key: cord-0963325-vtl3cd1x authors: Chen, Jing; Bai, Hualin; Liu, Jia; Chen, Ge; Liao, Qiuyue; Yang, Jie; Wu, Peng; Wei, Juncheng; Ma, Ding; Chen, Gang; Ai, Jihui; Li, Kezhen title: Distinct clinical characteristics and risk factors for mortality in female COVID-19 inpatients: a sex-stratified large-scale cohort study in Wuhan, China date: 2020-07-08 journal: Clin Infect Dis DOI: 10.1093/cid/ciaa920 sha: 74046d8957ccdb12e51883f32e9e52f8588bc08a doc_id: 963325 cord_uid: vtl3cd1x BACKGROUND: As the coronavirus disease 2019 (COVID-19) outbreak accelerates worldwide, it is highly significant to evaluate sex-specific clinical characteristics and outcomes, that may affect public health policies. METHODS: COVID-19 patients admitted to Tongji Hospital between January 18and March 27, 2020 were evaluated. Clinical features, laboratory data, complications and outcomes were compared between females and males. Risk factors for mortality in the whole population, females and males were determined respectively. RESULTS: There were 1667 (50.38%) females among the3309 patients included in this study. The mortality rate was only 5.9% in females but 12.7% in males. Compared with males, more females had no initial symptoms (11.1% vs 8.3%, p=0.008). Complications including acute respiratory distress syndrome, acute kidney injury, septic shock, cardiac injury and coagulation disorder were less common in females; critical illness was also significant less common in females (31.1% vs 39.4%, p<0.0001). Significantly fewer female patients received antibiotics treatment (p=0.001), antiviral therapy (p=0.025) glucocorticoids treatment (p<0.0001), mechanical ventilation (p<0.0001) and had Intensive Care Unit admission (p<0.0001). A lower risk of death was found in females (odds ratio 0.44, 95% confidence interval 0.34-0.58) after adjusting for age and coexisting diseases. Among females, age, malignancy, chronic kidney disease and days from onset to admission were significant associated with mortality, while chronic kidney disease was not risk factor in males. CONCLUSIONS: Significantly more mild illness and fewer deaths were found in female COVID-19 inpatients and risk factors associated with mortality varied among male and female population. A novel coronavirus, which is now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a cluster of pneumonia cases in Wuhan, China from December, 2019 [1] . Officially called coronavirus disease 2019 , this virus-related pneumonia quickly spread in China and more than 208 countries around the world, bringing a serious threat to global public health. Up to May 15, 2020 , there have been a cumulative 4,307,287 confirmed COVID-19 cases and more than 295,101 patients have been died from the disease, with a mortality rate of 6.85% according to the World Health Organization (WHO) COVID-19 situation dashboard [2] . Recent studies have revealed part of the epidemiology and clinical characteristics of COVID-19 in the general population. Older age, comorbidity, higher lymphocytes count, high level of lactate dehydrogenase, high sensitivity C-reactive protein (Hs-CRP) and d-dimer were found to be risk factors for mortality [3] [4] [5] , and age, neutrophilia and organ dysfunction help identify population that development to acute respiratory distress syndrome (ARDS) [6, 7] . Whether sex differences are associated with mortality and severity of the disease has not been well described. Given essential distinctions in lifestyle, physical structures and pathophysiology between men and women, there are tremendous differences in many diseases between the sex. In the past outbreaks of coronaviral related illness, namely Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), a correlation between sex and mortality was demonstrated. Males showed much higher risks of disease deterioration and higher mortality compared to females [8, 9] . Emerging researches have revealed the same A c c e p t e d M a n u s c r i p t pattern in COVID- 19 . A report the from Chinese Center for Disease Control and Prevention (China CDC) and epidemiological studies showed 54%-58% of severe cases and more than 60% of deceased patients were males [10, 11] . Nevertheless, the evidence is still insufficient to certify the conclusive effect of sex-specific for disease severity and prognosis due to presence of descriptive statistics and controversial results. Whether females and males had different risk factors for death was unknown. To compare clinical features and outcomes between female and male COVID-19 inpatients and clearly elucidate the relationship between sex and mortality, a large-scale population was retrospectively evaluated. The risk factors for mortality in female and male groups were further explored separately. The findings highlight the impact of sex on disease features and provide insight into different risk factors for prognosis in females and males. A big-data intelligence database (Yiducloud Technology, Beijing, China), which was established based on diagnosed outpatients and inpatients in three branches of Tongji A c c e p t e d M a n u s c r i p t was exempted in accordance with the urgent situation and Ethics Committee's rules. The demographic characteristics, recent comorbidities, clinical signs at onset, clinical period, laboratory findings, radiologic assessments and disease outcomes were electronic extracted from the database. All the results were captured, if a single patient had more than one test for laboratory index, positive or abnormal results were defined as one anomalous measurement. All data was organized by two clinicians (JC and BL), and any disagreements were resolved by KL. According to the Guidance for Corona Virus Disease 2020 (7th edition) by the National Health Commission of China, disease severity was classified as mild, moderate, severe, or critical. ARDS was defined according to the Berlin definition [12] . Acute kidney injury was defined according to the KDIGO clinical practice guidelines [13] . Cardiac injury was defined as the serum level of cardiac biomarkers e.g. hypersensitive cardiac troponin I (Hs-cTn I) was above the 99th percentile upper baseline limit or new abnormal changes in electrocardiography [14] . Heart failure was defined as the level of amino-terminal pro-brain natriuretic peptide (NT pro-BNP) exceeding the normal range [15] . Acute liver injury was identified as total bilirubin increase by 51.3 µmol/L and alanine aminotransferase increase to five times the upper reference limit or alkaline phosphatase increase to twice the upper reference limit. Coagulopathy was identified as extension of prothrombin time (PT) or activated partial thromboplastin time (APTT) by 3seconds or 5seconds respectively [11] . A c c e p t e d M a n u s c r i p t A total of 3309 patients with confirmed COVID-19 were included, of whom 1667 (50.38%) were females. The preexisting rate of diabetes was 12.4% in females, which was significantly lower than that in males (15.7%). Other comorbidities, including hypertension, M a n u s c r i p t cardiovascular disease, cerebrovascular disease, malignancy and chronic kidney disease were not significantly different between the male and female groups. Specific cancer types were also comparable between female and male patients (Supplementary Table 1 ). The most common primary symptoms were fever (68.8%) and cough (56.5%), followed by sputum production (41.7%) and dyspnea (31.7%) in the overall population. There were 185 (11.1%) women who had no initial symptoms, which was significantly more than the 137 (8.3%) cases in male group. Cough (58.2%), sputum production (43.6%) and nausea (6.9%) were more common in females on admission, but a significantly higher proportion of males presented with fever (73.6%). Regarding computed tomography (CT) examination results, males were more prone to have interstitial abnormalities in pulmonary manifestations (3.2% vs 1.5%). Laboratory confirmed COVID-19 cases accounted for 95.8% in the whole population and were comparable between females and males (95.7% vs 95.9%). Among female patients, the median interval time from signs or symptom onset to seeking outpatient care was 5 (IQR 1-9) days, the days from onset to admission was 12 (IQR 7-20), and the period from onset to discharge or death was 37 (IQR 27-48). Significant differences were observed between male and female group. Duration of clinical course were summarized in Supplementary During the course of disease, with the exception of heart failure, enormous significant differences in organic damage had developed among female and male (Table 2) . Acute kidney A c c e p t e d M a n u s c r i p t injury was more common in females (13.3%) than in males (10.9%). Compared to males, most complications were significantly rarer in female patient. Specifically, the observed complications in males included septic shock (54.8%), ARDS (46.8%) , cardiac injury (32.8%), coagulation disorder (21.5%) and acute liver injury (4.6%), of which the corresponding incidence in females were all significantly lower. Since coexisting diseases were comparable between males and females as shown in Table 1 , we speculate that the significant difference in complications between the two groups is due to acute t organ injury caused by the novel coronavirus. As summarized in Table 2 A c c e p t e d M a n u s c r i p t was significantly lower in female than in males (5.9% vs 12.7%). In addition, the laboratory findings were summarized in Table 3 In the univariable analysis ( Table 3 ). In addition, the sex-specific risk factors for mortality of COVID-19 inpatients were analyzed since they had significantly different outcomes. In the female group, age (>45 years), malignancy, chronic kidney disease, COPD and days from onset to admission were associated with mortality in the univariable model, and age (>45 years), malignancy, chronic kidney disease and days from onset to admission (≤12 days ) were identified as risk factors in the multivariable logistic regression models (Supplementary Table 4 and Figure 1A ). Among male patients, age (>45 years), hypertension, cardiovascular disease, malignancy, days from onset to admission (≤12 days) were related to death in the univariable logistic regression analysis (Supplementary Table 2) , and the multivariable models showed that age (>45 years), hypertension, malignancy and days from onset to admission (≤12 days) were factors that significantly influenced prognosis (Supplementary Table 5 and Figure 1B ). In terms of clinical presentation, more male patients suffered from organ damage and needed ICU admission, drug treatment and mechanical ventilation therapy. Interestingly, a preprint meta-analysis concluded that days from symptom onset to admission was related to death rates, with an approximately 1.27% increase for every day of delay [18] , whereas in our study, the onset to admission time was significantly longer in women than in men, which might due to the fact that most females had mild or general illness and did not need urgent medical care. Although sex differences seem to affect the prognosis of COVID-19, the exact mechanism of different outcomes between women and men is still unclear. Recently published studies A c c e p t e d M a n u s c r i p t involved laboratory test results may provide some insight into the underlying reasons. First, estrogen may protect females from seriously poor outcomes during coronavirus infection and women's immune systems are more specific to fight against SARS-CoV-2 [19, 20] . As shown in our results, the serum levels of IL-2R, IL-6 and IL-8 were significantly lower in women than in males, which indicated that the extreme immune attacks called the cytokine storms were less common in women. Second, in the analysis of preexisting diseases, we found that the proportion of patients with diabetes was significantly higher in males than in females. As we know, patients with diabetes are vulnerable to complicated infections [21, 22] , which may be the reason why we found infection-related indicators, such as Hs-CRP and procalcitonin, to be remarkably evaluated in men. Additionally, angiotensin-converting enzyme 2 (ACE2) is patients were unavailable to detect differences expression of ACE2 between males and females, so revealing molecular differences would be a key direction in the future. According to the multivariable analysis, we found that sex, age (>45 years), malignancy, chronic kidney disease, and the interval from symptom onset to admission were risk factors for death in the whole population. A previous meta-analysis including eight studies also addressed that most severe disease among COVID-19 patients was accompanied with higher proportions of cardiovascular disease, hypertension, respiratory disease [27], and older age A c c e p t e d M a n u s c r i p t and cancer patients had higher mortality [4, 28] . In contrast to previous research, we found that sex was independently related to risk of mortality among hospitalized COVID-19 patients, and the result was still reliable after adjustment for age and pre-existing illness. Our data indicated that males faced more than twice the risk of death from COVID-19. To our knowledge, the findings of this study concluded from cohort study with the largest sample-size for the comparison of clinical distinction between male and female hospitalized patients with COVID-19. Additionally, this is the first study to evaluate the risk factors for COVID-19 mortality in females and males separately. In the present study, cancer patients, females with chronic kidney disease and male with hypertension were identified high risks of death from COVID-19, which displayed preexisting comorbidities associated with mortality rates might vary in different populations. There are some limitations in our study. First, our medical center is one of the COVID-19 treatment-specific hospitals for severe or critical cases, thus, a low proportion of mild and general cases were included in our study. Next, some laboratory test ( The data used to support the findings of this study are available from the corresponding author upon request. 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RBC=Red blood cell. NT pro-BNP = amino-terminal pro-brain natriuretic peptide.Hs-cTnI=Hypersensitive cardiac troponin I. ALT=Alanine aminotransferase. AST= Aspartate aminotransferase.ATPP=activated partial thromboplastin time. Hs-CRP=High sensitivity C-reactive protein.