Bibliometric Analysis and Systematic Review of Global Coronavirus Research Trends Before COVID-19: Prospects and Implications for COVID-19 Research

Coronaviruses (CoV) cause respiratory and intestinal infections. We conducted this bibliometric analysis and systematical review to explore the CoV-related research trends from before COVID-19. We systematically searched the Ovid MEDLINE, Ovid Embase, and Web of Science (WOS) databases for published bibliometric analyses of CoV from database inception to January 24, 2021. The WOS Collection was searched from inception to January 31, 2020, to acquire the CoV-related publications before COVID-19. One-Way ANOVA and Bonferroni multiple-comparison tests were used to compare differences. Visualization mapping and keyword cluster graphs were made to illustrate the research topics and hotpots. We included 14,141 CoV-related publications for the bibliometric analysis and 16 (12 articles) CoV-related bibliometric analyses for the systematic review. Both the systematic review and bibliometric analysis showed (1) the number of publications showed two steep upward trajectories in 2003–2004 and in 2012–2014; (2) the research hotpots mainly focused on the mechanism, pathology, epidemiology, clinical diagnosis, and treatment of the coronavirus in MERS-CoV and SARS-Cov; (3) the USA, and China; the University of Hong Kong; and Yuen KY, came from the University of Hong Kong contributed most; (4) the Journal of Virology had the largest number of CoV related studies. More studies should focus on prevention, diagnosis, and treatment in the future.


INTRODUCTION
Coronaviruses (CoV) are a large family of positive-sense single-stranded RNA viruses that cause illnesses ranging from the common cold to more severe diseases (1,2). Some CoV are zoonotic and can cause respiratory and intestinal infections in animals and humans (3), and have even resulted in lethal endemics, such as Middle East Respiratory Syndrome Coronaviruses (MERS-CoV), Severe Acute Respiratory Syndrome Coronaviruses (SARS-CoV), and Coronavirus Disease 2019 (COVID-19) (4).
With the outbreak and epidemic of CoV-related diseases, an increasing number of studies discussed the epidemic characteristics, diagnosis, infection mechanisms, and prevention of CoV (4)(5)(6)(7)(8). The appearance of COVID-19 was accelerating such research, which was certainly unique in the history of science and led to an explosion of research output. This output includes many meaningful approaches, but some appear to be excessive and not scientifically sound (9,10). Against this background, it is very necessary to think about these compelling questions: Can we learn from previous research patterns regarding CoV? What influence do they have on future research? How can we use past efforts, their intensification, and the influences of research on CoV positively to better understand the needs for sustainable and appropriate research? (9). Therefore, it is very important to know about the global research on CoV in the time before COVID-19.
Systematically summarizing and analyzing the research of the CoV is helpful to understand the current state of research and provide references for future research. Bibliometric analysis is a statistical tool that is used to quantitatively and qualitatively measure and evaluate scientific publications (11)(12)(13). It consists of a review of the literature, and indicates the number, evaluation, and main trends of publications concerning a specific subject (14,15).
To the best of our knowledge, there have been two bibliometric studies on CoV-related research in English before the COVID-19 pandemic (16,17). One study published in 2016 assessed the characteristics of publications only focused on the MERS-CoV (18). Another study (19) analyzed the global research trends of the World Health Organization's top eight emerging infections including Ebola, Marburg, MERS, Severe Acute Respiratory Syndrome (SARS), and so on, but publications related to CoV were not systematically analyzed. A letter to the editor had simply investigated the publication characteristics of SARS-CoV, MERS-CoV, and COVID-19, but it only analyzed the number of publications and countries, which might not be enough to provide a reference for future research (20). In addition, several studies on coronavirus research trends were published in the time before the COVID-19 pandemic. However, some of the research focused on the specific periods, such as 2003 to March 2020. Therefore, we did a bibliometric analysis of all the publications before COVID-19. Additionally, these studies were based on various timespan and databases, and the findings did not well agree. We did this systematic review to summarize the findings of all the current bibliometric analyses in this topic to provide references for researchers focused on the emerging human CoV, and to provide ideas for finding effective control measures, drugs, and vaccines.

METHODS
This is a bibliometric analysis and systematic review, and the data we used were extracted from publications. Therefore, this study has no discernible ethical issues.

Data Source and Search Strategy
We searched PubMed, Cochrane Library, and Embase databases using the Medical Subject Headings (MeSH) to acquire the CoV-related terms. For the bibliometric analysis, we searched publications using these terms in the Web of Science (WOS) Core Collection from its inception to January 31, 2020. In terms of the systematic review, we systematically searched the Ovid MEDLINE, Ovid Embase, and WOS databases using terms relating to CoV and bibliometric analysis, for published bibliometric analysis from database inception to January 24, 2021. The detailed search strategy is displayed in Appendix (Appendix, Supplementary Tables 1, 2). No limitation was used. As the metrics are changing over time, all the searches and data exports were completed on the same day to avoid the possible bias caused by frequent updates of the databases.

Eligibility Criteria for Systematic Review
This systematic review included the bibliometric analyses of global CoV research trends. We excluded the bibliometric analyses without any indicators of publication and citation, journal, country or territory, affiliation and international cooperation, author, or subject/research topic. We also excluded conference abstracts, editorials, reviews, meta-analyses, and case reports or case series, as well as non-English and non-Chinese language publications and publications reporting duplicate data.

Data Collection and Cleaning
In terms of bibliometric analysis, we obtained (1) the characteristics of all the retrieved publications; (2) the 2019 journal impact factor (JIF) (21), 5 year JIF (21), and publication counts of the journals; (3) publication count per year, h-index, various citation values [average citations per item (ACPI), sum of times cited (STC) and No. citations of most-cited item (NCMCI)] and top-5 most-publications research areas (top-5 research areas) of the top-10 most-publications countries (top-10 countries); and (4) institutes, h-index, various citation values, and top-5 research areas of the top-10 most-publications authors (top-10 authors). All documents were downloaded in tab separator format.
We standardized the keywords with the same meaning but in different styles. For example, "coronavirus" was replaced by "coronavirus (cov)", "middle east respiratory syndrome coronavirus" was replaced by "MERS", etc.
As for the systematic review, one researcher (Y-PB) extracted the information from the included studies using a pre-piloted, standardized extraction table, and the other researcher (P-JY) checked the extraction. Any discrepancies between the reviewers were resolved by discussion. We extracted the following information: (1) study characteristics (first author, publication year, country, journal); (2) search strategies, and (3) indicators or findings on publication and citation, journal, country or territory, affiliation and international cooperation, author, subject/research topics, and keyword co-occurrence cluster.
Since there is no validated quality assessment tool that can be applied to bibliometric analyses, we did not assess the risk of bias or the methodological quality for the included bibliometric analyses.

Statistical Analysis
The data were entered into a spreadsheet program (Microsoft Excel 2016, Microsoft, Washington, USA). The statistical analyses and preparation of the figures were performed using  Stata, version 15 (Stata Corp, College Station, TX, USA). For all statistical tests, a two-tailed α level of 0.05 was used. We used VOSviewer 1.6.1 (Centre for Science and Technology Studies, Leiden University, Leiden, The Netherlands) to analyze the publication characteristics (22,23). Keywords co-occurrence can effectively reflect the research hotspots in the discipline fields, providing auxiliary support for scientific research (24). VOSviewer was also used for visualization mapping to present co-authorship and co-occurrence networks (25) and generate keywords clustering graph to present the research topic.

Basic Characteristics of CoV-Related Publications
A total of 14,141 publications were retrieved, of which around 77.27% were published as original articles, 8.36 % as reviews, 3.91% as proceedings papers, 3.13% as meeting abstracts, with the remaining being book chapters, etc., (Appendix, Supplementary Figure 1). For the book chapters, the Advances in Experimental Medicine and Biology (273), Advances in Virus Research (26), and Current Topics in Microbiology and  Immunology (27) were the top-3 most-publications, others were less than 10 records. Among these publications, 53.35% (7,544) records did not contain data in the funding agencies; 97.24 % (13,750) were published in English, 0.79 % (111) were in French, 0.75 % (106) were in German, and the remaining were in Spanish, Chinese, and 14 other languages.

Journals of CoV-Related Publications
The CoV-related publications were published in 500 journals. The 24 journals with more than 100 publications were listed. The journal with the most publications was the Journal of Virology (1,240), followed by Virology (546) and the Journal of General Virology (352). The 2019 JIF ranged from 1.306 (Avian Disease) to 9.580 (Proceedings of The National Academy of Science of The United States of America), and the 5 year JIF ranged from 1.330 to 10.600 (Figure 2).  (Figure 3A). Among the top-10 countries, 1/5 were from North America, 2/5 from Asia, and the rest from Europe ( Table 1). The CoV-related publication count of the top-10 countries over the 41 years is listed in Appendix (Appendix, Supplementary Table 3). Among these countries, a total of 6,753 institutions were involved in CoV-related publications. A network of 530 institutions with a frequency ≥ 10 was formed. The University of Hong Kong (China), the Chinese Academy of Sciences (China), Utrecht University (Netherlands), the University of Southern California (USA), and the University of Pennsylvania (USA) were at the center of the cooperation network and formed close cooperative relationships with other institutions (Figure 3B).

Countries and Regions of CoV-Related Publications
In terms of STC, h-index, and NCMCI of the top-10 countries, the USA was the most-contributed country with the highest hindex (156), STC (185,165), and NCMCI (1,823), followed by the Netherlands (107) and China (105) in h-index, China (73,101) and the Netherlands (47,486) in STC, and China (1,823) and Taiwan (1,823) in NCMCI ( Table 1).
The CoV-related publications of the top-10 countries mainly focused on the following research areas: virology, veterinary sciences, infectious diseases, immunology, biochemistry molecular biology, microbiology, and pharmacology ( Table 1, Appendix, Supplementary Figure 3). The most-contributed research area of the top-10 countries was virology, except for Taiwan, which focused on biochemistry molecular biology. The Netherlands contributed more to the virology area than any of the other nine countries (Appendix, Supplementary Figure 3).

Authors of CoV-Related Publications
A total of 43,476 authors were involved in the CoV-related publications, 402 authors with a frequency ≥ 10 times were included in the collaboration network analysis, and 27 cooperation networks were formed. Yuen KY (China), Baric RS (USA), and Drosten C (Germany) had the highest number of publications and were in the middle of the network diagram,  which shows that they formed close cooperative relationships with other authors (Figure 4). The top-10 authors with the most CoV-related publications mainly came from the USA (1/2) and China (1/5), and were focused in the University of Southern California and the University of Hong Kong ( Table 2). Most of the top-10 authors came from the departments of microbiology ( Table 2) and mainly focused on virology, microbiology, infectious diseases, immunology, and seven other research areas ( Figure 5, Table 2). The most-contributed research area of the top-10 authors was virology, except Drosten C who focused on infectious diseases ( Figure 5).
Yuen KY had the highest number of publications, h-index, and STC, followed by Perlman S and Baric (Figure 6).

Research Topics of CoV-Related Publications
The density map of 973 keywords is presented in the Appendix (Appendix, Supplementary Figure 4). "CoV (3,116 items), " "infection (1,413 items), " "identification" (1,393 items), etc. had the highest frequency in the red area, followed by "diagnosis (395 items), " and the "therapy (69 items)" in the yellow area and "treatment (35 items)" in the green area (Appendix, Supplementary Figure 4).

High-Frequent Citation Articles
Most of the top-10 most-cited publications came from the USA and were in high impact-factor journals such as New England Journal of Medicine, British Medical Journal, and Science. The most frequently cited article (1,823 citations) was published by Ksiazek et al. (28), followed by Drosten et al. (29) (1,732 citations) ( Table 3).

Study Characteristics of Published Bibliometric Analyses
A total of 17 (9,11,26,27,(30)(31)(32)(33)(34)(35)(36)(37)(38) CoV-related bibliometric analyses from 13 articles were included, of which one study (27) conducted five bibliometric analyses. All 17 bibliometric analyses were published in 2020 and included between 641 and 15,207 primary studies ( Table 4). Two included articles from India (26,38), one from Spain (34), one from Turkey (27), two from Israel (9,31), and the remaining 7 reports were from China (Appendix, Supplementary Table 4). All the 13 included articles were published in journals with IF from 0 to 5.993 (Appendix, Supplementary Table 4). Most of the CoV-related bibliometric analyses (88.2%, 15/17) retrieved data from the WOS up to 2020, and the types of original studies included were mainly articles and reviews. A majority of the CoV-related bibliometric analyses indicated that the annual publication count increased due to three notable epidemic events in history.  Table 4

Research Topics of CoV-Related Publications in Published Bibliometric Analysis
Four included bibliometric analyses (9,27,30,31) reported the total number of CoV-related research keywords (132-216). Most of the included bibliometric analyses showed that the main research fields of the CoV-related research focused on basic medical sciences (virology, microbiology, biochemistry & molecular biology, immunology, pharmacology, and pharmacy), clinical medicine (infectious diseases, pediatrics, and the respiratory system), veterinary sciences, and public health (public, environmental, and occupational health). The research hotpots mainly focused on the mechanisms, pathology, epidemiology, clinical diagnosis, and treatment of the coronavirus in MERS-CoV and SARS-Cov (    study found the USA and China were the most contributing countries in terms of STC, h-index, and NCMCI, which was supported by a previous study (20). This study showed that some institutes in the USA, China, and the Netherlands formed close cooperative relationships with other institutes. Because the USA is leading global scientific production, and the effort of the USA to foster international cooperation on CoV-related disease.
Keywords cluster analyses showed that the main research fields of the CoV-related research focused on basic medical sciences (virology, microbiology, biochemistry & molecular Notably, COVID-19 must become the research hotspot of coronavirus research, and clinical research on COVID-19 may be the key to defeating this epidemic. The most frequently assigned research fields are virology (2140); Infectious diseases (899); Veterinary sciences (720); Microbiology (622); Immunology (558).
1. The molecular and biological topics; 2. outlines the articles dealing with the SARS epidemic; 3. Combines the articles dealing with the MERS epidemic; 4. Focuses on the spike protein that is characteristic of CoV, its pathogenesis, and its connection to the other clusters.
The results underline the need for sustainable and forward-looking approaches that should not end with the containment of COVID-19. 1. Virology (including molecular, biology, and immunology); 2. Infectious diseases (including medicine, medical, and clinical); 3. Veterinary medicine.
The international cooperation is an important way to accelerate research progress and achieve success. Developing corresponding vaccines and drugs are the current hotspots and research directions. More research on prevention and treatment is needed according to an analysis of term density. Bibliometric analysis of the literature shows the research on coronavirus boomed when a novel coronavirus triggered outbreaks in people. With the end of the epidemic, the research tended to be cooling. Virus identification, pathogenesis, and coronavirus-mediated diseases attracted much attention. We must continue studying the viruses after an outbreak ended. (32) Virology; Veterinary sciences; Infectious diseases.
1. "Pathological research;" 2. "Epidemiology research;" 3. "Clinical research;" 4. "Mechanism research." The outbreak of the epidemic could promote coronavirus research, meanwhile, coronavirus research contributes to overcoming the epidemic. Attention should be drawn to the latest popular research, including "Spike protein," "Receptor binding domain," and "Vaccine." Therefore, more and more efforts will be put into mechanism research and vaccine research and development, which can be helpful to deal with the epidemic.  The most commonly used keywords were "Coronavirus" followed by "Virus," "Sars," and "Infection." The results of the study showed that the growth pattern was not uniform, USA, and the University of Hong Kong have played a major role in the contribution of Coronavirus research. Even though this depicts a higher scientific growth, it is an alarming sign to the community for preparedness. Under the prevailing situation of seeking better prevention, treatment and vaccination for COVID-19, in-depth research in the above portrayed metrics would be an added knowledge for the researchers. biology, immunology, pharmacology, and pharmacy), clinical medicine (infectious diseases, pediatrics, and the respiratory system), veterinary sciences, and public health (public, environmental, and occupational health). The research hotpots mainly focused on the mechanism, pathology, epidemiology, clinical diagnosis, and treatment of the coronavirus in MERS-CoV and SARS-Cov. These findings were in line with the findings of other published bibliometric analyses included in this study. However, the complete research process of virus includes the following: (1) studying the structure and function of the virus genome to fully understand the general morphology and structural characteristics of the virus; (2) exploring the replication, gene expression, and regulatory mechanism of the virus genome, to reveal the molecular nature of the virus infection and disease-causing; (3) researching and developing the virus genetic engineering vaccine and antiviral drugs; (4) studying the diagnosis, prevention, and treatment scheme of the virus infection disease (42,43). This study showed the current research on CoV mainly focused on the first two stages of virus research. Therefore, there still was a lack of enough research on the related clinical, epidemiological, diagnostic, and therapeutic aspects (44). As the WHO recommended, drugs and vaccines were considered to need accelerated research and development (45), and research on the diagnosis, vaccines, and treatment options for CoV-related diseases should be strengthened (46). Yuen KY from the University of Hong Kong contributed most to Cov-related research, especially in the fields of virology and microbiology. Followed by Baric RS and Drosten C, both of whom were members of the CoV Study Group (CSG) and assessed the novelty of the human pathogen tentatively named SARS-CoV-2 (47). The research of the CSG will improve understanding of virushost interactions in an ever-changing environment and enhance our preparedness for future outbreaks (47). In the future, CoV-related researchers can collaborate to conquer the virus.

STRENGTHS AND LIMITATIONS
To our best knowledge, this is the first systematic review of bibliometric analysis in global coronavirus research trends before COVID-19. We also explored the top-5 research areas of the top-10 countries and top-10 authors in this bibliometric analysis.
However, our study has some limitations.Firstly, for the bibliometric analysis,we only searched WOS, which may lead to the omission of some important studies (48)(49)(50). Secondly, some of the data we analyzed were automatically extracted from the downloaded publications by the software, such as author names. Since the software could not distinguish between authors with the same name, this might affect the results of our analyses. Thirdly, for the systematic review, the assessment of the risk of bias for the included studies was important, but we did not conduct the risk of bias assessment for lack of a valid assessment tool.

CONCLUSIONS
CoV-related publications before COVID-19 have shown a rapidly increasing trend. The USA and China have played a vital role in CoV-related researches. Yuen KY from the University of Hong Kong has made contributions. The research topics mainly involved the mechanisms, pathology, epidemiology, clinical diagnosis, and treatment of the coronavirus in MERS-CoV and SARS, and more researchers should focus on the prevention, diagnosis, and treatment in the future.

AUTHOR CONTRIBUTIONS
KY, PY, SW, and ML were responsible for the conception and design of the study. PY was in charge of the literature search data acquisition. PY, ML, ZL, JL, XH, YB, and YX collected, analyzed, and interpreted the data and wrote the first draft of the manuscript. YL was responsible for the editing and standardization of the tables and figures and gave critical advice on the manuscript. All authors reviewed the manuscript for important intellectual content and approved the final version for publication.