Higher severity and mortality in male patients with COVID-19 independent of age and susceptibility

Objective: The recent outbreak of Novel Coronavirus (SARS-CoV-2) Disease (COVID-19) has put the world on alert, that is reminiscent of the SARS outbreak seventeen years ago. We aim to compare the severity and mortality between male and female patients with both COVID-19 and SARS, to explore the most useful prognostic factors for individualized assessment. Methods: We extracted the data from a case series of 43 hospitalized patients we treated, a public data set of the first 37 cases died of COVID-19 in Wuhan city and 1019 survived patients from six cities in China. We also analyzed the data of 524 patients with SARS, including 139 deaths, from Beijing city in early 2003. Results: Older age and high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. The percentages of older age ( ≥ 65 years) were much higher in the deceased group than in the survived group in patients with both COVID-19 (83.8 vs. 13.2, P<0.001) and SARS (37.4 vs. 4.9, P<0.001). In the case series, men tend to be more serious than women (P=0.035), although age was comparable between men and women. In the public data set, age was also comparable between men and women in the deceased group or the survived group in patients with COVID-19. Meanwhile, gender distribution was exactly symmetrical in the 1019 survivors of COVID-19. However, the percentage of male were higher in the deceased group than in the survived group (70.3 vs. 50.0, P=0.015). The gender role in mortality was also observed in SARS patients. Survival analysis showed that men (hazard ratio [95% CI] 1.47 [1.05-2.06, P= 0.025) had a significantly higher mortality rate than women in patients with SARS. Conclusion: Older age and male gender are risk factors for worse outcome in patients with COVID. While men and women have the same susceptibility to both SARS-CoV-2 and SARS-CoV, men may be more prone to have higher severity and mortality independent of age and susceptibility.


Introduction
In early December 2019, an outbreak of a novel coronavirus disease  in Wuhan city and the rapidly spread throughout China has put the world on alert.
High-throughput sequencing has revealed a novel β -coronavirus that is currently named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 , which resembled severe acute respiratory syndrome coronavirus (SARS-CoV) 2 . Most patients with COVID-19 were mild. Moderate patients often experienced dyspnea after one week. Severe patients progressed rapidly to critical conditions including acute respiratory distress syndrome (ARDS), acute respiratory failure, coagulopathy, septic shock, and metabolic acidosis.
Early identification of risk factors for critical conditions is urgently warranted not only to identify the defining clinical and epidemiological characteristics with greater precision, but also facilitated appropriate supportive care and promptly access to the intensive care unit (ICU) if necessary.
The Chinese health authority has announced that the total number of confirmed cases on the Chinese mainland has reached 76,936, and 2,442 people have died of the disease as of Feb 23. Among the 2,442 deceased patients, most were old and two-thirds were males, though the detailed data has not been reported 3 . This raises a question: Are men more susceptible to getting and dying from COVID-19?
Here, we reported the clinical characteristics of a recent case series of 43 patients with 2019 SARS-CoV-2 infection we treated, a public data set of the first 37 cases died of SARS-CoV-2 in Wuhan city and the 1019 survived patients with SARS-CoV-2 from six cities with a high prevalence of the disease. We aimed to compare the severity and mortality in male and female patients with COVID-19, to explore the most useful prognostic factor for individualized assessment. SARS-CoV-2 infection is . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 25, 2020.

Patients and data sources
In the case series analysis, a recent case series of 43 patients with COVID-19 was treated at Wuhan Union Hospital by the medical team of Beijing Tongren Hospital from January 29, 2020 to February 15, 2020. Respiratory specimens were collected by local center for disease control and prevention (CDC) and then shipped to designated authoritative laboratories to detect SARS-CoV-2. The presence of SARS-CoV-2 in respiratory specimens was detected by real-time RT-PCR methods. The RT-PCR assay was conducted in accordance with the protocol established by the World Health Organization.
In the public data set, the first 37 cases died of COVID-19 in Wuhan city and the 1019 survived patients with COVID-19 from six cities with a high prevalence of the disease were obtained from the Chinese Public Health Science Data Center. Case data included basic demographic information, classification, date of symptom onset, date of diagnosis, date of hospitalization, date of discharge or date of death, etc.

Statistical analysis
Data were expressed as mean ± SD, median (interquartile range (IQR)) or percentage, as appropriate. Compared the differences between the two groups, mean values and percentages were compared between the two groups by student t-test, Mann-Whitney U test or chi-square (χ 2 ) test. Kaplan-Meier survival curves and the log-rank test was used for testing the survival between males and females. Statistical analyses were performed using the SAS software (version 9.4.). P< 0.05 (two-tailed) was considered to be statistically significant.

Case series of COVID-19
The demographic and clinical characteristics are shown in Table 1. The median age was 62 years (IQR, 51 to 70). Fever (95.3%) and cough (65.1%) were the most common symptoms, while diarrhea (16.3) were not common. 37.2% of patients had at least one underlying disorder (i.e., hypertension, diabetes, cardiovascular diseases and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted February 25, 2020. ; https://doi.org/10.1101/2020.02.23.20026864 doi: medRxiv preprint chronic lung diseases). Ages, symptoms and comorbidities were comparable between men and women. As expected, men had a higher level of hemoglobin. However, male patients also had elevated serum creatinine, white blood cells and neutrophils. Among the 43-case series, 13 (30.2%) were diagnosed with mild or common pneumonia. 14 (32.6%) and 16 (37.2%) were diagnosed with severe and critical pneumonia, respectively. Chi-square (χ 2 ) test for trend indicated that men tend to be more serious than women (P=0.035) according to the clinical classification of severity ( Figure 1).
However, of the 37 deceased patients, 26 (70.3%) were men. While men and women . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Case-control analysis of SARS in Beijing, in 2003
Between March 25 and May 22, 2003, a total of 139 patients died of SARS in Beijing area reported from 29 hospitals were enrolled in our analysis. Fever (98.4%) and cough (76.9%) were the most common symptoms, while diarrhea (6.7%) were not common. 57.0% of the patients had at least one of the concomitant diseases including hypertension, diabetes, cardiovascular diseases and chronic lung diseases. The mean duration from self-reported symptom to death was 15 (IQR: 10-19) days. Table 2 summarizes the clinical and biochemical characteristics of all SARS patients. The median age of the deceased patients was much higher than that of the survived patients (57 vs. 32, P<0.001). The rate of the concomitant diseases in the deceased patients was also higher than that of the survived patients (57.0% vs. 17.9%, P<0.001).
While the deceased patients were significantly older than the survived patients ( Figure   3A), ages were comparable between men and women in both deceased and survived patients with SARS ( Figure 3B). The proportion of male was higher in the deceased group than in the survived group (χ 2 test, P=0.016) ( Figure 3C). Survival analysis showed that men (hazard ratio [95% CI] 1.47 [1.05-2.06, P= 0.025) had a significantly higher mortality rate than women ( Figure 3D).

Discussion
Coronavirus are a large family of viruses that cause illness ranging from the common cold to severe pneumonia such as SARS 2  CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Older age and high number of comorbidities were associated with severity in patients with COVID-19 9-11 . Wang et al. reported that compared with patients not treated in the ICU (n=102) patients treated in the ICU (n=36) were older (median age, 66 years vs 51 years) 11 . Consistent with previous reports, older patient (≥65 years old), was more likely to have a severe type of COVID-19 in the case series patients in the present study. In the public data set, we also found that the percentage of older age (≥65 years) was much higher in the deceased patient than in the survived patients (83.8% in 37 deceased patient vs. 13.2% in 1019 survived patients). The results indicated that older age was associated with a high mortality in patients with

COVID-19.
This is the first preliminary study investigating the gender role in morbidity and mortality of SARS-CoV-2 infection. It is suggested that COVID-19 is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as ARDS 10 . Among the 425 patients with COVID-19, 56% were male, indicating males may be more susceptible to SARS-CoV-2 infection than females 6  Although the deceased patients were significantly older than the survived patients with COVID-19 in this study, ages were comparable between males and females in both the deceased and the survived patients. Consistent with this predominance, we . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted February 25, 2020. ; https://doi.org/10.1101/2020.02.23.20026864 doi: medRxiv preprint also found that the proportion of male was higher in the deceased group than in the survived group in SARS patients. Survival analysis showed that men had a significantly higher mortality rate than women in SARS patients. Therefore, Gender is a risk factor for higher severity and mortality in patients with both COVID-19 and SARS independent of age and susceptibility.
In early 2003, we participated in the Beijing Municipal Medical Taskforce of SARS 12 . Here, we re-analyzed the data of a large population of 520 SARS patients including 135 deaths in Beijing, and summarized the experience and lessons for present use, because SARS-CoV-2 and SARS-CoV attack cells via the same receptor, ACE2 3 . We have previously reported that high protein expression of ACE2 receptor in specific organs correlated with specific organ failures indicated by corresponding clinical parameters in SARS patients 12,13 . Interestingly, the ACE2 gene is located on the X-chromosome and it has been shown that circulating ACE2 levels are higher in men than in women and in patients with diabetes or cardiovascular diseases 14 .
Therefore, male patients may be more prone to die from SARS-CoV-2 because of high expression of ACE2, though further research on mechanism is needed. This study has some limitations. First, for severity analysis only a case series of 43 patients with SARS-CoV-2 were included, because detailed patient information, particularly regarding clinical outcomes was unavailable in the public data set; Second, for mortality analysis only the first 37cases died of SARS-CoV-2 in Wuhan city were included. However, this is the first preliminary data investigating the gender role in morbidity and mortality in patients with SARS-CoV-2. More clinical and basic research regarding gender and other prognostic factors for individualized assessment and treatment is needed in the future.
In conclusion, older age is a predominant risk factor for severity and morbidity in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted February 25, 2020. ; https://doi.org/10.1101/2020.02.23.20026864 doi: medRxiv preprint patients with both COVID-19 and SARS. While males and females have the same susceptibility to COVID-19, male patients may be more prone to dying independent of age.  Chi-square (χ 2 ) test for trend indicated that males tend to be more serious than females according to the clinical classification of severity including Mild+Common, Severe and Critical.  . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted February 25, 2020.  . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 25, 2020. ; https://doi.org/10.1101/2020.02.23.20026864 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 25, 2020. ; https://doi.org/10.1101/2020.02.23.20026864 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 25, 2020. ; https://doi.org/10.1101/2020.02.23.20026864 doi: medRxiv preprint