Front. Immunol. Frontiers in Immunology Front. Immunol. 1664-3224 Frontiers Media S.A. 10.3389/fimmu.2025.1658826 Immunology Systematic Review Efficacy of different allergen-specific immunotherapies for the treatment of allergic rhinitis in children and adults: an umbrella review He Yu 1 * Liu Xinghong 2 Zhou Bin 2 Dai Tianrong 3 1 School of Traditional Chinese Medicine, Chongqing University of Chinese Medicine, Chongqing, China 2 School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China 3 Otolaryngology Department, Ya’an People’s Hospital, Ya’an, China

Edited by: Olga Lourenço, University of Beira Interior, Portugal

Reviewed by: Gandhi Fernando Pavon, National Institute of Respiratory Diseases (INER), Mexico

Marcin Kurowski, Medical University of Lodz, Poland

*Correspondence: Yu He, 1873921076@qq.com

25 09 2025 2025 16 1658826 03 07 2025 05 09 2025 Copyright © 2025 He, Liu, Zhou and Dai. 2025 He, Liu, Zhou and Dai

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 Objective

The aim of this study was to summarize the therapeutic efficacy of various allergen immunotherapy (AIT) in the treatment of allergic rhinitis (AR) among different populations and for different allergens.

 Methods

Systematic reviews or meta-analyses related to the efficacy of AIT in the treatment of AR until October 2024 were retrieved from PubMed, Web of Science, Embase, and Cochrane Library. Each study was independently evaluated by two investigators in accordance with the inclusion and exclusion criteria. The methodological quality was assessed using AMSTAR 2, and the quality of evidence was evaluated by the GRADE system.

 Results

A total of 16 SRs/Mas were included. The methodological quality was evaluated by AMSTAR 2, with 5 rated as “low” and the remainder as “very low”. The quality of the evidence was assessed using the GRADE system. It was found that the quality of evidence in most studies was unsatisfactory. Among the included articles, six had moderate-quality evidence, six had low-quality evidence, and four had very low-quality evidence, with no high-quality evidence. There was a moderate degree of overlap among the included literature. After conducting an overall efficacy evaluation of the extracted data, it was found that SLIT, SCIT, and LNIT were effective in the treatment of AR, while cluster SCIT and ILIT had no significant efficacy compared with placebo.

 Conclusion

SLIT and SCIT are active and effective treatments for AR, and show significant efficacy in adults, children, and for different allergens. There are still relatively few meta-analyses and systematic reviews of cluster SCIT, ILIT, and LNIT, and there is still scope for further improvement in the assessment of their efficacy. Considering that the methodological quality and evidence of the systematic reviews and meta-analyses included in this study are generally low, more high-quality, large-scale, multicenter, randomized controlled clinical trials are indispensable in the future to firmly verify the efficacy of various AIT in the treatment of AR in different populations and allergens.

 Systematic review registration

https://www.crd.york.ac.uk/prospero/, identifier CRD42024600378.

 allergic rhinitis allergen immunotherapy efficacy meta-analysis systematic review umbrella assessment section-in-acceptance Vaccines and Molecular Therapeutics Introduction

Allergic rhinitis (AR) is a chronic Th2-type inflammatory reaction in the nasal mucosa, triggered by allergens and mediated by specific immunoglobulin E (IgE). Common symptoms include nasal itching, sneezing, clear discharge, and congestion (1). Key allergens are seasonal pollen, dust mites, and pet dander. In the US, physician-diagnosed AR prevalence is about 15% (2), rising to 30% based on self-reported symptoms (3). In China, AR is one of six major chronic diseases, with a prevalence rate nearing 40%, notably higher among children, impacting public health significantly (4).

Treatment primarily involves intranasal and oral medications, which manage but do not cure symptoms. Allergen immunotherapy (AIT), particularly subcutaneous (SCIT), sublingual (SLIT), intradermal (IDIT), epidermal (EPIT), and intralymphatic (ILIT) therapies, targets specific allergens and is increasingly recognized as the most effective treatment. IDIT and EPIT offer advantages like shorter treatment duration and lower allergen doses (5). ILIT involves ultrasound-guided injections into subcutaneous lymph nodes (6).

Existing reviews mainly focus on the efficacy of specific allergens or treatment regimens for AR, but few have compared different AIT administration routes. This study is the first to evaluate administration routes as a key factor, comparing their effectiveness in treating AR. The results provide a basis for choosing personalized clinical approaches and fill a research gap that previously focused mostly on SLIT and SCIT. An umbrella review (UR) is a type of overarching systematic review that aims to provide reliable evidence for decision-makers when there is a growing number of existing systematic reviews (7). The purpose of this UR is to synthesize evidence from systematic reviews and meta-analyses (SRs/MAs) in order to provide high-quality evidence regarding the efficacy of various administration routes of AIT for AR, enabling their comparison.

 Methods and materials Protocol and registration

This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (8). Additionally, it was registered with PROSPERO (CRD42024600378).

 Search strategy

To explore the efficacy of AIT in the treatment of AR, two investigators independently conducted searches in PubMed, Web of Science, Embase, and Cochrane Library for relevant articles. The search period extended from the establishment of each database until October 2024. Search terms included: “Allergic Rhinitides,” “Allergic Rhinitis,” “Immunologic Desensitizations,” “Hyposensitization Therapies,” “Hyposensitization Therapy,” “Allergen Immunotherapy,” “Allergen Immunotherapies,” “Venom Immunotherapy,” “Venom Immunotherapies,” “Allergy Shots,” “Allergy Shot,” “Systematic Review,” “Systematic Reviews,” “meta-analysis,” “Meta-analysis,” “data pooling,” “clinical trial overview,” “clinical trial overviews,” etc. The detailed PubMed search strategy is presented in Table 1 , and other databases were adjusted in accordance with the PubMed search strategy. Additionally, to prevent the omission of relevant meta-analyses in the initial search, references of relevant studies were reviewed.

PubMed search strategy.

Query Search term
#1 ((Rhinitis, Allergic[MeSH Terms]) OR (Allergic Rhinitides[Title/Abstract])) OR (Allergic Rhinitis[Title/Abstract])
#2 (((((((((Desensitization, Immunologic[eSH Terms]) OR (Immunologic Desensitizations[Title/Abstract])) OR (Hyposensitization Therapies[Title/Abstract])) OR (Hyposensitization Therapy[Title/Abstract])) OR (Allergen Immunotherapy[Title/Abstract])) OR (Allergen Immunotherapies[Title/Abstract])) OR (Venom Immunotherapy[Title/Abstract])) OR (Venom Immunotherapies[Title/Abstract])) OR (Allergy Shots[Title/Abstract])) OR (Allergy Shot[Title/Abstract])
#3 ((((((((Meta-Analysis as Topic[MeSH Terms]) OR (Meta Analysis as Topic[Title/Abstract])) OR (Clinical Trial Overviews[Title/Abstract])) OR (Clinical Trial Overview[Title/Abstract])) OR (Data Pooling[Title/Abstract])) OR (Data Poolings[Title/Abstract])) OR (Systematic Reviews[Title/Abstract])) OR (Systematic Review[Title/Abstract])) OR (Cochrane review[Title/Abstract])
#4 #1 AND #2 AND #3
Selection of studies

Systematic reviews and meta-analyses evaluating the efficacy of AIT in the treatment of AR were included. Each study was independently assessed by two investigators. The literature inclusion criteria were as follows: (1) Meta-analyses or systematic reviews and meta-analyses published in English; (2) The efficacy of AIT in the treatment of AR was studied; (3) Total effect sizes and 95% confidence intervals (CIs) were reported. Exclusion criteria were: (1) Repeatedly published studies; (2) The study population was non-AR patients with incomplete data or the required data could not be obtained from the original article; (3) Animal experiments, case reports, conference speeches, etc. Two investigators independently screened the literature by reading the title and abstract, and then the two investigators independently reviewed the full text to further confirm the inclusion or exclusion of relevant literature. In case of differences of opinion that could not be resolved through discussion, a third researcher determined whether to include the article.

 Data extraction

Upon completing the data extraction form, two researchers independently extracted the following data from each systematic review and meta-analysis: the author, the country of publication, the time of publication, the number of included studies, the population of participants, the allergen, the intervention, efficacy-related outcome measures, the effect model, the effect size and 95%CI, the p-value or the I (2) value of the heterogeneity test. All data were independently extracted by two researchers.

 Methodological and evidence quality evaluation

Two investigators independently assessed each including systematic review and meta-analysis. The methodological quality was evaluated using AMSTAR 2, with each item classified as “yes”, “partly yes” or “no” (9). The quality of evidence was appraised using the GRADE system, which clearly defines the quality of evidence and the strength of recommendations, and classifies the evidence into “high”, “moderate”, “low”, “very low” or “cannot be recommended” (10). The overlap of major studies included in the literature might mislead the results. To measure this overlap, the OVErviews (GROOVE) tool was employed, which computes the evidence matrix and corrected coverage area (CCA). Overlap was classified as mild if CCA<5%; If CCA≥5% and <10%, the classification was moderate. If CCA≥10% and <15%, it was classified as high. If CCA≥15%, it was classified as very high (11).

 Strategies for data synthesis

We chose symptom scores and medication scores for AIT treatment of AR as evidence of efficacy and extracted the relevant data. The 95% confidence intervals reported in each study were utilized to assess the overall efficacy. Heterogeneity among studies was evaluated using I (2), with values greater than 50% indicating high heterogeneity. Publication bias in systematic reviews and meta-analyses was determined using the Egger test, with a p-value less than 0.05 indicating bias. In some studies that could not be quantitatively and comprehensively analyzed, we carried out a descriptive analysis of the outcome indicators related to the efficacy of AIT in the treatment of AR (12). To provide more detailed insights into the efficacy of AIT in subgroups with different administration routes, we conducted a subgroup analysis of data on various allergens and patient populations across each administration route.

In addition to assessing the efficacy of different administration routes of AIT in AR through symptom scores and medication scores, the impact of AIT on the progression of allergic diseases remains a critical clinical concern. This includes the development of new-onset asthma in patients with AR, as well as the progression of AR in individuals with comorbid asthma. However, due to insufficient reporting of this outcome in the original reviews included in this study, inconsistencies in its definition, and variations in the duration of follow-up, the evidence regarding new-onset asthma or the progression of AR in combination with asthma is limited. Therefore, this study presents the available findings in the form of a literature discussion, highlighting it as an important area for future research.

 Results Search results

Based on the pre-defined search strategy, we initially retrieved 453 articles. After eliminating duplicates, the number of articles was 306. By perusing titles and abstracts, 261 articles irrelevant to the selected topic were excluded. After reading the full text, an additional 29 articles were eliminated. Eventually, through the literature screening process, 16 systematic reviews and meta-analyses were incorporated into this umbrella review (13–28), as depicted in Figure 1 . We summarized the efficacy measures of AIT in AR, using medication scores (MS) and/or symptom scores (SS) as a reference to assess the efficacy of AIT in AR, and extracted these data from the included studies.

Flow chart of the literature selection.

Flowchart depicting the article selection process for an umbrella review. Initially, 453 articles were identified. After removing 147 duplicates, 306 articles remained. Title and abstract screening excluded 262 records, leaving 44 for full-text assessment. Ultimately, 16 articles were included in the umbrella review after excluding 28 systematic reviews without meta-analysis or full text. Characteristics of included studies

The 16 systematic reviews and meta-analyses incorporated in this study were all published within the period from 2005 to 2023. The studies included in the analysis varied from 4 to 58, with sample sizes ranging from 134 to 3331. The AIT measures in the intervention group were also slightly different. Among them, 10 articles pertained to SLIT, 6 articles concerned SCIT, 2 articles encompassed a comprehensive study of AIT without differentiating between administration routes, and there was one related study each for cluster SCIT, ILIT, and local nasal immunotherapy (LNIT). The control group was mainly placebo. The principal characteristics of this study are elaborated in Table 2 .

Characteristics of the included studies.

Author Year Allergen Number of studies Study population Number of treatment groups Treatment intervention Number of control groups Control intervention Outcome measures Effect size 95%CI P-value I² value
Feng, B. H. et al. (13) 2017 HDM 25 1260 SLIT 1128 placebo SS SMD=-1.23 -1.74~-0.73 p<0.001 I²=96%
18 963 851 MS SMD=-1.39 -1.90~-0.88 p<0.001 I²=95%
12 Children only SS SMD=-0.70 -1.43~0.03 p=0.06
7 MS SMD=-1.66 -2.60~-0.71 p=0.006
10 Adults only SS SMD=-1.02 -1.53~-0.52 p<0.0001
6 MS SMD=-1.31 -2.12~-0.51 p=0.001
Feng, S. Y. et al. (14) 2014 4 103 cluster SCIT 77 placebo SS WMD=-5.91 -13.68~1.87 p=0.14 I²=89%
4 103 77 MS WMD=-1.27 -2.83~0.29 p=0.11 I²=94%
2 165 163 conventional SCIT SS WMD = 0.16 -0.18~0.51 p=0.36 I²=0%
2 165 163 MS WMD = -0.01 -0.16~0.13 p=0.88 I²=0%
Di Bona et al. (15) 2010 grass pollen 19 1518 SLIT 1453 placebo SS SMD=-0.32 –0.44~–0.21 p<0.0001 I²=55.8%
17 1430 1358 MS SMD=-0.33 -0.50~-0.16 p<0.0001 I²=78.5%
Li et al. (16) 2018 HDM 5 Adults only SLIT placebo SS SMD=-0.33 -0.54~-0.13 p=0.001 I²=74%
Aini et al. (17) 2021 3 36 ILIT 33 placebo SS SMD=-0.27 -0.91~0.38 p=0.420 I²=43%
2 25 23 MS SMD=-6.56 -21.48~8.37 p=0.390 I²=97%
Kim et al. (18) 2021 HDM 10 2803 SLIT-T 2941 placebo SS SMD=-0.329 -0.43~-0.23 p<0.01 I²=64%
9 2793 2932 MS SMD=-0.227 -0.37~-0.08 p<0.01 I²=85%
12 403 SLIT-D 363 SS SMD=-0.461 -0.80~-0.13 p<0.01 I²=77%
7 181 171 MS SMD=-0.546 -0.86~-0.23 p=0.08 I²=47%
6 125 SCIT 108 SS SMD=-1.669 -2.75~-0.59 p<0.01 I²=91%
4 79 66 MS SMD=-0.697 -1.04~-0.36 p=0.390 I²=0%
26 3331 AIT 3412 SS SMD=-0.543 -0.69~-0.40 p<0.01 I²=83%
18 3053 3169 MS SMD=-0.347 -0.48~-0.22 p<0.01 I²=76%
Compalati et al. (19) 2009 HDM 8 194 SLIT 188 placebo SS SMD=-0.95 -1.77~-0.14 p=0.02 I²=92%
4 89 86 MS SMD=-1.88 -3.65~-0.12 p=0.04 I²=95%
5 pediatric population 120 115 SS SMD=-0.49 -1.35~0.37 p=0.27 I²=88%
2 25 22 MS SMD=-2.43 -6.71~1.84 p=0.26 I²=96%
3 Adult population 74 73 SS SMD=-1.79 -3.89~0.31 p=0.09 I²=95%
2 64 64 MS SMD=-1.41 -3.72~0.89 p=0.23 I²=97%
Yang et al. (20) 2023 23 <18 2332 SLIT 2380 non-SLIT SS SMD=-0.99 -1.29~-0.69 p<0.001 I²=95.1%
17 1980 1902 MS SMD=-0.78 -1.09~-0.48 p<0.001 I²=94.4%
19 2113 2025 SS SMD=-1.07 -1.41~-0.74 p<0.001 I²=95.5%
14 1798 1731 MS SMD=-0.55 -0.82~-0.27 p<0.001 I²=92.1%
grass pollen 10 1544 1451 SS SMD=-0.32 -0.46~-0.19 p<0.001 I²=62.0%
grass pollen 9 1450 1371 MS SMD=-0.22 -0.36~-0.08 p=0.002 I²=61.7%
HDM 12 698 848 SS SMD=-2.11 -2.86~-1.36 p<0.001 I²=97.2%
HDM 7 440 450 MS SMD=-1.64 -2.73~-0.55 p=0.003 I²=97.4%
5 1279 SCIT 1223 non-SCIT SS SMD=-2.52 -3.59~-1.46 p<0.001 I²=95.9%
1 19 17 SS SMD=-0.54 -1.21~0.13 p=0.112
3 1154 1119 MS SMD=-1.42 -3.20~0.36 p=0.119 I²=96.9%
grass pollen 1 12 10 SS SMD=-0.91 -1.80~-0.03 p=0.044
grass pollen 1 12 10 MS SMD=-0.97 -1.86~-0.08 p=0.032
HDM 4 1267 1213 SS SMD=-2.94 -4.18~-1.70 p<0.001 I²=96.7%
HDM 2 1142 1109 MS SMD=-1.62 -3.99~0.75 p=0.180 I²=98.0%
Wilson et al. (21) 2005 21 484 SLIT 475 placebo SS SMD=–0.42 -0.69~-0.15 p=0.002 Chi-square=75.38
17 405 398 MS SMD=-0.43 -0.63~-0.23 p=0.00008 Chi-square=28,48
HDM 6 118 110 SS SMD=-0.58 -1.43~0.27 p=0.18
3 59 54 MS SMD=-0.85 -1.93~0.23 p=0.1
grass pollen 4 144 143 SS SMD=-0.37 -0.74~0 p=0.05
4 144 143 MS SMD=-0.41 -0.81~-0.01 p=0.04
5 children only 111 107 SS SMD=-0.31 -1.32~0.7 p=0.5 Chi-square=47.16
3 62 60 MS SMD=0.02 -0.34~0.37 p=0.9 Chi-square=0.43
16 adults only 373 368 SS SMD=-0.4 -0.61~-0.18 p=0.0003 Chi-square=28.17
14 343 338 MS SMD=-0.51 -0.73~-0.29 p<0.00001 Chi-square=22.52
Dhami et al. (22) 2017 16 602 SCIT 464 placebo MS SMD=-0.52 -0.75~-0.29 p<0.0001 I²=64%
16 632 499 SS SMD=-0.65 -0.86~-0.43 p<0.0001 I²=62%
58 2978 AIT 2746 SS SMD=-0.53 -0.63~-0.42 p<0.0001 I²=63%
12 <18 541 547 SS SMD=-0.25 -0.46~-0.05 p<0.015 I²=54%
23 >18 1557 1406 SS SMD=-0.56 -0.70~-0.42 p<0.0001 I²=62%
45 2098 1854 MS SMD=-0.38 -0.49~-0.26 p<0.0001 I²=60%
41 2285 SLIT 2187 SS SMD=-0.48 -0.61~-0.36 p<0.0001 I²=69%
29 1496 1390 MS SMD=-0.31 -0.44~-0.18 p<0.0001 I²=57%
Zhu et al. (23) 2022 4 64 SCIT 70 placebo SS SMD=-2.08 -3.68~-0.48 p=0.01 I²=98%
4 64 70 MS SMD=-1.43 -2.65~-0.21 p=0.02 I²=98%
Feng, B. et al. (24) 2017 26 children only 1147 SLIT 1065 placebo SS SMD=-0.55 -0.86~-0.25 p=0.0003 I²=90%
19 814 741 MS SMD=-0.67 -0.96~-0.38 p<0.00001 I²=83%
HDM 12 SS SMD=-0.70 -1.43~0.03 p=0.06
7 MS SMD=-1.66 -2.60~-0.71 p=0.0006
grass pollen 14 SS SMD=-0.43 -0.69~-0.17 p=0.001
12 MS SMD=-0.26 -0.44~-0.08 p=0.005
Hoang et al. (25) 2021 4 adults only 77 SCIT 76 placebo SS SMD=-2.59 -3.88~-1.29 p<0.01 I²=88%
4 77 76 MS SMD=-1.84 -3.10~-0.57 p<0.01 I²=92%
Radulovic et al. (26) 2011 49 2333 SLIT 2256 placebo SS SMD=-0.49 -0.64~-0.34 p<0.00001 I²=81%
38 1737 1642 MS SMD=-0.32 -0.43~-0.21 p<0.00001 I²=50%
HDM 9 232 232 SS SND=-0.97 -1.8~-0.3 p=0.02
5 95 94 MS SMD=-0.52 -1.09~-0.03 p=0.07
grass pollen 23 1549 1464 SS SMD=-0.35 -0.45~-0.24 p<0.00001
17 1201 1107 MS SMD=-0.23 -0.37~-0.1 p=0.0008
34 adults only 1631 1566 SS SMD=-0.44 -0.56~-0.31 p=0.0001
26 1168 1067 MS SMD=-0.4 -0.53~-0.26 p<0.00001
15 children only 702 690 SS SMD=-0.52 -0.94~-0.1 p=0.02
12 569 575 MS SMD=-0.16 -0.32~0 p=0.06
Calderon et al. (27) 2007 15 597 SCIT 466 placebo SS SMD=-0.73 -0.97~-0.50 p<0.00001
13 549 414 MS SMD=-0.57 -0.82~-0.33 p<0.00001
Kasemsuk et al. (28) 2022 11 147 LNIT 151 placebo SS SMD=-1.37 -2.04~-0.69 p<0.0001 I²=84%
11 139 142 MS SMD=-1.09 -1.35~-0.83 p<0.00001 I²=0%
Quality evaluation

The methodological quality was evaluated using AMSTAR 2. Among the 16 included articles, 5 were rated as “low”, and all the remaining ones were rated as “very low”. None of the articles presented a list of excluded literature and explained the reasons for exclusion. The majority of the studies had not been registered, published, or submitted to the research office or the ethics committee for review. Additionally, in some articles, researchers failed to provide a plausible explanation or discussion of the heterogeneity of findings. Some articles conducted quantitative analyses without a reasonable analysis of publication bias and a discussion of its possible impact on the results. Specific assessment details are provided in Table 3 .

Results of the AMSTAR 2 assessment.

References Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14 Q15 Q16 Overall quality
Feng, B. H. et al. (13) Y N Y PY Y Y N PY PY N Y N Y N Y Y CL
Feng, S. Y. et al. (14) Y N Y Y Y Y N Y PY N Y Y Y N Y N CL
Di Bona et al. (15) Y N Y N N N N PY PY N Y Y Y Y Y Y CL
Li et al. (16) Y N Y Y Y Y N PY PY N Y Y Y Y N Y CL
Aini et al. (17) Y Y Y Y Y Y N Y Y N Y Y Y Y N Y CL
Kim et al. (18) Y N Y Y Y Y N PY Y N Y Y Y Y N N CL
Compalati et al. (19) Y N Y Y Y Y N PY PY N Y Y Y Y N N CL
Yang et al. (20) Y Y Y Y Y Y N PY Y N Y Y Y Y Y Y L
Wilson et al. (21) Y N Y Y Y Y N PY PY N Y Y Y Y N N CL
Dhami et al. (22) Y Y Y Y Y Y N Y Y N Y Y Y Y Y Y L
Zhu et al. (23) Y N Y Y Y Y N PY Y N Y Y Y Y N Y CL
Feng, B. et al. (24) Y N Y Y N N N PY Y N Y Y Y N Y N CL
Hoang et al. (25) Y Y Y Y Y Y N PY Y N Y Y Y Y Y Y L
Radulovic et al. (26) Y PY Y Y Y N N PY Y N Y Y Y Y N Y CL
Calderon et al (27). Y PY Y Y Y Y N PY Y N Y Y Y Y Y N L
Kasemsuk et al. (28) Y Y Y Y Y Y N PY Y N Y Y Y Y Y Y L

Y, yes; PY, partial yes; N, no; CL, critically low; L, low; M, moderate; H, high.

The quality of the evidence was evaluated by using the GRADE system. It was discovered that the quality of evidence in most studies was not satisfactory. Among the included articles, six had evidence of moderate quality, six had low-quality evidence, and four had very low-quality evidence, while no high-quality evidence was found. Inconsistency was the most common factor for downgrading across programs, possibly due to the differences in the populations included in the studies, allergens, or interventions. None were downgraded because of Indirectness. Specific details of the assessments are provided in Table 4 .

Assessments of the GRADE.

References Risk of bias Inconsistency Indirectness Imprecision Publication bias Evidence quality
Feng, B. H. et al. (13) 0 -1 0 0 -1 L
Feng, S. Y. et al. (14) 0 -1 0 0 0 M
Di Bona et al. (15) 0 -1 0 0 0 M
Li et al. (16) 0 -1 0 0 0 M
Aini et al. (17) 0 -1 0 0 -1 L
Kim et al. (18) 0 -1 0 0 -1 L
Compalati et al. (19) 0 -1 0 0 -1 L
Yang et al. (20) 0 -1 0 0 0 M
Wilson et al. (21) 0 -2 0 0 -1 VL
Dhami et al. (22) 0 -1 0 0 0 M
Zhu et al. (23) -1 -1 0 0 -1 VL
Feng, B. et al. (24) -1 -1 0 0 -1 VL
Hoang et al. (25) 0 -1 0 -1 0 L
Radulovic et al. (26) -1 -1 0 0 -1 VL
Calderon et al (27). 0 -1 0 0 0 M
Kasemsuk et al. (28) 0 -1 0 -1 0 L

VL, very low; L, low; M, moderate; H, high.

We employed the GROOVE tool to evaluate the overlap of the main studies in the included literature. It was discovered that there was a moderate overlap among the included articles. The tool calculates the overlap rate by using the formula (N-r)/(rc-r). There were 120 nodes among the included articles, of which 84 nodes had a slight overlap, 11 nodes had a moderate overlap, 10 nodes had a high overlap, and 15 nodes had a very high overlap. The overall overlap was moderate, reaching 6.25%. The detailed evaluation results are presented in Figure 2 .

Overlapping of the included reviews.

Overall results and graphical data depict study overlap in reviews. The table shows metrics like columns, rows, and overlap interpretation as “moderate overlap.” The graphical representation, titled “Graphical Representation of Overlap for Overviews (GROOVE),” uses a color-coded system to indicate overlap percentages, categorized as slight, moderate, high, and very high. The chart visualizes overlaps among various studies and reviews, with percentages in each cell indicating the degree of overlap, summarized in a color legend. Evaluation of the efficacy outcome

Due to the diverse allergens of AR patients in the included literature, the varied interventions, and the distinct efficacies in adults and children, a subgroup analysis was conducted.

The efficacy of SLIT

A total of 10 articles dealt with the efficacy of SLIT. Among them, three studies failed to distinguish the age and allergen of the participants (21, 22, 26). All these three studies provided positive outcomes, demonstrating that SLIT reduced symptom scores and medication scores in AR patients compared with placebo. We extracted the 95%CI reported by each study to assess the overall efficacy. The results indicated that SLIT was effective in the population without discrimination of allergen and age (SS: SMD=-0.48, 95%CI=-0.57~-0.39, p = 2.41e-48, I²=0%, Egger’s test: p = 0.77; MS: SMD=-0.33, 95%CI=-0.41~-0.26, p = 9.38e-33, I²=0%, Egger’s test: p = 0.55) ( Figure 3 ). Five studies identified grass pollen as the allergen in patients with AR (15, 20, 21, 24, 26). As the study by Yang et al. focused on comparing SLIT with non-SLIT treatments, we extracted the 95% confidence intervals from the remaining four studies to assess the overall efficacy. The results indicated that SLIT could significantly reduce both symptom scores and medication scores in AR patients sensitized to grass pollen (SS: SMD=-0.35, 95%CI=-0.42~-0.27, p = 2.30e-39, I²=0%, Egger’s test: p = 0.71; MS: SMD=-0.27, 95%CI=-0.36~-0.18, p = 1.46e-17, I²=0%, Egger’s test: p = 0.55) ( Figure 4 ). Seven studies included patients with AR sensitized to HDM allergens (13, 18–21, 24, 26). After excluding the study by Yang et al., in which the control group received a different intervention, we assessed the overall efficacy of SLIT in the remaining studies. The results indicated that SLIT was effective in treating AR patients with HDM allergy (SS: SMD=-0.39, 95%CI=-0.48~-0.30, p = 1.46e-06, I²=83.86%, Egger’s test: p = 0.0012; MS: SMD=-0.39, 95%CI=-0.52~-0.27, p = 9.78e-05, I²=89.79%, Egger’s test: p = 0.0006) ( Figure 5 ). Our study results revealed high heterogeneity and Egger’s test P < 0.05, indicating bias in this study. Five articles provided study results in pediatric patients (19–21, 24, 26). Although the majority of the findings in these included studies did not reach statistical significance, the overall efficacy assessment indicated that SLIT demonstrated effectiveness in pediatric AR patients (SS: SMD=-0.52, 95%CI=-0.75~-0.29, p = 3.17e-10, I²=0%, Egger’s test: p = 0.74; MS: SMD=-0.24, 95%CI=-0.37~-0.11, p = 0.0356, I²=78.68%, Egger’s test: p = 0.34) ( Figure 6 ). We suspected that either the sample size of the studies included in the original meta-analysis was too small or there was bias in some of the studies, resulting in insignificant results. There were also five studies evaluating the efficacy of SLIT in adults (13, 16, 19, 21, 26). Among these, the study conducted by Li et al. reported only the symptom score results. Based on our comprehensive assessment, we found that SLIT is also effective in treating adult patients with AR (SS: SMD=-0.43, 95%CI=-0.53~-0.34, p = 2.69e-37, I²=0.0093%, Egger’s test: p = 0.0781; MS: SMD=-0.45, 95%CI=-0.56~-0.34, p = 5.62e-28, I²=0%, Egger’s test: p = 0.0398) ( Figure 7 ).

Forest plot of SLIT efficacy in a population without allergen or age discrimination. [(A) Symptom scores. (B) Medication scores].

Two forest plots comparing effect sizes (SMD) from multiple studies labeled A and B. Each plot shows individual study weights and combined results, including Wilson et al. 2005, Dhami et al. 2017, and Radulovic et al. 2011. Plot A displays a combined SMD of -0.48, with individual studies ranging from -0.42 to -0.49. Plot B shows a combined SMD of -0.33, with individual studies ranging from -0.32 to -0.43. Both plots include confidence intervals and scales for standardized mean difference.

Forest plot of the efficacy of SLIT in AR patients allergic to grass pollen. [(A) Symptom scores. (B) Medication scores].

Forest plots comparing study effect sizes. Panel C shows studies by Di Bona et al. (2010), Wilson et al. (2005), Radulovic et al. (2011), and Feng et al. (2017) with weights ranging from 3.88% to 48.14%. The combined effect size is -0.35. Panel D includes the same studies with updated weights ranging from 4.94% to 43.35%. The combined effect size is -0.27. Both panels show standardized mean differences with confidence intervals.

Forest plot of the efficacy of SLIT in AR patients allergic to HDM. [(A) Symptom scores. (B) Medication scores].

Two forest plots labeled E and F show the standardized mean differences (SMD) of several studies, with effect sizes and confidence intervals. Both plots display individual studies' weights and combined results using a random-effects model. Plot E shows a combined SMD of -0.60 (confidence interval: -0.84 to -0.36), while Plot F shows a combined SMD of -0.74 (confidence interval: -1.11 to -0.37). Both plots indicate varying weights and effect sizes across studies.

Forest plot of the efficacy of SLIT in children with AR. [(A) Symptom scores. (B) Medication scores].

Meta-analysis forest plots labeled G and H, display studies with weights, effect sizes, and confidence intervals. Plot G shows combined effect size of -0.52, while plot H shows -0.27. Both use a random effects model, with weights and standardized mean differences varying by study.

Forest plot of the efficacy of SLIT in adult AR patients. [(A) Symptom scores. (B) Medication scores].

Forest plots labeled I and J display standardized mean differences (SMD) for various studies. Both plots show weights, effect sizes, and confidence intervals for Wilson et al. 2005, Radulovic et al. 2011, Feng et al. 2017, and others. Plot I includes Li et al. 2018, while plot J excludes it. The combined effect size in plot I is -0.43, and in plot J is -0.45. Plots include a random effects (RE) model analysis. Horizontal lines represent confidence intervals, with diamonds indicating combined effect sizes. The efficacy of SCIT

A total of six studies evaluated the efficacy of SCIT (18, 20, 22, 23, 25, 27). A pooled analysis of all studies meeting the inclusion criteria for overall assessment indicated that the overall findings were valid (SS: SMD=-0.75, 95%CI=-0.90~-0.59, p = 1.17e-40, I²=0%, Egger’s test: p = 0.0007; MS: SMD=-0.60, 95%CI=-0.75~-0.45, p = 1.96e-29, I²=0.031%, Egger’s test: p = 0.0327) ( Figure 8 ). The results of our study demonstrated little heterogeneity, but Egger’s test indicated that the study was biased at p < 0.05.

Forest plots of SCIT efficacy in AR patients. [(A) Symptom scores. (B) Medication scores].

Side-by-side forest plots labeled K and L. Both plots display studies by Kim et al. 2021, Dhami et al. 2017, Zhu et al. 2022, Hoang et al. 2021, and Calderon et al. 2007. The plots show weights, standardized mean differences (SMD), and confidence intervals. The combined effect for K is -0.75 with SMD [-0.90, -0.59]; for L, it is -0.60 with SMD [-0.75, -0.45]. Both plots include an RE model summary. The efficacy of other interventions

Two studies failed to present specific AIT methods (18, 22), and the outcomes were positive. We also assessed the overall results (SS: SMD=-0.53, 95%CI=-0.62~-0.45, p = 5.07e-67, I²=0%, Egger’s test: p = 0.9275; MS: SMD=-0.37, 95%CI=-0.45~-0.28, p = 3.98e-32, I²=0%, Egger’s test: p = 0.9201) ( Figure 9 ). Additionally, there was another article concerning cluster SCIT (14) (SS: WMD=-5.91, 95%CI=-13.68~1.87, p = 0.14, I²=89%; MS: WMD=-1.27, 95%CI=-2.83~0.29, p = 0.11, I²=94%), suggesting that cluster SCIT did not achieve superior efficacy compared with placebo in the treatment of AR. Aini et al. (17), a meta-analysis of ILIT, also produced negative results (SS: SMD=-0.27, 95%CI=-0.91~0.38, p = 0.42, I²=43%; MS: SMD=-6.56, 95%CI=-21.48~8.37, p = 0.39, I²=97%). The meta-analysis by Kasemsuk et al. (28) on LNIT demonstrated positive results (SS: SMD=-1.37, 95%CI=-2.04~-0.69, p<0.0001, I²=84%; MS: SMD=-1.09, 95%CI=-1.35~-0.83, p < 0.00001, I²=0%).

Forest plot of the efficacy of AIT in AR patients. [(A) Symptom scores. (B) Medication scores].

Two forest plots labeled M and N showing meta-analysis results. Plot M includes studies by Kim et al., 2021 and Dhami et al., 2017, with a combined effect size of -0.53 and weights of 33.48% and 66.52%, respectively. Plot N also represents Kim et al., 2021 and Dhami et al., 2017, with a combined effect size of -0.37 and weights of 44.28% and 55.72%, respectively. Both plots show effect sizes with confidence intervals for each study and an overall random effects model. Impact on asthma progression

The included studies have demonstrated that AIT exhibits varying degrees of efficacy in the prevention and control of asthma among patients with AR, with differences in both effectiveness and safety across different administration routes. Among the available treatment options, SCIT has the strongest supporting evidence. According to Calderon et al. (27), SCIT significantly reduced bronchial symptom scores in patients with AR and asthma (SMD=-0.59, 95%CI=-1.06~-0.11, p = 0.02). Furthermore, SCIT can reduce the need for rescue medications (e.g., inhaled β2 agonists), thereby contributing to improved lung function, as indicated by increased forced expiratory volume in one second (FEV1) and decreased peak expiratory flow (PEF) variability. The therapeutic benefits of SCIT can be sustained for 3 to 5 years following the completion of a long-term treatment regimen (≥3 years). Additionally, the study highlights allergic rhinitis as a well-established risk factor for asthma, with 15% to 38% of individuals diagnosed with AR also developing asthma.

SLIT offers advantages in terms of safety and applicability for pediatric populations. Compalati et al. (19) demonstrated that SLIT could significantly reduce bronchial symptom scores in dust mite-allergic AR patients with asthma (SMD=-0.95, 95%CI=-1.74~-0.15, p < 0.05). In the subgroup of children, the reduction in symptoms was even more pronounced (SMD=-1.09, 95%CI=-1.96~-0.22, p = 0.01), accompanied by a significant decrease in asthma medication use (SMD=-1.48, 95%CI=-2.70~-0.26, p = 0.02). However, a high level of heterogeneity was observed (I (2) = 93%~96%), which may be attributed to variations in allergen dosage and treatment duration. Dhami et al. further confirmed that SLIT significantly improved both asthma symptoms (SMD=-0.49, 95%CI=-0.69~-0.30) and medication use (SMD=-0.37, 95%CI=-0.69~-0.30) in pollen-allergic AR patients with asthma. Moreover, symptom improvement was sustained for at least one year after discontinuation of treatment. A network meta-analysis by Kim et al. (18) indicated no significant difference between SLIT and SCIT in terms of asthma symptom control among pollen-allergic AR patients (p = 0.43). However, SLIT was associated with a lower incidence of local adverse reactions, such as oral pruritus (<5% vs. 10%~15%).

ILIT represents a novel approach to AIT. According to Aini et al. (17), ILIT demonstrated a significantly improved safety profile, with a reduced incidence of cutaneous reactions, such as localized swelling, compared to SCIT (RR = 0.31, 95%CI=0.13~0.72, p = 0.007). Furthermore, ILIT was associated with a more rapid decline in serum-specific IgE levels (3 months vs. 3 years). However, no statistically significant differences were observed between ILIT and placebo in terms of asthma symptom scores (SMD=-0.27, 95%CI=-0.91~0.38, p = 0.42) or medication usage. Given the high heterogeneity among trials (e.g., variations in allergen dosages and injection intervals) and the limited evidence supporting the efficacy of ILIT in modifying the course of asthma, ILIT is not recommended as the first-line allergen immunotherapy for patients with allergic rhinitis and asthma.

 Discussion

Allergic rhinitis is a highly common chronic disease, and its progression is also associated with asthma, sinusitis, and other disorders (29). Its pathogenesis is a non-infectious inflammatory response driven by helper T lymphocyte 2 (Th2) in atopic individuals upon inhalation of allergens (30). The occurrence of allergy might be related to the spread of antigenic determinants, and the mechanism of desensitization treatment is to reduce the spread of this determinant, continuously apply allergens to establish peripheral specific non-reactive T cells, and inhibit cytokine activity and T cell proliferation (31). Although AIT has been practiced for over a hundred years and is the sole treatment targeting the underlying pathophysiology and altering the natural course of AR, details regarding the practice of AIT during its evolution have varied globally. Since the 1980s, several national and regional allergy societies have endeavored to provide some guidance on AIT practice. However, it was not until 2009 that the World Allergy Organization (WAO) issued the consensus on SLIT for the first time. Up to now, no such global consensus document exists for other types of immunotherapy (32).

In recent years, the number of SRs/MAs regarding the application of AIT in the treatment of AR has increased. However, due to variations in evaluation systems, the quality of these studies is inconsistent, leading to suboptimal outcomes. This study introduces an innovative approach by shifting the core variable in treatment decision-making from “target/allergen” to “route of administration,” thereby enabling the direct translation of evidence into actionable clinical decisions. We conducted a detailed and comprehensive review of 16 studies. The findings indicated that the majority of the included SRs/MAs reported that various approaches of AIT in the treatment of AR were effective, particularly SLIT and SCIT. However, some studies still suggested that the efficacy of AIT in treating AR remained inconclusive, especially in pediatric populations and studies focusing on cluster SCIT and ILIT. We hypothesize that this inconsistency may be attributable to the limited or biased sample sizes of the included SRs/MAs. Additionally, the less pronounced therapeutic effects observed in children compared to adults may be associated with lower treatment compliance among pediatric patients.

Some other studies have included safety analyses. Feng, S.Y. and Calderon et al. discovered that the utilization of AIT might lead to side effects such as rhinoconjunctivitis, mild wheezing, urticaria, ear itching, palm/sole itching, and eyelid edema. The research of Radulovic and Yang et al. indicated that in comparison with the subcutaneous approach, the application of AIT could cause adverse effects like nasal conjunctivitis, mild wheezing, urticaria, ear itching, palm/sole itching, and eyelid edema. The sublingual route is safer and has fewer side effects, which is in line with previous studies (33). Compared to dosage forms, Li et al. found that SLIT tablets could better regulate the drug volume and achieve higher compliance than SLIT drops due to their safety and ease of transport, administration, and follow-up.

In addition to comparing the relative efficacy of different administration routes of AIT in the treatment of AR, this study also examined the potential long-term outcomes associated with allergic progression. Although the reviewed literature did not provide a systematic summary of the direct effects of AIT on the incidence of new-onset asthma or its progression in patients with AR, several studies suggest that AIT administered via various routes may have a beneficial impact on the prevention and alleviation of asthma. These findings hold clinical significance. In recent years, real-world studies have demonstrated that AIT, including both subcutaneous and sublingual administration—available in either liquid or tablet form—is effective for patients with AR, regardless of whether they have asthma or not. SCIT can effectively reduce symptom scores and the need for rescue medication in patients with moderate to severe stable asthma who suffer from HDM or pollen allergies. Furthermore, SCIT can decrease the frequency of acute exacerbations by 40% to 50%, with its long-term therapeutic effects lasting for 3 to 5 years (34, 35). SLIT liquid significantly reduced symptom scores (SMD=-0.30) and medication scores (SMD=-0.51) across 25 RCTs involving 1,830 cases. According to the French national study, SLIT liquid decreased the risk of asthma exacerbation and escalation of GINA treatment steps. Moreover, the reduction in the risk of new-onset asthma among children was particularly pronounced (HR = 0.51) (36, 37). SLIT tablets demonstrated efficacy in improving allergic rhinitis symptoms triggered by grass or birch pollen, particularly in patients with mild asthma (SMD=-0.36), as well as in reducing medication use (SMD=-0.29). The therapeutic effect was sustained even after a two-year period of treatment discontinuation. After six years of follow-up, the rate of asthma medication withdrawal was significantly higher in the SLIT group (49.1%) compared to the control group (35.1%) (38, 39). Children represent a key population for AIT in the prevention of asthma, while the benefits of AIT in adults primarily focus on disease control and delaying the progression of asthma. Despite encouraging evidence from real-world studies, higher-quality research is needed to clarify the role of different administration routes in the context of new-onset asthma. Future studies should incorporate new-onset asthma as a key outcome, with a standardized definition and systematic evaluation within prospective cohort studies.

A major advantage of this study lies in its utilization of an umbrella review to reevaluate the existing evidence and synthesize higher-level evidence. It is beneficial for clinicians to determine whether to select different AIT to treat AR with various allergens in different populations. Nevertheless, the study has certain limitations: (1) According to the AMSTAR 2 method, no high-quality studies were included; most studies were not registered, and most systematic reviews and meta-analyses failed to consider the bias risk of the included literature and the heterogeneity of the study results. (2) The assessment of methodological quality and evidence quality is subjective. Even if we conduct a detailed and objective evaluation of each item of the evaluation system, guidelines or authoritative third parties are needed to adjudicate disputes. There might still be some variations in the results. (3) Only studies published in English were incorporated, which might have a certain bias risk. (4) The main outcome index of the RCTs included in this study was the scoring scale, and there might be some differences in the content of the RCTs, which could have an impact on the treatment outcome and needs to be verified by objective indicators such as serum specific IgE level. (5) Both ILIT and cluster SCIT were each covered by only one study and were found to be ineffective. Due to the high heterogeneity among trials and the small sample sizes, future trials should involve more participants and report standardized management and outcome measures of the study. Given the limitations of this study, further high-quality research is necessary.

 Conclusion

In conclusion, both SLIT and SCIT are effective treatments for AR, showing significant efficacy in adults, children, and for various allergens. SLIT is relatively safe and easy to comply with. However, meta-analyses and systematic reviews of cluster SCIT, ILIT, and LNIT are limited, and their efficacy evaluation needs improvement. Additionally, the methodological quality and evidence of existing systematic reviews and meta-analyses are generally low, so these results should be interpreted cautiously. Therefore, more high-quality, large-scale, multicenter, randomized controlled trials are needed to firmly validate the efficacy of different AIT methods for treating AR across various populations and allergens.

 Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

 Author contributions

YH: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Visualization, Writing – original draft, Writing – review & editing. XL: Data curation, Formal analysis, Methodology, Visualization, Writing – review & editing. BZ: Formal analysis, Visualization, Writing – review & editing. TD: Software, Validation, Writing – review & editing.

 Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

 Acknowledgments

The authors express their gratitude to the authors of the relevant literature of the included studies as well as the participants of each of the original studies.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

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