Efficacy of Chinese herbal medicine on nasal itching in children with allergic rhinitis: a systematic review and meta-analysis

Background: Allergic rhinitis is prevalent among children and can cause nasal itching, fatigue, and even hinder growth and development. The main discomfort symptom of allergic rhinitis is nasal itching. Clinical reports suggest that Chinese herbal medicine (CHM) is effective in allergy rhinitis treatment. Therefore, we evaluate the clinical efficacy of Chinese herbal medicine in treating nasal itching caused by allergic rhinitis in children. Methods: Nine databases, including PubMed, Embase, The Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wan Fang Data, CQVIP, Chinese Biological Medicine, and ClinicalTrials.gov, were systematically searched from their inception until March 2023. Randomized controlled trials (RCTs) comparing the efficacy of Chinese herbal medicine, either alone or in combination with Western medicine, to Western medicine treatment or placebo intervention for treating allergic rhinitis in children were eligible for inclusion. The effectiveness of Chinese herbal medicines for nasal itching was mainly evaluated. The Risk of Bias tool 2.0 assessed the risk of bias. Statistical analysis using RevMan 5.3 and Stata/SE 12. The quality of evidence was evaluated by GRADEpro 3.6. Risk ratios (RR) with corresponding 95% confidence intervals (CI) were utilized to evaluate and present dichotomous data, while mean difference (MD) and standardized mean difference (SMD) were employed for continuous data. A fixed-effects model was applied in cases where the data exhibited homogeneity (p > 0.1, I2 < 50%), whereas a random-effects model was utilized for heterogeneous data. Statistical significance was determined by a p-value <0.05. This study was conducted by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and its review protocol was registered on the International Platform for Registered Systematic Reviews and Meta-Analysis Programs (INPLASY202340076). Results: The review incorporated 23 studies. The meta-analysis indicated that herbal medicine was significantly related to the reduction of nasal itching (MD = −0.59, 95%CI: −0.94–0.24) and the increase of interleukin 10 level (SMD = 1.47, 95% CI: 0.90–2.05). Compared to Western medicine, the combining herbs and Western medicine showed better efficacy in relieving nasal itching, inhibiting immunoglobulin E, interleukin 4 and 33, enhancing interleukin 10, improving therapeutic efficiency, and reducing recurrent. Oral herbal medicine was more effective in treating nasal itching (MD = −0.45, 95% CI: −0.62–0.29). Combining oral and external herbal medicines was more efficient in treating nasal itching (MD = −0.44, 95% CI: −0.54–0.33), inhibiting immunoglobulin E, interleukin 4 (SMD = −0.87, 95% CI: −1.24–0.50) and 33 (SMD = −1.16, 95% CI: −1.54–0.77), and improving therapeutic efficiency. External herbal medicine did not show differences compared to Western medicines. Regarding safety, herbal medicine alone exhibited fewer adverse events than Western medicine; combining herbal and Western medicine showed no significant variation in adverse event incidence. Conclusion: Chinese herbal medicine (CHM) holds great potential in alleviating symptoms, modulating immune factors levels, and reducing relapse in pediatric rhinitis. Meanwhile, CHM is relatively safe. However, the efficacy and safety of CHM in treating pediatric rhinitis still need to be confirmed due to the inclusion of studies with low methodological quality, small sample sizes, and potential heterogeneity. More high-quality research is necessary to provide reliable evidence for the clinical application of CHM. Systematic Review Registration: INPLASY.com, identifier INPLASY202340076


Introduction
Allergic rhinitis is a prevalent condition in children, mediated by immunoglobulin E. Its prevalence is approximately 40% and gradually rising (Zhang and Zhang, 2019;Hox et al., 2020).In China, the current prevalence of allergic rhinitis among children is about 18.61% (Ruikun et al., 2022).The main symptoms include nasal itching, congestion, runny nose, and sneezing.Since there is a correlation between allergic diseases, allergic rhinitis is closely linked to other conditions such as asthma, upper airway cough syndrome, and cough variant asthma (Marple, 2010;Zvezdin et al., 2015;Donaldson, 2023).Additionally, allergic rhinitis can affect children's nervous system, including attention deficit hyperactivity disorder and Tourette syndrome (Zhou et al., 2017;Xu et al., 2020;Liu X. et al., 2021).As a result, allergic rhinitis has become one of the research priorities in pediatric studies.
The pharmacological treatment of allergic rhinitis involves glucocorticoids, leukotriene receptor antagonists, antihistamines, and immunotherapy (Cobanoğlu et al., 2013;Klimek et al., 2019).These medications can have side effects such as impaired height growth, rhinorrhea, mental arousal, and drowsiness (Wolthers and Pedersen, 1993;Sastre et al., 2012;Mener et al., 2015;Marques et al., 2022), interfering with the standardized treatment of allergic rhinitis in children.Since allergic rhinitis can impede physical and intellectual development in children (He et al., 2017;Morais-Almeida et al., 2019;Sirufo et al., 2020), better management of its symptoms is required for optimal growth and development.Therefore, exploring alternative pharmacological therapies is necessary.
Chinese herbal medicine is a cornerstone of complementary alternative medicine, used in China for thousands of years.Herbal medicine can relieve allergic rhinitis nasal symptoms (Chan and Ng, 2020) by regulating inflammatory factors and immune function in affected children (Liu et al., 2022;Dou et al., 2023).Although some studies show the therapeutic effectiveness of herbal treatment in children with allergic rhinitis, meta-analyses examining the control of nasal symptoms from herbal medicine on allergic rhinitis in children are inconclusive.This review and meta-analysis aim to gather the appropriate evidence to comprehensively assess the overall therapeutic efficacy of herbal medicine on allergic rhinitis in children.trials; 3) compared Chinese herbal medicine (Including alone or in combination with western medicine) to Western medicine or placebo.No restrictions on the type, use, or duration of Chinese herbal medicine; 4) nasal itching score was reported in study.
Exclusion criteria were: 1) use acupuncture, massage, or any non-Chinese herbal treatments or control group treatment with Chinese medicine; 2) Children with other co-morbidities.Two independent reviewers (CYH and WJ) screened the studies based on the selection criteria.Any discrepancies between the assessments of these reviewers were resolved by a third reviewer (WLQ).

Types of outcome measures
The primary outcomes were nasal itching score (Gu and Dong, 2005), scored from 0-3 (The scoring system for itchy nose symptoms is as follows: a score of 0 indicates an absence of itchy nose symptoms, a score of 1 signifies occasional and intermittent itchy nose, a score of 2 represents a tolerable creeper sensation, and a score of 3 indicates the most severe level, characterized by an intolerable creeper sensation.).Secondary outcomes were efficiency, serum IgE levels, serum IL-4, IL-10, and IL-33 levels, recurrent rate, and adverse events.

Data extraction and bias assessment
Upon completing the literature search, we employed Endnote 20.0 software to manage the collected literature.Two reviewers (CYH and WJ) independently screened the identified studies' titles, abstracts, and full texts using the predetermined inclusion and exclusion criteria.Essential information from the included studies, such as authors' names, publication year, sample size, participant demographics (gender and age), intervention methods, outcome measures, and adverse effects, was extracted by the same two reviewers (CYH and WJ) utilizing a preestablished data collection form.Subsequently, this information was cross-validated by another two reviewers (CH and ZZW).In cases requiring additional details, one reviewer (ZY) proactively contacted the authors of specific studies via phone or email.Any reviewer disagreements will be resolved through discussion with another reviewer (WLQ).The Risk of Bias in included literature was evaluated by two independent reviewers (CYH and WJ) using the Risk of Bias 2 tool, which assessed six specific areas: randomization process, deviations from intended interventions, missing data, outcome measurement, selection of the reported result, and overall bias.After the data was extracted, we transformed raw continuous variable data into post-treatment minus pretreatment delta values following guidelines proposed by Cochrane (JPT et al., 2022).

Evidence synthesis and statistical analysis
The statistical analysis of this study was conducted using Review Manager 5.3 software and STATA/SE 12.0.The quality of evidence was evaluated using GRADE profiler 3.6.Effect sizes for dichotomous data were analyzed using risk ratio (RR) and their 95% confidence interval (CI).Mean difference (MD) effect sizes with 95% confidence intervals were used to analyze nasal itching data.Standardized mean difference (SMD) with 95% confidence interval was used for continuous variables represented in different units as reported in the original studies.A fixed effects model was utilized to analyze data with good homogeneity (I 2 < 50%, p > 0.1), while a random effects model was used for data with poor homogeneity.p < 0.05 were considered to be statistically significant.Heterogeneity sources were elucidated by subgroup analysis when appropriate.Begg's analysis was employed for studies with literature sizes equal to or greater than ten to ascertain publication bias.The stability of the study's findings was determined using sensitivity analysis.

Literature search results
The initial search yielded 2,826 articles, from which 1,034 duplicates were identified and removed.A total of 1,536 articles were subsequently excluded based on their titles/ abstracts according to the inclusion and exclusion criteria.After a full-text reading of the remaining 256 articles, 233 studies were excluded, leaving 23 RCTs (Huang et al., 2014;Wang and Zhao, 2016;Wang, 2017;Jiang et al., 2018;Chen, 2019;Lin, 2019;Shi et al., 2019;Wang et al., 2019;Yang et al., 2019;Yu and Wang, 2019;Zhang et al., 2019;Liu et al., 2020;Ma, 2020;Liu W. et al., 2021;Li and Guo, 2021;Sun et al., 2021;Zhang, 2021;Wang J. et al., 2022;Wang X. et al., 2022;Liu and Yang, 2022;Xu and Chen, 2022;Li et al., 2023;Wu et al., 2023) suitable for inclusion in this meta-analysis.Figure 1 illustrates the specific screening process, while Table 2 presents the distinctive characteristics of the analyzed studies.The drug utilization details, including dosage form, dose, and frequency, for each study and the duration of follow-up are presented in Table 2. Supplementary Table S1 provides additional information on the included studies' patient sources, TCM syndromes, and funding sources.The characteristics of the included CHM are presented in Table 3.
Nine of the 23 randomized controlled trials (RCTs) explicitly stated that the patients were sourced from the outpatient clinic.One RCT included patients from the outpatient clinic and inpatient wards, while the remaining 13 did not provide explicit information regarding the patient source (Supplementary Table S1).In the 23 RCTs, one RCT (Liu et al., 2020) compared oral Chinese herbal medicine with placebo.Seven RCTs compared Chinese herbal medicine versus Western medicine, including three (Sun

Risk of bias assessment
Only one study (Liu et al., 2020) reported low risk of randomization as the utilized of blinding, other studies did not utilize blinding so reported moderate risk of bias.All twenty-three studies lacked specification on study enrollment information, resulting in a moderate risk of selection of reported bias.All twenty-three studies reported low risk of deviations from intended intervention, missing outcome date, and measurement of outcome.The overall risk of bias for all twenty-three studies was moderate.The risk of article bias is presented in Figures 2, 3.

External treatment with CHM.
In two RCTs (Wang and Zhao, 2016;Li and Guo, 2021), external CHM combined with WM was compared to WM alone, with an intervention period lasting up to 4 weeks.Although the results of both RCTs indicated better efficacy of CHM in relieving nasal itching than WM, a random-effects model analysis did not show any significant difference between the two treatments (p = 0.03, I2 = 79%, n = 200, MD = −0.36,95% CI: −0.83 to 0.11, p = 0.14; Figure 6B).One study (Liu et al., 2020) compared CHM with Placebo.Fixed-effects models showed no statistical difference between the two groups (n = 60, RR = 1.41, 95% CI: 0.98 to 2.02, p = 0.06; Figure 7).

Recurrence rate
Two trials reported the recurrence rates.One (Liu et al., 2020) compared CHM to Placebo, and the other (Liu and Yang, 2022) compared the combination of CHM with WM to using WM alone.The fixed-effect (p = 0.34, I2 = 0%) models demonstrated no statistically significant difference between CHM and placebo groups (n = 60, RR = 0.67, 95% CI: 0.36 to 1.24, p = 0.20; Figure 12).However, a significant difference was observed between CHM with WM compared to WM alone, indicating

FIGURE 2
The result for the evaluation of selected studies by ROB2.0.

FIGURE 3
The result for the evaluation of selected studies by ROB2.0.

FIGURE 4
The result of meta-analysis of CHM versus placebo on nasal itching.

GRADE for the main comparisons
The GRADE quality of evidence for all outcomes was evaluated.The quality of Nasal itch, effective rate, IgE, IL10, IL33, and recurrent rate were low.The quality of IL4 was very low.The quality of adverse reaction was moderate (Supplementary Table S2).

FIGURE 7
The result of meta-analysis of CHM versus placebo on effective rate.

FIGURE 8
The result of meta-analysis of CHM versus WM on effective rate.

FIGURE 9
The result of meta-analysis of the combination of CHM and WM versus WM alone on effective rate.

Summary of evidence
Chinese herbal medicine is a widely used treatment for allergic rhinitis in children in China.Although previous Chinese studies have demonstrated the therapeutic effects of CHM on allergic rhinitis in children, their level of evidence was low.Therefore, we conducted a meta-analysis of 23 randomized controlled trials (RCTs) with 2,605 children to pool the information on CHM's efficacy for nasal itching symptom relief, modulation of immune imbalance (IgE,, relapse reduction, and safety.
The risk of bias assessment indicates the need for attention to the risk of bias in the randomization process and selective reporting of endpoints in the included studies.This concern primarily arises from the absence of blinding, lack of reporting on specific methods of random allocation concealment, and failure to report study protocols.
Our primary findings indicate that Chinese herbal medicine (CHM) is related to reducing nasal itching and raising interleukin-10 (IL-10) levels compared to placebo.When administered orally, herbal medicines alone alleviate nasal itching and suppress levels of immunoglobulin E (IgE), interleukin-4 (IL-4), and interleukin-33 (IL-33), while simultaneously increasing IL-10 levels in contrast to Western medicines.Additionally, the combination of oral and topical CHM substantially alleviates nasal itching.External CHM was overall similar to WM in relieving nasal itching, efficiency, and lowering IgE levels.The combined external application of CHM and WM did not differ statistically from using WM alone for relieving nasal itching.Both studies within the subgroup indicated that external CHM combined with WM was superior in relieving nasal itching, but the meta-analysis indicated the opposite result.This was due to the use of a randomized effect model to account for the high heterogeneity.When using a fixedeffects model can obtain a more significant result.Therefore, we believe that topical CHM combined with WM is beneficial in the treatment of nasal itching.Statistically significant advantages were also observed when CHM was used with WM in other indicators.For the same reason, we believe that oral combined with external CHM is effective in reducing IgE.Eight randomized controlled trials (RCTs) reported adverse effects such as headache, dizziness, malaise, and dry mouth; however, all self-heal and no serious adverse events were reported.Meta-analysis results suggest that CHM alone or combined with WM has a favorable safety profile.
We found that the results of using external CHM alone varied widely across studies.The effectiveness of external CHM may depend on the duration of intervention and the use of different WM controls.External CHM was more effective when the duration of treatment was longer than 4 weeks, with the control group using antihistamines.Conversely, when the duration of treatment was shorter, and the control group received glucocorticoids, the opposite result was observed.Nasal hormones act on glucocorticoid receptors in the nasal mucosa by reducing inflammatory factors and inhibiting inflammation cells, thus decreasing inflammatory factor-mediated hyperirritability of the nasal mucosa.These two explanations may account for the lack of efficacy of external CHM.

Implications for practice
We have compiled comprehensive information regarding the herbal medicines utilized in this study, encompassing their types, frequency of use, and the outcomes associated with CHM prescriptions incorporated within commonly used herbal medicines.The presented results are detailed below: Across the 23 studies analyzed, the detailed composition of the CHM varied widely and included over  methodological quality of the original studies included in this systematic review, we believe that additional high-quality basic and clinical studies are necessary to further validate the role of herbal and CHM prescriptions, as well as traditional Chinese medicine (TCM) evidence, in clinical practice.

Conclusion
Chinese herbal medicine (CHM) holds great potential in alleviating symptoms, modulating immune factors levels, and reducing relapse in pediatric rhinitis.Meanwhile, CHM is relatively safe.However, the efficacy and safety of CHM in treating pediatric rhinitis still need to be confirmed due to the inclusion of studies with low methodological quality, small sample sizes, and potential heterogeneity.More large-sample, high-quality RCTs are necessary to provide reliable evidence for the clinical application of CHM.
FIGURE 5The result of meta-analysis of CHM versus WM on nasal itching.(A) oral CHM; (B) external CHM; (C) combination of oral and external CHM.

FIGURE 6
FIGURE 6 The result of meta-analysis of Combination of CHM and WM versus WM alone.(A) oral CHM; (B) external CHM.

TABLE 2
Characteristics of the included studies.

TABLE 2 (
Continued) Characteristics of the included studies.

TABLE 2 (
Continued) Characteristics of the included studies.

TABLE 3
The characteristic of CHM of included studies.

TABLE 3 (
Continued) The characteristic of CHM of included studies.

TABLE 3 (
Continued) The characteristic of CHM of included studies.

TABLE 3 (
Continued) The characteristic of CHM of included studies.

TABLE 3 (
Continued) The characteristic of CHM of included studies.