key: cord-0844802-8fn4qdj9
authors: Weizman, Orianne; Mika, Delphine; Cellier, Joffrey; Geneste, Laura; Trimaille, Antonin; Pommier, Thibaut; Panagides, Vassili; Marsou, Wassima; Deney, Antoine; Attou, Sabir; Delmotte, Thomas; Ribeyrolles, Sophie; Chemaly, Pascale; Karsenty, Clément; Giordano, Gauthier; Gautier, Alexandre; Chaumont, Corentin; Guilleminot, Pierre; Sagnard, Audrey; Pastier, Julie; Duceau, Baptiste; Sutter, Willy; Fauvel, Charles; Pezel, Théo; Bonnet, Guillaume; Cohen, Ariel; Waldmann, Victor
title: Characteristics and impact of cardiovascular comorbidities on coronavirus disease 2019 in women: A multicentre cohort study
date: 2021-05-21
journal: Arch Cardiovasc Dis
DOI: 10.1016/j.acvd.2021.04.002
sha: 730199c31dbee66ed9096cfdbd993c7b6ccb6b42
doc_id: 844802
cord_uid: 8fn4qdj9

Background. – Although women account for up to half of patients hospitalized for coronavirus disease 2019 (COVID-19), no specific data have been reported in this population. Aims. − To assess the burden and impact of cardiovascular comorbidities in women with COVID-19. Methods. − All consecutive patients hospitalized for COVID-19 across 24 hospitals from 26 February to 20 April 2020 were included. The primary composite outcome was transfer to an intensive care unit or in-hospital death. Results. − Among 2878 patients, 1212 (42.1%) were women. Women were older (68.3 ± 18.0 vs 65.4 ± 16.0 years; P < 0.001), but had less prevalent cardiovascular comorbidities than men. Among women, 276 (22.8%) experienced the primary outcome, including 161 (13.3%) transfers to an intensive care unit and 115 (9.5%) deaths without transfer to intensive care unit. The rate of in-hospital death or transfer to an intensive care unit was lower in women versus men (crude hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.53–0.72). Age (adjusted HR 1.05 per 5-year increase, 95% CI 1.01–1.10), body mass index (adjusted HR 1.06 per 2-unit increase, 95% CI 1.02–1.10), chronic kidney disease (adjusted HR 1.57, 95% CI 1.11–2.22) and heart failure (adjusted HR 1.52, 95% CI 1.04–2.22) were independently associated with the primary outcome in women. Elevated B-type natriuretic peptide/N-terminal prohormone of B-type natriuretic peptide (adjusted HR 2.41, 95% CI 1.70–3.44) and troponin (adjusted HR 2.00, 95% CI 1.39–2.88) concentrations at admission were also associated with the primary outcome, even in women free of previous coronary artery disease or heart failure. Conclusions. – Although female sex was associated with a lower risk of transfer to an intensive care unit or in-hospital death, COVID-19 remained associated with considerable morbimortality in women, especially in those with cardiovascular diseases.

Bien que le sexe féminin soit associé avec un risque moindre de transfert en unité de soins intensifs ou de survenue de décès hospitalier, la COVID-19 reste associée avec un excès de morbi-mortalité chez la femme en particulier chez celle ayant une maladie cardiovasculaire sous-jacente.

J o u r n a l P r e -p r o o f 6

The world is facing the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Despite unprecedented reorganization of health resources and sanitary measures in most countries, hundreds of thousands of people have already died worldwide, and new wave(s) and seasonal re-emergence are feared [1] [2] [3] .

The main characteristics and profiles of patients hospitalized for COVID-19 have been reported in case series from China [4, 5] , Europe [6] [7] [8] [9] and the USA [10] [11] [12] . The association between cardiovascular comorbidities and the prognosis of COVID-19 was soon demonstrated [13] [14] [15] [16] .

Hypertension, diabetes, chronic kidney disease and other cardiovascular diseases have been associated with a significantly increased risk of death [17] [18] [19] [20] . Furthermore, male sex has been identified as a risk for severe clinical presentation of COVID-19, with men representing up to 80% of patients admitted to an intensive care unit (ICU) [8, 9] . However, although women accounted for 40-50% of patients in main series [4, 11, 12, 21] , no specific data have been reported so far in this population.

Through a large multicentre cohort of patients hospitalized for COVID-19, we aimed to describe the burden and impact of cardiovascular comorbidities in women.

The Critical COVID-19 France study is a retrospective observational multicentre study initiated by the According to World Health Organization criteria, SARS-CoV-2 infection is defined as a positive result of real-time reverse transcriptase polymerase chain reaction of nasal and pharyngeal swabs or lower respiratory tract aspirates (confirmed case), or as typical chest computed tomography patterns when laboratory testing results were inconclusive (probable case) [22] . Patients admitted directly to an ICU were excluded. Declaration of Helsinki and its later amendments. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and approved the manuscript as written.

All data were recorded by local investigators on an electronic case report form via REDCap software (Research Electronic Data Capture, Vanderbilt University, Nashville, TN, USA). Patient baseline information included demographic characteristics, main comorbidities and chronic medications. Heart failure was defined as history of heart failure with reduced or preserved left ventricular ejection fraction [23] . A glomerular filtration rate < 60 mL/min/1.73 m 2 (Modification of Diet in Renal Disease study equation) was considered to define chronic kidney disease [24] . Clinical variables, blood test results and chest computed tomography characteristics (when performed) were also recorded at admission. A cut-off value of B-type natriuretic peptide (BNP) > 50 pg/mL or N-terminal prohormone of BNP (NT-proBNP) > 300 pg/mL was used, and troponin elevation was defined as any value above each centre's threshold [25] . According to European guidelines, the degree of computed tomography lesions was based on visual assessment of parenchymal involvement, and categorized as limited (< 25%), moderate (25-50%) or severe (> 50%) [26] . Data on pharmacological therapies, mode of respiratory support and final vital status were also collected during hospitalization. The date of final follow-up for patients still hospitalized was 21 April 2020.

The primary composite outcome was transfer to an ICU or in-hospital death. An ICU was defined as a specialized hospital unit providing intensive care for critically ill or injured patients, staffed by specially were left to the discretion of the referring medical team.

This report was prepared in compliance with the STROBE checklist for observational studies [27] .

Categorical data are reported as counts and percentages. Continuous data are reported as means ± standard deviations for normally distributed data, and as medians (interquartile ranges) for nonnormally distributed data. Comparisons used the  2 test or Fisher's exact test for categorical variables, and Student's t test or the Mann-Whitney-Wilcoxon test, as appropriate, for continuous variables.

Survival curves were plotted by the Kaplan-Meier method, and adjusted on main confounders.

Censoring occurred when patients were still hospitalized without a primary outcome event at the end of follow-up. Cox proportional hazard models were used to identify factors associated with the primary and secondary outcomes. Variables with probability values < 0.20 in univariate analyses were considered in multivariable models, with final selection based on the most favourable goodness-of-fit measures (Bayesian information criterion). The amount of missing data for each variable is presented in Table 1 . A two-tailed P value < 0.05 was considered statistically significant. All data were analysed using R software, version 3.6.3 (R Project for Statistical Computing, Vienna, Austria).

Among 2878 consecutive patients hospitalized for COVID-19, 1212 (42.1%) were women (Fig. 1 ). The main baseline characteristics of patients are compared according to sex in Table 1 . Women were significantly older than men (68.3 ± 18.0 vs 65.4 ± 16.0 years; P < 0.001), but had less prevalent cardiovascular comorbidities, including smoking (7.8% vs 17.6%; P < 0.001), diabetes (21.1% vs 25.6%; P = 0.006), heart failure (9.3% vs 12.4%; P = 0.013), coronary artery disease (6.7% vs 16.9%; P < 0.001) and peripheral artery disease (3.2% vs 6.6%; P < 0.001). Women, however, more frequently presented with a history of asthma (8.5% vs 5.2%; P < 0.001) and venous thromboembolic disease (9.1% vs 6.1%; P = 0.003).

At hospital admission, women had lower blood concentrations of C-reactive protein (80.6 ± 76.9 vs 97.4 ± 76.5 mg/L; P < 0.001), fibrinogen (5.6 ± 1.5 vs 6.2 ± 1.7 g/L; P < 0.001) and ferritin (783 ± concentration was more frequently observed in women (57.5% vs 49.8%; P = 0.002), whereas troponin elevation tended to be less frequent compared with men (29.7% vs 34.2%; P = 0.06). Severe pulmonary infiltration (16.3% vs 21.0%; P = 0.006) and pulmonary embolism (3.7% vs 6.3%; P = 0.03) were also less frequently found on the computed tomography scan in women.

High-concentration oxygen therapy (13.3% vs 16.9%; P = 0.01), high-flow nasal cannula therapy (3.3% vs 6.8%; P < 0.001) and invasive ventilation (9.2% vs 15.5%; P < 0.001) were less frequently required in women (Table A. 1), The prescription of antibiotics was also less frequent in women (70.8% vs 77.1%; P < 0.001).

Overall, 276/1210 (22.8%) women experienced the primary outcome (n = 562/1663, 33.8% in men; P < 0.001), including 161 (13.3%) transfers to an ICU and 115 (9.5%) deaths without transfer to an ICU.

In addition, 24 women died in an ICU, giving a total of 139 (11.5%) deaths (n = 223, 13.4% in men; P = 0.14). The rate of in-hospital death or transfer to an ICU was lower in women versus men (adjusted hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.53-0.72 P < 0.001), whereas the observed difference in overall in-hospital deaths did not reach statistical significance (P = 0.41) (Fig. 2) . Table   A .2 shows the factors associated with death among women in the univariate analysis. After adjustment on age, body mass index, diabetes, chronic kidney disease and heart failure, female sex remained significantly associated with a lower risk of experiencing the primary outcome (adjusted HR 0.62, 95% CI 0.52-0.71; P < 0.001; Table A. 3). Women represented 29.2% of patients transferred to an ICU. As of 21 April 2020, 204 (16.8%) women were still hospitalized. The median length of hospitalization among the 866 (71.6%) women discharged alive was 7.0 (4-12) days, versus 8.9 (5-12) days in men (P = 0.003).

Factors associated with primary and secondary outcomes are presented in Table 2 and Table A independently associated with in-hospital death (Fig. 4) .

Among men, body mass index (adjusted HR 1.03, 95% CI 1.001-1.07 per 2-unit increase; P = 0.04) was the only factor that remained independently associated with the primary outcome (Fig. A.1 

Elevated BNP or NT-proBNP (crude HR 2.41, 95% CI 1.70-3.44; P < 0.001) and troponin elevation (crude HR 2.00, 95% CI 1.39-2.88; P < 0.001) at admission were strongly associated with outcomes in women (Table 2 and Table A 

less prevalent cardiovascular comorbidities. Although female sex was associated with a lower risk of a composite outcome (transfer to an ICU or in-hospital death), COVID-19 remained associated with high morbimortality in women with pre-existing cardiovascular diseases.

All published series reported a predominance of men among patients hospitalized for COVID-19, particularly among those with severe presentation; 50-60% of patients were men [4, 11, 12, 21] , and up to 80% of patients admitted to an ICU [8] . In this study, women accounted for 42% of patients hospitalized, and presented with a significantly lower prevalence of cardiovascular comorbidities. The primary outcome was less frequently experienced in women, mainly driven by fewer transfers to an ICU. In-hospital mortality between women and men was, however, similar.

Data regarding sex disparities in COVID-19 remain mostly speculative. Different mechanisms have been hypothesized to explain the lower propensity to develop severe forms in women. The higher prevalence of co-existing cardiovascular diseases in men probably partly underlies these differences. Our data, however, demonstrated that women less frequently experienced the primary outcome, even after consideration of main comorbidities. Another interesting potential explanation recently emerged from two independent cohorts of patients with heart failure, where plasma concentrations of angiotensin-converting enzyme 2 were higher in men than in women [28] .

Angiotensin-converting enzyme 2 is not only an enzyme, but also a functional receptor on cell surfaces for SARS-CoV-2, and is highly expressed in the heart, testis, kidneys and lungs [29] . These increased plasma concentrations might reflect higher tissue expression, which may explain why men are more vulnerable to infection with or the consequences of SARS-CoV-2. This assumption may underly the lower levels of inflammation observed in our study in women, with lower blood concentrations of C-reactive protein, fibrinogen and ferritin, and less severe pulmonary infiltration on initial computed tomography scan. Hormonal factors have also been identified from preliminary studies. In an animal model, oophorectomy or treating female mice with an oestrogen receptor antagonist resulted in increased mortality as a result of SARS-CoV2 infection [30] . Sex chromosome genes and sex hormones contribute to the differential regulation of immune responses between the sexes, and these findings suggest that oestrogen signalling may protect females. Lastly, other behavioural and social differences that may favour women have been suggested, with previous J o u r n a l P r e -p r o o f 12 studies reporting that women are more likely than men to follow hand hygiene practices and seek preventive care [31, 32] .

Our findings furthermore demonstrated that an elevation of BNP/NT-proBNP or troponin concentrations in women was associated with poorer outcomes, even after adjustment on heart failure or coronary artery disease status. Troponin concentration has already been highlighted as a risk factor for severe COVID-19, and seems rather to reflect a cardioinflammatory response than an authentic myocardial injury [33] [34] [35] . These findings are consistent with previous viral epidemics, such as seasonal influenza infection or Middle East respiratory syndrome coronavirus (MERS-CoV) infection [36, 37] . Similar results regarding NT-proBNP have been reported, even in heart failure-naïve patients [38] . The prognostic value of cardiac biomarkers, however, has not been assessed specifically in women. These results support the potential input of cardiac biomarkers in risk stratification of women hospitalized with COVID-19, even in those without known cardiovascular diseases.

Sex disaggregated data are essential for understanding the distributions of risk, infection and disease in the population, and the extent to which sex affects clinical outcomes. Whereas severe forms were less frequent in women, our results emphasized that morbimortality associated with COVID-19 remained considerable, especially in women with cardiovascular diseases. More than onethird of women with a history of heart failure experienced transfer to an ICU or death during hospitalization, and one-quarter died. Other independent factors associated with a higher risk of developing a severe form of COVID-19 included age, body mass index and chronic kidney disease.

Identifying specific risk factors for severe COVID-19 presentation in women is essential to help clinical care, optimize early triage of patients and fight against health inequities in preventing bias in treating men and women. The recognition of phenotypical differences in severe case manifestations of COVID-19 in men and women is also a fundamental step towards understanding the effects of this health emergency on different individuals and to provide equitable interventions. Although cardiovascular comorbidities are now well-recognized risk factors for severe COVID-19 [19] , no specific data had been reported in women. Poorer outcomes in men should not obscure the substantial morbimortality observed in women with COVID-19. Cardiovascular diseases are important to consider, and should incite careful follow-up and management of women with COVID-19.

short time between each patient hospitalization and gathering of their datamedian 14 (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) daysallowed investigators to easily recover a large amount of data of interest. Second, a non-negligible proportion of patients was still hospitalized at the end of follow-up, with similar percentages of women and men (16.8% vs 18.5%; P = 0.48). However, the probability of these hospitalized patients developing a severe form of disease was relatively low, because the primary outcome occurred most commonly during the first few days of hospitalization (median 3 days), whereas these patients were hospitalized for a median of 7 days. Furthermore, the heterogeneous durations of follow-up and censoring were integrated into our statistical approach using Cox regression analysis. Third, some patients with severe clinical presentations might not have been transferred to an ICU because of a lack of space, particularly the elderly. Considering patients with similar severity, it is, however, very unlikely that men were selected over women to be transferred to an ICU. Furthermore, our results are consistent with the literature demonstrating a higher risk of severe COVID-19 in men [39, 40] . Finally, although our results emerge from a large multicentre study, regional disparities may exist, and these findings need to be further investigated in other populations or health systems.

This multicentre study demonstrated that women hospitalized for COVID-19 were older than men and had less prevalent cardiovascular comorbidities. Although female sex was associated with a lower risk of transfer to an ICU or in-hospital death, COVID-19 remained associated with a significant morbimortality in women, especially in those with cardiovascular diseases. 

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