Use of Convalescent Plasma Therapy for COVID-19: A Scientometric Assessment of Global Publications during 2020-21

The study evaluates the global research output (820 records) on “Use of Convalescent Plasma Therapy for COVID-19” on metrics with the aim to understand the current status of research at the global, national, institutional, and individual author level. The study is based on publications and citations data sourced from the Scopus database during 2020-21. The publications and citations data was statistically analyzed on various metrics such as document type, country of publication, collaboration patterns, author affiliation, journal name, and citation patterns. The USA, China and India lead the world ranking of 15 most productive countries in the subject. China, U.K. and Netherlands lead in the ranking of most cited countries. In addition, the study maps key productive institutions, key authors, key source journals, as well as most significant keywords in the subject to visually present their inter-relationships using Biblioshiny and VOSviewer software. This results and findings from the study describe the progress made by the world in this hot area of global interest.


INTRODUCTION
Since December 2019, a pneumonia outbreak associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had caused a worldwide epidemic. World Health Organization (WHO) named this virus as coronavirus disease 2019 (COVID-19). It spread rapidly worldwide with a high rate of transmission and substantial mortality. COVID-19 symptoms range from mild, self-limited respiratory disease to severe progressive pneumonia, multiple organ failure, and even death. WHO declared it as a pandemic on March 11, 2020. As of February 2021, a total 103,631,793 confirmed cases and 2251613 deaths had been reported in 223 countries. 1 Considering that there has been no proven therapy in terms of effective vaccine (though it is now available) and specific antiviral medicine, it was necessary and urgent on the part of scientists and doctors to look for an alternative strategy or option for COVID-19 treatment, especially for the benefit of patients with sever symptoms. Ongoing research in this area has resulted a multiple studies on the use of convalescent plasma for COVID-19 to treat severely or critically ill COVID-19 patients, without unexpected or serious adverse events. 2 Convalescent plasma (CP) therapy (or passive immunization or serum therapy), a classic adaptive immuneotherapy, was born from the intuition of Behring and Kisato in the late 19 th century. It was widely used for the treatment of bacterial infections until the discovery of antibiotics, as well as during the viral pandemics of the 20 th century and in the beginning of the 21 st century. It still has clinical applications (e.g., tetanus prevention). The use of convalescent plasma involves transfusing plasma collected from patients who have already recovered from an illness, in an attempt to transfer neutralizing antibodies and confer passive immunity. The potential efficacy of convalescent plasma was first described during the Spanish influenza pandemic of the early 1900s Since then, convalescent plasma has been used to treat a wide range of viral infections, including measles, parvovirus B19, H1N1, Ebola and some coronaviruses. Among the many coronaviruses that are only mildly pathogenic to humans, there are three that have caused notably severe clinical manifestations and have been treated with convalescent plasma: i) severe acute respiratory syndrome coronavirus (SARS-CoV), ii) Middle East respiratory syndrome coronavirus (MERS-CoV) and iii) severe acute respiratory infections (SAR) viruses. 3 Virus neutralization by antibodies is the principle behind the functioning of plasma of patients recovered from SARS-CoV-2; high-titer-specific antibodies bind to SARS-CoV-2 neutralizing the viral particles, blocking access to cells, and activating potent effect or mechanisms, such as complement activation and phagocytosis. 4 Recently, in 2017, the WHO Blood Regulators Network (BRN) published a position paper, International Journal of Medicine and Public Health, Vol 11, Issue 2, Apr-Jun, 2021 recommending convalescent plasma as the first-choice treatment to be tested in the absence of authorized drugs; however, this strategy has not been followed. In the current epidemic, the principle of passive immunization through convalescent plasma has been applied in several circumstances and particularly in patients with serious complications. Also, the FDA of USA has proposed plasma treatment in order to face the increasingly complex situation and manage patients with serious or immediately life-threatening COVID-19 disease. Several studies and clinical programs are still ongoing and more extensive studies are now in the pipeline to provide a robust evidence for or against the use of convalescent plasma. Worldwide there are over 60 clinical trials actively recruiting COVID-19 patients to study the effect of convalescent plasma. 5 Given the ongoing trends in "Use of Convalescent Plasma Therapy for COVID-19" it is considered worthwhile that a bibliometric study be undertaken to understand and describe the current state of research in the subject based on global literature published till date.

Literature Review
Till date, quite a few studies have been undertaken to assess and describe the state of global research in COVID-19 literature using bibliometric methods. A review of such studies is described here. Zyoud and Al-Jabi 6 performed a bibliometric analysis to track the current hotspots and identify future directions in COVID-19 (19,044 publications). Research studies related to COVID-19 were obtained from the Scopus database during the early stage of the outbreak. The data was analyzed by using well-established bibliometric indices such as document type, country, collaboration patterns, affiliation, journal name, and citation patterns. Biblioshiny and VOSviewer were used to map and determine hot topics in this field. The most discussed topics of research in COVID-19 include "clinical features studies", "pathological findings and therapeutic design", "care facilities preparation and infection control", and "maternal, perinatal and neonatal outcomes". Philip Shapira 7 undertook a bibliometric study to analyze COVID-19 related scientific publications through to October of 2020 and described broad trends, fields, countries, and organizations in the subject. Two different databases were used for sourcing data: PubMed and the Web of Science. Yue Gong et al. 8 analysed the global literature related to COVID-19 using bibliometric methods, citation analysis, and knowledge mapping methods. Studies reported temporal patterns, main countries affected, and core subjects. The status and trends in COVID-19 research were explored from January 2020 to March 2020 to reveal the conceptual knowledge map in SARS-CoV-2. The results provide a reference point for the current and future coronavirus research studies for policymaking worldwide. Lou, Tian, Niu, Kang, Lian, Zhang and Zhang 9 analysed the publications about COVID-19 to summarize the research hotspots and make a review, to provide a reference point for researchers in the world. The authors searched PubMed using the keywords "COVID-19" from inception to March 1, 2020. They identified and analyzed the data which included title, corresponding author, language, publication time, publication type, research focus. It is evident from this literature review that not even a single bibliometric study has appeared so far on the topic of 'application of convalescent plasma therapy to COVID-19 patients' . Given this context, it was decided to undertake a bibliometric study in the proposed subject.

Objectives
The purpose of this study is to analyze and evaluate the literature on "Use of Convalescent Plasma Therapy for COVID-19" on bibliometric indicators as a way to understand the status of global research in the subject. The data for the study was sourced from the Scopus database covering the period 2020-2021. The study attempt to describe the global research on a series of metrics such as (I) publication output count, type and source, (ii) annual growth trends, (iii) citation trends, (iv) identify key countries, organizations, individual authors, (v) highlight most significant keywords, most sought after subject areas of interest, (vi) research collaborative linkages, (vii) most preferred source journals, and (viii) characterize bibliographic features of highly cited papers on this topic.

ANALYSIS AND RESULTS
The search on theme "Use of Convalescent Plasma Therapy for COVID-19" in Scopus database resulted in a total of 820 (2020=790; 2021=30) publications. The global publications (820) received 10641 citations, averaging to 12.98 citations per paper. Of the 820 publications, 170 (20.73%) resulted from research projects funded by 100+ funding agencies, received 4316 citations, averaging to 25.39 citations per paper. The major funding agencies supporting research projects are: National Institute of Health, USA (39 publications), National Natural Science Foundation of China (31 papers), National Institute of Allergy and Infectious Diseases (11 papers), Canadian Institute of Health Research, National Cancer Institute, National Heart, Lung and Blood Institute, USA and National Key Research and Development Program of China (7 papers each), etc.. Of the total output, articles and reviews account for the largest publications share (34.61% and 34.27%), followed by letters (12.07%), notes (6.83%) and the rest by others. English was the dominant publishing language (with 797 publications), followed by Chinese (6), Russian (5), French (3), Czech, Hungarian and Spanish (2 each) and 3 other languages with 1 each.

Top 15 Most Productive Countries
In all, 90 countries participated in global research on "Use of Convalescent Plasma Therapy for COVID-19" but the distribution of productivity by country of origin is highly skewed. For instance, 56 countries contributed 1-5 papers each, 15 countries 6-10 papers each, 8 countries 11-20 papers one line, it indicates that they collaborated to publish a single paper. The USA, U.K. and Italy collaborated with 13-14 countries and top the list with most collaborative linkages (131, 78 and 48). The bottom three countries (Turkey, France and Iran) collaborated with 6-11 countries but rank at the bottom with least number of collaborative linkages (6, Table 2).

Subject-Wise Distribution of Research Output
The Scopus database organized global research output on "Use of Convalescent Plasma Therapy for COVID-19" under four broad disciplines (Table 3). Medicine accounts for a 81.83% share of publications, followed by Immunology and Microbiology (18.41%), Pharmacology, Toxicology and Pharmaceutics (14.39%) and Biochemistry, Genetics and Molecular Biology (16.71%). In terms of discipline-wise research performance on citations, Immunology and Microbiology registered the each, 6 countries 21-50 papers each, 2 countries 51-100 papers each and 3 countries 104-286 papers each. The USA, China and India lead in global ranking with most publication share of 34.88%, 15.98% and 12.68% respectively, followed by 12 other countries which together accounted for a 36.46% global share. In terms of research citations performance only three countries -China (39.78 and 3.06), U.K. (23.64 and 1.82) and Netherlands (20.69 and 1.59) performed above the world average (14.33 CPP and 1.10 RCI) ( Table 1). A networks map of top 15 most productive countries, generated using VOSviewer software tool. Figure 1, visually presents their comparative productivity and their interrelations for collaborative research in the subject. The United States dominates in research productivity as well as in international collaboration, followed by China and India. The size of the circle of a country is proportional to its productivity. The thickness of links between countries represents the strength of their collaborative contributions to the research topic. Network visualization of countries is grouped into four clusters. Cluster 1 and 2, in red and green colour, and they represent 6 countries each -(the United States, China, India, Canada, Saudi Arabia and South Africa) and (Italy, the United Kingdom, France, Turkey, Germany and Netherlands), followed by clusters 3 illustrated in blue colour with 2 countries (Iran and Australia) and the last cluster in yellow colour comprises 1 country (Brazil).

Collaborative Linkages among Top 15 Countries
The country-wise collaboration links between countries are depicted in Figure 2. The size of the node is proportional to the collaborative activity of the country. The biblioshiny app web interface divides the most productive 15 countries grouped into 3 clusters. Cluster 1 orange colour represents the USA, India, and China are the biggest nodes and followed by the United Kingdom and Italy belong to the blue colour cluster 2 and Turkey belong to the red cluster 3 respectively. A line between the two countries indicates their collaborative linkages in research. The thickness of lines connecting the countries indicates the degree of their co-authorship in publications. When the two countries connected by  The circle size and font size in Figure 3A is proportional to the frequency of occurrence of a keyword. The links between the keywords show that these keywords co-occur in the literature.
On classifying global research publications on the theme "Use of Convalescent Plasma Therapy for COVID-19" under different patient highest rate of citations per paper (19.42 CPP) and it was the least for Pharmacology, Toxicology and Pharmaceutics (4.50 CPP) ( Table 3).

Significant Keywords
The keyword co-occurrence in research publications serves as a secondary support to get an insight into main topics and research trends in the "use of convalescent plasma therapy for COVID-19". Figure 3 (A&B) were generated through VOSviewer software and Biblioshiny app web interface application. Figure 3A is a networks map of keyword cooccurrences at a glance. Figure 3B presents textual data about keywords in a simple way. The keywords are listed in Table 5 in the decreasing order of the frequency of their occurrence in the literature. The most

Most Productive Global Organizations
In all, 457 organizations were found to have participated unevenly in global research on "Use of Convalescent Plasma Therapy in COVID-19 Patents". The productivity of top 25 most productive organizations varied from 8 to 21 publications per organization whereas the global average productivity of all organizations was just 1.79 per organization. Secondly, the organization-wise distribution of global research output is highly skewed. For instance, the top 25 organizations together contributed  The publications profile of top 25 most productive organizations is shown in Table 7. Six (shaded in green colour) out of top 25 organizations contributed above the group-25 average productivity (11.2), and four (shaded in yellow colour) registered their research performance (measured on metrics such as 'citations per paper' and 'relative citation index') above the group-25 average (28.45 CPP and 2.19 RCI).

Collaboration among top 25 organizations
The research collaboration network map (Figure 4) depicts top 25 organizations in 6 clusters. The Biblioshiny app was used to analyse the distribution and collaboration of top institutes in the field of "Use of Convalescent Plasma Therapy for COVID-19". The box size and font size of each node is proportional to its publication output in the field. The bigger the font and box size of the node, the higher its output.

Collaborative Linkages among Top authors
The  (Table 10).

Medium of Research Communication
All of the research publications on "Use of Convalescent Plasma Therapy for COVID-19", have appeared in journal medium. Of the total 470 journals which reported 820 articles, 331 published 1 paper each, 80 published 2 papers each, 47 published 3-5 papers each, 13 published 6-10 papers each, and 6 published 11-29 papers each. A co-citation networks map of top 25 most productive journals ( Figure  6) depicts journals in 11 clusters. In the map, two or more journals that cover closely related topics are placed close to one another, and those covering fundamentally different topics are located far from each other. The circle size and font size of a journal node is proportional to the frequency of its co-citations. Cluster 1 in red colour has 5 journals i.e.

SUMMARY AND CONCLUSION
This study evaluates global research on "Use of Convalescent Plasma Therapy for COVID-19 with the aim to describe research productivity, performance, and bibliometric mapping in the subject on bibliometric indicators. The data for the study was sourced from Scopus database covering the period 2020-2021. The global research on "Use of Convalescent Plasma Therapy for COVID-19 comprised a total of 820 publications, and these were contributed by 570 authors from 457 research organizations spread across 90 countries. The average research productivity in the subject was 1.43 per contributing author, and 1.79 per research organization. The global research output (820 publications) received a total of 10641 citations since publication. The average performance in the subject was 16.74 citations per paper for global research, and 25.39 citations per paper for the sponsored research. Only 1.95% (16 publications) share of 820 reported high citations above 100, between 101 and 977 citations per paper. The USA topped in the global ranking of most productive countries with a 34.88% global publication share, followed by China and India (15.98% and 12.68%), and 12 other most productive countries. Country-wise analysis of top 15 most productive countries reveal that only three countries -China, UK, and Netherlands had registered their citation performance above the group-15 average (14.33 CPP and 1.10 RCI). Furthermore, the study provides a window to key countries, key organizations, key authors, key source journals, popular areas of research interest, and significant keywords. The USA, China, India have provided leadership in research studies on "Use of Convalescent Plasma Therapy for COVID-19 as most productive countries. But at the institutional level and the individual author level the picture about country performance in terms of research productivity is different. At institutional level, the USA is the home country to five out of top 10 global institutions. China to three, and the UK to two institutions. India is the home country to one institution but ranked at 11 th position. At the individual author level, it is the USA which dominates as the home country to six out of top ten authors in the global output. Interestingly, international collaboration in convalescent plasma research is seen as the strongest among the USA, China, India vis-a-vis other top 12 countries.
accumulated high citations, 101 to 977 citations per paper since their publication during 2020-21, and averaging their performance to 394.81 citations per paper (cumulative total 6317 citations). The distribution of 16 highly cited papers is skewed: 6 papers received citations in the range 101-200 per paper, 5 papers were in the citation range 201-400, 4 papers in the citations range 401-607 and 1 paper received a high of 977 citations. Of the 16 highly cited papers, 7 were published as articles, 8 as review papers and 1 as a note. Of the 16 highly cited papers, 4 were contributed by one single organization per paper (as non-collaborative papers) and the remaining 12 resulted by two or multiple organizations per paper (9 appeared as national collaborative and 3 as international collaborative papers). The 16 highly cited papers involved 156 authors from 83 organizations. Tongji Medical College, China contributed 3 highly cited papers, the largest number of papers, followed by National University of Singapore, Renmin Hospital of Wuhan University (2 papers