Immunological landscape of hepatic alveolar echinococcosis: A bibliometric analysis

Abstract

BACKGROUND

Hepatic alveolar echinococcosis (HAE) is a chronic parasitic disease caused by the larval stage of Echinococcus multilocularis. Although significant research has been conducted on the pathogenesis and immunological aspects of HAE, comprehensive bibliometric analyses in this area are still lacking. This study sought to fill this gap by systematically analyzing the immunological literature on HAE using bibliometric methods.

AIM

To identify research trends, key contributors, and emerging developments and offer insights to guide future research in this field.

METHODS

Research articles on HAE published between 1983 and 2023 were retrieved from the Web of Science Core Collection database. A total of 319 articles were selected for bibliometric analysis, which was conducted using the CiteSpace and VOSviewer software. The analysis focused on key variables such as publication volume, authors, journals, countries, references, and keywords.

RESULTS

The analysis revealed a significant increase in research on HAE over the past four decades, particularly after 1995. China and Switzerland emerged as the leading countries in terms of publication volume, with Bruno Gottstein and Vuitton DA identified as the most influential authors in this field. Key research areas include the interaction between the pathogen and the host immune system, as well as advances in disease diagnosis and treatment strategies. The keyword co-occurrence analysis highlighted the primary themes and identified emerging trends within the research landscape.

CONCLUSION

This study provides a comprehensive framework for understanding HAE immunology and highlights research hotspots, future directions, key contributors, and the importance of international cooperation.

Key Words: Hepatic alveolar echinococcosis; Immune; Bibliometrics; Visualization; CiteSpace; Vosviewer

Core Tip: This study conducted a unique, comprehensive bibliometric analysis of immunological research on hepatic alveolar echinococcosis, highlighting the significant growth in publications since 1995. It identifies key contributors, including top authors and countries, and emphasizes emerging research areas, such as pathogen-host interactions and diagnostic advancements. These findings offer valuable insights for guiding future research on hepatic alveolar echinococcosis and for promoting international collaboration.

INTRODUCTION

Echinococcosis is a zoonotic disease caused by parasites of the genus Echinococcus and has a significant global public health relevance. The disease is particularly prevalent in agricultural communities and regions with frequent wildlife contact[1,2]. Echinococcosis is classified into two types: Cystic echinococcosis caused by Echinococcus granulosus (E. granulosus) and alveolar echinococcosis (AE) caused by E. multilocularis. These two types differ markedly in their clinical presentation, pathogenesis, and treatment approaches[3,4]. In AE, most primary lesions occur in the liver and often affect the right lobe. In advanced stages, the disease may metastasize to the lungs, brain, and other organs[1,3,5].

Hepatic AE (HAE) is particularly dangerous because of its chronic, progressive nature and potential lethality, posing a serious threat to patients’ health and quality of life[3]. E. multilocularis damages liver tissue through direct erosion and mechanical compression, leading to diffuse injury of the liver parenchyma and ischemic necrosis, which may ultimately result in liver failure and cirrhosis[6]. Upon infection with E. multilocularis, macrophages phagocytize parasites and release cytokines, whereas dendritic cells activate T lymphocytes. Natural killer cells directly kill infected cells. Additionally, CD4⁺ T helper (Th) cells enhance antibody production by both macrophages and B cells, whereas CD8⁺ cytotoxic T lymphocytes directly target and eliminate infected cells[7-9]. Although the host possesses various anti-infection mechanisms, E. multilocularis exhibits strong immune evasion capabilities. In patients with HAE, serum levels of cytokines, including interferon-γ, tumor necrosis factor-α, interleukin-4, and interleukin-6, were significantly elevated. This elevation promotes an imbalance between Th1 and Th2 cells, facilitating infection progression[10-12].

Bibliometric analysis, a precise quantitative tool, has been widely used in various scientific fields[13]. This method involves a systematic review of existing literature using advanced computer-assisted technologies to effectively identify and assess key contributors and focal research themes within these areas[14]. Furthermore, it provides an in-depth exploration of long-accumulated research outcomes, uncovering intrinsic connections and interactions among different research directions[15,16]. CiteSpace is a widely used information visualization software developed by Professor Chaomei Chen in 2004 based on the citation analysis theory[17]. Its distinctive feature is its ability to construct co-occurrence network graphs for countries, institutions, authors, keywords, and subject categories. Moreover, it uncovers networks of cited authors, references, and journals, offering profound insights into the literature[18]. VOSviewer is a powerful software tool designed specifically to create and explore maps based on network data[19,20]. It constructs complex networks involving elements such as scientific publications, journals, researchers, research organizations, countries, keywords, and terms. These networks interconnect various entries through multiple linking methods, including co-authorship, co-occurrence, citation, bibliographic coupling, and co-citation. This functionality reveals collaborative relationships and knowledge flows within and across academic fields[18,21]. The Web of Science Core Collection (WoSCC) database is widely recognized as one of the most comprehensive and frequently used academic resource repositories, encompassing a broad range of significant and academically valuable journals[22]. Renowned for its interdisciplinary coverage, particularly in clinical and basic experimental research fields, WoSCC provides researchers with a robust platform for information retrieval and academic discovery[23]. In this study, we employed a systematic retrieval strategy using WoSCC as the primary data source to ensure the breadth and high quality of research data.

MATERIALS AND METHODS

Data retrieval strategy

We conducted a comprehensive and systematic literature retrieval to ensure the breadth and depth of the research. This retrieval used the WoSCC online database as the primary platform for gathering information and ensuring extensive coverage of HAE-related literature in the field of immunology. The scope of the retrieval was strictly limited to the period from January 1, 1983, to December 31, 2023, with the keywords “HAE” and “immunology” ensuring the relevance and timeliness of the search content. To facilitate analysis and understanding, the language of the literature was restricted to English. Detailed search strategies and results are presented in Table 1. Through rigorous literature retrieval, we established a solid data foundation for subsequent bibliometric analyses, ensuring the scientific validity and practical utility of the research results.

Table 1 Search query.

Items	Search query	Database	Results
1	((TS = (Echinococcus multilocularis [Mesh])) OR (TS = (echinococcus AND multilocularis)) OR (TS = (E.multilocularis)) OR (TS = (alveolar echinococcosis)) OR (TS = (E.echinococcosis)) OR (TS = (alveolococcosis)) OR (TS = (echinococcus multilocularis infection)) OR (TS = (alveolar hydatid disease)) OR (TS = (multilocular echinococcosis)) OR (TS = (echinococc*)) OR (TS = (alveolar OR multilocularis OR canadensis) AND (TS = echinococc*)) OR (TS = (Echinococcus multiloculari*)) OR (TS = (multilocularis, Echinococcus)))	Web of Science Core Collection	10641
2	(TS = (Immun*))	Web of Science Core Collection	943566
3	1 and 2	Web of Science Core Collection	2067

Documents types: Articles. Language: English. Timespan: 1983-01-01 to 2023-12-31.

Data collection

To ensure a rigorous and comprehensive exploration of the literature on HAE within the field of immunology, we implemented a strict inclusion and exclusion scheme (Figure 1). The screening process was methodically divided into three phases, focusing exclusively on empirical studies published in Science Citation Index and Social Science Citation Index journals between 1983 and 2023, thereby refining our initial retrieval of 2067 articles. In the final phase, we manually reviewed the titles, abstracts, and reference lists of the shortlisted articles and conducted citation tracking of the seminal papers to ensure the credibility of the selected literature. This process led to the exclusion of further 1343 articles. Finally, 319 articles were considered suitable for inclusion in this study.

Figure 1  Flowchart for selecting references for the current study.

RESULTS

Total number of publications and trends

The historical development of a research field can often be traced and interpreted through fluctuations in its publication history[24]. As depicted in Figure 2, the publication trends from 1983 to 2023 indicate that HAE has emerged as an important and distinct branch within the medical field, gradually attracting the attention of the academic community. Since 1995, research on HAE has experienced a period of significant growth. After the year 2000, several highly influential core papers, including “Echinococcus multilocularis and its intermediate host: A model of parasite-host interplay”, “Immunoregulation in larval Echinococcus multilocularis infection”, and “Echinococcosis: Advances in the 21^st Century”, have further deepened the understanding and exploration of HAE research[6,25,26]. Owing to the relentless efforts and collaboration of researchers worldwide, diagnostic techniques and treatment methods for HAE continue to innovate and improve. These advances not only enhance disease management efficiency but also significantly improve treatment outcomes and the quality of life of patients.

Figure 2 Publication product. Number of articles per year from 1983 to 2023.

Geographical distribution

Figure 3A depicts the geographic distribution of academic publications and the close-knit network of collaborative research among countries and regions. This distribution was statistically inferred and summarized based on the geographic locations or affiliations of the corresponding authors’ institutions. As illustrated in Figure 3B, Switzerland ranked first, with 143 publications, highlighting its significant role in advancing research in relevant fields. This was followed by France with 134 publications, China with 131, Japan with 29, and Germany with 28. These data clearly demonstrate the active involvement of these regions, reflecting their strong focus on current research topics and emphasizing their strategic commitment to modern research methodologies. Figure 3C further reveals Switzerland’s substantial leadership in international academic cooperation. Switzerland has established extensive collaborative relationships with multiple countries, as visually represented by the color intensity of the lines connecting it to partner countries. This diverse network of cooperation not only enhances academic exchanges between nations but also provides a solid foundation for advancing global scientific progress and innovation[27].

Figure 3 Country scientific production. A: Country collaboration map; B: The leading countries and institutions with the highest number of publications; C: International cooperation; D: Institutional collaboration networks.

Institutional distribution

Figure 3B illustrates that China, France, and Switzerland are leading in publication volume in this field, with shares of 27.52%, 28.15%, and 30.04%, respectively, positioning them as the top three contributors. Notably, institutions such as Xinjiang Medical University, the University of Franche-Comté, and the University of Bern are highlighted for their significant publication output. In Figure 3D, an analysis of institutional collaboration networks using VOSviewer demonstrates that each color represents the connections between institutions. The University of Bern has the most extensive collaboration with other countries, underscoring its substantial contribution to the field of HAE. The line connecting Xinjiang Medical University and the University of Bern illustrates a strong collaborative relationship between Asia and Europe.

Author analysis

Figure 4A presents the h-index for five prominent authors, a metric that measures their academic impact based on the number of papers they have published that are cited at least ‘h’ times[28]. This metric highlights the substantial contribution of these individuals to their respective fields. By analyzing their publication volume, total citation frequency, and h-index, Bruno Gottstein, Vuitton DA, Wen H, Kern P, and Deplazes P emerged as pioneering researchers in the field. Their influential work, which began in the early 1980s, laid the groundwork for subsequent studies (Table 2). Among them, Bruno Gottstein had the highest citation count, with 2936 citations, demonstrating his far-reaching impact in academia. Furthermore, his 72 publications signify his ongoing and substantial engagement with the field, making him a key figure in advancing research in HAE and related areas.

Figure 4 Analysis of author. A: Analysis of author influence; B: Collaboration network.

Table 2 Top 10 authors with the most publications.

Rank	Authors	Articles	Total citation	H-index	G-index	PY-start
1	Gottstein B	72	2936	34	52	1988
2	Vuitton DA	44	1914	29	43	1984
3	Wen H	35	936	13	30	1994
4	Kern P	26	698	17	26	1993
5	Deplazes P	23	1025	15	23	1991
6	Ito A	20	560	13	20	1995
7	Lin RY	18	548	10	18	2011
8	Liance M	16	783	10	16	1988
9	Hemphill A	15	470	6	15	1995
10	Bressonhandi S	12	602	9	12	1988

As depicted in Figure 4B, in the author collaboration analysis of the literature in the field of HAE, Bruno Gottstein and Wen H were identified as core authors, having collaborated frequently in several important publications. This collaboration highlighted their significant academic influence. The collaboration network graph clearly illustrates the relationships between authors, with the size of the nodes reflecting the publication volume of each author and the thickness of the lines indicating the frequency of collaboration[27,29]. This analysis not only reveals the main contributors to HAE research but also highlights the increasing collaboration within the field, suggesting the potential for more interdisciplinary research partnerships in the future.

Keywords analysis

The analysis of keyword bursts offers significant insights into the evolving trends and temporal dynamics of key terms[30]. Using the CiteSpace software, we identified keywords with the most notable citation bursts, as illustrated in Figure 5A. The most frequent terms include “liver”, “resistant”, “E. multilocularis”, “hydatid disease”, “host”, and “antigens”. These keywords have been central to the field, reflecting major research areas and concerns over time. As depicted in Figure 5B, the VOSviewer keyword map reveals key trends and thematic structures in HAE research. In the early 2000s, the research focus was primarily on topics such as “antigens”, “resistance”, and “antibodies”, emphasizing the understanding of immune responses and diagnostic methods. By 2010, however, the focus had shifted significantly toward the development and improvement of therapeutic interventions, reflecting a broader trend toward treatment-oriented research. This transition underscores the evolving priorities of the field and the adaptability of the scientific community in addressing the changing challenges posed by the disease.

Figure 5 Research hotpots on hepatic alveolar echinococcosis. A: The 25 keywords with the strongest citation bursts; B: Network of keywords; C: Three-field plot. Left field: Author; Middle field: Affiliation; Right field: Keyword.

The associations among authors, institutions, and keywords in the HAE research field are further illustrated in the three-field plot in Figure 5C. For instance, Bruno Gottstein and Wen H, from the University of Bern and Xinjiang Medical University, respectively, exhibit close collaboration under keywords such as “E. multilocularis” and “alveolar echinococcosis”. The overlapping areas in the figure highlight the significant overlap in their research outputs, particularly in the study of immune mechanisms of echinococcosis. Xinjiang Medical University has led to these two keyword areas, underscoring the institution’s ongoing contributions, particularly in the clinical and fundamental research of parasitic immunology.

Reference analysis

Figure 6 displays the top 25 references that experienced the strongest citation bursts[30]. These references observed notable increases in citation frequency during specific periods, highlighting their significant impact on the field. For instance, a previous report witnessed a surge in citations between 2020 and 2023[6]. This work reviewed the latest advancements in the diagnosis, treatment, and prevention of HAE, providing crucial scientific evidence for improving the clinical approaches to the disease. Another noteworthy study experienced a significant increase in citations between 1995 and 1999[31]. This study used innovative mouse strains with different genetic backgrounds as experimental models, offering valuable insights into the host immune response to multi-chambered echinococcosis. By analyzing these citation bursts, we can identify key trends and emerging directions in the field, forming a solid foundation for future literature reviews and research.

Figure 6 Analysis of references. Top 25 references with the strongest citation bursts. The bars in red represent for a burst period for the references.

Journal distribution

Table 3 presents the top 10 journals by publication count, including two from the Q1 Journal Citation Reports quartile, four from the Q2 quartile, and three with an impact factor greater than 3. Among the top sources based on total citations, Parasite Immunology leads with 374 citations from 25 related articles, emphasizing its significant influence in the fields of parasitology and immunology. This was followed by Parasitology Research, with 362 citations across 21 articles, ranking second, and PLoS Neglected Tropical Diseases, with 349 citations from 16 articles, securing third place. These citation metrics highlight Parasite Immunology as a central hub for influential research and guide scientific progress in parasitology. In particular, it plays a crucial role in advancing studies on echinococcosis and other parasitic diseases, highlighting the journal’s substantial contribution to the field’s development and its broader impact on the scientific community.

Table 3 Top 10 journals with most publications.

Rank	Sources	Article	Country	TC	IF	JCR
1	Parasite Immunology	25	England	374	1.4	Q3
2	Parasitology Research	21	Germany	362	1.8	Q2
3	Plos Neglected Tropical Disease	16	United States	349	3.4	Q1
4	Parasitology	14	England	285	2.1	Q2
5	Journal Of Clinical Microbiology	11	United States	270	6.1	Q1
6	American Journal of Tropical Medicine and Hygiene	11	United States	260	1.9	Q2
7	Molecular And Biochemical Parasitology	110	Netherlands	221	1.4	Q3
8	Clinical And Experimental Immunology	9	England	185	3.4	Q3
9	Experimental Parasitology	9	United States	183	1.4	Q3
10	Infection And Immunity	8	United States	153	2.9	Q2

TC: Total citations; IF: Impact factor; JCR: Journal Citation Reports.

DISCUSSION

HAE is a zoonotic infection that presents substantial challenges to both public health and the livestock industry[1]. The disease is caused by E. multilocularis, which primarily affects the liver and can lead to severe complications such as liver failure and cirrhosis[3,4,6]. The complexity of HAE is rooted not only in its pathogenic mechanisms but also in the parasite’s immune evasion strategies, which hinder the host’s immune response[10-12]. Consequently, gaining a deeper understanding of the intricate interactions between pathogens and the host immune system is essential for the development of effective diagnostic tools and therapeutic strategies[6].

This study utilized the WoSCC online database for data collection, with the keywords “HAE” and “immunology,” restricting the publication time frame from January 1, 1983, to December 31, 2023, and considering only English-language articles. Finally, 319 publications were included in the analysis (Figure 1). A systematic bibliometric analysis framework was then applied to comprehensively examine the academic literature in the field of HAE immunology, as depicted in Figure 2. The initial phase involved extracting key information from the selected publications, including publication year, source details (such as journals, countries, and institutions), author lists, citation frequencies, and keywords. Next, CiteSpace and VOSviewer were employed to perform performance analysis and construct scientific maps.

Performance analysis, a descriptive approach, characterizes bibliometric research by evaluating quantitative metrics such as publication counts, citation frequencies, and the h-index[32-34]. These metrics assess academic productivity and the impact on countries, regions, journals, and authors. In this study, performance analysis was employed to examine the evolution of publication trends and sources in detail. Scientific mapping, a method that transforms abstract data into intuitive graphical representations, visualizes complex relationships among authors, publications, research institutions, and countries[20,24]. Specifically, scientific maps were used to display co-author networks, highlighting leading collaborative groups, co-citation analysis illustrating the interconnections among key publications, and keyword co-occurrence analysis to uncover the relationships between central concepts and themes within the research field.

From the publication trend analysis, as illustrated in Figure 2, over the past four decades, research on HAE has experienced significant growth, particularly since 1995, when this trend became more pronounced. This surge reflects the increasing recognition of HAE as a critical research focus in the medical community. The rise in research activity is likely driven by a combination of the growing awareness of the public health impact of the disease and advancements in research methodologies. Notably, since 2000, several influential papers have been published, significantly advancing our understanding of HAE and solidifying its prominence.

In any research field, the number of publications serves as a crucial indicator of a country’s or institution’s scientific capabilities. For this study, China, France, and Switzerland led the research output (Figure 3B). This can be attributed to sustained investments and the establishment of specialized research teams in these countries. As noted in the Introduction, the higher prevalence of HAE in certain regions may explain the elevated research output in these countries. Additionally, the collaborative networks formed by these nations highlight the importance of knowledge- and resource-sharing in tackling the complexities of HAE (Figure 3C). Among the top 10 institutions in terms of publications, Xinjiang Medical University (China), the University of Franche-Comté (France), and the University of Bern (Switzerland) have made significant contributions to HAE research (Figure 3C). These institutions have become key hubs for HAE research, fostering interdisciplinary collaboration and innovation. Their robust publication output reflects their strategic focus on advancing the scientific research on echinococcosis.

Over the past 40 years, scholars such as Bruno Gottstein, Vuitton DA, and Wen H have made significant contributions to echinococcosis research by publishing key papers on various aspects, including immune responses, immunodiagnosis, drug therapies, and surgical treatments (Table 2). Among their notable works, two highly cited papers by Gottstein et al[31] and Wen et al[6] laid the foundation for current research, providing valuable insights that guide future studies and highlight emerging trends in the field (Figure 6). The extensive contributions and close collaboration of these scholars have not only enhanced their academic influence but also established a solid foundation for future research. Their collaborative network emphasizes the collective effort needed to address the complexities of HAE.

The keyword analysis revealed evolving themes and research focus within the literature on HAE (Figure 5). Early studies primarily focused on understanding immune responses and diagnostic methods. However, recent trends have indicated a shift toward therapeutic interventions and vaccine development, reflecting the adaptability of the scientific community to address the evolving challenges of the disease. This shift highlights the importance of tracking emerging trends and adjusting research direction in a timely manner. Journal distribution analysis underscores the vital role of specific journals in disseminating HAE research findings. Journals such as Parasitology International and Parasitology Research have become key platforms for publishing HAE research, shaping the direction of the field (Table 3). The high citation rates and publication volumes of these journals further emphasize their central role in advancing research on echinococcosis and related parasitic diseases. By integrating performance analysis and scientific mapping, this study summarizes the developmental stages of the HAE immunology field, highlighting the key participating countries or regions, prominent research institutions and journals, core authors and their publications, emerging research themes, and critical issues. It also outlines current limitations and future research directions. This comprehensive analysis offers valuable insights to researchers in this field and provides guidance for future research.

However, this study has several limitations. First, the specific keywords used in the current study may have resulted in the exclusion of relevant studies. Future research should expand the range of keywords to enhance coverage. Second, the focus on English-language publications may overlook important contributions in other languages, such as Spanish and French. Incorporating multilingual literature into future studies would help to ensure a more holistic understanding of HAE research. Furthermore, while descriptive and co-occurrence analyses are useful for identifying research trends, they may not fully capture the complex interactions and emerging dynamics within the literature. To gain deeper insights, researchers should consider employing more advanced bibliometric techniques.

CONCLUSION

In conclusion, while research on HAE has made notable advancements in both quantity and quality, future studies should address limitations, such as language bias and keyword selection. Key areas for future research include fostering interdisciplinary collaboration, expanding the scope and depth of immunoecological studies, and enhancing research impact through international cooperation. These efforts are expected to yield valuable insights into improving the clinical management of HAE and inform the development of effective public health policies.