3.1 General publications and trend
Thirty-year trend analysis showed that there is a general increase in the published articles and reviews on HCQ treatment from 1991 to 2020, especially in recent 10 years (Figure1A). Regarding the contribution countries, there were 51 countries in total (Figure1B). Among them, the United States has obviously played a leading role in HCQ treatment research, with 785 papers published. The other top 10 countries are France (271), China (209), England (179), Italy (173), Germany (155), Canada (116), Spain (112), Netherlands (105) and India (100). Moreover, we picked the science citation index publications from all the documents and used bibliometrics online analysis platform to detect the distributions and cooperations on countries/regions. It found consistently that USA, France, China, UK and Italy ranked the top 5 countries (Figure 1C). It also showed there was a most frequent international cooperation between the United States and China, followed by the US and England. Dual-map overlays in CiteSpace act as citation links in visualization from a global citing base map to a global cited base map [19-21]. Different color of a link represents different source of the discipline and the labels show the subject covered by journals . Furthermore, the vertical and the horizontal axes of ellipses represent the number of articles and authors around the labels . There were three main citation paths in the middle of the dual-map. As the left and right sides respectively represent the map of citing and cited journals maps, the orange path indicated journals in the area labeled ‘molecule/biology/immunology’ were mostly cited by the publications in the ‘molecule/biology/genetics’ area. The other two green paths suggested all publications in ‘medicine/medical/clinical’ areas were respectively cited in the journals of ‘health/nursing/medicine’ and ‘molecule/biology/genetics’.
3.2 Analysis of HCQ research areas in recent 30 years
3.2.1 Analysis of keywords co-occurrence
Keywords which definitely summarize and condense the whole content reflect the most important information of a document . Therefore, the keywords of an article are often used to explore and identify hotspot in a research field . Under the condition we have set in CiteSpace, the node type was selected for “keyword,” the threshold was set to top 30, and ‘pathfinder and pruning the merged work’ were set as the pruning, which finally generated a map of keyword co-occurrence related to HCQ treatment. Nodes size reflects the number of publications or keywords frequency. Thus, the bigger the circle node, the more original articles the keyword involved. In our knowledge map, we constructed a network with 247 nodes and 377 links (Figure2A). The top 15 high-frequency keywords were hydroxychloroquine, treatment, rheumatoid arthriti, chloroquine, systemic lupus erythematosus, COVID-19, double blind, disease, methotrexate, efficacy, risk, sars-cov-2, autophagy, disease activity and coronavirus (Table1).
3.2.2 Time trends for the keywords of HCQ treatment studies
Time zone view comprised of keywords nodes showed the general evolution of research over time . The more articles during that period, the more important influential the research results are . Through the visualization analysis, HCQ treatment has already been a research hotspot in 1991 and was widely studied in rheumatoid arthritis, systemic lupus erythematosus and other autoimmune diseases since 1992 (Figure 2B). With the outburst of COVID-19 pandemic at the end of 2019, HCQ have become a hotpoint of research.
3.2.3 Keyword clusters revealed by CiteSpace
The keywords clustering map can provide insight into the main research topics in the intellectual base . In order to study the basic knowledge structure of HCQ research field, we used CiteSpace as a method for classifying information according to the similarity of literature research content. In CiteSpace project, we adopted LLR algorithm to conduct the cluster analysis. Generally, modularity Q values larger than 0.3 (Q>0.3) are considered as significant cluster, and a mean silhouette value which is greater than 0.5 (S>0.5) indicates that publications within a cluster contain highly consistent or similar content. The number of publications included decreases from top to bottom . Totally, there are 14 major keyword clusters (0#-13#) identified in our clustering map, with the labels extracted from keywords in the publications (Figure 3A). Most of the citation keywords in clusters were concentrated from 1998 to 2017. Clustering analysis showed cluster 0# ranked first was represented as ‘COVID-19’, containing 30 keywords with a mean silhouette value of 0.963. Cluster1# “sulfasalazine” was the second largest cluster including 25 frequencies, followed by cluster2# ‘gold sodium thiomalate’. The other clusters with relevant labels were explicitly listed in Table 2. Significantly, almost all the clusters were heavily intertwined, except for the cluster 8# and 10#. Cluster 8# centred on ‘autophagy’ mainly focused on the role and mechanism of HCQ in diseases. Thus, it has been demonstrated that HCQ was the only clinically-approved autophagy inhibitor, and widely studied in cancer experiments and clinical trials [28,29]. According to a high centrality value of cluster 10#, ‘COVID-19’ related research has definitely become a novel and urgent research hotspot.
Timeline view represents temporal characteristics of the research areas classified by clustering . The knowledge map clearly shows number of nodes in chronological order from left to right on a horizontal line in each cluster. All cluster labels are arranged on the right listed from top to bottom gradually. Time span was from 1991 to 2020, with newer articles placing closer to the right side. Keywords notes with purple circles usually serve as a pivotal step to connect with each cluster. As Figure 3B showed, the nodes on the horizontal line of cluster 0#, 3#, 6#, 7# and 10# are much more and bigger, indicating these areas are very important for more studies at the corresponding time. Especially, there were plenty of purple circles in cluster 0# which suggested scientists have made many remarkable achievements in HCQ field from 1991 to 1995. In addition, high frequency keywords in cluster 9# showed chloroquine and hydroxychloroquine, which shared the similar chemical structures of quinine , have always been explored in comparison with the therapeutic effect, mechanism and side reaction.
3.2.4 Burst detection of keywords
In order to analyze the research hotspots shifts from 1991 to 2020, we used CiteSpace to detect the strongest burst keywords identified as indicators of the research frontier topics (Figure3C). The map shows the years when hot keywords began to appear and ended. Blue line on burst knowledge map represents time intervals, and the period of keywords bursts is showed with red line. We have totally detected the top 25 strongest citation burst words of HCQ treatment in diseases. From the burst detection analysis, methotrexate (strength: 30.7304) was the most strength burst keyword in this field during the entire time period from 1996 to 2009, followed by sulfasalazine (22.1668), combination therapy (21.3015), toxicity (19.1906) and placebo (16.302).
3.3 Analysis of hydroxychloroquine in COVID-19 research
As a novel coronavirus epidemic broke out in China and quickly swept the world at the end of 2019, many researchers begin to focus on the role of hydroxychloroquine in COVID-19 treatment. Based on this research condition, we gathered the number of 568 articles and reviews from WOSCC, including 355 papers in Science Citation Index Expanded. Figure 4A showed the distribution of countries/regions and institutions of all the publications. Through the statistics of CiteSpace, there were mainly 38 countries involved in the study on HCQ treatment in COVID-19. The top10 country analysis indicated that the United States (183) had still been the largest contributor to this area, India (74), Italy (69), China (45), France (41), England (33) and Brazil (26) were followed. Differently, the data of SCI publications showed the USA (96), Italy (41), China (36), India (28), and France (21) were ranked in the top five (Figure 4B). Top 5 research institutions ordered by the publications from WOSCC included Aix Marseille Univ (14), Univ Tehran Med Sci (11), Univ Paris (8), Harvard Med Sch (8) and Huazhong Univ Sci & Technol (8) according to the CiteSpace analysis (Figure 4C). Besides, NEW ENGL J MED was the most frequent cited journal with 389 times, LANCET was cited 369 times and INT J ANTIMICROB AG was cited 354 times, the others were listed clearly in Figure 4D. Results of the dual-map overlays proved authoritative research on HCQ treatment in COVID-19 is already underway, covered by authority journals such as LANCET (Figure 4E). Citing journals of the 568 publications are mainly from the fields of neurology, ophthalmology, medical clinical, medicine, molecular and immunology. The cited journals are almost from the fields of health, nursing, medicine, molecular, biology and genetics. Especially, the molecular field was most concentrated in the cited journals shown in the center of the circle on the right (Figure 4E).