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

Abstract

Background

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a newly recognized illness that first appeared in Wuhan (Hubei Province), China and has since spread rapidly to other provinces in China and around the world [1–3]. Coronaviruses (CoVs) are enveloped RNA viruses that are widely distributed in humans, other mammals, and birds and that cause respiratory, intestinal, liver, and neurological diseases [2, 4]. There are seven CoV types known to be associated with human disease; four of these strains, including 229E, OC43, NL63 and HKU1, usually cause the common cold [5]. However, the other three types of CoV, severe acute respiratory syndrome-associated coronavirus (SARS-CoV) [6], Middle East respiratory syndrome-associated coronavirus (MERS-CoV) [7], and SARS-CoV-2 are highly pathogenic, leading to severe pneumonia and even death. World Health Organization (WHO) statistics at the time containment of the outbreak of SARS-CoV was announced on July 5, 2003 indicated that a total 8096 cases of SARS and 774 deaths were reported across 29 countries, with an overall case-fatality rate (CFR) of 9.6%. MERS-CoV infection has not yet been contained and is thus far responsible for 2494 confirmed cases and 858 deaths across 27 countries, with a CFR of 34.4% [8]. As of March 13, 2020, the WHO announced that SARS-CoV-2 infection had affected a cumulative number of 132,758 people worldwide and led to 2009 deaths [9]; the CFR was estimated to be about 3.7%. Although the estimated CFR for COVID-19 is not much higher than those of SARS and MERS, COVID-19 has led to more total deaths owing to a larger number of cases. Thus, infection with these CoVs merits urgent attention.

Similarities and differences have been reported among SARS-CoV-2, SARS-CoV, and MERS-CoV. First, viral gene sequencing of SARS-CoV-2 affecting the first patients has shown a 79.5% similarity with SARS [10]; in addition, as with SARS-CoV, bats and minks are potential hosts of SARS-CoV-2 [11]. Second, the estimated mean value of the basic regeneration index (R0) of SARS-CoV-2 is 3.28, which is much higher than those of SARS-CoV and MERS-CoV; thus, the transmissibility of SARS-CoV-2 appears to be much higher, thereby leading to a larger number of cases [12]. Furthermore, the incubation period of SARS is 4.5 (2–12) days and that of MERS is 4 (2–14) days; the estimated incubation period of COVID-19 is 3 (0–24) days [13, 14]. Third, although both SARS-CoV-2 and SARS-CoV invade human cells through spike protein binding to the ACE2 receptor, in comparative structural analysis, the invasiveness and virulence of SARS-CoV-2 differ from those of SARS-CoV [15]. The pathological features of COVID-19 also display some differences to those of SARS and MERS [16].

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 confirmed cases of COVID-19. As the three most important CoV strains to emerge during the first 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.

Methods

Results

As of February 19, 2020, a total 74,280 laboratory-confirmed or clinically diagnosed cases of COVID-19 infection were officially 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 significantly 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 significantly 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 inflammation 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 significantly 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 first 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 identified 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 significantly 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 significantly 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 affinity 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 finding 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 finding may be worth further investigation.

Among common symptoms of fever and cough, the proportion of patients with COVID-19 who had fever was significantly 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 influence 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 inflammation of the lungs, even with a small amount of phlegm. It is possible that patients with dry cough have very thick sputum that is difficult to discharge; therefore, patients in the hospital who have this symptom should be closely monitored.

In patients with COVID-19, prolific 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 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 inflammatory response [35]. It is known that these indexes exist in patients with COVID-19; however, further research is needed to confirm 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 identified 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 identified differences in the clinical profiles 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 identified 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.

Abbreviations

MERS: Middle East Respiratory Syndrome Coronavirus; SARS: Severe Acute Respiratory Syndrome; CoV: Coronavirus; CFR: Case Fatality Ratio; CHD: Chronic Heart Disease; LDH: Lactate Dehydrogenase; ACE2: Angiotensin Convetting Enzyme 2; CK: Creatine Kinase.

Declarations

Ethics approval and consent to participate:

Not applicable.

Consent for publication:

Not applicable.

Availability of data and material:

The data that support the findings 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:

The authors report no conflicts of interest.

Authors' contributions:

All authors fulfill the contribution requirements as per the International Committee of Medical Journal Editors’ role of authors and contributors’ guidelines. All authors conceptualized and designed the study and critically reviewed and revised the manuscript. Z.T.L and X.D.W carried out the analyses and wrote the initial manuscript. G.S.S extracted data and carried out analyses. Z.T.L and F.Y oversaw manuscript development.

Acknowledgments:

We like to thank Alan Schreier and Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac) for editing the English text in a draft of this manuscript.

References

1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, et al: A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 2020.
2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
3. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson K, Wilkerson S, Tural A, et al: First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020.
4. Weiss SR, Leibowitz JL. Coronavirus pathogenesis. Adv Virus Res. 2011;81:85–164.
5. Richman DD, Hayden WR FG, editors: Clinical virology, 4th End. Washington: ASM Press 2016.
6. Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003;348:1953–66.
7. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814–20.
8. Wu Z, McGoogan JM: Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020.
9. Organization WH. Coronavirus disease 2019 (COVID-19) Situation Report – 72. https:/pdf?sfvrsn=3dd8971b_2 Data as reported by national authorities by 10:00 CET 1 April 2020.
10. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, et al: A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020.
11. Guo Q, Li M, Wang C, Wang P, Fang Z, tan J, Wu S, Xiao Y, Zhu H. Host and infectivity prediction of Wuhan 2019 novel coronavirus using deep learning algorithm. bioRxiv preprint January 21, 2020.
12. Liu Y, Gayle AA, Wilder-Smith A, Rocklov J. The reproductive number of COVID-19 is higher compared to SARS coronavirus. J Travel Med 2020.
13. Arabi YM, Al-Omari A, Mandourah Y, Al-Hameed F, Sindi AA, Alraddadi B, Shalhoub S, Almotairi A, Al Khatib K, Abdulmomen A, et al. Critically Ill Patients With the Middle East Respiratory Syndrome: A Multicenter Retrospective Cohort Study. Crit Care Med. 2017;45:1683–95.
14. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, et al: Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020.
15. Lu RZX, Li J, et al.: Genomic characterization and epidemiology of 2019 novel coronavirus: implications of virus origins and receptor binding. Lancet 2020.
16. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, et al: Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020.
17. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13.
18. WHO: Clinical management of severe acute respiratory infection when Novel coronavirus (nCoV) infection is suspected: interim guidance. Jan 11. 2020. .
19. Yang ZJ, Liu J, Ge JP, Chen L, Zhao ZG, Yang WY, China National D, Metabolic Disorders Study G. Prevalence of cardiovascular disease risk factor in the Chinese population: the 2007–2008 China National Diabetes and Metabolic Disorders Study. Eur Heart J. 2012;33:213–20.
20. Zhong N, Wang C, Yao W, Chen P, Kang J, Huang S, Chen B, Wang C, Ni D, Zhou Y, et al. Prevalence of chronic obstructive pulmonary disease in China: a large, population-based survey. Am J Respir Crit Care Med. 2007;176:753–60.
21. Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, Chen M, He Q, Liao Y, Yu X, et al. Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet. 2012;379:815–22.
22. Prevention NCfCaNDCa. Report on chronic disease risk factor surveillance in China. Beijing. People’s Medical Publishing House 2007.
23. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135.
24. Chen Lei LH, Liu Wei L, Jing L, Kui S, Jin. Deng Yan, Wei Shuang: Analysis of clinical features of 29 patients with 2019 novelcoronavirus pneumonia. Chinese Medical Association February 4, 2020.
25. Wei-jie Guan Z-yN, Liang YuHWen-hua, Ou Chun-quan, He Jian-xing, Liu L, Shan H, Lei Chun-liang, David SC, Hui B, Du Lan-juan, Li G, Zeng K-Y, Yuen Ru-chong, Chen Chun-li, Tang T, Wang Ping-yan, Chen J, Xiang Shi-yue, Li, Jin-lin Wang, Zi-jing Liang, Yi-xiang Peng, Li Wei, Yong Liu, Ya-hua Hu, Peng Peng, Jian-ming Wang, Ji-yang Liu, Zhong Chen, G, Li, Zhi-jian Zheng, Shao-qin Qiu, Jie Luo, Chang-jiang Ye, Shao-yong Zhu, Nan-shan Zhong: Clinical characteristics of 2019 novel coronavirus infection in China. medRxiv preprint February 6, 2020.
26. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al: Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020.
27. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–13.
28. Wang M, Luo X, Xu S, Liu W, Ding F, Zhang X, Wang L, Liu J, Hu J, Wang W. Trends in smoking prevalence and implication for chronic diseases in China: serial national cross-sectional surveys from 2003 to 2013. Lancet Respir Med. 2019;7:35–45.
29. Wang C, Yu H, Horby PW, Cao B, Wu P, Yang S, Gao H, Li H, Tsang TK, Liao Q, et al. Comparison of patients hospitalized with influenza A subtypes H7N9, H5N1, and 2009 pandemic H1N1. Clin Infect Dis. 2014;58:1095–103.
30. Patel DM, Riedel DJ. Fever in immunocompromised hosts. Emerg Med Clin North Am. 2013;31:1059–71.
31. Zhang H, Kang Z, Gong H, Xu D, Wang J, Li Z, Cui X, Meng JXiao,T, Wang Z, et al: The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. bioRxiv preprint January 30, 2020.
32. Liu Yang Z, Yuhua, Baoyua C. Clinical Features and Risk Factors for Poor Outcome in a Major Outbreak of SARS. Chin Med. 2003;6:36–9.
33. Hung IF, Cheng VC, Wu AK, Tang BS, Chan KH, Chu CM, Wong MM, Hui WT, Poon LL, Tse DM, et al. Viral loads in clinical specimens and SARS manifestations. Emerg Infect Dis. 2004;10:1550–7.
34. Zheng Y, Huang Z, Yin G, Zhang X, Ye W, Zhiliang Hu, Chunmei Hu, Wei H, Zeng Y, Chi Y, et al: Comparative study of the lymphocyte change between COVID-19 and non-COVID-19 pneumonia cases suggesting uncontrolled inflammation might not be the main reason of tissue injury. medRxiv preprint doi: https://doiorg/101101/2020021920024885 February 19, 2020.
35. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39:529–39.

Tables

Table 1. Characteristics of patients hospitalized with COVID-19, SARS, and MERS

Abbreviations: COVID-19, coronavirus disease 2019; SARS, severe acute respiratory syndrome-associated coronavirus; MERS, Middle East respiratory syndrome-associated coronavirus.

Table 2. Age- and sex-adjusted risk factors for hospitalization

Abbreviations: COVID-19, coronavirus disease 2019; SARS, severe acute respiratory syndrome-associated coronavirus; MERS, Middle East respiratory syndrome-associated coronavirus.

Table 3. Signs and symptoms on admission

Abbreviations: COVID-19, coronavirus disease 2019; SARS, severe acute respiratory syndrome-associated coronavirus; MERS, Middle East respiratory syndrome-associated coronavirus.

Table 4. Laboratory results on admission

Abbreviations: COVID-19, coronavirus disease 2019; SARS, severe acute respiratory syndrome-associated coronavirus; MERS, Middle East respiratory syndrome-associated coronavirus. AST, aspartate transaminase; ALT, alanine transaminase; CK, creatinine kinase; CRP, C-reactive protein; LDH, lactate dehydrogenase.

Table 5, mentioned on page 9, was omitted by the authors in this version of the paper.