7.6 days in men; P = .472).
In-Hospital Management and Outcomes
The supportive and pharmacologic treatments of study patients and their outcomes are summarized in Appendix Table 3. During the in-hospital stay, men required oxygen supplementation more frequently than women. Noninvasive mechanical ventilation, invasive mechanical ventilation, and pronation were more commonly used in men. Chloroquine/hydroxychloroquine, antivirals, and antibiotics were the medications most widely used in our population (84.5%, 65.8%, and 74.4% of patients, respectively), without significant differences between male and female patients, with the exception of antibiotics, which were used more often in men (76.6% vs 71.1%). Immunomodulators (corticosteroids, tocilizumab, and interferon) were used more often in male patients.
After PSM (Table), men more frequently received immunomodulators (corticosteroids and tocilizumab), antibiotics, and pronation. No differences in invasive and noninvasive mechanical ventilation were observed.
Thirty-day outcome data were available for all patients included in the analysis. During the in-hospital stay, 48% of patients developed respiratory insufficiency, 18.8% systemic inflammatory response syndrome (SIRS), and 13.2% overt sepsis. Respiratory insufficiency and SIRS were more common in male patients. Mortality at 30 days in the raw population was 21.4%, and men died more often than women (23.5% vs 18.2%; P = .001).
The PSM analysis continued to show a higher 30-day mortality rate among men (Figure), as well as greater need for oxygen, pronation, and use of immunomodulators and antibiotics (Table).
The results of our study confirm that among patients with COVID-19, men have a poorer prognosis than women. Because of the design of the study, it is not possible to determine if men are more prone to SARS-CoV-2 infection in our population; however, given the prevalence of men in our unselected, all-comers population, we can assume that men are either infected more often and/or more frequently symptomatic.
After PSM analysis, the 30-day all-cause mortality remained higher among men than women. The poorer prognosis of male patients is attributable not only to a higher burden of cardiovascular risk factors, but may also be related to unmodifiable biological factors, such as sex differences in angiotensin-converting enzyme 2 expression.7,8 The worse prognosis observed in our study confirms the higher incidence of death in male patients that was observed in previous studies.9 Liu et al questioned the role of gender as an independent prognostic factor in COVID-1910; however, that study included fewer patients, who were also younger and had less severe disease.
The clinical presentation of COVID-19 also differed by gender in our study. Gastrointestinal symptoms and hyposmia/anosmia were more common in women, whereas fever was more common in men. The prevalence of olfactory and gustatory dysfunction in women has already been described,11,12 and these symptoms have been linked with milder disease.13 It is possible that women presenting to the hospital had milder forms of COVID-19, or that there were systematic differences in how men and women sought medical care. The results of our study emphasize the need for a high level of suspicion for COVID-19 infection in women, even in the presence of mild mucosal or gastrointestinal symptoms and/or relatively minor laboratory abnormalities.
Laboratory values indicative of more severe COVID-19 infection in men could suggest a higher inflammatory response to the infection. Men also received more immunomodulators and antibiotics in this study. A recent paper from Scully et al14 pointed out the different immune response to viruses observed in men that could partially explain the higher level of inflammation markers and the more severe disease observed in men.
Our study has several limitations. As an observational study of hospitalized patients, it may represent patients with more severe COVID-19. Men and women may have sought hospital care differently. Diagnosis, testing, and treatment were not standardized and may have been influenced by patient gender. Although we attempted to match patients on baseline medical conditions, we may not have completely controlled for differences in preexisting health. Finally, gender data were collected as binary and so did not capture other gender categories.
In our multicenter cohort of hospitalized COVID-19 patients, men had a higher burden of risk factors; different clinical presentations, with more fever and less olfactory and gastrointestinal symptoms; and a significantly poorer prognosis than women did at 30 days.
The authors thank Cardiovascular Excellence SL for their essential support regarding the database and HOPE web page as well as all HOPE researchers. The authors also thank Michael Andrews for his valuable contribution to the English revision.