Effect of Liuzijue breathing exercise on patients with stable chronic obstructive pulmonary disease:a systematic review and meta-analysis

Backgrounds:Chronic obstructive pulmonary disease(COPD) is a common,preventable disease of airow limitation that accounts for the third leading deaths of any disease process in the worldwide. Health benets of Liuzijue breathing exercise on patients with stable COPD has assessed. This study was designed to perform a systemic review and meta-analysis of the effect of Liuzijue breathing exercise on patients with stable COPD. Methods: Published articles from inception to 2020 were conducted using electronic searches. Two independents reviewers performed data extraction.The Cochrane risk of bias assessment tool was used to evaluate the quality of the included studies. Results:A total of 16 eligible trials with 1039 patients with stable COPD were identied. Compared with control group,the pool meta-analysis of Liuzijue breathing exercise showed a signicant improve in FEV1 [MD=-0.16,95%CI (0.09,0.23), P<0.00001], FEV1% [MD=9.71, 95%CI(8.44,10.98), P<0.00001], FEV1/FVC(%) [MD=4.81,95%CI(2.12,7.51),P=0.0005],6MWD [MD=21.89,95%CI (cid:0) 14.67, 29.11 (cid:0) ,P<0.00001] , health-related quality of life [SMD=-0.84,95%CI (cid:0) -1.12,-0.55 (cid:0) P<0.00001] and mMRC [MD= -0.73,95%CI (-0.96,-0.50), P<0.00001]. The observed effect was more pronounced for interventions that were short term and medium-term duration of study. Liuzijue interventions also showed improvement in the secondary outcome measures. Conclusions:In this systematic review and meta-analysis ,Liuzijue breathing exercise can improve lung function,exercise endurance and health-related quality of life of patients with stable COPD. chronic pulmonary


Background
Chronic obstructive pulmonary disease (COPD) is a respiratory system disease that is characterized by persistent respiratory tract symptoms and xed air ow limitation [1] . Its main clinical symptoms are dyspnea, chronic cough with mucous production,chest tightness and wheezing [2][3] .Currently, about 400 million people suffers from COPD which it is the third leading cause of death in the worldwide [4] .Additionally, the medical burden of COPD is signi cant ranking fth in the world's economic burden of disease [5] . According to statistics, the U.S. government spent nearly $50 billion on treatment of COPD in 2010 [6] .In China, about 1.5 million people die from COPD in China every year [7] .COPD presents a signi cant challenge to the health care provider worldwide [8][9] .
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends that patients with acute exacerbation of COPD should be given drug therapy, while patients in stable stage should actively cooperate with non-drug therapy base on drug therapy [9] . Non-drug treatments mainly include oxygen therapy and pulmonary rehabilitation training. Pulmonary rehabilitation training is widely used for COPD, and its purpose is to relieve symptoms, improve quality of life, reduce medical burden [10] .its e cacy is widely recognized [1,9,11] .
As one of the traditional tness exercises with Chinese national cultural characteristics, Liuzijue is a cheap, simple and effective lung rehabilitation training method, which plays a positive role in regulating respiratory system, exercise endurance and quality of life on patients with stable COPD according some clinical studies [12][13][14] .Despite the potential bene ts of Liuzijue breathing exercise for COPD management,various design and methodologic weaknesses have consistently been identi ed across studies.In addition, there lacks a systematic review and meta-analysis of clinical therapeutic effect about Liuzijue breathing exercise on patients with COPD. So this study is a systematic review and meta-analysis of published literature on the application of Liuzijue breathing exercise in patients with stable COPD, in order to provide high-quality evidence synthesis and decision basis for the rehabilitation of COPD patients.

Search strategy
The electronic database searched were PubMed Cochrane Library Web of Science China National Knowledge Infrastructure and Chinese WanFang Data,from their inception until September 2020.The medical subject headings(Mesh) terms were chronic obstructive pulmonary disease(COPD);liuzijue.The keywords were traditional chinese exercise;qigong; health qigong;liuzijue;liuzijue breathing exercise;Liuzijue respiratory gymnastic;randomized controlled trial;chronic obstructive pulmonary disease COPD .A details of Search Strategies are showed on Appendix.The search strategy of this study uses a combination of Mesh terms and keywords, and is determined after repeated pre-checks, supplemented by manual search, and retrospectively included references when necessary.

Inclusion criteria
(i) Only RCTs regarding the e cacy of Liuzijue exercise for COPD were included.(ii)Patients were diagnosed with COPD in a stable phase according to the Global Initiative for Chronic obstructive pulmonary disease (GOLD), and no acute exacerbation occurred in all patients within six months before entering the trial.(iii)The baseline interventions included routine basic treatment of western medicine ,oxygen therapy,usual care,conventional respiratory therapy,health education and were equally implemented in both groups.(iv)The experimental group participated in Liuzijue breathing exercise, while the control group received health education ,or conventional breathing exercise or or no intervention.

Exclusion criteria
(i)The trial design with not scienti c and rigorous was excluded; (ii)The full text which could not obtained through various channels was excluded; (iii)Qualitative studies, animal experiments, case reports and conference abstract reviews were excluded ;(iv)Documents with incomplete data or data problems were excluded ; (v)Documents with inconsistent main outcome indicators were excluded; (vi)Patients with COPD accompanied by other complications were excluded;(vi)Patients with COPD are in an unstable phase were excluded.

2.3.Data extraction and synthesis
Data were extracted independently by two reviewers(PG and FT) according to inclusion and exclusion criteria, and then cross-checked.If there is a dispute, it will be settled through discussion.The extracted contents included:(i) The basic materials of the literature, such as the author, the year of publication,journal, etc.;(ii) Speci c details of experimental design, such as randomization, allocation and concealment, blinding of participants and personnel, basic data, intervention program, outcome, duration of intervention and follow-up time of the study subjects.If the study data is found incomplete, contact the author by phone or email to obtain the data. If the relevant data is not obtained in the end, the research will be excluded.When RCT with multiple studies was involved, the experimental group and control group related to this study were extracted, as shown in Fig

Literature quality evaluation
Jadad score was used to evaluate the methodological quality of each RCTs included [15] , with a total score of 7 points. Scores < 4 were considered as low quality studies, while scores ≥ 4 were considered as high quality studies [16] .The risk of bias was assessed using the evaluation criteria recommended by the Cochrane Handbook 5.1.0 [17] , "low risk bias", "high risk bias" and "unclear" (lack of relevant information or uncertainty of bias) were assessed for each of the included literatures.The quality evaluation of literatures were conducted independently by two reviewers(PG and YM).Any controversy occurring during the evaluation process were discussed with a third reviewer(WL)and resolved by consensus.

Statistical analysis
The RevMan5.3 and Stata14.0 software were used for meta analysis.As an priori analysis,we also analyzed the property of data across three intervention durations,de ned as short-term(≤3months), medium-term (6 months), and long-term(12months). Heterogeneity test: judged by chi-2 test and I 2 test, if P < 0.05,I 2 ≤ 50% indicate that there is homogeneity among the studies, and xed effect model was used for analysis.If P ≤ 0.05 I 2 > 50%, indicating statistically heterogeneity, random effect model was used for analysis.Finally, we used the funnel plots and Egger's regression asymmetry test to detect publication bias .To prove the reliability of our meta-analysis results,a sensitivity analysis were conducted by removing each study one by one to evaluate the consistency and quality of results.If variables in the studies included in this meta-analysis were continuous, we used the mean difference (MD) and 95% con dence interval (CI) to analyze the studies,otherwise,standardized mean difference (SMD) was used when variables were inconsistent. We considered P values less than 0.05 to be statistically signi cant. 3. Result

Search results
The ow diagram of the selection process is summarized in Fig. 1. 349 potentially eligible reports or articles were founded through electronic searches.224 articles still remained by eliminating repeated records.We excluded 169articles of these based on the title, abstract. Of the 16 remaining articles, an additional 43 were excluded. The most common reasons for exclusion were a non-RCT design, unrelated outcomes,Non-clinical research,or patients in unstable phase of COPD. Eventually,16 RCTs were deemed eligible for inclusion and selected for the nal analysis.

3.6.Adverse events
None of the articles informed adverse events. Thence,this information could not be searched from the RCTs analyzed.

3.8.Publication bias
As shown from the Egger's asymmetry tests,there was little indication of publication bias on the these outcomes(p = 0.764 for FEV1;p = 0.436 for FEV1%;p = 0.076 for 6MWD;p = 0.348 for health-related quality,respectively),only the outcome of FEV1/FVC%(p = 0.048)was showed publication bias.

Discussion
To the best of our knowledge,this is the rst systematic review with meta-analytical method to objectively evaluate the therapeutic effects of Liuzijue breathing exercise for stable COPD patients.All eligible RCTs were published between 2008 and 2019,indicating that it is a newly broadening research hotspot. The purpose of this current review was to evaluate the e cacy and safety of Liuzijue exercise for COPD patients.No adverse events occurred in all studies, and the positive ndings in the current review are in line with previous meta-analyses of randomized controlled trials investigating the bene cial effects of other Chinese traditional exercises (eg.Tai Chi, Baduanjin and Meditative movement) for COPD patients [34][35][36] .
In our study,we created subgroups based on the different intervention duration time of Liuzijue breathing exercise to evaluate the overall effect and each subgroup's effect,which would informed COPD patients of the effect of different intervention duration times. Generally, compared with conventional therapy,our study found that Liuzijue breathing exercise was helpful for COPD rehabilitation as assessed by FEVI,FEV1(%), FEV1/FVC (%) ,6MWD,mMRC and health-related quality.
6MWD has been used as a simple and valid evaluation parameter for exercise tolerance of COPD patients [37][38][39] . In our study,we found the distance of the 6MWD in the Liuzijue group was increased compared with the distance in the control group.In subgroup analysis, whether it was a short-term intervention or a medium-term intervention ,Liuzijue breathing exercise had a positive effect for improving 6MWD of COPD patients.However, there was no signi cant effect in long-term duration of study,it may be lack of study of long-term intervention of LiuziJue breathing exercise on COPD patients.Declining of exercise endurance and lung function are the main characteristics of COPD, and there are numerous reasons for the decreasing of patients' exercise ability. It is generally believed that the patient's movement is restricted to air ow obstruction, lung hyperin ation and gas exchange barriers during the activity process [40][41] , furthermore, the movement restriction makes the patient unable to engage in related sports which causes the patient's exercise ability to further decline [42], then this will form a vicious circle. Liuzijue contains breathing exercises and limb movement, which it is not only bene cial to the exibility and functional coordination of the upper limb muscles, but it also strengthens the function of the lower limbs.Thus Liuzijue breathing exercise could prolong the 6MWD of COPD patients.
FEV1, FEV1%, FEV1/FVC (%) are important indicators to re ect the degree of airway ventilation and obstruction of COPD patients,which can assess the severity of the patient's clinical symptoms and disease severity [43] . In our study, Liuzijue breathing exercises improved patients' lung function [i.e.,FEV1, FEV1(%), FEV1/FVC (%) ]compared with control group by the pool effect of our meta-analysis.In subgroup analysis,Liuzijue exercise had a good effect on the three index of lung function [FEV1, FEV1(%) ] in COPD patients regarding short-term or mid-term duration intervention.This nding may be because Liuzijue can enhance the strength of respiratory muscle [44] ,Also "Xu, Si and He" word tactic of Liuzijue exercise can extend expiratory time, improve the airway pressure,avoid premature closure of the airway, increase pulmonary ventilation function in patients with COPD [45] .However,our nding is contrary to Tong HX [46] 's research viewpoint that the LiuziJue of traditional health qigong cannot improve the lung function of COPD patients. For this reason, we carefully read Tong's study of meta-analysis and found that there is only one article about Liuzijue's intervention in COPD patients included in his study of meta-analysis, which is not su cient to demonstrate the effectiveness of Liuzijue's intervention in COPD patients.In the actually practice of Liuzijue exercise, the breathing method is bene cial to improve the abdominal muscle tension, increase movement range of the diaphragm up and down, enhance the strength of respiratory muscle, and thus obtain the greatest improvement of lung function.So patients with COPD could choice Liuzijue breathing exercise for improving respiratory function.
Currently,improving COPD patients' dyspnea and enhancing their exercise endurance were the main target through Liuzijue exercise. Declining of exercise endurance and respiratory function directly affects the quality of life of COPD patients.Therefore, the assessment of the health-related quality of life of patients should be an important part of the effect of treating patients. CAT respiratory questionnaire and the SGRQ respiratory questionnaire were widely used for assessing the quality of life of patients with COPD.In our study,the overall effect size showed that Liuzijue breathing exercise signi cantly improved the health-related quality of life compared with the control group.Additional,good evidence was founded in our study that Liuzijue exercise decreased mMRC score of dyspnea. The underlying mechanism is that Liuzijue breathing exercise has a positive effect on the T cell immune function of patients with stable COPD and prevent patients from getting sick more easily [31] ,otherwise,as a form of traditional tness exercise ,limb training of Liuzijue can effectively relieve dyspnea symptoms during activities while adjusting the respiratory function and relaxing the whole body function, so it has better effects on health-related quality of life of COPD patients [47][48] .
In subgroup analysis of our study, Liuzijue exercise also had good evidence of the effect on FEV1,FEV1(%), FEV1/FVC (%),6MWD and health-related quality of life in both short term and medium-term duration of study.However,the long-term intervention duration of Liuzijue breathing exercise had no effect may be because there is too little literature to prove the evidence. From our study,we suggested that the intervention duration of Liuzijue lasts at least 3 to 6 months.

Limitation
Athough,we has comprehensive analysis and assess all eligible studies,it still has some limitation.First,15 of sixteen RCTs in this meta-analysis were published in Chinese and little of relevant foreign RCTs,there may be publication bias that the result of this study were regional.Secondly,In our study,some results had high heterogeneity with regards to intervention intensity, duration,and frequency that may have contributed to unwanted heterogeneity and may have further in uenced the outcomes. Even though our classi cation of intervention durations (i.e., short, medium and long term), the relatively small number of studies included in each category did not allow us to effectively explanation the heterogeneity underlying the different studies in our random effect models. Thirdly, most of the studies showed only the randomized trials, but no speci c methods of random sequence generation, RCTs of allocation concealment, and blinding of outcome assessment.There were only three studies which reported single blinding. The methodological quality of many of the included RCTs was generally low and might have a high risk of bias.

Practical implications
First, research design should be carried out with stable COPD patients as the inclusion objects, high-quality, large sample RCT.Secondly, Liuzijue exercise is a kind of aerobic exercise with medium and low intensity, so we should try to improve the exercise intensity of the traditional tness method in the research.Thirdly,currently,the mechanism of COPD is still under further exploration,so it is necessary to add some other index to comprehensively evaluate the e cacy of COPD patients, such as acute exacerbation of COPD, BODE index, peripheral muscle strength and cellular immune factors.

Conclusion
In summary, this meta-analysis of RCTs suggested that Liuzijue breathing exercise had positive effects in eld of lung function, exercise endurance,healthrelated quality of life and dyspnea of patients with stable COPD.

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
All authors agree to publish this article Availability of data and materials The data analysed and materials used in this study are available from the corresponding author on reasonable request.