Male gender is a predictor of higher mortality in hospitalized adults with COVID-19

Introduction The coronavirus disease 2019 (COVID-19) pandemic continues to be a global threat, with tremendous resources invested into identifying risk factors for severe COVID-19 illness. The objective of this study was to analyze the characteristics and outcomes of male compared to female adults with COVID-19 who required hospitalization within US academic centers. Methods Using the Vizient clinical database, discharge records of adults with a diagnosis of COVID-19 between March 1, 2020 and November 30, 2020 were reviewed. Outcome measures included demographics, characteristics, length of hospital stay, rate of respiratory intubation and mechanical ventilation, and rate of in-hospital mortality of male vs female according to age, race/ethnicity, and presence of preexisting comorbidities. Results Among adults with COVID-19, 161,206 were male while 146,804 were female. Adult males with COVID-19 were more likely to have hypertension (62.1% vs 59.6%, p <0.001%), diabetes (39.2% vs 36.0%, p <0.001%), renal failure (22.3% vs 18.1%, p <0.001%), congestive heart failure (15.3% vs 14.6%, p <0.001%), and liver disease (5.9% vs 4.5%, p <0.001%). Adult females with COVID-19 were more likely to be obese (32.3% vs 25.7%, p<0.001) and have chronic pulmonary disease (23.7% vs 18.1%, p <0.001). Gender was significantly different among races (p<0.001), and there was a lower proportion of males versus females in African American patients with COVID-19. Comparison in outcomes of male vs. female adults with COVID-19 is depicted in Table 2. Compared to females, males with COVID-19 had a higher rate of in-hospital mortality (13.8% vs 10.2%, respectively, p <0.001); a higher rate of respiratory intubation (21.4% vs 14.6%, p <0.001); and a longer length of hospital stay (9.5 ± 12.5 days vs. 7.8 ± 9.8 days, p<0.001). In-hospital mortality analyzed according to age groups, race/ethnicity, payers, and presence of preexisting comorbidities consistently showed higher death rate among males compared to females (Table 2). Adult males with COVID-19 were associated with higher odds of mortality compared to their female counterparts across all age groups, with the effect being most pronounced in the 18–30 age group (OR, 3.02 [95% CI, 2.41–3.78]). Conclusion This large analysis of 308,010 COVID-19 adults hospitalized at US academic centers showed that males have a higher rate of respiratory intubation and longer length of hospital stay compared to females and have a higher death rate even when compared across age groups, race/ethnicity, payers, and comorbidity.


Introduction
The coronavirus disease 2019 (COVID-19) pandemic continues to spread globally with more than 25 million confirmed cases and nearly 450,000 deaths in the United States (US) [1]. A top priority of the Centers for Disease Control and Prevention (CDC) is to identify risk factors for severe COVID-19 illness that can lead to hospitalization or death [1]. Some of the current known risk factors for hospitalization and death include older age and patients with certain underlying medical conditions such as diabetes, obesity, immunocompromised state, and pulmonary, cardiac, or renal dysfunction [1]. Additionally, several COVID-19 studies have demonstrated that male is a predictor for higher death rate [2][3][4][5]. The objective of this study was to analyze the characteristics and outcomes of male compared to female adults with COVID-19 who required hospitalization within US academic centers.

Materials and methods
The data for this study were obtained from the Vizient clinical database (CDB/RM TM ) which is an administrative, clinical, and financial database of more than 650 academic centers and their affiliates. Approval for the use of the data was obtained from Vizient and from the Institutional Review Board of the University of California, Irvine as exempted status.
Discharge records of male and female adults (�18 years) with a diagnosis of COVID-19 between March 1, 2020 and November 30, 2020 were reviewed. COVID-19 diagnosis was identified using International Classification of Disease, Tenth edition code of U07.1. Outcome measures included demographics, characteristics, length of hospital stay, rate of respiratory intubation and mechanical ventilation, and rate of in-hospital mortality of male vs female according to age, race/ethnicity, and presence of preexisting comorbidities. Race/ethnicity was self-reported by the patient. Chi-Square Test of Independence was performed to determine if statistically significant associations exist between categorical variables. No post hoc analyses were performed. P-values were not adjusted for multiple comparisons. Statistical significance was set at P <0.05. R version 4.0.3 was used for statistical analysis.

Results
Among adults with COVID-19 discharged during this time period, 161,206 (52.3%) were male while 146,804 (47.7%) were female. All adult patients admitted and discharged during the time

PLOS ONE
Male gender is a predictor of higher mortality in hospitalized adults with COVID-19 PLOS ONE | https://doi.org/10.1371/journal.pone.0254066 July 9, 2021 2 / 6 Funding: The authors received no specific funding for this work. Vizient was used as the source of our data but did not fund our study. Vizient provided support in the form of salaries for Sam Hohmann, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.

Discussion
This large analysis of 308,010 adults with COVID-19 hospitalized at US academic centers showed that males have higher death rate compared to females. This finding was consistently observed across all age groups, race/ethnicity, payers, and preexisting comorbidities. Our finding is in concordance with other studies showing that male sex is a strong predictor for higher risk of death in hospitalized adults with COVID-19 [2][3][4][5]. The CDC has reported that 54% of COVID-19 deaths have been among men [1]. In a meta-analysis of 3,111,714 reported global cases, male patients had a higher odds of death compared to female patients (Odds ratio = 1.4; 95% confidence interval = 1.31, 1.47) [5]. This raises the question of the importance of co-morbidities as drivers for mortality risk leading to the differences noted between sexes or differences in the immune system response between sexes [3]. Surprisingly, although the presence of pulmonary disease was higher in our female cohort, the mortality remained higher in males even when accounting for this comorbidity. The association of higher odds of mortality in males with COVID-19 compared to female across age groups also raises the question of the role of sex hormones in immune response, and the effect that age has on sex hormone concentration [6]. There are some limitations to this retrospective study. Data for this study is based on the Vizient database which has potential for misclassification and inaccuracy of coding, and missing data. The designation of male vs. female sex in the Vizient database is selfreported which has the potential for subjective bias. Despite these limitations, this study provides data from a large cohort of adults with COVID-19 documenting the consistent association of males with higher death rate. Further studies are needed to determine the underlying mechanisms for this differential risk of death between male vs. female adults with COVID-19.