Comparison of clinical characteristics and risk factors in hospitalized patients with SARS-CoV-2, MERS-CoV, and SARS-CoV infection

Herein, we compared the risk factors, clinical presentation of patients hospitalized with SARS-CoV-2, SARS-CoV, or MERS-CoV infection. Our data sources include PubMed, Embase, CNKI, and Ovid/Medline. The proportion of male patients with COVID-19 was higher than who with SARS but lower than who with MERS (p<0.001). More patients with COVID-19 had coexisting chronic medical conditions than those with SARS (p<0.001) but fewer than those with MERS (p<0.001), and the prevalence of hypertension (17%) and smoking history (14%) was higher than in patients with SARS (p<0.001). Furthermore, the symptom of fever (53%), hemoptysis (1%), diarrhea (4%) and vomiting (3%) of COVID-19 were signicantly lower than that in patients with SARS or MERS. The level of ALT and AST in COVID-19 was signicantly lower (p<0.001), however, thrombocytopenia, high LDH were common. Summary, male, smoking history and hypertension were the most common risk factors for hospitalization with COVID-19; and the clinical feature was less severe in COVID-19.

As yet, no comprehensive comparison exists of the clinical characteristics and risk factors of these highly pathogenic CoVs, which is very important for clinical diagnosis and differential diagnosis as well as for improving the clinical understanding of these infectious agents. Current studies have reported the clinical characteristics of a large number of clinically diagnosed and con rmed cases of COVID-19. As the three most important CoV strains to emerge during the rst decade of the 21st century, we sought to assess whether the SARS-CoV-2 genotype translates into a distinct clinical phenotype in humans, to provide insight into the pathogenesis of COVID-19. To this end, we performed a comparison of the risk factors, clinical presentation, and progression of patients hospitalized with SARS-CoV-2, MERS-CoV, and SARS-CoV infection.

Systematic literature review
We conducted a systematic literature review according to the WHO clinical guidelines and interim clinical guidelines for COVID-19, SARS, and MERS. We searched PubMed, Embase, CNKI, and Ovid/Medline on February 17, 2020, using the strategy "(((COVID-19) OR (SARS[Title])) OR (MERS)) OR (2019 novel coronavirus)". We limited our search to studies in English and Chinese language. We reviewed the identi ed publications regarding SARS-CoV, MERS-CoV, and COVID-19/SARS-CoV-2. In addition, the references of key articles were searched to identify additional eligible studies (Fig. 1).

Eligibility criteria
The eligibility of each article for inclusion was assessed according to the following criteria: 1) clinical research study reporting clinical characteristics; 2) all included patients meet the current SARS, MERS, or COVID-19 diagnostic standards; 3) more than 10 included patients; 4) the proportion of patients with clinical symptoms and laboratory test results is reported or could be extracted or estimated using reported data.

Data extraction
Studies were categorized according to clinical symptoms into a basic information group, underlying disease group, and admission for laboratory testing group. The results for all ranges were converted to quartiles, median, and standard deviation 17 . In cases with missing data for an included study, the corresponding author was contacted to request additional data.

Database
All patients with CoV infection reported in this manuscript were hospitalized. COVID-19 cases were diagnosed based on the WHO interim guidance 18 . Patients with laboratory-con rmed COVID-19 were all hospitalized in China between December 1, 2019 and January 29, 2020. The Chinese cases of SARS represent all hospitalized patients with laboratory-con rmed or clinically diagnosed SARS-CoV infection detected between December 22, 2002 andJune 20, 2003

Risk factors for hospitalization and death
To assess the importance of putative risk factors of hospitalization for each CoV subtype, we estimated the relative risk of being hospitalized in individuals with and without risk factors. Data on the prevalence of each risk factor for the general Chinese population were used as denominators for the risk estimates and to weight (adjust) the overall relative risk estimates by age and sex. Data on age-and sex-speci c population prevalence were available for chronic heart disease (CHD), chronic liver disease, chronic lung disease, chronic neurological disease, chronic renal disease, immunosuppression, diabetes, hypertension, smoking, and obesity. Age-speci c but not sex-speci c population prevalence data were available for asthma [19][20][21][22] . The age-and sex-strati ed population prevalence of CHD (excluding isolated hypertension) was estimated from a study that recorded a prior history of hospitalization with coronary artery disease (history of hospitalization for myocardial infarction or a surgical history of coronary balloon angioplasty or coronary stent implantation or coronary artery bypass) 20 . We assumed that the age distribution of coronary artery disease is a valid proxy for the age distribution of CHD. Where surveys assessed disease prevalence only in older adults, we assumed that the prevalence was zero in those younger than the lower age limit of the survey. Because we were unable to source relevant baseline data for the Greater Toronto Area and Saudi Arabia, we assumed that the age distribution of chronic diseases is similar in the Chinese, Greater Toronto Area, and Saudi Arabia populations.

Statistical methods
We compared the characteristics of patients infected with different subtypes of CoV using Fisher's exact test or the χ2 test for comparing proportions and Wilcoxon signed-rank test for comparing medians of continuous variables. To evaluate the association between risk factors and the risk of hospitalization, Poisson regression was used to estimate the incidence rate ratios associated with each risk factor, adjusted for age and sex. Sample sizes were large and the distribution of the outcome similar to the normal distribution; the width of the interquartile range will be approximately 1.35 standard deviations.
For ease of analysis, we treated all data reported as median as the mean and standard deviation 23 .

Results
As of February 19, 2020, a total 74,280 laboratory-con rmed or clinically diagnosed cases of COVID-19 infection were o cially recorded worldwide. Of these, we included 1406 patients who required hospitalization for medical reasons and laboratory testing in this study 2,24−27 . Data were included for 4175 patients hospitalized with SARS-CoV infection (China = 4013; Greater Toronto Area = 144), and 512 patients hospitalized with MERS-CoV infection in Saudi Arabia (Fig. 1).
Our analysis showed that the proportion of men with COVID-19 was signi cantly higher than in those with SARS (p < 0.001) but lower than in patients with MERS (p < 0.001). The proportion of patients with COVID-19 who had any coexisting chronic medical conditions was signi cantly higher than in those with SARS (p < 0.001) but lower than this proportion in patients with MERS (p < 0.001). The prevalence of hypertension among patients with COVID-19 (17%) was higher than that of patients with SARS (p < 0.001). The prevalence of immunosuppression and malignancy was lower among patients with COVID-19 than among those with MERS who had CHD, chronic lung disease, chronic renal disease, and chronic neurological disease (p < 0.001). A history of smoking, male sex, any coexisting chronic medical condition and hypertension were found to be the most common risk factors for hospitalization with COVID-19 (Table 1). We compared all hospitalization risk factor data with the average prevalence and sex ratio for COVID-19 in the Chinese population. We found that men were more susceptible than women to COVID-19 (p < 0.001). Patients with COVID-19 had a higher rate of any coexisting chronic medical conditions (p < 0.001) and a higher prevalence of heart-related diseases (p < 0.001). Rates of chronic kidney disease, chronic central nervous disease, hypertension, malignant tumor, and smoking history were all lower among patients with COVID-19 than those in the average Chinese population (p < 0.001), among which hypertension was the strongest risk factor for hospitalization (p < 0.001) ( Table 2). Signs and symptoms at hospital admission were compared for COVID-19 with SARS and COVID-19 with MERS. Fewer patients with COVID-19 exhibited fever, diarrhea, vomiting, nausea than those with the other two diseases (p < 0.001). Patients with COVID-19 were less likely to report myalgia and fatigue than those with SARS (p < 0.001). Cough symptoms were more prevalent among patients with COVID-19 than in those with SARS (p < 0.001), including for the subgroups productive cough, dry cough, and yellow sputum (p < 0.001). Only 1% of patients with COVID-19 had hemoptysis on admission, as compared with 2% with SARS and 17% with MERS (p < 0.001) ( Table 3). The values of hematological, liver, and renal function tests as well as in ammation markers on admission are shown in Table 5. The proportion of patients with COVID-19 who had elevated alanine transaminase (ALT) and aspartate transaminase (AST) was signi cantly lower than in those with SARS or MERS (p < 0.001). Fewer patients with COVID-19 had lymphopenia than did those with SARS, and elevated creatinine kinase was less prevalent in patients with COVID-19 than in patients with SARS (p < 0.001). However, thrombocytopenia, high lactate dehydrogenase (LDH), and elevated C-reactive protein (CRP) were more common in patients with COVID-19 than in those with SARS (p < 0.001).

Discussion
Herein, we report results of the rst comparison of clinical characteristics and risk factors among hospitalized patients with SARS-CoV-2, MERS-CoV, or SARS-CoV infection. In our statistical analysis of the available published data, we determined that man sex and hypertension were the most common risk factors for COVID-19. Moreover, in comparison with patients with SARS or MERS, patients with COVID-19 showed lower prevalence of fever, diarrhea, vomiting, or nausea, but higher prevalence of cough symptoms thrombocytopenia, high LDH, and elevated CRP.
For all three CoVs investigated, men were found to be relatively more susceptible than women; we also identi ed a higher sex ratio in our study population than that in the general population of China, which may be a trait of CoV infection (Table 1). Surprisingly, in patients with COVID-19 who had high blood pressure, although the prevalence was higher than that among patients with SARS, it is still signi cantly lower the prevalence of hypertension in the national population of China. Among the CoV infection groups, the median age of patients with MERS is 57 years, and the prevalence of hypertension is signi cantly higher than the population average. However, the average age of patients with SARS or COVID-19 was younger (48 for COVID-19; 38 for SARS) (Tables 1 and 2), and these patients had a relatively low incidence of hypertension. Additionally, ACE2 has a strong a nity with the Ang II type 1 and type 2 receptors, regulating blood pressure, and the gene encodes a protein that is a functional receptor for the S glycoproteins of SARS-CoV-2 and SARS-CoV. Which may be another reason for the low incidence of hypertension in COVID-19.
Interestingly, we found that a smoking history was associated with lower risk of hospitalization among patients with COVID-19 than among the general Chinese population (p < 0.001). This nding may be owing to differences in the statistical methods used in the included studies, or owing to the small proportion of past smokers (only 3.1%) among women in our study 28 . However, a similar phenomenon has been reported for other viral agents 29 ; this nding may be worth further investigation.
Among common symptoms of fever and cough, the proportion of patients with COVID-19 who had fever was signi cantly lower than that in patients with SARS or MERS ( Table 3). The prevalence of coexisting chronic diseases among patients with COVID-19 was not only higher than that among patients with SARS and MERS but was also higher relative to the average in the Chinese population. It believed that the disease history, such as low immunity 30 , will also in uence the common symptoms, relative to SARS and MERS have more higher rate of disease history ( Table 1). Symptoms of the digestive tract are also less frequent in COVID-19, and the effect of SARS-CoV-2 on the digestive tract may be more limited than that of other viruses 14 . However, a recent study SARS-CoV-2 has been found in the feces of patients, indicating that fecal-oral transmission may be possible and replication in the digestive tract cannot be ruled out 31 . The probability of cough symptoms was 68% overall, and among the subgroups, dry cough symptoms was the most frequent ( Table 3). The cause of frequent dry cough is in ammation of the lungs, even with a small amount of phlegm. It is possible that patients with dry cough have very thick sputum that is di cult to discharge; therefore, patients in the hospital who have this symptom should be closely monitored.
In patients with COVID-19, proli c thrombocytopenia, hemoptysis, elevated LDH, and elevated CRP were common (Table 4). Decreased lymphocytes and elevated AST, ALT, and CK are common in patients with SARS and are associated with a more severe prognosis. In one study, elevated LDH was found to be a risk Page 11/19 factor for acute respiratory distress syndrome (ARDS) in patients with SARS 32 . In patients hospitalized for SARS, a lower absolute lymphocyte count was associated with poorer prognosis 33 . Hematological and serum chemical abnormalities indicate that hospitalized patients with COVID-19 have serious systemic disease 34 .
It is yet to be determined whether this is the result of severe pneumonia and poor tissue oxygenation (such as in SARS) or an excessive in ammatory response 35 . It is known that these indexes exist in patients with COVID-19; however, further research is needed to con rm the correlation with severity of disease and whether these affect the course of this disease.   Certainly, there are some limitations in this study. First, this was a meta-analysis and there were some missing data. Second, COVID-19 is a newly identi ed infectious disease, the understanding of which is still evolving; some clinical data and outcomes may be updated in the future.

Conclusion
This comparative analysis showed that patients hospitalized with SARS-CoV-2 infection share some risk factors with those hospitalized for SARS-CoV and MERS-CoV infection. However, we identi ed differences in the clinical pro les of infection with these CoVs. Generally, clinical signs and symptoms of SARS-CoV-2 infection were less severe than those of SARS-CoV and MERS-CoV infection, which may be the cause of low mortality owing to COVID-19. However, male sex, smoking history, and hypertension were identi ed as the most common risk factors for hospitalization owing to COVID-19 in this study. Greater attention is needed for patients with these risk factors in clinical practice, to improve clinical treatment and control the rate of SARS-CoV-2 infection.

Declarations
Ethics approval and consent to participate: Not applicable.

Consent for publication:
Not applicable.
Availability of data and material: The data that support the ndings of this study are available from [PubMed, Embase, CNKI, and Ovid/Medline] but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of [PubMed, Embase, CNKI, and Ovid/Medline].

Funding:
The research was supported by the COVID-19 emergency clinical research project from Guangdong provincial bureau of traditional Chinese medicine (2020ZYYJ05).
Competing interests: Figure 1 Flow chart showing the process of screening the published data.

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