The effectiveness and safety of HuangQiXiXin decoction for cough variant asthma:protocol for a systematic review

Qing-Qing Xia,Cong Wang,Yu-Feng Zhang,Wei-Long Jiang*,Jia Qi

1Department of Respiratory Medicine,Jiangyin Hospital of Traditional Chinese Medicine,Jiangyin,Jiangsu 214400,China.2Department of Pharmacy,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China.

Abstract Objective: A comprehensive and updated systematic review is needed to evaluate the effectiveness and safety of HuangQiXiXin decoction (HQXXD) for cough variant asthma(CVA).The aim of this systematic review protocol is to comprehensively assess the effectiveness and safety of HQXXD for CVA.Methods: An overall search for studies in main English and Chinese electronic databases from their inception to January 2021 will be performed.Randomized controlled trials regarding HQXXD for CVA will be included.We will use RevMan 5.3 software to perform statistical analysis and meta-analysis.Results: The findings of this systematic review will be disseminated through peer-reviewed publications.Conclusion: The systematic review will provide more evidence regarding the effectiveness and safety of HQXXD for CVA.

Keywords: HuangQiXiXin decoction;cough variant asthma;protocol;systematic review

Introduction

Cough variant asthma (CVA) is a special type of asthma with chronic cough as the main or only clinical manifestation [1].The pathogenesis of CVA is not entirely clear,which is the same as asthma,and its pathophysiological changes are characterized by chronic airway inflammation and airway hyperresponsiveness [2].CVA is the most common cause of chronic cough in China and Japan and the second most common cause of chronic cough in Korea [3-5].

So far,guidelines have suggested that regular inhalation of corticosteroids and long-acting β2-agonists can be the recommended treatment modality for CVA patients [6,7].However,the long-term treatment effect of some patients is not ideal,the recurrence rate of CVA is still high,and a few side effects such as allergic reactions and mental or neurological reactions may occur [8,9].

CVA is characterized by wind cough,stubborn cough or wheezing cough,whose main syndrome type attributes qi deficiency and vigorous wind in traditional Chinese medicine (TCM) theory [10].Recently,TCM has been used in the treatment of CVA based on these aspects and the treatment effect is obvious [11,12].HQXXD is modified from the TCM prescription Zhisou powder and Yupingfeng powder [13].It mainly consists of Astragalus Root,Asarum,Schizonepeta Stem,Saposhnikoviae Root,Scute,Atractylodis Rhizome,Tuckahoe,Cicada Molting,Pinellia Rhizome,Stemona Root and Licorice Root,whose pharmaceutical Latin name asRadix Astragali(RA),Herba cum Radix Asari(HRA),Herba Schizonepetae(HS),Radix Saposhnikoviae(RS),Radix Scutellariae,Rhizoma Atractylodis Macrocephalae,Poria,Periostracum Cicadae,Rhizoma Pinelliae Preparatum,Radix StemonaeandRadix Glycyrrhizae;and Chinese pinyin name as Huangqi,Xixin,Jingjie,Fangfeng,Huangqin,Baizhu,Fuling,Chantui,Banxia,Baibu and Gancao,respectively.RA,HRA,HS and RS are the main active herbs in HQXXD which are regarded as monarch and minister herbs in TCM theory.RA could tonify lung qi;HRA,HS,and RS could strengthen the effect of RA by tonifying the spleen and stomach and dispelling wind dampness[14].

To date,a number of clinical researches of HQXXD in the treatment of CVA has been reported[13,15,16].A systematic review showed no significant difference in the total effective rate of HQXXD in treating CVA compared with the control group [13].Our latest study showed that HQXXD acted on CVA through multiple compounds,multiple targets and multiple pathways and performed a meta-analysis of the clinical curative effect of HQXXD on CVA [14].However,it did not evaluate the other indicators,such as recurrence rate,biochemical test index and safety.Therefore,a comprehensive and updated systematic review is needed to evaluate the effectiveness and safety of HQXXD for CVA,the aim of this study is to comprehensively assess the effectiveness and safety of HQXXD for CVA.

Materials and methods

Protocol and registration

This protocol has been registered on PROSPERO platform (https://www.crd.york.ac.uk/PROSPERO/) with an assigned registration number CRD42021235772.In addition,this review will also obey the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2015 guidelines (Supplementary File 1).

Ethics consideration

This systematic review will gather published data from open database.All eligible studies have been approved by the local institutional review committee and the ethics committee,including the written informed consent of the participants.This systematic review does not directly involve the patient's privacy,which does not require further ethical approval.In addition,the findings of this systematic review will be disseminated through peer-reviewed publications.

Search strategy

We will perform an overall search for published studies in main English and Chinese electronic databases from their inception to January 2021,which include MEDLINE via PubMed,EMBASE via Ovid,Cochrane Central Register of Controlled Trials (CENTRAL),CINAHL,AMED,Chinese National Knowledge Infrastructure,Chongqing VIP information,Wanfang database and Chinese Biomedical Database.Current Controlled Trials,World Health Organization clinical trials registry,Clinical Trials.gov trials registry and Chinese Clinical Trial Registry will also be searched to identify clinical trials which are ongoing.We will try to contact authors to obtain the data we need.The references of literature included and systematic reviews will also be checked.The search strategies for selecting the fields of title,abstract or keyword will be adjusted according to different characteristics of databases.Search strategies based on the Cochrane Handbook (search strategy in PubMed for example) will be presented in Supplementary File 2,and the keyword“cough variant asthma”will combine with the following keywords respectively:“HuangQiXiXin decoction”;“Astragalus”;“Asarum”;“Schizonepeta”;“Saposhnikoviae”;“traditional Chinese Medicine”;“Chinese Medicine”;“herbal medicine”.Some keywords will be adjusted slightly from each electronic database.

Eligibility criteria

The eligibility criteria will be strictly complied with PICOS(participant,intervention,comparison,outcome and study design)principles.

Study designRandomized controlled trials regarding the effectiveness and safety of HQXXD for CVA will be included in this research.Thus,we will exclude case reports,observational researches,quasi clinical trials and animal researches.

ParticipantRegardless of ages,gender,races,educational levels,economic and marital status,patients diagnosed with CVA by using clearly defined or internationally recognized criteria will be included.

Patients with other respiratory disease like bronchiectasis,chronic obstructive pulmonary disease;severe liver,kidney,heart disease will be excluded.

InterventionHQXXD treating for CVA will be included.HQXXD prescription can be modified,but it must contain monarch and minister herbs (RA,HRA,HS and RS).Eligible treatments could be used as monotherapy or combined conventional western medicine treatments.Studies of combined with other TCM treatment will be excluded.

ComparisonComparators will include placebo,conventional western medicine,and no interventions.Studies comparing other TCM prescription treatment interventions will be excluded.

OutcomesAll the outcome indicators from the included studies will be extracted and evaluated.We will perform a meta-analysis if the indicators can be done a meta-analysis and perform descriptive analysis if meta-analysis cannot be done.The main outcomes include total clinical efficacy rate,recurrence rate,airway reactivity,biochemical test index and adverse events.

Study selection,data extraction and quality assessment

Study selectionAll the literature will be retrieved independently by three reviewers (Xia,Wang and Zhang).Initially,identified references from searching databases will be exported to NoteExpress 3.2.0 software.Then,the duplicate studies will be eliminated with NoteExpress software duplication models.Then,the three reviewers will independently screen out the titles,abstracts,and keywords of each study to choose possible eligible studies according to the pre-defined evaluation criteria.Finally,the three reviewers will scrutinize and cross-check the full-text of previous eligible studies in the second stage and confirm the final inclusion for this systematic review.In this stage,the reasons for excluding each study will be recorded in details.Discussion will be done to resolve the disagreements of the three reviewers at any stage of the selection process.Another reviewer (Qi) will be invited as an arbitrator to make a final decision if the disagreements cannot be solute after the discussion among the three reviewers.The identification and selection process of this systematic review will be summarized in PRISMA-compliant flow chart (Figure 1).

Figure 1 PRISMA-compliant flow chart

Data extraction and dealing with missing dataThree reviewers(Xia,Wang and Zhang) will conduct data extraction procedure independently after completing a standard data extraction sheet.The three reviewers will cross-check these results and examine any differences.

Discussion will be done to resolve the inconsistent opinions of the three reviewers.Another reviewer (Qi) will also be invited as an arbitrator to judge these disagreements.The following list information extracted from the original articles will be saved in a standard data extraction sheet:(1) title,study year,country and authors;(2) study design;(3) methodology:randomization,allocation concealment,patient blinding,assessor blinding,incomplete outcome data,selective outcome reporting and other risks of bias;(4) sample size;(5) age and gender in each group;(6) diagnostic criteria;(7) follow-up;(8)intervention group (methods of treatment,major composition of HQXXD prescription;duration of treatment);(9) control group(methods of treatment,duration of treatment);(10) main outcomes;(11) adverse events.

We will try our best to E-mail the corresponding authors of each study if the above information is missing.

Quality assessmentThree reviewers (Xia,Wang and Zhang) will assess the quality of each eligible study independently according to the Cochrane risk of bias tool(random sequence generation,allocation concealment,patient blinding,assessor blinding,incomplete outcome data,selective outcome reporting and other risks of bias) from the Cochrane Handbook V.5.1.0.Each item will be classified as one of the followings:high risk,uncertain risk,or low risk [17,18].

In terms of other bias,we will carefully assess the baseline imbalance and different sources of funding support.

Any disagreements will be discussed with another reviewer (Qi).

Statistical analysis and assessment of heterogeneity

We will use RevMan 5.3 software to perform statistical analysis,.We will measure the dichotomous data using risk ratio with 95%confidence interval and continuous data using mean difference with 95% confidence interval to perform meta-analysis.

To explore the heterogeneity,chi-square and I2test will be performed.When I2＜50% andP＞0.1,there is homogeneity between each study.Thus,Mantel-Haenszel fixed effect model will be used for meta-analysis.Otherwise,if I2≥50% orP＜0.1,the included studies will be considered as heterogeneous.Initially,to explore possible factors affecting the clinical heterogeneity,we will re-assess the demographic characteristics of the CVA patients and variation of interventions between each included study.If the clinical heterogeneity really exists in this systematic review,we will perform descriptive analysis.Otherwise,a random effects model based on inverse variance statistical approach will be used for further meta-analysis after getting rid of the clinical heterogeneity [19,20].

Subgroup analysis

If heterogeneity is high and the number of included studies is sufficient,subgroup analysis will be carried out to assess the heterogeneity as follow:(1) different interventions (monotherapy or combined conventional western medicine treatments);(2) different control (placebo,conventional western medicine,or no interventions);(3) different duration of treatment.

Sensitivity analysis

Sensitivity analysis will be performed based on the following:(1)methodological quality:low-quality studies will be omitted to re-evaluation the results of this meta-analysis.(2) statistical model:random-effects model or fixed-effects model will be chosen to analysis.(3) sample size:omit studies with low sample size will be omitted to re-evaluation the results of this meta-analysis.

Publication bias

If the number of included studies in the meta-analysis are greater than 10,we will use RevMan 5.3 software to assess publication bias with funnel plot.We will use meta-analysis model from STATA 14.0 software to perform Begg test for quantitative analysis of publication bias if necessary [21].

Summary of evidence

We will use the GRADEpro web tool (https://gradepro.org/) to evaluate the quality of each main outcome in this systematic review,which will be categorized into 4 grades:high,medium,low,or very low[22].

Discussion

TCM has been used in the treatment of CVA based on tonifying lung qi and dispelling wind dampness and the treatment effect is obvious.HQXXD,in which RA,HRA,HS and RS are monarch and minister herbs could tonify lung qi and dispel wind dampness to treat CVA according the TCM Theory [13,14].

Based on a network pharmacology approach,previous study investigated the multi-component,multi-target,and multi-pathway characteristics of HQXXD acting on CVA and the clinical curative effect of HQXXD on CVA [14].Basic and clinical study of HQXXD treating CVA deserves further study.

However,there is no systematic review showing the comprehensive evidence regarding the effectiveness and safety of HQXXD for CVA patients.We really hope our systematic review can bring HQXXD or TCM prescription to routinely treat CVA,or provide a basis for further real-world randomized clinical trials (RCT) research of HQXXD and obtain more evidence-based medical evidence for better application of TCM.

This systematic review may have some potential limitations.HQXXD prescription origin in China,the results of this review may limit in Asian patients although the internationalization of TCM is becoming more and more extensive.Differences in the composition of other herbs except RA,HRA,HS and RS,and the inequable duration of treatment may cause heterogeneity in the clinical practice.Therefore,we use the the keyword“cough variant asthma”will combine with the following keywords respectively:“HuangQiXiXin decoction”;“Astragalus”;“Asarum”;“Schizonepeta”;“Saposhnikoviae”;“traditional Chinese Medicine”;“Chinese Medicine”;“herbal medicine”.By reading the full text,we will retrieve all related studies including RA,HRA,HS and RS whenever possible.

Conclusion

The systematic review will provide more evidence regarding the effectiveness and safety of HQXXD for CVA and make a decision for clinicians to treat CVA patients.In addition,it can provide a basis for future basic and clinical research.