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ORIGINAL ARTICLE

Knowledge mapping of immunotherapy for allergic rhinoconjunctivitis: a bibliometric study (2002–2021)

Na Chena, Kun Zhangb, Youwei Lic*, Ying Liub*

aChinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

bHead and Neck Rehabilitation Center, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China

cDepartment of Radiology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China

Abstract

Background: Allergic rhinoconjunctivitis (ARC) is a common chronic inflammatory disease. Numerous studies on the treatment of ARC have been published. By contrast, there are few bibliometric studies on immunotherapy for ARC. The purpose of this article is to describe the current treatments for ARC and to identify the trends in immunotherapy for ARC.

Methods: Publications were searched from the Web of Science (WOS) Core Collection on April 25, 2022. CiteSpace and Microsoft Excel software were used for further bibliometric analysis.

Results: A total of 969 publications on immunotherapy for ARC in English were retrieved. The number of relevant publications has been continuously increasing over the past 20 years, with many of the publications coming from Germany and the United States of America. In terms of institutions, the ALK Company in Denmark, Imperial College London in United Kingdom, and Charite–Universitatsmedizin Berlin in Germany published the most articles on immunotherapy for ARC. Meanwhile, Allergy and Journal of Allergy and Clinical Immunology published the most number of studies, and Oliver Pfaar from Germany authored the most number of articles. “Subcutaneous immunotherapy,” “international consensus,” “allergen immunotherapy,” and “recommendation” were the most popular subjects. Thus, directions in research can be predicted as studies regarding mechanisms of ARC, clinical trials, and extracts have reported high-quality results.

Conclusion: Over the past 20 years, the overall quality of research on immunotherapy for ARC has gradually improved, allowing the introduction of specific and targeted treatment. Currently, the main focus of ARC research is the novel routes of drug delivery and combined treatment with biological agents.

Key words: Allergic rhinoconjunctivitis, bibliometric study, CiteSpace, immunotherapy

*Corresponding authors: Youwei Li, Department of Radiology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China. Email address: [email protected]; Ying Liu, Department of Ophthalmology, Head and Neck Rehabilitation Center, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China. Email address: [email protected]

Received 2 July 2022; Accepted 3 October 2022; Available online 1 January 2023

DOI: 10.15586/aei.v51i1.714

Copyright: Chen N, et al.
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/

Introduction

Allergic rhinoconjunctivitis (ARC) is a common chronic inflammatory disease1 that includes allergic rhinitis (AR) and allergic conjunctivitis (AC) and affects approximately 20% of the global population. AR is characterized by clinical symptoms, such as nasal congestion, rhinorrhea, paroxysmal sneezing, or itching of the nose2 and is usually accompanied by AC, which manifests as itching of the eyes, conjunctival redness, and swelling.3 Patients with ARC often visit otolaryngology or ophthalmology clinics. ARC affects the quality of sleep, occupational activities, and quality of life of patients, with severe ARC increasing the economic burden on the patients and healthcare systems.

During the past two decades, researchers around the world have made great advances in the epidemiology, diagnosis, and therapy of ARC. Currently, the management of allergic diseases includes environmental control, immunotherapy, and pharmacotherapy. Modern medicine is effective in the treatment of ARC, but long-term control is difficult. In 2011, a paper published in The Lancet suggested that allergen immunotherapy alone has the potential to alter the natural history of AR.4 Allergen immunotherapy, which can be classified as subcutaneous (SCIT) or sublingual (SLIT), is the only currently available treatment that may modify the disease by modulating the innate and adaptive immune responses of the body.5,6 In the recent years, new molecules and biomarkers for allergen immunotherapy and their combination with biological agents have been the focus of research.7

There have been numerous reports regarding the pathophysiology, diagnosis, and treatment of ARC, with many articles reporting on allergen immunotherapy.8,9 However, no bibliometric study focusing on the current knowledge and trends in the development of immunotherapy for ARC has been conducted. Bibliometric analysis is a method used to visually reveal numerous facets and research trends in a field of study and is widely used to summarize research hotspots and trends.1011

The present study aims to evaluate the literature on immunotherapy for ARC from 2002 to 2021 and to describe and reveal trends in the current state of research on ARC.

Material and Methods

Search strategy

Relevant publications on immunotherapy for ARC were searched from Science Citation Index-Expanded (SCI-Expanded) in the Web of Science (WOS) Core Collection on 25 April 2022. The main search terms were “allergic rhinitis,” “allergic conjunctivitis,” “ARC,” and “immunotherapy”. The search strategy was used: ((((TS = (“allergic rhinitis”)) OR (TS = (“hay fever”))) AND ((TS = (“allergic conjunctivitis”)) OR (TS = (conjunctivitis)))) OR ((TS = (“allergic rhinoconjunctivitis”)) OR (TS = (rhinoconjunctivitis)))) AND TS = (Immunotherapy OR Immunotherapies OR immunotherapeutic OR “immunological therapy” OR SLIT OR SCIT OR “immune therapy”). Restrictions: (1) Languages (English), (2) Document types (article or review), and (3) Timespan (2002∼2021).

Bibliometric analysis

The searched publications were downloaded, which included a full record and all cited references and then imported to Microsoft Excel (2016) and CiteSpace (5.8.R4, Chaomei Chen, Drexel University, Philadelphia, PA, USA) for further analysis. Microsoft Excel was used to draw the line graph for showing the trend of published articles by year. Visualization analysis including annual publications, authors, institutions and countries, keywords, and keywords with the strongest citation bursts were carried out by CiteSpace. The parameters of CiteSpace were as follows: time span (2002∼2021), year of slice (1 year), selection criteria (Top 50), and visualization (cluster view-static and show-merged network).

Ethical approval

Ethical approval was not applicable in the present study.

Results

Annual publications

A total of 969 publications on immunotherapy for ARC in English published between 2002 and 2021 were retrieved, including 727 articles and 242 reviews. The line graph shows that the number of publications related to immunotherapy for ARC over the past 20 years has increased and has a steady growth rate (Figure 1A). The annual trend in the number of publications associated with immunotherapy for ARC per country is shown in Figure 1B. Notably, the number of published studies from 2011 to 2018 remarkably increased from previous years.

Figure 1 (A) Annual number of studies on immunotherapy for ARC published from 2012 to 2021. (B) Annual number of studies on immunotherapy for ARC per country published from 2012 to 2021.

Analysis of countries/regions and institutions

From 2002 to 2021, there were 969 publications from 72 countries and 321 cooperations on ARC (Figure 2). As shown in Table 1, the countries with the most number of publications were Germany (n = 215, centrality = 0.11), the United States (n = 213, centrality = 0.06), and Italy (n = 129, centrality = 0.13). Additionally, among all countries, less than half published more than 10 papers. Notably, extensive cooperation between several countries/regions was also observed (Figure 2A).

Figure 2 (A) Cooperation map of countries involved in research on immunotherapy for ARC. (B) Network map of the institutions involved in research on immunotherapy for ARC.

Table 1 Top 10 countries with the most publications from 2002 to 2021.

Rank Country Counts Centrality
1 GERMANY 215 0.11
2 USA 213 0.06
3 ITALY 129 0.13
4 UK 126 0.03
5 DENMARK 105 0.15
6 SPAIN 95 0.05
7 FRANCE 94 0.02
8 AUSTRIA 75 0.09
9 PEOPLES R CHINA 54 0
10 CANADA 53 0.04

The CiteSpace software was used to analyze 544 institutions that published studies on immunotherapy for ARC (Figure 2B); 6.07% published more than nine papers, and 14.89% published more than four papers. Table 2 shows the institutions with the most number of studies published from 2002 to 2021. The ALK Company in Denmark (n = 90, centrality = 0.19), Imperial College London in the United Kingdom (n = 61, centrality = 0.07), and Charite–Universitatsmedizin Berlin in Germany (n = 53, centrality = 0.21) were the institutions with the most number of studies published. Additionally, 10 institutions published 416 studies, accounting for 42.93% of the 969 publications from 2002 to 2021; four of these institutions are in Germany.

Table 2 Top 10 institutions with the most publications from 2002 to 2021.

No. Institution Country Counts Centrality
1 ALK
(ALK Company)
Denmark 90 0.19
2 Imperial Coll London
(Imperial College London)
UK 61 0.07
3 Charite Univ Med Berlin
(Charite–Universitatsmedizin Berlin)
Germany 53 0.21
4 Ctr Rhinol & Allergol
(Centre of Rhinology & Allergology, Wiesbaden)
Germany 43 0.04
5 Univ Genoa
(University of Genoa)
Italy 39 0.15
6 Univ Cologne
(University of Cologne)
Germany 31 0.05
7 Heidelberg Univ
(Heidelberg University)
Germany 28 0.02
8 Med Univ Vienna
(Medical University of Vienna)
Austria 26 0.04
9 Johns Hopkins Univ
(Johns Hopkins University)
USA 23 0.05
10 Merck & Co Inc
(Merck Company)
USA 22 0.01

Analysis of journals and co-cited journals

The 969 articles were published in 213 different journals. Table 3 shows the 10 journals and co-cited journals that published the most number of studies on immunotherapy for ARC during the past 20 years. Among them, Allergy (n = 116), Journal of Allergy and Clinical Immunology (n = 83), Clinical and Experimental Allergy (n = 52), Annals of Allergy and Asthma Immunology (n = 45), and Current Opinion in Allergy and Clinical Immunology (n = 38) published the most number of studies, with Allergy having the highest Impact Fact (IF) of 13.146.

Table 3 Top 10 productive journals and co-cited journals from 2002 to 2021.

Rank Journal Article counts Impact factor Rank Cited journal Citations Impact factor
1 Allergy 116 13.146 1 Journal of Allergy and Clinical Immunology 927 10.793
2 Journal of Allergy and Clinical Immunology 83 10.793 2 Allergy 909 13.146
3 Clinical and Experimental Allergy 52 5.018 3 Clinical and Experimental Allergy 752 5.018
4 Annals of Allergy and Asthma Immunology 45 6.347 4 Annals of Allergy and Asthma Immunology 613 6.347
5 Current Opinion in Allergy and Clinical Immunology 38 3.142 5 International Archives of Allergy and Immunology 496 2.749
6 International Archives of Allergy and Immunology 37 2.749 6 Journal of Investigational Allergology and Clinical Immunology 339 4.333
7 Journal of Investigational Allergology and Clinical Immunology 33 4.333 7 New England Journal of Medicine 333 91.245
8 Allergy and Asthma Proceedings 29 2.587 8 Current Opinion in Allergy and Clinical Immunology 316 3.142
9 Pediatric Allergy and Immunology 28 6.377 9 Pediatric Allergy and Immunology 304 6.377
10 Immunotherapy 26 4.196 10 Allergy and Asthma Proceedings 301 2.587

The most frequently co-cited journal was the Journal of Allergy and Clinical Immunology (927 citations), followed by Allergy (909 citations) and Clinical and Experimental Allergy (752 citations). Among the most co-cited journals, New England Journal of Medicine had the highest IF of 91.245. As shown in Figure 3, there were active mutual relationships between these journals.

Figure 3 A network map of the co-cited journals involved in research on immunotherapy for ARC.

The dual-map overlay of journals demonstrates the topic distribution of the journals (Figure 4). The mapping identifies three colored citation pathways: two green citation paths suggested that studies from molecular/biology/genetics journals and health/nursing/medicine journals were frequently cited in studies from medicine/medical/clinical journals, whereas the orange path suggested that studies from molecular/biological/genetics journals were frequently cited from studies in molecular/biological/immunology journals.

Figure 4 A dual-map overlay of journals related to research on immunotherapy for ARCa.

aFrom left to right, the colored lines depict the citation paths. The citing journals are on the left of the map and the cited journals are on the right.

Analysis of authors and co-cited authors

Authors who wrote the most number of studies as well as the most cited authors are listed in Table 4, and the author and co-cited author network are shown in Figure 5. The authors who wrote the most number of studies on immunotherapy for ARC were Oliver Pfaar (n = 67), Ludger Klimek (n = 47), and Ralph Mösges (n = 38), who were all from Germany, followed by Stephen R Durham (n = 38) from the United Kingdom, Hendrik Nolte (n = 29) from the United States, and Giorgio Walter Canonica (n = 19) from Italy.

Table 4 Top 10 productive authors and cited authors from 2002 to 2021.

Rank Author (Country) Counts Centrality Rank Cited Author (Country) Citations
1 Oliver Pfaar
(Germany)
67 0.16 1 Bousquet J
(France)
554
2 Ludger Klimek
(Germany)
47 0.04 2 Durham SR
(UK)
434
3 Ralph Mösges
(Germany)
38 0.05 3 Canonica GW
(Italy)
339
4 Stephen R Durham
(UK)
38 0.15 4 Calderon MA
(UK)
304
5 Hendrik Nolte
(USA)
29 0.04 5 Pfaar O
(Germany)
229
6 Giorgio Walter Canonica
(Italy)
19 0.03 6 Passalacqua G
(Italy)
229
7 Pascal Demoly
(France)
13 0.01 7 Cox L
(USA)
223
8 Giovanni Passalacqua
(Italy)
13 0.01 8 Didier A
(France)
205
9 Moises A Calderon
(UK)
12 0.01 9 Dahl R
(France)
195
10 Harold S Nelson
(USA)
12 0.02 10 Moller C
(Denmark)
180

Figure 5 (A) A network map of the authors involved in research on immunotherapy for ARC. (B) A network map of the cited authors involved in research on immunotherapy for ARC.

The most cited author was Bousquet J (554 citations) from France, who focused on asthma and AR, followed by Durham SR (434 citations) and Canonica GW (339 citations).

Analysis of references

The most co-cited references are summarized in Table 5. Most of them (7/10) were published in the Journal of Allergy and Clinical Immunology. Among them, the article “Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study)” published by Möller C et al. was the most cited (n = 744).

Table 5 Top 10 co-cited references from 2002 to 2021.

Rank Article title First author Citations Journal (Impact factor)
1 Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study) Möller C29 744 Journal of Allergy and Clinical Immunology
IF=10.793
2 Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study Jacobsen L30 666 Allergy
IF=13.146
3 SLIT with once-daily grass allergen tablets: A randomized controlled trial in seasonal ARC Durham SR31 429 Journal of Allergy and Clinical Immunology
IF=10.793
4 Allergen-specific immunotherapy with recombinant grass pollen allergens Jutel M32 396 Journal of Allergy and Clinical Immunology
IF=10.793
5 Optimal dose, efficacy, and safety of once-daily SLIT with a 5-grass pollen tablet for seasonal AR Didier A33 389 Journal of Allergy and Clinical Immunology
IF=10.793
6 Coseasonal SLIT reduces the development of asthma in children with ARC Novembre E34 362 Journal of Allergy and Clinical Immunology
IF=10.793
7 Efficacy and safety of SLIT with grass allergen tablets for seasonal ARC Di Bona D35 354 JAMA Internal Medicine
IF=21.873
8 SQ-standardized sublingual grass immunotherapy: Confirmation of disease modification 2 years after 3 years of treatment in a randomized trial Durham SR36 351 Journal of Allergy and Clinical Immunology
IF=10.793
9 Clinical Practice Guideline: AR Seidman MD37 340 Otolaryngology Head & Neck Surgery
IF=3.497
10 SLIT for hazelnut food allergy: A randomized, double-blind, placebo-controlled study with a standardized hazelnut extract Enrique E38 326 Journal of Allergy and Clinical Immunology
IF=10.793

We used CiteSpace to construct the network of co-cited references and found eight clusters (Figure 6A). The clusters were as following: #0 “clinical trials,” #1 “phleum pratense,” #2 “allergy immunotherapy,” #3 “intralymphatic immunotherapy,” #4 “cytokines,” #5 “children,” #6 “allergy prophylaxis,” and #7 “blocking IgG antibodies.” The references with the strongest citation bursts are shown in Figure 6B. Among them, three clusters (#0 “clinical trials,” #3 “intralymphatic immunotherapy,” and #6 “allergy prophylaxis”) have bursts that have persisted until the present.

Figure 6 (A) A line map of the cluster of co-cited references involved in research on immunotherapy for ARC. (B) References with the strongest citation burstsa.

aThe blue line represents the period from 2002 to 2021, and the periods of each burst keyword are plotted by the red line.

Analysis of keywords

CiteSpace was used to construct a network map of keywords (Figure 7A and Table 6) and keywords with the strongest citation bursts (Figure 8). Figure 7B shows a network of nine clusters of keywords as follows: #0 “allergic rhinitis,” #1 “sublingual immunotherapy,” #2 “recombinant allergens,” #3 “allergen immunotherapy,” #4 “grass pollen,” #5 “subcutaneous immunotherapy,” #6 “regulatory T,” #7 “transforming growth factor beta,” and #8 “treatment efficacy.”

Table 6 Top 20 keywords in 2002–2021.

No. Keyword Counts No. Keyword Counts
1 Rhinoconjunctiviti 346 11 Immunotherapy 115
2 Asthma 334 12 Clinical efficacy 111
3 Rhiniti 295 13 Quality of life 100
4 Double blind 290 14 Allergic rhiniti 97
5 Efficacy 290 15 Follow-up 95
6 Children 232 16 Impact 86
7 Sublingual immunotherapy 205 17 Tablet 74
8 Safety 202 18 Extract 65
9 House dust mite 146 19 Sensitization 64
10 Controlled trial 132 20 Grass pollen immunotherapy 61

Figure 7 (A) Network map of the keywords involved in research on immunotherapy for ARC. (B) Map of the clusters of keywords involved in research on immunotherapy for ARC.

Figure 8 Keywords with the strongest citation burstsa.

aThe blue line represents the period from 2002 to 2021, and the periods of each burst keyword are plotted by the red line.

As shown in Figure 8, the strongest burst (house dust mite) occurred in 2003, with a burst strength of 9.18 that lasted for 3 years. However, what we were more concerned about were the current hotspots, including “SCIT” (strength 7.62, 2015–2021), “international consensus” (strength 4.8, 2018–2021), “allergen immunotherapy” (strength 4.02, 2018–2021), and “recommendation” (strength 4.86, 2019–2021).

Discussion

In this study, we searched for articles and reviews regarding immunotherapy for ARC from 2002 to 2021 from the WOS Core Collection. A total of 969 publications comprising 213 journals from 544 institutions in 72 different countries were retrieved and used to perform a bibliometric analysis. As can be observed from the number of annual publications, the number of studies on immunotherapy for ARC is gradually increasing, indicating that this field has received sustained and significant attention during the past years.

In terms of countries/regions, Germany, the United States, and Italy contributed the most number of studies on immunotherapy for ARC in the last 20 years. Additionally, Oliver Pfaar, Ludger Klimek, and Ralph Mösges, who authored the most articles, were all from Germany. Notably, although Denmark had only one institution (ALK Company) among the 10 countries with the most number of studies published, this institution published the most number of studies among all institutions worldwide. Additionally, 4 of the 10 institutions that published the most studies are in Germany. Moreover, most of these papers were published in Allergy, Journal of Allergy and Clinical Immunology, and Clinical and Experimental Allergy, which belong to allergy and immunology. Meanwhile, the Journal of Allergy and Clinical Immunology and Allergy were the most cited journals.

Keywords are the summary and generalization of the article, and keyword clusters can classify the degree of similarity between indicators. Therefore, keywords and clusters serve as important indices to reflect research hotspots and the focus of the literature in a field of study. Co-cited references and keyword analyses showed that research on immunotherapy for ARC revolved around different immunotherapy pathways and mechanisms. “International consensus,” “allergen immunotherapy,” and “recommendation” are the keywords with the strongest citation bursts that are currently still active. Therefore, research directions for immunotherapy for ARC can be predicted as follows: mechanism research related to different pathways, clinical trials and allergen extracts that meet standards, and the recommended international consensus.

The European Academy of Allergy and Clinical Immunology (EAACI) is an association dedicated to improving the health of people affected by allergic diseases. In 2010, the GA(2)LEN/EAACI pocket guide,12 which has been presented in several meetings, offered comprehensive recommendations on the daily use of immunotherapy in ARC and asthma. In the latest guidelines prepared by the EAACI,13 allergen immunotherapy is recommended as first-line treatment.

Currently, in clinical practice, allergen immunotherapy includes classical SCIT and SLIT.14,15 Allergen immunotherapy reduces the immune response through long-term repeated exposure to specific allergens. The efficacy of conventional allergy immunotherapy in ARC has been established, and both SCIT and SLIT are effective. The gold standard in the treatment of allergic diseases is SCIT due to its long-term benefits for patients. However, only 5% receive SCIT mainly due to its frequency of administration that must be performed in a hospital, unpredictable adverse reactions, and long duration of treatment.16,17 For some patients, especially children and those afraid of needles, SLIT is an alternative option. However, there may be issues with compliance due to long-term oral medication.

In recent years, intralymphatic immunotherapy (ILIT)18,19 was developed as a novel route of delivery. ILIT induces tolerance after only three administrations and delivers lower doses of an allergen to a highly immunocompetent lymph node to maximize chances for tolerance induction with fewer adverse events.20 ILIT is deemed safe and promising based on the results of clinical trials, although long-term follow-up with standard scoring criteria is needed.21 Witten et al. revealed that intralymphatic injections with grass pollen allergen extracts induced a regulatory T-cell response and increased IgG4 levels but there was no improvement in clinical symptoms;22 hence, they doubted whether ILIT can already be introduced for clinical use. Currently, there are no officially approved commercial allergen extracts for intravenous administration. Meanwhile, epicutaneous immunotherapy is also a novel form of immunotherapy, but further research is required to determine its efficacy and safety.23

Immunoglobulin E (IgE), which acts as the central mediator in the pathogenesis of type I allergic reactions, plays an important role in the occurrence and development of AR and ARC. Twenty years ago, Kuehr et al. designed the first clinical trial to investigate the effects of anti-IgE with specific allergen immunotherapy.24 Thereafter, several studies have shown that the anti-IgE monoclonal antibody omalizumab is effective for the treatment of allergic diseases, especially asthma.25,26 A clinical trial conducted by Larenas-Linnemann et al. showed that omalizumab use with allergen immunotherapy alleviated clinical symptoms and reduced treatment time while having fewer adverse reactions.27 It is thought that omalizumab binds to the CH3 domain of the Fc portion of IgE, preventing IgE from binding to the high-affinity IgE receptor FcεRI.28

Limitation

A few limitations of this visualization analysis must be considered. First, all publications were retrieved from the WOS Core Collection database, and articles in other databases were excluded. Our findings in this study may not be comprehensive because of the limited amount of literature. Second, the publications were limited to those in English, which can lead to bias. Third, the CiteSpace software cannot distinguish the first author from the corresponding author. However, we still believe that the results of this study can be used to determine hotspots and emerging trends in this field of study.

Conclusion

The number of publications related to immunotherapy for ARC is gradually increasing. Germany and the United States published the most studies on immunotherapy for ARC. Oliver Pfaar from Germany authored the most number of studies, and Bousquet J from France was the most cited author. Allergen immunotherapy includes classical SCIT and SLIT and the novel ILIT, with omalizumab emerging as a novel biological therapy. Currently, research regarding immunotherapy for ARC is now focusing on specific and targeted treatment. Additionally, the direction of future research on allergen immunotherapy includes new routes of drug delivery and combined application with biological agents. Meanwhile, improving the efficacy of allergen immunotherapy and reducing side effects need further exploration and research.

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