May 29, 2023

Ning Gao,1,* Meng Li,2,* Weiming Wang,1 Lei Wang,3 Zhen Liu,4 Yufeng Guo1 1Department of Acupuncture and Moxibustion, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 2Department of Gastroenterology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 3Department of Dermatology, China-Japan Friendship Hospital, Beijing, 100020, People’s Republic of China; 4Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, People’s Republic of China *These authors contributed equally to this work Correspondence: Zhen Liu, Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, No. 1 Xiyuan Playground, Haidian District, Beijing, People’s Republic of China, Email [email protected] Yufeng Guo, Department of Acupuncture and Moxibustion, Guang’ an Men Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange St., Xicheng District, Beijing, People’s Republic of China, Email [email protected] Background: In recent years, the incidence of herpes zoster has risen steeply, the exact pathogenesis of the acute pain and the transformation into postherpetic neuralgia are still obscure, and the absence of effective management remains a major therapeutic challenge. The purpose of this study was to perform a qualitative and quantitative bibliometric analysis of the 100 most cited papers on herpes zoster. Materials and methods: Related literature were retrieved from the Web of Science Core Collection. Excel and VOSviewer software were applied to quantitatively analyze, and construct the bibliometric network charts. Results: The Top 100 most-cited papers published between 2000 and 2018 showed a fluctuating downward trend. The most studies were published in the year of 2000 (n = 12). The article entitled “A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults” from Oxman MN, was the most-cited publication. The United States was the most contributing country, followed by the United Kingdom, and Italy. Finland occupied the highest citations per publication (CPP). The University of Colorado topped the list of institutions with the most publications with 18 articles and also had the most citations (average citations: 281.78 per article). Myron J Levin from the University of Colorado School of Medicine is the most published and most cited researcher overall, whereas Duke University’s John W Gnann tops the list in terms of average CPP. Conclusion: In terms of the quantity of T100 articles, researchers, and organizations, the US is the predominant country. The most T100 papers were published in the special journal Clinical Infectious Diseases. The most academic focus remain the remedies for postherpetic neuralgia and vaccine development for individualized groups. Keywords: herpes zoster, bibliometric study, top-cited, citation, VOSviewer Introduction Varicella zoster virus (VZV) belongs to the genus varicella virus of the family Herpesviridae and is transmitted in the population mainly through the respiratory tract. 1 It was first isolated in tissue culture in 1953. 2 Herpes zoster (HZ) is a cutaneous disease caused by reactivation of the VZV in the host. 3 When immunity to VZV declines due to aging or immunosuppression, VZV reactivation occurs. 4 The clinical presentation is typically a cluster of rashes and vesicles on a red base in a unilateral, dermatomal distribution, with intense neuralgia along the peripheral nerves near the skin lesion. 4 Some patients may develop systemic symptoms such as nausea, fatigue and fever. 3 The risk of HZ increases with age (>50 years). 5 The classical risk factors also include immunosuppression, infections, and psychological stress. 5 According to the Centers for Disease Control and Prevention (CDC), nearly one out of every three people in the United States will suffer from HZ during their lifetime. 6 An estimated 19.4% of patients with HZ experienced postherpetic neuralgia (PHN), as observed in Chinese outpatients, 7 which is one of the most common complications of HZ, with severe neuralgia in the affected dermatome after the rash recedes. 8 The overall incidence of HZ has linearly increased over the past few decades, most likely due to an aging population and an increase in the number of immunocompromised people, 9 which not only affects the quality of life of patients, but also poses a significant clinical and economic burden. 10 , 11 Currently, the optimal treatment for immunocompetent patients with acute HZ usually consists of conventional antiviral drugs and analgesic therapy as well as topical treatment. 12 However, the effective therapy reliably relieved the pain of PHN is absent. 4 Recently, VZV reactivation has been observed following the administration of various Corona Virus Disease 2019 (COVID-19) vaccinations, although the causality is not clear. 13 Until now, the exact pathogenesis that how VZV causes acute pain and the mechanisms underlying the transition to PHN are far from explicit, so effective treatments remain a major therapeutic challenge. 14 Highly cited papers are recognized as influential papers in the field of study and reflect research trends and scientific advancements in the field. 15 In contrast to traditional literature reviews, bibliometrics is one of the key approaches to objectively measure the impact of scholarly publications by extracting measurements from knowledge in publications and then performing statistical analysis. 16 This approach has now been applied to research in a variety of disciplines, such as dermatology, 17 oncology, 18 neurology. 19 To our knowledge, no bibliometric analysis of highly cited publications has been conducted in the HZ field. In this study, we aimed to identify the 100 most cited HZ-related papers and analyze their bibliometric characteristics in order to identify research hotspots and future directions in this field for medical professionals and researchers. Methods Data Sources We performed a literature search from the Web of Science Core Collection (WOSCC) on October 24th, 2022. Index selection is Science Citation Index Expanded (SCIE). Since the subject search and abstract search will retrieve a large number of non-relevant documents, the title search was chosen to ensure the validity of the search data source. 20 In this study, the search formula in the WoSCC database were as follows: TI = (Herpes Zoster) OR TI = (Shingles) OR TI = (Zoster) OR TI = (Postherpetic Neuralgia). Inclusion Criteria We included the research articles or reviews in the English language, which were published between January 1st, 2000 to October 24th, 2022, which contained the search term (herpes zoster) in the title and/or abstract. A total of 4655 articles were identified as eligible, including 4199 articles and 456 reviews. The literature search strategy and screening process of this study are shown in Figure 1 . Figure 1 Flow chart of literature screening. Data Collection and Statistical Analysis The following information is extracted from the WoS database for each publication: author, institution, country, keywords, number of citations, year of publication. The impact factor (IF) of journals is defined through the Journal Citation Report (2021) ( https://JCR.Clarivate.com/ ). Quantitative analysis of data was performed using Microsoft Excel and a co-linear network of countries, institutions, authors and keywords was plotted using VOSviewer (version 1.6.18). Different nodes in the network represent different terms, while the size of the nodes represents the frequency of occurrence, and the links between nodes indicate co-occurrence relationships. In addition, to eliminate the impact of the time of publication on article citations, we calculated the average citations per year (ACY) score of the article: ACY=citation times/(2021-publication year+1). Quality Control Two investigators (NG and ML) independently performed the data retrieval and screening. Divergences were resolved by discussion or the arbitration of a third reviewer. Data retrieval and export were completed on the same day (October 24, 2022), preventing bias caused by database updates. Under the guidance of senior experts (ZL and YFG), the two researchers finally reached an agreement on the T100 papers. This study did not include any animals or experiments and therefore did not require ethics committee approval. Results We retrieved the 100 most frequently cited papers related to HZ and ranked them in descending order based on the citation count of the articles. Of the 100 papers, 88 were articles and 12 were reviews. A comprehensive list of 100 publications and article information is presented in Table 1 . In terms of research type, the top 100 most cited papers (T100 papers) were divided into four categories: (1) Observational studies (OS), including epidemiological, randomized controlled trials (RCTs), case-control, and cohort studies; (2) Basic science research (BS), including pathology, experimental and animal studies; (3) clinical guidelines; (4) review articles, including meta-analyses and systematic reviews. Table 1 List of the Top 100 Most Cited Papers in Herps Zoster (2000–2022) Year of Publication The T100 papers were published between 2000–2018. Figure 2 illustrates the annual number of articles published during this 19-year period, and overall, the highly cited publications show a fluctuating downward trend. The highest number of T100 papers was published in the year 2000 (n = 12), followed by year 2004 (n = 9). Figure 2 Annual number of the published publications in herpes zoster research. Citations The T100 papers were cited a total of 6743 times, with citations ranging from 129 to 1646, with a median of 197, and we found seven papers cited more than 500 times. The most cited article was conducted by Oxman MN et al on HZ prevention, published in New England Journal of Medicine in 2005, and this article also has the highest ACY ( Table 1 ). Figure 3 shows the total number of citations per year and the average number of citations per year. The year 2005 had the highest number of citations, with 2943, and the average number of citations per year has been increasing. Figure 3 The annual total citations and average annual citations. Contributions of Countries A total of 25 countries contributed to the T100 papers, with the United States (US) being the leading contributor (n=72), followed by the United Kingdom (UK) (n=28), Canada (n=10) and Japan (n=7). The top 10 countries in terms of number of the T100 papers are shown in Figure 4A . In terms of the average citation rate of publications, Finland occupies the highest CPP, followed by Spain, Belgium and Japan. Figure 4B shows the regional distribution of publication volume, with North America publishing the most articles (n=83), followed by Europe (n=78). We constructed a collaborative network between countries through VOSviewer ( Figure 4C ). The US has the highest total link strength (TLS=260) and has established collaborative relationships with 20 countries, with the strongest collaborative linkages being the UK, Canada, Japan and Germany. Figure 4 The distribution of countries in herpes zoster research. (A) The distribution of countries in HZ research. (B) Worldwide distribution of the top 100 most-cited papers in herps zoster. (C) Map of cooperation network between countries or regions. In addition, we also find that: (1) the participation of less economically developed countries such as West Asia, North Africa and South America is low, and there are obvious regional differences in research in this field; (2) in recent years, countries such as Australia, Sweden, Mexico and Brazil have positively engaged in international research cooperation and become a new force in research in the field of HZ. Contributions of Institutions A total of 279 institutions contributed to the T100 papers, of which 209 (74.91%) published only one paper. The top 10 institutions in terms of number of the T100 papers published all had at least six papers ( Table 2 ). The University of Colorado topped the list with 18 articles, totaling 5072 citations, followed by Duke University (n=10) and Harvard University (n=10), both with more than 1800 citations. In its collaborative network, the University of Colorado collaborates with 94 different institutions. Of these, it collaborates most closely with the University of California, San Diego, Duke University, Harvard University, and the University of Tampere ( Figure 5 ). Table 2 Top 10 Institutions in the Top 100 Most-Cited Publications Figure 5 Co-authorship overlay visualization map of institutions. Major Contributing Authors A total of 507 authors were involved in T100 papers in the field of HZ, and there were 10 authors who contributed more than five highly cited publications ( Table 3 ). Myron J Levin from University of Colorado Medical School and Kenneth E Schmader from Duke University were the top contributors with 11 articles. The most cited author was Myron J Levin (n=2974), and the article by John W Gnann Jr had the highest average number of citations (n=376.80). Table 3 Top 10 Authors in the Top 100 Most-Cited Publications Figure 6 shows the author collaboration network, with Myron J Levin having the highest TLS (TLS=170), having successively collaborated with 100 authors. Among them, the closest collaboration is with Michael N Oxman, Kenneth E Schmader and Ivan S F Chan, who have co-authored seven research articles and formed a relatively stable collaborative team. Figure 6 Co-authorship overlay visualization map of authors. Distribution of Journals The T100 papers were published in 49 journals, of which 31 journals published only one T100 article. Table 4 shows the top 10 journals that published the most T100 articles. All journals belong to Q1 or Q2 according to the JCR categories. The journal with the highest IF was Lancet at 202.73. Clinical Infectious Diseases published the most articles (n=9), followed by Journal of Infectious Diseases (n=8) and New England Journal of Medicine (n=7). New England Journal of Medicine was the most frequently cited journal (n=4469), followed by Clinical Infectious Diseases (n=1898) and Neurology (n=1685). Table 4 Top 10 Journals in the Top 100 Most-Cited Publications Co-Occurrence Analysis of Keywords Keywords are high-level summaries and condensations of topics in an article. 21 High-frequency keywords represent popular topics in a research field. 22 A total of 448 keywords were included in this study, of which 326 keywords were studied at a frequency of one. In addition to the search terms, the most frequently studied keywords were postherpetic neuralgia (n=34), epidemiology (n=28), pain (n=27), and vaccine (n=24) ( Table 5 ). The keyword co-occurrence network was created using VOSviewer ( Figure 7 ), and the size of each node in the figure represents the research frequency of a keyword. According to the color of the nodes, the keywords can be divided into four clusters, which are as follows: Cluster 1 (red): drug therapy, including acyclovir, amitriptyline, gabapentin and other nine keywords; Cluster 2 (green): Immunoprophylaxis, including vaccine, immune-responses, immunogenicity and other nine keywords; Cluster 3 (blue): including diagnosis, DNA, epidemiology and other six keywords; Cluster 4 (yellow): Complications, including postherpetic neuralgia, infection, neuropathic pain and other five keywords. Table 5 Top 20 Keywords in the Top 100 Most-Cited Publications Figure 7 Map of keyword clustering in herpes zoster research. Discussion Basic Information Analysis In this study, we identified the 100 most influential papers correlated to HZ from 2000 to 2022. The 100 papers were also assessed for specific characteristics, including year of publication, number of citations, country of origin, institution, journal, author, and subject. The earliest cited researches in the highly cited literature were published in 2000. The most-cited publication was Michael N Oxman’s 2005 article titled “A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults”, which marked the introduction of a vaccine for shingles, offering new hope for the prevention of this afflicting disease. 23 The top 10 institutions in terms of the number of published T100 papers are all from the US and the UK. The institution with the highest number of publications (n=18) and the highest citation frequency (average citations: 281.78 citations per article) is the University of Colorado. The Clinical Infectious Diseases has published the most highly cited articles. Among the authors who published T100 papers, Myron J Levin from the University of Colorado is the most published and most cited researcher overall, followed by Kenneth E Schmader from Duke University, whereas Duke University’s John W Gnann Jr tops the list in terms of average citations per article. Myron J Levin is engaged in investigating an effective, low side-effect HZ vaccine for people of different age groups 24 , 25 and health backgrounds. 26 In addition, as principal investigator of the PROVENT trial, he is involved in the development of the Evusheld long-acting antibody combination for pre-exposure prophylaxis of COVID-19, which has received emergency authorization in the US. 27 John W Gnann Jr from Duke University, who has contributed to the efficacy and safety study of the HZ vaccine. 28 Myron J Levin, Michael N Oxman, and Kenneth E Schmader, established a relatively stable cooperative group. The academic community mainly studied the impact of HZ on patients’ quality of life 29 and the corresponding social burden, 30 , 31 and also participated in the publication of high-quality recommendations for the management of HZ. 32 The academic group’s co-published research mainly focused from 2007 to 2015. Research Hotspots and Fronts Based on the analysis of co-cited references, high-frequency keywords, keyword clusters and keyword burst, we believe that the research hotspots in the HZ field are mainly focused on: (1) Drug Therapy; (2) Immunoprophylaxis; (3) Complications. In this study, the top four keywords were counted according to the frequency of research in each hotspot and displayed in Table 6 . Acyclovir, vaccine, and PHN were the most important research items in each research hotspot. Table 6 The Top Four Keywords in Three Research Hotspots Drug Therapy Prompt administration of antiviral drugs within 72 hours of the onset of the rash can reduce viral replication, shorten the duration of symptoms, and prevent complications. 33 Studies have shown that the main antiviral drugs currently used in clinical practice for HZ are valacyclovir and famciclovir, while the frequency of acyclovir use is gradually decreasing. 34 Acyclovir was first mentioned in 1974 by Nick Oliver 35 and then its antiviral properties were first discovered by Peter Collins and John Bauer of Wellcome Laboratories in Beckenham, the UK. 36 The anti-herpetic activity of acyclovir is achieved by inhibition of herpes-specific replicative DNA polymorphases. 37 Acyclovir has been shown to be significantly more effective against herpes simplex virus types 1 and 2 than against varicella virus. 38 The duration of maximum drug concentration for intravenous acyclovir and initial oral doses is approximately one hour and two hours, respectively. 39 Compared with placebo, oral administration of aciclovir within 47 hours after the onset of the disease reduced the average time to the last day of new lesion formation by 0.5 days, 1.8 days, and 2.2 days. 40 In some studies, Famciclovir has been shown to be superior to aciclovir in reducing shingles-related pain. 41 Timely initiation of treatment with high-dose acyclovir, valacyclovir, or famciclovir may limit the severity, duration, and complications of the disease outbreak. 42 Immunoprophylaxis In addition to innate immunity, acquired immunity, represented by T-cell-mediated immunity (CMI), plays a decisive role in the host’s defense against VZV infection. 43 , 44 One study found that HZ is more severe in immunocompromised patients and has a higher risk of serious complications. 45 For example, HZ has become a common complication of HIV infection. 46 Due to the limited efficacy of pharmacological interventions, immunoprophylaxis is now the preferred option to address VZV infection. 47 As of 2018, approximately 24.1% of the US population ≥50 years of age was expected to have been vaccinated against HZ. 48 Currently, only two HZ vaccines are available 49 and the live-attenuated zoster vaccine (ZVL, Zostavax, Merck Sharp & Dohme Corp) is one of them. It is similar in composition to the vaccine used to prevent primary VZV infection, but is more potent. 50 The ZVL vaccine is recommended by The Advisory Committee on Immunization Practices for immunization of people aged 60 years and older. 51 One study found that the efficacy of ZVL exhibited the following characteristics: (i) A decrease with age, 23 for example, 64% in subjects aged 60–69 years and only 18% in subjects ≥80 years; 52 (ii) The effectiveness rate decreases with the duration of vaccination, and will decrease from 68% to 32% at eight years after vaccination. 53 It is also noted at the time of vaccination that since ZVL is a live vaccine, it is contraindicated for immunocompromised individuals. 25 Another vaccine is recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Brentford, the UK), approved for marketing in October 2017, 54 a double-dose subunit vaccine containing recombinant somatic glycoprotein E and AS01B adjuvant. 55 The Advisory Committee on Immunization recommended setting the lower age limit for RZV vaccination at 50 years. 56 Meanwhile, immunocompromised patients are an important target population for RZV, 25 showing good safety and efficacy. 47 In addition, immune serum globulin is used clinically for prophylaxis in immunocompromised populations and in high-risk groups exposed to VZV. 57 In 1969, Varicella zoster immunoglobulin (VZIG) was first extracted in humans from patients recovering from VZV infection. 58 In 2012, Varicella zoster immune globulin (VARIZIG, Saol Therapeutics, Roswell, GA, the US) was approved for marketing to replace VZIG, which had been in clinical use for more than 20 years. 59 Derived from human plasma containing high levels of anti-VZV antibodies, VARIZIG is recommended for use within 96 hours of VZV exposure for passive immunization. 60 Complications PHN is a chronic neuropathic pain syndrome 61 and is also the most common complication of HZ. 62 Approximately 5.8% of patients with HZ will develop PHN. 63 It is now generally accepted that the diagnosis of PHN needs to be met by pain in the skin area lasting more than three months after the lesions of HZ have subsided. 64 More than 30% of patients have had pain for more than one year. 65 The site of disease is concentrated in the chest and abdomen. 66 The nature of the pain is pins and needles, burning or electric shock-like. 67 In some patients, the pain is uncontrollable and leads to depression, fatigue and sleep disturbances. 68 There is no agreement on the time requirement for diagnosis, for example, 30 days after the onset of HZ, 69 pain lasting one month after the onset of rash, 70 and pain lasting 90 days after the onset of blistering. 23 Risk factors for the development of PHN include advanced age, female sex, and severe immunosuppression. 71 The pathogenesis of PHN is still unclear 72 and may be related to acute nerve injury, local ischemia, and neurotrophic disorders. 73 Prevention of PHN, timely and effective pain control, and improvement of the patient’s quality of life have become the focus of PHN interventions. 74 , 75 In recent decades, the standard treatment regimen for PHN has included the use of opioids, antiepileptics, and the addition of tricyclic antidepressants when necessary. 64 , 76 However, the above therapeutic effects remain controversial. 77 For example, the efficacy of oral gabapentin for moderate to severe PHN was only 14–17% higher than that of the placebo group 78 and there is a risk of adverse effects such as thirst, dizziness, and drowsiness. 79 , 80 In addition, interventional therapy represented by spinal radiofrequency therapy as an emerging therapy to intervene in PHN 81 has the advantages of less trauma, significant efficacy, and high safety. 82 Since the National Institutes of Health (NIH) consensus conference in 1998, 83 acupuncture has been widely used in Europe and the United States and other countries for the management of chronic pain. 63 Systematic reviews have shown that acupuncture reduces pain intensity, relieves anxiety, and improves quality of life in patients with PHN, and its efficacy is superior to that of drug controls. 84 Our study also has several limitations. First, some recent prominent papers may have been excluded due to the lack of time to obtain as many citations as the T100 articles; second, the citation analysis was influenced by many factors, such as self-citations. We did not remove the number of citations that were influenced by other factors. Conclusion In terms of the quantity of T100 articles, researchers, and organizations, the US is the predominant country. From 2000 to 2022, the most T100 papers were published in the special journal Clinical Infectious Diseases. The most academic focus remain the remedies for postherpetic neuralgia and vaccine development for individualized groups. Abbreviations ACY, average citations per year; CDC, Centers for Disease Control and Prevention; CMI, T-cell-mediated immunity; CPP, number of citations per publication; HZ, herps zoster; IF, impact factor; NIH, National Institutes of Health; PHN, postherpetic neuralgia; RCTs, randomized controlled trials; RZV, recombinant zoster vaccine; SCIE, Science Citation Index Expanded; T100 papers, top 100 most-cited papers; TC, total citations; TLS, total link strength; TP, total publications; UK, United Kingdom; US, United States; VARIZIG, varicella zoster immune globulin; VZIG, varicella zoster immunoglobulin; VZV, varicella-zoster virus; WOSCC, web of science core collection; ZVL, live-attenuated zoster vaccine. Data Sharing Statement