Meta-analysis and Construction of Core Indicator Field of Pediatric Bronchitis Treated by Chinese Herbs Acupoint Application Therapy

Abstract Objective  Our objective was to explore the commonly used herbs, acupoints, and efficacy evaluation indicators of Chinese herbs acupoint application therapy in the treatment of pediatric bronchitis, screen and construct the core index field, and systematically evaluate the efficacy and safety of Chinese herbs acupoint application therapy in the treatment of this disease. Methods  Chinese periodical databases such as China National Knowledge Infrastructure, Wanfang database, VIP Information, and Chinese Biomedical Literature database were searched, and the literature information was extracted manually to establish data tables for data analysis and the key efficacy evaluation index field. The quality of the included studies was assessed using the Cochrane Systematic Bias Risk Assessment Tool and the relevant efficacy indicators were meta-analyzed using RevMan 5.3 software. Results  The most commonly used herbs in acupoint application therapy were wind-cold dispersing herbs and cough-asthma relieving herbs. Feishu (BL 13), Danzhong (RN 17), and Tiantu (RN 22) were the main acupoints. The core indicators were effective rate, improvement of main symptoms/signs, onset time, disappearance time, traditional Chinese medicine (TCM) syndrome score, and symptom score. Meta-analysis results showed that the total effective rate was 0.11 (0.08, 0.33) ( Z  = 8.64, p  < 0.00001), I 2  = 39%; due to the heterogeneity of cough, expectoration, asthma, and other indicators, the meta-analysis was abandoned. Conclusion  In terms of total efficiency, Chinese medicine acupoint application therapy is superior to conventional Western medicine in efficacy and shortening the time of symptoms of pediatric asthmatic bronchitis. However, as the quality of the evidence included in the study is medium and low, and in the selection of indicators, there are more composite and relatively subjective indicators such as total effective rate, TCM syndrome score, and symptom score. Therefore, it is necessary to further standardize the efficacy indicators in this field and carry out high-quality and detailed Chinese medicine clinical randomized controlled trials.


Introduction
Bronchitis is a common disease in pediatrics. It is usually caused by biological, physical, chemical stimuli, and allergies. Cough, expectoration, and asthma are the main symptoms in clinical practice. Its pathological manifestations are congestion and edema of bronchial mucosa and infiltration of lymphocytes and neutrophils, and it can be accompanied by damage and shedding of cilia epithelial cells. When mucous glandular hypertrophy and hyperplasia are accompanied by bacterial infection, the secretion is purulent. Routine treatment of this disease mainly includes symptomatic treatment such as anti-infection and atomization.
It is classified as "cough" by traditional Chinese medicine (TCM). Regarding the records of pediatric cough, there is a saying in Treatise on Causes and Manifestations of Various Diseases (Zhu Bing Yuan Hou Lun) that "a person who coughs is due to invasion of wind-cold to the lung," in which exogenous pathogens, especially wind pathogen is the main pathogenic factor. The pathogenesis of the disease is mainly lung qi failing in dispersing, and the treatment is mainly ventilating lung qi and relieving cough. However, due to children's weak constitution and poor compliance, the medical compliance of oral administration is poor and this affects its clinical efficacy. Chinese herbs acupoint application therapy belongs to the external treatment. Based on the meridian theory, the herbs are grounded into fine powder, mixed with water, ginger juice, vinegar, yellow rice wine, honey, medical solution, etc., and then directly applied to the acupoints. In recent years, with the development of transdermal technology, Chinese herbs acupoint application therapy has also been valued by doctors. In the previous clinical retrospective studies, it was found that Chinese herbs acupoint application therapy had good curative effects on common clinical diseases in the primary clinics, such as fever, diarrhea, cough, and sore throat and, to some extent, the dosage of antibiotics was reduced. The purpose of this study was to provide evidence-based medical evidence for the correct clinical use of this method by conducting a metaanalysis of randomized controlled trials of Chinese herbs acupoint application therapy or conventional Western medicine in pediatric asthmatic bronchitis.

Source of Data
The Chinese periodical databases such as China National Knowledge Infrastructure, Wanfang database, VIP Information, and Chinese Biomedical Literature database were searched, and the keywords such as Xue Wei Tie Fu (acupoint application), Tie Fu Liao Fa (acupoint application therapy), Zhong Yao Tie Fu (acupoint application with Chinese herbs), Yao Tie (herbal patch), Xiao Er Zhi Qi Guan Yan (pediatric bronchitis), Xiao Er Chuan Xi Xing Zhi Qi Guan Yan (pediatric asthmatic bronchitis), and Xiao Er Ji Xing Zhi Qi Guan Yan (pediatric acute bronchitis) were searched. Retrieval time was from the establishment of the database to December 28, 2022, according to the nanofiltration standard, and 48 literature works were obtained in the preliminary examination. After removing the duplication, irrelevant literature, and unclear efficacy indicators, 36 literature works were finally included, involving 19 prescriptions, 73 Chinese herbs, 21 acupoints, and 12 efficacy evaluation indicators.

Inclusion Criteria
Inclusion criteria were based on the following factors: (1) research type: randomized controlled clinical trials (RCTs) and case-control trials; (2) research subjects: children with a definite diagnosis of bronchitis, acute bronchitis, and asthmatic bronchitis; (3) intervention: the treatment group focused on acupoint application therapy; the control group was treated with conventional Western medicine and the symptomatic treatment in the treatment group was the same as that in the control group; and (4) outcome indicators: efficacy evaluation indicators above 1.

Literature Screening and Data Extraction
The retrieved title information was imported into NoteExpress 3.0 software; the obviously irrelevant literature was screened out through the title and abstract; the full texts were downloaded, read, and screened strictly according to the inclusion criteria; and Excel form was established to prepare the document information extraction form. Extraction contents were basic information, intervention, and control measures, outcome indicators, and adverse reactions of the included research.

Literature Quality Evaluation
The Cochrane bias risk assessment tool was used to evaluate seven aspects of random sequence generation, allocation concealment, subject-blinded implementation, outcome evaluator-blinded implementation, incomplete outcome report, and selective outcome report. The literature search, literature screening, data extraction, and quality evaluation of the included literature were independently conducted by two investigators and cross-checked. The inconsistent contents were discussed and determined through consultation. If it was still uncertain, a third investigator would make the judgment.
there are more composite and relatively subjective indicators such as total effective rate, TCM syndrome score, and symptom score. Therefore, it is necessary to further standardize the efficacy indicators in this field and carry out high-quality and detailed Chinese medicine clinical randomized controlled trials.

Statistical Analysis
Herbal use, acupoint selection, and efficacy indicator analysis: the collected data were entered into Excel 2013 for standardized pretreatment and frequency analysis. Metaanalysis: RevMan5.3 statistical software was used, and mean difference (MD) was used for the measurement data. Relative risk was used for counting data or binary variables. Each effect size was expressed as a 95% confidence interval (95% CI). The statistical heterogeneity of the I 2 values included in the study was calculated. If I 2 < 50% and p > 0.05, the fixed effect model was used for meta-analysis. If I 2 50% and p < 0.05, the random effect model was used. When there was obvious heterogeneity, the source of heterogeneity was explored for subgroup analysis and sensitivity analysis. If the heterogeneity was too large or the source of the data could not be found, the meta-analysis was discarded and only descriptive analysis was performed. If the same control type included more than 10 studies, a backward funnel plot was used to analyze publication bias.

Basic Information of Literature
Finally, 36 literature works were included, including 4,545 cases, with 2,335 cases in the acupoint application therapy group and 2,210 cases in the control group. The details are shown in ►Table 1. In the literature quality evaluation, it was found that only the randomized method was reported in the included studies, and the blinding, allocation concealment, and selectivity reports were not reported. See ►Fig. 1 for details.

Medication Statistics
Finally, 36 literature works were included. The statistics of Chinese herbs for acupoint application used in the included literature showed that 73 kinds of herbs were used. The most frequently used herbs were Xixin (Asari Radix et Rhizoma), Baijiezi (Sinapis alba L.), Xingren (Armeniacae Semen Amarum), etc. A total of 18 kinds of Chinese herbs were used with herb frequency > twice. The efficacy was classified by reference to the efficacy of Chinese herbs 1 (►Table 2). The most common herbs were wind-cold dispersing herbs and coughrelieving and asthma-calming herbs. The specific herb efficacy radar figure is shown in ►Fig. 2.

Analysis of Acupoints
Statistics on the selected acupoints in the Chinese herbs acupoint application therapy for the treatment of pediatric bronchitis included in the study showed that 21 acupoints were involved. Among them, the most frequently used acupoints were Feishu (BL 13), Danzhong (RN 17), Tiantu (RN 22), etc., as shown in ►Fig. 3.

Analysis of Efficacy Indicators
The efficacy indicators involved in the included literature were statistically analyzed, screened, and combined, and the key efficacy indicators were screened according to the frequency. The results showed that there were 12 efficacy indicators for the evaluation of acupoint application therapy in pediatric bronchitis, among which the key efficacy indicators were the total effective rate, main symptoms/physical signs improvement, onset time, disappearance time, TCM syndrome score, and symptom score (►Fig. 4).
The literature with clinical symptoms/signs as efficacy evaluation indicators was further analyzed. The results showed that cough, expectoration, asthma, and pulmonary rales occurred frequently. Therefore, these four indicators were selected as efficacy evaluation indicators in the subsequent meta-analysis.

Meta-analysis
According to the screening results of the key efficacy indicators above, the total effective rate, the onset, and improvement time of main symptoms/signs were selected as the efficacy evaluation indicators based on the frequency, and the effect of acupoint application therapy on pediatric bronchitis was further meta-analyzed. Meta-analysis results showed that the I 2 value of each index was greater than 50%, indicating that the results were heterogeneous and the reasons for the heterogeneity were needed to be discussed by excluding the literature one by one. In the meta-analysis, the total effective rate I 2 value was 53% (►Fig. 5). After excluding one RCT, the total effective rate was 0.11 (0.08, 0.13) (Z ¼ 8.64, p < 0.00001) and I 2 ¼ 39%, indicating that this RCT may be the source of heterogeneity. 2 Through further analysis of this literature, it was found that the therapeutic effect of the test group and the control group was significantly different 48 hours after administration, so the heterogeneity was large. In addition, the meta-analysis of cough, expectoration, asthma, rale, and other symptom indicators showed that I 2 values were greater than 90%, indicating that there was significant heterogeneity, which was not suitable for meta-analysis.

Publication Bias Analysis
A total of 36 clinical randomized controlled trials were included in this study. The risk of bias was analyzed by funnel plot according to the effective rate, as shown in ►Fig. 6.

Discussion
The lung is a delicate Zang organ with clear, weak, and tender features. Children are not yet fully developed and easy to be impaired by pathogens. Pediatric bronchitis is a common respiratory disease in pediatrics. Chinese herbs acupoint application therapy is a commonly used external therapy in TCM. The few adverse reactions and good acceptance increase its compliance.
In this study, the previously published TCM clinical randomized controlled trials were conducted to summarize the commonly used acupoint application herbs, selected acupoints, and evaluation indicators of efficacy in pediatric bronchitis. The results showed the following factors. (1) The selection of acupoint application herbs: wind-colddispersing herbs and cough-relieving and asthma-calming       curative effects on panting, dysphagia, chest pain, scanty lactation, palpitations, dysphoria, and cough. (3) Construction of the core: according to previous studies, it was found that the efficacy indicators of pediatric acute bronchitis were mostly effective rate, improvement of main symptoms/signs, onset time, disappearance time, TCM syndrome score and symptom score, etc. According to the results of the data mining, the metaanalysis of the core indicators was further performed. It was found that the therapeutic effect of Chinese herbs acupoint  Pediatric Bronchitis Treated by Chinese Herbs Acupoint Application Therapy Qian et al. e26 application therapy combined with Western medicine was accurate. For example, the total effective rate was 0.11 (0.08, 0.13) (Z ¼ 8.64, p < 0.00001) after removing the heterotypicity. The symptoms of cough, expectoration, and asthma were not analyzed by meta-analysis because of obvious heterogeneity. The analysis of comprehensive results showed that when the effective rate was taken as the evaluation index of efficacy, the efficacy of combined acupoint application therapy was better than that of nonacupoint application therapy group. Regarding cough, expectoration, asthma, and other symptoms as the end point of efficacy evaluation, this study failed to reach superior conclusion through meta-analysis. In view of the fact that most of the clinical studies included in the study use a single endpoint as the main outcome indicator, and for the clinical studies of endpoint outcome indicators, the efficacy evaluation method is different from the traditional single endpoint evaluation method, so in future studies, it is better to further explore the outcome evaluation of multiple endpoints and composite endpoints.
In this study, the following problems were also found in the related TCM clinical randomized controlled trials in this field: (1) Literature quality evaluation: almost all studies only described randomized methods, but there was no hint of blinding, allocation concealment, etc., indicating that it lacks reasonable and standardized trial design in the field of TCM randomized controlled trials. (2) Efficacy evaluation indicators: according to previous studies, the core indicator field was constructed, and it was found that most of the efficacy indicators for the evaluation of pediatric acute bronchitis were effective rate, main symptoms/signs improvement, onset time, disappearance time, TCM syndrome score and symptom score, etc., which had obvious TCM characteristics. However, these "composite indicators" were poorly defined, and the judgment criteria were vague or subjective and unable to be quantified. The subjective judgment of doctors or patients could not provide a reference for other researchers. Only some studies reported objective physical and chemical examinations such as lung function and immune function, which made it easy to exaggerate the study results. 3 (3) Adverse reaction report: only a few reports have reported adverse reactions, which makes the results of the systematic review unable to clarify the safety of Chinese medicine.