The Progress and Research Trends in Coronavirus (COVID-19) Research Publications: Epidemiological and Bibliometrical Approaches

COVID-19, Scopus, Top Authors, Institutes, Countries and Co-Words Analysis The main objective of the present study is to summarize the research output about COVID19. The search was conducted in Scopus, the largest abstract and citation database of peerreviewed literature, and later it was analyzed on VOSviewer. Total 34716 research documents have been published about COVID-19 till September 2020. We focused on three parameters, i.e., co-authorship pattern, citations, and co-words analysis. Based on the total number of publications, h-index, total citations, and citations per document, we provided the list of the top ten authors, institutes, and countries. Based on the total number of publications, the topranked author is Wiwanitkit, V., and the top institute is Harvard Medical School, USA. It is worthy to note that more than 150 countries have contributed to research output. Based on the total publications, citations, and h-index, we provided details for each continent. Later, we provided the list of the top ten countries. The highest documents are published by the USA (25.35%). We analyzed the 343682 keywords from all publications to provide a general overview or the common trends in publications. We also analyzed the top 2000 most cited documents and provided the details of the top ten authors, institutes, and countries. Based on the VOSviewer' analysis, the information on the co-occurrence of words in titles, abstracts, and keywords is provided. This may help to depict the common trends in research publications. Based on the bibliometrics results, significant work has been published on pathogenesis, diagnosis, treatment, and prevention of this pandemic.

The structural protein named spike (S) protein, which mediates the virus attachment as well as entry into the host cells and is known as a target for the neutralizing antibodies. S-protein with two subunits of S1, and S2 is defined as a surface spike glycoprotein leading virulence by binding to the human angiotensin-converting enzyme 2 (ACE-II) receptors. Previous literature also revealed two strains of coronavirus consisting of type S and L, which directly involved disease severity [19]. In addition, hemagglutinin-esterase dimer (HE) has been located on the surface of the virus that presumably participates in virus entry and appears to be important for conferring infectivity.
Immune Responses Following the Infection SARS-CoV-2-specific antibodies (Abs), as well as cell-mediated responses, are stimulated following the infection. Previous evidence suggested that these humoral immune responses are partially protective. However, it is not established that whether all infected patients acquired enough immunity or not. Nevertheless, the detectable serum antibodies against the receptor-binding domain of the viral spike protein in the large portion of recovered patients were developed [20], which drop over several months [21]. Of note, detectable neutralizing antibodies are most likely associated with the disease severity and could not identify in mild infection [22,23]. However, it has been estimated that cell-mediated immunity such as T cells subsets (CD4 and CD8) appear to have more stability in convalescent patients [24].

SARS-CoV-2 Mechanism of Action
The infection of COVID-19 primarily depends on cell entry by specific receptors. As mentioned above, the main host receptor for SARS-CoV-2 internalization refers to the angiotensin-converting enzyme 2 (ACE2) receptors as a membrane-associated zinc metalloprotease [25]. ACE2 related gene is ubiquitously expressed in various human tissues, e.g., lung, kidney, vascular endothelium, gastrointestinal track, and cardiac muscle [26]. Besides, the cellular transmembrane protease serine 2 (TMPRSS2) appears to be critical for virus conferring infectivity [27]. In detail, SARS-CoV-2 binds to the ACE2 receptor through the receptor-binding domain of its spike protein and subsequently enters into the cell through the plasma membrane fusion or endocytosis [27]. In this regard, after screening the amino acid changes in spike protein among a large sequence database, it has been surprisingly found that D614G substitution, as a glycine for aspartic acid, causes a dominant polymorphism [28]. Viral genome replication commonly occurs in the cytoplasm via the double-membrane vesicles from the endoplasmic reticulum (ER). Pp1a and pp1ab termed as two imperative polyproteins also play a pivotal role in viral replication and transcription [29,30] and simultaneously propagate the release of functional polypeptides of a spike, envelop, membrane, nucleoprotein, replicas, and polymerase. After that, newly synthesized viral RNA packs are incorporated into the virions. Following the vesicular transportation, the matured virions can export from the host cells through the exocytosis process [31]. In lung tissue, SARS-CoV-2 is transmitted by respiratory aerosols to cause a presumable infection in upper or lower respiratory tract. Some respiratory complications induced by coronaviruses include tracheobronchial lymphadenopathy, multifocal pulmonary atelectasis, lymphocytic bronchiolitis, type II pneumocyte hyperplasia, edema and consolidation [32].

Therapeutic Interventions for COVID-19 Treatment
The understanding of COVID-19 is evolving moment by moment, leading us to achieve an effective therapeutic approach besides the vaccines. The common symptoms of COVID-19 include headache, dry cough, dizziness, myalgia, fever, sore throat, dyspnea, which can progress to the ARDS [33]. Many clinical trials are also being carried out to pre-and post-exposure prophylaxis to determine the drug's safety and efficacy against the COVID-19. In this regard, hydroxychloroquine (HCQ) and anti-malaria drug were considered as a candidate therapeutic agent in both pre-or postexposure prophylactic settings. However, further available data suggested that HCQ could not be effective in terms of the COVID-19 treatment and preventing the SARS-CoV-2 infection [34]. Recently, an anti-viral drug named remdesivir (Veklury) revealed clinically desirable impacts against the diseases, especially in the complicated form of the disease, and makes it the first officially FDA-approved therapeutic agent once received the authorization of emergency application in May 2020, for all adult patients and pediatrics (12 years and older) with diagnosed COVID-19. Remdesivir is known as a prodrug of adenosine analogue with the potential to inhibit RNA polymerase activity [35]. Similarly, favipiravir, another antiviral drug with a broad spectrum inhibitory effects of viral RNA polymerase, is commonly prescribed for outpatients [36,37]. Furthermore, it has been proposed that lopinavir/ritonavir (Kaletra), as a protease inhibitor, has therapeutic potential for COVID-19 treatment. The recent literature clarified that lopinavir/ritonavir significantly improved the outcomes in hospitalized patients; In contrast, according to the results of the recovery clinical trial, it has been suggested that monotherapy with lopinavir/ritonavir is not to be an effective therapeutic candidate, while the combination with interferon-beta would be remarkably more effective [38]. Notably, the recovery trial provided evidence for the administration of dexamethasone in ill patients admitted to IUC. The results of this comprehensive study established that the use of dexamethasone can significantly drop the 28-day mortality in those under invasive mechanical ventilation conditions [39]. The development of monoclonal antibodies is also being evaluated to neutralize SARS-CoC-2 in the post-exposure manner [40]. For example, tocilizumab (TCZ), a monoclonal antibody against interleukin-6 (IL-6), was recommended as an alternative treatment to quench the cytokine storm in ill patients with COVID-19 [40]. Besides, the stimulated non-specific immune responses against the SARS-CoV-2 infection following the Bacille-Calmette-Guerin (BCG) vaccine have also recently attracted researchers' attention in this era [41].

Bibliometric Analysis
Bibliometric analysis can be defined as a statistical evaluation of published scientific articles, books, chapters of a book, journals, broad research areas, institutions, and any specific country. The literature analysis is a very important means of sharing data information about the quantity and quality of scientific work [42,43]. Various parameters like citation, co-citation, co-words analysis, H-index, impact factors are used for analysis purposes. These analytical tools can help researchers to understand the regularities and patterns in their specialized domain. The field of bibliometric was first introduced in information and library sciences, but now every field of study, either social science, physical or biological sciences, can implement it to evaluate trends and expansion in respective domains [42,43]. It is a reliable method for studying the intellectual structure of every field. This technique helps evaluate individual authors, institutes, and countries in the scientific literature. It also provides a guideline for quick survey among inter-disciplinary researchers [42,43].
It is worthy to note that several articles are published about bibliometric analysis of COVID-19; however, they covered a comparatively smaller number of publications [7][8][9][10] Comparatively, a more comprehensive study was conducted by Hojat et al., which studied the publication pattern of 923 documents published until 1 st April 2020 [44][45][46][47]. The present study was designed to perform the bibliometric analysis of COVID-19 publications. The following three basic parameters will be covered: Co-authorships, and Citations and Co-words analysis. We will precisely focus on the most productive scientists, institutes, and countries. The graphical overview of the bibliographic data will be provided by using visualization of similarities (VOSviewer) software.

Material and Method Source of Information
Scopus (Elsevier BV Company, USA) is the largest database of scientific literature. The data was retrieved between 1 st and 10 th September 2020 using the code name . It is worthy to note that only those documents were considered for analysis that contained the word "COVID-19" in the titles of the publications. The data was collected by all authors and downloaded in CSV format. Later, it was quantitatively and qualitatively analyzed in Microsoft Excel 2013 for access type, year, author name, document type, keywords, affiliations, and country.

VOSviewer Analysis or Visualization Maps
Considerable literature is available which confirms the importance of analysis of co-authorship, bibliographic coupling, and co-citation networks. It has a long history, with early work dating back to the 1960s [48]. We used VOSviewer version 1.6.9 for viewing and creating the desired bibliometric maps. The software was developed by Van Eck and Waltman [49] for constructing and visualizing bibliometric networks [49]. For more information, please see http://www.vosviewer.com/. By default, at most, 1,000 lines are displayed and represent the 1,000 strongest links between items. The distance between two items in the visualization approximately indicates the relatedness of the items. The results are presented as network visualization maps.
We also highlighted the details of the top ten (10)

Co-Authorship Analysis for Researchers, Institutions, and Countries
As scientific research has grown, a significant increase in the productivity rate (total publications) has been observed. H-index is an authentic parameter for the analysis of the productivity index. Hirsch introduced the parameter in 2005. This indicator measures the productivity and impact factor of researchers as well as of scientific journals. Total citation is another important indicator used for the evaluation of the author's output. This parameter acknowledges the quality of the work of authors, institutes, and countries. It is important to note that this parameter is effective in a comparative study. Self-citation is the reference given to a document from the same journal or the same work. Self-citation has some limitations as it affects the impact of both author and a journal. Citation per paper/document is also used to indicate the citation received per document in a journal. Based on the number of total publications, h-index, total citations, and self-citations, we provided the lists of top-rank authors, institutes, and countries.  Table 1. Table 1 The The  Table 2.   Irrespective of the region, the list of the top 10 countries is described in Appendix 1. Based on the number of publications, USA is the top country with 8711 (or 25.35 %) publications, followed by China (n = 4164/ 12.12%), United Kingdom (n = 4051/11.79%), Italy (n = 3806/11.08%), and India (n = 2238/6.51%). While, based on total citations, China is the top-ranked country (n = 56606), followed by USA (n = 50736), United Kingdom (n = 23725), Italy (n = 21382) and France (n = 9486). On the basis of H-index, China (n = 107), USA (n = 93), UK (n = 67), Italy (n = 60) and France (n = 43) can also be ranked as top five countries. Similarly, we can also depict the publications and citation data as citation per document (CPD). In this way, China can be termed as the top-ranked country (CPD = 14). France, Germany, UK, the USA, and Italy have a CPD score of six (n = 6), while the CPD for Canada, Australia, Spain, and India are four (4), four (4), and two (2), respectively.

The Analysis of Top-Ranked Author, University and Country
We also quantitatively analyzed the top-ranked author, university, and country. This may help in explaining that a single author, university, and country can affect collaboration and networking. For this purpose, we focused on three fundamental factors, i.e., the total number of co-authors, institutes and collaborations with international countries were elucidated. As stated earlier, based on the total number of publications, the top-ranked author is Wiwanitkit, V. (n = 93). In all of his publications, ten authors have collectively contributed. Similarly, 69 different institutes of departments have contributed to publications.
In Harvard Medical School publications (n = 705), more than 3500 authors have contributed. However, 50 authors have published at least five or more than five publications. The names of all authors are provided in Figure 1.

Co-Words Analysis of the COVID-19 Literature
The study of the co-occurrence of at least two technical words in research documents is termed as co-words analysis. It indicates the topics addressed in research articles and helps to explore the overall trend. With the help of this tool, researchers would better understand the hotspots and disciplinary structures of their research. It can also help to understand the progress and existing regularities in research output. To explore the major focus of COVID-19 related studies, we retrieved data consisting of 343682 keywords from more than 34000 research documents using the Scopus database. After a critical analysis, we categorized the collected data under different themes. The exact number and percentage of each group is depicted in Appendix 2.

COVID-19 Pandemic (152896 / 44%)
SARS-Cov-19 was diagnosed as a novel strain of Coronavirus declared a pandemic by WHO on January 30, 2020. Now the viral infection is named severe acute respiratory syndrome corona virus-2 (SARS-COV-2). These are RNA positive strain of the Corona family. The symptom of this virus looks like the common flu. Structurally, this virus has crown-like structures attached to ACE 2 (Angiotensin-converting enzyme 2) of the epithelium cells and cause severe respiratory disease. Researchers proposed several mechanisms for a viral invasion to CNS, most acceptable is via the olfactory route, thus leading to cause different neurological manifestations in patients. This

Subject (56850 / 16%)
Medical experts and scientists mostly studied COVID-19 related research that has been analyzed mostly on humans of different age groups. This group consists of 16% of the total keywords. We compiled similar words that highlighted the trend in this field. The following words are Human, minimize the prevalence of virus transmission. The local communities are made aware of public health about disease transmission, isolation, purification, medical education, education, infection risk, and communicable disease control via social media.

Prevention Parameters (12990 / 10%)
Under this theme, 10% of keywords are compiled that elaborate the prevention factors taken by medical specialists to minimize the erupt effects of COVID-19 infection. For this purpose, we collected a group of relevant words like emergency health service, follow up, incidence, isolation, hand washing, metabolism, personal protective equipment, prevalence, prevention, and control, prognosis, protective equipment, tocilizumab, treatment outcome, unclassified drug, and World Health Organization.

Pathophysiology (10004 / 10%)
Under this title, 10% of the retrieved keywords are collected that reflect several Laboratory Technique, Clinical Laboratory Techniques for the diagnosis of infection. The elevation observed in the cytokine storm, D Dimer accelerates the invasion of pathophysiological disorders. C Reactive Protein, Reverse Transcription Polymerase Chain Reaction, Interleukin 6, Blood, Polymerase Chain Reaction, Pathology, Pathogenicity, Epidemiology, Epidemiology were also added to this class.

Treatment (5932 / 6%)
The appearance of the deadly virus in human beings triggered many complicated pathologies. With the help of medical specialists, researchers collectively proposed treatment and/ or therapies to overcome the infection by synthesizing drugs/ medicines, effectively contributing to the recovery of COVID-19 patients. This class comprised 6% of the total retrieved keywords. The words like Drug Effect, Antiviral Agents, Antivirus Agent, Azithromycin, Remdesivir, Chloroquine, Lopinavir Plus Ritonavir, and Hydroxychloroquine were compiled under this title to understand the trend in this domain.
Diagnostic Techniques (5362 / 5%) Five (5%) of the keywords highlighted the trend of research on the COVID-19 pandemic. Scientists used different instrumental tools like Diagnostic Imaging, Computer Assisted Tomography, Retrospective Study, X-ray Computed Tomography, Tomography, and X-Ray Computed to examine the internal damage caused by the virus. Thorax Radiography is a sensitive technique to identify the early symptoms of viral infection that could be useful for the prognosis of COVID-19.

Countries (5359 / 5 %)
The viral wave affects different countries of the world. However, about 5% of research highlighted the most affected countries such as China, Italy, the United States, and the United Kingdom (to name a few).

The VOSviewer Analysis of the Top Two Thousand (2000) Most Cited Documents
In all 2000 publications, more than 9300 authors have contributed. However, fifty-nine (n = 59) authors have published at least ten research documents. The details are provided in Table 4  The USA publishes the highest documents (n = 664), followed by China (n = 552) and Italy (n = 304). One the basis of citations, China (n = 49566) overtakes USA (n = 37915), followed by UK (n = 17914). While based on CPD, Vietnam holds the top position (CPD = 165), followed by Peru (n = 96) and United Arab Emirates (n = 92). The top ten list is provided in the Table 6.

Co-Occurrence of Words in Titles, Abstracts and Keywords in the Top 2000 Cited Documents
In this part, we focused on the co-occurrence of words in titles, abstracts, and keywords of the publications. In titles, total terms or words were found to be 3859. Furthermore, 80 of them repeated at least ten times, as shown in Figure 3. Based on the words co-occurrence, we can describe the general tendency or broader aspects of these publications. First of all, we will state that different words such asacute respiratory distress syndrome, coronavirus, coronavirus disease, covid, novel coronavirus, novel coronavirus disease, and severe coronavirus disease were used in titles to represent the COVID-19 pandemic. Different cases, case reports, case series, challenges, clinical characteristics, and clinical features were described, with the main focus on detection, diagnosis, risks factors, spread, severity, transmission, implications, and prevention in the patients. Furthermore, the authors tried to provide an association of COVID-19 with cancer, infection, mental health, pneumonia, pregnancy, and obesity. Different measures like lockdown, control on the pandemic, management, lesson learned, or outcome are also described. Other words also appeared to represent countries and the time frame of the pandemic, such as February, Wuhan, China, India, Italy, the USA, and Singapore.
A total of 19766 words were appeared in all (n = 2000) abstracts, of which101 appeared at least 50 times (Figure 4). It can be stated that the overall pattern or tendency of co-words was similar with titles. For example, the authors majorly elaborated on different symptoms and association of COVID 19 with other complications like cough, diabetes, fever, hypertension, illness, infection, intensive care unit, pneumonia, mortality, death, etc. Other months, areas, and countries also appeared, such as December, January, February, March, April, Hubei Province, China, Italy, the USA, and India. Different words were also found in the abstract, which can provide direct information of the hospital admission, to diagnosis and data interpretations. Some examples of the words used in the abstract are admission, hospitalization, disease, diagnosis, knowledge, laboratory, data, and interpretation. While the total authors' keywords in 2000 documents were found to be 9280, of which 50 were repeated at least 103 times or 100 words were repeated at least 103 times ( Figure 5). To further explore the broader trend in these documents (n = 2000), we also retrieved 42645 keywords to understand. After a critical analysis, it was observed that the authors used different terminology for the virus such as coronavirinae, coronavirus, coronavirus disease 2019, coronavirus infection, COVID-, adult respiratory distress syndrome, SARS-CoV-2, SARS virus, SARScoronavirus. They also highlighted the viral association with different receptors or enzymes like angiotensin-converting enzyme 2, angiotensin II receptor antagonists that accelerate cytokine, cytokine storm, D dimer in the patient's body. Other words like anxiety, cardiovascular disease, comorbidity, depression, diabetes mellitus, diarrhea, fatigue, fever, headache, hypertension, mental health, myalgia, pneumonia, severity of illness index, sore throat, disease association, disease course, disease outbreaks, disease progression, disease severity, disease surveillance, and disease transmission indicate that the authors tried to elucidate the possible association of these disorders with COVID 19 infections. In addition, hydroxychloroquine, corticosteroid, chloroquine are the effective drugs suggested for the patients. Similarly, different laboratory techniques for diagnosis and/or therapies were described in detail. For example, x-ray computed tomography, tomography, x-ray computed, thorax radiography, and oxygen therapy. In addition, the authors focused on quarantine, social distance, risk factors, and prevalence of COVID 19 in patients in different types of studies and reports like articles, case reports, controlled studies, and letters.

Conclusion
Although SARS-CoV-2 infected more than 10 million people, many aspects of the COVID-19 pathophysiology remain unclear. Therefore, the comprehensive bibliometric analysis on basic and clinical investigations and public health and clinical interventions can promote advances in COVID-19 management. Since COVID-19 emerged as a severe threat to public health, the number of publications on different aspects of this infection, such as epidemiology, pathogenesis, transmission, and prevention, etc., has dramatically increased. In-country analysis sections, it was found that more than 150 countries are vastly working and producing scientific documents to find a solution for this pandemic.