HAN Jing, JIA Yan-kun, HAN Ze-Llu, ZHAO Rui-heng, YIN Ze-tao, LIN Jiang-tao

1. Clinical Medical College (China-Japan Friendship Hospital), Beijing University of Chinese Medicine, Beijing 100029, China

2. Department of Respiratory and Critical Care Medicine, China-Japan Friendship Hospital, Beijing 100029, China

Keywords:Hanchuan Zupa granule Asthma RCTs Systematic review Meta-analysis

ABSTRACT Objective: To systematically evaluate the clinical efficacy and safety of Hanchuan Zupa granule(HCZPG) in the treatment of bronchial asthma. Methods: The Cochrane Library,Pubmed, EMBASE, CNKI, CBM, VIP and Wanfang were searched up to June 2021.Randomized controlled trials, which assessed the effects of HCZPG in the treatment of bronchial asthma, were included in this review, and the references included in the selected studies were also tracked. The methodological quality of eligible studies were assessed by the Cochrane Collaboration’s tool. Data of the included studies were extracted independently by two authors and meta-analysis was conducted using RevMan5.3. Results: A total of 97 relevant literatures were retrieved, and 13 studies were finally included, involving 1 189 patients.The aggregated meta-analysis results indicated that HCZPG improved total clinical efficacy[RR=1.18,95% CI (1.13,1.24),P＜0.000 01], FEV1(L)[WMD=0.48,95% CI (0.22,0.74),P=0.000 3], FVC(L)[WMD=1.23,95% CI (0.5,1.96),P=0.001], FEV1/FVC(%) [WMD=7.37,95% CI(5.91,8.84),P＜0.000 01], PEF [SMD=1.19,95% CI (0.82,1.56),P＜0.000 01], IL-4 [WMD=-12.13,95% CI (-16.36,-7.90), P＜0.000 01], IL-6 [WMD=-29.55,95% CI (-40.71,-18.39),P＜0.000 01], TNF-α[SMD=-2.73,95%CI (-3.57,-1.88),P＜0.000 01],PaO2[WMD=8.97,95% CI(6.09,11.85),P＜0.000 01], but the risk of adverse events were not statistically significant between the two groups [RR=0.68,95%CI (0.39,1.18),P=0.17]. Conclusion: HCZPG shows good clinical curative effects in treating bronchial asthma without increasing the incidence of adverse events.

1. Introduction

Bronchial asthma (hereinafter referred to as asthma) is a heterogeneous disease, which consists of a variety of cells including eosinophils, mast cells, T lymphocytes, neutrophils, smooth muscle cells, airway epithelial cells, etc. and cellular components Involved in chronic inflammatory diseases of the airways. The typical clinical manifestations are recurrent wheezing, dyspnea, chest tightness,and coughing, which often attack or worsen at night and early in the morning, which seriously affect the patient's quality of life,work and school. With social development and lifestyle changes,the prevalence of asthma has increased year by year in recent years.There are at least 300 million asthma patients in the world, and about 30 million asthma patients in China[1].At present, GINA still regards the control of asthma as the core of asthma treatment[2]. The current routine treatment of asthma is inhaled corticosteroids (ICS)+ long-acting beta-2 agonist (LABA), but there are side effects of growth in children, osteoporosis, risk of infection, poor compliance,high medical expenses, etc.[3,4]

Hanchuan Zupa Granules is a Chinese Uyghur medicine-Hanchuan Zupa San, a traditional Chinese medicine compound preparation, from the classic Uyghur medicine "Ruyi Prescription",the main components include licorice extract, hyssop, fennel, celery seeds, Russula, fenugreek, nettle, maidenhair fern, rose flower, etc.,have the effect of reducing phlegm, relieving asthma, moisturizing the lungs and relieving cough. It is often used to treat respiratory diseases, including asthmatic pneumonia, cough variant asthma,bronchial asthma, and chronic obstructive pulmonary disease, etc.[5],has now been listed in the National Medical Products Administration(NMPA) in the protected varieties of traditional Chinese medicine.In recent years, studies[6-14] have found that Hanchuan Zupa granule has certain clinical efficacy in the treatment of asthma. However,due to the small sample size and differences in research methods,there is still a lack of evidence-based medical evidence to support the verification of the clinical efficacy of Hanchuan Zupa granule in the treatment of asthma. This study systematically reviewed the domestic and foreign related Hanchuan Zupa Granules in the treatment of asthma RCTs, and used the Cochrane system evaluation method to analyze the clinical efficacy and adverse reactions of Hanchuan Zupa Granules alone or in combination with Western medicine in the treatment of asthma, for Hanchuan Zupa Granules treating asthma curative effect and safety of providing evidencebased medical evidence, in order to better guide clinical work.

2. Materials and methods

2.1 Literature inclusion criteria

(1)The research type is RCTs, regardless of whether blinding is used, and there are no requirements and restrictions on language and publication type; (2)The research object is patients with bronchial asthma (in line with the diagnostic criteria of the Respiratory Group of the Chinese Medical Association[19], or the global bronchus Asthma Prevention and Control Initiative Bronchial Asthma Guidelines[2]), regardless of gender, age, race, time of onset, duration of disease, severity of disease, clinical treatment, and comorbidities.(3)Intervention measures: The experimental group was treated with Hanchuan Zupa granules alone or combined with other conventional treatments (medications recommended in accordance with clinical practice guidelines[20]), and the control group was a blank control or placebo combined with other conventional treatments; (4)The outcome index: The main outcome indicators are clinical total effective rate, lung function indicators [forced expiratory volume per second (FEV1), forced vital capacity (FVC), FEV1/FVC (%),peak expiratory flow rate (PEF)], secondary outcome indicators Inflammatory factor indicators (IL-4, IL-6, TNF-α), arterial blood gas analysis indicators (PaCO2, PaO2), and the incidence of adverse events in Hanchuan Zupa granules.

2.2 Literature exclusion criteria

Research involving any of the following can be excluded: (1)Repetitively published literature; (2)Incomplete information, wrong data or data that cannot be extracted; (3)Reviews, popular science,animal experiments and opinions literature; (4)Uncontrolled clinical Test; (5)The research object is atypical asthma such as cough variant asthma.

2.3 Retrieving resources

From the establishment of the database to June 2021, a comprehensive search was carried out in 7 major English and Chinese databases. The retrieved databases were Cochrane Library,Pubmed, EMBASE, Chinese Academic Journal Full-text Database(CNKI), and Chinese Biology. Medical Literature Database(CBM), VIP Chinese Sci-tech Journal Database (VIP) and Wanfang Digital Resource Library (Wangfang). Check the clinical trial/trial registration website (Clinical trial, CHICTR) to track and view the studies that have uploaded trial results. In order to include other eligible studies, manually searched the reference list of related articles and searched for articles that were not published in the electronic journal.

2.4 Search strategy

A search method combining subject terms and free words is used.Chinese search terms: [(bronchial asthma) OR (asthma)] AND ("Han Chuan Zu Pa Granule" OR "Han Chuan Zu Pa"); English search terms: (asthma) [MeSH] OR asthmatic) AND ("Han Chuan Zu Pa Granule" OR "Han Chuan Zu Pa" OR HCZP*), the specific retrieval method is shown in Table 1.

Table 1 Literature searching strategry

2.5 Literature screening

Two researchers (Han, Jia) judge the literature based on the title and abstract of the literature. If it does not meet the inclusion criteria or (and) the exclusion criteria, it will be eliminated. If there is any ambiguity in the literature judgment results, the dispute should be resolved through discussion with a third party (Lin). The literature screening process will be presented in the results in the form of a PRISMA flowchart.

2.6 Data extraction

Two researchers (Han, Jia) each extract the required information in the literature and cross-check. The data is extracted and entered into a predefined Excel table. The content of the extracted data includes:(1)Basic information of the document, including title, author, and publication date; (2)The demographic data of the research object,the detailed information of the experimental group and the control group, the outcome indicators, Duration of treatment, adverse events. During the extraction process, if it is found that the units of the same test index are different among the studies, the conversion will be unified. If the data in the literature is missing or incomplete,contact the corresponding author. If the data cannot be obtained, the literature will be eliminated.

2.7 Literature quality assessment

Two researchers will assess the risk of bias independently of included studies. Any disagreement will be resolved by discussion until consensus is reached or by consulting a third researcher in assessment. If the results or data of articles are insufficient to meet the our requirements of pool statistics, correspondent authors will be contacted by E-mail. Evaluation of the quality of the included literature will be conducted by using the bias risk assessment tool recommended in Cochrane System Evaluator Manual 5.3, which includes: (1) Random sequence generation(selection bias); (2)Allocation concealment(selection bias); (3) Blinding of participants and personnel (performance bias); (4) Blinding of outcome assessment (detection bias); (5) Incomplete outcome data(attrition bias); (6) Selective reporting(reporting bias); (7) Other sources of bias.Each item is classified as "low risk", "high risk" or "unclear",and the reasons will be recorded to support its judgment.

2.8 Statistical analysis

Meta-analysis is performed by RevMan5.3 software. Relative ratio(RR) is used to present the binary variable. For continuous outcomes,if the measuring tool were consistent with the measurement unit, the weighted mean difference (WMD) would be used to present it; if the measuring tool were not consistent with the measurement unit, the standard mean difference (SMD) would be used to present it. All of these were present by a 95% confidence interval (CI). Chi-squared and I2 value judged heterogeneity. If P .1, I2≤50% indicated the heterogeneity was low, a meta-analysis would be conducted by the fixed effect model. If P＜.1, I2＞50% indicated heterogeneity among studies, the source of heterogeneity would be analyzed. Clinical heterogeneity was performed by subgroup analysis. If there were no obvious clinical heterogeneity or methodological heterogeneity,statistical heterogeneity would be considered, and a randomeffects model would be conducted. If the clinical heterogeneity was too obvious, and subgroup analysis could not be conducted, the descriptive analysis would be performed but not a meta-analysis.Forest plots are used to show the combined effect size of the analysis targets, and funnel plots are used to show the publication bias of experimental studies.

3. Results

3.1 Literature Screening

The screening of literatures was carried out in strict accordance with the PRISMA literature screening process [20], 84 literatures were retrieved from major databases, and a total of 13 literatures were obtained from other resources, a total of 97 articles, and 61 duplicate articles were excluded; proceed according to the inclusion and exclusion criteria Titles and abstracts were preliminarily screened for literature, 3 reviews, 1 animal experiment study, and 11 articles that did not match the subject were excluded; the full text screening excluded 2 articles that did not match the intervention measures, 5 articles that had no available data, and 1 article did not match the study type; finally included 13 documents that meet the standards, the PRISMA document screening process is shown in Figure 1.

Figure 1 Flow chart of study screening

3.2 The quality evaluation of the included studies

All the literatures reported random allocation, of which 9 articles reported the specific operation method of random allocation; no literature reported allocation hiding, no literature reported the use of blinding methods for subjects and researchers, 8 The results of the literature are accurate and complete, 12 literatures have no selective reports, and most of the literature does not have other risks of bias.RevMan5.3 software generates a bias risk map as shown in Figure 2 and Figure 3.

3.3 Basic characteristics of the literature

The total sample size included in the literature is 1 189 cases, 596 cases in the Hanchuan Zupa granule group, and 593 cases in the control group; 4 articles [7,12,14,16] The subjects are adult bronchial asthma patients, and the remaining 9 Articles [6,8-11,13,15,17,18]study subjects are children with bronchial asthma. The intervention methods of the control group included salbutamol aerosol,budesonide formoterol powder inhalation, budesonide aerosol,dihyprophylline tablets, fluticasone propionate inhalation aerosol,salmeterol ticasone powder Inhalants, montelukast sodium tablets,terbutaline sulfate aerosol, prednisone acetate tablets; the intervention method of the experimental group is Hanchuan Zupa granules alone or the control group with Hanchuan Zupa in addition to conventional treatment Granules, the usual dose is 2-12g/time, 2 times a day.The shortest course of treatment is 1 week, and the longest course of treatment is 3 months. The included research indicators include clinical total effective rate, lung function indicators, inflammatory factors, etc. See Table 2 for details.

3.4 Meta analysis results

3.4.1 Total clinical effective rate

12 articles [6,7,9-18] reported the total clinical effective rate of Hanchuan Zupa Granules in relieving bronchial asthma. The effect size RR value of the total clinical effective rate of the two groups was tested for heterogeneity, and it was found that I2=0%, indicating that there is no heterogeneity between the studies, and the fixedeffects model comprehensive effect size was adopted. Meta results in terms of the total clinical effective rate, the clinical efficacy of the experimental group is better than that of the control group [RR=1.19,95%CI (1.13, 1.25), P＜0.000 01], indicating the total clinical effective rate of the experimental group and the control group in the treatment of bronchial asthma. The difference is statistically significant. The total clinical effective rate of the experimental group is higher than that of the control group, as shown in Figure 4.

Figure 2 Risks of bias of the selected literature(1)

Figure 3 Risks of bias of the selected literature(2)

3.4.2 Lung function

9 literatures [6-9, 11, 13, 15-17] reported the effects of Hanchuanzopa granules on pulmonary function [FVC (L), FEV1 (L), FEV1/FVC(%), PEF (L/min)], among which 5 literatures [6,8,9,11, 13] provided the FVC data of the experimental group and the control group after the intervention, 5 articles [6,8,9,15,16] provided the FEV1 data of the experimental group and the control group after the intervention, 6 articles [6, 8, 9, 13, 15, 17] provided the change of FEV1/FVC before and after the intervention, 8 articles [7-9, 11, 13, 13, 15-17] provides the change in PEF before and after the intervention.

Meta-analysis of FVC(L) in the experimental group and control group after treatment, heterogeneity test I2=99%, suggesting that there is heterogeneity between the studies, the random effect model is used to comprehensive effect size, and the difference in FVC after treatment between the two groups is found Statistically significant[WMD=1.23, 95%CI (0.5, 1.96), P=0.001] (Figure 5); Meta-analysis of FEV1 (L) after treatment in the experimental group and control group, heterogeneity test I2= 98%, there is heterogeneity between the studies, using the random effects model, the difference in FEV1 between the two groups is statistically significant [WMD=0.48,95%CI (0.22, 0.74), P=0.000 3] (Figure 6); Meta-analysis of FEV1/FVC (%) in the experimental group and control group after treatment, heterogeneity test I2=59%, using random effects model, the two groups of FEV1/FVC have statistically significant differences [WMD=7.37, 95%CI (5.91, 8.84), P＜0.000 01] (Figure 7); Meta-analysis of PEF (L/min) after treatment in the test group and control group, the heterogeneity test I2=82%, indicating that there is heterogeneity between the studies The combined effect size of the random effects model is adopted, and the difference in PEF (L/min) between the two groups is statistically significant [SMD=1.19,95%CI (0.82, 1.56), P＜0.000 01] (Figure 8).

Table 2 Characteristics of the literature included

Figure 4 Meta-analysis of total clinical efficacy

Figure 5 Meta-analysis of FVC in the experiment group and control group after the treatment

Figure 6 Meta-analysis of FEV1(L) in the experiment group and control group after the treatment

Figure 7 Meta-analysis of FEV1/FVC(%) in the experiment group and control group after the treatment

3.4.3 Inflammatory factors

8 articles [6-11,17,18] reported the effect of Hanchuan Zupa Granules on inflammatory factors (IL-4, IL-6, TNF-α). Among them, 4 articles reported on IL-4 [6,8,9,17], 5 articles [6,7,10,11,18] reported on IL-6,6 articles [7 -10,17,18]reported on the indicator TNF-α.

Meta-analysis of the index IL-4, heterogeneity test I2=90%,suggesting that there is heterogeneity among the studies, the random effects model is used to synthesize the effect size, the difference between the two groups of IL-4 is statistically significant [WMD=-12.13, 95% CI (-16.36, -7.90), P＜0.000 01] (Figure 9); Meta-analysis of the index IL-6, heterogeneity test I2=99%, suggesting that there is heterogeneity between studies, Using the random effects model,the difference in IL-6 between the two groups was statistically significant [WMD=-29.55, 95%CI (-40.71, -18.39), P＜0.000 01](Figure 10). Meta-analysis for TNF-α, heterogeneity test I2=92%,suggesting that there is heterogeneity among the studies, using random effects model comprehensive effect size, the difference between the two groups of TNF-α is statistically significant [SMD=-2.73, 95% CI (-3.57, -1.88), P＜0.000 01] (Figure 11).

Figure 8 Meta-analysis of PEF in the experiment group and control group after the treatment

Figure 9 Meta-analysis of IL-4 in the experiment group and control group after the treatment

Figure 10 Meta-analysis of IL-6 in the experiment group and control group after the treatment

Figure 11 Meta-analysis of TNF-α in the experiment group and control group after the treatment

3.4.4 Arterial blood gas analysis

4 articles [6,7,9,10] reported the influence of Hanchuan Zupa Granules on the arterial blood gas analysis indexes (PaCO2, PaO2) of asthma patients.

Meta-analysis of the index PaCO2, the heterogeneity test I2=99%,suggests that the heterogeneity between the studies is large, and the random effects model is used to integrate the effect size. There is no statistically significant difference in PaCO2 between the two groups [WMD=-5.75, 95 %CI (-17.46, 5.95), P=0.34] (Figure 12), sensitivity analysis (Figure 16); Meta-analysis of the index PaO2, heterogeneity test I2=60%, suggesting the existence of different studies Heterogeneity, using the random effects model for comprehensive effect size, the difference in PaO2 between the two groups is statistically significant [WMD=8.97, 95%CI (6.09, 11.85),P＜0.000 01] (Figure 13).

3.4.5 Adverse events

8 articles [6-10,15,16,18] reported the occurrence of adverse events in clinical studies, 1 article [9] had no adverse events, and the other 7 reported adverse events including nose and throat Dryness,throat discomfort, hoarseness, allergic reactions, rash, dizziness,palpitations, gastrointestinal discomfort, nausea, vomiting, muscle cramps, etc. Based on whether adverse events occurred in the two groups, a heterogeneity test was performed on the RR value of the incidence of adverse events and found that I2=0%, and a fixed-effects model was used. The results showed that the RR of adverse events between the two groups after intervention was 0.68 [95%CI (0.39,1.18), P=0.17], and there was no statistically significant difference in the incidence of adverse events, as shown in Figure 14.

Figure 12 Meta-analysis of PaCO2 in the experiment group and control group after the treatment

Figure 13 Meta-analysis of PaCO2 in the experiment group and control group after the treatment

Figure 14 Meta-analysis of adverse event incidences in the experiment group and control group

3.5 Publication bias

A funnel chart was drawn for the outcome indicator of clinical total effective rate to detect publication bias. The results showed that:scattered points are distributed near the midline and close to the top,suggesting that there is no obvious publication bias, as shown in Figure 15.

Figure 15 Publish bias funnel plots (total clinical efficacy)

3.6 Sensitivity analysis

Analysis of the two groups of lung function indicators (FVC,FEV1, FEV1/FVC, PEF), inflammatory factor indicators (IL-4, IL-6,TNF-α), arterial blood gas indicators (PaCO2, PaO2), Meta results are quite heterogeneous. After subgroup analysis, the heterogeneity cannot be ruled out. Random effects model is used to combine effect size and sensitivity analysis is performed. It was found that removing any study had no effect on the combined results, suggesting that the meta-analysis results have good stability. The index PaCO2was subjected to sensitivity analysis, excluding the literature [10], and the results obtained were statistically significant [WMD=-11.32, 95%CI(-15.82, -6.82), P＜0.000 01] (Figure 16).

4. Discussion

Figure 16 Meta-analysis of PaCO2 in the experiment group and control group (sensitive analysis)

In recent years, in the prevention and treatment of bronchial asthma, traditional Chinese medicines and proprietary Chinese medicines have been used more and more. Hanchuan Zupa Granules is a Uyghur traditional Chinese medicine compound preparation,which is commonly used to relieve and treat colds, coughs,asthma and other diseases. Acute asthma attacks are most related to airway hyperresponsiveness caused by airway inflammation.When the body encounters an allergen, the airway is stimulated,the bronchial mucosa is chronically inflammatory, a large number of epithelial cells fall off, smooth muscle infection, and nerve endings are exposed. Sensitivity to stimulation is accelerated, and nerve excitability is enhanced, causing premature and excessive contraction and spasm of the airway, thereby inducing asthma.Domestic research results also suggest that airway inflammation is an important mechanism of airway hyperresponsiveness and the pathological basis of airway hyperresponsiveness [22].Previous animal experiments[23] showed that Hanchuanzupa granule can relieve cough caused by sulfur dioxide and capsaicin, reduce the levels of TNF-α, IL-13 and other inflammatory factors in mice with acute lung injury, and inhibit the increase of airway resistance caused by histamine and acetylcholine. This study found that compared with conventional treatment, Hanchuan Zupa granules combined with conventional treatment can reduce blood inflammatory factor levels (IL-4, IL-6, TNF-α) in patients with asthma, and improve the patient’s lung function and arterial blood gas. This suggests that Hanchuan Zupa Granules may inhibit the release of IL-4, IL-6,TNF-α and other inflammatory factors in patients with asthma, and on the basis of the benefits of existing treatments, further reduce airway hyperresponsiveness and improve asthma. Patient's lung function and arterial blood gas.

Drug safety is one of the important issues in clinical research in the field of Chinese medicine. In this study, the incidence of adverse events was used as an observation indicator to analyze the incidence of adverse events in the experimental group and the control group.The results found that compared with conventional treatment,Hanchuan Zupa granules combined with conventional treatment did not significantly increase the incidence of adverse events. ,Suggesting that Hanchuan Zupa Granules combined with western medicine has good safety in the treatment of asthma.

The clinical studies of Hanchuan Zupa Granules in the treatment of asthma have been reported in my country in the past ten years, but there are big differences in the design of these studies. A systematic review published in 2019 [24] showed that Hanchuan Zupa Granules has a good effect on the treatment of respiratory diseases, which can significantly relieve asthma symptoms and improve the relevant efficacy indicators of patients’ lungs. Based on previous studies,this article further restricted the study population to patients with bronchial asthma, using lung function, inflammatory factors, and blood gas as the efficacy evaluation indicators. In addition, the incidence of adverse events was added as a safety index to analyze the effectiveness and safety of Hanchuanzupa granule in the treatment of bronchial asthma, which is an extension of the previous research on Hanchuanzupa granule. Comprehensive evaluation of asthma control level is the basis of making asthma treatment plan and adjusting asthma medication.

This study also has the following shortcomings: The research sample size of the included literature is relatively small, so there is no subgroup analysis based on different control interventions,and the comprehensive result is suspicious; ②The majority of the included literature does not have methodological design. The random concealment and blinding method may have certain selectivity bias;specific methods such as indicator monitoring and measurement tools are not reflected in the literature, and different methods may lead to bias bias in the study; trial drug dosage, treatment duration,combined diseases, and outcome indicators defining differences may introduce other potential biases. ③The results of the study did not involve long-term follow-up, and could not prove the long-term efficacy and safety of Hanchuan Zupa Granules in the treatment of bronchial asthma.

There are certain particularities in the research of Chinese medicine. At present, the existing domestic research still has certain limitations. High-quality, large-sample, multi-center RCTs need to be developed. In the future, it is recommended to adopt a doubleblind double-simulation design method to reduce the bias as much as possible to further verify the effectiveness and safety of Hanchuan Zupa Granules in the treatment of bronchial asthma. In addition,this Meta-analysis found that there is a lack of subjective indicators for asthma control assessment in the efficacy evaluation, and only 2 documents involve [11,15], and it is impossible to further evaluate the control level of Hanchuan Zupa Granules on asthma. In the future,RCT should pay more attention to the assessment of the control level of asthma patients, such as the use of asthma control test (ACT) and other evaluation tools, to make up for the gaps in existing research results.

Author contribution:

Scheme design: Han Jing, Jia Yankun;

Data collection: Han Jing, Jia Yankun;

Literature search: Han Jing, Han Zelu;

Software operation: Jia Yankun, Han Jing;

Overall evaluation of the scheme: Lin Jiangtao, Zhao Ruiheng, Yin Zetao;

The paper was written by Han Jing and Jia Yankun, and Lin Jiangtao was reviewed.